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Phonetik und Phonologie im deutschsprachigen Raum, Phonetik und Phonologie im deutschsprachigen Raum

Diese Dokumentation enthält eine Zusammenfassung des Korpus gelesener geschlechtergerechter Sprache (KGGS) v2. Weiterhin werden die Erhebungsmethode, das verwendete Annotationsschema und die Annotationsebenen beschrieben. This documentation contains a summary of the Korpus gelesener geschlechtergerechter Sprache (KGGS) v2 (corpus of read gender-neutral language), as well as a description of the method used, the annotation scheme and the annotation tiers. &nbsp

Additional file 1.

WKD3Lists2 created lists of regionally relevant commercial fish and shellfish species (and higher order taxa) for the use of Article 8 reporting by EU member states under Descriptor 3 of the Marine Strategy Framework Directive (MSFD). The regional taxa lists were based on landings data from the Fisheries Dependent Information data base (FDI) provided by EU member states and compiled by the Joint Research Centre (JRC). The taxonomy of landings data was consolidated by regional experts and the consolidated data were combined to obtain absolute and proportional landing weights and values for each (sub)re-gion, which were used to apply dual (weight and vale) selection thresholds to compile (sub)re-gional D3-taxa-lists. Regional D3-taxa-lists were produced for two MSFD regions (Baltic Sea & Black Sea) and eight MSFD subregions: The Greater North Sea, Celtic Seas, the Bay of Biscay and Iberian Coast, Mac-aronesia, Western Mediterranean, the Ionian Sea & Central Mediterranean, the Adriatic Sea and the Aegean-Levantine Sea. To exclude taxa with very low landing weights or value from the final lists, two types of thresh-olds (cumulative and minimum) with differing cut-off values were evaluated (90%, 95%, 98% and 99% for cumulative and 0.1% and 1% for minimum thresholds). Depending on the cut-off value, the number of taxa included varied substantially and in most (sub)regions the application of thresholds reduced the initial number of taxa by more than 50%. WKD3Lists2 did not recommend any threshold type or cut-off value to be applied generically in all (sub)regions, but identified trade-offs between inclusiveness and parsimony of relevant con-tent i.e. higher cut-off values will lead to longer lists including many taxa with relatively low landings weights/values. In some (sub)regions, thresholds with lower cut-off values (90% to 95%) were considered feasible by regional experts (Mediterranean subregions, Bay of Biscay and Iberian Coast, Macaronesia), whereas in other MSFD (sub)regions cut-off values in the range of 98-99% were considered as appropriate (Baltic Sea, Greater North Sea, Celtic Seas). The regional D3-taxa lists by WKD3Lists2 were created without considering the availability of data or assessments i.e. many species are included, for which no assessment information is avail-able. WKD3Lists2 decided on this approach because a representative selection of commercially targeted taxa was considered to indicate knowledge and data gaps in current data collection and assessment schemes. Regional species lists shall be used by EU member states for the national reporting of D3. Stocks and species from the regional lists shall be considered by member states, and additional stocks/species can be added where appropriate (e.g. those stocks/species of national or local of importance that do not appear on the regional lists). x WKD3Lists2 discussed and compiled recommendations on how Member States can complement the regional lists of D3-taxa. A key recommendation is to maintain taxa reported in 2018 under D3, even if they are not part of the regional D3-taxa list for 2024. Wherever possible, Member States should report on stock level. WKD3Lists2 also discussed linkages between D1 and D3-reporting of commercial taxa. info:eu-repo/semantics/publishedVersion

Staying within the 2 °C (preferably 1.5 °C) limit requires fast and fundamental system changes, also in urban passenger transport. Shifting car traffic to environmentally friendly transport modes is one central strategy to make urban transport more sustainable and climate friendly. However, in most cities car use remains high. Therefore, this paper analyzes what course change is needed regarding direction, scale and speed of change for urban sustainability and climate protection reasons. The paper analyzes the role of modal shift as a strategy in itself and in relation to land-use (avoid) and efficiency (improve) measures. The paper draws on insights from European frontrunning cities and explorative forecasting scenarios calculated with the sophisticated integrated land-use transport model “Ruhr Region 2050”. The paper suggests that a significant reduction of urban car use is needed (direction) that roughly equals a fast halving of car use (scale), which has proven feasible under the current socio-political conditions by annual reduction rates of 0.5 to 1.5 percentage points of the trip-based modal share of car use (speed). Significantly reducing car use requires comprehensive and high-intensive measures that go far beyond usual practices. Modal shift measures need to play a crucial role in integrated approaches with land-use (avoid) and efficiency (improve) measures because they have the potential to significantly reduce car use and CO2 emissions and because they can produce comparatively fast effects – which makes modal shift measures first aid approaches to achieve a fast “bending of the curve” of excessive car use and growing CO2 emissions.

It has been widely recognized that there is an urgent need for more sustainable urban transport policy and planning. To understand ambitious policy approaches, "relatively successful" cities are regularly subject of analyses. This paper also focuses on relatively successful cities - by reviewing the application documents of the winner cities of the European Green Capital Award (EGCA). Award schemes not only aim to reward leading participants, but likewise aim to contribute to knowledge transfer and the dissemination of good practice examples to non-participants. So far award schemes and good practice approaches have received limited attention by research. This paper reviews and analyses the application forms of the EGCA winning cities to learn about ambitious policy approaches to sustainable and climate-friendly urban transport.

Nicaragua hat eine der höchsten Teenager-Geburtenraten in Lateinamerika. Das Ziel dieser Studie ist es, die subtilen Konzepte, Wahrnehmungen, Überzeugungen und Einflussfaktoren zu verstehen, die zu unterschiedlichen Fertilitätsentscheidungen junger Frauen führen können. Die Ergebnisse basieren auf qualitativen Daten, die im städtischen Nicaragua erhoben wurden. Die Studie zeigt, dass zwei strukturelle Beschränkungen die Wahlmöglichkeiten von Frauen und ihre Fähigkeit beeinflussen, aktiv an der Definition ihrer Lebenswege teilzunehmen: Armut und traditionelle Geschlechternormen. In einer armen Umgebung aufzuwachsen, bedeutet nicht nur finanzielle Benachteiligung, sondern auch mangelnde Bildungsqualität, Mangel an effektivem und zeitnahem Zugang zu Gesundheitsdiensten, Gewalt in den Wohnvierteln, Mangel an Chancen auf dem Arbeitsmarkt, Mangel an positiven Vorbildern. Darüber hinaus beeinflussen traditionelle Geschlechternormen das sexuelle Verhalten junger Frauen, ihre Interaktionen mit ihren Familien und Partnern und die Art und Weise, wie sie sich ihr Leben vorstellen. Diese Faktoren haben nicht nur Auswirkungen auf den Entscheidungsprozess, sondern auch auf die Konsequenzen dieser Entscheidungen für die jungen Frauen und ihre Kinder., Nicaragua has one of the highest adolescent fertility rates in the region. The objective of this study is to understand the subtle concepts, perceptions, beliefs, and influencing factors that may lead to different fertility outcomes among young women. The results are based on qualitative data collected in urban Nicaragua. The study shows that two structural constraints affect women’s choices and their capacity to actively participate in defining their life paths: poverty and traditional gender norms. Growing up in a poor environment not only means monetary deprivation, but also exposure to a lack of quality education, a lack of effective and timely access to health services, violence in neighborhoods, an absence of opportunities in the labor market, and a lack of positive role models. In addition, traditional gender norms affect young women’s sexual behavior, their interactions with their families and partners, and the way they envision their lives. Those factors have implications not only for the process of decision-making, but also for the outcomes of those decisions for the young women and their children.

O presente estudo teve como objetivo analisar as principais normativas nacionais referentes à Educação Especial em uma perspectiva inclusiva buscando estabelecer conexões com as normativas do município de Canoas e como objetivo específico: analisar de quais formas as normativas definidas pelo município de Canoas se efetivam nas práticas cotidianas quanto aos quesitos: Atendimento Educacional Especializado, avaliação e identificação e profissional de apoio. As questões norteadoras foram as indagações: Quais ações ou fatores influenciam na efetivação ou não das resoluções municipais? Como as políticas de Educação Especial estão sendo compreendidas pelos professores, gestores do município? Há indicações de adesão, divergência ou resistência por parte do município em relação às normativas federais? Esta pesquisa assume um caráter qualitativo, onde analisei os dados disponibilizados pela Secretaria Municipal de Educação e complementados com entrevistas semiestruturadas com perguntas abertas a um gestor do setor de inclusão escolar e dois professores do Atendimento Educacional Especializado. Alguns autores foram escolhidos como base teórica no que tange às Políticas da Educação Especial na Perspectiva Inclusiva: Claudio Roberto Baptista, Katia Regina Moreno Caiado, Cláudia Freitas, Clarissa Hass, Denise Meyrelles de Jesus, Fabiane Bridi, Maria Teresa Mantoan, José Geraldo Bueno, Rosângela Gavioli Prieto, entre outros. Bem como as normativas da Educação e da Educação Especial, dentre elas: Constituição Federal de 1988; Lei de Diretrizes e Bases da Educação Nacional de 1996, Política Nacional de Educação Especial na Perspectiva Inclusiva (2008), Resolução 04 de 2009, Nota técnica 04 de 2014 e Lei Brasileira de Inclusão (2015). A análise de dados foi organizada em três eixos: Atendimento educacional Especializado, Avaliação e identificação e Profissional de Apoio. Os resultados dos levantamentos de dados demonstram um aumento expressivo no número de matrículas de alunos da Educação Especial. As evidências das entrevistas apontam que a rede municipal de ensino tem buscado manter-se consoante às normativas federais, e há elementos que demonstram avanços nas ações de inclusão escolar com a valorização dos profissionais do magistério, formação especifica do professor que atua no AEE e profissionais de apoio em todas as escolas. Contudo, há grandes desafios no processo de efetivação da inclusão escolar. This study aimed to analyze the main national regulations regarding Special Education in an inclusive perspective, seeking to establish connections with the regulations in the city of Canoas, with the specific objective of analyzing in which ways the regulations defined by the city are effective in everyday practices for the following questions: Specialized Educational Assistance, evaluation and identification, and support professionals. The guiding questions were these: Which actions or factors influence the effectiveness or not of municipal resolutions? How are Special Education policies being understood by teachers and managers of the city? Are there signs of adherence, divergence or resistance of the city in relation to federal regulations? This research has a qualitative character, in which we analyzed the data made available by the Municipal Department of Education and complemented with semi-structured interviews with essay questions for a manager of the school inclusion sector and two teachers of the Specialized Educational Assistance. Some authors were chosen as the theoretical basis for the Special Education Policies in the Inclusive Perspective: Claudio Roberto Baptista, Katia Regina Moreno Caiado, Cláudia Freitas, Clarissa Hass, Denise Meyrelles de Jesus, Fabiane Bridi, Maria Teresa Mantoan, José Geraldo Bueno, Rosângela Gavioli Prieto, among others. As well as the regulations of Education and Special Education, such as: the Federal Constitution of 1988; the National Education Policy and Guidelines Act, from 1996; the National Policy on Special Education in the Inclusive Perspective, from 2008; the Resolution 04, from 2009; the Technical Note 04, from 2014; and the Brazilian Inclusion Law, from 2015. The data analysis was organized in three axes: Specialized Educational Assistance, Evaluation and identification, and Support professionals. The results of the data surveys showed a significant increase in the enrollment of Special Education students. The evidence from the interviews shows that the municipal education network has sought to keep up with federal regulations, implementing the actions of school inclusion with the appreciation of teaching professionals, specific training of teachers who work in the ESA and support professionals in all schools. However, there are major challenges in the process of achieving school inclusion.

The beginning of gravitational-wave astronomy dates from the 14th of September 2015, when the Laser Interferometer Gravitational-wave Observatories (LIGO) measured a gravitational wave for the first time. This signal originated from a pair of merging black holes, providing direct confirmation of the existence of binary systems formed by two black holes. To date, a total of five confirmed and one candidate gravitational-wave signals from binary black holes have been announced. Furthermore, a gravitational-wave signal from a neutron star binary has been observed jointly with electromagnetic radiation. These observations entail a breakthrough in the astronomy of compact binaries and provide insight into highly relativistic systems. In this work we cover several areas from the gravitational-wave astronomy of compact binary coalescences. We begin by introducing data analysis techniques used during the second generation of ground-based gravitational-wave observatories. Using real results from astrophysical signals, we explain the procedures to estimate the statistical significance of gravitational-wave signals. We observe a specific type of short noise transients in the data, commonly known as blip glitches, that is particularly harmful for transient gravitational-wave searches. Here we introduce a method to identify occurrences of blip glitches. With the results obtained, we investigate the origin of these noise transients and present here the current state of these investigations. Astrophysical gravitational-wave signals allow for tests of general relativity that would otherwise not be possible. For instance, the ringdown phase of a compact binary coalescence is characteristic of the nature of a Kerr black hole. With Bayesian inference and using only this ringdown signature, we develop a method to estimate the parameters of the remnant black hole after a binary coalescence. This method lays the foundations to perform tests of the no-hair theorem and of the black hole area increase law. In this work we focus on the latter, for which we also need to use the inspiral signature of the coalescence. We devise a well-defined condition for the end of the inspiral stage by combining information from post-Newtonian theory with the exact Kerr test-mass limit. Our result is called the hybrid MECO (Minimum Energy Circular Orbit). We develop a method to test the area increase law in which this hybrid MECO is used to separate the inspiral part of the signal and measure the initial parameters of the binary. Comparing the inspiral measurements with the ringdown parameters on a simulated signal, we find that the area theorem could be confirmed to ~74.6% confidence with current sensitivity. This result can improve to ~99.9% confidence using future design sensitivities.

Visual selective attention is the fundamental cognitive ability to filter out irrele-vant sensory information in favor of relevant information. In order to make this possi-ble, an integration of exogenous, stimulus-dependent, and endogenous, context-dependent, attentional factors is necessary. The anatomical basis for this integration is formed by a highly complex network of cortical feedforward and feedback projections which connect areas at every sensory processing level. Lesions in distinct areas of this attention network lead to the clinical pathology of visual unilateral neglect, in which the failure of one network component results in the inability to orient or respond to stimuli appearing in the visual field contralateral to a lesion. Frequently, in humans as well as in animal models, a gradual improvement up to a complete restoration of the behavioral performance can be observed some time after the initial lesion. Based on findings from behavioral studies, it has been suggested that a significant imbalance of neuronal activity levels between the two hemispheres and a resulting unequal distri-bution of limited attention capacities could be the neural basis of visual neglect. Ac-cordingly, a functional recovery would be accompanied by a restoration of the activity balance between the two hemispheres. Current concepts of the underlying mechanisms of neglect are mainly based on results from behavioral experiments or data collected in anesthetized animals. To date, there are no neurophysiological studies in awake animals which consider the neglect syndrome and its recovery in the behavioral context. The aim of the present study was to close this gap on the one hand, and on the other, to provide a detailed characterization of feedback-mediated attention signals in the early visual cortex.

Development of new methods for improved determination of vitamin D metabolic markers using advanced analytical mass spectrometry techniques. New derivatization and separation techniques were used and their benefit on the performance of the new methodology was shown in comparison to established vitamin D determination methods. Die Enwicklung neuer Methoden zur besseren Bestimmung von Vitamin D unter der Verwendung der analytischen Massenspektrometrie. Als Schwerpunkt wurden neue Derivatisierungs- undTrenntechniken entwickelt und deren Nutzen im Vergleich zu etablierten Vitamin D Messmethoden gezeigt.

NOSTRIN belongs to the family of F-BAR proteins, which are multi-domain adaptor proteins that have emerged as important regulators of membrane remodeling and actin dynamics in a variety of vital cellular processes. They have been analyzed structurally and biochemically and overexpression studies have revealed their potential in inducing membrane curvature and tubulation. Several studies have begun to decipher the function of individual proteins, but the understanding of F-BAR protein functions in vivo is still quite limited. The F-BAR protein NOSTRIN is mainly expressed in endothelial cells and has originally been described as interaction partner of the endothelial nitric oxide synthase (eNOS), modulating eNOS subcellular localization. The phenotypic characterization of NOSTRIN knockout mice revealed decreased nitric oxide (NO) and cGMP levels, an increase in systolic blood pressure and an impairment of the acetylcholine-induced, NO-dependent relaxation of aortic rings from mice with global as well as endothelial cell-specific knockout of the NOSTRIN gene (ECKO) . These findings implied that NOSTRIN plays a role in regulating NO production in vivo, but the underlying molecular mechanisms were unclear. Therefore, this study was aimed at addressing the mechanism causing the inhibited vasodilation specifically upon stimulation with acetylcholine in NOSTRIN KO and ECKO mice, and at exploring additional roles of NOSTRIN in the signal transduction of endothelial cells. The major acetylcholine receptor that mediates vessel relaxation upon stimulation with acetylcholine is the muscarinic acetylcholine receptor subtype M3 (M3R). In the present study NOSTRIN was identified as novel interaction partner of the M3R and important factor for the correct spatial distribution and functionality of the M3R. Moreover, it provides the first example of an F-BAR protein regulating a GPCR. Confocal immunofluorescence microscopy analysis of isolated aortae from NOSTRIN KO and WT mice indicated that NOSTRIN was necessary for the proper subcellular localization of the M3R and targeted it to the plasma membrane. A series of pulldown experiments revealed a direct interaction of NOSTRIN with the M3R. The binding required the SH3 domain of NOSTRIN and the third intracellular loop of the M3R, which has a recognized role in receptor regulation. The interaction of NOSTRIN with the M3R was confirmed by co-localization of NOSTRIN and the M3R upon overexpression in mammalian cells. Expression levels of the M3R as well as eNOS were not affected by the loss of NOSTRIN in accordance with the finding, that NOSTRIN impacts on the acetylcholine/eNOS signaling axis through regulation of the subcellular trafficking of its binding partners. Furthermore, there were first indications for a role of NOSTRIN in facilitating the carbachol-induced calcium response in M3R-expressing cells, suggesting that NOSTRIN might influence M3R activation. in the absence of NOSTRIN, the function of the M3R in mammalian cells overexpressing the M3R was markedly impaired, resulting in abolition of the calcium response to the M3R agonist carbachol. In accordance, the activated eNOS fraction associated with the Golgi complex was markedly reduced in aorta explants from NOSTRIN knockout and ECKO mice. Moreover, NOSTRIN knockout inhibited the carbachol-induced, activating phosphorylation of eNOS in murine aortae as well as primary mouse lung endothelial cells confirming its role as important regulator of eNOS activity in vivo. F-BAR Proteine sind eine Familie von Adapterproteinen, die über verschiedene funktionelle Domänen verfügen und an der Schnittstelle zwischen Membran und Aktinzytoskelett eine Vielzahl essentieller zellulärer Prozesse regulieren. Die strukturellen und biochemischen Eigenschaften einer Reihe von F-BAR Proteinen wurden bereits detailliert untersucht und Überexpressionsstudien belegen die Fähigkeit von F-BAR Proteinen, Membrankrümmungen und kleine Membrankanäle zu erzeugen. Das Wissen über die spezifische Funktion einzelner F-BAR Proteine in vivo ist hingegen noch immer begrenzt. Das F-BAR Protein NOSTRIN wird vor allem von Endothelzellen exprimiert und wurde ursprünglich als Interaktionspartner und Regulator der subzellulären Lokalisation der endothelialen Stickstoffmonoxid-Synthase (eNOS) beschrieben. NOSTRIN-KO-Mäuse weisen erniedrigte Stickstoffmonoxid (NO) und cGMP-Spiegel, einen erhöhten systolischen Blutdruck und eine deutliche Beeinträchtigung der acetylcholinabhängigen Relaxation isolierter Aortenringe auf, was darauf hindeutet, dass NOSTRIN eine wichtige Rolle in der Regulation der NO-Produktion in vivo spielt. Die Zielsetzung der vorliegenden Arbeit war, den molekularen Mechanismus aufzuklären, der der Beeinträchtigung der acetylcholin-abhängigen Vasorelaxation zugrunde liegt, und darüberhinaus weitere mögliche Funktionen von NOSTRIN in der Signaltransduktion von Endothelzellen zu untersuchen. Die acetylcholinabhängige Vasorelaxation wird über den muskarinergen Acetylcholinrezeptor vom Subtyp M3 (M3R) vermittelt. In der vorliegenden Arbeit wurde NOSTRIN als neuer Interaktionspartner des M3R identifiziert. Dies stellt die erste Beschreibung eines F-BAR Proteins als Regulator eines GProtein-gekoppelten Rezeptors dar. Mit Hilfe von konkofaler Immunfluoreszemzmikroskopie an Aortenexplantaten konnte nachgewiesen werden, dass NOSTRIN für die korrekte räumliche Lokalisation des M3R an der Plasmamembran von Endothelzellen verantwortlich ist. Mit einer Reihe von Pulldown-Experimenten wurde die Wechselwirkung von NOSTRIN mit dem M3R als eine direkte Protein-Protein-Interaktion charakterisiert. Die Interaktion wird über die SH3-Domäne von NOSTRIN und die dritte intrazelluläre Schleife des M3R vermittelt, welche eine wichtige Rolle in der Regulation der Rezeptorfunktion einnimmt. Die Interaktion von NOSTRIN mit dem M3R wurde zusätzlich durch die Kolokalisation der beiden überexprimierten Proteine in Säugerzellen bestätigt. Darüber hinaus konnte gezeigt werden, dass NOSTRIN keinen Einfluss auf die Expression des M3R hat, was unterstreicht, dass NOSTRIN die Acetylcholin/eNOS-Signalkaskade durch die Regulation der subzellulären Lokalisation seiner Interaktionspartner beeinflusst. Die Ergebnisse der vorliegenden Arbeit gaben zudem erste Hinweise darauf, dass NOSTRIN den Carbachol-induzierten Kalziumeinstrom in M3Rexprimierenden Zellen ermöglicht. Das deutet darauf hin, dass NOSTRIN die Funktionalität des M3R beeinflusst. In Übereinstimmung damit war die Carbachol-induzierte aktivierende Phosphorylierung der eNOS in Aorten und primären Endothelzellen in der Abwesenheit von NOSTRIN inhibiert und die mit dem Golgi-Apparat-assozieerte eNOS-Fraktion im NOSTRIN-KO und –ECKO deutlich reduziert. NOSTRIN stellt somit einen neuen, wichtigen Interaktionspartner des M3R dar und der Verlust von NOSTRIN beeinträchtigt die dem M3R nachgeschalteten Signalwege, einschliesslich der Aktivierung der eNOS. Bei der Untersuchung weiterer Funktionen von NOSTRIN wurde in Endothelzellen von NOSTRIN-KO-Mäusen eine Beeinträchtigung der Anordnung von kortikalem Aktin, Aktin-Stressfasern und der PECAM-1-Membranfärbung beobachtet. Sowohl das Aktinzytoskelett als auch PECAM-1 sind maßgeblich an der Reaktion der Endothelzellen auf Schubspannung beteiligt. Um der Frage nachzugehen, ob NOSTRIN an der Ausbildung und Ausrichtung von Stressfasern in Richtung des Blutflusses beteiligt ist, wurde eine Flusskammer gebaut. Mit Hilfe dieser konnten Aortenexplantate definiertem Fluss entweder in der physiologischen Flussrichtung oder rechtwinklig dazu ausgesetzt werden. Immunofluoreszenzfärbungen der Aortenexplantate ergaben Hinweise darauf, dass die Fähigkeit der Endothelzellen, ihren Zellkörper und ihre Stressfasern mit der Flussrichtung auszurichten, in Aorten von NOSTRIN-KO-Mäusen beeinträchtigt war. Diese Daten bilden die Grundlage für zukünftige Studien zur Rolle von NOSTRIN bei der Mechanotransduktion in Endothelzellen.

Die vorliegende Studie untersucht mütterliche Einflüsse auf die Gesundheit von Neugeborenen. Zahlreiche vorangegangene Untersuchungen zeigten, dass bereits das intrauterine Milieu und intrauterine Expositionsbedingungen wichtige Faktoren zur Entwicklung von chronischen Erkrankungen darstellen können (sogenannte Barker-Hypothese). Ziel der Untersuchung war die nähere Beschreibung von Einflüssen der mütterlichen Nierenfunktion und Harnsäure als kardiometabolische Risikomarker auf gesundheitsrelevante Kenngrößen des Neugeborenen wie Geburtsgewicht und small for gestation age-Geburtlichkeit. Aus bisherigen Studien ließ sich eruieren, dass die mütterliche Nierenfunktionseinschränkung mit geringerem Geburtsgewicht beim Neugeborenen assoziert war. Die Basisuntersuchung der Ulmer SPATZ Studie als großangelegte Geburtskohortenstudie fand von April 2012 bis Mai 2013 an der Universitätsfrauenklinik Ulm statt. Die Studienpopulation umfasste 970 Mütter und 1006 Neugeborene, die hier genauer beleuchtete Analysepopulation bestand aus 885 Müttern (91,2 % der Gesamtpopulation) und deren 885 neugeborene Einlingen. Anhand von Laborchemie, eines Fragebogens zu verschiedenen soziodemografischen, gesundheitlichen sowie psychologischen Merkmalen, von Mutterpass und elektronischen Patientenakten wurden die notwendigen Daten für die Studie erhoben. Die Serumharnsäure der Mutter korrelierte statistisch signifikant positiv mit dem mütterlichen hochsensitiven C-reaktiven Protein, Leptin, glykosylierten Hämoglobin, retinol binding protein 4, Insulin sowie den Triglyceriden. Des Weiteren zeigte die bivariate Analyse einen Zusammenhang der Serumharnsäurewerte mit dem Alter der Mutter, der Nationalität, Alkoholkonsum während der Schwangerschaft, Entbindungsmodus, geringerer Anzahl vorangegangener Geburten, höherem mütterlichem BMI, vorliegendem Diabetes und Hypertonie. Mütterliches Serum-Cystatin C korrelierte mit dem mütterlichen glykosylierten Hämoglobin und retinol binding protein 4. Die bivariate Analyse ergab einen Zusammenhang von höheren Cystatin-C-Serumwerten mit einer geringeren Anzahl vorangegangener Geburten sowie dem Geschlecht des Neugeborenen (Mütter männlicher Neugeborener hatten höhere Werte). Das durchschnittliche Geburtsgewicht der Kinder betrug 3278,6 ± 534,5 g, damit fielen 87 Kinder (9,8%) in den small for gestational age-Bereich (bezogen auf das Geburtsgewicht). Von den teilnehmenden Müttern hatten je nach Bestimmungsmethode der glomerulären Filtrationsrate 62,7 – 75,7% leicht- bis höhergradige Nierenfunktionseinschränkungen, jedoch lediglich 0,7-4,6% der Mütter eine Funktionseinschränkung im Stadium drei oder darüber. Insgesamt ergab sich, dass steigende Cystatin C-Serumkonzentrationen mit einem sinkenden Risiko für SGA-Geburtlichkeit einhergingen. Diese Tendenz war auch bei verschiedenen statistischen Analyseansätzen stabil und ergab vor allem bei der Betrachtung der Nierenfunktion einen statistisch signifikanten inversen Zusammenhang zwischen dem Cystatin C-Wert beziehungsweise der Nierenfunktion und dem Geburtsgewicht, der Geburtsgröße, dem längenassoziierten Geburtsgewicht sowie für zunehmende Nierenfunktionsstörungen und längenassoziiertes Geburtsgewicht. Dieser Zusammenhang war auch nach Einbeziehung von möglichen Störgrößen sichtbar. So hatten beispielsweise Neugeborene, deren mütterliche Cystatin C-Werte im obersten Quartil lagen ein Risiko von 0,45 (95% KI 0,22-0,90) für eine Geburtsgröße unter dem 10. altersspezifische Perzentil. Ein möglicher positiver Zusammenhang zwischen Nierenfunktion und Geburtsgewicht auf welchen bisherige Studien hinwiesen, wurde in der vorliegenden teilnahmestärkeren Studie nicht bestätigt. Vielmehr war diese Assoziation gegenläufig. Besonders das Einbeziehen von Cystatin C als Indikator für die Nierenfunktion der Mutter stellte ein Novum dar. Die einzige große Studie, die den Zusammenhang zwischen mütterlicher Nierenfunktion und kindlichem Geburtsgewicht untersuchte, nutzte Kreatinin als Berechnungsgrundlage für die mütterliche Nierenfunktion. Die weitere Beobachtung der Kinder bezüglich der Entwicklung chronischer Erkrankungen bleibt bezüglich weiterer Erkenntnisse über mögliche Zusammenhänge zu analysieren.

Das Wilmstumorgen WT1 kodiert für einen Tumorsuppressor, bei dessen Funktionsverlust es zur Ausbildung von Wilmstumoren, frühkindlichen Nierentumoren, kommen kann. Durch Translation alternativ gespleisster WT1-Transkripte entstehen verschiedene Proteinisoformen, von denen manche als Transkriptionsfaktoren wirksam sind, während andere vermutlich bei der posttranskriptionellen mRNA-Prozessierung eine Rolle spielen. WT1 ist entscheidend an der embryonalen Organogenese beteiligt und notwendig für die normale Entwicklung von Nieren, Gonaden und Mesothel. Neuere Untersuchungen haben gezeigt, dass WT1 auch für die Funktion bestimmter Organe im erwachsenen Organismus erforderlich ist. Die Inaktivierung von WT1 in adulten Mäusen verursacht eine schwere Osteoporose. Weiterhin fiel bei diesen Mäusen eine verminderte Serumkonzentration von IGF-I auf. Eine genomweite Microarray- Analyse zeigte eine enge Korrelation zwischen den mRNA-Niveaus von WT1 und IGFBP5. IGFBP5 ist eines von sechs IGF-bindenden Proteinen, gehört der IGF- Achse an und ist ein wichtiger Regulator der IGF-Aktivität im Knochen. Außerdem wird das Protein in einer Vielzahl von Tumoren exprimiert. Im Rahmen dieser Arbeit wurde die Lokalisation von IGFBP5 im embryonalen (Maus, Ratte) und adulten Organismus (Maus, humane Zelllinien) untersucht. In der vorliegenden Arbeit sollte überprüft werden, ob eine Korrelation zwischen der Expression von WT1 und IGFBP5 besteht. Weiterhin sollten die molekularen Mechanismen einer möglichen Regulation der IGFBP5-Expression durch WT1 analysiert werden. Es konnte gezeigt werden, dass WT1 und IGFBP5 in verschiedenen Zelllinien koreguliert werden. Mittels siRNA-Knockdown wurde nachgewiesen, dass die Expression von Igfbp5 in murinen Mesonephroszellen Wt1-abhängig erfolgt. Die Induktion von WT1 in UB27-Osteosakomzellen führte zu einer Hochregulierung von IGFBP5-mRNA und IGFBP5-Protein. Durch eine in- silico-Analyse ließen sich vier potenzielle WT1-Bindungsstellen im IGFBP5-Promotor identifizieren. Hinweise auf eine mögliche Regulation des IGFBP5-Gens durch Sauerstoffmangel lieferte die Identifizierung eines HIF-1-Bindungsmotivs. Mit Hilfe von Reportergenassays konnte gezeigt werden, dass die transkriptionell wirksame WT1(-KTS)-Variante den IGFBP5-Promotor aktiviert. WT1(+KTS)-Protein, das vermutlich an der posttanskriptionellen mRNA-Prozessierung beteiligt ist, hatte hingegen keinen signifikanten Einfluss auf die Promotoraktivität. Mittels Chromatin-Immunpräzipation wurde die Bindung von WT1(-KTS) an den IGFBP5-Promotor in UB27-Zellen in vivo überprüft. In Osteosarkom- und in Neuroblastomzellen ließ sich die Expression von IGFBP5 durch Hypoxie stimulieren. Mittels quantitativer RT-PCR wurde die IGFBP5-mRNA in verschiedenen Organen der adulten Maus ermittelt. Eine besonders starke Expression zeigten Herz, Niere, ZNS und Skelettmuskel. Mittels Immunhistochemie ließ sich IGFBP5 in der embryonalen Niere und im Knochen der Ratte darstellen. Die Ergebnisse dieser Arbeit zeigen, dass die IGFBP5-Expression durch den Wilmstumor-Transkriptionsfaktor reguliert wird. Dieser Regulationsmechanismus scheint vor allem im normalen und pathologisch veränderten Knochen eine Rolle zu spielen, die es weiter zu charakterisieren gilt., The Wilms’ tumor gene, WT1, encodes a zinc finger transcription factor that functions as a tumor suppressor and key regulator of developmental processes. WT1 encodes several protein isoforms, of which WT1(-KTS) acts as a transcriptional regulator, while WT1(+KTS) is involved in RNA-processing. Recent findings indicate that WT1 is necessary for maintaining physiological bone integrity in the adult organism. Insulin-like growth factor binding protein-5 (IGFBP5) is one of six IGF-binding proteins, member of the IGF- family and also involved in osteogenesis and bone metabolism. As WT1, IGFBP5 is expressed in a number of malignant tumors. In the present study, we aimed at clarifying the role of IGFBP5 as a novel candidate target gene of WT1. Genome-wide cDNA-microarray-analysis revealed a close correlation between the mRNA-levels of WT1 and IGFBP5. While IGFBP5 is mainly expressed in kidney and muscle tissues, WT1- and IGFBP5-proteins were co-localized by immunohistochemistry in the kidney and bone of embryonic rats and mice. siRNA- mediated silencing of Wt1 in the murine mesonephros-derived cell line M15 reduced Igfbp5-mRNA-levels by approximately 80% compared to a non-targeting siRNA. IGFBP5-transcripts- and IGFBP5–protein-levels were increased significantly in osteosarcomacells expressing the transcriptionally active WT1(-KTS)-protein. In contrast, the WT1(+KTS)-isoform, which has a presumed role in mRNA-processing rather than in transcriptional regulation, did not significantly change IGFBP5-expression in these cells. Bioinformatic analysis revealed four putative WT1-binding-sites in the 5´-flanking region of the human IGFBP5-gene. Reporter-gene-assays showed that WT1(-KTS) activates the IGFBP5-promoter, while WT1(+KTS) did not show any significant effect. By gradual shortening of the IGFBP5-promoter-construct, which abolished the putative WT1-binding-elements, this effect was abrogated. Chromatin- immunoprecipitation verified WT1 binding to the IGFBP5-promoter in vivo. Moreover, several hypoxia-responsive-elements (HREs = binding sites of hypoxia-inducible factors) could be detected, which is especially relevant given the hypoxic regulation of both WT1 itself and a number of its target genes. Indeed, expression of IGFBP5 in osteosarcoma and neuroblastoma cells was stimulated by hypoxia. These findings indicate that IGFBP5 may act as a novel downstream effector of WT1 with potential roles in both normal and pathological bone-related processes, which remain to be elucidated.

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