CXCL4 triggers monocytes and macrophages to produce PDGF-BB, culminating in fibroblast activation: Implications for systemic sclerosis

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Significance Analysis of Tourist Sports Events

Import 04/11/2015Cílem této bakalářské práce je popsání významu sportovních akcí v cestovním ruchu. Práce je rozdělena do dvou částí. První část představuje teoretická východiska zaměřená na cestovní ruch, sportovní událost, sportovní marketing a metody použité v práci. Druhá část práce obsahuje analýzu mezinárodních sportovních událostí v podobě olympijských her, Mistrovství světa ve fotbale. Podrobněji analyzuji sportovní události v České republice v roce 2015, Mistrovství Evropy ve fotbale do 21 let, Světový pohár v Biatlonu, Halové Mistrovství Evropy v Atletice a nejdůkladněji zkoumám Mistrovství světa v ledním hokeji 2015. Dotazník směřovaný pro návštěvníky hokejové sportovní události zkoumá dopady na turismus a cestovní ruch.The aim of this bachelor thesis is to describe significance analysis of tourist sports events. This thesis is divided in two parts. The first part presents the theoretical basis of tourist, sports events and sports marketing and methods used in work. The second part contains an analysis of international sporting events as the Olympic games and FIFA World Cup. I explain the influence of significant sport events in Czech republic in 2015, European Football Championship under 21 years, Biathlon World Cup and European Athletic Indoor Championships. I analyze in detail IIHF Hockey World Championship 2015. Questionnaire was made with questions focused on impact of tourism destinations and tourism.115 - Katedra managementuvýborn

Serum microRNA screening and functional studies reveal miR-483-5p as a potential driver of fibrosis in systemic sclerosis

Abstract Objective MicroRNAs (miRNAs) are regulatory molecules, which have been addressed as potential biomarkers and therapeutic targets in rheumatic diseases. Here, we investigated the miRNA signature in the serum of systemic sclerosis (SSc) patients and we further assessed their expression in early stages of the disease. Methods The levels of 758 miRNAs were evaluated in the serum of 26 SSc patients as compared to 9 healthy controls by using an Openarray platform. Three miRNAs were examined in an additional cohort of 107 SSc patients and 24 healthy donors by single qPCR. MiR-483-5p expression was further analysed in the serum of patients with localized scleroderma (LoS) (n = 22), systemic lupus erythematosus (SLE) (n = 33) and primary Sjogren's syndrome (pSS) (n = 23). The function of miR-483-5p was examined by transfecting miR-483-5p into primary human dermal fibroblasts and pulmonary endothelial cells. Results 30 miRNAs were significantly increased in patients with SSc. Of these, miR-483-5p showed reproducibly higher levels in an independent SSc cohort and was also elevated in patients with preclinical-SSc symptoms (early SSc). Notably, miR-483-5p was not differentially expressed in patients with SLE or pSS, whereas it was up-regulated in LoS, indicating that this miRNA could be involved in the development of skin fibrosis. Consistently, miR-483-5p overexpression in fibroblasts and endothelial cells modulated the expression of fibrosis-related genes. Conclusions Our findings showed that miR-483-5p is up-regulated in the serum of SSc patients, from the early stages of the disease onwards, and indicated its potential function as a fine regulator of fibrosis in SSc

Histone modifications underlie monocyte dysregulation in patients with systemic sclerosis, underlining the treatment potential of epigenetic targeting.

Background and objective S ystemic sclerosis (SSc) is a severe autoimmune disease, in which the pathogenesis is dependent on both genetic and epigenetic factors. Altered gene expression in SSc monocytes, particularly of interferon (IFN)-responsive genes, suggests their involvement in SSc development. We investigated the correlation between epigenetic histone marks and gene expression in SSc monocytes. Methods C hromatin immunoprecipitation followed by sequencing (ChIPseq) for histone marks H3K4me3 and H3K27ac was performed on monocytes of nine healthy controls and 14 patients with SSc. RNA sequencing was performed in parallel to identify aberrantly expressed genes and their correlation with the levels of H3K4me3 and H3K27ac located nearby their transcription start sites. ChIP-qPCR assays were used to verify the role of bromodomain proteins, H3K27ac and STATs on IFNresponsive gene expression. Results 1046 and 534 genomic loci showed aberrant H3K4me3 and H3K27ac marks, respectively, in SSc monocytes. The expression of 381 genes was directly and significantly proportional to the levels of such chromatin marks present near their transcription start site. Genes correlated to altered histone marks were enriched for immune, IFN and antiviral pathways and presented with recurrent binding sites for IRF and STAT transcription factors at their promoters. IFN\u3b1 induced the binding of STAT1 and STAT2 at the promoter of two of these genes, while blocking acetylation readers using the bromodomain BET family inhibitor JQ1 suppressed their expression. Conclusion SS c monocytes have altered chromatin marks correlating with their IFN signature. Enzymes modulating these reversible marks may provide interesting therapeutic targets to restore monocyte homeostasis to treat or even prevent SSc

Nuclear Receptor Subfamily 4A Signaling as a Key Disease Pathway of CD1c+ Dendritic Cell Dysregulation in Systemic Sclerosis

OBJECTIVE: This study was undertaken to identify key disease pathways driving conventional dendritic cell (cDC) alterations in systemic sclerosis (SSc). METHODS: Transcriptomic profiling was performed on peripheral blood CD1c+ cDCs (cDC2s) isolated from 12 healthy donors and 48 patients with SSc, including all major disease subtypes. We performed differential expression analysis for the different SSc subtypes and healthy donors to uncover genes dysregulated in SSc. To identify biologically relevant pathways, we built a gene coexpression network using weighted gene correlation network analysis. We validated the role of key transcriptional regulators using chromatin immunoprecipitation (ChIP) sequencing and in vitro functional assays. RESULTS: We identified 17 modules of coexpressed genes in cDCs that correlated with SSc subtypes and key clinical traits, including autoantibodies, skin score, and occurrence of interstitial lung disease. A module of immunoregulatory genes was markedly down-regulated in patients with the diffuse SSc subtype characterized by severe fibrosis. Transcriptional regulatory network analysis performed on this module predicted nuclear receptor 4A (NR4A) subfamily genes (NR4A1, NR4A2, NR4A3) as the key transcriptional regulators of inflammation. Indeed, ChIP-sequencing analysis indicated that these NR4A members target numerous differentially expressed genes in SSc cDC2s. Inclusion of NR4A receptor agonists in culture-based experiments provided functional proof that dysregulation of NR4As affects cytokine production by cDC2s and modulates downstream T cell activation. CONCLUSION: NR4A1, NR4A2, and NR4A3 are important regulators of immunosuppressive and fibrosis-associated pathways in SSc cDCs. Thus, the NR4A family represents novel potential targets to restore cDC homeostasis in SSc

The picture of immune senescence in inflammatory diseases

The immune system, as complex and plastic as it is, requires adequate cooperation between multiple internal and external cofactors with respect to each immune cell-subset. Consistent with chronic inflammation, immune cells undergo various challenges in attempt to dispose and neutralize pathogens and inflammatory triggers. In the meanwhile, immune cells secrete pro-inflammatory mediators and cytokines. Also, the immune cells undergo damage on account of i.a. phagocytosis of the pathogens. Not to forget, immune cells are contrived to adapt upon varying tissues and organ substances while migrating to reach the site of inflammation. These circumstances force the immune cells to proliferation c.q. cell division and DNA/cellular repair. Like all dividing eukaryotic cells with end replication limitation, immune cells also have a restricted number of cell divisions that they can undergo in order to proliferate and or repair. With each cycle of cell division, DNA loses parts of its protecting telomeres eventuating in completely eroded telomeres that leave the coding DNA unprotected and eventuates DNA loss. Critically eroded telomeres initiate a sustained form of signalling with respect to the damaged DNA that will predict the faith of the cell depending on its characteristics and type. Finally, increased cell-turnover that accelerates telomere erosion, enhances the state of immune senescence. The main hypothesis of this thesis is that patients with chronic immune mediated diseases have an “aged immune system” in terms of replicative senescence. In other words, we hypothesize that chronic inflammation paints the phenomenon of inflamm-ageing. The picture of an aged immune system however, demonstrates cells with multiple morphological and behavioural deviations that are incapable of adequate and appropriate functioning. Consequently, inflamm-ageing and immune deficiencies could eventuate in the development of various systemic and local disorders with a chronic inflammatory signature. We elaborated on some of the chronic inflammatory disorders, with respect to inflamm-ageing. This thesis touches upon Birdshot uveitis, Fibromyalgia, Systemic Sclerosis, RA and Gout. The main future perspective of this thesis relies on the detailed insights on potential biomarkers such as telomere length that could potentially be applied as a laboratory test for patients with inflammatory disorders and could indicate an enhanced state of immune senescence, or a marker for cumulative inflammation over time. Accordingly, individuals with an aged immune biology that are more susceptible to develop senescence-associated disease, can receive adequate and prelude directions and treatment. The necessity to gain a better understanding on the available indications might unravel potential novel targeting possibilities. Even the research in this regard is quite young and in early stages. Although the gained knowledge could be translated in treatment strategies that might diminish the prevalence of ageing associated diseases, prolong healthy ageing and increase the quality of life in ageing individuals and concomitant burden of economic health costs

Beneficis de l’activitat física moderada aquàtica i terrestre, tant per a la dona gestant com per al fetus, durant l’embaràs

[cat] L’activitat física durant l’embaràs té molts beneficis, tant per a la dona gestant com per al fetus. En el procés de gestació el cos de la dona experimenta una sèrie de canvis anatòmics, fisiològics i emocionals. Davant aquestes modificacions es planteja el dubte de quin tipus d’activitat física és més adequada per a les embarassades i per als fetus. S’ha realitzat una revisió sistemàtica dels darrers 10 anys, identificant els millors articles de la literatura que aporten evidència científica respecte a aquest tema. L’objectiu d’aquest treball de fi de grau és identificar quins beneficis aporta la realització d’activitat física moderada durant l’embaràs, tant per a la dona gestant com per al fetus, i analitzar quin tipus d’exercici físic és més adequat durant la gestació, el que es desenvolupa en medi aquàtic o en medi terrestre. Es pot afirmar que l’activitat física moderada en medi aquàtic és més beneficiosa per a la dona embarassada i per al fetus. Entre els principals beneficis que aporta la realització d’activitat física durant l’embaràs trobem la prevenció d’augment de pes de l’embarassada, la prevenció de la diabetis mellitus gestacional, disminució de la lumbàlgia, prevenció de la depressió postpart, prevenció dels trastorns del son, ajuda a combatre la fatiga causada per l’embaràs, disminució de l’edema, prevenció de la preclàmpsia, augmenta la força dels músculs del sòl pelvià evitant així els trastorns que hi ha associats com la incontinència urinària, disminució del nombre d’episiotomies i de cesàries, entre d’altres

Aberrant leukocyte telomere length in Birdshot Uveitis

PURPOSE: Birdshot Uveitis (BU) is an archetypical chronic inflammatory eye disease, with poor visual prognosis, that provides an excellent model for studying chronic inflammation. BU typically affects patients in the fifth decade of life. This suggests that it may represent an age-related chronic inflammatory disease, which has been linked to increased erosion of telomere length of leukocytes. METHODS: To study this in detail, we exploited a sensitive standardized quantitative real-time polymerase chain reaction to determine the peripheral blood leukocyte telomere length (LTL) in 91 genotyped Dutch BU patients and 150 unaffected Dutch controls. RESULTS: Although LTL erosion rates were very similar between BU patients and healthy controls, we observed that BU patients displayed longer LTL, with a median of log (LTL) = 4.87 (= 74131 base pair) compared to 4.31 (= 20417 base pair) in unaffected controls (P<0.0001). The cause underpinning the difference in LTL could not be explained by clinical parameters, immune cell-subtype distribution, nor genetic predisposition based upon the computed weighted genetic risk score of genotyped validated variants in TERC, TERT, NAF1, OBFC1 and RTEL1. CONCLUSIONS: These findings suggest that BU is accompanied by significantly longer LTL

PD-1+CD8+ T cells are clonally expanding effectors in human chronic inflammation

Chronic inflammatory diseases are characterized by recurrent inflammatory attacks in the tissues mediated by autoreactive T cells. Identity and functional programming of CD8+ T cells at the target site of inflammation still remain elusive. One key question is whether, in these antigen-rich environments, chronic stimulation leads to CD8+ T cell exhaustion comparable to what is observed in infectious disease contexts. In the synovial fluid (SF) of juvenile idiopathic arthritis (JIA) patients, a model of chronic inflammation, an overrepresentation of PD-1+CD8+ T cells was found. Gene expression profiling, gene set enrichment analysis, functional studies, and extracellular flux analysis identified PD-1+CD8+ T cells as metabolically active effectors, with no sign of exhaustion. Furthermore, PD-1+CD8+ T cells were enriched for a tissue-resident memory (Trm) cell transcriptional profile and demonstrated increased clonal expansion compared with the PD-1- counterpart, suggesting antigen-driven expansion of locally adapted cells. Interestingly, this subset was also found increased in target tissues in other human chronic inflammatory diseases. These data indicate that local chronic inflammation drives the induction and expansion of CD8+ T cells endowed with potential detrimental properties. Together, these findings lay the basis for investigation of PD-1-expressing CD8+ T cell targeting strategies in human chronic inflammatory diseases

The effects of selective hematopoietic expression of human IL-37 on systemic inflammation and atherosclerosis in LDLr-deficient mice

The human cytokine interleukin (IL)-37 has potent anti-inflammatory capacities, and hematopoietic cell-specific transgenic overexpression of IL-37 in mice protects against septic shock and colitis. In the present study we investigated the effect of hematopoietic expression of IL-37 on atherosclerosis development under low-grade inflammatory conditions. Low-density lipoprotein receptor (LDLr)-deficient mice were lethally irradiated and transplanted with bone marrow from IL-37-transgenic or control wild-type mice and fed a Western-type diet (WTD; 1% cholesterol) for eight weeks. Metabolic and inflammatory parameters were monitored and atherosclerosis was assessed in the aortic valve area. Hematopoietic IL-37 expression did not influence body weight, food intake and plasma cholesterol levels during the study. Plasma soluble E-selectin levels were increased with WTD-feeding as compared to chow-feeding, but were not influenced by IL-37 expression. IL-37 expression reduced the inflammatory state as indicated by reduced white blood cell counts and by reduced basal and lipopolysaccharide-induced cytokine response by peritoneal macrophages ex vivo. IL-37 expression did not influence the atherosclerotic lesion area. Lesion composition was marginally affected. Smooth muscle cell content was decreased, but macrophage and collagen content were not different. We conclude that under low-grade inflammatory conditions, hematopoietic IL-37 expression reduces the inflammatory state, but does not influence atherosclerosis development in hyperlipidemic LDLr-deficient mice.</p