The regulation of sequence specific NF-kB DNA binding and transcription by IKKβ phosphorylation of NF-kB p50 at serine 80

peer-reviewedPhosphorylation of the NF-kB transcription factor is an important regulatory mechanism for the control of transcription. Here we identify serine 80 (S80) as a phosphorylation site on the p50 subunit of NF-kB, and IKKβ as a p50 kinase. Transcriptomic analysis of cells expressing a p50 S80A mutant reveals a critical role for S80 in selectively regulating the TNF inducible expression of a subset of NF-kB target genes including pro-inflammatory cytokines and chemokines. S80 phosphorylation regulates the binding of p50 to NF-kB binding ( B) sites in a sequence specific manner. Specifically, phosphorylation of S80 reduces the binding of p50 at B sites with an adenine at the −1 position. Our analyses demonstrate that p50 S80 phosphorylation predominantly regulates transcription through the p50:p65 heterodimer, where S80 phosphorylation acts in trans to limit the NF- kB mediated transcription of pro-inflammatory genes. The regulation of a functional class of pro-inflammatory genes by the interaction of S80 phosphorylated p50 with a specific kB sequence describes a novel mechanism for the control of cytokine-induced transcriptional responses

Realising the European network of biodosimetry: RENEB-status quo

Creating a sustainable network in biological and retrospective dosimetry that involves a large number of experienced laboratories throughout the European Union (EU) will significantly improve the accident and emergency response capabilities in case of a large-scale radiological emergency. A well-organised cooperative action involving EU laboratories will offer the best chance for fast and trustworthy dose assessments that are urgently needed in an emergency situation. To this end, the EC supports the establishment of a European network in biological dosimetry (RENEB). The RENEB project started in January 2012 involving cooperation of 23 organisations from 16 European countries. The purpose of RENEB is to increase the biodosimetry capacities in case of large-scale radiological emergency scenarios. The progress of the project since its inception is presented, comprising the consolidation process of the network with its operational platform, intercomparison exercises, training activities, proceedings in quality assurance and horizon scanning for new methods and partners. Additionally, the benefit of the network for the radiation research community as a whole is addressed

Co-Regulation of NF-κB and Inflammasome-Mediated Inflammatory Responses by Myxoma Virus Pyrin Domain-Containing Protein M013

NF-κB and inflammasomes both play central roles in orchestrating anti-pathogen responses by rapidly inducing a variety of early-response cytokines and chemokines following infection. Myxoma virus (MYXV), a pathogenic poxvirus of rabbits, encodes a member of the cellular pyrin domain (PYD) superfamily, called M013. The viral M013 protein was previously shown to bind host ASC-1 protein and inhibit the cellular inflammasome complex that regulates the activation and secretion of caspase 1-regulated cytokines such as IL-1β and IL-18. Here, we report that human THP-1 monocytic cells infected with a MYXV construct deleted for the M013L gene (vMyxM013-KO), in stark contrast to the parental MYXV, rapidly induce high levels of secreted pro-inflammatory cytokines like TNF, IL-6, and MCP-1, all of which are regulated by NF-κB. The induction of these NF-κB regulated cytokines following infection with vMyxM013-KO was also confirmed in vivo using THP-1 derived xenografts in NOD-SCID mice. vMyxM013-KO virus infection specifically induced the rapid phosphorylation of IKK and degradation of IκBα, which was followed by nuclear translocation of NF-κB/p65. Even in the absence of virus infection, transiently expressed M013 protein alone inhibited cellular NF-κB-mediated reporter gene expression and nuclear translocation of NF-κB/p65. Using protein/protein interaction analysis, we show that M013 protein also binds directly with cellular NF-κB1, suggesting a direct physical and functional linkage between NF-κB1 and ASC-1. We further demonstrate that inhibition of the inflammasome with a caspase-1 inhibitor did not prevent the induction of NF-κB regulated cytokines following infection with vMyxM013-KO virus, but did block the activation of IL-1β. Thus, the poxviral M013 inhibitor exerts a dual immuno-subversive role in the simultaneous co-regulation of both the cellular inflammasome complex and NF-κB-mediated pro-inflammatory responses

Doing Gender Im Technisch-Naturwissen-Schaftlichen Bereich

Für die Lösung des Nachwuchsproblems in den Technikwissenschaften spielt die Gewinnung von Frauen eine zentrale Rolle. Die in der Expertise dargestellten Befunde verdeutlichen dreierlei: (1) In den Natur- und Technikwissenschaften "verliert" man Frauen sehr früh im Lebensverlauf. (2) Wie beim Durchlauf eines Trichters (leaking pipeline) verringert sich mit jeder Bildungs- und Karrierestufe die Anzahl von Frauen in diesen Fächern und Berufen. (3) Die Erhöhung des Interesses für Technikwissenschaften von Mädchen und Frauen ist nicht nur "ein Problem" für das Bildungssystem, sondern ganz wesentlich auch des Arbeitsmarktes. Die Befunde der Expertise zeigen, dass es unbedingt notwendig ist, jungen Frauen, die in technischen Berufen gut ausgebildet sind, eine höhere Chance als bisher zu geben, (a) ihren Beruf aus dem Bereich Mathematik, Informatik, Naturwissenschaften, Technik (im Folgenden kurz: MINT) auszuüben und (b) dies auch mit den gleichen Gratifikationen wie Männer. Diese Herausforderung muss - und zwar unabhängig von der Nachfrage nach neuem Personal in technischen Berufen - schnell gemeistert werden, wenn Wirtschaft und Politik ein ernst gemeintes Interesse an "Frauen in MINT-Berufen" besitzen

The impact of social constraints and sense of coherence on the psychological adjustment of adolescents and young adults with CF

In the last two decades, the medical understanding of Cystic Fibrosis (CF) has dramatically improved, however, there are still significant gaps in our understanding of the psychological adjustment of families coping with CF. We examined the utility of the Social Cognitive Processing (SCP) Model in understanding the interactions of parents and young people with CF. We also examined the relationship between social constraints, a key construct in the SCP model, sense of coherence (SOC) and other psychological adjustment indicators for young people with CF. Participants comprised 49 individuals with CF, aged 16–25, recruited through state-based CF organisations in Australia. The results indicated that participant ratings of difficulties with communication (social constraints) were positively associated with ratings of depression, anxiety, and stress and negatively related to ratings of positive affect and seeing life challenges as predictable, manageable and meaningful (SOC). Ratings of SOC were also positively related to ratings of positive affect and negatively related to ratings of depression, anxiety and stress. A significant mediating effect of SOC was also identified in the relationships between social constraints and positive affect and social constraints and stress. The theoretical and clinical implications of these findings are discussed

Variance of an anisotropic Bose-Einstein condensate

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