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Espeli M.,University of Cambridge | Clatworthy M.R.,University of Cambridge | Bokers S.,University of Cambridge | Bokers S.,University of Erlangen Nuremburg | And 6 more authors.
Journal of Experimental Medicine | Year: 2012

Genetic variants of the inhibitory Fc receptor FcγRIIb have been associated with systemiclupus erythematosus in humans and mice. The mechanism by which Fcgr2b variants contribute to the development of autoimmunity is unknown and was investigated by knocking in the most commonly conserved wild mouse Fcgr2b promoter haplotype, also associated with autoimmune-prone mouse strains, intothe C57BL/6 background. We found that in the absence of an AP-1-binding site in its promoter, FcγRIIb failed to be up-regulated on activated and germinal center (GC) B cells. This resulted in enhanced GC responses, increased affinity maturation, and autoantibody production. Accordingly, inthe absence of FcγRIIb activation-induced up-regulation, mice developed more severe collagen-induced arthritis and spontaneous glomerular immune complex deposition. Our data highlight how natural variation in Fcgr2b drives the development of autoimmune disease. They also show how the study of such variants using a knockin approach can provide insight into immune mechanisms not possible using conventional genetic manipulation, in this case demonstrating an unexpected critical role forthe activation-induced up-regulation of FcγRIIb in controlling affinity maturation, autoantibody production, and autoimmunity. © 2012 Espéli et al. Source


Schnabel R.,Robert Bosch GmbH | Mittelstrab D.,Robert Bosch GmbH | Binzer T.,Robert Bosch GmbH | Waldschmidt C.,Robert Bosch GmbH | Weigel R.,University of Erlangen Nuremburg
IEEE Microwave Magazine | Year: 2012

The ambition of achieving road traffic without serious injuries, since 1997 referred to as Vision Zero, has influenced the development of new car generations during the last decades. Since the early beginnings, radar sensors have taken responsibility for receiving this goal and played a major role for achieving the subsequent vision of accident-free driving. An increasing list of applications already covers comfort and safety functions for various traffic conditions. Besides already established applications like adaptive cruise control (ACC) as illustrated in Figure 1, other examples are the lane change assistant (LCA), watching for traffic when starting an overtaking maneuver (see Figure 2) and cross traffic alert (CTA), warning of approaching vehicles at a junction. However, those examples are just a few of the constantly increasing list of functions [1][2]. © 2012 IEEE. Source


Shan B.,Max Planck Institute of Psychiatry | Gerez J.,University of Buenos Aires | Haedo M.,University of Buenos Aires | Fuertes M.,University of Buenos Aires | And 5 more authors.
Endocrine-Related Cancer | Year: 2012

The recently cloned small RWD-domain containing protein RSUME was shown to increase protein levels of hypoxia-inducible factor-1α (HIF-1α). The latter is the oxygen-regulated subunit of HIF-1, the most important transcription factor of the cellular adaptive processes to hypoxic conditions. It is also a major regulator of vascular endothelial growth factor-A (VEGF-A), which is critically involved in the complex process of tumour neovascularisation. In this study, the expression and role of RSUME in pituitary tumours was studied. We found that RSUME mRNA was up-regulated in pituitary adenomas and significantly correlated with HIF-1α mRNA levels. Hypoxia (1% O 2) or treatment with hypoxia-mimicking CoCl 2 enhanced RSUME and HIF-1α expression, induced translocation of HIF-1α to the nuclei and stimulated VEGF-A production both in pituitary tumour cell lines and primary human pituitary adenoma cell cultures. When RSUME expression was specifically down-regulated by siRNA, the CoCl 2-induced increase VEGF-A secretion was strongly reduced which was shown to be a consequence of the RSUME knockdown-associated reduction of HIF-1α synthesis. Thus, RSUME plays an important role in initiating pituitary tumour neovascularisation through regulating HIF-1α levels and subsequent VEGF-A production and may therefore be critically involved in pituitary adenoma progression. © 2012 Society for Endocrinology Printed in Great Britain. Source


Shan B.,Max Planck Institute of Psychiatry | Schaaf C.,Max Planck Institute of Psychiatry | Schmidt A.,Max Planck Institute of Psychiatry | Lucia K.,Max Planck Institute of Psychiatry | And 10 more authors.
Journal of Endocrinology | Year: 2012

Curcumin (diferuloylmethane), a polyphenolic compound derived from the spice plant Curcuma longa, displays multiple actions on solid tumours including anti-angiogenic effects. Here we have studied in rodent and human pituitary tumour cells the influence of curcumin on the production of hypoxia inducible factor 1α (HIF1A) and vascular endothelial growth factor A (VEGFA), two key components involved in tumour neovascularisation through angiogenesis. Curcumin dose-dependently inhibited basal VEGFA secretion in corticotroph AtT20 mouse and lactosomatotroph GH3 rat pituitary tumour cells as well as in all human pituitary adenoma cell cultures (nZ32) studied. Under hypoxia-mimicking conditions (CoCl2 treatment) in AtT20 and GH3 cells as well as in all human pituitary adenoma cell cultures (nZ8) studied, curcumin strongly suppressed the induction of mRNA synthesis and protein production of HIF1A, the regulated subunit of the hypoxia-induced transcription factor HIF1. Curcumin also blocked hypoxiainducedmRNAsynthesis and secretion ofVEGFAinGH3 cells and in all human pituitary adenoma cell cultures investigated (nZ18). Thus, curcumin may inhibit pituitary adenoma progression not only through previously demonstrated antiproliferative and pro-apoptotic actions but also by its suppressive effects on pituitary tumour neovascularisation. © 2012 Society for Endocrinology. Source


Schnabel R.,Robert Bosch GmbH | Steinbuch D.,Robert Bosch GmbH | Weigel R.,University of Erlangen Nuremburg
European Microwave Week 2013, EuMW 2013 - Conference Proceedings; EuRAD 2013: 10th European Radar Conference | Year: 2013

More and more applications and a steadily increasing market penetration are showing the success of radar based driver assistance systems. While in recent years most of those systems were focussing on the advance of the drivers' comfort, today many safety applications are offered. As those systems can directly influence the vehicle dynamics, functional safety in terms of new normative requirements, such as the ISO 26262 is gaining more interest. Therefore, in this paper a built-in self-test is presented which is able to monitor multiple receiver paths by measuring the amplitude and phase imbalance among all channels. Four different types of coupling elements to feed a test signal into receiver paths are investigated and evaluated in terms of their precision. Furthermore, a method for a baseband evaluation is proposed. © 2013 EMA. Source

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