Obesity-induced insulin resistance is the major determinant of metabolic syndrome, which precedes the development of type 2 diabetes mellitus and is thus the driving force behind the emerging ...diabetes epidemic. The precise causes of insulin resistance are varied, and the relative importance of each is a matter of ongoing research. Here, we offer a Perspective on the heterogeneous etiology of insulin resistance, focusing in particular on the role of inflammation, lipid metabolism, and the gastrointestinal microbiota.
In obesity, macrophages and other immune cells accumulate in insulin target tissues, promoting a chronic inflammatory state and insulin resistance. Galectin-3 (Gal3), a lectin mainly secreted by ...macrophages, is elevated in both obese subjects and mice. Administration of Gal3 to mice causes insulin resistance and glucose intolerance, whereas inhibition of Gal3, through either genetic or pharmacologic loss of function, improved insulin sensitivity in obese mice. In vitro treatment with Gal3 directly enhanced macrophage chemotaxis, reduced insulin-stimulated glucose uptake in myocytes and 3T3-L1 adipocytes and impaired insulin-mediated suppression of glucose output in primary mouse hepatocytes. Importantly, we found that Gal3 can bind directly to the insulin receptor (IR) and inhibit downstream IR signaling. These observations elucidate a novel role for Gal3 in hepatocyte, adipocyte, and myocyte insulin resistance, suggesting that Gal3 can link inflammation to decreased insulin sensitivity. Inhibition of Gal3 could be a new approach to treat insulin resistance.
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•Galectin-3 blood levels are elevated in human and rodent obesity•Galectin-3 directly impairs insulin action in myocytes, adipocytes, and hepatocytes•Galectin-3 treatment causes systemic insulin resistance in vivo•Galectin-3 loss of function improves insulin sensitivity in obesity
A circulating lectin secreted by macrophages in obese individuals drives insulin resistance and glucose intolerance by directly binding the insulin receptor and antagonizing downstream metabolic responses.
Knowledge of the hazards and associated risks from chemicals discharged to the environment has grown considerably over the past 40 years. This improving awareness stems from advances in our ability ...to measure chemicals at low environmental concentrations, recognition of a range of effects on organisms, and a worldwide growth in expertise. Environmental scientists and companies have learned from the experiences of the past; in theory, the next generation of chemicals will cause less acute toxicity and be less environmentally persistent and bioaccumulative. However, researchers still struggle to establish whether the nonlethal effects associated with some modern chemicals and substances will have serious consequences for wildlife. Obtaining the resources to address issues associated with chemicals in the environment remains a challenge.
The development of intestinal permeability and the penetration of microbial products are key factors associated with the onset of metabolic disease. However, the mechanisms underlying this remain ...unclear. Here we show that, unlike liver or adipose tissue, high fat diet (HFD)/obesity in mice does not cause monocyte/macrophage infiltration into the intestine or pro-inflammatory changes in gene expression. Rather HFD causes depletion of intestinal eosinophils associated with the onset of intestinal permeability. Intestinal eosinophil numbers were restored by returning HFD fed mice to normal chow and were unchanged in leptin-deficient (Ob/Ob) mice, indicating that eosinophil depletion is caused specifically by a high fat diet and not obesity per se. Analysis of different aspects of intestinal permeability in HFD fed and Ob/Ob mice shows an association between eosinophil depletion and ileal paracelullar permeability, as well as leakage of albumin into the feces, but not overall permeability to FITC dextran. These findings provide the first evidence that a high fat diet causes intestinal eosinophil depletion, rather than inflammation, which may contribute to defective barrier integrity and the onset of metabolic disease.
With the enormous growth in interest and use of generative artificial intelligence (AI) systems seen since the launch of ChatGPT in autumn 2022 have come questions both about the legal status of AI ...outputs, and of using protected works as training inputs. It is inevitable that UK higher education institution (HEI) library copyright advice services will see an increase in questions around use of works with AI as a result. Staff working in such library services are not lawyers or able to offer legal advice to their academic researchers. Nonetheless, they must look at the issues raised, consider how to advise in analogous situations of using copyright material, and offer opinion to researchers accordingly. While the legal questions remain to be answered definitively, copyright librarians can still offer advice on both open licences and use of copyright material under permitted exceptions. We look here at how library services can address questions on copyright and open licences for generative AI for researchers in UK HEIs.
Recent trends in research funder policies and guidelines increasingly point to requirements for more detailed plans for data management, curation, and sharing with an emphasis on including allowable ...costs in grant budgets to support these activities as well. As a result, libraries and other collaborating units at academic institutions have an opportunity to develop streamlined models that allow researchers to incorporate institutional resources for data management, curation, and sharing into their grant proposals along with costs to support these resources. While the current literature contains examples and discussions of general funding approaches to activities like data curation and long-term preservation, little has been written on formal models or strategies for incorporating data management and curation support into the grant proposal and budget process itself. This article describes the development and implementation of a tiered grant support model at the University of Colorado Boulder that provides three levels of services, infrastructure, and expertise to researchers who are looking to incorporate support and costs for data management, curation, and sharing into their grant proposals. The article also presents lessons learned since the soft launch of the grant support model as well as key challenges that have emerged. This model may serve as an example for other institutions to use or adapt to continue to help researchers meet funder requirements while simultaneously increasing the visibility of existing data management and curation resources and identifying potential new revenue or cost recovery streams.
•A multiple-level system was proposed for risk rank of PPCPs in waters.•12 PPCPs showed environmental risks in Chinese surface waters.•Detected frequency, exposure and effect distribution were ...important to risk ranking.
Interest in the risks posed by trace concentrations of pharmaceuticals and personal care products (PPCPs) in surface waters is increasing, particularly with regard to potential effects of long-term, low-dose exposures of aquatic organisms. In most cases, the actual studies on PPCPs were risk assessments at screening-level, and accurate estimates were scarce. In this study, exposure and ecotoxicity data of 50 PPCPs were collected based on our previous studies, and a multiple-level environmental risk assessment was performed. The 50 selected PPCPs are likely to be frequently detected in surface waters of China, with concentrations ranging from the ng L−1 to the low-g L−1, and the risk quotients based on median concentrations ranged from 2046 for nonylphenol to 0 for phantolide. A semi-probabilistic approach screened 33 PPCPs that posed potential risks to aquatic organisms, among which 15 chemicals (nonylphenol, sulfamethoxazole, di (2-ethylhexyl) phthalate, 17β-ethynyl estradiol, caffeine, tetracycline, 17β-estradiol, estrone, dibutyl phthalate, ibuprofen, carbamazepine, tonalide, galaxolide, triclosan, and bisphenol A) were categorized as priority compounds according to an optimized risk assessment, and then the refined probabilistic risk assessment indicated 12 of them posed low to high risk to aquatic ecosystem, with the maximum risk products ranged from 1.54% to 17.38%. Based on these results, we propose that the optimized risk assessment was appropriate for screening priority contaminants at national scale, and when a more accurate estimation is required, the refined probability risk assessment is useful. The methodology and process might provide reference for other research of chemical evaluation and management for rivers, lakes, and sea waters.
Perfluoroalkyl substances (PFASs) have become a recognized concern due to their mobility, persistence, ubiquity and health hazards in the environment. In this study, ten types of vegetables and three ...types of grain crops were collected in two open-air fields with different distances (0.3 km, 10 km) from a mega fluorochemical industrial park (FIP), China. Bioaccumulation characteristics of PFASs in light of crop types and organs were explored, followed by analyzing human exposure and risks to local residents with different age groups and dietary habits. Elevated levels of ∑PFASs were found nearby the FIP ranging from 79.9 ng/g to 200 ng/g in soils and from 58.8 ng/g to 8085 ng/g in crops. Perfluorooctanoic acid (PFOA) was the predominant PFAS component in soil; while shorter-chain perfluoroalkyl carboxylic acids (PFCAs), especially perfluorobutanoic acid (PFBA), were the major PFAS contaminants in multiple crops, resulting from their bioaccumulation preference. Depending on the crop types, the bioaccumulation factors (BAFs) of ∑PFASs for edible parts varied from 0.36 to 48.0, and the highest values were found in shoot vegetables compared with those in fruit vegetables, flower vegetables, root vegetables and grain crops. For typical grains, the BAFs of ∑PFASs decreased in the order of soybean (Glycine max (Linn.) Merr.), wheat (Triticum aestivum L.) and corn (Zea mays L.), possibly related to their protein and lipid content. Among specific organs in the whole plants, leaves exhibited the highest BAFs of ∑PFASs compared with corresponding roots, stems, husks or grains. With increasing carbon chain lengths of individual PFCAs (C4-C8), the logarithm of their BAFs for edible parts of various crops showed a linear decrease (0.1–1.16 log decrease per CF2 unit), and the largest decrease was observed in grains. Human exposure to PFOA via the consumption of contaminated crops represents a health risk for local residents, especially for low-age consumers or urban consumers with higher vegetable diet. Implications for planting optimization and food safety were provided aiming to reduce health hazards of PFASs.
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•Industrial emission caused serious PFASs pollution to nearby agricultural system.•Vegetables and grains have bioaccumulation preference to shorter-chain PFASs.•For edible parts, shoot vegetables showed highest BAFs of ∑PFASs in multiple crops.•The logarithm of BAFs exhibited linear decrease with carbon chain lengths of PFCAs.•Health risk of PFASs via crop consumption varied for different ages or diet habits.
The number of genome-wide association studies (GWAS) is growing rapidly leading to the discovery and replication of many new disease loci. Combining results from multiple GWAS datasets may ...potentially strengthen previous conclusions and suggest new disease loci, pathways or pleiotropic genes. However, no database or centralized resource currently exists that contains anywhere near the full scope of GWAS results.
We collected available results from 118 GWAS articles into a database of 56,411 significant SNP-phenotype associations and accompanying information, making this database freely available here. In doing so, we met and describe here a number of challenges to creating an open access database of GWAS results. Through preliminary analyses and characterization of available GWAS, we demonstrate the potential to gain new insights by querying a database across GWAS.
Using a genomic bin-based density analysis to search for highly associated regions of the genome, positive control loci (e.g., MHC loci) were detected with high sensitivity. Likewise, an analysis of highly repeated SNPs across GWAS identified replicated loci (e.g., APOE, LPL). At the same time we identified novel, highly suggestive loci for a variety of traits that did not meet genome-wide significant thresholds in prior analyses, in some cases with strong support from the primary medical genetics literature (SLC16A7, CSMD1, OAS1), suggesting these genes merit further study. Additional adjustment for linkage disequilibrium within most regions with a high density of GWAS associations did not materially alter our findings. Having a centralized database with standardized gene annotation also allowed us to examine the representation of functional gene categories (gene ontologies) containing one or more associations among top GWAS results. Genes relating to cell adhesion functions were highly over-represented among significant associations (p < 4.6 x 10(-14)), a finding which was not perturbed by a sensitivity analysis.
We provide access to a full gene-annotated GWAS database which could be used for further querying, analyses or integration with other genomic information. We make a number of general observations. Of reported associated SNPs, 40% lie within the boundaries of a RefSeq gene and 68% are within 60 kb of one, indicating a bias toward gene-centricity in the findings. We found considerable heterogeneity in information available from GWAS suggesting the wider community could benefit from standardization and centralization of results reporting.
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