111 research outputs found

    Stress, the cortisol awakening response and cognitive function

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    There is evidence that stress-induced disruption of the circadian rhythm of cortisol secretion, has negative consequences for brain health. The cortisol awakening response (CAR) is the most prominent and dynamic aspect of this rhythm. It has complex regulatory mechanisms making it distinct from the rest of the cortisol circadian rhythm, and is frequently investigated as a biomarker of stress and potential intermediary between stress and impaired brain function. Despite this, the precise function of the CAR within the healthy cortisol circadian rhythm remains poorly understood. Cortisol is a powerful hormone known to influence cognition in multiple and complex ways. Studies of the CAR and cognitive function have used varied methodological approaches which have produced similarly varied findings. The present review considers the accumulating evidence linking stress, attenuation of the CAR and reduced cognitive function, and seeks to contextualize the many findings to study populations, cognitive measures, and CAR methodologies employed. Associations between the CAR and both memory and executive functions are discussed in relation to its potential role as a neuroendocrine time of day signal that synchronizes peripheral clocks throughout the brain to enable optimum function, and recommendations for future research are provided

    Inactivation of Effector Caspases through Nondegradative Polyubiquitylation

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    Ubiquitin-mediated inactivation of caspases has long been postulated to contribute to the regulation of apoptosis. However, detailed mechanisms and functional consequences of caspase ubiquitylation have not been demonstrated. Here we show that the Drosophila Inhibitor of Apoptosis 1, DIAP1, blocks effector caspases by targeting them for polyubiquitylation and nonproteasomal inactivation. We demonstrate that the conjugation of ubiquitin to drICE suppresses its catalytic potential in cleaving caspase substrates. Our data suggest that ubiquitin conjugation sterically interferes with substrate entry and reduces the caspase’s proteolytic velocity. Disruption of drICE ubiquitylation, either by mutation of DIAP1’s E3 activity or drICE’s ubiquitin-acceptor lysines, abrogates DIAP1’s ability to neutralize drICE and suppress apoptosis in vivo. We also show that DIAP1 rests in an “inactive” conformation that requires caspase-mediated cleavage to subsequently ubiquitylate caspases. Taken together, our findings demonstrate that effector caspases regulate their own inhibition through a negative feedback mechanism involving DIAP1 “activation” and nondegradative polyubiquitylation

    Control of complexity in virtual organizations: the role of enterprise modelling

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    In general it can be staled that re-design and optimisation of a (virtuaI) enterprise is not facilitated but hindered by infonnation systems. Too much of lhe 'way of working' of the existing situalion is tixed in the existing systems to aJlow for easy changes. This problem is reinforeed by the requiremenls for differentiation between similar but not identical business processes that further emphasize the need for increased flexibility, and the problems as caused by the current generation if enterprise information systems. Adequale redcsign of both the business processes of a (virtual) organization and the associated infonnation systems requires enterprise modelling. In this paper we will, based on experiences gained in the area of product data modelling, develop a number of requirements for enterprise modelling methodologies. reference architectures, and languages. In this we will mainly focus on the areas of semantics, dynamics and complexity

    Transcriptome sequencing supports a conservation of macrophage polarization in fish

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    Mammalian macrophages can adopt polarization states that, depending on the exact stimuli present in their extracellular environment, can lead to very diferent functions. Although these diferent polarization states have been shown primarily for macrophages of humans and mice, it is likely that polarized macrophages with corresponding phenotypes exist across mammals. Evidence of functional conservation in macrophages from teleost fsh suggests that the same, or at least comparable polarization states should also be present in teleosts. However, corresponding transcriptional profles of marker genes have not been reported thus far. In this study we confrm that macrophages from common carp can polarize into M1- and M2 phenotypes with conserved functions and corresponding transcriptional profles compared to mammalian macrophages. Carp M1 macrophages show increased production of nitric oxide and a transcriptional profle with increased pro-infammatory cytokines and mediators, including il6, il12 and saa. Carp M2 macrophages show increased arginase activity and a transcriptional profle with increased anti-infammatory mediators, including cyr61, timp2b and tgm2b. Our RNA sequencing approach allowed us to list, in an unbiased manner, markers discriminating between M1 and M2 macrophages of teleost fsh. We discuss the importance of our fndings for the evaluation of immunostimulants for aquaculture and for the identifcation of gene targets to generate transgenic zebrafsh for detailed studies on M1 and M2 macrophages. Above all, we discuss the striking degree of evolutionary conservation of macrophage polarization in a lower vertebrate.Tis work was supported by the European Commission under the 8th (H2020) Framework Program for Research and Technological Development of the European Union (PARAFISHCONTROL Grant No. 634429) and by the 7th Framework program [NEMO Grant No. PITN-GA-2008–214505].Peer reviewe
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