Identification of DNA-Damage DNA-Binding Protein 1 as a Conditional Essential Factor for Cytomegalovirus Replication in Interferon-γ-Stimulated Cells

The mouse cytomegaloviral (MCMV) protein pM27 represents an indispensable factor for viral fitness in vivo selectively, antagonizing signal transducer and activator of transcription 2 (STAT2)-mediated interferon signal transduction. We wished to explore by which molecular mechanism pM27 accomplishes this effect. We demonstrate that pM27 is essential and sufficient to curtail the protein half-life of STAT2 molecules. Pharmacologic inhibition of the proteasome restored STAT2 amounts, leading to poly-ubiquitin-conjugated STAT2 forms. PM27 was found in complexes with an essential host ubiquitin ligase complex adaptor protein, DNA-damage DNA-binding protein (DDB) 1. Truncation mutants of pM27 showed a strict correlation between DDB1 interaction and their ability to degrade STAT2. SiRNA-mediated knock-down of DDB1 restored STAT2 in the presence of pM27 and strongly impaired viral replication in interferon conditioned cells, thus phenocopying the growth attenuation of M27-deficient virus. In a constructive process, pM27 recruits DDB1 to exploit ubiquitin ligase complexes catalyzing the obstruction of the STAT2-dependent antiviral state of cells to permit viral replication

Differential effects of ifosfamide on dendritic cell-mediated stimulation of T cell interleukin-2 production, natural killer cell cytotoxicity and interferon-gamma production.

Ifosfamide is a DNA-alkylating agent used frequently in chemotherapy of human malignancies. Ifosfamide and its major decomposition products deplete intracellular glutathione (GSH). Glutathione is the major intracellular thiol reductant that protects cells against oxidative injury. Ifosfamide depletion of intracellular GSH in human dendritic cells (DC), T cells and natural killer (NK) cells impairs their functional activity which can be restored by reconstituting GSH. Here we assessed the effect of ifosfamide on DC-mediated stimulation of NK cell proliferation via T cells and on direct DC stimulation of NK cell cytotoxicity and interferon (IFN)-gamma production. Indirect DC stimulation of NK cell proliferation via T cells and T cell-derived interleukin (IL)-2 were reduced by ifosfamide treatment of DC and reconstitution of GSH in DC restored both responses. When DC and NK cells were treated with ifosfamide, DC could overcome the negative effect of ifosfamide on NK cytotoxic function whereas NK cell IFN-gamma production was less efficiently restored. The ability of IL-2 activated NK cells to kill autologous immature DC or to induce DC maturation was reduced moderately by treatment of both cell types with ifosfamide. Overall, our results suggest that DC may stimulate anti-tumour effector cells in patients even if they had received treatment with chemotherapeutic agents such as ifosfamide

Finding Synonymous Attributes in Evolving Wikipedia Infoboxes

Wikipedia Infoboxes are semi-structured data structures organized in an attribute-value fashion. Policies establish for each type of entity represented in Wikipedia the attribute names that the Infobox should contain in the form of a template. However, these requirements change over time and often users choose not to strictly obey them. As a result, it is hard to treat in an integrated way the history of the Wikipedia pages, making it difficult to analyze the temporal evolution of Wikipedia entities through their Infobox and impossible to perform direct comparison of entities of the same type. To address this challenge, we propose an approach to deal with the misalignment of the attribute names and identify clusters of synonymous Infobox attributes. Elements in the same cluster are considered as a temporal evolution of the same attribute. To identify the clusters we use two different distance metrics. The first is the co-occurrence degree that is treated as a negative distance, and the second is the co-occurrence of similar values in the attributes that are treated as a positive evidence of synonymy. We formalize the problem as a correlation clustering problem over a weighted graph constructed with attributes as nodes and positive and negative evidence as edges. We solve it with a linear programming model that shows a good approximation. Our experiments over a collection of Infoboxes of the last 13 years shows the potential of our approach

Molekulare Virologie am Beispiel des Hepatitis-B-Virus

Die nachfolgend beschriebenen Forschungsprojekte der Nachwuchsgruppe I am Robert Koch-Institut (RKI) befassen sich am Beispiel des Hepatitis-B-Virus (HBV) mit der Charakterisierung intrazellulärer Signalkaskaden und der Analyse ihrer Bedeutung für den viralen Lebenszyklus (Replikaktionsprozess) sowie für die Entstehung von HBV assoziierten Tumoren. Darüber hinaus werden auf der Basis eines neuen, aus dem HBV-Oberflächenprotein isolierten zellpermeablen Peptides neue Strategien zum Protein- und Gentransfer entwickelt