Gp130-Dependent Release of Acute Phase Proteins Is Linked to the Activation of Innate Immune Signaling Pathways

Background: Elevated levels of acute phase proteins (APP) are often found in patients with cardiovascular diseases. In a previous study, we demonstrated the importance of the IL-6-gp130 axis-as a key regulator of inflammatory acute phase signaling in hepatocytes-for the development of atherosclerosis. Background/Principal Findings: Gp130-dependent gene expression was analyzed in a previously established hepatocytespecific gp130 knockout mouse model. We performed whole transcriptome analysis in isolated hepatocytes to measure tissue specific responses after proinflammatory stimulus with IL-6 across different time points. Our analyses revealed an unexpected small gene cluster that requires IL-6 stimulus for early activation. Several of the genes in this cluster are involved in different cell defense mechanisms. Thus, stressors that trigger both general stress and inflammatory responses lead to activation of a stereotypic innate cellular defense response. Furthermore, we identified a potential biomarker Lipocalin (LCN) 2 for the gp130 dependent early inflammatory response. Conclusions/Significance: Our findings suggest a complex network of tightly linked genes involved in the early activatio

Interoperable Metadatenmodelle und Repositories

Um elektronische Publikationen in einem größeren Kontext (international und interdisziplinär) verfügbar zu machen, ist die Vernetzung von Repositories durch übergreifende Services eine wesentliche Voraussetzung. Dabei werden i.d.R. nicht die elektronischen Publikationen ausgetauscht, sondern die standardisierten Beschreibungen derselben, also die Metadaten. Damit bekommen Interoperabilität und Standardisierung von Metadatenmodellen entscheidende Bedeutung. Die Mehrzahl der Repositorien stellt für die Nachnutzung der Metadaten das OAI-PMH zur Verfügung. Dieses Protokoll berücksichtigt die Forderung nach Metadaten-Interoperabilität, indem es Dublin Core Simple als Mindeststandard für den Austausch von Metadaten fordert, gleichzeitig aber die Erweiterung dieses Mindeststandards durch domainspezifisch und lokal benötigte Metadatenelemente erlaubt. Die Verwendung von DC Simple erweist sich jedoch dann als problematisch, wenn beim Zusammenführen der Daten verschiedener Herkunft deutlich wird, dass die Data Provider bei der Datenerfassung unterschiedliche Regeln bezüglich Syntax und Semantik anwenden. Hier gilt es Lösungen zu finden, die sowohl den Forderungen der Data Provider nach möglichst einfacher Metadatenerfassung als auch den Forderungen der Service Provider nach möglichst großer syntaktischer und semantischer Interoperabilität entgegenkommen. Der Vortrag wird beispielhaft die Probleme, die sich beim Zusammenführen von Metadaten aus unabhängigen Repositorien ergeben, deutlich machen und die aktuellen theoretischen Lösungsansätze aus der Dublin Core Community (DCAM, Singapore Framework, SWAP) vorstellen

Towards the Development of a Metadata Model for a Digital Cultural Heritage Collection with Focus on Provenance Information

This project report describes the first steps of the development of a metadata model for the contextualization of heterogeneous objects from different cultural heritage collections with focus on provenance information. The project started with the assumption that aims and objectives of researchers working with cultural heritage collections differ from discipline to discipline. Accordingly, use cases and requirements for the description of objects are heterogeneous. To provide a model that would be usable not only within but also across academic disciplines the project needed to know where these requirements differ and where they match. Therefore the first part of the project was focused on the investigation of use cases and requirements. On the base of the common requirements a generic model will be built that allows the merging of data from a variety of disciplines using different metadata standards. The model’s structure will be a combination of prevalent metadata standards mapped to each other. Another peculiarity of the model will be the modular design of micro -ontologies, sets of domain-specific class structures that are, nevertheless, available on a meta-level in terms of substructures. Applying the DCMI dumb-down principle these subproperties and subclasses will be assigned to a who-what-where-when model, a base structure for the description of objects.The project divided the work process of the project into seven steps. As the project is still work in progress, only four steps will be explained in detail in this report. The three remaining steps will be presented in an outlook

Applying a linked data compliant model: The usage of the Europeana Data Model by the Deutsche Digitale Bibliothek

In 2013/14 the Deutsche Digitale Bibliothek (DDB) switched its data model from the CIDOC conceptual reference model to the Europeana Data Model (EDM). This decision was taken on the background of two major mandates the DDB has to fulfill: The DDB is as a portal and a platform providing access to digital objects from German cultural heritage and research institutions. On the other hand the DDB aims to become the German aggregator for Europeana. Using EDM as the internal DDB data model was approved as the most reasonable solution to meet these challenges. The DDB uses the model for all portal functions that require semantic links between metadata (search facets, hierarchies, links between authority files and digital objects). The application of EDM for the DDB portal raised some difficulties since not all necessary classes and properties were entirely implemented in Europeana-EDM at that time. Therefore, a DDB-EDM application profile was developed. The DDB publishes metadata under the CC0 Public Domain Dedication license in EDM-RDF/XML via an OAI-PMH interface to serve Europeana and also via an Application Programming Interface (API) for external users to develop new applications on the basis of metadata harmonized by the DDB

Depletion of Ly6G-Expressing Neutrophilic Cells Leads to Altered Peripheral T-Cell Homeostasis and Thymic Development in Neonatal Mice

Newborns and especially preterm infants are much more susceptible to infections than adults. Due to immature adaptive immunity, especially innate immune cells play an important role in a newborn’s infection defense. Neonatal neutrophils exhibit profound differences in their functionality compared to neutrophils of adults. In particular, neonates possess a relevant population of suppressive neutrophils, which not only inhibit but also specifically modulate the function of T-cells. In this study, we investigated whether neonatal neutrophils are already involved in T-cell development in the thymus. For this purpose, we used a newly developed model of antibody-mediated immune cell depletion in which we administered a depleting antibody to pregnant and then lactating dams. Using this method, we were able to sufficiently deplete Ly6G-positive neutrophils in offspring. We demonstrated that the depletion of neutrophils in newborn mice resulted in altered peripheral T-cell homeostasis with a decreased CD4+/CD8+ T-cell ratio and decreased expression of CD62L. Neutrophil depletion even affected T-cell development in the thymus, with increased double positive thymocytes and a decreased CD4+/CD8+ single positive thymocyte ratio. Altogether, we demonstrated a previously unknown mechanism mediating neutrophils’ immunomodulatory effects in newborns

Gut Microbiota-Derived Small Extracellular Vesicles Endorse Memory-like Inflammatory Responses in Murine Neutrophils

Neutrophils are classically characterized as merely reactive innate effector cells. However, the microbiome is known to shape the education and maturation process of neutrophils, improving their function and immune-plasticity. Recent reports demonstrate that murine neutrophils possess the ability to exert adaptive responses after exposure to bacterial components such as LPS (Gram-negative bacteria) or LTA (Gram-positive bacteria). We now ask whether small extracellular vesicles (EVs) from the gut may directly mediate adaptive responses in neutrophils in vitro. Murine bone marrow-derived neutrophils were primed in vitro by small EVs of high purity collected from colon stool samples, followed by a second hit with LPS. We found that low-dose priming with gut microbiota-derived small EVs enhanced pro-inflammatory sensitivity as indicated by elevated levels of TNF-α, IL-6, ROS and MCP-1 and increased migratory and phagocytic activity. In contrast, high-dose priming resulted in a tolerant phenotype, marked by increased IL-10 and decreased transmigration and phagocytosis. Alterations in TLR2/MyD88 as well as TLR4/MyD88 signaling were correlated with the induction of adaptive cues in neutrophils in vitro. Taken together, our study shows that small EVs from stools can drive adaptive responses in neutrophils in vitro and may represent a missing link in the gut–immune axis