34 research outputs found

    On the Place of Origin of the Old Greek of Psalms

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    Sphingosine 1-phosphate receptor 5 mediates the immune quiescence of the human brain endothelial barrier

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    BACKGROUND: The sphingosine 1-phosphate (S1P) receptor modulator FTY720P (Gilenya®) potently reduces relapse rate and lesion activity in the neuroinflammatory disorder multiple sclerosis. Although most of its efficacy has been shown to be related to immunosuppression through the induction of lymphopenia, it has been suggested that a number of its beneficial effects are related to altered endothelial and blood–brain barrier (BBB) functionality. However, to date it remains unknown whether brain endothelial S1P receptors are involved in the maintenance of the function of the BBB thereby mediating immune quiescence of the brain. Here we demonstrate that the brain endothelial receptor S1P(5) largely contributes to the maintenance of brain endothelial barrier function. METHODS: We analyzed the expression of S1P(5) in human post-mortem tissues using immunohistochemistry. The function of S1P(5) at the BBB was assessed in cultured human brain endothelial cells (ECs) using agonists and lentivirus-mediated knockdown of S1P(5). Subsequent analyses of different aspects of the brain EC barrier included the formation of a tight barrier, the expression of BBB proteins and markers of inflammation and monocyte transmigration. RESULTS: We show that activation of S1P(5) on cultured human brain ECs by a selective agonist elicits enhanced barrier integrity and reduced transendothelial migration of monocytes in vitro. These results were corroborated by genetically silencing S1P(5) in brain ECs. Interestingly, functional studies with these cells revealed that S1P(5) strongly contributes to brain EC barrier function and underlies the expression of specific BBB endothelial characteristics such as tight junctions and permeability. In addition, S1P(5) maintains the immunoquiescent state of brain ECs with low expression levels of leukocyte adhesion molecules and inflammatory chemokines and cytokines through lowering the activation of the transcription factor NFκB. CONCLUSION: Our findings demonstrate that S1P(5) in brain ECs contributes to optimal barrier formation and maintenance of immune quiescence of the barrier endothelium

    P-Glycoprotein Acts as an Immunomodulator during Neuroinflammation

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    Background: Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system in which autoreactive myelin-specific T cells cause extensive tissue damage, resulting in neurological deficits. In the disease process, T cells are primed in the periphery by antigen presenting dendritic cells (DCs). DCs are considered to be crucial regulators of specific immune responses and molecules or proteins that regulate DC function are therefore under extensive investigation. We here investigated the potential immunomodulatory capacity of the ATP binding cassette transporter P-glycoprotein (Pgp). P-gp generally drives cellular efflux of a variety of compounds and is thought to be involved in excretion of inflammatory agents from immune cells, like DCs. So far, the immunomodulatory role of these ABC transporters is unknown. Methods and Findings: Here we demonstrate that P-gp acts as a key modulator of adaptive immunity during an in vivo model for neuroinflammation. The function of the DC is severely impaired in P-gp knockout mice (Mdr1a/1b-/-), since both DC maturation and T cell stimulatory capacity is significantly decreased. Consequently, Mdr1a/1b-/- mice develop decreased clinical signs of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. Reduced clinical signs coincided with impaired T cell responses and T cell-specific brain inflammation. We here describe the underlying molecular mechanism and demonstrate that P-gp is crucial for the secretion of pro-inflammatory cytokines such as TNF-alpha and IFN-gamma. Importantly, the defect in DC function can be restored by exogenous addition of these cytokines. Conclusions: Our data demonstrate that P-gp downmodulates DC function through the regulation of pro-inflammatory cytokine secretion, resulting in an impaired immune response. Taken together, our work highlights a new physiological role for P-gp as an immunomodulatory molecule and reveals a possible new target for immunotherap

    MicroRNAs regulate human brain endothelial cell-barrier function in inflammation: implications for multiple sclerosis.

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    Blood-brain barrier (BBB) dysfunction is a major hallmark of many neurological diseases, including multiple sclerosis (MS). Using a genomics approach, we defined a microRNA signature that is diminished at the BBB of MS patients. In particular, miR-125a-5p is a key regulator of brain endothelial tightness and immune cell efflux. Our findings suggest that repair of a disturbed BBB through microRNAs may represent a novel avenue for effective treatment of MS

    On the Place of Origin of the Old Greek of Psalms

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    Die alten Textzeugen des Jesajabuches: Ein Beitrag zur Textgeschichte des Alten Testaments

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    Wetensch. publicati

    Bible exegesis in Dutch ecclesial documents on homosexuality

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    CITATION: Van der Kooij, A. 2001. Bible exegesis in Dutch ecclesial documents on homosexuality. Scriptura, 77:251-257, doi:10.7833/77-0-1274.The original publication is available at https://scriptura.journals.ac.zaThe use of the Bible in documents about homosexuality, produced by two Reformed churches in the Netherlands in the early 1980's (the "Nederlandse Hervormde Kerk" and the "Gereformeerde Kerken in Nederland"), serves as a case study within the project entitled "The influence of different contexts of social transformation on biblical interpretation". In the first article on this topic (cf. Van der Kooij 2000) the focus was on the background (developments in the study of the Bible since the 18th century in Western Europe) and the setting (social and cultural dynamics in the last forty years in the Netherlands and abroad) of the biblical interpretation as presented in these documents. At the end of the first article, the two church documents were briefly described and characterized. This second article will concentrate on the biblical interpretation itself in the documents concerned. Particular attention will be paid to the exegesis of texts in the book of Leviticus. Furthermore, hermeneutical questions as raised in the documents will be discussed. Finally, the topic of the research project, the relationship between social transformation and biblical interpretation will be addressed.https://scriptura.journals.ac.za/pub/article/view/1274Publisher's versio

    Conférence de M. Arie van der Kooij

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    van der Kooij Arie. Conférence de M. Arie van der Kooij. In: École pratique des hautes études, Section des sciences religieuses. Annuaire. Tome 106, 1997-1998. 1997. pp. 247-254

    Conférences de M. Arie van der Kooij

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    Kooij Arie van der. Conférences de M. Arie van der Kooij. In: École pratique des hautes études, Section des sciences religieuses. Annuaire. Tome 114, 2005-2006. 2005. pp. 269-271

    Conférences de M. Arie van der Kooij

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    Kooij Arie van der. Conférences de M. Arie van der Kooij. In: École pratique des hautes études, Section des sciences religieuses. Annuaire. Tome 114, 2005-2006. 2005. pp. 269-271
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