The mRNA m6A reader YTHDF2 suppresses proinflammatory pathways and sustains hematopoietic stem cell function

The mRNA N6-methyladenosine (m6A) modification has emerged as an essential regulator of normal and malignant hematopoiesis. Inactivation of the m6A mRNA reader YTHDF2, which recognizes m6A-modified transcripts to promote m6A-mRNA degradation, results in hematopoietic stem cell (HSC) expansion and compromises acute myeloid leukemia. Here we investigate the long-term impact of YTHDF2 deletion on HSC maintenance and multilineage hematopoiesis. We demonstrate that Ythdf2-deficient HSCs from young mice fail upon serial transplantation, display increased abundance of multiple m6A-modified inflammation-related transcripts, and chronically activate proinflammatory pathways. Consistent with the detrimental consequences of chronic activation of inflammatory pathways in HSCs, hematopoiesis-specific Ythdf2 deficiency results in a progressive myeloid bias, loss of lymphoid potential, HSC expansion, and failure of aged Ythdf2-deficient HSCs to reconstitute multilineage hematopoiesis. Experimentally induced inflammation increases YTHDF2 expression, and YTHDF2 is required to protect HSCs from this insult. Thus, our study positions YTHDF2 as a repressor of inflammatory pathways in HSCs and highlights the significance of m6A in long-term HSC maintenance

Metabolite ratios as potential biomarkers for type 2 diabetes:a DIRECT study

Aims/hypothesis Circulating metabolites have been shown to reflect metabolic changes during the development of type 2 diabetes. In this study we examined the association of metabolite levels and pairwise metabolite ratios with insulin responses after glucose, glucagon-like peptide-1 (GLP-1) and arginine stimulation. We then investigated if the identified metabolite ratios were associated with measures of OGTT-derived beta cell function and with prevalent and incident type 2 diabetes. Methods We measured the levels of 188 metabolites in plasma samples from 130 healthy members of twin families (from the Netherlands Twin Register) at five time points during a modified 3 h hyperglycaemic clamp with glucose, GLP-1 and arginine stimulation. We validated our results in cohorts with OGTT data (n = 340) and epidemiological case–control studies of prevalent (n = 4925) and incident (n = 4277) diabetes. The data were analysed using regression models with adjustment for potential confounders. Results There were dynamic changes in metabolite levels in response to the different secretagogues. Furthermore, several fasting pairwise metabolite ratios were associated with one or multiple clamp-derived measures of insulin secretion (all p Conclusion/interpretation In this study we have shown that the Val_PC ae C32:2 metabolite ratio is associated with an increased risk of type 2 diabetes and measures of insulin secretion and resistance. The observed effects were stronger than that of the individual metabolites and independent of known risk factors.</p

Cohort Profile : The DynaHEALTH consortium - a European consortium for a life-course bio-psychosocial model of healthy ageing of glucose homeostasis

Peer reviewe

Sensory and molecular characterisation of the protective effect of storage at -80 ºC on the odour profiles of human milk

The aim of this study was to investigate if storage at -80 °C prevents off-odour formation from oxidative fatty acid degradation, as previously observed for storage at -19 °C. This was carried out on milk from mothers being supplemented with fish oil, as well as on milk from those receiving no supplementation (control group). The rationale for this approach was that human milk fatty acid profiles have previously been shown to be highly influenced by maternal fatty acid dietary intake. Also, (poly)unsaturated fatty acids have been shown to be the precursors for off-odour generation during storage at -19 °C. Therefore, determination of aroma marker odourants originating from unsaturated fatty acids was performed on milk from both groups that had been stored at -80 °C, showing that, unlike the previously reported dramatic flavour changes in human milk stored at -19 °C, aroma profiles of milk from both groups remained generally unmodified after storage at -80 °C

Impact of Dietary Macronutrient Intake during Early and Late Gestation on Offspring Body Composition at Birth, 1, 3, and 5 Years of Age

Dietary intake during pregnancy as a possible modifiable risk factor for childhood obesity is poorly explored. In a prospective observational study, two multivariable regression models were therefore used to associate maternal diet at 15 and 32 weeks&rsquo; gestation with offsprings&rsquo; body composition and fat distribution at birth, 1, 3, and 5 years. Mean energy intake was 2157 &plusmn; 375 kcal (n = 186) in early and 2208 &plusmn; 460 kcal (n = 167) in late gestation. The partition model showed mostly no significant associations between maternal diet in early pregnancy and offspring body composition. In late pregnancy, higher fat intake was negatively associated with clinical outcomes at birth, 1, and 5 years. Protein intake was negatively associated with BMI z score (zBMI) at 3 and 5 years. A 10 g increase in fiber was associated with an increase of 3.50 mm2 abdominal subcutaneous fat at 1, 172.49 g fat mass at 3, and 0.23 zBMI at 5 years. Results were largely comparable in the substitution model. An incremental increase in fat and protein at the expense of carbohydrates in late but not early pregnancy may be associated with lower fat mass up to 5 years. Findings require confirmation by additional prospective studies

Accuracy and Reproducibility of Adipose Tissue Measurements in Young Infants by Whole Body Magnetic Resonance Imaging

<div><p>Purpose</p><p>MR might be well suited to obtain reproducible and accurate measures of fat tissues in infants. This study evaluates MR-measurements of adipose tissue in young infants <i>in vitro</i> and <i>in vivo</i>.</p><p>Material and Methods</p><p>MR images of ten phantoms simulating subcutaneous fat of an infant’s torso were obtained using a 1.5T MR scanner with and without simulated breathing. Scans consisted of a cartesian water-suppression turbo spin echo (wsTSE) sequence, and a PROPELLER wsTSE sequence. Fat volume was quantified directly and by MR imaging using k-means clustering and threshold-based segmentation procedures to calculate accuracy <i>in vitro</i>. Whole body MR was obtained in sleeping young infants (average age 67±30 days). This study was approved by the local review board. All parents gave written informed consent. To obtain reproducibility <i>in vivo</i>, cartesian and PROPELLER wsTSE sequences were repeated in seven and four young infants, respectively. Overall, 21 repetitions were performed for the cartesian sequence and 13 repetitions for the PROPELLER sequence.</p><p>Results</p><p><i>In vitro</i> accuracy errors depended on the chosen segmentation procedure, ranging from 5.4% to 76%, while the sequence showed no significant influence. Artificial breathing increased the minimal accuracy error to 9.1%. <i>In vivo</i> reproducibility errors for total fat volume of the sleeping infants ranged from 2.6% to 3.4%. Neither segmentation nor sequence significantly influenced reproducibility.</p><p>Conclusion</p><p>With both cartesian and PROPELLER sequences an accurate and reproducible measure of body fat was achieved. Adequate segmentation was mandatory for high accuracy.</p></div

<i>Absolute values</i> of the whole body fat measurements in the ten infants of the different sequences (prop: PROPELLER TSE; cart: cartesian TSE) and segmentation algorithms (k-means: k-means clustering; thr150, thr250: threshold-based with different threshold settings of 150 and 250)) for whole body adipose tissue (total), subcutaneous and intra-abdominal adipose tissue.

<p>The separation in intra-abdominal and subcutaneous fat was only possible with the k-means clustering segmentation algorithm.</p><p><i>Absolute values</i> of the whole body fat measurements in the ten infants of the different sequences (prop: PROPELLER TSE; cart: cartesian TSE) and segmentation algorithms (k-means: k-means clustering; thr150, thr250: threshold-based with different threshold settings of 150 and 250)) for whole body adipose tissue (total), subcutaneous and intra-abdominal adipose tissue.</p

Five representative slices of one infant.

<p>Left row: cartesian wsTSE sequence; middle row: original segmentation using the k-means clustering algorithm; right row: manually corrected segmentation with separation of internal (green) and external fat (red). This scan represents a case with insufficient water suppression at the arms, where the most user interaction among all scanned infants was required. The complete scan is available as (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0117127#pone.0117127.s001" target="_blank">S1 Fig.</a>).</p

Infant scans with the cartesian wsTSE sequence (A), the k-means clustering segmentation of subcutaneous fat (B), and one threshold-based segmentation of subcutaneous fat using a threshold of 150 (C).

<p>The k-means clustering segmentation better matches the visual findings (inserts).</p