Integrative analyses of TEDDY Omics data reveal lipid metabolism abnormalities, increased intracellular ROS and heightened inflammation prior to autoimmunity for type 1 diabetes.

BACKGROUND: The Environmental Determinants of Diabetes in the Young (TEDDY) is a prospective birth cohort designed to study type 1 diabetes (T1D) by following children with high genetic risk. An integrative multi-omics approach was used to evaluate islet autoimmunity etiology, identify disease biomarkers, and understand progression over time. RESULTS: We identify a multi-omics signature that was predictive of islet autoimmunity (IA) as early as 1 year before seroconversion. At this time, abnormalities in lipid metabolism, decreased capacity for nutrient absorption, and intracellular ROS accumulation are detected in children progressing towards IA. Additionally, extracellular matrix remodeling, inflammation, cytotoxicity, angiogenesis, and increased activity of antigen-presenting cells are observed, which may contribute to beta cell destruction. Our results indicate that altered molecular homeostasis is present in IA-developing children months before the actual detection of islet autoantibodies, which opens an interesting window of opportunity for therapeutic intervention. CONCLUSIONS: The approach employed herein for assessment of the TEDDY cohort showcases the utilization of multi-omics data for the modeling of complex, multifactorial diseases, like T1D.

Sharing Marks: H3K4 Methylation and H2B Ubiquitination as Features of Meiotic Recombination and Transcription.

Meiosis is a specialized cell division that gives raise to four haploid gametes from a single diploid cell. During meiosis, homologous recombination is crucial to ensure genetic diversity and guarantee accurate chromosome segregation. Both the formation of programmed meiotic DNA double-strand breaks (DSBs) and their repair using homologous chromosomes are essential and highly regulated pathways. Similar to other processes that take place in the context of chromatin, histone posttranslational modifications (PTMs) constitute one of the major mechanisms to regulate meiotic recombination. In this review, we focus on specific PTMs occurring in histone tails as driving forces of different molecular events, including meiotic recombination and transcription. In particular, we concentrate on the influence of H3K4me3, H2BK123ub, and their corresponding molecular machineries that write, read, and erase these histone marks. The Spp1 subunit within the Complex of Proteins Associated with Set1 (COMPASS) is a critical regulator of H3K4me3-dependent meiotic DSB formation. On the other hand, the PAF1c (RNA polymerase II associated factor 1 complex) drives the ubiquitination of H2BK123 by Rad6-Bre1. We also discuss emerging evidence obtained by cryo-electron microscopy (EM) structure determination that has provided new insights into how the "cross-talk" between these two marks is accomplished.

Palm Oil on the Edge.

Internationally recognized Spanish experts in the food industry, nutrition, toxicology, sustainability, and veterinary science met in Madrid on July 2018 to develop a consensus about palm oil (PO) as a food ingredient. Their aim was to provide a useful, evidence-based point of reference about PO. Scientific evidence about the role of PO in food safety, nutrition and sustainability was analyzed. Main conclusions were: (1) RSPO foundation responded to the environmental impact of palm crops. The Amsterdam Declaration pursues the use of 100% sustainable PO in Europe by 2020. Awareness about choosing sustainable products will help to maintain local economies and environments in the producing countries; (2) evidence shows that a moderate intake of PO within a healthy diet presents no risks for health. No evidence justifies any change fat intake recommendations; (3) food industry is interested in assuring safe, sustainable and high-quality products. The use of certified sustainable PO is increasing; and (4) there is no evidence associating PO consumption and higher cancer risk, incidence or mortality in humans. Tolerable daily intake (TDI) for toxic contaminants (2-and 3-monochloropropanediols (MCPDs), glycidyl esters (GEs)) have been established by JECFA and EFSA. Consequently, the European Commission has modified the Contaminants Regulation for GEs and it is still working on 3-MCPDs'.

A role for Mog1 in H2Bub1 and H3K4me3 regulation affecting RNAPII transcription and mRNA export.

Monoubiquitination of histone H2B (to H2Bub1) is required for downstream events including histone H3 methylation, transcription, and mRNA export. The mechanisms and players regulating these events have not yet been completely delineated. Here, we show that the conserved Ran-binding protein Mog1 is required to sustain normal levels of H2Bub1 and H3K4me3 in Saccharomyces cerevisiae Mog1 is needed for gene body recruitment of Rad6, Bre1, and Rtf1 that are involved in H2B ubiquitination and genetically interacts with these factors. We provide evidence that the absence of MOG1 impacts on cellular processes such as transcription, DNA replication, and mRNA export, which are linked to H2Bub1. Importantly, the mRNA export defect in mog1Δ strains is exacerbated by the absence of factors that decrease H2Bub1 levels. Consistent with a role in sustaining H2Bub and H3K4me3 levels, Mog1 co-precipitates with components that participate in these modifications such as Bre1, Rtf1, and the COMPASS-associated factors Shg1 and Sdc1. These results reveal a novel role for Mog1 in H2B ubiquitination, transcription, and mRNA biogenesis.

An exon three-way junction structure modulates splicing and degradation of the SUS1 yeast pre-mRNA.

The SUS1 gene of Saccharomyces cerevisiae is unusual as it contains two introns and undergoes alternative splicing, retaining one or both introns depending on growth conditions. The exon located between the two introns can be skipped during splicing and has been detected in circular form. This exon (E2) has also been found to influence the splicing of the flanking introns, an unusual situation in budding yeast where splicing mainly relies on intron recognition. Using SHAPE (selective 2'-hydroxyl acylation analyzed by primer extension), NMR spectroscopy, gel electrophoresis and UV thermal denaturation experiments combined with computational predictions, we show that E2 of SUS1 comprises a conserved double-helical stem topped by a three-way junction. One of the hairpins emerging from the junction exhibited significant thermal stability and was capped by a purine-rich loop structurally related to the substrate loop of the VS ribozyme. Cellular assays revealed that three mutants containing altered E2 structures had impaired SUS1 expression, and that a compensatory mutation restoring the conserved stem recovered expression to wild-type levels. Semi-quantitative RT-PCR measurements paralleled these results, and revealed that mutations in E2 altered splicing and transcript degradation processes. Thus, exon structure plays an important role in SUS1 RNA metabolism.

The feasibility and acceptability of reducing salt in partially baked bread: a Spanish case study.

OBJECTIVE: Bread is a staple of the Mediterranean diet but contributes substantially to its salt content (19 % in Spain). The objective of the present study was to assess the feasibility and acceptability of salt reduction in partially baked breads, partly replacing salt (NaCl) with a potassium salt, with subsequent follow-up. DESIGN: During 2013, nine breads already on the market (1·8 % NaCl flour basis) had 0·5 % of NaCl replaced with potassium citrate (27·7 % reduction in sodium) and were commercialized in Spain. Later, breads were baked in bake-off stores and sold ready-to-eat to consumers. This market test was evaluated by comparing the sales between standard- v. reduced-salt breads and the complaints related to flavour attributes. The wholesalers involved in the market test were then surveyed. SETTING: Spain. RESULTS: The market test confirmed good acceptance of the reduced-salt breads, as 2013 sales were 3678 tonnes v. 2012 sales of 3577 tonnes for the same standard breads. No complaints were received. The wholesaler survey showed, in general, little awareness of salt reduction. CONCLUSIONS: It is feasible that potassium citrate can reduce the salt content of bread without negatively affecting sales or complaints. This shows potential for introducing this type of bread on a larger scale.

Effect of Functional Bread Rich in Potassium, γ-Aminobutyric Acid and Angiotensin-Converting Enzyme Inhibitors on Blood Pressure, Glucose Metabolism and Endothelial Function: A Double-blind Randomized Crossover Clinical Trial.

Because it has been suggested that food rich in γ-aminobutyric acid (GABA) or angiotensin-converting enzyme inhibitor (ACEI) peptides have beneficial effects on blood pressure (BP) and other cardiovascular risk factors, we tested the effects of low-sodium bread, but rich in potassium, GABA, and ACEI peptides on 24-hour BP, glucose metabolism, and endothelial function.A randomized, double-blind, crossover trial was conducted in 30 patients with pre or mild-to-moderate hypertension, comparing three 4-week nutritional interventions separated by 2-week washout periods. Patients were randomly assigned to consume 120 g/day of 1 of the 3 types of bread for each nutritional intervention: conventional wheat bread (CB), low-sodium wheat bread enriched in potassium (LSB), and low-sodium wheat bread rich in potassium, GABA, and ACEI peptides (LSB + G). For each period, 24-hour BP measurements, in vivo endothelial function, and biochemical samples were obtained.After LSB + G consumption, 24-hour ambulatory BP underwent a nonsignificant greater reduction than after the consumption of CB and LSB (0.26 mm Hg in systolic BP and -0.63 mm Hg in diastolic BP for CB; -0.71 mm Hg in systolic BP and -1.08 mm Hg in diastolic BP for LSB; and -0.75 mm Hg in systolic BP and -2.12 mm Hg in diastolic BP for LSB + G, respectively). Diastolic BP at rest decreased significantly during the LSB + G intervention, although there were no significant differences in changes between interventions. There were no significant differences between interventions in terms of changes in in vivo endothelial function, glucose metabolism, and peripheral inflammatory parameters.Compared with the consumption of CB or LSB, no greater beneficial effects on 24-hour BP, endothelial function, or glucose metabolism were demonstrated after the consumption of LSB + G in a population with pre or mild-to-moderate hypertension. Further studies are warranted to clarify the effect of GABA on BP, preferably using a specific design for noninferiority trials and ambulatory BP monitoring as a measure of BP.This study was registered at Current Controlled Trials as ISRCTN31436822.

Salt in bread in Europe: potential benefits of reduction.

Bread is widely considered to be the foodstuff that provides the most dietary salt to the diet. As such, it is one of the key public health targets for a salt reduction policy. In this respect, it has been shown that a reduction in the salt content of bread is possible, and an alternative approach involves partial replacement with other, mainly potassium-based salts, which also counteract the effects of sodium. This replacement should be undertaken on the basis of criteria that maintain the product's sensory profile, and it tends to be more successful in breads with more naturally flavorful taste. The present review was conducted to examine salt intake in Europe and the health problems associated with its excessive consumption; particular focus is placed on the salt content of bread and the effects of its possible reduction and/or correction. The beneficial effects of such changes are highlighted by way of a theoretical calculation in baguette-type wheat bread. European legislation in the field of nutrition and health claims allows the positive aspects of such salt reduction and replacement methods to be stated.

High insoluble fibre content increases in vitro starch digestibility in partially baked breads.

Wheat breads prepared from frozen partially baked breads were characterized by their content of rapidly digestible starch (RDS) and slowly digestible starch (SDS) by the in vitro starch digestibility method developed by Englyst. Breads with different contents and types of fibre and breads prepared with different fermentation processes were studied. Bread with inulin and with a double fermentation had the lowest RDS content of 58.8 ± 1.7 and 60.0 ± 1.9 (% dry matter), respectively. Wheat bran bread, seeded bread, triple fermentation white bread and baguette-type bread showed values of RDS between 63.1 ± 1.7 and 65.7 ± 1.7 with no significant differences between them (p < 0.05). The fraction of SDS was higher in wheat breads than in breads with added fibre. The highest values of the starch digestive rate index (SDRI) were obtained by the three types of breads with added fibre, which ranged from 91.8 ± 3.5 to 95.8 ± 3.5 versus 80.2 ± 3.5 to 87.5 ± 3.5 for white wheat breads. A significant (p < 0.01) positive linear correlation between the insoluble fibre content and SDRI was obtained (R² = 0.96). Insoluble fibre dilutes and disrupts gluten network and probably weakens the interaction between gluten and starch, which protects starch from digestive enzymes action. Scanning electronic microscopy microstructure of bread crumbs corroborated this statement.

Prolonged frozen storage of partially-baked wheat bread increases in vitro slowly digestible starch after final bake.

We have studied the effect of the frozen storage time of industrially produced partially-baked wheat bread on starch digestibility, as the conventional production process is substantially modified for this type of bread, and alterations in its nutritional characteristics are therefore possible. The objective of the present study was to determine the effects of frozen storage on in vitro starch digestibility of partially-baked bread after final bake, with the Englyst analytical method. The rapidly digestible starch, expressed as percentage of dry matter +/- 95% confidence interval, fell significantly at 63 days, from 51.9 +/- 2.9 to 42.7 +/- 2.9 whereas the slowly digestible starch increased over this period, from 18.8 +/- 5.5 to 29.9 +/- 2.7 (P < 0.05). During the frozen storage, changes occur in the composition and structure of partially-baked bread, modifying the in vitro starch digestibility, with a significant reduction in rapidly digestible starch, which is associated with a lower glycaemic response.

Evaluation of lipid oxidation after ingestion of bakery products enriched with phytosterols, beta-carotene and alpha-tocopherol.

BACKGROUND AND AIMS: The aim of this study was to investigate the effect of the consumption of croissants and magdalenas (Spanish muffins), enriched with sterol esters, alpha-tocopherol and beta-carotene, on plasma lipid peroxidation. TBA and conjugated dienes were used as markers of lipid peroxidation. METHODS: The study was made to a population without changes in their diet or lifestyle, and based on a randomized double-blind controlled repeated measures design. The sample size was 57. During 8 weeks, the subjects of the control group (29) received two daily pieces (standard croissant and muffin), whereas those of the experimental group (28) received the same products, but enriched with sterol-esters, alpha-tocopherol and beta-carotene. RESULTS: The treatment has a positive effect on TBA value for control group and that given to experimental group has negative effect. The mean difference between two groups is 3.16 (P = 0.044). Also TBA was found to be significantly correlated with HDL-, LDL-cholesterol and alpha-tocopherol, both before and after treatment, but TBA was only significantly correlated with beta-carotene before treatment. Finally, the effects on LDL-cholesterol, alpha-tocopherol and TBA presented similar correlation matrices in the two groups, most correlation coefficients being significant at group level, in spite of the low sample sizes, revealing the association between treatment effects.

Bakery products enriched with phytosterol esters, alpha-tocopherol and beta-carotene decrease plasma LDL-cholesterol and maintain plasma beta-carotene concentrations in normocholesterolemic men and women.

The hypocholesterolemic effects of phytosterols have not been evaluated in bakery products, and the addition of liposoluble antioxidants to the carrier has never been tested. We investigated the effects of consuming croissants and magdalenas (Spanish muffins) enriched with sterol esters, alpha-tocopherol and beta-carotene on plasma lipid and fat-soluble antioxidant concentrations in normocholesterolemic, habitual consumers of bakery products following their usual diet and lifestyle. Using a randomized, double-blind, placebo-controlled design, the control (C) group (n = 29) received two pieces daily (standard croissant and muffin) and the sterol ester (SE) group (n = 28), the same products with sterol esters added (3.2 g/d) for 8 wk. Total and LDL cholesterol (LDL-C) decreased in the SE group by 0.24 mmol/L (P < 0.01) and 0.26 mmol/L (P < 0.005), respectively, whereas these variables did not change in the control group. The total difference in total and LDL-C changes between groups was 0.38 mmol/L (8.9%) and 0.36 mmol/L (14.7%), respectively (P < 0.001). Within-group changes in HDL cholesterol, triacylglycerol or lipoprotein(a) concentrations did not differ. Similarly, within-group changes over time in plasma tocopherol and carotenoid concentrations did not differ between groups. Our findings suggest that bakery products are excellent carriers for phytosterols, and their consumption is associated with a decrease in total and LDL-C concentrations, with no changes in alpha-tocopherol and beta-carotene. The ability of bakery products to include sufficient quantities of beta-carotene to compensate for a potential deficiency, and the fact that their efficacy was not associated with the time of day at which they were consumed, are interesting findings.