Shifting new media: from content to consultancy, from heterarchy to hierarchy

This is a detailed case history of one of London’s iconic new media companies, AMX Studios. Some of the changes in this firm, we assume, are not untypical for other firms in this sector. Particularly we want to draw attention to two transformations. The first change in AMX and in London’s new media industry more generally refers to the field of industrial relations. What can be observed is a shift from a rather heterarchical towards a more hierarchical organized new media industry, a shift from short-term project networks to long-term client dependency. The second change refers to new media products and services. We want to argue for a shift from cool content production towards consultancy and interactive communications solutions

Relationship between solidification microstructure and hot cracking susceptibility for continuous casting of low-carbon and high-strength low-alloyed steels: A phase-field study

© The Minerals, Metals & Materials Society and ASM International 2013Hot cracking is one of the major defects in continuous casting of steels, frequently limiting the productivity. To understand the factors leading to this defect, microstructure formation is simulated for a low-carbon and two high-strength low-alloyed steels. 2D simulation of the initial stage of solidification is performed in a moving slice of the slab using proprietary multiphase-field software and taking into account all elements which are expected to have a relevant effect on the mechanical properties and structure formation during solidification. To account for the correct thermodynamic and kinetic properties of the multicomponent alloy grades, the simulation software is online coupled to commercial thermodynamic and mobility databases. A moving-frame boundary condition allows traveling through the entire solidification history starting from the slab surface, and tracking the morphology changes during growth of the shell. From the simulation results, significant microstructure differences between the steel grades are quantitatively evaluated and correlated with their hot cracking behavior according to the Rappaz-Drezet-Gremaud (RDG) hot cracking criterion. The possible role of the microalloying elements in hot cracking, in particular of traces of Ti, is analyzed. With the assumption that TiN precipitates trigger coalescence of the primary dendrites, quantitative evaluation of the critical strain rates leads to a full agreement with the observed hot cracking behavior. © 2013 The Minerals, Metals & Materials Society and ASM International

Current european regulatory perspectives on insulin analogues

Insulin analogues are increasingly considered as an alternative to human insulin in the therapy of diabetes mellitus. Insulin analogues (IAs) are chemically different from human insulin and may have different pharmacokinetic or pharmacodynamic properties. The significance of the modifications of the insulin molecule for the safety profile of IAs must be considered. This review describes the regulatory procedure and the expectations for the scientific content of European marketing authorization applications for innovative IAs submitted to the European Medicines Agency. Particular consideration is given to a potential cancer hazard. Specific regulatory guidance on how to address a possible carcinogenic or tumor promoting effect of innovative IAs in non-clinical studies is available. After marketing authorization, the factual access of patients to the new product will be determined to great extent by health technology assessment bodies, reimbursement decisions and the price. Whereas the marketing authorization is a European decision, pricing and reimbursement are national or regional responsibilities. The assessment of benefit and risk by the European Medicines Agency is expected to influence future decisions on price and reimbursement on a national or regional level. Collaborations between regulatory agencies and health technology assessment bodies have been initiated on European and national level to facilitate the use of the European Medicines Agency's benefit risk assessment as basis on which to build the subsequent health technology assessment. The option for combined or joint scientific advice procedures with regulators and health technology assessment bodies on European level or on a national level in several European Member States may help applicants to optimize their development program and dossier preparation in regard of both European marketing authorization application and reimbursement decisions

Recruitment of the Linear Ubiquitin Chain Assembly Complex Stabilizes the TNF-R1 Signaling Complex and Is Required for TNF-Mediated Gene Induction

TNF is a key inflammatory cytokine. Using a modified tandem affinity purification approach, we identified HOIL-1 and HOIP as functional components of the native TNF-R1 signaling complex (TNF-RSC). Together, they were shown to form a linear ubiquitin chain assembly complex (LUBAC) and to ubiquitylate NEMO. We show that LUBAC binds to ubiquitin chains of different linkage types and that its recruitment to the TNF-RSC is impaired in TRADD-, TRAF2-, and cIAP1/2- but not in RIP1- or NEMO-deficient MEFs. Furthermore, the E3 ligase activity of cIAPs, but not TRAF2, is required for HOIL-1 recruitment to the TNF-RSC. LUBAC enhances NEMO interaction with the TNF-RSC, stabilizes this protein complex, and is required for efficient TNF-induced activation of NF-κB and JNK, resulting in apoptosis inhibition. Finally, we demonstrate that sustained stability of the TNF-RSC requires LUBAC's enzymatic activity, thereby adding a third form of ubiquitin linkage to the triggering of TNF signaling by the TNF-RSC. © 2009 Elsevier Inc. All rights reserved

Columnar and Equiaxed Solidification of Al-7 wt.% Si Alloys in Reduced Gravity in the Framework of the CETSOL Project

International audienceDuring casting, often a dendritic microstructure is formed, resulting in a columnar or an equiaxed grain structure, or leading to a transition from columnar to equiaxed growth (CET). The detailed knowledge of the critical parameters for the CET is important because the microstructure affects materials properties. To provide unique data for testing of fundamental theories of grain and microstructure formation, solidification experiments in microgravity environment were performed within the European Space Agency Microgravity Application Promotion (ESA MAP) project Columnar-to-Equiaxed Transition in SOLidification Processing (CETSOL). Reduced gravity allows for purely diffusive solidification conditions, i.e., suppressing melt flow and sedimentation and floatation effects. On-board the International Space Station, Al-7 wt.% Si alloys with and without grain refiners were solidified in different temperature gradients and with different cooling conditions. Detailed analysis of the microstructure and the grain structure showed purely columnar growth for nonrefined alloys. The CET was detected only for refined alloys, either as a sharp CET in the case of a sudden increase in the solidification velocity or as a progressive CET in the case of a continuous decrease of the temperature gradient. The present experimental data were used for numerical modeling of the CET with three different approaches: (1) a front tracking model using an equiaxed growth model, (2) a three-dimensional (3D) cellular automaton–finite element model, and (3) a 3D dendrite needle network method. Each model allows for predicting the columnar dendrite tip undercooling and the growth rate with respect to time. Furthermore, the positions of CET and the spatial extent of the CET, being sharp or progressive, are in reasonably good quantitative agreement with experimental measurements

On the Deformation of Dendrites During Directional Solidification of a Nickel-Based Superalloy

Abstract: Synchrotron X-ray imaging has been used to examine in situ the deformation of dendrites that takes place during the solidification of a nickel-based superalloy. By combining absorption and diffraction contrast imaging, deformation events could be classified by their localization and permanence. In particular, a deformation mechanism arising from thermal contraction in a temperature gradient was elucidated through digital image correlation. It was concluded that this mechanism may explain the small misorientations typically observed in single crystal castings