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An der Universität Bamberg wird aktuell ein Forschungsinformationssystem (FIS) auf Basis der Open-Source Software DSpace-CRIS eingeführt. Um dabei die Sichtbarkeit der eigenen Forschungsleistungen zu fördern, wird die Bereitstellung der öffentlichen Inhalte des FIS als RDF-Triple (Linked Open Data, LOD) über einen vollwertigen SPARQL-Endpoint unter Berücksichtigung von Sicherheit und Performance angestrebt. Nach Evaluation unterschiedlicher Ansätze haben wir uns entschieden, ein eigenständiges DSpace-CRIS-Modul auf Basis des bestehenden DSpace-Moduls für LOD zu entwickeln. Dieses kann, neben Publikationen, auch CRIS-Entitäten wie Auszeichnungen, Forschendenprofile oder Projekte und deren Beziehungen als LOD darstellen.

Only few cell-based test methods are described by Organisation for Economic Co-operation and Development (OECD) test guidelines or other regulatory references (e.g., the European Pharmacopoeia). The majority of toxicity tests still falls into the category of non-guideline methods. Data from these tests may nevertheless be used to support regulatory decisions or to guide strategies to assess compounds (e.g., drugs, agrochemicals) during research and development if they fulfill basic requirements concerning their relevance, reproducibility and predictivity. Only a method description of sufficient clarity and detail allows interpretation and use of the data. To guide regulators faced with increasing amounts of data from non-guideline studies, the OECD formulated Guidance Document 211 (GD211) on method documentation for the purpose of safety assessment. As GD211 is targeted mainly at regulators, it leaves scientists less familiar with regulation uncertain as to what level of detail is required and how individual questions should be answered. Moreover, little attention was given to the description of the test system (i.e., cell culture) and the steps leading to it being established in the guidance. To address these issues, an annotated toxicity test method template (ToxTemp) was developed (i) to fulfill all requirements of GD211, (ii) to guide the user concerning the types of answers and detail of information required, (iii) to include acceptance criteria for test elements, and (iv) to define the cells sufficiently and transparently. The fully annotated ToxTemp is provided here, together with reference to a database containing exemplary descriptions of more than 20 cell-based tests. Correction in: ALTEX-ALTERNATIVES TO ANIMAL EXPERIMENTATION, Volume: 37, Issue:1, Pages:164-164DOI:10.14573/altex.1909271e

Ihren Ursprung fand vorliegende Arbeit in der Aussage Michel Foucaults, Sexualität habe im 18. Jahrhunderts eine diskursive Explosion erfahren. Es galt zu untersuchen, inwiefern diese Entwicklung auch in der Literatur festzustellen sei. Im ersten Teil der Diplomarbeit werden sozialgeschichtliche Umstände beleuchtet, Sexualität etwa im medizinischen Kontext untersucht. Dabei geht es vor allem um die Beschreibung einer sich entfaltenden Form der bürgerlichen Sexualität: Ein erstarkendes Bürgertum, das sich von der Aristokratie und dem einfachen Volk abzugrenzen versucht, entwickelt sein eigenes Konzept der Liebe und der Sexualität. Vor allem dient dieser erste Teil der Arbeit auch der Präsentation zweier ideengeschichtlicher Entwürfe, die als gegensätzliche Pole die Darstellung von Sexualität beeinflussen werden: Einerseits der französische Materialismus, der einer libertinären Lebensphilosophie Vorschub leistet, andererseits die Bewegung der Empfindsamkeit, die durch ihren Freundschaftskult eine Desexualisierung zur Folge hat. Vor dem Hintergrund dieses Spannungsfeldes soll im zweiten Teil die Analyse von literarischen Werken erfolgen: Als Untersuchungsgegenstand werden primär bürgerliche Romane aus Frankreich, England und Deutschland herangezogen. Dabei wird auf zwei Ebenen gearbeitet: Erstens wird die sprachliche Darstellung betrachtet. Wie bereits der Titel vorliegender Diplomarbeit verrät, wird die Darstellbarkeit analysiert. Es wird die Frage gestellt, bis zu welchem Grad sich eine Benennung des Geschlechtlichen mit dem Begriff der Tugendhaftigkeit als vereinbar erweist. Auf zweiter Ebene werden bürgerliche Motive untersucht, besonders in Hinblick auf deren Repräsentation eines genuin bürgerlichen Sexualkonzepts. Das Ergebnis der Textanalysen ist schließlich die Bestätigung der Ansicht Foucaults: Sexualität scheint im Roman des 18. Jahrhunderts allgegenwärtig. Die Wiedergabe einer entsexualisierten Welt erweist sich als unmöglich, da selbst die Tugendhaftigkeit ihre Unschuld verloren hat (Richardson, Gellert). Das Wissen um die Sexualität ist bereits zu sehr ausgebildet, als dass eine tugendhafte Reinheit unhinterfragt bleiben kann. Dieses Wissen spiegelt sich auch auf lexikaler Ebene: Das 18. Jahrhundert ist das Jahrhundert des double entendre. Autoren wie Laurence Sterne, Denis Diderot oder Henry Fielding arbeiten mit Doppeldeutigkeiten und dehnen somit den bürgerlichen Moralkodex der Wohlanständigkeit. Eine dichotome Gegenüberstellung von sexuell impliziter und sexuell expliziter Darstellung erweist sich als irrelevant: Während der pornographische Roman eines John Cleland durch seine exzessive Metaphorik den Blick verstellt, verweisen die Romane Wielands oder auch Richardsons durch geschickte Aussparungen auf einen sexuellen Sachverhalt und spielen mit der Macht der Einbildungskraft. Dadurch sind sie wohl nicht unschuldiger als der sexuell explizite Roman.

1. CD19+ B lymphocytes were purified from the peripheral blood of normal and atopic subjects to analyse and compare the phosphodiesterase (PDE) activity profile, PDE mRNA expression and the importance of PDE activity for the regulation of B cell function. 2. The majority of cyclic AMP hydrolyzing activity of human B cells was cytosolic PDE4, followed by cytosolic PDE7-like activity; marginal PDE3 activity was found only in the particulate B cell fraction. PDE1, PDE2 and PDE5 activities were not detected. 3. By cDNA-PCR analysis mRNA of the PDE4 subtypes A, B (splice variant PDE4B2) and D were detected. In addition, a weak signal for PDE3A was found. 4. No differences in PDE activities or mRNA expression of PDE subtypes were found in B cells from either normal or atopic subjects. 5. Stimulation of B lymphocytes with the polyclonal stimulus lipopolysaccharide (LPS) induced a proliferative response in a time- and concentration-dependent manner, which was increased in the presence of interleukin-4 (IL-4). PDE4 inhibitors (rolipram, piclamilast) led to an increase in the cellular cyclic AMP concentration and to an augmentation of proliferation, whereas a PDE3 inhibitor (motapizone) was ineffective, which is in accordance with the PDE profile found. The proliferation enhancing effect of the PDE4 inhibitors was partly mimicked by the cyclic AMP analogues dibutyryl (db) cyclic AMP and 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole-3',5'-cyclic monophosphorothioate, Sp-isomer (dcl-cBIMPS), respectively. However, at concentrations exceeding 100 microM db-cyclic AMP suppressed B lymphocyte proliferation, probably as a result of cytotoxicity. Prostaglandin E2 (PGE2, 1 microM) and forskolin (10 microM) did not affect B cell proliferation, even when given in combination with rolipram. 6. Inhibition of protein kinase A (PKA) by differentially acting selective inhibitors (KT 5720, Rp-8-Br-cyclic AMPS) decreased the proliferative response of control cells and reversed the proliferation enhancing effects of rolipram. 7. Importantly, PDE4 activity in LPS/IL-4-activated B lymphocytes decreased by about 50% compared to unstimulated control values. 8. We conclude that an increase in cyclic AMP, mediated by down-regulation of PDE4 activity, is involved in the stimulation of B cell proliferation in response to LPS/IL-4. B cell proliferation in response to a mitogenic stimulus can be further enhanced by pharmacological elevation of cyclic AMP.

Thirty years ago liver pathology defined apoptosis as a novel mode of cell death. Recently, experimental models of liver injury have been made available for examining the signaling molecules and receptors of apoptotic mechanisms as well as their pathological relevance. Experimental evidence suggests the involvement of apoptosis not only in various inflammatory liver disorders, but also in conditions of poisoning with xenobiotic hepatotoxins. The presence of several differentially regulated apoptosismediating receptors and their ligands on hepatocytes may explain the liver's susceptibility to autoimmune reactions, toxins, and viruses causing chronic liver disease, as well as the differential sensitivity of this system in various metabolic and pathologic conditions. Tumor necrosis factor (TNF) and its receptors (TNF-R), as well as CD95L and its receptor (CD95), are well-known cytokine/cytokine receptor systems relevant to hepatic disease and to apoptosis. Neutralization of endogenously released TNF prevents hepatocyte apoptosis associated with inflammatory liver damage. Direct injection of TNF in sensitized mice results in large scale hepatocyte apoptosis which is exclusively and selectively mediated by the 55-kDa TNF-R. Fulminant apoptotic liver damage is also triggered upon stimulation of CD95. Possible triggering cells include hepatocytes that express CD95L under pathological conditions. Despite the lack of interaction between TNF-R and CD95 on the receptor level, their signal transduction inside the cell seems to involve common proteolytic steps since inhibition of proteases of the caspase family blocks hepatocyte death, liver damage, or lethality in mice signaled by either receptor.

The systemic inflammatory response syndrome has still an unpredictable outcome, and patients often die of multiple organ failure despite circulatory stabilization therapy. The still incompletely understood pathophysiological mechanisms include organ damage due to direct toxic actions of cytokines elicited by overactivation of the host response. To study this process of organ failure in experimental septic shock, we injected mice with a lethal dose of endotoxin and examined apoptotic and necrotic tissue damage biochemically, histologically, and ultrastructurally. Endotoxin administration caused oligonucleosomal as well as random DNA fragmentation in liver, lung, kidney, and intestine. In the liver, DNA fragmentation was not restricted to hepatocytes but also occurred in nonparenchymal cells. The DNA fragmentation was mediated by tumor necrosis factor and attenuated by endogenous nitric oxide release. Unlike the situation in D-galactosamine-sensitized mice, in which injection or release of tumor necrosis factor causes massive hepatocyte apoptosis, liver failure due to high doses of endotoxin was characterized by single-cell necrosis, a low incidence of apoptosis, and simultaneous damage to nonparenchymal cells. We conclude that, even though endotoxin causes cytokine-mediated DNA fragmentation in several organs including the liver, hepatocyte apoptosis itself seems to be a minor phenomenon in high-dose endotoxic shock in mice.

Concanavalin A activates T lymphocytes in vitro and causes T-cell-dependent hepatic injury in mice. T lymphocytes were previously identified as effector cells of concanavalin A-induced liver injury. Here we report that hepatic injury is characterized by apoptotic cell death. On concanavalin A challenge, the cytokines tumor necrosis factor-α (TNFα), interleukin-2, granulocyte macrophage-colony stimulating factor, and interferon-γ were detectable in the circulation of the mice. Pretreatment of mice with anti-mouse TNF-α antiserum protected them from concanavalin A-induced liver injury. Nude mice failed to release TNF-α or interleukin-2 after concanavalin A challenge and were protected from liver injury. Lymph node cell transfer from responder mice to resistant nude mice resulted in susceptibility of the latter towards concanavalin A, i.e., to induction of cytokine release and hepatotoxicity. These experiments suggest that immunocompetent T cells play a pivotal role in concanavalin A-stimulated TNF-α release in vivo. After intravenous administration of fluorescein isothiocyanate-labeled concanavalin A to mice, the most fluorescence was found within the liver. In vitro, concanavalin A stimulation of separate cultures of mouse lymph node cells or nonparenchymal liver cells induced the release of minute amounts of TNF, whereas stimulation of cocultures of these cells resulted in production of substantial amounts of TNF-α. These findings may explain the hepatotropic effect of concanavalin A. In conclusion, T-cell-dependent concanavalin A-induced apoptotic liver injury in mice is related to immunological and cytokinemediated disorders and possibly to autoreactive hepatic processes.

We investigated the role of hepatocyte apoptosis in four different murine models of acute inflammatory liver failure. Liver damage induced in D-galactosamine-sensitized mice by endotoxin infection was initiated by processes typical of apoptosis, ie, chromatin condensation, DNA fragmentation, and formation of intracellular apoptotic bodies. DNA was cleaved into oligonucleosomal fragments in the liver before a significant rise of alanine aminotransferase in plasma occurred. Passive immunization against tumor necrosis factor (TNF) completely inhibited the injury caused by endotoxin. Direct injection of recombinant TNF-alpha also caused DNA fragmentation followed by alanine aminotransferase release into the plasma. Pretreatment of mice with interleukin-1 beta, which is known to suppress TNF-induced lethality, completely prevented apoptosis and liver failure in this model. These results demonstrate the causal role of TNF in endotoxin-induced hepatic apoptosis. TNF-inducible hepatocyte apoptosis in vivo was not only observed in D-galactosamine-sensitized mice, but also when the alternative transcriptional inhibitor actinomycin D was used. In mice injected with the TNF-inducing T cell mitogen concanavalin A, hepatic apoptosis was even noticed without requirement of additional sensitizers. We conclude that TNF-induced hepatocyte apoptosis is an early, general, and possibly causal event during experimental liver failure triggered by inflammatory stimuli.