Der präfrontale Kortex wird im Allgemeinen mit exekutiven Funktionen in Verbindung gebracht, die unter anderem Aufmerksamkeitskontrolle, Inhibition, Arbeitsgedächtnis oder die Erkennung und Bewertung neuartiger Reize beinhalten. Für die situationsgerechte Anpassung der verschiedenen Kontrollmechanismen ist in dieser Hirnregion, wie sich in zahlreichen Studien gezeigt hat, der Neurotransmitter Dopamin entscheidend. Dieser liegt, u.a. bedingt durch den Val108/158Met-Polymorphismus der Catechol-O-Methyl-Transferase, interindividuell in verschiedenem Ausmaß vor und sollte dadurch Unterschiede in präfrontalen Funktionen zwischen einzelnen Individuen maßgeblich beeinflussen. Ziel dieser Arbeit war es, diesen Einfluss mittels EEG und ereigniskorrelierten Potenzialen genauer zu bestimmen und zusätzlich herauszuarbeiten, welche kognitiven Prozesse genau durch den COMT-Genotyp beeinflusst werden. 60 gesunde Probanden absolvierten hierzu unter EEG-Ableitung eine Aufgabe mit variablem Aufmerksamkeitsbedarf. Es wurde zunächst der Zusammenhang zwischen den ereigniskorrelierten Potenzialen N200 und P300 mit präfrontalen Funktionen wie Aufmerksamkeitskontrolle, Inhibition und Konfliktdetektion bzw. –verarbeitung untersucht. Zusätzlich wurden sowohl das Verhalten als auch die elektrophysiologische Aktivität zwischen den sorgfältig gematchten Genotyp-Gruppen Val/Val, Val/Met und Met/Met (je 11 Probanden) verglichen. Es zeigte sich, dass die N200 v.a. durch eine Veränderung der Aufmerksamkeitsrichtung zwischen globalen und lokalen Stimuluseigenschaften beeinflusst wurde. Die P300 wurde dagegen sowohl von der Aufmerksamkeitsrichtung als auch der Konfliktstärke (lokale im Vergleich zu globalen Stimuluseigenschaften sowie erhöhter Konflikt mit vermehrter Beanspruchung von Aufmerksamkeitsressourcen) beeinflusst. Wir konnten keine Auswirkungen der COMT-Ausprägung auf die Performanz (Korrektheit und Reaktionsgeschwindigkeit) im VAC-Test feststellen. Die hirnelektrische Aktivität (N200 und P300) unterlag dagegen einem deutlichen Einfluss des COMT-Genotyps: Met-Allel-Homozygote zeigten ein effizienteres Arbeiten - es lag eine bessere Aktivierung des Kortex (höhere P300) sowie ein geringerer Bedarf an Inhibition bei gleicher Leistung wie bei Val-Allel-Trägern vor (niedrigere N200- Amplitude). Es zeigte sich zudem bei den Met-Allel-Homozygoten kaum Variabilität der Hirnaktivierung über alle Schwierigkeitsstufen hinweg, was möglicherweise Ausdruck einer geringeren kognitiven Flexibilität im Vergleich zu Val-Allel-Trägern ist. / The prefrontal cortex is reported to be associated with executive functions such as attentional control, inhibition, working memory or recognition and evaluation of new stimuli. To the aim of appropriate adaptation of the variable control mechanisms in this brain region, the neurotransmitter dopamine is crucial, as reported in numerous studies. Due to the Val108/158Met polymorphism (amongst others) the neurotransmitter is available in a varying amount and should therefore effect prefrontal functions amongst individuals importantly. The aim of this study was to define this influence using EEG and event related potentials and to identify in addition the cognitive processes influenced by the COMT genotype. 60 healthy individuals therefore passed a variable attentional control task during the recording of an EEG. The association of the event-related potentials N200 and P300 with prefrontal functions (attentional control, inhibition and conflict detection) was analyzed. Additionally performance and electrophysiological activity of the carefully matched genotype groups Val/Val, Val/Met and Met/Met were compared. We found N200 mainly being influenced by an attentional shift between global and local stimulus characteristics - in contrast to P300, which was affected both by attentional focus and amount of conflict (local in comparison to global stimulus characteristics as well as an increased amount of conflict with a higher demand for attentional resources). We found no influence of COMT genotype on performance (reaction time and correctness) in our task whereas electric brain activity is subject to a considerable impact of the COMT genotype: Met allele homozygotes showed more efficient working expressed by a better cortical activation (higher P300) and less inhibitory demand (lower N200) for equal performance compared to Val allele carriers. Furthermore Met allele homozygotes showed only very little variability in cortical activation throughout all conditions – maybe a sign of less cognitive flexibility compared to Val allele carriers.

Orientador: Fadel David Antonio Turma Filho / Banca: Rosana Figueiredo Salvi / Banca: Maria Dalva de Souza Dezan / Banca: Enéas Rente Ferreira / Banca: Luciene Cristina Risso / Resumo: Esse estudo realiza uma leitura sobre a transformação socioespacial no bairro Praia de Iracema, situado na cidade de Fortaleza, capital do Estado do Ceará-Brasil, a partir da representação dos seus moradores e amigos. Este bairro, espaço de referência e tradição da cidade de Fortaleza, foi palco da cultura, boemia e arte da cidade durante décadas. Na busca por um caminho teórico-metodológico, o estudo apresenta considerações de diferentes autores a respeito das representações sociais como instrumento de análise da realidade geográfica. De início, apresenta um breve histórico do bairro Praia de Iracema, lugar considerado o berço da história e de efervescência cultural de Fortaleza, frequentado por intelectuais, músicos e toda sociedade fortalezense. Depois, faz ponderações sobre a abordagem cultural na Geografia, quando estabelece diálogo entre cultura e espaço, e demonstra as consequências advindas das transformações espaciais ocorridas, ao longo do tempo, naquele ambiente urbano. Tece considerações a respeito das representações sociais na Praia de Iracema, pontuando autores que já desenvolveram trabalho nessa linha teórico-metodológica, e discorre sobre projetos de requalificações, executados e em implantação no bairro, com o intuito de transformar a Praia de Iracema em principal polo de turismo e lazer da cidade. Situa as estratégias de apropriação do espaço da Praia de Iracema pelo poder público e o resultado da análise discursiva da pesquisa empírica, de inspiração fenomenológica, portanto, predominantemente qualitativa. Esse estudo demonstra que as transformações socioespaciais verificadas na Praia de Iracema foram impulsionadas por força da política econômica, que nem sempre reflete os interesses dos moradores do lugar. Tal fato corrobora a tese de que, dentre as representações... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: This study performs a reading on the socio-spatial transformation in the neighborhood Praia de Iracema, located in the city of Fortaleza, Ceará State capital- Brazil, from the representation of its residents and friends. This neighborhood, reference space and tradition of the city of Fortaleza, hosted the culture, art and bohemian city for decades. In the search for a theoretical methodological way, the study presents considerations of different authors about social representations as a tool for analysis of geographic reality. At first presents a brief history of the neighborhood Praia de Iracema, place considered the cradle of history and cultural effervescence of Fortaleza, frequented by intellectuals, musicians and by the rest of Fortaleza's society. Then, do weights on the cultural approach in geography when establishes dialogue between culture and space, and demonstrates the consequences resulting from the ocurred spatial transformations over time on the urban environment. Presents considerations regarding the social representations on Praia de Iracema, punctuating authors who have developed work in this line theory and method, and discusses retraining projects, implemented and under implementation in the neighborhood, in order to transform the Praia de Iracema into main hub of tourism and leisure city. Situates strategies of space appropriation of Praia de Iracema by the government and the result of discursive analysis of the empirical research, the phenomenological therefore largely qualitative. This study demonstrates that the socio-spatial transformations observed in Praia de Iracema were driven by force of economic policy, which does not always reflect the interests of the residents of the place. This corroborates the thesis that among the identified social representations, those derived from the ideology that... (Complete abstract click electronic access below) / Doutor

Recent findings have shown an inverse association between the circulating levels of pentadecanoic acid (C15:0) and heptadecanoic acid (C17:0) with the risk of pathological development in type 2 diabetes, cardio vascular disease and neurological disorders. From previously published research, it has been said that both these odd chain fatty acids are biomarkers of their dietary intake and are significantly correlated to dietary ruminant fat intake. However, there are profound studies that show the contrary where they do not display this biomarker correlation. Additionally, several astute studies have suggested or shown odd chain fatty acid endogenous biosynthesis, most often suggested via alpha oxidation; the cleavage of a single carbon unit from a fatty acid chain within the peroxisomes. To better understand the correlations and interactions between these two fatty acids with pathological development, the origin of these odd chain fatty acids needed to be determined, along with confirming their association with the disease aetiology. To minimise animal & human experimentation we made use of existing sample sets made available through institutional collaborations, which produced both animal and human interventional study samples suitable for odd chain fatty acid investigations. These sample collaborations allowed us to comprehensively investigate all plausible contributory sources of these odd chain fatty acids; including from the intestinal microbiota, from dietary contributions, and derived from novel endogenous biosynthesis. The investigations included two intestinal germ-free studies, two ruminant fat diet studies, two dietary fat studies and an ethanol intake study. Endogenous biosynthesis was assessed through: a stearic acid infusion, phytol supplementation, and an Hacl1 knockout mouse model. A human dietary intervention study was used to translate the results. Finally, a study comparing circulating baseline C15:0 and C17:0 levels with the development of glucose intolerance. We found that the circulating C15:0 and C17:0 levels were not significantly influenced by the presence or absence of intestinal microbiota. The circulating C15:0 levels were significantly and linearly increased when the C15:0 dietary composition increased; however, there was no significant correlation in the circulating C17:0 levels with intake. Circulating levels of C15:0 were affected by the dietary composition and factors affecting the dietary intake, e.g. total fat intake and ethanol, whereas circulating C17:0 levels were found to be independent of these variables. In our studies, the circulating C15:0 levels were not significantly affected by any expected variations in alpha oxidation caused by pathway substrate inhibition or gene knockout. However, C17:0 was significantly related, demonstrating it is substantially endogenously biosynthesised. Furthermore, we found that the circulating C15:0 levels, when independent of any dietary variations, did not correlate with the progression of glucose intolerance when induced, but the circulating C17:0 levels did significantly relate and linearly correlated with the development of glucose intolerance. To summarise, the circulating C15:0 and C17:0 levels were independently derived; the C15:0 levels substantially correlated with its dietary intake, whilst the C17:0 levels proved to be separately derived from its endogenous biosynthesis via alpha oxidation of stearic acid. C15:0 was found to be minimally endogenously biosynthesised via a single cycle of beta oxidation of C17:0 in the peroxisomes, however, this did not significantly contribute to the circulating levels of C15:0. Additionally, only the baseline levels of C17:0 significantly correlated with the development of glucose intolerance. These findings highlight the considerable differences between both of these odd chain fatty acids that were once thought to be homogeneous and similarly derived. On the contrary, they display profound dietary, metabolic, and pathological differences.

Submitted by Luiz Nova (luiznova1@gmail.com) on 2018-12-06T14:29:57Z No. of bitstreams: 1 0 - CULTURA, POLÍTICA E DIREITOS CULTURAIS NAS POLÍTICAS ESTATAIS DE CULTURA - TESE FINAL.pdf: 960752 bytes, checksum: e782ea39cef50efa1f2b88562d3fcc1f (MD5) / Approved for entry into archive by Setor de Periódicos (per_macedocosta@ufba.br) on 2018-12-07T20:14:58Z (GMT) No. of bitstreams: 1 0 - CULTURA, POLÍTICA E DIREITOS CULTURAIS NAS POLÍTICAS ESTATAIS DE CULTURA - TESE FINAL.pdf: 960752 bytes, checksum: e782ea39cef50efa1f2b88562d3fcc1f (MD5) / Made available in DSpace on 2018-12-07T20:14:58Z (GMT). No. of bitstreams: 1 0 - CULTURA, POLÍTICA E DIREITOS CULTURAIS NAS POLÍTICAS ESTATAIS DE CULTURA - TESE FINAL.pdf: 960752 bytes, checksum: e782ea39cef50efa1f2b88562d3fcc1f (MD5) / A tese discute as políticas estatais de cultura como ação de dimensão pública, a partir do entendimento dos direitos culturais como parte dos direitos humanos fundamentais. Para isto, analisa a reconhecida centralidade contemporânea da cultura para entender o lugar das políticas estatais deste campo. A compreensão da relação políticas estatais de cultura e sua dimensão pública sustenta-se em duas formulações utilizadas como parâmetros de análise. São as formulações sobre a centralidade compartilhada e a transversalidade mútua que ocorrem na interconexão entre cultura, política e economia, como parte constitutiva da modernidade. A compreensão de interconexão e relativa autonomia entre os três campos parte do entendimento de que são diferentes as origens do Iluminismo e a luta contra o absolutismo, em relação ao surgimento do capitalismo, modo de produção. A modernidade – cultura, política e economia - se constitui então no imbricamento destes dois movimentos distintos, de um lado, o Iluminismo - valores, arte e cidadania – e a luta contra o absolutismo, de outro, o modo de produção capitalista. Este com origem na relação econômica de arrendamento da terra, na Inglaterra, como formula Ellen Wood (2001). Com esta compreensão, a centralidade compartilhada ressalta-se enquanto configuração do contemporâneo, com base nos conceitos de hegemonia, sociedade civil, Estado Integral, momento econômico-corporativo e momento ético-político, de Antonio Gramsci. Também faz parte da análise, a sistematização de Boaventura Sousa Santos (2005) quanto à permanente tensão da modernidade entre regulação e emancipação. Este quadro teórico fundamenta a formulação da tese de que as políticas estatais de cultura, portanto sua dimensão pública, precisam superar a fase econômico-corporativa, em que a identidade de campo se vincula destacadamente à produção e circulação. O entendimento é que esta etapa seminal, identitária, de constituição do campo cultural reforça a dimensão cultural hegemônica, reproduz o dominante. Resulta, portanto, contemporaneamente, no fortalecimento da dominante indústria cultural, ao não colocar o desafio ético-político, como parte intrínseca à dimensão pública de qualquer ação estatal, em particular, da cultura. A tese propondo que, a partir das conquistas acumuladas pelo campo da cultura na primeira década do século XXI, no Brasil, o desafio ético-político se impõe, inclusive como sobrevivência do conquistado. / The thesis discusses the state policies of culture as a public action, from the understanding of cultural rights as part of fundamental human rights. For this, it analyzes the acknowledged contemporary centrality of culture to understand the place of state policies in this field. The understanding of the relation between state policies of culture and its public dimension is based on two formulations used as parameters of analysis. It is the formulations about shared centrality and mutual transversality that take place in the interconnection between culture, politics and economics as a constituent part of modernity. The understanding of interconnection and relative autonomy between the three fields is based on the understanding that the origins of the Enlightenment and the struggle against absolutism in relation to the emergence of capitalism, mode of production, are different. Modernity - culture, politics and economy - is then the overlap between these two distinct movements, on the one hand, the Enlightenment - values, art and citizenship - and the struggle against absolutism, on the other, the capitalist mode of production. This one originates in the economic relation of lease of the land, in England, as formulates Ellen Wood (2001). With this understanding, shared centrality emerges as a configuration of the contemporary, based on the concepts of hegemony, civil society, the Integral State, the economic-corporate moment and the ethical-political moment of Antonio Gramsci. It is also part of the analysis, the systematization of Boaventura Sousa Santos (2005) regarding the permanent tension of modernity between regulation and emancipation. This theoretical framework supports the formulation of the thesis that state cultural policies, and therefore their public dimension, must overcome the economic-corporate phase, in which the field identity is strongly linked to production and circulation. The understanding is that this seminal, identity-building stage of the cultural field reinforces the hegemonic cultural dimension, reproduces the dominant. Consequently, at the same time, it strengthens the dominant cultural industry by not placing the ethical-political challenge as an intrinsic part of the public dimension of any state action, in particular, of culture. The thesis proposes that, based on the accumulated achievements of the field of culture in the first decade of the twenty-first century in Brazil, the ethical-political challenge imposes itself, including the survival of the conquered. / La tesis discute las políticas estatales de cultura como acción de dimensión pública, a partir del entendimiento de los derechos culturales como parte de los derechos humanos fundamentales. Para ello, analiza la reconocida centralidad contemporánea de la cultura para entender el lugar de las políticas estatales de este campo. La comprensión de la relación política estatal de cultura y su dimensión pública, se sustenta en dos formulaciones utilizadas como parámetros de análisis. Son las formulaciones sobre la centralidad compartida y la transversalidad mutua que ocurren en la interconexión entre cultura, política y economía, como parte constitutiva de la modernidad. La comprensión de interconexión y relativa autonomía entre los tres campos parte del entendimiento de que son diferentes los orígenes de la Ilustración y la lucha contra el absolutismo, en relación al surgimiento del capitalismo, modo de producción. La modernidad -cultura, política y economía- se constituye entonces en el imbricamiento de estos dos movimientos distintos, por un lado, el Iluminismo - valores, arte y ciudadanía - y la lucha contra el absolutismo, por otro, el modo de producción capitalista. Este con origen en la relación económica de arrendamiento de la tierra, en Inglaterra, como formula Ellen Wood (2001). Con esta comprensión, la centralidad compartida se resalta como configuración del contemporáneo, con base en los conceptos de hegemonía, sociedad civil, Estado Integral, momento económico-corporativo y momento ético-político, de Antonio Gramsci. También forma parte del análisis, la sistematización de Boaventura Sousa Santos (2005) en cuanto a la permanente tensión de la modernidad entre regulación y emancipación. Este cuadro teórico fundamenta la formulación de la tesis de que las políticas estatales de cultura, por lo tanto su dimensión pública, necesitan superar la fase económico-corporativa, en que la identidad de campo se vincula de forma destacada a la producción y circulación. El entendimiento es que esta etapa seminal, identitaria, de constitución del campo cultural refuerza la dimensión cultural hegemónica, reproduce al dominante. Por lo tanto, resulta, contemporáneamente, en el fortalecimiento de la dominante industria cultural, al no plantear el desafío ético-político, como parte intrínseca a la dimensión pública de cualquier acción estatal, en particular, de la cultura. La tesis proponiendo que, a partir de las conquistas acumuladas por el campo de la cultura en la primera década del siglo XXI, en Brasil, el desafío ético-político se impone, incluso como supervivencia del conquistado.

Unsere Bemühungen die Natur individueller Unterschiede der Emotionsregulation zu verstehen, involviert das Verständnis der Gene. In dieser Arbeit werden Gene (Kandidatengene), die für Proteine als Rezeptoren, Transporter oder Enzyme im Neurotransmitterstoffwechsel Serotonin und Dopamin kodieren, untersucht. Serotonin und Dopamin sind mit Angststörungen in verschiedener Weise assoziiert. Sie sind wichtige Neurotransmitter in Teilen des Gehirns, die mit Angstkonditionierung im Zusammenhang stehen. Polymorphismen in diesen Genen verändern die Struktur und Funktion der Genprodukte und nehmen damit Einfluss auf die Funktion von Hirnstrukturen und -systemen. Phobien sind äußerst intensive und persistente Furchtreaktionen, welche durch spezifische Situationen oder Objekte ausgelöst werden und von dem zwingenden Wunsch begleitet sind, diese Situationen oder Objekte zu vermeiden. Die Intensität der Furchtreaktion erscheint einem Außenstehenden, entsprechend der realen Gefahr dieser Situation, unangemessen und eigentümlich. Zumeist hat der Phobiker selbst auch Einsicht in diese Irrationalität seiner Furchtreaktion, vermag sie aber nicht willentlich unter Kontrolle zu halten. In dieser Arbeit wurden als Beispiel einer assoziierten Angst die Zahnbehandlungsphobie und als Beispiel einer nicht-assoziierten Angst die Spinnenphobie untersucht. Es wurden 53 Zahnbehandlungsängstliche, 52 Spinnenphobiker und 37 Kontrollpersonen mittels Fragebogen (SPF,FAS,STAI trait, DCQ, DFS, ASI, PANAS, R-IDCI) getestet. Die Probanden wurden durch PCR-Analyse von Mundschleimhautabstriche je einem Polymorphismus der untersuchten Kandidatengene zugeordnet. Es handelte sich dabei um die Gene für den Serotonintransporter 5HTT, den Serotoninrezepor 5HT1A, den Dopaminrezeptor DRD4, den Dopamintransporter DAT, BDNF und das in den Katecholaminabbau involvierte COMT-Enzym. Die untersuchten Polymorphismen weisen in der Literatur einen Einfluss auf die Angstausprägungen auf. In der statistischen Auswertung wurde auf signifikante Zusammenhänge zwischen einem Polymorphismus und der Ausprägung einer Phobie geachtet. Desweiteren wurden die verschiedenen Polymorphismen mit den Ergebnissen der Fragebogentests in Zusammenschau gebracht. Ein direkter Einfluss eines der untersuchten Gene auf die Ausprägung einer Phobie konnte nicht nachgewiesen werden. In der Gruppe der Dentalphobiker zeigten sich Hinweise auf einen Einfluss des BDNF G-Allels und des COMT G-Allels auf erhöhte Ängstlichkeit. / Understanding of individual differences in emotions is related to the understanding of genes. This paper analyses genes (candidate genes) that code for proteins as receptors, transporters or enzymes in the metabolism of neurotransmitter serotonin and dopamine. Serotonin and dopamine are in different ways associated with anxiety disorders. They are important neurotransmitter in parts of the brain that are associated with anxiety conditioning. Polymorphisms in these genes change the structure and function of gene products and have effect on the function of brain structures. In literature the analysed polymorphisms show influence on characteristics of anxiety. Phobias are very intense and persistent fearreactions, which are triggered by specific situations or objects. They are accompanied by the desire to avoid these specific objects/situations. The intensity of this fearreactions seems inadequate according to real danger. The phobic person himself realises the irrationality of the reaction, but cannot control it. In this paper dental phobia, as an example for associated anxiety, and spider phobia, as an example for non-associated anxiety, are analysed. 53 dentalphobic, 52 spiderphobic and 37 control persons are tested by questionnaires (SPF,FAS,STAI trait, DCQ, DFS, ASI, PANAS, R-IDCI). The test persons were related to each one polymorphism of a candidate gene by PCR-analysing of mouth mucosa samples. Analysed candidate genes are serotonin-transporter 5HTT, serotonin-receptor 5HT1A, COMT, dopamine-receptor DRD4, dopamine-transporter and neutrophin BDNF. The relationship between a polymorphism and the characteristics of a phobia was examined statistically. Further the questionnaire results and polymorphisms were analysed for relations. No direct influence could be shown for candidate genes on phobia characteristics. In the group of dental phobia, hints for influence of the BFNF G-allele and COMT G-allele on anxiety could be made.

The abundance of good reservoir and source rocks offshore Cabinda, Angola, makes the area an attractive and successful hydrocarbon province. Block 0, offshore Cabinda, lies in the Lower Congo basin along the western coast of Africa. The stratigraphy of Block 0 consists of two major oil-rich sequences: the rift sequence (primarily lacustrine) and the post-rift sequence (primarily marine). These are separated by a thick section of evaporites, and thus are referred to as the pre-salt sequence and post-salt sequence, respectively. The Chela Formation, mid-Aptian in age, was deposited before the salt. It consists of sandstones and conglomerates locally interbedded with carbonates. It is the youngest unit of the pre-salt sequence. The top of the Chela Formation is gradational into the salt, whereas the base of the Chela unconformably overlies older pre-salt units. The regional pre-Chela unconformity corresponds to the "break up unconformity" developed as a direct response of Gondwanaland rifting that resulted in the opening of the South Atlantic Ocean and culminated with the separation of the South American and African continents. In this context, the Chela Formation represents an early post-rift transgressive unit that spans the transition from continental to marine conditions. The thickness of the Chela Formation in Block O is variable. This unit thickens westward from O to 305 m. Environments of deposition within the Chela Formation range from coastal non-marine to shallow-marine environments. The Chela Formation onshore Cabinda is a fining-upward sequence with coarse sandstone and conglomerate in the base grading to finer sandstone interbedded with mudstone. Offshore, the unit is represented by a sequence of very-fine to fine-grained sandstone, grading to siltstone, and locally interbedded with dolomitic carbonates. Sediment in the Chela Formation has a continental-block provenance, evidence that Chela detritus was supplied from an external granitic source on the southern African continent. Although no commercial accumulations of hydrocarbons have been found offshore in the Chela sandstones to date, the unit represents a potential reservoir because of hydrocarbons log porosities between 15 and 30 porosity units, the presence of hydrocarbon shows onshore, and an excellent overlying seal of thick salt.

Der brustgewebsspezifische Metabolismus des weiblichen Sexualhormons 17β-Estradiol (E2) spielt eine wichtige Rolle bei der Brustkrebsentstehung. In der Brust wird E2 durch die humanen Cytochrom P450-abhängigen Monooxygenasen (CYP) Isoenzyme 1A1 (hCYP1A1) und 1B1 (hCYP1B1) zu 2-Hydroxy (2-OH) und 4-HO-E2 oxidiert und vorrangig durch die Catechol-O-Methyltransferase (COMT) entgiftet. Bei unzureichender O-Methylierung können diese Catecholestrogene zu elektrophilen Chinonen oxidiert werden, welche mit der DNA reagieren und somit Mutationen induzieren können. Eine niedrige COMT-Aktivität, durch Polymorphismen und/oder durch Nahrungsbestandteile, die mit dem Enzym selbst oder seiner Genexpression wechselwirken, könnte daher die Mutagenität von E2 und dessen Catecholestrogenen beeinflussen. Im Rahmen der vorliegenden Arbeit wurde der Einfluss der Hemmung der COMT-Aktivität auf die Mutagenität von E2 und dessen Catecholestrogenen untersucht. Zu diesem Zweck wurden der Hypoxanthin-Guanin-Phosphoribosyltransferase (HPRT)-Test und der Mikrokern-Test eingesetzt. Die Untersuchungen erfolgten in kultivierten Lungenfibroblasten des Chinesischen Hamsters (V79-Zellen) und in V79-Zellen, die mit hCYP1A1 transfiziert wurden. Begleitend zu den Mutagenitätsuntersuchungen wurde das Metabolitenprofil der Testsubstanzen anhand von Gaschromatographie gekoppelt mit Massenspektrometrie bestimmt. Nach Inkubation mit 0,08 µM 2 HO-E2 wurde dieses vollständig zu dessen Methylcatecholen umgesetzt, ab 2,5 µM hingegen war zusätzlich 2 HO-E2 im Medium nachweisbar. Demnach war die Hemmung der COMT-Aktivität bei der Inkubation mit 0,08 µM 2 HO-E2 vollständig und ab 2,5 µM partiell. Mit und ohne Hemmung der COMT-Aktivität war 2 Methoxyestradiol der Hauptmetabolit. 2-HO-E2 induzierte im Konzentrationsbereich 0,08 µM - 5 µM, mit und ohne Hemmung der COMT-Aktivität, keine Erhöhung der Mutantenfrequenz im hprt-Lokus von V79-Zellen. Im Gegensatz hierzu induzierte 2 HO-E2 ab 2,5 µM, mit und ohne Hemmung der COMT-Aktivität, mindestens eine Verdreifachung der Mikrokernrate im Vergleich zur Kontrollpopulation, wobei dieser Effekt ohne Inhibierung der COMT-Aktivität stärker ausgeprägt war. Über den gesamten getesteten Konzentrationsbereich (5 - 40 µM) wurde 4 HO-E2 zu dessen beiden Methylcatecholen umgesetzt, wobei 4-Methoxyestradiol den größten Anteil der detektierten Verbindungen (≥ 86%) ausmachte. Nach der Behandlung mit 3,5-Dinitrocatechol waren keine Methylierungsprodukte mehr nachweisbar, weswegen von einer vollständigen Hemmung der COMT-Aktivität im gesamten getesteten Konzentrationsbereich auszugehen war. 4-HO-E2 induzierte über den gesamten getesteten Konzentrationsbereich keine Genmutationen im hprt-Lokus. Erst nach Hemmung der COMT-Aktivität und Behandlung mit 20 µM 4 HO-E2 wurde eine Verdreifachung der Mutantenfrequenz im Vergleich zur Kontrollpopulation beobachtet. Mit und ohne Hemmung der COMT-Aktivität induzierte 4 HO E2 ab 20 µM eine Verdopplung der Mikrokernrate im Vergleich zur Kontrollpopulation. Im Kulturmedium der V79 hCYP1A1-Zellen, die mit 0,1 und 1 µM E2 für bis zu drei Wochen behandelt wurden, machten über die gesamte Versuchsdauer E2 (> 86%) und Estron (> 10%, bezogen auf die Summe aller Peakflächen) den größten Anteil der detektierten Verbindungen aus. Wie erwartet, waren nach Hemmung der COMT-Aktivität keine Methylierungsprodukte mehr nachweisbar. Die durchgehende, zwei- und dreiwöchige Behandlung mit jeweils 0,1 und 1 µM E2 bewirkte keine Induktion von Genmutationen im hprt-Lokus. Demgegenüber erhöhte sich die Mutantenfrequenz nach Hemmung der COMT-Aktivität und dreiwöchiger Behandlung mit 0,1 µM E2 um Faktor 4 im Vergleich zur Kontrollpopulation. Was die Mikrokerninduktion betrifft, so wurde nach 24-stündiger Inkubation mit 0,1 und 1 µM E2, mit und ohne Hemmung der COMT-Aktivität, keine Erhöhung der Mikrokernrate im Vergleich zur Kontrollpopulation beobachtet. Über die gesamte Dauer der Mutagenitätstests von E2 und dessen Catecholestrogenen unterschieden sich die Zellzyklusverteilung, die Wachstumskurven und die Koloniebildungsfähigkeit zum Zeitpunkt der Selektion, mit und ohne Hemmung der COMT-Aktivität, nicht statistisch signifikant von denjenigen der Kontrollpopulationen. Demnach war von einer sicheren Detektion von Mutationen im HPRT-Test und im Mikrokerntest auszugehen. Zusammenfassend bestätigen die durchgeführten Untersuchungen, dass die zelluläre COMT-Aktivität eine essentielle Rolle zur Entgiftung mutagener Catecholestrogene spielt. Eine hundertprozentige Inhibierung der Aktivität dieses Enzyms führt zur Induktion von Genmutationen durch 4 HO-E2 in V79-Zellen ohne CYP-Aktivität und durch E2 in V79-Zellen, die hCYP1A1 exprimieren. Demnach könnte eine Reduktion der COMT-Aktivität durch Polymorphismen und/oder durch Nahrungsbestandteile, die mit dem Enzym selbst oder seiner Genexpression wechselwirken, die Induktion von Genmutationen durch E2 und dessen Catecholestrogenen begünstigen. / Oxidative metabolism of the female sex hormone 17β-estradiol (E2) is considered to play a major role in the initiation of hormone-induced carcinogenesis. In extrahepatic tissues, E2 undergoes metabolic activation by human cytochrome P450-dependent monooxygenase (CYP) isozymes 1A1 (hCYP1A1) and 1B1 (hCYP1B1) to 2-hydroxy (HO)- and 4-HO-E2. If not conjugated these catecholestrogens can further oxidize to electrophilic quinones, which may react with DNA and induce thereby mutations. Conjugation of these catechols in extrahepatic tissues is mainly catalyzed by catechol-O-methyltransferase (COMT). A low COMT activity, caused for example by polymorphisms and certain food components, which influence the enzyme activity or its gene expression, may therefore enhance quinone formation and thereby the induction of mutations. The aim of the present work was to determine the effect of inhibition of COMT on the mutagenic potential of a) the catechols 2- and 4-HO-E2 in V79 wild type cells without CYP activity and b) E2 in V79 cells expressing hCYP1A1. 3,5-dinitrocatechol (20 μM) served as COMT inhibitor. Gene and chromosomal mutations were assessed using the hypoxanthine-guanine-phosphoribosyltransferase (HPRT) and the micronuclei assay. In addition, the metabolite profile of E2 and its catechols in the culture medium was analyzed via gas chromatography/mass spectrometry. After incubation of V79 cells with 2-HO-E2, 2-methoxyestradiol was the major metabolite, whereas in the presence of the COMT inhibitor, disappearance (0.08 μM) and a decreased amount (2.5 μM or more) of methylated inactivation products was observed. Treatment of V79 cells with 0.08 μM – 5 μM 2-HO-E2, neither with nor without inhibition of COMT activity induced a significant increase in mutant frequency at the hprt locus. In contrast, at concentrations above or equal to 2.5 μM 2-HO-E2, at least a 3-fold increase of the micronuclei rate compared to control cells was observed with and without inhibition of COMT activity. Over the entire concentration range (5-40 μM) 4-HO-E2 was mainly converted to its methylation products, 4-methoxyestradiol being the major metabolite (≥ 86%) of the detected compounds. After treatment with 3,5-dinitrocatechol no methylation products were detected, thus indicating a complete inhibition of COMT over the entire concentration range. 4-HO-E2 did not induce gene mutations at the hprt locus in V79 cells with active COMT. Yet, after inhibition of COMT and treatment with 20 μM 4-HO-E2, a 3-fold increase in the mutant frequency was observed in comparison to control cells. Like 2-HO-E2, induction of micronuclei by 20 µM 4-hydroxyestradiol and more, was not affected by inhibition of COMT. In the culture medium of V79 cells expressing hCYP1A1, which were incubated with 0.1 and 1 μM E2 for up to three weeks, over the entire assay duration, E2 and estrone (86% and 10% of the sum of all peak areas, respectively) were the major metabolites. As expected, no methylation products were detected after inhibition of COMT. Treatment of V79 cells expressing hCYP1A1, for two and three weeks with 0.1 and 1 μM E2 did not induce gene mutations at the hprt locus. In contrast, a 4-fold increase in mutant frequency was observed in comparison to control cells after inhibition of COMT and treatment with 0.1 μM E2 for three weeks. With and without inhibition of COMT, no increase in micronuclei rate compared to control cells was observed after incubation with 0.1 and 1 μM E2 for 24 hours. Over the entire duration of the mutagenicity assays of E2 and its catechols, cell cycle distribution, cell growth and plating efficiency at the time of mutant selection, with and without inhibition of COMT, did not differ statistically significant from control cells; therefore a reliable detection of mutations in the micronuclei and the HPRT assay can be assumed. The present work confirms that cellular COMT is essential for the inactivation of mutagenic catechols. Complete inhibition of its enzyme activity results in the induction of gene mutations by 4-HO-E2 in V79 wildtype cells without CYP activity and also by E2 in cells expressing hCYP1A1. Polymorphisms and food components lowering COMT activity could therefore mediate the potential of E2 and its metabolites to induce gene mutations.

Theories of attention deficit hyperactivity disorder (ADHD) aetiology have placed a focus on impaired behavioural inhibition presumably leading to executive function (EF) deficits. Neuroimaging studies report neurophysiological findings consistent with these hypothesised impairments, and investigations of functional brain activation from a network perspective report hypoactivation in the frontoparietal network as well as hyperactivation in the dorsal attention network. Studies investigating the acute effects of stimulant medication on EF show an improvement on behavioural EF measures including working memory. In addition, methylphenidate (MPH) was shown to up-regulate the task-positive/ frontoparietal network in children and adolescents with ADHD. So far, there are only few studies investigating the impact of ADHD on behavioural and neurophysiological EF measures as well as the effect of several weeks of stimulant medication in adult patients. The importance of the catechol-O-methyltransferase (COMT) enzyme for subcortical and cortical dopaminergic and noradrenergic functioning furthermore led to studies investigating a potential interactive impact of COMT genotype and ADHD on neuropsychological functioning, with a particular focus on working memory. The results of these studies were very heterogeneous. In addition, as none of the studies compared the results of ADHD patients to those of a healthy control group, possible differential effects of COMT in patients and healthy controls could not be examined. The aim of this dissertation was to investigate selective attention properties of the central executive component during a working memory task and to transfer this task to fMRI. A third study then aimed to investigate the effects of adult ADHD (aADHD), MPH, and COMT genotype on working memory with a particular focus on activation of the task-positive network during the analysis of the fMRI data. The first study (EEG) could replicate and extend the results from previous research. This study could furthermore connect the overall activation in frontal areas to suppression efficiency in posterior visual areas as well as establish the impact of hyperactive/ impulsive ADHD symptoms on task performance. The second study (fMRI) allowed the successful transfer of the paradigm to fMRI, and the further replication and extension of previous findings. In addition, this study showed the sensitivity of the task to the effects of the COMT genotype. The third study (fMRI) was one of the first studies that exploratorily investigated the effects COMT in a sample of aADHD patients and a comparable healthy control group. This study showed an interactive effect of these two factors on neuropsychological measures as well as on fMRI activation during a classic n-back working memory task. In addition, this task led to more activation in the task-positive network of the aADHD group compared to a healthy control group in the absence of performance differences, pointing towards compensatory activation in the aADHD group. Furthermore, activation in the frontal cortex was increased in patients taking MPH compared to a placebo. The fMRI data from the selective attention task moreover showed decreased activation in the right DLPFC of the patient group, which was associated with reduced suppression efficiency across all participants. The clinical effect of MPH in the third study was visible but did not reach significance, which is probably attributable to a lack of experimental power. The studies in this dissertation could successfully replicate and extend previous findings. A goal for future studies should be the further investigation of the interactive effects of COMT genotype and aADHD on neuropsychological test results and fMRI activation, but also on medication response and adverse effects. In this context, the adaptation of a network perspective during the analysis of fMRI data seems to be the best way to detect existing between-group differences. / Theorien zur Ätiologie der Aufmerksamkeitsdefizit-/ Hyperaktivitätsstö-rung (ADHS) konzentrieren sich oft auf defizitäre Prozesse der Verhaltensinhibition, die wiederum zu Defiziten der Exekutivfunktionen (EF) führen. Übereinstimmend mit diesen Beeinträchtigungen berichteten Neuroimaging-Studien von Hypoaktivierung im frontoparietalen Netzwerk sowie Hyperaktivierung im dorsalen Aufmerksamkeitsnetzwerk. Studien zur Wirkung von Stimulanzien zeigten eine Verbesserung von EF-Maßen einschließlich des Arbeitsgedächtnisses sowie eine Hochregulierung des aufgabenpositiven/ frontoparietalen Netzwerks durch Methylphenidat (MPH). Bis jetzt untersuchten nur wenige Studien die Auswirkungen von ADHS auf neurophysiologische und Verhaltensmaße der EF sowie den Effekt von länger andauernder Stimulanziengabe bei erwachsenen Patienten. Die Wichtigkeit des Enzyms Catechol-O-Methyltransferase (COMT) für subkortikale und kortikale dopaminerge und noradrenerge Funktionen führte darüber hinaus zu Studien, die eine potentielle Interaktion in der Wirkung des COMT Genotyps und ADHS auf neuropsychologische Funktionen und insbesondere auf das Arbeitsgedächtnis untersuchten. Die Ergebnisse dieser Studien waren recht heterogen. Da zudem keine der Studien die Ergebnisse der ADHS-Patienten mit denen einer gesunden Kontrollgruppe verglich, konnten möglicherweise vorhandene unterschiedliche Einflüsse von COMT bei Patienten und gesunden Kontrollprobanden nicht angemessen ermittelt werden. Das Ziel dieser Dissertation waren zunächst die Untersuchung von selektiven Aufmerksamkeitsprozessen, die durch die Zentrale Exekutive vermittelt werden, sowie die Übertragung der dazu verwendeten Arbeitsgedächtnisaufgabe ins fMRT. Eine dritte Studie strebte die Untersuchung der Auswirkungen von ADHS bei Erwachsenen (aADHS), MPH und COMT Genotyp auf das Arbeitsgedächtnis an. Ein besonderer Fokus bei der Analyse der fMRT-Daten lag hierbei auf der Aktivierung des aufgabenpositiven Netzwerks. Die erste Studie (EEG) konnte bisherige Forschungsergebnisse replizieren und erweitern. Zudem konnte diese Studie die Gesamtaktivierung in frontalen Bereichen mit der Unterdrückungseffizienz in posterioren visuellen Bereichen in Verbindung bringen sowie einen Einfluss von hyperaktiv/ impulsiver ADHS-Symptomatik auf die Verhaltensleistung feststellen. Die zweite Studie (fMRT) zeigte eine erfolgreiche Übertragung des Paradigmas auf das fMRT und eine weitergehende Replizierung und Erweiterung vorheriger Forschungsergebnisse. Es konnte außerdem die Sensitivität der Aufgabe für die Effekte des COMT Genotyps gezeigt werden. Die dritte Studie (fMRT) war eine der ersten Studien, die exploratorisch die Effekte von COMT in einer Stichprobe von aADHS-Patienten und einer vergleichbaren gesunden Kontrollgruppe untersuchte. Hier zeigte sich eine Interaktion von COMT Genotyp und aADHS auf die erhobenen neuropsychologischen Maße sowie auf die fMRT-Aktivierung während einer n-back Arbeitsgedächtnisaufgabe. Die Aufgabe führte zu mehr Aktivierung im aufgabenpositiven Netzwerk der aADHS-Gruppe im Vergleich zur Kontrollgruppe. Da keine Leistungsunterschiede zwischen den Gruppen zu erkennen waren, weist diese Hyperaktivierung auf eine kompensatorische Aktivierung in der aADHS-Gruppe hin. Zudem zeigte sich eine erhöhte Aktivierung im Frontalkortex bei Patienten, die MPH statt einem Placebo einnahmen. Die fMRT-Daten der Aufgabe zur selektiven Aufmerksamkeit zeigten außerdem eine reduzierte Aktivierung im rechten DLPFC der Patientengruppe, die über alle Probanden hinweg mit einer reduzierten Unterdrückungseffizienz assoziiert war. Der klinische Effekt von MPH in der Patientenstichprobe war sichtbar, erreichte aber keine Signifikanz, was vermutlich auf eine zu geringe experimentelle Power zurückzuführen ist. Die Studien in dieser Dissertation konnten vorherige Befunde erfolgreich replizieren und erweitern. Ein Ziel für zukünftige Studien sollte die weitergehende Untersuchung dieser Fragestellungen sein. Vor allem in Bezug auf eine Interaktion von COMT Genotyp und aADHS auf neuropsychologische Testergebnisse und fMRT-Aktivierung, aber auch auf Medikamenten-Response und Nebenwirkungen ist dies von großer Bedeutung. Die Übernahme einer Netzwerkperspektive bei der Analyse von fMRT-Daten scheint zudem der beste Weg, existierende Unterschiede zwischen den Gruppen zu finden.

Bibliography: leaves 129-158. / xvii, 159, [11] leaves, [24] leaves of plates : ill. (some col.) ; 35 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / The major estrogen inducible protein in zebra fish liver has been purified to homogeneity by FPLC using anion exchange chromatography (Mono-Q Pharmacia) with purification being monitored by SDS-PAGE electrophoresis. / Thesis (Ph.D.)--University of Adelaide, Dept. of Obstetrics and Gynaecology, 1995?

In the oil industry, there is a special class of pipelines used for the transportation of refined products. The problem of sequencing the inputs to be pumped through this type of pipeline seeks to generate the optimal sequence of batches of products and their destination as well as the amount of product to be pumped such that the total operational cost of the system, or another operational objective, is optimized while satisfying the product demands according to the requirements set by the customers. This dissertation introduces a new modeling approach and proposes a solution methodology for this problem capable of dealing with the topology of all the scenarios reported in the literature so far. The system representation is based on a 1-0 multi commodity network flow formulation that models the dynamics of the system, including aspects such as conservation of product flow constraints at the depots, travel time of products from the refinery to their depot destination and what happens upstream and downstream the line whenever a product is being received at a given depot while another one is being injected into the line at the refinery. It is assumed that the products are already available at the refinery and their demand at each depot is deterministic and known beforehand. The model provides the sequence, the amounts, the destination and the trazability of the shipped batches of different products from their sources to their destinations during the entire horizon planning period while seeking the optimization of pumping and inventory holding costs satisfying the time window constraints. A survey for the available literature is presented. Given the problem structure, a decomposition based solution procedure is explored with the intention of exploiting the network structure using the network simplex method. A branch and bound algorithm that exploits the dynamics of the system assigning priorities for branching to a selected set of variables is proposed and its computational results for the solution, obtained via GAMS/CPLEX, of the formulation for random instances of the problem of different sizes are presented. Future research directions on this field are proposed.