Coronary artery disease (CAD) is the leading cause of death worldwide and is commonly caused by a constellation of risk factors called the metabolic syndrome. We characterized a family with autosomal dominant early CAD, features of the metabolic syndrome (hyperlipidemia, hypertension, and diabetes), and osteoporosis. These traits showed genetic linkage to a short segment of chromosome 12p, in which we identified a missense mutation in LRP6, which encodes a co-receptor in the Wnt signaling pathway. The mutation, which substitutes cysteine for arginine at a highly conserved residue of an epidermal growth factor-like domain, impairs Wnt signaling in vitro. These results link a single gene defect in Wnt signaling to CAD and multiple cardiovascular risk factors.Coronary artery disease (CAD) due to atherosclerosis results in myocardial infarction (MI) and is the leading cause of death worldwide (1). Epidemiologic studies and clinical intervention trials have established the key roles of specific risk factors for CAD, including smoking, hypertension, high low-density lipoprotein (LDL) cholesterol, high triglycerides, low highdensity lipoprotein (HDL) cholesterol, and diabetes mellitus (2-4). Surprisingly, many of these risk factors cluster with one another more often than expected by chance (5,6). This metabolic syndrome is recognized to be a common cause of CAD; however, the molecular mechanisms that unify their association have been obscure.The marked increase in risk of early cardiovascular mortality to a second monozygotic twin when the first has died from early CAD provides evidence for a strong genetic effect and supports investigation of families with early disease (7). Such studies have the capacity to

Obesity is associated with insulin resistance and inflammation thought to be caused by a visceral adipose tissue (VAT)–localized reduction in immunoregulatory cells and increase in proinflammatory immune cells. We previously found that VAT regulatory T cells (Tregs) normally express high levels of IL-10 and that expression of this cytokine in VAT Tregs is specifically reduced in mice fed a high-fat diet. In this study, we further investigated the phenotype of VAT Tregs and found that the majority of IL-10–expressing Tregs in the VAT of lean mice also expressed the ST2 chain of the IL-33R. In addition to high expression of IL-10, ST2+ Tregs in lean VAT expressed higher proportions of Th2-associated proteins, including GATA3 and CCR4, and Neuropillin-1 compared with ST2− Tregs. The proportion of ST2+ Tregs in VAT was severely diminished in obese mice that had been fed a high-fat/sucrose diet, and this effect could be completely reversed by treatment with IL-33. IL-33 treatment also reversed VAT inflammation in obese mice and resulted in a reduction of hyperinsulinemia and insulin resistance. These data suggest that IL-33 contributes to the maintenance of the normal pool of ST2+ Tregs in the VAT, and that therapeutic administration of IL-33 results in multiple anti-obesity effects, including the reversal of VAT inflammation and alleviation of insulin resistance.

Background Akkermansia muciniphila is one of the most dominant bacteria that resides on the mucus layer of intestinal tract and plays key role in human health, however, little is known about its genomic content.ResultsHerein, we for the first time characterized the genomic architecture of A. muciniphila based on whole-genome sequencing, assembling, and annotating of 39 isolates derived from human and mouse feces. We revealed a flexible open pangenome of A. muciniphila currently consisting of 5644 unique proteins. Phylogenetic analysis identified three species-level A. muciniphila phylogroups exhibiting distinct metabolic and functional features. Based on the comprehensive genome catalogue, we reconstructed 106 newly A. muciniphila metagenome assembled genomes (MAGs) from available metagenomic datasets of human, mouse and pig gut microbiomes, revealing a transcontinental distribution of A. muciniphila phylogroups across mammalian gut microbiotas. Accurate quantitative analysis of A. muciniphila phylogroups in human subjects further demonstrated its strong correlation with body mass index and anti-diabetic drug usage. Furthermore, we found that, during their mammalian gut evolution history, A. muciniphila acquired extra genes, especially antibiotic resistance genes, from symbiotic microbes via recent lateral gene transfer.ConclusionsThe genome repertoire of A. muciniphila provided insights into population structure, evolutionary and functional specificity of this significant bacterium.Electronic supplementary materialThe online version of this article (10.1186/s12864-017-4195-3) contains supplementary material, which is available to authorized users.

Regulatory T cells (Tregs) are suppressive T cells that have an essential role in maintaining the balance between immune activation and tolerance. Their development, either in the thymus, periphery, or experimentally in vitro, and stability and function all depend on the right mix of environmental stimuli. This review focuses on the effects of cytokines, metabolites, and the microbiome on both human and mouse Treg biology. The role of cytokines secreted by innate and adaptive immune cells in directing Treg development and shaping their function is well established. New and emerging data suggest that metabolites, such as retinoic acid, and microbial products, such as short-chain fatty acids, also have a critical role in guiding the functional specialization of Tregs. Overall, the complex interaction between distinct environmental stimuli results in unique, and in some cases tissue-specific, tolerogenic environments. Understanding the conditions that favor Treg induction, accumulation, and function is critical to defining the pathophysiology of many immune-mediated diseases and to developing new therapeutic interventions.

IntroductionThis research aims to estimate the relative risks of responsibility for a fatal accident linked to driving under the influence of cannabis or alcohol, the prevalence of these influences among drivers and the corresponding attributable risk ratios. A secondary goal is to estimate the same items for three other groups of illicit drugs (amphetamines, cocaine and opiates), and to compare the results to a similar study carried out in France between 2001 and 2003.MethodologyPolice procedures for fatal accidents in Metropolitan France during 2011 were analyzed and 300 characteristics encoded to provide a database of 4,059 drivers. Information on alcohol and four groups of illicit drugs derived from tests for positivity and potential confirmation through blood analysis. The study compares drivers responsible for causing the accident, that is to say having directly contributed to its occurrence, to drivers involved in an accident for which they were not responsible, and who can be assimilated to drivers in general.ResultsThe proportion of persons driving under the influence of alcohol is estimated at 2.1% (95% CI: 1.4–2.8) and under the influence of cannabis at 3.4% (2.9%-3.9%). Drivers under the influence of alcohol are 17.8 times (12.1–26.1) more likely to be responsible for a fatal accident, and the proportion of fatal accidents which would be prevented if no drivers ever exceeded the legal limit for alcohol is estimated at 27.7% (26.0%-29.4%). Drivers under the influence of cannabis multiply their risk of being responsible for causing a fatal accident by 1.65 (1.16–2.34), and the proportion of fatal accidents which would be prevented if no drivers ever drove under the influence of cannabis is estimated at 4.2% (3.7%-4.8%). An increased risk linked to opiate use has also been found to be significant, but with low prevalence, requiring caution in interpreting this finding. Other groups of narcotics have even lower prevalence, and the associated extra risks cannot be assessed.ConclusionAlmost a decade separates the present study from a similar one previously conducted in France, and there have been numerous developments in the intervening years. Even so, the prevalence of drivers responsible for causing fatal accidents under the influence of alcohol or narcotics has stayed remarkably stable, as have the proportion of fatal accidents which could in theory be prevented if no drivers ever exceeded the legal limits. The overall number of deaths from traffic accidents has dropped sharply during this period, and the number of victims attributable to alcohol and/or cannabis declined proportionally. Alcohol remains the main problem in France. It is just as important to note that one in two drivers considered to be under the influence of cannabis was also under the influence of alcohol. With risks cumulating between the two, it is particularly important to point out the danger of consuming them together.

No abstract

Chronic inflammation and excessive protease activity have a major role in the persistence of non-healing wounds. Granzyme B (GzmB) is a serine protease expressed during chronic inflammation that, in conjunction with perforin, has a well-established role in initiating apoptotic cell death. GzmB is also capable of acting extracellularly, independent of perforin and can degrade several extracellular matrix (ECM) proteins that are critical during wound healing. We used apolipoprotein E (ApoE) knockout (AKO) mice as a novel model of chronic inflammation and impaired wound healing to investigate the role of GzmB in chronic wounds. Wild-type and AKO mice were grown to 7 weeks (young) or 37 weeks (old) of age on a regular chow or high-fat diet (HFD), given a 1-cm diameter full thickness wound on their mid dorsum and allowed to heal for 16 days. Old AKO mice fed a HFD exhibited reduced wound closure, delayed contraction, chronic inflammation and altered ECM remodeling. Conversely, GzmB/ApoE double knockout mice displayed improved wound closure and contraction rates. In addition, murine GzmB was found to degrade both fibronectin and vitronectin derived from healthy mouse granulation tissue. In addition, GzmB-mediated degradation of fibronectin generated a fragment similar in size to that observed in non-healing mouse wounds. These results provide the first direct evidence that GzmB contributes to chronic wound healing in part through degradation of ECM.

No abstract