Visualization and functional characterization of CD4+ T cell stimulation in the ileal lamina propria

Multiple sclerosis (MS) is characterized is by immune cell infiltration into the central nervous system (CNS) causing inflammation and subsequent demyelination associated with neuronal degeneration. According to the leading paradigm of the etiology of MS, pre-existing autoreactive T cells are primed in the periphery before invading the CNS. Combined with the increasingly important role of microbiota as potential triggers of autoimmune diseases, the gut possibly constitutes the site of action. The main aim of this study was to investigate whether encephalitogenic T cells get stimulated in gut-associated lymphoid tissues prior to experimental autoimmune encephalomyelitis (EAE), a rodent model for MS. Given that intracellular calcium signaling is a prerequisite for effective activation of T cells, cytosolic calcium levels constitute a useful indicator of stimulation. By combining the Förster resonance energy transfer (FRET)-based calcium sensor Twitch-2B with intravital two-photon microscopy, this study demonstrates that T cells specific for the CNS antigen myelin oligodendrocyte glycoprotein (MOG) as well as T cells specific for the control antigen ovalbumin (OVA) but not polyclonal T cells get stimulated in the ileal lamina propria. To investigate whether the ileal stimulation lead to activation-induced gene expression, transcriptome analysis of CD4+ T cells from the efferent mesenteric lymph, i.e. downstream of the stimulation in the small intestine, was performed. The RNA sequencing of MOG-specific CD4+ T cells from mice housed under specific pathogen-free (SPF) conditions indicated that stimulation in the small intestine induces Th17 cells with a pathogenic phenotype. In contrast, neither in germ-free mice, i.e. in the absence of microbiota, nor in polyclonal T cells, i.e. in the absence of extended calcium signaling in the ileal lamina propria, the upregulation of Th17 markers was observed. Furthermore, the transfer of gut-stimulated antigen-specific T cells to immunized recipient mice and subsequent analysis of the T cells’ migration capacities demonstrated that the ileal stimulation does not only alter gene expression but also influences T cell behavior. CD4+ T cells that had previously been stimulated by microbiota migrated more efficiently to lymphoid organs than T cells devoid of this stimulation. The second part of this study focused on another crucial event in the pathogenesis of MS/EAE, i.e. the infiltration of encephalitogenic T cells into the CNS. The requirement of specific adhesion molecules for T cell extravasation was examined by intravital two-photon imaging of encephalitogenic T cells at the blood-brain barrier in a transfer EAE model in the Lewis rat. This enabled visualization of the mode of action of antibodies blocking the entry of encephalitogenic T cells into the CNS. Furthermore, this study confirmed that the blocking antibody against integrin α4, which is already in use as treatment for MS, has the most pronounced therapeutic effect. The findings of the present study add to the mechanistic understanding of two critical steps in the pathogenesis of EAE, i.e., the peripheral stimulation by microbiota and the subsequent infiltration of encephalitogenic T cells into the CNS. Especially the priming process of autoreactive T cells in the periphery preceding CNS inflammation remains one of the least deciphered processes in the pathogenesis of CNS autoimmunity affecting millions of people worldwide

A solution NMR approach to determine the chemical structures of carbohydrates using the hydroxyl groups as starting points

An efficient NMR approach is described for determining the chemical structures of the monosaccharide glucose and four disaccharides, namely, nigerose, gentiobiose, leucrose and isomaltulose. This approach uses the 1H resonances of the −OH groups, which are observable in the NMR spectrum of a supercooled aqueous solution, as the starting point for further analysis. The 2D-NMR technique, HSQC-TOCSY, is then applied to fully define the covalent structure (i.e., the topological relationship between C–C, C–H, and O–H bonds) that must be established for a novel carbohydrate before proceeding to further conformational studies. This process also leads to complete assignment of all 1H and 13C resonances. The approach is exemplified by analyzing the monosaccharide glucose, which is treated as if it were an “unknown”, and also by fully assigning all the NMR resonances for the four disaccharides that contain glucose. It is proposed that this technique should be equally applicable to the determination of chemical structures for larger carbohydrates of unknown composition, including those that are only available in limited quantities from biological studies. The advantages of commencing the structure elucidation of a carbohydrate at the −OH groups are discussed with reference to the now well-established 2D-/3D-NMR strategy for investigation of peptides/proteins, which employs the −NH resonances as the starting point

Regional problems – regional solutions? Taking stock of the recent mediation efforts in the Middle East

"For decades the Middle East has been one of the most unstable and unsafe regions in the world. Trying to resolve the regional conflicts is a prime goal on the agenda of many governments and international institutions. Nevertheless, most of the peace initiatives proposed by outside actors so far have failed, as their proposed solutions to the conflicts often did not really take into account the political realities in the region, but instead were more oriented towards the interests of the external actors. This instance is particularly apparent in the case of the current US administration. After having already failed at attempting to reorganize the political landscape of the Middle East through power politics, the administration of President George W. Bush turned to diplomacy in order to achieve its goals in the region. However, when that change of attitude gradually evolved the credibility of his administration was already weakened to such an extent that none of the regional players appeared to accept them as a serious partner in the handling and, ultimately, resolving of the various conflicts. What is more, its rhetoric notwithstanding, the US also failed to offer a promising solution to the conflicts. At the same time, neither the so-called Middle-East Quartet (consisting of the US, the European Union, Russia, and the United Nations), nor the Europeans themselves have been able to step in and fill the growing diplomatic vacuum. Instead regional actors have taken on the task of settling the regional disputes. Saudi Arabia, Turkey, and Qatar, to only name a few. Their approach: refraining from proposing ready-made solutions, and instead focusing on the negotiation process, including the stake-holders and taking into account their specific interests, dealing with a single issue at a time, and not putting pressure on anyone by officially proclaiming a great breakthrough before anything has been officially agreed upon. What are the prospects of these regional initiatives? Has US engagement in the region become obsolete? And what implications does this have for the European Union? What should its role be? These questions shall be addressed in this paper." (author's abstract

Technomoral Resilience as a Goal of Moral Education

In today’s highly dynamic societies, moral norms and values are subject to change. Moral change is partly driven by technological developments. For instance, the introduction of robots in elderly care practices requires caregivers to share moral responsibility with a robot (see van Wynsberghe 2013). Since we do not know what elements of morality will change and how they will change (see van der Burg 2003), moral education should aim at fostering what has been called “moral resilience” (Swierstra 2013). We seek to fill two gaps in the existing literature: (i) research on moral education has not paid enough attention to the development of moral resilience; (ii) the very limited literature on moral resilience does not conceptualise moral resilience in relation to new technological developments. We argue that philosophical accounts of moral education need to do justice to the importance of moral resilience, and that a specific form of moral resilience should be conceptualised as “technomoral resilience” to underline the added value of cultivating moral resilience in relation to technomoral change. We illustrate the role of technomoral resilience in practice by looking at the context of elderly care. To make the first step towards an account of how technomoral resilience can be fostered in moral education, we propose that moral education shall focus on a triangle of capacities: (1) moral imagination, (2) a capacity for critical reflection, and (3) a capacity for maintaining one’s moral agency in the face of disturbances

Assister au spectacle

No abstract available

Comparison of parameter optimization techniques for a music tone onset detection algorithm

Design of experiments is an established approach to parameter optimization for industrial processes. In many computer applications, however, it is usual to optimize the parameters via genetic algorithms or, recently, via sequential parameter optimization techniques. The main idea of this work is to analyse and compare parameter optimization approaches which are usually applied in industry with those applied for computer optimization tasks using the example of a tone onset detection algorithm. The optimal algorithm parameter setting is sought in order to get the best onset detection accuracy. We vary in our work essential options of the parameter optimization strategies like size and constitution of the initial designs in order to assess their in uence on the evaluation results. Furthermore we test how the instrumentation and the tempo of music pieces affect the optimal parameter setting of the onset detection algorithm

Einfluss der Musikinstrumente auf die Güte der Einsatzzeiterkennung

Erkennung der Toneinsätze in Musikaufnahmen ist der erste und sehr wichtige Schritt bei der Musiktranskription. Es existieren bereits sehr viele Algorithmen, die diesem Ziel dienen. Bei den meisten davon werden die Algorithmusparameter mittels genetischer Verfahren so optimiert, dass diese Algorithmen für alle Musikinstrumente durchschnittlich die besten Erkennungsraten liefert. Dabei sind die Klangeigenschaften von Instrumenten verschiedener Instrumentenarten sehr unterschiedlich, so dass es sinnvoll ist, optimale Parametereinstellungen in Abhängigkeit von Instrumentenklassen zu bestimmen. Bei Musikstücken, die von mehreren Instrumenten gespielt werden, ist dieses Problem allerdings komplizierter. Ziel dieses Berichtes ist, einen einfachen Algorithmus zur Einsatzzeiterkennung auf Tonabfolgen verschiedener Musikinstrumente zu testen, um zunächst grobe Zusammenhänge zwischen Einstellungen von Algorithmusparametern und Instrumentenart zu bestimmen. Wegen großer Unterschiede zwischen echten und synthetischen Musiktönen bezüglich ihrer Klangeigenschaften wird großer Wert auf die Erzeugung von Tonabfolgen mittels echter Tonaufnahmen gelegt. Dazu wird in dieser Arbeit ein Verfahren vorgestellt

Measuring the diversity of each party's candidates in the German election

Opinion polls suggest six parties will enter the Bundestag in Germany's election on Sunday, two more than crossed the electoral threshold in the last elections in 2013. But what does this apparent fragmentation of the German party system mean for the diversity of candidates, particularly in terms of the fair representation of women and minority groups? Paul C. Bauer and Julia Schulte-Cloos present a detailed analysis of the numbers of women and foreign-born candidates on each party’s candidate list. They find that parties on the left/libertarian end of the scale are more inclusive of women, but that the left-wing Die Linke and right-wing AfD have the highest percentage of foreign-born candidates