Sex bias in celiac disease: XWAS and monocyte eQTLs in women identify TMEM187 as a functional candidate gene.

Background: Celiac disease (CeD) is an immune-mediated disorder that develops in genetically predisposed individuals upon gluten consumption. HLA risk alleles explain 40% of the genetic component of CeD, so there have been continuing efforts to uncover non-HLA loci that can explain the remaining heritability. As in most autoimmune disorders, the prevalence of CeD is significantly higher in women.

rMSIfragment: improving MALDI-MSI lipidomics through automated in-source fragment annotation.

Matrix-Assisted Laser Desorption Ionization Mass Spectrometry Imaging (MALDI-MSI) spatially resolves the chemical composition of tissues. Lipids are of particular interest, as they influence important biological processes in health and disease. However, the identification of lipids in MALDI-MSI remains a challenge due to the lack of chromatographic separation or untargeted tandem mass spectrometry.

Two-Sample Mendelian Randomization detects bidirectional causality between gut microbiota and celiac disease in individuals with high genetic risk.

Background: Celiac Disease (CeD) is an autoimmune disorder triggered by gluten intake in genetically susceptible individuals. Highest risk individuals are homozygous for the Human Leucocyte Antigen (HLA) DQ2.5 haplotype or DQ2.

What are we imaging? Software tools and experimental strategies for annotation and identification of small molecules in mass spectrometry imaging.

Mass spectrometry imaging (MSI) has become a widespread analytical technique to perform nonlabeled spatial molecular identification. The Achilles' heel of MSI is the annotation and identification of molecular species due to intrinsic limitations of the technique (lack of chromatographic separation and the difficulty to apply tandem MS). Successful strategies to perform annotation and identification combine extra analytical steps, like using orthogonal analytical techniques to identify compounds; with algorithms that integrate the spectral and spatial information.

Genetic Contribution of Endometriosis to the Risk of Developing Hormone-Related Cancers.

Endometriosis is a common gynecological disorder that has been associated with endometrial, breast and epithelial ovarian cancers in epidemiological studies. Since complex diseases are a result of multiple environmental and genetic factors, we hypothesized that the biological mechanism underlying their comorbidity might be explained, at least in part, by shared genetics. To assess their potential genetic relationship, we performed a two-sample mendelian randomization (2SMR) analysis on results from public genome-wide association studies (GWAS).

Serum metabolic biomarkers for synucleinopathy conversion in isolated REM sleep behavior disorder.

Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is a prodromal stage of Lewy-type synucleinopathies (LTS), which can present either with an initial predominant parkinsonism (Parkinson's disease (PD)) or dementia (dementia with Lewy bodies (DLB)). To provide insights into the underlying pathogenic mechanisms, the lipoprotein and protein glycosylation profile of 82 iRBD patients, collected before and/or after their conversion to an overt LTS, and 29 matched control serum samples were assessed by nuclear magnetic resonance (NMR) spectroscopy. Data were statistically analyzed to identify altered metabolites and construct predictive models.

Dietary Macronutrient Composition in Relation to Circulating HDL and Non-HDL Cholesterol: A Federated Individual-Level Analysis of Cross-Sectional Data from Adolescents and Adults in 8 European Studies.

Background: Associations between increased dietary fat and decreased carbohydrate intake with circulating HDL and non-HDL cholesterol have not been conclusively determined.

Objective: We assessed these relations in 8 European observational human studies participating in the European Nutritional Phenotype Assessment and Data Sharing Initiative (ENPADASI) using harmonized data.

Methods: Dietary macronutrient intake was recorded using study-specific dietary assessment tools.

A Systematic Two-Sample Mendelian Randomization Analysis Identifies Shared Genetic Origin of Endometriosis and Associated Phenotypes.

Endometriosis, one of the most common gynecological disorders, is a complex disease characterized by the growth of endometrial-like tissue in extra-uterine locations and is a cause of pelvic pain and infertility. Evidence from observational studies indicate that endometriosis usually appears together with several other phenotypes. These include a list of autoimmune diseases, most of them more prevalent in women, anthropometric traits associated with leanness in the adulthood, as well as female reproductive traits, including altered hormone levels and those associated with a prolonged exposure to menstruation.

Polygenic Markers in Patients Diagnosed of Autosomal Dominant Hypercholesterolemia in Catalonia: Distribution of Weighted LDL-c-Raising SNP Scores and Refinement of Variant Selection.

Familial hypercholesterolemia (FH) is associated with mutations in the low-density lipoprotein (LDL) receptor (), apolipoprotein B (), and proprotein convertase subtilisin/kexin 9 () genes. A pathological variant has not been identified in 30-70% of clinically diagnosed FH patients, and a burden of LDL cholesterol (LDL-c)-raising alleles has been hypothesized as a potential cause of hypercholesterolemia in these patients. Our aim was to study the distribution of weighted LDL-c-raising single-nucleotide polymorphism (SNP) scores (weighted gene scores or wGS) in a population recruited in a clinical setting in Catalonia.

Nucleotide depletion reveals the impaired ribosome biogenesis checkpoint as a barrier against DNA damage.

Many oncogenes enhance nucleotide usage to increase ribosome content, DNA replication, and cell proliferation, but in parallel trigger p53 activation. Both the impaired ribosome biogenesis checkpoint (IRBC) and the DNA damage response (DDR) have been implicated in p53 activation following nucleotide depletion. However, it is difficult to reconcile the two checkpoints operating together, as the IRBC induces p21-mediated G1 arrest, whereas the DDR requires that cells enter S phase.

miR-10b and miR-223-3p in serum microvesicles signal progression from prediabetes to type 2 diabetes.

Purpose: Type 2 diabetes frequently remains undiagnosed for years, whereas early detection of affected individuals would facilitate the implementation of timely and cost-effective therapies, hence decreasing morbidity. With the intention of identifying novel diagnostic biomarkers, we characterized the miRNA profile of microvesicles isolated from retroactive serum samples of normoglycemic individuals and two groups of subjects with prediabetes that in the following 4 years either progressed to overt diabetes or remained stable.

Methods: We profiled miRNAs in serum microvesicles of a selected group of control and prediabetic individuals participating in the PREDAPS cohort study.

Epigenetic Regulation at the Interplay Between Gut Microbiota and Host Metabolism.

Gut microbiota communities have coevolved for millions of years in a symbiotic relationship with their mammalian hosts. Elucidating and understanding the molecular mechanisms by which microbiota interacts with its host and how this contributes to the homeostasis of the host is crucial. One of these molecular relationships is the so-called chemical crosstalk between microbiota and host metabolisms, including the poorly explored epigenetic regulation of host tissues by the metabolic activity of gut microbiota in response to changes in diet.

Relevance of VEGFA in rat livers subjected to partial hepatectomy under ischemia-reperfusion.

We examined the effects of VEGFA on damage and regeneration in steatotic and non-steatotic livers of rats submitted to PH under I/R, and characterized the underlying mechanisms involved. Our results indicated that VEGFA levels were decreased in both steatotic and non-steatotic livers after surgery. The administration of VEGFA increased VEGFA levels in non-steatotic livers, reducing the incidence of post-operative complications following surgery through the VEGFR2-Wnt2 pathway, independently of Id1.

Mendelian randomization analysis of celiac GWAS reveals a blood expression signature with diagnostic potential in absence of gluten consumption.

Celiac disease (CeD) is an immune-mediated enteropathy with a strong genetic component where the main environmental trigger is dietary gluten, and currently a correct diagnosis of the disease is impossible if gluten-free diet (GFD) has already been started. We hypothesized that merging different levels of genomic information through Mendelian randomization (MR) could help discover genetic biomarkers useful for CeD diagnosis. MR was performed using public databases of expression quantitative trait loci (QTL) and methylation QTL as exposures and the largest CeD genome-wide association study conducted to date as the outcome, in order to identify potential causal genes.

Adaptation to HIF1α Deletion in Hypoxic Cancer Cells by Upregulation of GLUT14 and Creatine Metabolism.

Hypoxia-inducible factor 1α is a key regulator of the hypoxia response in normal and cancer tissues. It is well recognized to regulate glycolysis and is a target for therapy. However, how tumor cells adapt to grow in the absence of HIF1α is poorly understood and an important concept to understand for developing targeted therapies is the flexibility of the metabolic response to hypoxia via alternative pathways.

A novel RT-QPCR-based assay for the relative quantification of residue specific m6A RNA methylation.

N6-methyladenosine (m6A) is the most common and abundant RNA modification. Recent studies have shown its importance in the regulation of several biological processes, including the immune response, and different approaches have been developed in order to map and quantify m6A marks. However, site specific detection of m6A methylation has been technically challenging, and existing protocols are long and tedious and often involve next-generation sequencing.

The methylome of the celiac intestinal epithelium harbours genotype-independent alterations in the HLA region.

The Human Leucocyte Antigen (HLA) locus and other DNA sequence variants identified in Genome-Wide Association (GWA) studies explain around 50% of the heritability of celiac disease (CD). However, the pathogenesis of CD could be driven by other layers of genomic information independent from sequence variation, such as DNA methylation, and it is possible that allele-specific methylation explains part of the SNP associations. Since the DNA methylation landscape is expected to be different among cell types, we analyzed the methylome of the epithelial and immune cell populations of duodenal biopsies in CD patients and controls separately.

Exosomes and diabetes.

Diabetes is a group of metabolic diseases characterized by elevated blood glucose levels that drive the development of life-threatening complications. Diabetes results from a situation of insufficient insulin action, either by deficient production of the hormone by the pancreas, or by the development of insulin resistance in peripheral tissues such as liver, muscle, or the adipose depots. Communication between organs is thus central to the maintenance of glucose homoeostasis.

Obesity-associated exosomal miRNAs modulate glucose and lipid metabolism in mice.

Obesity is frequently associated with metabolic disease. Here, we show that obesity changes the miRNA profile of plasma exosomes in mice, including increases in , , , and Importantly, treatment of lean mice with exosomes isolated from obese mice induces glucose intolerance and insulin resistance. Moreover, administration of control exosomes transfected with obesity-associated miRNA mimics strongly induces glucose intolerance in lean mice and results in central obesity and hepatic steatosis.

Mind the Gap: Mapping Mass Spectral Databases in Genome-Scale Metabolic Networks Reveals Poorly Covered Areas.

The use of mass spectrometry-based metabolomics to study human, plant and microbial biochemistry and their interactions with the environment largely depends on the ability to annotate metabolite structures by matching mass spectral features of the measured metabolites to curated spectra of reference standards. While reference databases for metabolomics now provide information for hundreds of thousands of compounds, barely 5% of these known small molecules have experimental data from pure standards. Remarkably, it is still unknown how well existing mass spectral libraries cover the biochemical landscape of prokaryotic and eukaryotic organisms.

Transcription Factor Binding Site Enrichment Analysis in Co-Expression Modules in Celiac Disease.

The aim of this study was to construct celiac co-expression patterns at a whole genome level and to identify transcription factors (TFs) that could drive the gliadin-related changes in coordination of gene expression observed in celiac disease (CD). Differential co-expression modules were identified in the acute and chronic responses to gliadin using expression data from a previous microarray study in duodenal biopsies. Transcription factor binding site (TFBS) and Gene Ontology (GO) annotation enrichment analyses were performed in differentially co-expressed genes (DCGs) and selection of candidate regulators was performed.

Joint Data Analysis in Nutritional Epidemiology: Identification of Observational Studies and Minimal Requirements.

Background: Joint data analysis from multiple nutrition studies may improve the ability to answer complex questions regarding the role of nutritional status and diet in health and disease.

Objective: The objective was to identify nutritional observational studies from partners participating in the European Nutritional Phenotype Assessment and Data Sharing Initiative (ENPADASI) Consortium, as well as minimal requirements for joint data analysis.

Methods: A predefined template containing information on study design, exposure measurements (dietary intake, alcohol and tobacco consumption, physical activity, sedentary behavior, anthropometric measures, and sociodemographic and health status), main health-related outcomes, and laboratory measurements (traditional and omics biomarkers) was developed and circulated to those European research groups participating in the ENPADASI under the strategic research area of "diet-related chronic diseases.

Positional Enrichment by Proton Analysis (PEPA): A One-Dimensional H-NMR Approach for C Stable Isotope Tracer Studies in Metabolomics.

A novel metabolomics approach for NMR-based stable isotope tracer studies called PEPA is presented, and its performance validated using human cancer cells. PEPA detects the position of carbon label in isotopically enriched metabolites and quantifies fractional enrichment by indirect determination of C-satellite peaks using 1D- H-NMR spectra. In comparison with C-NMR, TOCSY and HSQC, PEPA improves sensitivity, accelerates the elucidation of C positions in labeled metabolites and the quantification of the percentage of stable isotope enrichment.