Peroxisomal β-oxidation acts as a sensor for intracellular fatty acids and regulates lipolysis

To liberate fatty acids (FAs) from intracellular stores, lipolysis is regulated by the activity of the lipases adipose triglyceride lipase (ATGL), hormone-sensitive lipase and monoacylglycerol lipase. Excessive FA release as a result of uncontrolled lipolysis results in lipotoxicity, which can in turn promote the progression of metabolic disorders. However, whether cells can directly sense FAs to maintain cellular lipid homeostasis is unknown. Here we report a sensing mechanism for cellular FAs based on peroxisomal degradation of FAs and coupled with reactive oxygen species (ROS) production, which in turn regulates FA release by modulating lipolysis. Changes in ROS levels are sensed by PEX2, which modulates ATGL levels through post-translational ubiquitination. We demonstrate the importance of this pathway for non-alcoholic fatty liver disease progression using genetic and pharmacological approaches to alter ROS levels in vivo, which can be utilized to increase hepatic ATGL levels and ameliorate hepatic steatosis. The discovery of this peroxisomal β-oxidation-mediated feedback mechanism, which is conserved in multiple organs, couples the functions of peroxisomes and lipid droplets and might serve as a new way to manipulate lipolysis to treat metabolic disorders

Autoantibody profiling to identify biomarkers of key pathogenic pathways in mucinous ovarian cancer

Mucinous epithelial ovarian cancers are clinically and morphologically distinct from the other histopathologic subtypes of ovarian cancer. Unlike other ovarian subtypes, epidemiologic studies have indicated that tobacco exposure is a significant risk factor for developing mucinous ovarian cancer. Detection of autoantibody reactivity is useful in biomarker discovery and for explaining the role of important pathophysiologic pathways in disease. In order to study if there are specific antibody biomarkers in the plasma samples of mucinous ovarian cancer patients, we have initiated a screen by employing a “reverse capture antibody microarray” platform that uses native host antigens derived from mucinous ovarian tissues as “baits” for the capture of differentially labeled patient and control autoantibodies. 35 autoantibodies that were significantly elevated in the cancer plasma samples compared with healthy controls, and six autoantibodies that segregated smoking and nonsmoking patients were identified. Functional annotation of the antibody targets has identified nine target antigens involved in integrin and Wnt signaling pathways. Immunohistochemistry of archived ovarian specimens showed significant overexpression of eight of the nine target antigens in mucinous ovarian tumor tissues, suggesting that plasma autoantibodies from mucinous ovarian cancer patients might have heightened reactivities with epitopes presented by these overexpressed antigens. Autoantibody profiling may have an unexpected utility in uncovering key signaling pathways that are dysregulated in the system of interest

Orbital decay in an accreting and eclipsing 13.7 minute orbital period binary with a luminous donor

We report the discovery of ZTF J0127+5258, a compact mass-transferring binary with an orbital period of 13.7 minutes. The system contains a white dwarf accretor, which likely originated as a post-common envelope carbon-oxygen (CO) white dwarf, and a warm donor ($T_{\rm eff,\,donor}= 16,400\pm1000\,\rm K$). The donor probably formed during a common envelope phase between the CO white dwarf and an evolving giant which left behind a helium star or helium white dwarf in a close orbit with the CO white dwarf. We measure gravitational wave-driven orbital inspiral with $\sim 35\sigma$ significance, which yields a joint constraint on the component masses and mass transfer rate. While the accretion disk in the system is dominated by ionized helium emission, the donor exhibits a mixture of hydrogen and helium absorption lines. Phase-resolved spectroscopy yields a donor radial-velocity semi-amplitude of $771\pm27\,\rm km\, s^{-1}$, and high-speed photometry reveals that the system is eclipsing. We detect a {\it Chandra} X-ray counterpart with $L_{X}\sim 3\times 10^{31}\,\rm erg\,s^{-1}$. Depending on the mass-transfer rate, the system will likely evolve into either a stably mass-transferring helium CV, merge to become an R Crb star, or explode as a Type Ia supernova in the next million years. We predict that the Laser Space Interferometer Antenna (LISA) will detect the source with a signal-to-noise ratio of $24\pm6$ after 4 years of observations. The system is the first \emph{LISA}-loud mass-transferring binary with an intrinsically luminous donor, a class of sources that provide the opportunity to leverage the synergy between optical and infrared time domain surveys, X-ray facilities, and gravitational-wave observatories to probe general relativity, accretion physics, and binary evolution.Comment: 13 pages, 7 figures, 2 tables, submitted to ApJ

Meta-analysis of genome-wide DNA methylation and integrative omics of age in human skeletal muscle

International audienceBackground: Knowledge of age-related DNA methylation changes in skeletal muscle is limited, yet this tissue is severely affected by ageing in humans.Methods: We conducted a large-scale epigenome-wide association study meta-analysis of age in human skeletal muscle from 10 studies (total n = 908 muscle methylomes from men and women aged 18-89 years old). We explored the genomic context of age-related DNA methylation changes in chromatin states, CpG islands, and transcription factor binding sites and performed gene set enrichment analysis. We then integrated the DNA methylation data with known transcriptomic and proteomic age-related changes in skeletal muscle. Finally, we updated our recently developed muscle epigenetic clock (https://bioconductor.org/packages/release/bioc/html/MEAT.html).Results: We identified 6710 differentially methylated regions at a stringent false discovery rate <0.005, spanning 6367 unique genes, many of which related to skeletal muscle structure and development. We found a strong increase in DNA methylation at Polycomb target genes and bivalent chromatin domains and a concomitant decrease in DNA methylation at enhancers. Most differentially methylated genes were not altered at the mRNA or protein level, but they were nonetheless strongly enriched for genes showing age-related differential mRNA and protein expression. After adding a substantial number of samples from five datasets (+371), the updated version of the muscle clock (MEAT 2.0, total n = 1053 samples) performed similarly to the original version of the muscle clock (median of 4.4 vs. 4.6 years in age prediction error), suggesting that the original version of the muscle clock was very accurate.Conclusions: We provide here the most comprehensive picture of DNA methylation ageing in human skeletal muscle and reveal widespread alterations of genes involved in skeletal muscle structure, development, and differentiation. We have made our results available as an open-access, user-friendly, web-based tool called MetaMeth (https://sarah-voisin.shinyapps.io/MetaMeth/)

Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits

We evaluate the shared genetic regulation of mRNA molecules, proteins and metabolites derived from whole blood from 3029 human donors. We find abundant allelic heterogeneity, where multiple variants regulate a particular molecular phenotype, and pleiotropy, where a single variant associates with multiple molecular phenotypes over multiple genomic regions. The highest proportion of share genetic regulation is detected between gene expression and proteins (66.6%), with a further median shared genetic associations across 49 different tissues of 78.3% and 62.4% between plasma proteins and gene expression. We represent the genetic and molecular associations in networks including 2828 known GWAS variants, showing that GWAS variants are more often connected to gene expression in trans than other molecular phenotypes in the network. Our work provides a roadmap to understanding molecular networks and deriving the underlying mechanism of action of GWAS variants using different molecular phenotypes in an accessible tissue

Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits

We evaluate the shared genetic regulation of mRNA molecules, proteins and metabolites derived from whole blood from 3029 human donors. We find abundant allelic heterogeneity, where multiple variants regulate a particular molecular phenotype, and pleiotropy, where a single variant associates with multiple molecular phenotypes over multiple genomic regions. The highest proportion of share genetic regulation is detected between gene expression and proteins (66.6%), with a further median shared genetic associations across 49 different tissues of 78.3% and 62.4% between plasma proteins and gene expression. We represent the genetic and molecular associations in networks including 2828 known GWAS variants, showing that GWAS variants are more often connected to gene expression in trans than other molecular phenotypes in the network. Our work provides a roadmap to understanding molecular networks and deriving the underlying mechanism of action of GWAS variants using different molecular phenotypes in an accessible tissue

Quantifying the climate impacts of albedo changes due to biofuel production: a comparison with biogeochemical effects

Lifecycle analysis is a tool widely used to evaluate the climate impact of greenhouse gas emissions attributable to the production and use of biofuels. In this paper we employ an augmented lifecycle framework that includes climate impacts from changes in surface albedo due to land use change. We consider eleven land-use change scenarios for the cultivation of biomass for middle distillate fuel production, and compare our results to previous estimates of lifecycle greenhouse gas emissions for the same set of land-use change scenarios in terms of CO _2 e per unit of fuel energy. We find that two of the land-use change scenarios considered demonstrate a warming effect due to changes in surface albedo, compared to conventional fuel, the largest of which is for replacement of desert land with salicornia cultivation. This corresponds to 222 gCO _2 e/MJ, equivalent to 3890% and 247% of the lifecycle GHG emissions of fuels derived from salicornia and crude oil, respectively. Nine of the land-use change scenarios considered demonstrate a cooling effect, the largest of which is for the replacement of tropical rainforests with soybean cultivation. This corresponds to − 161 gCO _2 e/MJ, or − 28% and − 178% of the lifecycle greenhouse gas emissions of fuels derived from soybean and crude oil, respectively. These results indicate that changes in surface albedo have the potential to dominate the climate impact of biofuels, and we conclude that accounting for changes in surface albedo is necessary for a complete assessment of the aggregate climate impacts of biofuel production and use

Malignant Leakage After Sleeve Gastrectomy: Endoscopic and Surgical Approach

PURPOSE: Gastric leak occurs after sleeve gastrectomy (SG) in 2% of cases. Most staple-line disruptions (SLD) can be successfully treated with first-line endoscopic procedures. Less favorable situations may lead to more complex therapeutic strategies, like conversion to Roux-en-Y gastric bypass (RYGBP). The aim of our study is to predict the factors of endoscopic treatment failure and to assess the safety of conversion to RYGBP. METHODS: We included all patients treated in two centers of academic excellence (n = 100) between 2013 and 2017 who had a malignant SLD after SG. A "malignant" leakage met one of the following poor prognosis criteria suggested in the literature: unsuccessfully treated by the first-line endoscopic treatment; generalized peritonitis; anatomical anomalies; gastro-cutaneous or gastro-pleural fistula (GCF/GPF); or chronic leaks (\textgreater 4 weeks). RESULTS: No deaths occurred during the follow-up (20 ± 12 months). The endoscopy reported an anatomically abnormal gastric tube in 35 (35%) patients (stenosis [n = 21 (21%)], twist [n = 9 (9%)], or both [n = 5 (5%)]). We could maintain the SG in place in 92% of cases without stenosis, twist, or GCF/GPF. Conversion to RYGBP due to leakage was necessary in 37 (37%) patients. Stenosis, twist, or GCF/GPF significantly prevented healing in multivariate analysis (respectively: p = 0.020, OR = 0.17, and p \textless 0.001, OR = 0.07-logistic regression). CONCLUSION: Endoscopy is the treatment of choice for the management of chronic leaks after SG. The association of anatomical anomalies and GCF/GPF should lead to consideration of conversion to RYGBP

Post-bariatric surgery changes in quinolinic and xanthurenic acid concentrations are associated with glucose homeostasis

Background: An increase of plasma kynurenine concentrations, potentially bioactive metabolites of tryptophan, was found in subjects with obesity, resulting from low-grade inflammation of the white adipose tissue. Bariatric surgery decreases low-grade inflammation associated with obesity and improves glucose control. Objective: Our goal was to determine the concentrations of all kynurenine metabolites after bariatric surgery and whether they were correlated with glucose control improvement. Design: Kynurenine metabolite concentrations, analysed by liquid or gas chromatography coupled with tandem mass spectrometry, circulating inflammatory markers, metabolic traits, and BMI were measured before and one year after bariatric surgery in 44 normoglycemic and 47 diabetic women with obesity. Associations between changes in kynurenine metabolites concentrations and in glucose control and metabolic traits were analysed between baseline and twelve months after surgery. Results: Tryptophan and kynurenine metabolite concentrations were significantly decreased one year after bariatric surgery and were correlated with the decrease of the usCRP in both groups. Among all the kynurenine metabolites evaluated, only quinolinic acid and xanthurenic acid were significantly associated with glucose control improvement. The one year delta of quinolinic acid concentrations was negatively associated with the delta of fasting glucose (p = 0.019) and HbA1c (p = 0.014), whereas the delta of xanthurenic acid was positively associated with the delta of insulin sensitivity index (p = 0.0018). Conclusion: Bariatric surgery has induced a global down-regulation of kynurenine metabolites, associated with weight loss. Our results suggest that, since kynurenine monoxygenase diverts the kynurenine pathway toward the synthesis of xanthurenic acid, its inhibition may also contribute to glucose homeostasis.12 page(s