Introdução: Mucopolissacaridose IVA ou Síndrome de Morquio A é uma doença autossômica recessiva causada pela deficiência da enzima lisossomal Nacetilgalactosamina- 6-sulfatase (GALNS), que resulta no acúmulo lisossomal dos glicosaminoglicanos: Queratan sulfato e Condroitin-6-sulfato nos tecidos causando as manifestações clínicas. Os fenótipos variam da forma clássica à forma atenuada, ambas sem comprometimento cognitivo. A prevalência de MPS IVA varia de 1/76.000 a 1/640.000 nascidos vivos. Objetivos: Analisar e caracterizar o genótipo de pacientes brasileiros com MPS IVA através de estudos de mutações no gene da GALNS, possibilitando a estimativa de frequência de mutações recorrentes e o estabelecimento um protocolo de rotina para triagem dessas mutações. Métodos: Análise molecular do gene da GALNS foi realizada em 26 pacientes brasileiros inicialmente através de PCR-ARMS para detecção de seis mutações recorrentes (p.G116S/ p.G139S/ p.L307P/ p.N164T/ p.R386C e p.S341R) seguidas pela amplificação de regiões codificantes por PCR e sequenciamento. Resultados: Essas mutações foram encontradas em 61,5% da nossa amostra, com uma frequência alélica de 55,8%. Destas, a mutação mais frequente foi p.S341R (26,9%), seguida de p.R386C (21,1%) e p.G116S (7,7%). As mutações p.N164T, p.G139S, p.L307P não foram encontradas em nossa amostra. Além destas, foi encontrada por sequenciamento do éxon 5 uma mutação nova p.C165Y. Conclusão: O protocolo usado para detecção de mutações comuns mostrou-se adequado como um screening inicial de mutações no gene da GALNS, identificando mutações em 61,5% dos pacientes e permitiu a caracterização de 55,8% dos alelos. A mutação p.S341R foi encontrada apenas em pacientes do Nordeste. A identificação de indivíduos heterozigotos nessas famílias será importante para aconselhamento genético e para estimar a prevalência da doença nessa região. Estudos adicionais para identificação da origem dessa mutação, incluindo análises de segregação e haplótipo estão em andamento, e serão avaliadas em conjunto com dados epidemiológicos. / Background: Mucopolysaccharidosis IVA or Morquio A syndrome, is an autosomal recessive disorder caused by deficiency of lysosomal enzyme Nacetylgalactosamine- 6-sulfatase (GALNS), which results in lysosomal storage of glycosaminoglycans: Keratan sulfate and Chondroitin-6-sulfate in tissues causing clinical manifestations. The phenotypes vary from the classical to attenuated form, both without cognitive impairment. The prevalence of MPS IVA ranges from 1/76.000 to 1/640.000 live births. Objective: To analyze and characterize the genotype of Brazilian patients with MPS IVA, through molecular study of mutations in the GALNS gene, enabling the estimative of frequency of recurrent mutations and the establishment of a protocol for routine screening of these mutations. Methods: Molecular analysis of GALNS gene was performed in 26 Brazilian patients initially by ARMS-PCR to detect six recurrent mutations (p.G116S/ p.G139S/ p.L307P/ p.N164T/ p.R386C and p.S341R) followed by amplification of coding regions by PCR and sequencing. Results: These mutations were found in 61.5% of our sample, which were present in 55.8% of the alleles. The most frequent mutation was p.RS341R (26.9%), followed by p.R386C (21.1%) and p.G116S (7.7%). Mutations p.N164T, p.G139S, p.L307P were not found in our sample. A novel mutation p.C165Y was found after sequencing of exon 5. Conclusion: The protocol used for detection of common mutations was shown to be adequate for a first screening of mutations at the GALNS gene, once it identified the genotype in 61.5% of patients and allowed the characterization of 55.8% of alleles. The p.S341R was found only in patients from the Northeast. The identification of heterozygous individuals within these families will be important for genetic counseling and for estimating the disease prevalence in this region. Further studies to identify the origin of this mutation, including haplotype and segregation analyses are in progress, and will be evaluated in conjunction with epidemiological data.

Orientador: Ljubica Tasic / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-16T13:55:17Z (GMT). No. of bitstreams: 1 Borin_PaulaFernandaLacarini_M.pdf: 1689128 bytes, checksum: c3f8712ed17691069b7fabb711257101 (MD5) Previous issue date: 2010 / Resumo: A Xanthomonas axonopodis pv. citri (Xac) é uma bactéria Gram-negativa que parasita plantas cítricas e é responsável pela doença conhecida como cancro cítrico, que apresenta grande importância econômica em todo mundo. Acredita-se que a infecção da célula hospedeira ocorre com atuação dos sistemas de secreção, onde fatores macromoleculares de virulência, normalmente proteínas ou complexos de ácidos nucléicos com proteínas, são excretados para o citosol da célula no caso dos sistemas do tipo III e IV, onde irão interferir no processo celular do hospedeiro. O alvo do estudo é a proteína hipotética XACb0033, codificada pelo locus virB do plasmídio pXac64. Ela foi identificada como possível chaperona secretória do sistema de secreção tipo IV, por apresentar diversas características destas proteínas, como baixo peso molecular, pI ácido e propensão a formação de dímeros, entre outras. A XACb0033 foi clonada no vetor de expressão pET23a(+) e expressa na bactéria Escherichia coli utilizando técnicas de biologia molecular de clonagem e expressão. Os resultados da expressão foram satisfatórios, obtendo-se a proteína em quantidade suficiente para sua purificação seguida pela caracterização estrutural. A XACb0033 foi analisada por Espectrometria de Massas (MALDI-Tof MS), Dicroísmo Circular (CD), fluorescência de emissão estática e dinâmica, Ressonância Magnética Nuclear de Hidrogênio-1 (RMN de H) e Espalhamento de raios-X a baixo ângulo (SAXS). Todos os dados indicam que a XACb0033 apresenta estrutura enovelada, não interage com os nucleotídeos (ATP e ADP) e tende em agir em forma dimerica seguindo o modelo de uma chaperona secretória, e, por fim, a estrutura do seu envelope molecular foi obtida. / Abstract: Xanthomonas axonopodis pv. citri (Xac) is a Gram-negative bacterium that parasites citric plants all over the world and is responsible for causing the citrus canker with significant economic importance. It is believed that infection of the host cell occurs with activity of Xac¿s secretion systems, where macromolecular virulence factors, usually proteins or nucleic acid complexes with proteins, are excreted into the cytosol of the host cells as in the case of type III and IV systems, where they will interfere with the key cell processes. The aim of our study was structural characterization of the XACb0033, Xac¿s hypothetical protein, encoded by the locus virB of pXac64 plasmid. This protein was identified as a possible type IV secretion system chaperona because it presents many features of these proteins, such as low molecular weight, acidic pI, and propensity to form dimers, among others. The XACb0033 was cloned at expression vector pET23a (+) and expressed in Escherichia coli using molecular biology techniques for cloning and expression. The expression results were satisfactory, obtaining sufficient protein for its purification followed by structural characterization. The XACb0033 was analyzed by Mass Spectrometry (MALDI-Tof MS), Circular Dichroism (CD), static and dynamic Fluorescence, Nuclear Magnetic Resonance (H NMR) and by Small Angle X-ray Scattering (SAXS). All collected data indicated that XACb0033 has folded structure, does not interact with nucleotides (ATP and ADP) and tends to act in dimeric form, following a model of a secretory chaperona, and, at last but not at least, its molecular envelope structure has been obtained. / Mestrado / Quimica Organica / Mestre em Química

Orientador: Pedro Paulo A. Funari / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Filosofia e Ciencias Humanas / Made available in DSpace on 2018-07-29T05:17:30Z (GMT). No. of bitstreams: 1 Oliveira.JulioCesarMagalhaesde_M.pdf: 10602387 bytes, checksum: 311b826b4dc434b9d08a18d8ba5323d1 (MD5) Previous issue date: 2001 / Resumo: Este é um estudo sobre algumas das formas da atuação do povo nas cidades do Império Romano Tardio. O texto se concentra numa análise do caso particular das relações entre a plebe cristã e a Igreja no norte da África, mas apresenta essas relações no contexto mais amplo da política urbana do Império tardio (do século IV às primeiras décadas do século V). O objetivo é compreender como, neste contexto, as multidões urbanas podiam ser mobilizadas e engajadas e quais eram as expectativas, as motivações e as formas de ação coletiva da plebe urbana / Abstract: This study is about some of the (political and religious) activities of the common people in the cities of the Later Roman Empire. We focus our attention to the relations between the Christian plebs and the Church in Northern Africa. Our approach, though, is by presenting the relations in the broader context of the urban policies of the Later Empire. We aim to understand how the urban mob would be mobilized and led to take an active part in political and religious disputes, what its motivations and expectations were, and how it would act in order to achieve certain goals / Mestrado / Mestre em História

Memoria (licenciado en ciencias jurídicas y sociales) / El presente trabajo contiene un análisis del nuevo Título IV de la Ley N° 18.575, Orgánica Constitucional de Bases Generales de la Administración del Estado, incorporado por el artículo 32 de la Ley N° 20.500, sobre Asociaciones y Participación Ciudadana en la Gestión Pública. En particular, realizaremos un análisis jurídico de dicho Título IV y las características que presentan el debido proceso administrativo clásico y el proceso de participación. En primer lugar, analizaremos la normativa de participación ciudadana respecto de los Ministerios Secretaría General de Gobierno, de Educación y del Medio Ambiente; en seguida veremos si existe relación entre esos textos legales con la Ley N° 19.880, que establece Bases de los Procedimientos Administrativos que rigen los actos de los órganos de la Administración del Estado; y, en tercer lugar, estableceremos las fortalezas y precariedades del debido proceso de participación ciudadana actualmente vigente. Como cuarto aspecto, y en función de las conclusiones a que nos lleven dichos análisis, propondremos algunas modificaciones legales que tengan por objeto elevar progresivamente los índices de participación en el Gobierno Central de Chile. Finalmente, además del estudio jurídico a que hemos hecho referencia, llevaremos a cabo un análisis práctico que evalúe la aplicación del Título IV desde su publicación en 2011 hasta el año 2017, respecto de las tres carteras de Estado antes mencionadas. Para ello, efectuaremos un estudio individual y comparativo que dé cuenta de las fortalezas y debilidades de la participación ciudadana desde su implementación. Esta tesis pretende servir de complemento al estudio del derecho y proceso de participación ciudadana que actualmente vivimos en nuestro país

Les ducs-comtes de Bourgogne ont hérité, en 1330, d’un domaine déjà bien constitué, dont les points forts épousent les axes de pénétration du relief, selon une diagonale sud-ouest/nord-est. Bien que partiellement et provisoirement démembré au gré de houleux partages successoraux, il n’a connu que des modifications de détail, ayant pour but de renforcer le maillage du territoire. Il s’appuie sur un réseau administratif ancien constitué de prévôtés, de châtellenies et, accessoirement, de mairies. Son caractère archaïque est compensé par la réorganisation, sous Eudes IV, du ressort des baillis, qui aboutit à une partition entre deux bailliages, d’Amont et d’Aval. Ce prince est également à l’origine de la création de la gruerie, et de la mise en place de structures comptables visant à optimiser le circuit de la production et de la commercialisation du sel.Les ducs-comtes ont utilisé pleinement les ressources de la féodalité pour renforcer et étendre leur réseau vassalique. Ils se heurtent aux intérêts des grandes familles - Faucogney, Montbéliard, Neuchâtel, Chalon-Arlay et Chalon-Auxerre - maîtresses des positions frontalières, dont la puissance leur permet de rivaliser avec le prince. Le principat d’Eudes IV est parcouru de fortes tensions avec la noblesse comtoise, victime de la politique d’affirmation de ce duc-comte. Elles s’expriment régulièrement par le recours aux armes de toute une partie de la haute aristocratie, qui trouve des appuis chez les princes voisins et surtout auprès du roi d’Angleterre. Un apaisement relatif survient avec l’avènement de Philippe de Rouvres : il suscite l’émergence de nouveaux équilibres en proposant aux grands féodaux de participer au gouvernement de la province. Eudes IV a quant à lui joué contre les barons la carte de la petite et moyenne noblesse, qu’il a intégrée aux rouages du pouvoir par le biais des offices et du service armé. Le nombre de ralliements obtenus prouve la réussite de cette politique d’association de la noblesse modeste aux retombées financières des domaines du prince, et notamment des revenus de l’industrie du sel, originalité de la province comtoise.En revanche, le bilan de l’affirmation du pouvoir princier, encore en pleine élaboration en Franche-Comté, est mitigé. Si la souveraineté du prince est clairement affirmée dans son principe, elle n’est pas toujours effective dans les faits, même si les ducs-comtes, et particulièrement Eudes IV, y ont porté tous leurs efforts, en tentant notamment de créer à leur profit l’ébauche d’un espace politique, judiciaire et économique étendu aux fiefs des grands. Ces entreprises se heurtent aux exigences d’un droit féodal toujours vivace, et souffrent de la conjoncture générale de la guerre de Cent ans, qui contraint le roi de France à ménager ses forces en donnant satisfaction aux féodaux contre leur prince. Néanmoins, les institutions se renforcent, particulièrement en ce qui concerne l’exercice de la justice. La guerre pousse à redéfinir les fonctions des officiers et à en créer de nouveaux. Et, fait majeur, le pouvoir législatif et normatif du prince est entré dans les mentalités. Le terrain est donc amplement préparé pour la construction de l’État bourguignon sous les ducs Valois. / The Dukes-Counts of Burgundy inherited in 1330 within a domain already well established, whose strengths espouse the axes of penetration of the relief, according to a diagonal southwest / northeast. Although only partially and temporarily dismembered at the option of boisterous successional divisions, it has had only minor changes, aimed at strengthening the territorial mesh. It relies on a network of former administrative provosts, castellanies and, incidentally, town halls. Its archaic character is offset by the reorganization, under Eudes IV, the competence of bailiffs, which results in a partition between two bailiwicks, Upstream and Downstream. The prince is also responsible for creating the gruerie, and implementation of accounting structures to optimize the circuit for the production and marketing of salt. The Dukes-Counts have fully used the resources of the feudalism to strengthen and expand their network of vassalage. They clash with the interests of large families - Faucogney, Montbéliard, Neuchâtel, Chalon-Arlay and Chalon-Auxerre - mistresses border positions whose power allows them to compete with the prince. The government of Eudes IV is traversed by strong tensions with the nobility of the County, victim of the affirmation of the Duke-Count policy. They are expressed regularly by the use of weapons in any part of the aristocracy, which finds support among neighboring princes and especially to the king of England. A relative easing occurs with the accession of Philip of Rouvres: it raises the emergence of new balances by offering to the great vassals to participate in the government of the province. Eudes IV, meanwhile, played against the barons the card of small and medium nobility, which he included to the machinery of power through the offices and the armed service. The number of rallies proves the achieved success of this modest nobility association policy to the financial impact of the prince’s domain, including income from the salt industry, originality of the province. However, the record of the assertion of princely power, still in full development in the county of Burgundy, is mixed. If the sovereignty of the prince is clearly affirmed in principle, it is not always effective in practice, even if the Dukes-Counts, especially Eudes IV, have focused all their efforts, notably by trying to create for their benefit a draft of political, judicial and economic space, extended to fiefdoms. These enterprises face the demands of a still alive feudal law, and suffer from the general economic conditions of the Hundred Years War, which forced the King of France to spare his strength by giving satisfaction to the great vassals against their prince. However, institutions are strengthened, particularly in relation to the exercise of justice. The war drives to redefine the functions of the officers and to create new ones. And major fact, the legislative and normative power of the prince entered mentalities. The land is fully prepared for the construction of the Burgundian state under the Valois dukes.

The need for alternative cognitive enhancers has risen due to the fact that clinical trial results of the drugs currently approved for treating these disorders have not been satisfactory. IRAP has become a possible drug target for treating cognitive impairment brought about by Alzheimer’s disease, head trauma or cerebral ischemia, among others. This came after the revelation that Angiotensin IV enhances memory and learning. Angiotensin IV, the endogenous ligand of IRAP has been structurally modified with the aim of producing potent IRAP inhibitors. However, the peptidic nature of these inhibitors restricts their use; they are not likely to cross the blood brain barrier. Other strategies for generating IRAP inhibitors have been through structure-based design and receptor based virtual screening. These drug-like molecules have exhibited positive results in animal studies. IRAP inhibitors have been identified via a HTS of 10500 low-molecular weight compounds to give the hit based on a spirooxindole dihydroquinazolinone scaffold, with an IC50 value of 1.5 µM. In this project, some analogues to this hit compound have successfully been synthesized using a known method, whereas others have been synthesized after additional method development. The application of the developed method was found to be limited, because poor yield was obtained when a compound with an electron withdrawing substituent on the aniline was synthesized. As a result of this, modification of this method may be required or new methods may have to be developed to synthesize these types of analogues. Inhibition capability of 5 new spirooxindole dihydroquinazolinones was tested through a biochemical assay. Compound 6e emerged as the most potent inhibitor in the series, with an IC50 value of 0.2 µM. This compound will now serve as a lead compound and should be used as a starting point for future optimization in order to generate more potent IRAP inhibitors.

L’angiogenèses par bourgeonnement est associée à une réorganisation majeure de la matrice extracellulaire (MEC). Nous avons déjà démontré que la lysyl oxydase-like 2 (LOXL2), une enzyme responsable du crosslinking de la MEC, régule la formation de vaisseaux intersomitiques dans les embryons de poisson zèbre et de capillaires en hydrogels 3D. Dans ce manuscrit, nous avons examiné les mécanismes impliqués dans cette régulation. Nous avons constaté l’association intracellulaire de LOXL2 avec la fibronectine et le collagène IV, avant d’être incorporée dans des structures fibrillaires dès l’exocytose. De plus, l’inhibition de l’expression de LOXL2 entraine des défauts de déposition de la MEC et diminue sa rigidité, inhibant secondairement la maturation des structures d'adhésion cellulaire. Alors que LOXL2 n‘est pas nécessaire pour la formation de capillaires dans un modèle 2D sur MEC de fibroblastes, les défauts de déposition de MEC sont corrélés à l'inhibition de formation des capillaires en hydrogel 3D. Ni l’addition de LOXL2 exogène, ni l’augmentation de la rigidité des hydrogels ne compense la perte d’expression de LOXL2. Enfin, nous avons pu montrer que ni l'activité catalytique ni le domaine catalytique de LOXL2 ne sont essentiels pour la formation de capillaire dans le poisson zèbre et dans les hydrogels et pour l’assemblage du collagène IV par des cellules endothéliales. L’ensemble de ces données suggère donc que les domaines SRCR de LOXL2 exprimés par des cellules endothéliales régulent l’échafaudage de fibronectine et de collagène IV dans la MEC qui est nécessaire à la formation de capillaires. / Sprouting angiogenesis is associated with major extracellular matrix (ECM) remodelling, consisting in both degradation of the microenvironment and generation of a new basement membrane. We have previously reported that lysyl oxidase-like 2 (LOXL2), an enzyme responsible for ECM crosslinking, regulates formation of intersomitic vessels (ISV) of zebrafish embryos and of capillaries in 3D hydrogels. In this manuscript we investigated the mechanisms involved. We found that LOXL2 associates with fibronectin and collagen IV intracellulary before direct incorporation in fibrillar structures of the ECM upon exocytosis. In addition, silencing LOXL2 demonstrated its involvement in ECM deposition as both composition and stiffness of the ECM were affected, which subsequently altered maturation of cell adhesion structures. Whereas LOXL2 is not required for formation of capillaries on top of a fibroblast monolayer, in a 2D assay, ECM defaults were associated with altered formation of capillaries in 3D hydrogels.Neither addition of exogenous LOXL2, nor increasing the stiffness of hydrogels could restore capillary formation. Moreover, we could show that neither the catalytic activity nor the catalytic domain were required for capillary formation in vivo and in 3D hydrogels, and for collagen IV deposition by endothelial cells. Altogether, these data suggest that the SRCR domains of LOXL2 expressed by endothelial cells regulate 3D capillary morphogenesis through scaffolding of fibronectin and collagen IV in the ECM.

No description available.

La transformation naturelle est la capacité de certaines bactéries à incorporer et à recombiner activement de l’ADN extra-cellulaire. Ce procédé majeur augmente la plasticité et l’adaptabilité des bactéries à Gram positif et négatif en réalisant des échanges génétiques intra- et inter-espèces. S. pneumoniae est un pathogène majeur de l’Homme. Cette bactérie est responsable d’infections sévères telles que des pneumonies, des méningites et des septicémies. Dans cette espèce, la transformation naturelle est corrélée au phénomène de changement de capsule et à la baisse d’efficacité des vaccins. La plupart des bactéries à Gram positif naturellement transformables possèdent un opéron comG, semblable aux opérons codant pour la famille des pili de type IV, extrêmement répandus chez les bactéries à Gram négatif. Il a été proposé que l’opéron comG est responsable de la formation d’un petit filament, nommé pseudo- pilus. Cependant, un tel filament n’a jamais été observé. Par des techniques de mutagenèse, de caractérisation biochimique, de microscopie optique et électronique, nous sommes parvenus à identifier des filaments de plusieurs micromètres de long à la surface de bactéries S. pneumoniae compétentes. Nous avons confirmé l’appartenance de ces filaments à la famille des pili de type IV. Par conséquent, nous avons infirmé l’hypothèse de la formation d’un pseudo-pilus par l’opérons comG chez S. pneumoniae. De plus, nous avons montré que les pili se lient à l’ADN et qu’ils sont requis pour la capture de l’ADN extra-cellulaire. Ces résultats apportent des informations cruciales concernant les premières étapes de capture de l’ADN durant la transformation naturelle. Nous proposons un nouveau modèle dans lequel le pilus agirait comme un « piège à ADN », capturant l’ADN à la surface des bactéries compétentes pour le guider jusqu’au pore d’entrée dans la cellule. / Natural transformation is the ability of bacteria to actively take up and recombine extracellular DNA. This crucial process increases genome plasticity and adaptability of Gram-negative and Gram-positive bacteria through intra- and inter-species genetic exchange. S. pneumoniae is a major human pathogen responsible for severe diseases such as pneumonia, meningitis and septicemia. In this species, transformation has been linked to capsular serotype switching and reduced vaccine efficiency. Most transformable Gram-positive bacteria carry a comG operon that resembles operons encoding a widespread family of pili in Gram-negative bacteria, the type IV pili. It has been commonly proposed that the comG operon is responsible for the formation of a short pseudo-pilus filament. However, such an appendage had never been visualized in any bacterium. By mutagenesis, biochemical characterization, optical and electron microscopy techniques we were able to identify long, micrometer-sized appendages protruding from the surface of competent S. pneumoniae. We confirmed the Type IV pili nature of these appendages, we showed that they bind DNA, and are absolutely required for DNA uptake. We consequently overthrew the pseudopilus hypothesis at least in S. pneumoniae, and provided crucial information concerning the initial step of DNA uptake. We propose a revised model in which the transformation pilus acts as a “DNA trap” capturing DNA at the surface of competent cells, guiding it to the translocation channel.

Sprague-Dawley rats were administered daily, subcutaneous injections of methylmercuric chloride at a dose of 5 mg/Hg/kg beginning on postnatal day 5. By their fourth postnatal week, animals exhibited a constellation of neurological signs of motor impairment which resembled the cerebral palsy syndrome of humans perinatally exposed to methylmercury. Routine histological examination of the brain revealed no gross differences between methylmercury-treated (MeHg), normal control (NC) or weight-matched littermates. The histochemical localization of the mitochondrial enzyme cytochrome oxidase (CO) was utilized in Experiment I to examine possible alterations in the metabolic activity of motor nuclei which might contribute to the observed movement and postural disorders. A population of intensely-staining cytochrome oxidase neurons (ICONs) in the magnocellular portion of the red nucleus (RMC) and interrubral mesencephalon (IRM) were conspicuously present in all MeHg animals at the onset of motor impairment. These morphologically, histochemically, and anatomically distinct neurons did not exhibit intense CO staining in control animals. Conversely, a significant decrease was demonstrated in the oxidative metabolic activity of many neurons in the substantia nigra, zona reticulata of MeHg animals. In Experiment II, the postnatal appearance of ICONs was morphometrically quantified in MeHg animals sacrificed at PND 14, 16, 18, 20, 22, or 25. The histochemically-defined onset of increased metabolic activity in ICONs was first observed on PND 16, at least one week before the onset of clinical signs of neurological impairment. This was the earliest manifestation of methylmercury neurotoxicity yet described in this animal model. A subsequent four-fold increase in the total number of ICONs at PND 18 was followed by a gradual decrease in number to PND 25. Significantly more of the ICONs were found in the IRM than in the RMC at PND 18 & 20. The possibility that the increased activity of ICONs may result from disinhibition of specific afferents to the red nucleus was addressed by introducing either hemidecortication or hemicerebellectomy on PND 10 and then morphometrically determining the deviation from symmetry in the bilateral distribution of the total number of ICONs in the RMC and IRM at PND 22. The distribution of ICONs was symmetrical and not different in either hemidecorticate or unoperated controls. A significant (36%) decrease in the total number of ICONs was observed in both the RMC and IRM contralateral to hemicerebellectomy. The identical ipsilateral regions did not differ from control or hemidecorticate MeHg animals. In Experiment III, the anatomical distribution of major histocompatability complex antigens (MHC) in the brain of MeHg animals was examined using immunohistochemical methods. MHC immunoreactivity was widely distributed throughout the brain of MeHg animals. Areas with low immunoreactivity, or lack of it, stand out and include all of the hippocampus, thalamus, pyriform and entorhinal cortex, and lateral cerebellar hemispheres. Moderate staining intensity was observed in neocortical areas, basal forebrain, caudate-putamen and cerebellar vermis. Strong immunoreactivity was found in red nucleus, substantia nigra, cingulate cortex, retrosplenial cortex, presubiculum, parasubiculum and vestibular nuclei. It was suggested that the increased activity of ICONs likely contributes to the movement and postural disorders resulting from methylmercury intoxication. The increased activity in ICONs was determined to be, at least partially, dependent upon cerebellar input. The results are discussed with reference to the toxic effects of methylmercury and specifically to the susceptibility of GABAergic interneurons in perinatal trauma. Possible analogies are drawn between the mechanisms of methylmercury-induced cerebral palsy syndrome and those of other developmental movement and postural disorders. / Medicine, Faculty of / Graduate