1,720,964 research outputs found
‐induced EAE through ERK and Akt signalling
No full textFibroblast growth factors (FGFs) and their receptors (FGFRs) are involved in demyelinating pathologies including multiple sclerosis (MS). In our recent study, oligodendrocyte‐specific deletion of FGFR1 resulted in a milder disease course, less inflammation, reduced myelin and axon damage in EAE. The objective of this study was to elucidate the role of oligodendroglial FGFR2 in MOG‐induced EAE. Oligodendrocyte‐specific knockout of FGFR2 (Fgfr2) was achieved by application of tamoxifen; EAE was induced using the MOG peptide. EAE symptoms were monitored over 62 days. Spinal cord tissue was analysed by histology, immunohistochemistry and western blot. Fgfr2 mice revealed a milder disease course, less myelin damage and enhanced axonal density. The number of oligodendrocytes was not affected in demyelinated areas. However, protein expression of FGFR2, FGF2 and FGF9 was downregulated in Fgfr2 mice. FGF/FGFR dependent signalling proteins were differentially regulated; pAkt was upregulated and pERK was downregulated in Fgfr2 mice. The number of CD3(+) T cells, Mac3(+) cells and B220(+) B cells was less in demyelinated lesions of Fgfr2 mice. Furthermore, expression of IL‐1β, TNF‐α and CD200 was less in Fgfr2 mice than controls. Fgfr2ind−/− mice showed an upregulation of PLP and downregulation of the remyelination inhibitors SEMA3A and TGF‐β expression. These data suggest that cell‐specific deletion of FGFR2 in oligodendrocytes has anti‐inflammatory and neuroprotective effects accompanied by changes in FGF/FGFR dependent signalling, inflammatory cytokines and expression of remyelination inhibitors. Thus, FGFRs in oligodendrocytes may represent potential targets for the treatment of inflammatory and demyelinating diseases including MS
Effects of FGFR tyrosine kinase inhibition in OLN-93 oligodendrocytes
Get PDFFibroblast growth factor (FGF) signaling is involved in the pathogenesis of multiple sclerosis (MS). Data from neuropathology studies suggest that FGF signaling contributes to the failure of remyelination in MS. In MOG-induced EAE, oligodendrocyte-specific deletion of FGFR1 and FGFR2 resulted in a less severe disease course, reduced inflammation, myelin and axon degeneration and changed FGF/FGFR and BDNF/TrkB signaling. Since signaling cascades in oligodendrocytes could not be investigated in the EAE studies, we here aimed to characterize FGFR-dependent oligodendrocyte-specific signaling in vitro. FGFR inhibition was achieved by application of the multi-kinase-inhibitor dovitinib and the FGFR1/2/3-inhibitor AZD4547. Both substances are potent inhibitors of FGF signaling; they are effective in experimental tumor models and patients with malignancies. Effects of FGFR inhibition in oligodendrocytes were studied by immunofluorescence microscopy, protein and gene analyses. Application of the tyrosine kinase inhibitors reduced FGFR1, phosphorylated ERK and Akt expression, and it enhanced BDNF and TrkB expression. Furthermore, the myelin proteins CNPase and PLP were upregulated by FGFR inhibition. In summary, inhibition of FGFR signaling in oligodendrocytes can be achieved by application of tyrosine kinase inhibitors. Decreased phosphorylation of ERK and Akt is associated with an upregulation of BDNF/TrkB signaling, which may be responsible for the increased production of myelin proteins. Furthermore, these data suggest that application of FGFR inhibitors may have the potential to promote remyelination in the CNS
Anti‐inflammatory and remyelinating effects of fexagratinib in experimental multiple sclerosis
No full textAbstract Background and Purpose FGF, VEGFR‐2 and CSF1R signalling pathways play a key role in the pathogenesis of multiple sclerosis (MS). Selective inhibition of FGFR by infigratinib in MOG 35‐55 ‐induced experimental autoimmune encephalomyelitis (EAE) prevented severe first clinical episodes by 40%; inflammation and neurodegeneration were reduced, and remyelination was enhanced. Multi‐kinase inhibition of FGFR1‐3, CSFR and VEGFR‐2 by fexagratinib (formerly known as AZD4547) may be more efficient in reducing inflammation, neurodegeneration and regeneration in the disease model. Experimental Approach Female C57BL/6J mice were treated with fexagratinib (6.25 or 12.5 mg·kg −1 ) orally or placebo over 10 days either from time of EAE induction (prevention experiment) or onset of symptoms (suppression experiment). Effects on inflammation, neurodegeneration and remyelination were assessed at the peak of the disease (Day 18/20 post immunization) and the chronic phase of EAE (Day 41/42). Key Results In the prevention experiment, treatment with 6.25 or 12.5 mg·kg −1 fexagratinib prevented severe first clinical episodes by 66.7% or 84.6% respectively. Mice treated with 12.5 mg·kg −1 fexagratinib hardly showed any symptoms in the chronic phase of EAE. In the suppression experiment, fexagratinib resulted in a long‐lasting reduction of severe symptoms by 91 or 100%. Inflammation and demyelination were reduced, and axonal density, numbers of oligodendrocytes and their precursor cells, and remyelinated axons were increased by both experimental approaches. Conclusion and Implications Multi‐kinase inhibition by fexagratinib in a well‐tolerated dose of 1 mg·kg −1 in humans may be a promising approach to reduce inflammation and neurodegeneration, to slow down disease progression and support remyelination in patients
Efficacy of Fibroblast Growth Factor Receptor (FGFR) inhibitor Infigratinib on Experimental Autoimmune Encephalomyelitis (EAE), a mouse model of Multiple sclerosis (MS)
Get PDFMultiple sclerosis (MS) is associated with oligodendrocytes damage resulting in demyelination, failure of remyelination and functional loss of neurons. Present therapeutic disease modifying drugs for MS are acting predominantly anti-inflammatory and there is a lack of substances with improving mechanisms of myelin repair. Recent findings in MS patients and its animal models suggested that fibroblast growth factors (FGF) and its receptor (FGFR) signalling plays a role in the pathology of MS and its models. Recent studies on the function of FGFR in MOG35-55-induced experimental autoimmune encephalitis (EAE) showed that deletion of FGFR1 and FGFR2 in oligodendrocytes leads to a less severe disease course, decreased lymphocyte and macrophage infiltration and increased remyelination. Here, we hypothesized that the oral application of a selective FGFR inhibitor infigratinib decreases disease severity and enhance neuronal protection in experimental autoimmune encephalomyelitis. Oral application of infigratinib resulted in a constant decline of disease severity in MOG35-55-induced EAE. The ameliorated disease course was associated with a reduction of cellular inflammation in the CNS, as well as neuroprotective and neuroregenerative effects. The number of mature oligodendrocytes within demyelinating lesions was increased, degeneration of myelin and axons was reduced following application of infigratinib. The limited expression of FGFRs in the spinal cord suggests that infigratinib crosses over the blood-brain barrier and acts in the CNS. Further, infigratinib induces the increased expression of BDNF/TrkB and myelin proteins MBP, PLP, CNPase in spinal cord. The results of this study suggest that short-term administration of infigratinib has the efficiency of ameliorating the severity of EAE by reducing immune cell infiltration and enhancing myelin protein expression
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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