| 11. |
- Lauc, Gordan, et al.
(författare)
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Loci Associated with N-Glycosylation of Human Immunoglobulin G Show Pleiotropy with Autoimmune Diseases and Haematological Cancers
- 2013
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 9:1, s. e1003225-
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Tidskriftsartikel (refereegranskat)abstract
- Glycosylation of immunoglobulin G (IgG) influences IgG effector function by modulating binding to Fc receptors. To identify genetic loci associated with IgG glycosylation, we quantitated N-linked IgG glycans using two approaches. After isolating IgG from human plasma, we performed 77 quantitative measurements of N-glycosylation using ultra-performance liquid chromatography (UPLC) in 2,247 individuals from four European discovery populations. In parallel, we measured IgG N-glycans using MALDI-TOF mass spectrometry (MS) in a replication cohort of 1,848 Europeans. Meta-analysis of genome-wide association study (GWAS) results identified 9 genome-wide significant loci (P<2.27x10(-9)) in the discovery analysis and two of the same loci (B4GALT1 and MGAT3) in the replication cohort. Four loci contained genes encoding glycosyltransferases (ST6GAL1, B4GALT1, FUT8, and MGAT3), while the remaining 5 contained genes that have not been previously implicated in protein glycosylation (IKZF1, IL6ST-ANKRD55, ABCF2-SMARCD3, SUV420H1, and SMARCB1-DERL3). However, most of them have been strongly associated with autoimmune and inflammatory conditions (e. g., systemic lupus erythematosus, rheumatoid arthritis, ulcerative colitis, Crohn's disease, diabetes type 1, multiple sclerosis, Graves' disease, celiac disease, nodular sclerosis) and/or haematological cancers (acute lymphoblastic leukaemia, Hodgkin lymphoma, and multiple myeloma). Follow-up functional experiments in haplodeficient Ikzf1 knock-out mice showed the same general pattern of changes in IgG glycosylation as identified in the meta-analysis. As IKZF1 was associated with multiple IgG N-glycan traits, we explored biomarker potential of affected N-glycans in 101 cases with SLE and 183 matched controls and demonstrated substantial discriminative power in a ROC-curve analysis (area under the curve=0.842). Our study shows that it is possible to identify new loci that control glycosylation of a single plasma protein using GWAS. The results may also provide an explanation for the reported pleiotropy and antagonistic effects of loci involved in autoimmune diseases and haematological cancer.
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| 12. |
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| 13. |
- Marković, Slobodan B., et al.
(författare)
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The relationship between the loess stratigraphy in the Vojvodina region of northern Serbia and the Saalian and Rissian Stage glaciations – a review
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Ingår i: Boreas. - 0300-9483.
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Tidskriftsartikel (refereegranskat)abstract
- The regional loess stratigraphy in the Vojvodina region, in the southeastern Carpathian Basin, has often been successfully correlated to the global palaeoclimate. This is a quasi-continuous sedimentary record that provides detailed environmental reconstruction during the last four glacial/interglacial cycles. In this study, we present a standardized loess stratigraphy and illustrate how it correlates with the marine oxygen isotope and Chinese loess stratigraphical records. We argue that the loess stratigraphy in Vojvodina region is an important link in the integration of European terrestrial stratigraphical schemes and the deep-sea stratigraphical model. We highlight how the loess record can better illustrate terrestrial environmental change through multiple glacial cycles than other records, such as glacial records. The investigated loess record enables direct links to be made between the loess sediments and their glacial sources. This reveals evidence of glaciations during every glacial cycle of the Saalian Stage complex, equivalent to Marine Isotope Stage (MIS) 10, 8 and 6. Therefore, Serbian loess has the potential to provide a direct link between terrestrial glaciations and wider records of global climate change, which is an enigma for many other continental records. These loess records display a strong relationship with the intensity of European glaciations during different glacial cycles. Loess sedimentation rates are highest in the most intensive European glaciation of the Saalian complex (MIS 6) and much lower during the weaker ‘missing’ glaciations equivalent to MIS 8 and 10. A key observation from the Vojvodina loess is the gradual increase in interglacial aridity through the late Middle Pleistocene. The explanation for the progressively increasing aridity in the investigated region at this time is still unclear. However, this trend is consistent with the idea of the Saalian complex as representing a 400 ka mega glacial cycle modulated by shorter classic 100 ka glacial cycles.
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| 14. |
- Moltubakk, S. N., et al.
(författare)
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The educational gradient in dental caries experience in Northern- Norway: a cross-sectional study from the seventh survey of the Tromsø study
- 2023
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Ingår i: Bmc Oral Health. - 1472-6831. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Although, studies from Norway indicate a reduction in dental caries experience, in Northern-Norway this non-communicable oral condition is still prevalent. There is conflicting evidence of presence of social inequalities in dental caries in an adult population. Therefore, the aim of this study was to assess an association between educational level and dental caries experience in adults in urban Tromso municipality, Northern-Norway, using The World Health Organization (WHO) Commission on Social Determinants of Health (CSDH) framework of health determinants.Methods Data from 3752 participants having recorded dental caries status and educational level in the seventh survey of the Tromso Study: Tromso7 were included. Dental status was examined clinically as decayed-, missing-, filled-teeth (DMFT score). For statistical analyses DMFT score was grouped into lower (DMFT < 19) and higher (DMFT >= 20). Educational level was obtained from a questionnaire and categorized as primary/partly secondary education, upper secondary education, tertiary education, short and tertiary education, long. Data on social and intermediary determinants was also self-reported. Univariable and multivariable binary logistic regression analyses were applied.Result This study included 1939 (52%) women and the mean age of the participants was 57.11. The mean DMFT score was 18.03. The odds of having higher DMFT score followed a gradient based on educational level. Participants who reported lower than secondary education had 2.06 -fold increased odds of having higher DMFT score than those with tertiary education, long (OR: 2.06, 95% CI: 1.50-2.83). Those with upper secondary education had 60% higher odds of having higher DMFT score (OR: 1.60, 95% CI: 1.21-2.11), and those with tertiary education, short had 66% higher odds of having higher DMFT score (OR: 1.66, 95% CI: 1.24-2.22).Conclusion The current cross-sectional study suggested an educational gradient in dental caries experience in an adult population of Northern- Norway. Further studies validating our results and investigating mechanisms of educational inequalities in oral health are warranted.
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| 15. |
- Morales-Berstein, Fernanda, et al.
(författare)
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Ultra-processed foods, adiposity and risk of head and neck cancer and oesophageal adenocarcinoma in the European Prospective Investigation into Cancer and Nutrition study : a mediation analysis
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Ingår i: European Journal of Nutrition. - 1436-6215.
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To investigate the role of adiposity in the associations between ultra-processed food (UPF) consumption and head and neck cancer (HNC) and oesophageal adenocarcinoma (OAC) in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.METHODS: Our study included 450,111 EPIC participants. We used Cox regressions to investigate the associations between the consumption of UPFs and HNC and OAC risk. A mediation analysis was performed to assess the role of body mass index (BMI) and waist-to-hip ratio (WHR) in these associations. In sensitivity analyses, we investigated accidental death as a negative control outcome.RESULTS: During a mean follow-up of 14.13 ± 3.98 years, 910 and 215 participants developed HNC and OAC, respectively. A 10% g/d higher consumption of UPFs was associated with an increased risk of HNC (hazard ratio [HR] = 1.23, 95% confidence interval [CI] 1.14-1.34) and OAC (HR = 1.24, 95% CI 1.05-1.47). WHR mediated 5% (95% CI 3-10%) of the association between the consumption of UPFs and HNC risk, while BMI and WHR, respectively, mediated 13% (95% CI 6-53%) and 15% (95% CI 8-72%) of the association between the consumption of UPFs and OAC risk. UPF consumption was positively associated with accidental death in the negative control analysis.CONCLUSIONS: We reaffirmed that higher UPF consumption is associated with greater risk of HNC and OAC in EPIC. The proportion mediated via adiposity was small. Further research is required to investigate other mechanisms that may be at play (if there is indeed any causal effect of UPF consumption on these cancers).
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| 16. |
- Saksida, Tamara, et al.
(författare)
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Galectin-3 deficiency protects pancreatic islet cells from cytokine-triggered apoptosis in vitro
- 2013
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Ingår i: Journal of Cellular Physiology. - : Wiley. - 1097-4652 .- 0021-9541. ; 228:7, s. 1568-1576
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Tidskriftsartikel (refereegranskat)abstract
- Beta cell apoptosis is a hallmark of diabetes. Since we have previously shown that galectin-3 deficient (LGALS3/) mice are relatively resistant to diabetes induction, the aim of this study was to examine whether beta cell apoptosis depends on the presence of galectin-3 and to delineate the underlying mechanism. Deficiency of galectin-3, either hereditary or induced through application of chemical inhibitors, -lactose or TD139, supported survival and function of islet beta cells compromised by TNF-+IFN-+IL-1 stimulus. Similarly, inhibition of galectin-3 by -lactose or TD139 reduced cytokine-triggered apoptosis of beta cells, leading to conclusion that endogenous galectin-3 propagates beta apoptosis in the presence of an inflammatory milieu. Exploring apoptosis-related molecules expression in primary islet cells before and after treatment with cytokines we found that galectin-3 ablation affected the expression of major components of mitochondrial apoptotic pathway, such as BAX, caspase-9, Apaf, SMAC, caspase-3, and AIF. In contrast, anti-apoptotic molecules Bcl-2 and Bcl-XL were up-regulated in LGALS3/ islet cells when compared to wild-type (WT) counterparts (C57BL/6), resulting in increased ratio of anti-apoptotic versus pro-apoptotic molecules. However, Fas-triggered apoptotic pathway as well as extracellular signal-regulated kinase 1/2 (ERK1/2) was not influenced by LGALS-3 deletion. All together, these results point to an important role of endogenous galectin-3 in beta cell apoptosis in the inflammatory milieu that occurs during diabetes pathogenesis and implicates impairment of mitochondrial apoptotic pathway as a key event in protection from beta cell apoptosis in the absence of galectin-3. J. Cell. Physiol. 228: 15681576, 2013. (c) 2012 Wiley Periodicals, Inc.
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| 17. |
- Volarevic, Vladislav, et al.
(författare)
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Gal-3 regulates the capacity of dendritic cells to promote NKT-cell-induced liver injury
- 2015
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Ingår i: European Journal of Immunology. - : Wiley. - 1521-4141 .- 0014-2980. ; 45:2, s. 531-543
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Tidskriftsartikel (refereegranskat)abstract
- Galectin-3 (Gal-3), an endogenous lectin, exhibits ro- and anti-inflammatory effects in various disease conditions. In order to explore the role of Gal-3 in KT-cell-dependent pathology, we induced hepatitis in C57BL/6WT and al-3-deficient mice by using specific ligand for KT cells: alpha-galactosylceramide, glycolipid Ag presented by CD1d. The injection of alpha-galactosylceramide significantly enhanced expression of Gal-3 in liver NKT and dendritic cells (DCs). Genetic deletion or selective inhibition of Gal-3 (induced by Gal-3-inhibitor TD139) abrogated the susceptibility to NKT-cell-dependent hepatitis. Blood levels of pro-inflammatory cytokines (TNF-alpha-, IFN-gamma, IL-12) and their production by liver DCs and NKT cells were also downregulated. Genetic deletion or selective inhibition of Gal-3 alleviated influx of inflammatory CD11c(+) CD11b(+) DCs in the liver and favored tolerogenic phenotype and IL-10 production of liver NKT and DCs. Deletion of Gal-3 attenuated the capacity of DCs to support liver damage in the passive transfer experiments and to produce pro-inflammatory cytokines in vitro. Gal-3-deficient DCs failed to optimally stimulate production of pro-inflammatory cytokines in NKT cells, in vitro and in vivo. In conclusion, Gal-3 regulates the capacity of DCs to support NKT-cell-mediated liver injury, playing an important pro-inflammatory role in acute liver injury.
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| 18. |
- Volarevic, Vladislav, et al.
(författare)
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Galectin-3 deficiency prevents concanavalin A-induced hepatitis in mice
- 2012
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Ingår i: Hepatology. - : Ovid Technologies (Wolters Kluwer Health). - 1527-3350 .- 0270-9139. ; 55:6, s. 1954-1964
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Tidskriftsartikel (refereegranskat)abstract
- We used concanavalin A (Con A)-induced liver injury to study the role of galectin-3 (Gal-3) in the induction of inflammatory pathology and hepatocellular damage. We tested susceptibility to Con Ainduced hepatitis in galectin-3-deficient (Gal-3-/-) mice and analyzed the effects of pretreatment with a selective inhibitor of Gal-3 (TD139) in wild-type (WT) C57BL/6 mice, as evaluated by a liver enzyme test, quantitative histology, mononuclear cell (MNC) infiltration, cytokine production, intracellular staining of immune cells, and percentage of apoptotic MNCs in the liver. Gal-3-/- mice were less sensitive to Con Ainduced hepatitis and had a significantly lower number of activated lymphoid and dendritic cells (DCs) in the liver. The level of tumor necrosis factor alpha (TNFa), interferon gamma (IFN?), and interleukin (IL)-17 and -4 in the sera and the number of TNFa-, IFN?-, and IL-17- and -4-producing cluster of differentiation (CD)4+ cells as well as IL-12-producing CD11c+ DCs were lower, whereas the number of IL-10-producing CD4+ T cells and F4/80+ macrophages were significantly higher in livers of Gal-3-/- mice. Significantly higher percentages of late apoptotic Annexin V+ propidium-idodide+ liver-infiltrating MNCs and splenocytes were observed in Gal-3-/- mice, compared to WT mice. Pretreatment of WT C57BL/6 mice with TD139 led to the attenuation of liver injury and milder infiltration of IFN?- and IL-17- and -4-producing CD4+ T cells, as well as an increase in the total number of IL-10-producing CD4+ T cells and F4/80+ CD206+ alternatively activated macrophages and prevented the apoptosis of liver-infiltrating MNCs. Conclusions: Gal-3 plays an important proinflammatory role in Con Ainduced hepatitis by promoting the activation of T lymphocytes and natural killer T cells, maturation of DCs, secretion of proinflammatory cytokines, down-regulation of M2 macrophage polarization, and apoptosis of MNCs in the liver. (HEPATOLOGY 2012;55:19541964)
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| 19. |
- Wahlund, CJE, et al.
(författare)
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Sarcoidosis exosomes stimulate monocytes to produce pro-inflammatory cytokines and CCL2
- 2020
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1, s. 15328-
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Tidskriftsartikel (refereegranskat)abstract
- Pulmonary sarcoidosis has unknown etiology, a difficult diagnostic procedure and no curative treatment. Extracellular vesicles including exosomes are nano-sized entities released from all cell types. Previous studies of exosomes from bronchoalveolar lavage fluid (BALF) of sarcoidosis patients have revealed pro-inflammatory components and abilities, but cell sources and mechanisms have not been identified. In the current study, we found that BALF exosomes from sarcoidosis patients, but not from healthy individuals, induced a dose-dependent elevation of intracellular IL-1β in monocytes. Analyses of supernatants showed that patient exosomes also induced release of IL-1β, IL-6 and TNF from both PBMCs and enriched monocytes, suggesting that the observed effect is direct on monocytes. The potently chemotactic chemokine CCL2 was induced by exosomes from a subgroup of patients, and in a blocking assay the exosome-induced CCL2 was reduced for 13 out of 19 patients by the asthma drug Montelukast, a cysteinyl leukotriene receptor antagonist. Further, reactive oxygen species generation by PBMCs was induced to a higher degree by patient exosomes compared to healthy exosomes. These findings add to an emerging picture of exosomes as mediators and disseminators of inflammation, and open for further investigations of the link between CCL2 and exosomal leukotrienes in sarcoidosis.
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