Epigenetic changes associated with hyperglycaemia exposure in the longitudinal D.E.S.I.R. cohort

International audienceAim: - Understanding DNA methylation dynamics associated with progressive hyperglycaemia exposure could provide early diagnostic biomarkers and an avenue for delaying type 2 diabetes mellitus (T2DM). We aimed to identify DNA methylation changes during a 6-year period associated with early hyperglycaemia exposure using the longitudinal D.E.S.I.R. cohort. Methods: - We selected individuals with progressive hyperglycaemia exposure based on T2DM diagnostic criteria: 27 with long-term exposure, 34 with short-term exposure and 34 normoglycaemic controls. DNA from blood at inclusion and at the 6-year visit was subjected to methylation analysis using 850K methylation-EPIC arrays. A linear mixed model was used to perform an epigenome-wide association study (EWAS) and identify methylated changes associated with hyperglycaemia exposure during a 6-year time-period. Results: - We did not identify differentially methylated sites that reached false discovery rate (FDR)-significance in our cohort. Based on EWAS, we focused our analysis on methylation sites that had a constant effect during the 6 years across the hyperglycaemia groups compared to controls and found the most statistically significant site was the reported cg19693031 probe (TXNIP). We also performed an EWAS with HbA1c, using the inclusion and the 6-year methylation data and did not identify any FDR-significant CpGs. Conclusions: - Our study reveals that DNA methylation changes are not robustly associated with hyperglycaemia exposure or HbA1c during a short-term period, however, our top loci indicate potential interest and should be replicated in larger cohorts

High morbidity and mortality in children with untreated congenital deficiency of leptin or its receptor.

The long-term clinical outcomes of severe obesity due to leptin signaling deficiency are unknown. We carry out a retrospective cross-sectional investigation of a large cohort of children with leptin (LEP), LEP receptor (LEPR), or melanocortin 4 receptor (MC4R) deficiency (n = 145) to evaluate the progression of the disease. The affected individuals undergo physical, clinical, and metabolic evaluations. We report a very high mortality in children with LEP (26%) or LEPR deficiency (9%), mainly due to severe pulmonary and gastrointestinal infections. In addition, 40% of surviving children with LEP or LEPR deficiency experience life-threatening episodes of lung or gastrointestinal infections. Although precision drugs are currently available for LEP and LEPR deficiencies, as yet, they are not accessible in Pakistan. An appreciation of the severe impact of LEP or LEPR deficiency on morbidity and early mortality, educational attainment, and the attendant stigmatization should spur efforts to deliver the available life-saving drugs to these children as a matter of urgency

A framework for conducting time-varying genome-wide association studies:An application to body mass index across childhood in six multiethnic cohorts

Genetic effects on changes in human traits over time are understudied and may have important pathophysiological impact. We propose a framework that enables data quality control, implements mixed models to evaluate trajectories of change in traits, and estimates phenotypes to identify age-varying genetic effects in genome-wide association studies (GWASs). Using childhood body mass index (BMI) as an example, we included 71,336 participants from six cohorts and estimated the slope and area under the BMI curve within four time periods (infancy, early childhood, late childhood and adolescence) for each participant, in addition to the age and BMI at the adiposity peak and the adiposity rebound. GWAS on each of the estimated phenotypes identified 28 genome-wide significant variants at 13 loci across the 12 estimated phenotypes, one of which was novel (in DAOA) and had not been previously associated with childhood or adult BMI. Genetic studies of changes in human traits over time could uncover novel biological mechanisms influencing quantitative traits. </p

Biallelic Mutations in P4HTM Cause Syndromic Obesity

International audienceWe previously demonstrated that 50% of children with obesity from consanguineous families from Pakistan carry pathogenic variants in known monogenic obesity genes. Here, we have discovered a novel monogenetic recessive form of severe childhood obesity using an in-house computational staged approach. The analysis included whole-exome sequencing data of 366 children with severe obesity, 1,000 individuals of the Pakistan Risk of Myocardial Infarction Study (PROMIS) study, and 200,000 participants of the UK Biobank to prioritize genes harboring rare homozygous variants with putative effect on human obesity. We identified five rare or novel homozygous missense mutations predicted deleterious in five consanguineous families in P4HTM encoding prolyl 4-hydroxylase transmembrane (P4H-TM). We further found two additional homozygous missense mutations in children with severe obesity of Indian and Moroccan origin. Molecular dynamics simulation suggested that these mutations destabilized the active conformation of the substrate binding domain. Most carriers also presented with hypotonia, cognitive impairment, and/or developmental delay. Three of the five probands died of pneumonia during the first 2 years of the follow-up. P4HTM deficiency is a novel form of syndromic obesity, affecting 1.5% of our children with obesity associated with high mortality. P4H-TM is a hypoxia-inducible factor that is necessary for survival and adaptation under oxygen deprivation, but the role of this pathway in energy homeostasis and obesity pathophysiology remains to be elucidated

Determination of the

The neutron capture cross section of $$^{232}Th$$ has been measured with the time-of-flight technique in the energy range from 10 to 200 keV at the back-streaming white neutron beam-line (Back-n) of China Spallation Neutron Source (CSNS). The pulse height weighting technique (PHWT) was applied with four C$$_{6}$$D$$_{6}$$ liquid scintillators to measure the prompt gamma-ray energy release following neutron capture. The measurement data, corrected with the PHWT, have been normalized to the saturated resonances at 21.8 eV. The background was determined by a lead sample measurement and detailed Monte Carlo simulations. The $$^{232}Th(n,\gamma )$$ average cross sections have been determined relative to the $$^{197}Au(n,\gamma )$$ reaction cross sections. The results are consistent with the evaluation values of CENDL-3.2 and JENDL-5. The total uncertainties, including the PHWT, normalization, background subtraction, corrections, and relative measurement, are in the range of 4.5–4.8%

Measurement of relative differential cross sections of the neutron-deuteron elastic scattering for neutron energy from 13 to 52 MeV

The measurement of the relative differential cross sections of the neutron-deuteron ($$n-d)$$ elastic scattering, i.e., the $$^{2}$$H(n, el)$$^{2}$$H reaction, for 12 neutron energies from 13.56 MeV to 52.48 MeV has been carried out at the Back-n White Neutron Source of the China Spallation Neutron Source (CSNS). By detection of the recoil deuterons using the light charged particle detector array (LPDA) system, the relative differential cross sections of the neutrons in the center-of-mass frame were obtained and then compared with previous measurements, the theoretical calculations performed using the Nijmegen I nucleon-nucleon potential in the Faddeev formalism, and the evaluated from libraries including the ENDF-B/VIII.0, JEFF-3.3, JENDL-4.0, CENDL-3.2, and FENDL-3.2. The present work was the first measurement relative differential cross sections of the n-d scattering for the 30 MeV $$<E_{\mathrm{n}} \le$$ 60 MeV neutron energy range using a white neutron source

Measurement of the relative differential cross sections of the

The relative differential cross sections of the $$^{1}\hbox {H}(n, \,el)$$ reaction have been measured at the China Spallation Neutron Source (CSNS) Back-n white neutron source. A low-density polyethylene sample and a graphite foil were prepared for the foreground and background measurements, respectively. The charged particles were detected using the $${\vartriangle }E-E$$ telescope array of the Light-charged Particle Detector Array (LPDA) system. With 10 $${\vartriangle }E-E$$ telescopes, the relative differential cross sections of the $$^{1}\hbox {H}(n, \,el)$$ reaction were obtained from 70$$^{\circ }$$ to 160$$^{\circ }$$ in the center-of-mass system in the neutron energy ($$E_{\mathrm{n}}$$) range from 6.14 to 52.48 MeV (23 energy points). The present work was the first experiment using the $${\vartriangle }E-E$$ telescope array of the LPDA system at CSNS. The present results are in good agreement with previous measurements, evaluations and theoretical calculations. Furthermore, this work is the first measurement in the 6.52 MeV $$\le E_{\mathrm{n}} \le$$ 9.09 MeV, 10.57 MeV $$\le E_{\mathrm{n}} \le$$ 12.43 MeV, and 18.05 MeV $$\le$$$$E_{\mathrm{n}} \le$$ 20.05 MeV regions

Measurement of Gamma-Ray from Inelastic Neutron Scattering on 56Fe

In nuclear reactors, inelastic neutron scattering is a significant energy-loss mechanism which has deep impacts on designments of nuclear reactor and radiation shielding. Iron is an important material in reactor. However, for the existing nuclear data for iron, there exists an obvious divergence for the inelastic scattering cross sections and the related gamma production sections. Therefore the precise measurements are urgently needed for satisfying the demanding to design new nuclear reactors (fast reactors), Accelerator Driven Subcritical System (ADS), and other nuclear apparatus. In this paper, we report a new system with an array of HPGe detectors, electronics and acquisition system. Experiments had been carried out on three neutron facilities