How will Brexit shape conflict resolution between the UK and other European countries?

How will Brexit shape conflict resolution within and between EU member states? In this post, Johannes Karreth (Ursinus College) observes that Brexit may pose a challenge not only to peace in Ireland but also for disputes between the UK and other European countries, such as the recent Franco-British "scallop war", that the EU has helped to keep at bay. He concludes that after Brexit there will be a great need for subsequent international agreements to make up for the loss of the EU institutional framework for conflict resolution and prevention

Modulation of oncogenic transformation by Raf proteins

Die abnormale Aktivierung des MAP Kinasen Signalweges ist von grundlegender Bedeutung für die Transformation zahlreicher Zelltypen. Dies kann durch häufig in menschlichen Tumoren vorkommenden Ras und B-Raf Punktmutationen erreicht werden. Obwohl die kausale Rolle des hyperaktiven MAPK Signalweges in der Krebsenstehung etabliert ist, ist die Regulierung des Signalweges durch das komplexe Zusammenspiel von Ras und Raf Proteinen nur teilweise bekannt. In dieser Arbeit zeige ich, daß das Proto-onkogen C-Raf der onkogenen Aktivität der am häufigsten im Krebs vorkommenden B-Raf Mutante (B-RafV600E) entgegenwirkt, indem es einen B-RafV600E–C-Raf Komplex mit verminderter Kinaseaktivität bildet. Interessanterweise werden B-RafV600E–C-Raf Komplexe von onkogenem Ras stabilisiert, was das Fehlen von gemeinsam auftretenden Ras und B-Raf Mutationen in humanem Krebs erklären könnte. Um den hemmenden Einfluß von C-Raf auf B-RafV600E in vivo untersuchen zu können, wurde ein B-RafV619E Mausmodell entwickelt (murines B-RafV619E entspricht dem humanen B-RafV600E). B-RafV619E transformiert von diesen Mäusen gewonnene MEFs und induziert Überpigmentierung wenn B-RafV619E in den Melanozyten dieser Mäuse aktiviert wird. Da die Expression von B-RafV619E zur Zelltransformation in vitro und in vivo führt, kann dieses Mausmodell zur weiteren Aufklärung der B-RafV600E–C-Raf Beziehung herangezogen werden. Da C-Raf einen negative Effekt auf B-RafV600E ausübt, wurde untesucht, ob C-Raf in der K-RasG12D-induzierten Zelltransformation eine Rolle spielt. Der homozygote Knock-out von C-Raf unterdrückt K-RasG12D-induzierte Lungenkrebsentstehung und die anti-apoptotische Funktion von K-RasG12D in MEFs. Im Gegensatz dazu reguliert K-RasG12D die Zellteilung von Lungenkrebszellen in vivo und MEFs in vitro durch B-Raf. Zusammenfassend habe ich gezeigt, daß Raf Proteine sowohl den Krebs begünstigende als auch unterdrückende Rollen spielen können und daß dies von dem onkogenen Kontext abhängig ist.Aberrant activation of the MAP kinase pathway is of fundamental importance for the transformation of numerous cell types. This can be achieved by oncogenic Ras and B-Raf missense mutations, which are common genetic lesions found in human cancers. Although a causal role of MAP kinase pathway hyperactivation in cancer development has been established, modulation of the pathway by the complex interplay of Ras and Raf proteins remains poorly understood. Here, I show that proto-oncogenic C-Raf antagonizes the oncogenic activity of the most frequent cancer-associated B-Raf mutant, B-RafV600E, through the formation of B-RafV600E–C-Raf complexes with low kinase activity. B-Raf–C-Raf association is promoted by oncogenic Ras, providing a potential explanation for the exclusivity of oncogenic Ras mutations and B-RafV600E in human cancer. To study the suppressive function of C-Raf on B-RafV600E in vivo, a mouse model of B-RafV600E was developed. Activated murine B-RafV619E, analogous to human B-RafV600E, transforms MEFs and, when expressed in melanocytes, induces hyper-pigmentation in mice. As B-RafV619E expression results in a transformed phenotype in vitro and in vivo, this mouse model will be useful to further evaluate the relationship between C-Raf and B-RafV600E. As C-Raf has adverse effects on B-RafV600E-induced transformation, its role in mediating transformation by oncogenic K-RasG12D was examined. Homozygous loss of C-Raf impairs K-RasG12D-mediated lung tumor initiation and cell survival in MEFs. In contrast, B-Raf is required for the proliferative advantage conferred by K-RasG12D in vitro and in vivo. Together, I demonstrate that Raf proteins can have cancer promoting as well as preventing roles depending on the oncogenic context

Activated mutant NRasQ61K drives aberrant melanocyte signaling, survival, and invasiveness via a rac1-Dependent mechanism

Around a fifth of melanomas exhibit an activating mutation in the oncogene NRas that confers constitutive signaling to proliferation and promotes tumor initiation. NRas signals downstream of the major melanocyte tyrosine kinase receptor c-kit and activated NRas results in increased signaling via the extracellular signal–regulated kinase (ERK)/MAPK/ERK kinase/mitogen-activated protein kinase (MAPK) pathways to enhance proliferation. The Ras oncogene also activates signaling via the related Rho GTPase Rac1, which can mediate growth, survival, and motility signaling. We tested the effects of activated NRasQ61K on the proliferation, motility, and invasiveness of melanoblasts and melanocytes in the developing mouse and ex vivo explant culture as well as in a melanoma transplant model. We find an important role for Rac1 downstream of NRasQ61K in mediating dermal melanocyte survival in vivo in mouse, but surprisingly NRasQ61K does not appear to affect melanoblast motility or proliferation during mouse embryogenesis. We also show that genetic deletion or pharmacological inhibition of Rac1 in NRasQ61K induced melanoma suppresses tumor growth, lymph node spread, and tumor cell invasiveness, suggesting a potential value for Rac1 as a therapeutic target for activated NRas-driven tumor growth and invasiveness

Identifying and Targeting Sporadic Oncogenic Genetic Aberrations in Mouse Models of Triple-Negative Breast Cancer

Triple-negative breast cancers (TNBC) are genetically characterized by aberrations in TP53 and a low rate of activating point mutations in common oncogenes, rendering it challenging in applying targeted therapies. We performed whole-exome sequencing (WES) and RNA sequencing (RNA-seq) to identify somatic genetic alterations in mouse models of TNBCs driven by loss of Trp53 alone or in combination with Brca1. Amplifications or translocations that resulted in elevated oncoprotein expression or oncoprotein-containing fusions, respectively, as well as frameshift mutations of tumor suppressors were identified in approximately 50% of the tumors evaluated. Although the spectrum of sporadic genetic alterations was diverse, the majority had in common the ability to activate the MAPK/PI3K pathways. Importantly, we demonstrated that approved or experimental drugs efficiently induce tumor regression specifically in tumors harboring somatic aberrations of the drug target. Our study suggests that the combination of WES and RNA-seq on human TNBC will lead to the identification of actionable therapeutic targets for precision medicine–guided TNBC treatment.National Institutes of Health (U.S.) (Grant R35 CA197588)National Institutes of Health (U.S.) (Grant R01 GM041890)National Institutes of Health (U.S.) (Grant PSOC U54 CA210184)Breast Cancer Research Foundation (award BCRF-16-021)Jon and Mindy Gray FoundationEntertainment Industry Foundation. Stand Up to Cancer Colorectal Cancer Dream Team (Tranlational Research Grant No. SU2C-AACR-DT22-17)Susan Komen postdoctoral fellowshipBreast Cancer AllianceNovo Nordisk STAR Postdoctoral Fellowshi

Union members at the polls in diverse trade union landscapes

This article investigates to what extent social democratic parties still benefit from the support of union members at the polls. Not only are social democratic parties confronted with new competitors in the party systems, but also the union confederations of the socialist labour movement are in some countries losing their dominant position due to the rise of separate professional confederations. It is argued in the article that the effect of union membership on voting choice is conditioned by the structure of the trade union movement. The support of union members for social democracy is fostered by the strength of the confederations historically close to this party family, while it is hampered when strong separate (or politically unaffiliated) white-collar confederations exist. Using European Social Survey and Swedish Public Opinion data, the article shows that social democratic parties still enjoy important support from trade union members, but at the same time are under fierce competition from bourgeois and green parties among members of white-collar confederations. This reinforces the challenges for social democracy to build new voters’ coalitions in post-industrial societies

Kinetic modelling of competition and depletion of shared miRNAs by competing endogenous RNAs

Non-conding RNAs play a key role in the post-transcriptional regulation of mRNA translation and turnover in eukaryotes. miRNAs, in particular, interact with their target RNAs through protein-mediated, sequence-specific binding, giving rise to extended and highly heterogeneous miRNA-RNA interaction networks. Within such networks, competition to bind miRNAs can generate an effective positive coupling between their targets. Competing endogenous RNAs (ceRNAs) can in turn regulate each other through miRNA-mediated crosstalk. Albeit potentially weak, ceRNA interactions can occur both dynamically, affecting e.g. the regulatory clock, and at stationarity, in which case ceRNA networks as a whole can be implicated in the composition of the cell's proteome. Many features of ceRNA interactions, including the conditions under which they become significant, can be unraveled by mathematical and in silico models. We review the understanding of the ceRNA effect obtained within such frameworks, focusing on the methods employed to quantify it, its role in the processing of gene expression noise, and how network topology can determine its reach.Comment: review article, 29 pages, 7 figure

The BRAF pseudogene functions as a competitive endogenous RNA and induces lymphoma in vivo

SummaryResearch over the past decade has suggested important roles for pseudogenes in physiology and disease. In vitro experiments demonstrated that pseudogenes contribute to cell transformation through several mechanisms. However, in vivo evidence for a causal role of pseudogenes in cancer development is lacking. Here, we report that mice engineered to overexpress either the full-length murine B-Raf pseudogene Braf-rs1 or its pseudo “CDS” or “3′ UTR” develop an aggressive malignancy resembling human diffuse large B cell lymphoma. We show that Braf-rs1 and its human ortholog, BRAFP1, elicit their oncogenic activity, at least in part, as competitive endogenous RNAs (ceRNAs) that elevate BRAF expression and MAPK activation in vitro and in vivo. Notably, we find that transcriptional or genomic aberrations of BRAFP1 occur frequently in multiple human cancers, including B cell lymphomas. Our engineered mouse models demonstrate the oncogenic potential of pseudogenes and indicate that ceRNA-mediated microRNA sequestration may contribute to the development of cancer