The role of consuming different types of fatty acids (FA) at the expense of carbohydrates (CHO), on the blood lipid profile of adolescents is largely unknown, as is the modulating effect of different ...levels of physical activity (PA). Children from the GINIplus and LISA birth cohorts, with complete data on dietary FA (assessed by food-frequency questionnaires), objectively-measured PA (assessed by accelerometers) and blood lipids (lipoprotein cholesterol and triglycerides) at age 15 years, were included (
= 837). Sex-stratified associations between dietary FA and blood lipids were assessed by linear regression in substitution models which represented isocaloric replacements of CHO with saturated FA (SFA), monounsaturated FA (MUFA), n-3 polyunsaturated FA (PUFA) or n-6 PUFA. To assess the interactions with PA, analyses were then performed stratified by tertiles of different PA levels (sedentary, lifestyle, moderate-to-vigorous (MVPA)). Both sexes presented a significant inverse association between MUFA and triglycerides, and females a direct association between n-3 PUFA and high-density lipoprotein. Stratifying by PA tertiles, associations were mainly restricted to participants with the lowest levels of lifestyle PA, or the highest time spent sedentary. The effects of dietary FA on the lipid profile vary in an activity-specific manner, emphasizing possible synergistic roles of diet and PA.
Human interleukin 2 (IL-2; Proleukin) is an approved therapeutic for advanced-stage metastatic cancer; however, its use is restricted because of severe systemic toxicity. Its function as a central ...mediator of T-cell activation may contribute to its efficacy for cancer therapy. However, activation of natural killer (NK) cells by therapeutically administered IL-2 may mediate toxicity. Here we have used targeted mutagenesis of human IL-2 to generate a mutein with approximately 3,000-fold in vitro selectivity for T cells over NK cells relative to wild-type IL-2. We compared the variant, termed BAY 50-4798, with human IL-2 (Proleukin) in a therapeutic dosing regimen in chimpanzees, and found that although the T-cell mobilization and activation properties of BAY 50-4798 were comparable to human IL-2, BAY 50-4798 was better tolerated in the chimpanzee. BAY 50-4798 was also shown to inhibit metastasis in a mouse tumor model. These results indicate that BAY 50-4798 may exhibit a greater therapeutic index than IL-2 in humans in the treatment of cancer and AIDS.
Fatty acids exert a range of different biological activities that could be relevant in the development of atopic dermatitis (AD). This study investigated the association of glycerophospholipid fatty ...acids (GPL-FA) with AD, and their interactions with single nucleotide polymorphisms (SNP) of the FADS1-3 gene cluster. Among 390 infants of the Indonesian ISADI study, GPL-FA were measured in umbilical plasma (P-0y) and in buccal cells at birth (B-0y), and again in buccal cells at AD onset or one year (B-1y). Prospective and cross-sectional associations with AD were assessed by logistic regression. Interactions of GPL-FA with 14 SNP were tested assuming an additive model. AD was diagnosed in 15.4% of participants. In B-1y, C18:2n-6 was inversely associated with AD; and positive associations were observed for C18:1n-9, C20:4n-6, C22:6n-3 and C20:4n-6/C18:2n-6. There were no prospective associations with AD, however, a significant interaction between the SNP rs174449 and B-0y C14:0 (myristic acid) was observed. This study indicates that Indonesian infants with AD have increased rates of endogenous long-chain polyunsaturated fatty acid production, as well as higher C18:1n-9 levels. GPL-FA measured at birth do not predict later AD incidence; however, genotype interactions reveal novel effects of myristic acid, which are modified by a FADS3 variant.
In industrial practice, there is a demand for a reference standard for viscosity that is established for a readily available fluid to simplify the calibration of industrial viscometers for moderately ...high viscosities (50 to 125) mPa·s. Diisodecyl phthalate (DIDP) has been suggested as that reference fluid, and a number of studies of its properties have been carried out in several laboratories throughout the world, within the auspices of a project coordinated by the International Association for Transport Properties. That project has now progressed to the point where it is possible to collate the results of studies of the viscosity of the fluid by a number of different techniques, so as to lead to a proposed standard reference value which will be included in the paper. To support this recommended value, the various measurements conducted have been critically reviewed, and the sample purity and other factors affecting the viscosity have been studied. Density and surface tension measurements have also been performed. This paper does not describe the individual viscosity determinations carried out in independent laboratories because these are the subject of individual publications, but it does describe the ancillary studies conducted and their relevance to the viscosity standard. In addition, the paper contains recommended values for the viscosity of liquid DIDP. The samples of DIDP to which the recommended values refer are isomeric mixtures available commercially from certain suppliers, with a minimum purity by gas chromatography of 99.8 %. The recommended values result from a critical examination of all the measurements conducted to date and are supported by careful arguments dealing with the likely effects of the isomeric content of the sample as well as of other impurities. The proposed reference standard is intended particularly to serve an industrial need for a readily available calibration material with a viscosity close to that required in practical situations. To that end, the recommended value has an overall relative uncertainty of approximately 1 %. It is therefore not intended to supersede for the reference value for the viscosity of water at 20 °C, which is known much more accurately, but rather to complement it.
The MHC region harbors the strongest loci for latent autoimmune diabetes in adults (LADA); however, the strength of association is likely attenuated compared with that for childhood-onset type 1 ...diabetes. In this study, we recapitulate independent effects in the MHC class I region in a population with type 1 diabetes and then determine whether such conditioning in LADA yields potential genetic discriminators between the two subtypes within this region.
Chromosome 6 was imputed using SNP2HLA, with conditional analysis performed in type 1 diabetes case subjects (
= 1,985) and control subjects (
= 2,219). The same approach was applied to a LADA cohort (
= 1,428) using population-based control subjects (
= 2,850) and in a separate replication cohort (656 type 1 diabetes case, 823 LADA case, and 3,218 control subjects).
The strongest associations in the MHC class II region (rs3957146, β SE = 1.44 0.05), as well as the independent effect of MHC class I genes, on type 1 diabetes risk, particularly
(β SE = 1.36 0.17), were confirmed. The conditional analysis in LADA versus control subjects showed significant association in the MHC class II region (rs3957146, β SE = 1.14 0.06); however, we did not observe significant independent effects of MHC class I alleles in LADA.
In LADA, the independent effects of MHC class I observed in type 1 diabetes were not observed after conditioning on the leading MHC class II associations, suggesting that the MHC class I association may be a genetic discriminator between LADA and childhood-onset type 1 diabetes.
C3 glomerulopathy is a recently introduced pathological entity whose original definition was glomerular pathology characterized by C3 accumulation with absent or scanty immunoglobulin deposition. In ...August 2012, an invited group of experts (comprising the authors of this document) in renal pathology, nephrology, complement biology, and complement therapeutics met to discuss C3 glomerulopathy in the first C3 Glomerulopathy Meeting. The objectives were to reach a consensus on: the definition of C3 glomerulopathy, appropriate complement investigations that should be performed in these patients, and how complement therapeutics should be explored in the condition. This meeting report represents the current consensus view of the group.
Ontologically distinct populations of macrophages differentially contribute to organ fibrosis through unknown mechanisms.We applied lineage tracing, single-cell RNA sequencing and single-molecule ...fluorescence
hybridisation to a spatially restricted model of asbestos-induced pulmonary fibrosis.We demonstrate that tissue-resident alveolar macrophages, tissue-resident peribronchial and perivascular interstitial macrophages, and monocyte-derived alveolar macrophages are present in the fibrotic niche. Deletion of monocyte-derived alveolar macrophages but not tissue-resident alveolar macrophages ameliorated asbestos-induced lung fibrosis. Monocyte-derived alveolar macrophages were specifically localised to fibrotic regions in the proximity of fibroblasts where they expressed molecules known to drive fibroblast proliferation, including platelet-derived growth factor subunit A. Using single-cell RNA sequencing and spatial transcriptomics in both humans and mice, we identified macrophage colony-stimulating factor receptor (M-CSFR) signalling as one of the novel druggable targets controlling self-maintenance and persistence of these pathogenic monocyte-derived alveolar macrophages. Pharmacological blockade of M-CSFR signalling led to the disappearance of monocyte-derived alveolar macrophages and ameliorated fibrosis.Our findings suggest that inhibition of M-CSFR signalling during fibrosis disrupts an essential fibrotic niche that includes monocyte-derived alveolar macrophages and fibroblasts during asbestos-induced fibrosis.
Neovascular age-related macular degeneration causes vision loss from destructive angiogenesis, termed choroidal neovascularization (CNV). Cx3cr1
mice display alterations in non-classical monocytes ...and microglia with increased CNV size, suggesting that non-classical monocytes may inhibit CNV formation. NR4A1 is a transcription factor that is necessary for maturation of non-classical monocytes from classical monocytes. While Nr4a1
mice are deficient in non-classical monocytes, results are confounded by macrophage hyper-activation. Nr4a1
mice lack a transcriptional activator, resulting in non-classical monocyte loss without macrophage hyper-activation.
We subjected Nr4a1
and Nr4a1
mice to the laser-induced CNV model and performed multi-parameter flow cytometry. We found that both models lack non-classical monocytes, but only Nr4a1
mice displayed increased CNV area. Additionally, CD11c
macrophages were increased in Nr4a1
mice. Single-cell transcriptomic analysis uncovered that CD11c
macrophages were enriched from Nr4a1
mice and expressed a pro-angiogenic transcriptomic profile that was disparate from prior reports of macrophage hyper-activation.
These results suggest that non-classical monocytes are dispensable during CNV, and NR4A1 deficiency results in increased recruitment of pro-angiogenic macrophages.
The true severity of infection due to COVID-19 is under-represented because it is based on only those who are tested. Although nucleic acid amplifications tests (NAAT) are the gold standard for ...COVID-19 diagnostic testing, serological assays provide better population-level SARS-CoV-2 prevalence estimates. Implementing large sero-surveys present several logistical challenges within Canada due its unique geography including rural and remote communities. Dried blood spot (DBS) sampling is a practical solution but comparative performance data on SARS-CoV-2 serological tests using DBS is currently lacking. Here we present test performance data from a well-characterized SARS-CoV-2 DBS panel sent to laboratories across Canada representing 10 commercial and 2 in-house developed tests for SARS-CoV-2 antibodies. Three commercial assays identified all positive and negative DBS correctly corresponding to a sensitivity, specificity, positive predictive value, and negative predictive value of 100% (95% CI = 72.2, 100). Two in-house assays also performed equally well. In contrast, several commercial assays could not achieve a sensitivity greater than 40% or a negative predictive value greater than 60%. Our findings represent the foundation for future validation studies on DBS specimens that will play a central role in strengthening Canada's public health policy in response to COVID-19.
Latent autoimmune diabetes in adults (LADA) shares clinical features with both type 1 and type 2 diabetes; however, there is ongoing debate regarding the precise definition of LADA. Understanding its ...genetic basis is one potential strategy to gain insight into appropriate classification of this diabetes subtype.
We performed the first genome-wide association study of LADA in case subjects of European ancestry versus population control subjects (
= 2,634 vs. 5,947) and compared against both case subjects with type 1 diabetes (
= 2,454 vs. 968) and type 2 diabetes (
= 2,779 vs. 10,396).
The leading genetic signals were principally shared with type 1 diabetes, although we observed positive genetic correlations genome-wide with both type 1 and type 2 diabetes. Additionally, we observed a novel independent signal at the known type 1 diabetes locus harboring
, encoding a regulator of glycolysis and insulin signaling in type 2 diabetes and inflammation and autophagy in autoimmune disease, as well as an attenuation of key type 1-associated HLA haplotype frequencies in LADA, suggesting that these are factors that distinguish childhood-onset type 1 diabetes from adult autoimmune diabetes.
Our results support the need for further investigations of the genetic factors that distinguish forms of autoimmune diabetes as well as more precise classification strategies.
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