1,720,978 research outputs found
Gut–Brain Interactions and Their Impact on Astrocytes in the Context of Multiple Sclerosis and Beyond
Full text linkMultiple Sclerosis (MS) is a chronic autoimmune inflammatory disease of the central nervous system (CNS) that leads to physical and cognitive impairment in young adults. The increasing prevalence of MS underscores the critical need for innovative therapeutic approaches. Recent advances in neuroimmunology have highlighted the significant role of the gut microbiome in MS pathology, unveiling distinct alterations in patients’ gut microbiota. Dysbiosis not only impacts gut-intrinsic processes but also influences the production of bacterial metabolites and hormones, which can regulate processes in remote tissues, such as the CNS. Central to this paradigm is the gut–brain axis, a bidirectional communication network linking the gastrointestinal tract to the brain and spinal cord. Via specific routes, bacterial metabolites and hormones can influence CNS-resident cells and processes both directly and indirectly. Exploiting this axis, novel therapeutic interventions, including pro- and prebiotic treatments, have emerged as promising avenues with the aim of mitigating the severity of MS. This review delves into the complex interplay between the gut microbiome and the brain in the context of MS, summarizing current knowledge on the key signals of cross-organ crosstalk, routes of communication, and potential therapeutic relevance of the gut microbiome. Moreover, this review places particular emphasis on elucidating the influence of these interactions on astrocyte functions within the CNS, offering insights into their role in MS pathophysiology and potential therapeutic interventions.European research CouncilGerman Research Foundatio
Astrocyte-Derived Pleiotrophin Mitigates Late-Stage Autoimmune CNS Inflammation
Full text linkAstrocytes are the most abundant glial cells in the central nervous system (CNS) with the capacity to sense and react to injury and inflammatory events. While it has been widely documented that astrocytes can exert tissue-degenerative functions, less is known about their protective and disease-limiting roles. Here, we report the upregulation of pleiotrophin (PTN) by mouse and human astrocytes in multiple sclerosis (MS) and its preclinical model experimental autoimmune encephalomyelitis (EAE). Using CRISPR-Cas9-based genetic perturbation systems, we demonstrate in vivo that astrocyte-derived PTN is critical for the recovery phase of EAE and limits chronic CNS inflammation. PTN reduces pro-inflammatory signaling in astrocytes and microglia and promotes neuronal survival following inflammatory challenge. Finally, we show that intranasal administration of PTN during the late phase of EAE successfully reduces disease severity, making it a potential therapeutic candidate for the treatment of progressive MS, for which existing therapies are limited
Harnessing the protective potential of reactive astrocytes in the context of neuroinflammation
Full text linkMultiple sclerosis (MS) is a debilitating autoimmune disease of the central nervous system (CNS), characterized by chronic inflammation and neurodegeneration. Despite numerous available therapies that effectively target the inflammatory aspects of MS, there is a significant need to address the degenerative processes associated with progressive stages of the disease. These degenerative mechanisms are in part driven by the early loss of tissue-protective signals, thereby causing increased vulnerability to inflammatory processes that initiate chronic deterioration. However, the triggers of this failure are poorly defined. In this context, particularly astrocytes have emerged as key targets, given their capacity to not only drive but also suppress neuroinflammatory and degenerative processes.
The central premise of this thesis was to identify defunct tissue protective pathways that drive disease progression in MS, investigate the mechanisms that lead to their loss, and ultimately use this knowledge to therapeutically reinstate their functions.
In light of these aims, this thesis defines two astrocyte-derived factors that are important for the recovery from autoimmune CNS inflammation. Both factors are upregulated during early stages of MS but lost during progressive disease. CRISPR/Cas9-genetic perturbations, in silico analyses, as well as in vitro and in vivo models of neuroinflammation shed light on the mechanisms that lead to their loss during late-stage CNS inflammation and reveal that these protective astrocyte functions are governed by similar environmental cues. Finally, this thesis explores novel therapeutic strategies that leverage the anti-inflammatory and tissue-supportive functions of both astrocyte-derived factors in order to attenuate disease severity and promote recovery in acute and progressive disease stages of autoimmune neuroinflammation. Altogether, the findings presented in this thesis pave the way for the development of novel astrocyte-centered therapies for acute and progressive stages of MS, which may furthermore be of relevance for inflammatory, degenerative and neoplastic disorders of the CNSMultiple Sklerose (MS) ist eine häufig auftretende Autoimmunerkrankung des zentralen Nervensystems, die sich durch wiederkehrende Schübe mit neurologischen Defiziten auszeichnet. Eine besondere Herausforderung stellen die progressiven Stadien der Erkrankung dar, da diese nur schwer durch aktuell verfügbare Ansätze therapierbar sind. Diese progressiven Stadien zeichnen sich durch vermehrt degenerative Prozesse aus, welche teilweise durch den frühen Verlust von gewebeschützenden Signalen induziert werden. Die entsprechenden Auslöser, die zum Verlust der gewebsprotektiven Signale führen, sind jedoch kaum untersucht. In diesem Zusammenhang spielen besonders Astrozyten eine wichtige Rolle, da sie nicht nur entzündliche und neurodegenerative Prozesse antreiben, sondern auch unterdrücken können. Das Ziel dieser Doktorarbeit war, den Verlust gewebsprotektiver Signale im Verlauf der MS genauer zu charakterisieren und therapeutische Strategien zu entwickeln, um diese Funktionen wiederherzustellen.
Im Rahmen dieser Arbeit wurden zwei gewebsprotektive Faktoren identifiziert, die von aktivierten Astrozyten in frühen Stadien der MS produziert werden, jedoch im Laufe der Erkankung ihre Funktion verlieren. Mithilfe von Astrozyten-spezifischen Knockout Modellen, sowie umfangreicher Charakterisierung in vitro und in vivo konnte gezeigt werden, dass der Verlust gewebsprotektiver Funktionen in progressiven Stadien der MS teilweise durch epigenetische Mechanismen vermittelt wird. Abschließend konnte das therapeutische Potential der beiden Faktoren in präklinischen Tiermodellen der MS gezeigt werden.
Zusammenfassend unterstreichen die Ergebnisse die elementare Rolle von Astrozyten im Verlauf der MS und ebnen den Weg für die Entwicklung neuer Therapien für akute und progressive Stadien der MS
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe 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
The Aryl Hydrocarbon Receptor-Dependent TGF-α/VEGF-B Ratio Correlates With Disease Subtype and Prognosis in Multiple Sclerosis
Full text linkObjective To evaluate the aryl hydrocarbon receptor (AHR)-dependent transforming growth factor alpha (TGF-alpha)/vascular endothelial growth factor B (VEGF-B) ratio, which regulates the effects of metabolic, dietary, and microbial factors on acute and chronic CNS inflammation, as a potential marker in multiple sclerosis (MS). Methods TGF-alpha, VEGF-B, and AHR agonistic activity were determined in serum of 252 patients with relapsing-remitting (RR) MS, primary and secondary progressive MS, as well as during active disease (clinically isolated syndrome [CIS] and RRMS relapse). Results The TGF-alpha/VEGF-B ratio and AHR agonistic activity were decreased in all MS subgroups with a stable disease course as compared to controls. During active CNS inflammation in CIS and RRMS relapse, the TGF-alpha/VEGF-B ratio and AHR agonistic activity were increased. Conversely, in patients with minimal clinical impairment despite long-standing disease, the TGF-alpha/VEGF-B ratio and AHR agonistic activity were unaltered. Finally, the TGF-alpha/VEGF-B ratio and AHR agonistic activity correlated with neurologic impairment and time to conversion from CIS to MS. Conclusions The AHR-dependent TGF-alpha/VEGF-B ratio is altered in a subtype, severity, and disease activity-specific manner and correlates with time to conversion from CIS to MS. It may thus represent a novel marker and serve as additive guideline for immunomodulatory strategies in MS. Classification of Evidence This study provides Class III evidence that serum levels of AHR, TGF-alpha, and VEGF-B distinguish subtypes of MS and predict the severity and disease activity of MS
Variations on the Author
Full text link“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
Full text linkWe 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
Full text linkWe 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
- …
