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International Journal of Inflammation
International Journal of Inflammation / 2019 / Article
AbstractIntroductionMaterials and MethodsResultsDiscussionConclusionsConflicts of InterestAuthors' ContributionsAcknowledgmentsSupplementary MaterialsReferencesCopyright
Epigenetics and Inflammatory Markers: A Systematic Review of the Current Evidence
Valentina Gonzalez-Jaramillo ,1,2 Eliana Portilla-Fernandez ,1,3 Marija Glisic,1,4 Trudy Voortman,1 Mohsen Ghanbari,1,5 Wichor Bramer,6 Rajiv Chowdhury,7 Tamar Nijsten,8 Abbas Dehghan,1,9 Oscar H. Franco,1,2 and Jana Nano1,10,11
1Department of Epidemiology, Erasmus MC, Erasmus University Medical Center, 3015 CN, Rotterdam, Netherlands
2Institute of Social and Preventive Medicine (ISPM), University of Bern, 3012, Bern, Switzerland
3Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus University Medical Center, 3015 CN, Rotterdam, Netherlands
4Leibniz Institute for Prevention Research and Epidemiology-BIPS, Bremen, Germany
5Department of Genetics, School of Medicine, Mashhad University of Medical Sciences, 13131, Mashhad, Iran
6Medical Library, Erasmus MC, Erasmus University Medical Center, 3015 CN, Rotterdam, Netherlands
7Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, CB1 8RN, Cambridge, UK
8Department of Dermatology, Erasmus MC, Erasmus University Medical Center, 3015 CN, Rotterdam, Netherlands
9Department of Biostatistics and Epidemiology, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, W2 1PG, London, UK
10Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Epidemiology, D-85764, Neuherberg, Germany
11German Center for Diabetes Research (DZD), D-85764, Munich-Neuherberg, Germany
Academic Editor: Jian-Dong Li
Accepted07 Apr 2019
Published08 May 2019
Epigenetic mechanisms have been suggested to play a role in the genetic regulation of pathways related to inflammation. Therefore, we aimed to systematically review studies investigating the association between DNA methylation and histone modifications with circulatory inflammation markers in blood. Five bibliographic databases were screened until 21 November of 2017. We included studies conducted on humans that examined the association between epigenetic marks (DNA methylation and/or histone modifications) and a comprehensive list of inflammatory markers. Of the 3,759 identified references, 24 articles were included, involving, 17,399 individuals. There was suggestive evidence for global hypomethylation but better-quality studies in the future have to confirm this. Epigenome-wide association studies (EWAS) (n=7) reported most of the identified differentially methylated genes to be hypomethylated in inflammatory processes. Candidate genes studies reported 18 differentially methylated genes related to several circulatory inflammation markers. There was no overlap in the methylated sites investigated in candidate gene studies and EWAS, except for TMEM49, which was found to be hypomethylated with higher inflammatory markers in both types of studies. The relation between histone modifications and inflammatory markers was assessed by one study only. This review supports an association between epigenetic marks and inflammation, suggesting hypomethylation of the genome. Important gaps in the quality of studies were reported such as inadequate sample size, lack of adjustment for relevant confounders, and failure to replicate the findings. While most of the studies have been focused on C-reactive protein, further efforts should investigate other inflammatory markers.
Inflammation is a critical response to pathogens and injuries in the human body. Specifically, chronic low-grade inflammation plays a key role in the pathogenesis of chronic conditions and diseases like obesity, diabetes mellitus, and cardiovascular disease [1–3]. A better understanding of factors that contribute to the development of inflammation and its consequences on disease is essential to improve prevention strategies in inflammation-related disorders.
Genome-wide association studies have identified several genetic variants associated with inflammatory markers such as C-reactive protein, the most widely studied marker [4, 5], but the explained variance is relatively small. In addition, nongenetic factors such as smoking and dietary behaviours have been shown to exhibit a strong influence on the inflammatory response [6, 7]. Emerging evidence suggests that epigenetic processes, reflecting changes in gene expression that occur without sequence mutations, may offer opportunities to understand the pathophysiology of inflammation processes. The role of epigenetic determinants is increasingly being recognized as a link between environmental factors and disease risk. Moreover, epigenetic modifications are also involved in differentiation of the immune cells, a key component of the inflammatory process. Epigenetics is defined as a group of chemical modifications of the DNA sequence, which could be affected by external factors such as BMI, smoking, and inflammation and can be transmitted from one generation of cells to the others [8]. The molecular basis of epigenetic mechanisms is complex and comprises DNA methylation, modifications of histones, and gene regulation by noncoding RNAs [9]. Unlike genetic variation, epigenetic modifications are dynamic and potentially reversible and, therefore, could be modified by lifestyle and other therapeutic approaches.
Until now, a comprehensive and systematic appraisal of the current literature on the role of epigenetic modifications in inflammation measured by levels of inflammatory markers is missing. Therefore, we aimed to identify and synthetize all available evidence conducted in humans and quantify the association of two of the major epigenetic modifications, DNA methylation, and histone modifications, with circulation inflammatory markers in blood.
This review was conducted and reported using a predefined protocol and in accordance with the PRISMA [10] and MOOSE [11] guidelines (Supplement Material S1 and S2). We sought studies published before 21 November of 2017 (date last searched) in five electronic databases: Embase.com, Medline (Ovid), Web-of-Science, Cochrane Central, and Google Scholar. We did the search with the help of an experienced medical information specialist. In databases where a thesaurus was available (Embase and Medline), articles were searched by thesaurus terms, title and/or abstract and in other databases, only by title and/or abstract. The search combined terms related to the exposure (e.g., epigenetic, hypomethylation, hypermethylation, DNA methylation, and histone acetylation) and outcome (e.g., inflammation, C-reactive protein, and cytokine). We did not apply any language restriction, but we restricted the search to studies on humans alive. The full search strategies of all databases are provided in Supplement Material S3. The study identification also included manual search, based on the screening of the citations of the relevant studies.
Information about study selection and inclusion criteria, data extraction process, and risk of bias assessment is described in Supplement Material S4.
After deduplication, we identified 3,759 potentially relevant citations. Based on the title and abstract, 3,679 studies were excluded due to inappropriate exposure (gene mutations, gene polymorphism, and microRNA), inappropriate outcome (autoimmune diseases, cancer, and inflammation-related diseases such as asthma), or both. We also excluded investigations conducted in mice or rats (n=298). Additionally, we excluded studies that reported methylation levels in inflamed body areas or inflamed cells without quantitative investigation with inflammation markers, as well as studies that assessed methylation changes before and after immunotherapy. The final set of 80 studies were considered for full-text assessment. Of these, 24 unique studies met our eligibility criteria and were included in this review. The other 56 articles were excluded for reasons shown in Figure 1.
Flowchart of studies included in the systematic review.
3.1. Characteristics of the Included Studies
Detailed characteristics of the included studies are summarized in Tables 1–3. All included studies were of cross-sectional design, except one study of prospective design [12]. Overall, 17,399 individuals were participating in these studies. Nine studies included participants from the USA, three studies from China, three studies from Canada, and the rest included participants from Brazil, Colombia, India, Ireland, Germany, Greece, Mexico, Spain, and Sweden. One of the studies [13] included participants from different cohorts such as USA, UK, Italy, Germany, and Netherlands. The majority (n=23) of studies assessed epigenetic signatures in blood, whereas other assessed epigenetic marks in tumour specimens (glioblastomas).
Author, Year Study design Outcome Tissue type Population
Sex/Age/Sample size/Country Adjustment Main findings
LINE-1 methylation
Baccarelli et al., 2010 [16] CS VCAM-1, ICAM-1 and CRP WB M /73.8 ± 6.7/n=593/USA Age, BMI, smoking, pack years of smoking, IHD or stroke. Inverse association for VCAM-1. No association for ICAM-1 and CRP.
Perng et al., 2012 [17] CS CRP WBC M and W/ 8.8 ± 1.7/n=568/ Colombia Sex, vitamin A, maternal BMI and household socioeconomic stratum. Higher CRP was related to lower LINE-1 methylation.
Zhang et al., 2012 [14] CS CRP WBC M and W/ 18-78/n=165/USA No association (β coefficient=-0.02, p=0.81).
Narayan & Dangi, 2017 [18] CS CRP WB M and W/7.9 ± 1.5/n=600/India Sex, plasma Vitamin A, socioeconomic status Global DNA methylation was inversely related to CRP concentrations and the association was stronger in male children.
5mdC
Murphy et al., 2015 [19] CS IL-6 (protein and serum levels) WB M and W/mean=33.04/ n=47/Ireland No association (r = -0.125, p=0.46).
CS: cross-sectional; VCAM-1: vascular cell adhesion molecule 1; ICAM-1: intercellular adhesion molecule 1; CRP: C-Reactive protein; WB: whole blood; M: men; BMI: body mass index; WBC: white blood cells; IL: interleukin; W: women.
Global DNA methylation and inflammatory markers.
Author Study design Outcome Tissue type Population
Sex/Age/Sample size/ Country Methylation sites/ method Adjustment Main findings Clinical condition associated with the main findings
Piperi et al., 2010 [20] CS IL-6, IL-8, VEGF, COX-2 Tumour specimens M and W/25-76/n=23/Greece MGMT, RARβ, RASSF1A, CDH13/MS-PCR IL-6: positive correlation with the four genes; IL-8 and COX-2: no correlation for any gene; VEGF: positive correlation with MGMT and RARβ, no correlation with RASSF1A and CDH13. IPA: Cancer, neurological diseases, ophthalmic diseases.
Uddin et al., 2010 [27] CS IL-6, CRP PBMC M and W/ 45.3±16.7/ n=100/ USA IL-6/Illumina HumanMethylation27K DNA Analysis BeadChip Among patients with lifetime depression, there was a significant inverse correlation between methylation of IL-6 and serum levels of IL-6 and CRP (Pearson r=-0.54, p=0.001 and Pearson r=-0.48, p=0.006, respectively. IL-6: Rheumatic diseases, inflammatory bowel disease, Kaposi sarcoma.
Fu et al., 2011 [28] CS IL-10 (mRNA) PBMC M and W/39 ± 10.8/ n=40/ China IL-10 promoter, 5 CpG sites/ Pyro Q-CpG system Hypomethylation of -145C was correlated with higher IL-10 mRNA expression (r=-0.746, p=0.001). The authors did not report the results for the other CpG sites. IL-10: Susceptibility to HIV type 1, rheumatic conditions, cutaneous leishmaniasis.
Zhang et al., 2012 [14] CS CRP PB M and W/18-78/ n=165/USA IL-6 promoter, 6 sites/ bisulfite treatment Age, sex, race, dietary folate intake, prudent diet pattern, western diet With a spearman correlation coefficient of 0.11 (p=0.18), no association was found. Not applicable
García-Cardona et al., 2014 [29] CS Leptin PB M and W/ 10-16/ n=106/ Mexico LEP promoter/ MS-PCR No significant correlation was observed between the circulating levels of leptin and the methylation frequencies of the two selected CpG sites of LEP promoter (at − 51 and − 31 nt). Not applicable
Lai et al., 2014 [24] CS IL-6, TNF-α and CRP PB M and W/ 36-80/ n=46/China SOCS-1 gene, 11 CpG sites/ Bisulfite method A positive trend between the levels of SOCS-1 methylation and CRP levels was observed (R2=0.1127, p=0.0278). Patients with serum IL-6 above median showed a significantly higher SOCS-1 methylation than the patients with serum IL-6 below median (p<0.001). Similar results were observed for TNF-α (p<0.001). SOCS-1: Cancer, hepatic system diseases, ophthalmological diseases.
Smith et al., 2014 [12] CS and prospective sTNFR2, IL-6 PBMC W/56.4 ± 9.4/ n=61/USA USP2, TMEM49, SMAD3, DTNB, 8 CpG sites/ HumanMethylation 450 Bead Cheap At baseline, lower methylation at each of the 8 CpG sites was significantly correlated with increased sTNFR2 and IL-6. IPA: Gastrointestinal diseases, hepatic system diseases, cancer (like gynaecological cancer), dermatological diseases.
Wang et al., 2014 [22] CS Fibrinogen and CRP PB M and W/16.2 ±1.2/ n=703/ USA LY86 gene, 6 CpG sites / HumanMethylation 27 BeadChip and ThumanMethylation 450 BeadChip from Illumina Age, sex, race, BMI and batch They performed a principal component analysis to combine the six CpG sites into one score. The score of these CpG sites was significantly associated with fibrinogen (partial r=0.145, p<0.001) and CRP (partial r=0.114, p=0.005). LY86: Pelvic inflammation, pulmonary interstitial emphysema.
Wei et al., 2016 [21] CS CRP WBC M and W/ /n=673/China IL-6 promoter/EZ DNA Methylation Kit Age and sex Plasma CRP levels were significantly associated with IL-6 promoter methylation (p=0.025). One interquartile range increase in plasma CRP was associated with a decrease in IL-6 methylation by 0.78% (95% CI: -1.47% to -0.1%). IL-6: Rheumatic diseases, inflammatory bowel disease, Kaposi sarcoma.
Arpón et al., 2017 [25] CS TNF-α, VCAM-1, sICAM-1, CRP, leptin PB M and W/63.8±2.74/ n=36/ Spain EEF2, COL18A1, IL4I1, LEPR, PLAGL1, IFRD1, MAPKAPK2 and PPARGC1B/ llumina Infinium HumanMethylation 450K BeadChip Results showed correlations between LEPR methylation and concentration of LEP (r=-0.24, p=0.047). Also, between EEF2 methylation and concentration of TNF-α (r=0.24, p= 0.0408) and CRP (r=0.24, p=0.0457). IPA: Inflammatory response, cardiovascular disease, reproductive system diseases.
Min A Jhun. et al., 2017 [23] CS CRP, IL-6, IL-18, fibrinogen PBL M and W/66 7.5/n=822/ USA Cg0363183 in F2RL3/ Illumina Infinium HumanMethylation 27 BeadChips and the Illumina BeadXpress reader. Age, sex, four principal component, five cell proportions, plate and random intercepts for family. DNA methylation level of Cg03636183 in F2RL3 was significantly associated with log (IL-18) levels (-0.11, 95% CI (-0.19, -0.04)). Unknown.
Miller et al., 2017 [26] CS CRP WBC M and W/32.08±8.36/ n=286/ USA AIM2,cg10636246/
llumina Infinium HumanMethylation 450K Log CRP levels were negatively correlated with cg10636246
(r=-0.264, p<0.001). AIM2: Skin disease, melanoma.
We used Ingenuity Pathway Analysis (IPA) for studies that found significant association between multiple inflammatory markers and/or methylation in multiple genes [12, 20, 25]. For the other studies, the connection between findings and disease was assessed through literature review and gene cards (https://www.genecards.org/).
CS: cross-sectional; IL: interleukin; VEGF: vascular endothelial growth factor; Cox-2: cyclooxygenase; M: men; W: women; MS-PCR: methylation-specific PCR; IPA: ingenuity pathway analysis; PBMC: peripheral blood mononuclear cells; HIV: human immunodeficiency virus; PB: peripheral blood; TNF- α: tumour necrosis factor-alpha; sTNFR2: soluble tumour necrosis factor receptor 2; BMI: body mass index; WBC: white blood cells; VCAM-1: vascular cell adhesion molecule 1; sICAM-1: soluble intercellular adhesion molecule 1; PBL: peripheral blood leucocytes.
Gene-specific DNA methylation and inflammatory markers.
Sex/Age/Sample size/ Country Methylation sites/ method Adjustment Main findings
Epigenome-Wide Association Study
Guénard et al., 2013 [34] CS CRP WB M and W/12.25±5.77/ n=50/Canada Infinium HumanMethylation 450K BeadChip Age and sex From 17 genes involved in the IL-8 signalling pathway, significant correlations between gene methylation and plasma CRP levels were found for 16 genes. Of these, 9 showed inverse correlation and 7 positive. Out of those 16 genes, 13 remained significant after adjustments.
Sun et al., 2013 [43] CS CPR PBL M and F/ 66.27±7.58/ n=966/ USA Infinium HumanMethylation 27K BeadChip Age, sex, BMI, smoking 207 out of 257 CRP-associated DNAm sites showed an inverse correlation of greater methylation with lower level of CRP. Twenty-four out of the top 30 CpGs remained significant in both replication subsets with KLK10, LMO2 and TM4SF4 as top genes (p=5.85x10−12, p=1.69x10−11 and p=2.05x10−10, respectively).
Ligthart et al., 2016 [13] CS CRP WB M and W/mean age between 60 and 87/n=8,863/ Consortia Illumina Infinium HumanMethylation 27K and 450K BeadChip. Age, sex, white blood cell proportion, technical covariates, smoking, BMI. 218 CpG sites were significantly associated with CRP. Of those, 125 CpGs were positively associated and 93 were negatively associated.
58 CpG sites, in 47 genes, were still significantly associated in the replication cohort (n=4,111). The top CpG sites were located in AIM, RPS6KA2 and PHOSPHO1 (P = 2.53x10−27, 2.06x10−26 and 4.87x10−25, respectively).
Marzi et al., 2016 [33] CS CRP PB M and W/60.9±8.89/ n=1741/ Germany Illumina HumanMethylation 450K BeadChip Age, sex, BMI, smoking, white blood cells composition. Four CpG sites were significantly hypomethylated at high CRP concentrations. They were located at AQP3, BCL3, SOCS3, and intergenic at chromosome 19p13.2. Those four sites were replicated in three subcohorts: CpG at AQP3 remained significant in two of the subcohorts and the one at SOCS3 remained significant in one of the subcohorts.
Ahsan et al., 2017 [30] CS 121 biomarkers related with inflammation, cancer, and cardiovascular disease. PBL M and W/ 14-97/ n=698/Sweden Illumina HumanMethylation 450K BeadChip Age, sex, batch and plate effects, year of sampling and cell fractions. For 36% of the studied biomarkers (44/121), the abundance level was associated with DNA methylation, but for 52% of these biomarkers (23/44), the associations were explained by genetic variants. For a subset of biomarkers, the association with DNA methylation was confounded by environmental factors (e.g., smoking), but for the majority of the associations, no such relationship could be found.
Verschoor et al., 2017 ("The relation between…") [31] CS TNF, IL-6, IL-8, IL-10 WB M and W/48-78/n=14/Canada Illumina Infinium HumanMethylation 450 K BeadChip Age and sex Serum IL-10 levels exhibited the most substantial association to DNA methylation patterns, followed by TNF, IL-6 and IL-8.
Verschoor et al., 2017 ("DNA methylation…") [32] CS TNF, IL-6, IL-1β, IL-10 and CRP PBMC M and W/82-98/n=23/Canada Illumina Infinium HumanMethylation 450 K BeadChip Authors performed linear regression between each factor assessed and the scores of top 10 principal components (PCs) of the DNA methylation dataset. Only IL-6 and IL-10 were found to be associated, both of which with PC7 (ln IL-6, p = 0.002; ln IL-10, p= 0.03). ln CRP was positively associated with DNA methylation age using Hannum's approach (β = 0.21, p = 0.007), which relates to approximately 5-years age acceleration per 1-unit change in ln CRP (β= 0.20, p =0.008).
Histone acetylation
da Silva et al., 2017 [15] CS IL-4, IL-6, IL-9, INF- γ and TGF-β PBMC M and W/ 68.5±6.49/n=10/ Brazil Global Histone H4 Acetylation Assay Kit At 24th session, the basal values of global histone H4 acetylation levels were correlated with basal IL-4 and IL-8 levels (r =−0.65, p= 0.04 and r=0.85, p=0.01, respectively).
CS: cross-sectional; WB: whole blood; M: men; W: women; IL: interleukin; PBL: peripheral blood leucocytes; BMI: body mass index; PB: peripheral blood; TNF: tumour necrosis factor; PBMC: peripheral blood mononuclear cells; INF-γ: interferon-gamma; TGF-β: transforming growth factor-beta.
Epigenome-wide and histone acetylation approaches and inflammatory markers.
Of the 24 studies included, four studies assessed only global DNA methylation, eleven studies assessed only DNA methylation in specific candidate genes, and seven studies used genome-wide approaches. One additional study examined both global DNA methylation and methylation in specific candidate genes [14]. Only one study assessed histone modification in relation to inflammation markers [15].
The most studied marker was C-reactive protein (CRP), which was evaluated in 17 studies. Interleukins like IL-4, IL-6, IL-8, IL-9, IL-10, and IL-18 were evaluated in 11 studies. TNF-α was assessed in three studies, fibrinogen was assessed in two studies, and other markers such as VCAM, ICAM, VEFG, COX2, leptin, TNFR2, C-CAM1, alpha interferon, and TGF-β were assessed one single time. Nine studies were judged at medium risk of bias whereas the rest were at high risk of bias.
3.2. Global DNA Methylation and Inflammatory Markers
Five studies examined the association between global DNA methylation and inflammatory markers in blood samples (Table 1). Four of these studies assessed methylation in long-interspersed nuclear element (LINE-1). A large portion of methylation sites within the genome are found in these repeat sequences and transposable elements and correlate well with total genomic methylation content. From the four studies, two [14, 16] reported no association between global DNA methylation and CRP levels, while the other two showed lower methylation to be related with higher CRP levels [17, 18].
One study [16], in addition to CRP levels, also evaluated the association of global DNA methylation at LINE-1 with VCAM-1 and ICAM-1 and reported an inverse association with VCAM-1 but no association with ICAM-1. One study quantified global DNA methylation by measuring the amount of methylated cytokines in the sample (5 mc) relative to global cytidine (5mC + dC) in a positive control and found no association between global DNA methylation and IL-6 serum levels [19].
3.3. Gene-Specific DNA Methylation and Inflammatory Markers
Twelve studies examined the relation of inflammatory markers with methylation sites in, or near, candidate genes (Table 2). One study measured DNA methylation in tumour specimens [20], whereas the other studies used blood samples to assess the DNA methylation.
Of the twelve studies, eight did not report any level of adjustment or control for confounders, one of them controlled for age and sex [21], and the others controlled for these two confounders plus additional ones such as diet and race [14, 22, 23]. Of the twelve studies, three focused solely on CRP as outcome, one solely on interleukins, and one solely on leptin and the others assessed a set of inflammatory markers including interleukins, TNF-α, and fibrinogen.
In total, eight studies assessed CRP as inflammatory marker. Overall, these studies found higher levels of CRP to be associated with higher degree of methylation of SOCS-1 [24], LY86 [22], and EEF2 [25] and higher levels of CRP to be associated with lower degree of methylation of AIM2 [26], IL-6 [27], and IL-6 promoter gene [21]. One additional study that examined methylation levels of IL-6 promoter and CRP reported no association [14]. In addition, no association was found between methylation status of F2RL3 in peripheral blood cells and CRP levels.
Five studies evaluated the association of gene-specific DNA methylation with IL-6. They found higher degree of methylation of MGMT, RARβ, RASSF1A, and CDH13 in tumour specimens and of SOCS-1 in peripheral blood with higher levels of IL-6, while others found less degree of methylation of USP2, TMEM49, SMAD3, DTNB, and IL-6 promoter with higher levels of IL-6. Other interleukins such as IL-8, IL-10, and IL-18 were only evaluated once [20, 23, 28]. No significant correlation was found for IL-8, whereas for IL-10 and IL-18 inverse association was found with DNA methylation in IL-10 promoter and F2RL3, respectively (Table 2).
Two studies evaluated leptin as outcome, showing contradictory results. One reported inverse association between leptin levels and Leptin Receptor methylation [25], whereas the other reported no association between Leptin promoter and leptin levels [29].
Two studies assessed the association of DNA methylation and TNFα levels. Higher levels of methylation of EEF2 [25] and SOCS-1 [24] were found with higher levels of TNFα.
Additionally, six studies reported the association between methylation at different genes (MGMT, RARβ, RASSF1A, CDH13, USP2, TMEM49, EEF2, COL18A1, IL4I1, LEPR, PLAGL1, IFRD1, MAPKAPK2, PPARGC1B, SMAD3, DTNB, LY86, and F2RL3) with levels of several inflammatory markers other than CRP and interleukins (VEGF, VCAM1, C-CAM1, COX-2, sTNFR2, and fibrinogen) (Supplement Table 1).
3.4. Epigenome-Wide Analysis and Inflammatory Markers
Seven studies investigated differentially methylated regions in the genome in a hypothesis-free approach. Six of them adjusted at least for age and sex. Of these six, four adjusted additionally for BMI, smoking, and/or other confounders. All of the studies used blood samples to assess DNA methylation.
One study assessed 121 biomarkers related with inflammation, cancer, and cardiovascular disease [30] and five studies assessed CRP. The remaining two studies evaluated TNF and interleukins such as IL-1β, IL-6, IL-8, and IL-10 [31, 32] (Table 3).
Three out of seven studies used replication to validate their findings: two of them [13, 33] used external validations and one [34] internal validation.
The identified genes were enriched by pathways such as atherosclerosis, IL-6, IL-9, IL-8, growth hormone, and JAK/STAT signalling pathways.
Among the genes reported to be differentially methylated, SOCS3 and BCL3 were found to be significantly hypomethylated in two studies [13, 33]. BCL3 was no longer significant in the replication cohort, whereas SOCS3 remained significant after replication.
3.5. Histone Modifications and Inflammatory Markers
Only one study examined the association between histone modifications and inflammatory markers [15]. The authors assessed levels of acetylated histone H4 in the peripheral blood mononuclear cells of Chronic Obstructive Pulmonary Disease (COPD) patients and reported higher acetylation levels in patients with higher IL-8 levels and in patients with lower IL-4 levels.
This is the first attempt to summarize current literature on the role of epigenetic marks in chronic inflammation. There is suggestive evidence for hypomethylation of overall genome in inflammatory processes, but better-quality studies have to confirm these results. Histone modification and inflammatory markers are scarcely investigated. Given the complexity and variability of proteins involved in the inflammation network, most of the studies focused on exploring CRP levels with few studies on IL-6 and fewer investigations on IL-8, IL-10, IL-18, VEGF, Cox-2, TNF-α, sTNFR2, leptin, and fibrinogen levels. The largest epigenome-wide association study up to date found AIM2 and SOCS3 to be top genes related to CRP levels in whole blood.
4.1. Global DNA Methylation
There were either no or an inverse association of inflammatory markers such as CRP, VCAM-1, and ICAM-1 in whole blood. Because we identified only a small number of studies, we cannot make any firm inferences on the overall hypomethylation of the genome due to inflammation. Moreover, populations were hardly comparable as two of the studies were conducted on children while the others on adults. As global DNA hypomethylation has become the hallmark of most human cancers, stroke, and heart disease [35–38], the need to measure this epigenetic signature has become more essential. Global methylation would enable the ability to associate, for example, LINE-1 or 5-mdC levels, with correlative factors such as patient history or clinical outcome. The observed hypomethylation could lead to activation of dormant repeat elements and the subsequent aberrant expression of associated genes or may contribute to genomic instability and increased mutation rates. More intense efforts in studies investigating global DNA methylation through different methodologies such as Alu repeats and LUMA can hold future prospects for guiding risk stratification in individuals with high levels of inflammatory markers at an increased risk of chronic diseases.
4.2. EWAS vs. Candidate Gene Approaches
Ligthart et al. identified and validated 58 CpG sites located in 45 unique loci in whole blood among 12,974 individuals of European and African descent [13]. The top signal near AIM2 gene was found to be inversely associated with gene expression levels and with lower CRP levels. AIM2 is a key regulator of human innate immune response implicated in defence mechanism against bacterial and viral pathogens [39, 40]. Several of these hits including cg18181703 (SOCS3), cg06126421 (TUBB), and cg05575921 (AHRR) were associated with future incidence of coronary heart disease and smoking [13], whereas two other CpGs were recently identified in an EWAS of type 2 diabetes [41]. The gene SOCS3, suppressor of cytokine signalling 3, plays a pivotal role in the innate immune system as a regulator of cytokine signalling along the JAK/STAT pathway and was previously reported to have an important role in the processes of atherosclerosis [42]. Moreover, another epigenome-wide association study conducted among 1,741 individuals of European descent reported SOCS3, among others, to be significantly associated with systemic CRP levels, not only in peripheral blood tissue, but also in human liver tissue [33].
Given the reported association of CRP levels and these cardiometabolic clinical outcomes, it seems that inflammation-related epigenetic features may explain part of the observed associations reported in epidemiology. However, the results should be interpreted with caution, as the association of CRP and DNA methylation were not adjusted for these factors. Most of the replicated CpG sites reported in the study of Lighart et al. were associated with different cardiometabolic phenotypes (body mass index, fasting glucose, fasting insulin, triglycerides, total cholesterol, and HDL-cholesterol), highlighting the evidence of a pleiotropic network of epigenetics across various phenotypes. This information is promising as it holds new insights into shared epigenetic mechanisms and provides opportunities to link the inflammation processes with clinical outcomes. Moreover, two large cohorts (KORA and GENOA) observed hypomethylation to be related with higher levels of CRP [33, 43]. The latter, reported a similar trend of hypomethylation among individuals of older age and suggested that these patterns of modifications of DNA methylation on CpG islands between aging and inflammatory markers may indicate shared molecular mechanisms underlying chronic diseases through epigenetic changes [43].
Differentially methylated genes associated with CRP levels and other inflammatory markers did not directly overlap with the genes identified from previously reported genome-wide association studies influencing CRP levels and other biomarkers. The nonoverlap between GWAS and EWAS identified genes shows that clinical phenotypes are being influenced by different molecular mechanism, all of them important to explain phenotypical variation. Most of the identified genes are involved in common inflammation pathways related to cancer, rheumatic diseases, and gastrointestinal pathologies [24, 27]. Nevertheless, candidate gene approaches have less stringent criteria to assign significance on the expense of a narrower focus on genes. This might explain the absence of reproducibility of results in the reviewed epigenome-wide association studies, except for TMEM49, which was found to be inversely associated with sTNFR2 and IL-6 levels in the candidate gene approach study of Smith et al, and shared the same direction of association with CRP levels, in the EWAS study of Lighart et al.
4.3. Histone Modification
This review demonstrated that evidence involving inflammation and histone modification mechanisms are inexistent. Histone modifications are another epigenetic mark that play a pivotal role in the epigenetic regulation of transcription and other functions in cells. In addition, histone modifications have been linked to other inflammatory-related disorders, such as dyslipidaemia, obesity, diabetes, cancer, and cardiovascular disease [44–46]. Future studies on histone modifications and inflammation markers might shed light on their functional role in chronic diseases and might provide novel target therapies for inflammatory conditions.
4.4. Bias, Confounding, and Tissue Specificity
There is quite ample evidence showing differential DNA methylation differing by ethnicity [47]. Therefore, it is recommended that studies investigating epigenetics of genes related to inflammation should replicate their findings in diverse populations. The largest to date epigenome-wide association study investigating DNA methylation and CRP levels used as discovery set a large European population (n = 8,863) and sought transethnic replication in African Americans (n = 4,111) [13]. As in genetic studies, the importance of replication of the significant findings in epigenetic association studies is a paramount in order to prevent false-positive results [48, 49].
Unlike genetic association studies that are less prone to confounding, epigenetic signatures throughout the genome are highly labile due to temporal or spatial factors affecting DNA such as age, gender, demographics, lifestyle, comorbidities, and medication use. It has been shown that methylation investigations harbour new information in explaining the variation of complex traits such as inflammation characterized by a strong influence of environment [4, 13, 50]. Inflammatory markers such as CRP, one of the most studied, are affected by both genetic and environmental factors. Therefore, controlling for confounders in epigenetic studies is crucial. In our review, the majority of our studies (62.5%) were classified as low quality largely explained by the lack of proper adjustment in the statistical models. While epigenome-wide studies controlled for life-style factors such as smoking, alcohol consumption, and BMI, candidate-gene approach studies were heavily suffering from incomplete adjustments.
Most of the inflammatory markers, and especially the ones of the acute phase, are predominantly synthesized in liver cells and hepatocytes and are regulated via transcription factors such as STAT3, C/EBP family members, and NF-kappa B by the proinflammatory cytokines IL-6 and IL-1β [51, 52]. Nevertheless, extrahepatic expression to a lesser degree has been reported for adipose tissue and blood cells [52]. DNA methylation profiles have been commonly studied in whole blood due to the easy access to the biological samples. Environmental exposure signatures such as smoking, alcohol, and other conditions involving the circulatory system and the immune response are well reflected in whole blood. This tissue is primarily composed of leukocytes, a key component of the human immune system and, therefore, highly relevant to systematic inflammation. However, since peripheral blood constitutes a heterogeneous admixture of different cell populations, it is possible that the results reflect inflammation-related DNA methylation changes that influence a single cell type component of blood cells. Adjusting for measured or estimated blood cell proportions, or future studies conducted in cell specific tissues, would help to rule out presence of any residual confounding caused by white blood cell distribution.
4.5. Causality and Study Designs
In the last years, the GWAS have resulted in the identification of many genetic variants that are associated with clinical traits and diseases. However, together, these variants explain only a small fraction of the variability. It has been suggested that epigenetics might hold promise to uncover the rest of the missing heritability. Moreover, it has been commonly hypothesized that epigenetic signatures are a cause for disease, rather than consequence. With the current evidence, it is unclear if epigenetic variation is causal to these inflammatory markers. In a recent study of Ahsan et al, the authors investigated the genetic and epigenetic influence in a large set of disease-related inflammatory markers [30]. Combining results of GWAS/EWAS in around 1,069 individuals and employing a complex bidirectional model to asses causality between genetic variation-DNA methylation-inflammation markers, it was concluded that DNA methylation has a limited direct effect on inflammatory markers. It reflects the underlying pattern of genetic variants, environmental exposures or secondary effect of the disease pathogenesis. In line with recent evidence, rather than a cause, DNA methylation seems to be a consequence of clinical traits, such as BMI [53].
All of the included studies in this systematic review were of cross-sectional design, except for one [47], meaning that both epigenetic signatures and outcomes were measured at the same time. This design challenges further inferences concerning causal relation, a typical vulnerability of epigenetic studies. In longitudinal cohort designs, repeated measurements for both inflammatory markers and dynamic methylation changes could improve our knowledge of the directionality of events. Furthermore, statistical approaches like Mendelian Randomization, in which genetic variants are used as proxies for DNA methylation and the outcome of interest, offer new opportunity to investigate the directionality of evidence from cross-sectional data [54]. The identification, directionality, and molecular pathways underlying the relation between epigenetic signatures and inflammatory markers represent promising targets for future functional studies.
4.6. Epigenetic Screening
In the last years, many advances in technologies related to measurements of epigenetic signatures have been developed to respond to the fast-growing pace of the field [55]. These techniques allow the investigation of DNA methylation either on candidate genes or on the whole-genome level. However, as the number of genes of interest increases along with the number of tissues of relevance, investigating the role of DNA methylation in different clinical traits could be very costly and time consuming. Progressing to more cost-effective solutions, high-throughput technologies have open new opportunities for epigenome-wide investigations in large-scale screening such as in population-based cohort studies. Furthermore, gene-specific assays such as bisulfite conversion provide a quick and efficient result for epigenetic investigations requiring relatively low DNA input with minimum DNA loss [56, 57]. Cloning, the gold standard method for gene-specific DNA methylation studies, followed by Sanger sequencing is another technological option [58]. Although the time for the procedure has been significantly reduced, the sequencing step might introduce several sources of errors [55, 59]. Another technique, pyrosequencing, represents a high throughput quantitative method used for bisulfite sequencing [60, 61]. This technique, which can be used for both DNA methylation and genetic variation (single nucleotide polymorphism) analysis, takes less time than cloning providing accurate reads within each run. Yet, optimal DNA quality is important to avoid misreads of pyrosequencing [55]. Mass spectrometry assay, on the other side, is a tool that can be used for the discovery and quantification of DNA methylation sites based on difference in fragments weights that have been cleaved depending on the methylation status [59]. This technology is highly sensitive and has the ability to sequence reads up to 600 bp, which is considerably longer than other methods. Quantitative Polymerase Chain Reaction (qPCR) arrays are another alternative of methylation quantification techniques operating on fluorophore-labelled probes that emit fluorescence when bound to a complementary DNA sequence. This method might not be ideal for regions with multiple CpG sites because many probes need to be created, resulting rather costly. However, if a region is characterized by a few CpGs, qPCR method might provide a simple and relatively inexpensive way to conclude a high-powered study [55].
Other chip techniques for epigenetic studies, in particular for histone modifications, include chromatin immunoprecipitation (ChIP), methylated DNA immunoprecipitation (MeDIP) platforms, and methyl-binding protein immunoprecipitation platforms. A major limitation to these techniques in epigenome-wide analysis is the quality of the antibody, which plays an important role in the proper enrichment of DNA. In general, the immunoprecipitation techniques require the availability of large sample volumes and only measure relative enrichment of epigenetic markers.
Concerning large-scale epigenetic analysis, the most widely used platforms, as shown from our review, are from Illumina. Illumina methylation profiling is based on bisulfite converted DNA genotyping [62]. For example, The Illumina Infinium HumanMethylation27 (27,000 CpG site) and Human-Methylation450 Bead (450,000 CpG sites) arrays provide genome-wide coverage, featuring methylation status at CpG islands, CpG shores, non-CpG sites, promoter regions, 5′ UTR, 3′ UTR, and gene bodies. More recent platforms, such as Infinium MethylationEPIC BeadChip Kit, have increased the number of interrogated sites to more than 850,000 CpGs across the genome at single-nucleotide resolution for only of 250 ng DNA as input quantity [63]. Moreover, TruSeq Methyl Capture EPIC Library Prep Kit, is another option that combines whole-genome bisulfite sequencing with methylation arrays that can support both screening and biomarker discovery studies targeting over 3.3 million CpGs [64]. These technologies rapidly produce a large amount of data at relatively low costs and are mostly preferred in population studies. On the other hand, epigenome-wide sequencing is another technology that is holding high hopes for future discoveries in the field of epigenetics. Currently, its widespread use is hampered by the high costs and computation burden of the analysis.
4.7. Clinical Implications
Understanding the epigenomic regulation of loci related to inflammatory markers might hold the possibility of discovering attractive targets for controlling inflammatory processes and, consequently, improving therapeutic interventions for chronic diseases that share in their aetiology, inflammatory-related pathophysiology. The identified epigenetic patterns may be used not only in functional studies to provide further insights into molecular mechanisms of inflammatory processes but also in biomarker studies using whole blood to improve the prediction of inflammation-related clinical disorders or events.
Current evidence suggests a potential role of epigenetics on the level of inflammatory markers in blood. Studies reporting on the association of inflammation with global DNA methylation show a hypomethylation trend. However, this evidence is not conclusive. Further studies are recommended to explore this relation. Moreover, studies on the role of histone modifications in inflammation markers are scarce. While most of the studies have been focused on CRP, reporting replicated genes across cohorts such as SOCS3, further efforts should focus on other biomarkers of the inflammatory cascade such as interleukins. Most importantly, given the systemic nature of inflammation, validation of the methylation sites among different tissues is paramount. The identified and reported genes so far involve epigenetics of inflammation with cardiometabolic factors, but also cancer and rheumatic diseases highlighting the potential of these regions as translational targets in the future. Given that we observed a lack of high quality investigations included in this review, we recommend future studies to improve some of the most urging factors such as an appropriate study design. This might be done by involving repeated measurements or with a prospective design that would allow drawing insights on one of the most important drawbacks of epigenetic data, assessing the directionality of the effects. Another important aspect to improve is to increase the sample size in order to provide adequate power and to perform proper adjustment of analysis to account for the role of environment on both epigenetics and inflammation. Lastly, the identified genes need to be validated in functional (in vitro and in vivo) studies in order to draw valuable and conclusive insights into the epigenetic mechanisms of inflammatory markers.
The authors declare that there is no conflict of interest regarding the publication of this paper.
The contributions of the authors were as follows: Valentina Gonzalez-Jaramillo, Eliana Portilla-Fernandez, and Marija Glisic screened title/abstract. Valentina Gonzalez-Jaramillo obtained full text, determined eligibility of articles, and participated in data extraction. Valentina Gonzalez-Jaramillo and Eliana Portilla-Fernandez assessed the quality of the included studies. Eliana Portilla-Fernandez participated in data synthesis/analysis and interpretation of the data. Valentina Gonzalez-Jaramillo, Eliana Portilla-Fernandez, and Jana Nano drafted the final manuscript. All authors contributed to the critical revision of the manuscript and approved the final version.
This project was completed thanks to grant funded by Metagenics Inc.
Supplement Material S1: PRISMA guidelines checklist for reporting systematic reviews. Supplement Material S2: MOOSE guidelines checklist for reporting systematic reviews. Supplement Material S3: Search strategy. It provides a full description of the search strategies of all databases used in this systematic review. Supplement Material S4: Methods. It describes information about study selection and inclusion criteria, data extraction process, and risk of bias assessment. Supplement Table 1: Methylation of genes among candidate-gene approach studies. (Supplementary Materials)
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While originally used as a feminine surname in the Netherlands, Nicole has since become a popular given name. After exploring its origin, I've learned the meaning of the name Nicole.
Meaning of the name Nicole: Derived from the Greek words nikē and Laos, the meaning of the name Nicole is "victory of the people" or "people's victory." The two Greek words were combined to form the feminine given name, Nicole.
The origins of the given name Nicole can be traced back to Ancient Greece, during which the words nikē and Laos were used to describe "victory" and "people," respectively. While Nicole wasn't used as a given name in Ancient Greece, these two words were eventually joined to create the given name Nicole, hence the meaning of the name Nicole.
In addition to being used as a given name, Nicole has also been used as a surname. However, etymologists believe the surname Nicole originated in the Netherlands. During the Middle Ages, Dutch families began using Nicole as a surname. As Nicole became a more common surname, its popularity as a given name increased as well.
The popularity of Nicole as a feminine given name has fluctuated over the years. In 1938, only nine newborn girls in the United States were named Nicole, making it the country's 3,091st most popular girls' name at the time. From there, Nicole gained momentum while climbing the charts. In 1945, Nicole was the 992nd most popular girls' name in the United States. In 1955, Nicole was the 903rd most popular girls' name in the country.
The late 1960s was a pivotal time for the name Nicole, as it finally broke into double-digit popularity. In 1969, Nicole was the 47th most popular girls' name in the United States. In 1970, Nicole was the 30th most popular girls' name in the country. Nicole peaked in 1982 when it ranked as the 6th most popular girls' name in the United States. While Nicole no longer holds this rank, it's still a very popular feminine given the name in English-speaking countries.
Famous women named Nicole include American actress Nicole Kidman, American actress Nicole Sullivan, American singer Nicole Parker, Canadian actress Nicole de Boer, American author Nicole Krauss, Thai singer Nicole Theriault, American tennis player Nicole Arendt, American bodybuilder, and wrestler Nicole Bass and Canadian writer Nicole Markotic.
Popular variants of the name Nicole include Nikki, Nicki, Cole, and Nic.


This week is Metallic Madness. I've been trying a few different things with this plate for a while. This week's theme gave me the inspiration for something better!
I would say I took some liberties with the madness part of this challenge. I used China Glaze Stone Cold and Pure Ice Platinum. Stone Cold dries matte, but it ended up with a satin finish with a shiny topcoat. I had to use a different black for the black swan because the stamper couldn't fully pick up Stone Cold.
To get the swan facing the opposite direction, I stamped with my XL stamper and then onto my Salon Express stamper before my nail. This is definitely a trial and error method, but it eventually worked out well. I wasn't a fan of the asymmetrical wings on this plate, but it actually turned out better that way for me on this manicure. My pinky nail is way to small for the wing size on the left. I used the stamper transfer method on my right hand to get the wings on the correct fingers too.
I love this design! Very clever and very pretty!


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Home Auto Industry News Now You Can Wirelessly Charge Phone From Anywhere Within The Car
Now You Can Wirelessly Charge Phone From Anywhere Within The Car
Surendhar M
Yank Technologies has come up with a new solution that makes wirelessly charging from anywhere within the car reality without exposing to harmful radiations
Consumer Electronics Show (CES) in Las Vegas acts as a popular platform for brands to showcase new and revolutionary future technologies while consolidating on the existing ones. This year's edition saw Sony coming up and surprising all with an electric sedan concept of its own called Vision-S with electronic wizard it had been able to munch in at the highest level.
In 2019, the Indian automotive scene has seen a sudden spike in in-car technologies and connectivity features with cloud-based integration and third-party app control. Almost all new premium vehicles are offered with wireless charging facility, Hyundai Venue, Kia Seltos and upcoming Hyundai Aura for instance, as it has become a necessary feature.
Yank Technologies has taken the wireless charging technology seriously and improved its accessibility. As opposed to the typical Qi wireless charging pads, Yank's version is based on a three-dimensional antenna array and advanced amplifier developments. This lead to your smartphone getting charged anywhere within the cabin. More interestingly, it does not require any physical contact between charge pad and your mobile device.
The Yank charger is capable of providing charge to multiple devices and the major requirement is that the devices should support wireless charging facility. The technology operates in low megahertz frequency bands and due to which the system emits only 0.06 W/kg of radio wave radiation according to the brand and it has been measured by Federal Communications Commission.
The total charging output is a healthy 30 watts, thus even key fob can be charged if it has the facility to adopt it. The Yank charger transmits more power than a phone but at a longer wavelength to be safer for the users. A smartphone used during a regular call emits 1.1-1.5 watts per kilogram in comparison.
With technologies improving seemingly day-by-day, automobile manufacturers are taking advantage of the advancements made and do everything they possible can to offer them on to their products as convenience, versatility and availability of the services play key roles in their success.

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text:
Where Was This Is Not a Comedy Filmed?
Arka Mukhopadhyay
Envisioned by the dynamic duo Rodrigo Guardiola and Gabriel Nuncio, the indie drama movie 'This Is Not A Comedy' ('El Comediante') comes off as a thoughtful, melancholic exploration of the lonely life of an artist. Gabriel Nuncio also portrays the central role as a fictionalized version of himself, a writer-comedian unsure of his place in the world. Life often fails to meet Gabriel's expectations between his dreams of fatherhood, the pursuit of recognition, and an existential crisis.
Meanwhile, a mysterious girl urges him to take the trip to the fabled Amethyst Mountain — she may or may not be a member of the Intergalactic Federation. The profound and serene story takes us to familiar and distant places — an event venue, a soundstage, and on a lonely planet — but you may wonder where the movie was filmed. If the question is bugging you, let us begin an investigation.
This Is Not A Comedy Filming Locations
'This Is Not A Comedy' was filmed in and around Mexico, especially Mexico City. The directors and the cast and crew members presumably wanted to retain the regional essence of the story. Thus, they chose to film the movie in the exact location as its setting. Characterized by a vibrant confluence of cultures, Mexico provides fertile ground for independent and large-scale productions. All productions shot in Mexico and showcased elsewhere are exempted from Value Added Tax.
Some Mexican states and cities offer additional incentives if the producers film in their jurisdiction. Moreover, the favorable exchange rate encourages directors and creators to take their productions to the country. María Secco, whose previous credits include the 2013 Un Certain Regard selection 'The Golden Dream,' handled the cinematography gracefully. Sebastián Narbona served as the production designer for the movie. Let us now take you to the specific locations where the movie was filmed.
Most parts of the filming took place in and around Mexico City, Mexico's dense and culturally opulent capital. The cast and crew members filmed sequences in a studio in the city and some outdoor locations. Sometimes, they ventured out into the valley to capture additional sequences. The Mars sequences were presumably filmed in the Valley of Mexico.
A post shared by Gabriel Nuncio (@gabrielnuncio)
Towering skyscrapers characterize the cosmopolitan city of contemporary times, but its history goes way back in time. The town of Mexico-Tenochtitlan, the historic center of the city, was founded by the indigenous Mexica people in 1325. In the colonial era, the city saw expansion at the hands of the colonizers, becoming the capital of New Spain. Tourists from all over the globe flock to the city today — while some seek history lessons, some bask in the vibrant nightlife.
Read More: This Is Not A Comedy Ending, Explained


text:
Gegants de Sant Josep de Calassanç són dos gegants vinculats a la ciutat de Barcelona. En Quintí i la Peguera són uns gegants que representen una parella de reis medievals i es construïren per participar en les festes de la parròquia de Sant Josep de Calassanç, situada al carrer de Joan de Peguera i a les del casal de Sant Josep de Calassanç al carrer Sant Quintí.

Les figures foren dissenyades i modelades pel mestre imatger barceloní Domènec Umbert i Vilaseró, que les va elaborar a la parròquia mateix, i s'estrenaren el juny del 1982. Des d'aleshores també han sortit a les festes del Clot i del Camp de l'Arpa, a més de les de la ciutat —la Mercè i Santa Eulàlia.

L'any 1999 s'encarregà la restauració de la parella de gegants a l'escultor Manel Casserras i Solé.

Quan surten, en Quintí i la Peguera van acompanyats de tres capgrossos —un català i dos macers— i celebren la trobada cada any per les festes del Clot – Camp de l'Arpa, el primer cap de setmana de novembre.

Referències

Sant Josep De Calassanc
El Camp de l'Arpa del Clot

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text: Q: Как работать на сайте У меня есть свой сайт (от megagroup.ru) Хочу писать статьи. Как научиться пользоваться всеми возможностями сайта?? изображения, активные ссылки и.т.д Можете поделиться где я могу найти книгу, статью??


This collection, Fairy Tales from the Arabian Nights presents a re-telling of some classic Middle Eastern and South Asian folk tales by E. Dixon – beautifully illustrated by John D. Batten. Whilst the narratives differ greatly in their origins, characters, and motifs – they all stem from the initial 'frame story' of the ruler Shahryār, and his wife Scheherazade. She tells a different tale each night, never revealing the ending – in order that the King may spare her life….
Tales within this book include: 'The King of Persia and the Princess of the Sea', 'Prince Beder and the Princess Giauhara', The Three Princes and Princess Nouronnihar', 'Prince Ahmed and the Fairy', 'Prince Camaralzaman and the Princess of China', 'The Loss of the Talisman', ' The Seven Voyages of Sinbad the Sailor' and others.
John Dickson Batten (1860-1932) was a British painter, illustrator and print maker,who was a leading light in the Art Nouveau movement. He illustrated a series of fairy tale books written by Joseph Jacobs as well as this English language version of Arabian Nights, and Dante's Inferno. His illustrations are strongly influenced by the printmakers of Japan and are characterised by an intense romanticism and refined technique.
Presented alongside the text, Batten's enchanting creations serve to further refine and enhance the classic Arabian storytelling – making this a book to be enjoyed and appreciated, by both young and old alike.
With works such as Fairy Tales From The Arabian Nights – Illustrated by John D. Batten, Pook Press celebrates the great 'Golden Age of Illustration' in children's literature – a period of unparalleled excellence in book illustration from the 1880s to the 1930s.


text:
French roundabouts are also about revolution of a political kind
France has more roundabouts than any other country – we trace their history and how they have come to symbolise deep worries about French cultural identity
Aerial view of one of the Loire-Atlantique's many roundabouts, in Chéméré Pic: Drone Altitude_shutterstock
By Théophile Larcher
Driving in Nantes can sometimes give the impression you are going around in circles, rather than getting anywhere fast.
This might be because the city has the most roundabouts (ronds-points) in France – an estimated 1,100, or one for every 298 inhabitants. Together, they make up a third of the Loire-Atlantique department's total.
While Nantes might have a glut, roundabouts have mushroomed on every road and avenue of the territory since the 1960s.
So much so that France now has the dubious honour of being the country with the most roundabouts in the world.
As of the latest figures available (August 5, 2018), it had some 65,127 roundabouts – almost twice as many as the United Kingdom (32,599), according to data collected by the website Beyond the Maps, although no official government record on the topic exists.
Congestion to cultural identity
Roundabouts were initially conceived to help modern cities combat congestion and cut road accidents.
They also gained popularity with local politicians and artists as a tool to market their town or work. By law, any new road must have a certain amount of its budget allocated to artwork to adorn it, which is why you see so many artworks by motorways – and hence, roundabout art abounds.
However, in 2018, the gilets jaunes protests, which centred on roundabouts, gave credence to theories that the structures had come to symbolise deeper worries about French cultural identity.
Occupying them became a form of resistance for people who felt excluded from society.
Read more: Who are the gilets jaunes today?
Eric Alonzo is an architect and teacher at the Ecole d'architecture de la ville et des territoires, Paris, and France's expert on all things roundabout-related, having written a book on the subject in 2005.
"Roundabouts in France are the story of a technical norm that sprawled nationwide," he said.
History of roundabouts
Modern roundabouts have their roots in 17th-century forests and parks and were installed by André Le Nôtre, Louis XIV's personal gardener, in various places around Paris along what would become the Champs-Elysées.
The first proper ones in France were implemented at the start of the 20th century by the architect and highly influential urban planner Eugène Hénard, who devoted much of his life to finding solutions to growing traffic problems in Paris.
Read more: Frenchman pioneered concept of roundabouts
By 1906, there were an estimated 65,543 vehicles in the capital. One of the most congested and most dangerous places to navigate, even then, was the Place de l'Etoile, with the Arc de Triomphe in its centre and 12 roads converging on to it, as there were no rules for moving round, entering or exiting the circuit.
In 1897, a British man, Holroyd Smith, came up with the idea that there should only be movement in one direction in a circle.
The concept was applied in 1907 by Mr Hénard at both the Place de l'Etoile and the Place de la Nation in Paris. He called them carrefours à girations.
Who had the idea first?
His work came around the same time the United States installed New York's Columbus Circle (1904), and the circular junction at Letchworth Garden City opened in the United Kingdom (1909), with the three countries disputing who had come up with the idea first.
Michel Dalloni, a journalist from Le Monde who wrote a six-part series on roundabouts for the newspaper last year, said: "It is hard to track the creator of the modern roundabout since it appeared in several cities confronted by the new car congestion phenomenon."
The US started to give up on roundabouts after World War One. So, too, did France, and the 1920s to 1960s were wilderness years, although some were built.
'British roundabouts'
It was not until engineer Léon de Paulou-Massat experimented with them in Essonne department to lower fatal crashes at crossroads that they caught on once more.
Here again, the UK proved a source of inspiration. Mr Paulou-Massat's idea was to shrink the size of roundabouts and use a British 'give way' system, said Mr Alonzo.
"The French referred to them as 'British roundabouts'. Some argued that the concept was so 'typically British' – relying on fair play and trust from drivers – that it would never work elsewhere."
In fact, the experiment went so well that it prompted some of his students and admirers to extend the use of roundabouts to Brittany and southern France.
In the 1980s, former Prime Minister Jean-Marc Ayrault, then mayor of Saint-Herblain (Loire-Atlantique), was taken on a trip to the UK to observe the mini-roundabouts the country had started to install to resolve congestion and accidents.
It inspired the government to pass a decree in 1983 adopting the give-way-on-entry rule at all roundabouts.
When socialist president François Mitterrand opened France to more decentralisation and allowed regions to manage road systems as they liked, roundabouts exploded.
Mayors saw them as relatively cheap ways to lower accidents and, by putting art installations in the middle, to give drivers a good impression of their town.
Symbols of alienation
However, Mr Alonzo in his book, as well as a growing number of sociologists and anthropologists, started highlighting how they had also become symbols of alienation.
In his final chapter, Mr Alonzo showed how they had moved away from their original road safety and traffic-easing purposes to take on political connotations.
Pierre Goetschel, a French filmmaker, developed this theory in a documentary on roundabouts in 2009.
"I wanted to explore the things surrounding us that we never question," he said, adding that by this time roundabouts had become a symbol of France breaking up into separate, isolated spaces.
He said he was inspired by French writer Georges Perec, as well as anthropologist Marc Augé, who had included roundabouts as part of his 'non-places' theory to refer to spaces of transience where human beings remain anonymous.
Gilets jaunes protests
Unbeknown to Mr Goetschel, the documentary was 10 years ahead of its time.
The gilets jaunes protesters occupied roundabouts to express feelings of anger at being relegated from society.
"Protesters took to roundabouts as the space that personified their invisibility the most," said Mr Goetschel.
No surprise that his documentary benefited from a 'second life' on TV in the aftermath of the protests.
The documentary also included other comments from Marc Augé that have found an echo in wider society in the wake of the Covid pandemic.
Mr Augé said roundabouts exemplify how modern society gives the illusion of free movement while the reality is a small elite are reaping the fruits of globalisation while throngs of people are "imprisoned at home" and destined to be "mere consumers feeding the machine".
'Peanut roundabout' in Nozay
None of these concerns has stopped Loire-Atlantique experimenting further with roundabouts.
In January 2020, the town of Nozay unveiled its so-called 'peanut roundabout' in the shape of an elongated circle, a new twist on the traditional shape, designed to slow vehicles down.
Read more: French drivers welcome new 'peanut-shaped roundabout'
Novel shape notwithstanding, it is surely still easier to navigate than the UK's notorious 'Magic Roundabout' in Swindon.
Who has priority at roundabouts?
'Transforming Paris' ring road could help unify the city or divide it'
A guide to driving in France
More from Explore France
From Renaissance to Hockney - 12 Spring exhibitions to see in France
The Paris suburb housing estate that is like no other in France
MBE awarded to British woman who trained WW2 spies for French missions
France's Catholic 'influencers' find new audience online
Smart water meters let households track usage in France


The President of Salisbury and District Chamber of Commerce & Industry, Andy Rhind-Tutt, attended the City of Salisbury Mayor Making Service on Saturday 14th May, 2016.
This annual Ceremony is the official handover of the Mayoral Chain of office and this year it passed from Cllr Andrew Roberts to Cllr Derek Brown OBE who became the 756th Worshipful Mayor of the City of Salisbury. Over 200 Civic Dignitaries and guests, including Mayors from neighbouring towns and cities as well as the Mayors of Salisbury's twin cities of Saintes and Xanten were present. President Andy proudly represented our members of Salisbury and Districts business community, congratulated the new Mayor on his inauguration and is looking forward to working closely with the City Council to provide a collective voice from our businesses to help steer the regeneration of Salisbury over the coming years.


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Who Will Fix Cars in 2025?
This article first appeared on audatex.ca
Your mechanic, no?
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It's coming fast, and there's a huge problem facing the Canadian auto aftermarket, attacking on two fronts: rapidly advancing vehicle technology and a shortage of skilled tradespeople....
The Lead Battery Industry Faces Competition From a Surprising Place: Your Phone
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text:
group of physical, mental and spiritual practices originating from ancient India
For other uses, see Yogi (disambiguation).
Yoga is an old discipline of Hindu philosophy from India. It is both spiritual and physical. Yoga uses breathing techniques, exercise and meditation. It helps to improve health and happiness. Yoga is the Sanskrit word for union. Patanjali was a pioneer of classical yoga. He defined yoga as "the cessation of the modification of the mind" (stopping changing the mind).
Statue of Shiva doing Yogic meditation. The statue is in Bangalore, India.
A person doing yoga will move from one posture (called asana) to another, but there are also other aspects which are important in yoga, such as breath-work, mantras, mudras (postures of the hands and fingers), meditation and much more (for more information, check out the Yoga Sutras). For example, the "sun-salutation" contains 12 poses of asanas, one after the other, and is said to help balance body and soul. There is a specific mantra for each asana. The "sun-salutation" is popularly known as "Suryanamaskar".
2 Important yoga words
3 Types of yoga
4 Some popular Yogasanas
6 Other websites
Yoga was introduced by Indian Ascetic. Ascetic practices (tapas) are referenced in the Brāhmaṇas (900 to 500 BC), early commentaries on the Vedas. Gavin D. 1996. An introduction to Hinduism. Cambridge University Press, p94.</ref> Several seals discovered at Indus Valley Civilization (~3300–1700 B.C.) sites in Pakistan depict figures in positions resembling a common yoga or meditation pose. The pose shows "a form of ritual discipline, suggesting a precursor of yoga", according to archaeologist Gregory Possehl.[1] Scholars think there must be some type of connection between the Indus Valley seals and later yoga and meditation practices, though there is no conclusive evidence.
Jonathan Mark Kenoyer describes one figure as "seated in yogic position".[2]
Karel Werner writes that " Archeological discoveries allow us therefore to speculate with some justification that a wide range of Yoga activities was already known to the people of pre-Aryan India".[3]
Important yoga wordsEdit
Yama: Positive Rules of meditations.
Niyama: Prohibitory Rules of meditations.
Asanas: Physical postures and movements.
Pranayama: Breathing techniques
Pratyahara: Controlling the mind.
Dharana: Gazing inward.
Dhyana: Meditation with object.
Samadhi: Meditation without object.
Types of yogaEdit
Classification based on mind and body.
Rajayoga: Raja yoga focuses on meditation and contemplation in order to fully realize the self.
Hathayoga: Hatha yoga is the practice of yoga postures, or asana, using the body as a vehicle for self-transformation.
Classification based on way of spiritual life.
Gyanyoga: It is a way of knowledge.
Karmayoga: It is a way of work.
Bhaktiyoga: It is a way of worship. [4]
Classification based on a way of other things.
Swaryoga: Emphasizes the most on breathing.
Kriyayoga: Emphasizes the most on blending Karmayoga (Tapa), Gyanyoga (Swadhyay) and Bhaktiyoga (Ishwar Pranidhan).
Some popular YogasanasEdit
Pawanmuktasana (gas release pose) used generally to release the gases in the stomach
Ushtrasana
A yogasana is a pose in which a person can sit. The intention of yogasana is to exercise the body and make it free of pains and problems.
Yogi is a person who has mastered yoga or has achieved great success in yoga. Yogasanas are also called Asana or Asanas (plural). A Yogi can sit in any asana for a given time.
Pawanmuktasana
This yogasana helps to release gas in the stomach.
This yogasana makes the spine more relaxed.[5][6]
↑ Possehl, Gregory 2003. The Indus Civilization: a contemporary perspective. AltaMira Press, 144/5. ISBN 978-0-7591-0172-2
↑ Around the Indus in 90 Slides by Jonathan Mark Kenoyer
↑ Werner, Karel 1998. Yoga and Indian philosophy. Motilal Banarsidass Publ. ISBN 81-208-1609-9 [1]
↑ "Types of yoga". Yoga Type. Retrieved May 5, 2022.
↑ "Ushtrasana". Yoga Point. Yoga Vidya Gurukul. Retrieved 23 July 2016.
↑ link, Yoga; Importance, Other. "The History of Yoga and its Importance Today". Sarthak Sharma. Retrieved 14 September 2022.
Other websitesEdit
Wikimedia Commons has media related to Yoga.
Yoga Diary - articles on yoga 2022
Retrieved from "https://simple.wikipedia.org/w/index.php?title=Yoga&oldid=8610747"


text:
Der Distrikt Bilaspur befindet sich im nördlichen Teil des indischen Bundesstaates Chhattisgarh.

Er erstreckt sich über eine Fläche von 5818,49 km². Der Fluss Arpa durchfließt den Distrikt in südlicher Richtung, passiert die Distrikthauptstadt Bilaspur und mündet im Süden in den Shivnath, der die südliche Distriktgrenze bildet. Weitere Fließgewässer im Distrikt sind Maniyari und Lilagar, beides ebenfalls linke Nebenflüsse des Shivnath. Der Höhenrücken Amarkantak-Lapha Hill Range trennt den südlichen Distriktteil vom nördlichen. Dort liegen die Tehsils  Marwahi, Pendra und  Pendra Road.

Geschichte
Der Distrikt Bilaspur existierte schon vor der Gründung des Bundesstaates Chhattisgarh am 1. November 2000 und war zuvor Teil des Bundesstaates Madhya Pradesh.

Bevölkerung
Der Distrikt Bilaspur hatte im Jahr 2011 2.663.629 Einwohner auf einer Fläche von 8272 km².
Am 1. Januar 2012 spalteten sich die drei westlich gelegenen Tehsils Mungeli, Lormi und Pathariya ab und bilden seitdem den neu gegründeten Distrikt Mungeli. Dadurch verkleinerte sich die Distriktfläche auf 5818,49 km². Die entsprechende Einwohnerzahl betrug gemäß dem Zensus 2011 knapp 2 Millionen.
Die Geschlechterverteilung lag bei 1000 Männern auf 970 Frauen. Die Alphabetisierungsrate betrug 72,9 %.

Verwaltungsgliederung
Der Distrikt ist in 8 Tehsils gegliedert: Bilaspur, Bilha, Kota, Marwahi, Masturi, Pendra, Pendra Road und Takhatpur.
Die Distrikthauptstadt Bilaspur ist eine Municipal Corporation. Daneben gibt es noch 16 Städte und 899 Dörfer.

Weblinks
 Offizielle Webseite des Distrikts Bilaspur

Einzelnachweise

Distrikt in Chhattisgarh