1,721,703 research outputs found
The Immune Memory Response and Metabolic Requirements of Human Gamma Delta T Cells
Full text linkγδ T cells are unconventional T cells that can mediate pro-inflammatory, cytotoxic, phagocytotic and professional antigen presenting properties. Sharing the features of both adaptive and innate immunity, γδ T cells also showed signs of induction of both adaptive immune memory and innate immune memory responses. These multi-functional cells therefore play indispensable roles in acquired immunity, host defense against infection and immune surveillance against cancer. In the first part of this thesis, I reviewed the concept and recent advances of innate immune memory and showed the discovery of the trained immunity phenotype in γδ T cells by BCG and MMR vaccination, demonstrating for the first time that γδ T cells can mount both adaptive and innate memory. In the second part of the thesis, I focused on investigating the effect of manipulating mevalonate metabolism on the immune function of γδ T cells as well as the metabolic and immune functional changes of γδ T cells in autoinflammatory and immunodeficient disorders. The result of these studies encouraged us to take into account the adverse effects of mevalonate pathway inhibitors on gd T cells and provided possible reasons for the limited effectiveness and efficiency of the current γδ T cellbased therapy. Altogether, my thesis offered additional knowledge to facilitate the development of next-generation vaccines and a better γδ T cell-based therapy for cancer and infectious diseases in the future
Pharmacologic intervention in macrophage metabolism: Mitochondrial pyruvate carrier inhibition by Mitoglitazone modulates inflammation
Full text linkUpon Toll-like receptor (TLR) activation, macrophages rapidly change their transcriptional- and translational network and rewire their metabolism. Mitochondrial pyruvate import via the mitochondrial pyruvate carrier (MPC) is essential to the metabolic changes controlling inflammatory responses. Thus, the MPC is a promising target to pharmacologically intervene in inflammatory diseases. Mitoglitazone is an MPC inhibitor currently under clinical investigation for insulin sensitization and amelioration of neurodegeneration. Yet, its effects on macrophage metabolism and inflammation remain undescribed.
Here, it is reported that Mitoglitazone inhibits the MPC in macrophages and decreases their inflammatory response following TLR4- or TLR7/8 activation. Metabolic analyses showed rerouting of glucose metabolism and, concomitantly, inhibition of the glycolytic switch and maximal respiration of inflammatory macrophages. Accordingly, Mitoglitazone decreased inflammatory cytokine transcription and release as well as nitric oxide production. Sustained effects of Mitoglitazone under pharmacologic inhibition or in the absence of the nuclear receptor PPARγ emphasize its mode of action via MPC inhibition. In an acute sepsis mouse model Mitoglitazone decreased LPS-induced cytokines, demonstrating its immunomodulatory effect also in vivo.
These findings give new insights into the integrative network of macrophage metabolism and their inflammatory response, and highlight the potential of MPC inhibition by Mitoglitazone as a strategy to ameliorate erroneous inflammation
Chromatin Architecture Shapes the Immune System : Chromatinopathies Perspective
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Lesion size is associated with genetic polymorphisms in TLR1, TLR6, and TIRAP genes in patients with major abscesses and diabetic foot infections
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218691.pdf (Publisher’s version ) (Open Access)Genetic variation in Toll-like receptors (TLRs) has previously been associated with susceptibility to complicated skin and skin structure infections (cSSSIs). The aim of this study was to investigate associations between the severity of cSSSIs, i.e., major abscesses and diabetic foot infections (DFIs), and a set of genetic polymorphisms in the Toll-like receptor pathway. A total of 121 patients with major abscesses and 132 with DFIs participating in a randomized clinical trial were genotyped for 13 nonsynonymous single-nucleotide polymorphisms (SNPs) in genes coding for TLRs and the signaling adaptor molecule TIRAP. Infection severity was defined by lesion size at clinical presentation for both types of infections. The PEDIS infection score was also used to define severity of DFIs. Linear regression models were used to study factors independently associated with severity. In patients with large abscesses, hetero- or homozygosity for the allelic variant TLR6 (P249S) was associated with significantly smaller lesions while homozygosity for the allelic variant TLR1 (R80T) was associated with significantly larger lesions. PRRs genes were not significantly associated with PEDIS. However, patients with DFI hetero- or homozygous for the allelic variant TLR1 (S248N) had significantly larger lesions. Polymorphisms in TLR1 and TLR6 influence the severity of cSSSIs as assessed by the lesion size of major abscesses and DFIs. ClinicalTrial.gov Identifier: NCT00402727
Aspergillus fumigatus morphology and dynamic host interactions
No full textAspergillus fumigatus is an environmental filamentous fungus that can cause life-threatening disease in immunocompromised individuals. The interactions between A. fumigatus and the host environment are dynamic and complex. The host immune system needs to recognize the distinct morphological forms of A. fumigatus to control fungal growth and prevent tissue invasion, whereas the fungus requires nutrients and needs to adapt to the hostile environment by escaping immune recognition and counteracting host responses. Understanding these highly dynamic interactions is necessary to fully understand the pathogenesis of aspergillosis and to facilitate the design of new therapeutics to overcome the morbidity and mortality caused by A. fumigatus. In this Review, we describe how A. fumigatus adapts to environmental change, the mechanisms of host defence, and our current knowledge of the interplay between the host immune response and the fungus
How Trained Immunity Shapes Atherosclerosis : From Mechanism to Disease
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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
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
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