The extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) signalling pathway regulates many cellular functions, including proliferation, differentiation, and transformation. To reliably convert external stimuli into specific cellular responses and to adapt to environmental circumstances, the pathway must be integrated into the overall signalling activity of the cell. Multiple mechanisms have evolved to perform this role. In this review, we will focus on negative feedback mechanisms and examine how they shape ERK1/2 MAPK signalling. We will first discuss the extensive number of negative feedback loops targeting the different components of the ERK1/2 MAPK cascade, specifically the direct posttranslational modification of pathway components by downstream protein kinases and the induction of de novo gene synthesis of specific pathway inhibitors. We will then evaluate how negative feedback modulates the spatiotemporal signalling dynamics of the ERK1/2 pathway regarding signalling amplitude and duration as well as subcellular localisation. Aberrant ERK1/2 activation results in deregulated proliferation and malignant transformation in model systems and is commonly observed in human tumours. Inhibition of the ERK1/2 pathway thus represents an attractive target for the treatment of malignant tumours with increased ERK1/2 activity. We will, therefore, discuss the effect of ERK1/2 MAPK feedback regulation on cancer treatment and how it contributes to reduced clinical efficacy of therapeutic agents and the development of drug resistance.

Cloud services are exploding and organizations are converging their data centres in order to take advantage of the predictability, continuity, and quality of service delivered by virtualization technologies. In parallel, energy-efficient and high-security networking is of increasing importance. Network operators, service and product providers require a new network solution to efficiently tackle the increasing demands of this changing network landscape. Software-Defined Networking has emerged as an efficient network technology capable of supporting the dynamic nature of future network functions and intelligent applications while lowering operating costs through simplified hardware, software, and management. In this article, the question of how to achieve a successful carrier grade network with Software-Defined Networking is raised. Specific focus is placed on the challenges of network performance, scalability, security and interoperability with the proposal of potential solution directions.

Democracies are less likely to fight wars with each other. They are also more likely to prevail in wars with autocratic states. I offer an explanation of this syndrome of powerful pacifism drawn from the microeconomic theory of the state. State rent seeking creates an imperialist bias in a country's foreign policy. This bias is smallest in democracies, where the costs to society of controlling the state are relatively low, and greatest in autocracies, where the costs are higher. As a result of this bias, autocracies will be more expansionist and, in turn, war-prone. In their relations with each other, where the absence of this imperialist bias is manifest, the relative pacifism of democracies appears. In addition, democracies, constrained by their societies from earning rents, will devote greater absolute resources to security, enjoy greater societal support for their policies, and tend to form overwhelming countercoalitions against expansionist autocracies. It follows that democracies will be more likely to win wars.

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