The transcription factor MITF is a critical regulator of GPNMB expression in dendritic cells

BACKGROUND: Dendritic cells (DC) are the most potent antigen-presenting cells (APC) with the unique ability to activate naïve T cells and to initiate and maintain primary immune responses. Immunosuppressive and anti-inflammatory stimuli on DC such as the cytokine IL-10 suppress the activity of the transcription factor NF-κB what results in downregulation of costimulatory molecules, MHC and cytokine production. Glycoprotein NMB (GPNMB) is a transmembrane protein, which acts as a coinhibitory molecule strongly inhibiting T cell responses if present on APC. Interestingly, its expression on human monocyte-derived dendritic cells (moDC) is dramatically upregulated upon treatment with IL-10 but also by the BCR-ABL tyrosine kinase inhibitors (TKI) imatinib, nilotinib or dasatinib used for the treatment of chronic myeloid leukemia (CML). However, the molecular mechanisms responsible for GPNMB overexpression are yet unknown. RESULTS: The immunosuppressive cytokine IL-10 and the BCR-ABL TKI imatinib or nilotinib, that were examined here, concordantly inhibit the PI3K/Akt signaling pathway, thereby activating the downstream serine/threonine protein kinase GSK3ß, and subsequently the microphthalmia-associated transcription factor (MITF) that is phosphorylated and translocated into the nucleus. Treatment of moDC with a small molecule inhibitor of MITF activity reduced the expression of GPNMB at the level of mRNA and protein, indicating that GPNMB expression is in fact facilitated by MITF activation. In line with these findings, PI3K/Akt inhibition was found to result in GPNMB overexpression accompanied by reduced stimulatory capacity of moDC in mixed lymphocyte reactions (MLR) with allogeneic T cells that could be restored by addition of the GPNMB T cell ligand syndecan-4 (SD-4). CONCLUSIONS: In summary, imatinib, nilotinib or IL-10 congruently inhibit the PI3K/Akt signaling pathway thereby activating MITF in moDC, resulting in a tolerogenic phenotype. These findings extend current knowledge on the molecular mechanisms balancing activating and inhibitory signals in human DC and may facilitate the targeted manipulation of T cell responses in the context of DC-based immunotherapeutic interventions. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12964-015-0099-5) contains supplementary material, which is available to authorized users

The moral muteness of managers: an Anglo-American phenomenon? German and British managers and their moral reasoning about environmental sustainability in business

Several studies in the Anglo-American context have indicated that managers present themselves as morally neutral employees who act only in the best interest of the company by employing objective skills. The reluctance of managers to use moral arguments in business is further accentuated in the now common argument presented as a neutral fact that the company must always prioritise shareholder value. These and other commercial aims are seen as an objective reality in business, whilst questions about sustainability, environmental problems or fair trade are seen as emotional or moral ones; a phenomenon described as ‘moral muteness’. This research explores whether this ‘moral muteness’ is an Anglo-American phenomenon and/or whether managers in other countries - in this case Germany - might express themselves in a different way. The focus is on moral arguments around environmental sustainability and the implications of this study for cross-cultural management. This article is based on a qualitative, comparative cross-cultural study of British and German managers in the Food Retail and Energy Sectors. In line with the studies mentioned above, British managers placed a strong emphasis on their moral neutrality. In contrast, German managers tended to use moral arguments when discussing corporate greening, often giving such arguments more weight than financial arguments. Overall, the study suggests that the ‘moral muteness’ of managers is a British phenomenon and quite distinct from the German approach. The article ends in a short exploration of how this understanding can help managers better manage people, organisations and change across cultures

Geometric characterization of nodal domains: the area-to-perimeter ratio

In an attempt to characterize the distribution of forms and shapes of nodal domains in wave functions, we define a geometric parameter - the ratio $\rho$ between the area of a domain and its perimeter, measured in units of the wavelength $1/\sqrt{E}$. We show that the distribution function $P(\rho)$ can distinguish between domains in which the classical dynamics is regular or chaotic. For separable surfaces, we compute the limiting distribution, and show that it is supported by an interval, which is independent of the properties of the surface. In systems which are chaotic, or in random-waves, the area-to-perimeter distribution has substantially different features which we study numerically. We compare the features of the distribution for chaotic wave functions with the predictions of the percolation model to find agreement, but only for nodal domains which are big with respect to the wavelength scale. This work is also closely related to, and provides a new point of view on isoperimetric inequalities.Comment: 22 pages, 11 figure

Theory for phonon-induced superconductivity in MgB2_2

We analyze superonductivity in MgB$_2$ observed below $T_c=39$ K resulting from electron-phonon coupling involving a mode at $\hbar \omega_1 = 24$ meV and most importantly the in-plane B-B $E_{2g}$ vibration at $\hbar \omega_2=67$ meV. The quasiparticles originating from $\pi$- and $\sigma$-states couple strongly to the low-frequency mode and the $E_{2g}$-vibrations respectively. Using two-band Eliashberg theory, $\lambda_{\pi} = 1.4$ and $\lambda_{\sigma} = 0.7$, we calculate the gap functions $\Delta^{i}(\omega,0)$ ($i=\pi$, $\sigma$). Our results provide an explanation of recent tunneling experiments. We get $H^{ab}_{c_2}/H^{c}_{c_2} \approx 3.9$.Comment: revised version, accepted for publication in PR

Polygenic risk scores for Alzheimer's disease are related to dementia risk in APOE ɛ4 negatives

Introduction: Studies examining the effect of polygenic risk scores (PRS) for Alzheimer's disease (AD) and apolipoprotein E (APOE) genotype on incident dementia in very old individuals are lacking. / Methods: A population‐based sample of 2052 individuals ages 70 to 111, from Sweden, was followed in relation to dementia. AD‐PRSs including 39, 57, 1333, and 13,942 single nucleotide polymorphisms (SNPs) were used. / Results: AD‐PRSs (including 39 or 57 SNPs) were associated with dementia (57‐SNPs AD‐PRS: hazard ratio 1.09, confidence interval 1.01–1.19, P = .03), particularly in APOE ɛ4 non‐carriers (57‐SNPs AD‐PRS: 1.15, 1.05–1.27, P = 4 × 10–3, 39‐SNPs AD‐PRS: 1.22, 1.10–1.35, P = 2 × 10–4). No association was found with the other AD‐PRSs. Further, APOE ɛ4 was associated with increased risk of dementia (1.60, 1.35–1.92, P = 1 × 10–7). In those aged ≥95 years, the results were similar for the AD‐PRSs, while APOE ɛ4 only predicted dementia in the low‐risk tertile of AD‐PRSs. / Discussion: These results provide information to identify individuals at increased risk of dementia

Reculturing schools in England: how ‘cult’ values in education policy discourse influence the construction of practitioner identities and work orientations

The imperative of continuous improvement has now become normative in education policy discourse, typically framed as setting ‘aspirational’ targets for pupil performance as a prerequisite for gaining competitive advantage in the global economy. In this context, teachers, leaders, teacher assistants and other practitioners working in schools across England have been under increasing pressure to raise standards. This article focuses on how values are deployed in reculturing and regulating practitioners to develop identities and work orientations which are congruent with the policymakers’ agendas. G.H. Mead’s concept of ‘cult’ values illuminates the process of fostering homogeneity with the dominant policy discourse through an inclusion/exclusion dynamic. Interview data collected in two primary schools revealed a significant convergence of practitioner discourse with policy objectives. Delivering improvement affects how practitioners talk about their work and see themselves as educators. The ‘cult’ of continuous improvement appears to inhibit a critical approach to the implementation of education policies by school practitioners in their everyday work

Decentring emotion regulation: from emotion regulation to relational emotion

YesThis article takes a critical approach to emotion regulation suggesting that the concept needs supplementing with a relational position on the generation and restraint of emotion. I chart the relational approach to emotion, challenging the ‘two-step’ model of emotion regulation. From this, a more interdisciplinary approach to emotion is developed using concepts from social science to show the limits of instrumental, individualistic and cognitivist orientations in the psychology of emotion regulation, centred on appraisal theory. Using a social interactionist approach I develop an ontological position in which social relations form the fundamental contexts in which emotions are generated, toned, and restrained, so that regulation is decentred and seen as just one moment or aspect in the relational patterning of emotion

Ideologies of time: How elite corporate actors engage the future

Our paper deals with how elite corporate actors in a Western capitalist-democratic society conceive of and prepare for the future. Paying attention to how senior officers of ten important Danish companies make sense of the future will help us to identify how particular temporal narratives are ideologically marked. This ideological dimension offers a common sense frame that is structured around a perceived inevitability of capitalism, a market economy as the basic organizational structure of the social and economic order, and an assumption of confident access to the future. Managers envisage their organization?s future and make plans for organizational action in a space where ?business as usual? reigns, and there is little engagement with the future as fundamentally open; as a time-yet-to-come. In using a conceptual lens inspired by the work of Fredric Jameson, we first explore the details of this presentism and a particular colonization of the future, and then linger over small disruptions in the narratives of our interviewees which point to what escapes or jars their common sense frame, explore the implicit meanings they assign to their agency, and also find clues and traces of temporal actions and strategies in their narratives that point to a subtly different engagement with time