111 research outputs found

    Wnt4 and LAP2alpha as pacemakers of Thymic Epithelial Senescence

    Get PDF
    Age-associated thymic involution has considerable physiological impact by inhibiting de novo T-cell selection. This impaired T-cell production leads to weakened immune responses. Yet the molecular mechanisms of thymic stromal adipose involution are not clear. Age-related alterations also occur in the murine thymus providing an excellent model system. In the present work structural and molecular changes of the murine thymic stroma were investigated during aging. We show that thymic epithelial senescence correlates with significant destruction of epithelial network followed by adipose involution. We also show in purified thymic epithelial cells the age-related down-regulation of Wnt4 (and subsequently FoxN1), and the prominent increase in LAP2α expression. These senescence-related changes of gene expression are strikingly similar to those observed during mesenchymal to pre-adipocyte differentiation of fibroblast cells suggesting similar molecular background in epithelial cells. For molecular level proof-of-principle stable LAP2α and Wnt4-over-expressing thymic epithelial cell lines were established. LAP2α over-expression provoked a surge of PPARγ expression, a transcription factor expressed in pre-adipocytes. In contrast, additional Wnt4 decreased the mRNA level of ADRP, a target gene of PPARγ. Murine embryonic thymic lobes have also been transfected with LAP2α- or Wnt4-encoding lentiviral vectors. As expected LAP2α over-expression increased, while additional Wnt4 secretion suppressed PPARγ expression. Based on these pioneer experiments we propose that decreased Wnt activity and increased LAP2α expression provide the molecular basis during thymic senescence. We suggest that these molecular changes trigger thymic epithelial senescence accompanied by adipose involution. This process may either occur directly where epithelium can trans-differentiate into pre-adipocytes; or indirectly where first epithelial to mesenchymal transition (EMT) occurs followed by subsequent pre-adipocyte differentiation. The latter version fits better with literature data and is supported by the observed histological and molecular level changes

    Role of CD248 as a potential severity marker in idiopathic pulmonary fibrosis

    Get PDF
    BACKGROUND: CD248 or Endosialin is a transmembrane molecule expressed in stromal cells binding to extracellular matrix (ECM) components. It has been previously implicated in kidney fibrosis, rheumatoid arthritis as well as in tumour-stromal interactions. This study investigates the role of CD248 in the pathogenesis of fibrotic diseases in Idiopathic Pulmonary Fibrosis (IPF). METHODS: CD248 quantitative immunohistochemistry (IHC) was performed on lung samples from 22 IPF patients and its expression was assayed in cultured pulmonary fibroblasts and epithelial cells. Effects of CD248 silencing was evaluated on fibroblast proliferation and myofibroblast differentiation. RESULTS: IHC revealed strong CD248 expression in mesenchymal cells of normal lung structures such as pleura and adventitia but not in epithelium. Fibrotic areas showed markedly stronger staining than unaffected lung tissue. The extent of CD248 staining showed a significant negative correlation to lung function parameters FEV1, FVC, TLC, and TLCO (r2 > 0 · 35, p < 0 · 01). CD248 protein levels were significantly greater in IPF-derived lung fibroblasts vs normal lung fibroblasts (p < 0 · 01) and CD248 silencing significantly reduced the proliferation of lung fibroblasts, but did not affected myofibroblast differentiation. CONCLUSION: We conclude that CD248 overexpression is possibly involved in the pathogenesis of IPF and it has potential as a disease severity marker. Given that CD248 ligands are collagen type I, IV and fibronectin, we hypothesise that CD248 signalling represents a novel matrix-fibroblast interaction that may be a potential therapeutic target in IPF. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12890-016-0211-7) contains supplementary material, which is available to authorized users

    The HIBEAM program: search for neutron oscillations at the ESS

    Full text link
    With the construction of the European Spallation Source, a remarkable opportunity has emerged to conduct high sensitivity searches for neutron oscillations, including a first search for thirty years for free neutrons converting to antineutrons. Furthermore, searches can be made for transitions of neutrons and antineutrons to sterile neutron states. The HIBEAM program provides an increase in sensitivity of an order of magnitude compared to previous work. The HIBEAM program corresponds to baryon number violation by one and two units. The observation of a process satisfying a Sakharov condition addresses the open question of the origin of the matter-antimatter asymmetry in the Universe. Sterile neutron states would belong to a `dark' sector of particles which may explain dark matter. As electrically neutral, meta-stable objects that can be copiously produced and studied, neutrons represent an attractive portal to a `dark' sector. This paper describes the capability, design, infrastructure, and potential of the HIBEAM program. This includes a dedicated beamline, neutron optical system, magnetic shielding and control, and detectors for neutrons and antineutrons.Comment: 41 pages, 12 figure

    A comparative study of biomolecule and polymer surface modifications by a surface microdischarge

    Full text link
    Cold atmospheric plasma (CAP) sources are attractive sources of reactive species with promising industrial and biomedical applications, but an understanding of underlying surface mechanisms is lacking. A kHz-powered surface microdischarge (SMD) operating with N2/O2 mixtures was used to study the biological deactivation of two immune-stimulating biomolecules: lipopolysaccharide (LPS) and peptidoglycan (PGN), found in bacteria such as Escherichia coli and Staphylococcus aureus, respectively. Model polymers were also studied to isolate specific functional groups. Changes in the surface chemistry were measured to understand which plasma-generated species and surface modifications are important for biological deactivation. The overall goal of this work is to determine which effects of CAP treatment are generic and which bonds are susceptible to attack. CAP treatment deactivated biomolecules, oxidized surfaces, and introduced surface bound NO3. These effects can be controlled by the N2 fraction in O2 and applied voltage and vary among different target surfaces. The SMD was compared with an Ar/O2/N2-fed kHz-powered atmospheric pressure plasma jet and showed much higher surface modifications and surface chemistry tunability compared to the jet. Possible mechanisms are discussed and findings are compared with recent computational investigations. Our results demonstrate the importance of long-lived plasma-generated species and advance an atomistic understanding of CAP-surface interactions

    Sociomateriality and information systems success and failure

    Get PDF
    The aim of this essay is to put forward a performative, sociomaterial perspective on Information Systems (IS) success and failure in organisations by focusing intently upon the discursive-material nature of IS development and use in practice. Through the application of Actor Network Theory (ANT) to the case of an IS that transacts insurance products we demonstrate the contribution of such a perspective to the understanding of how IS success and failure occur in practice. The manuscript puts our argument forward by first critiquing the existing perspectives on IS success and failure in the literature for their inadequate consideration of the materiality of IS, of its underling technologies and of the entanglement of the social and material aspects of IS development and use. From a sociomaterial perspective IS are not seen as objects that impact organisations one way or another, but instead as relational effects continually enacted in practice. As enactments in practice IS development and use produce realities of IS success and failure
    • …
    corecore