Fetus-derived DLK1 is required for maternal metabolic adaptations to pregnancy and is associated with fetal growth restriction.

Pregnancy is a state of high metabolic demand. Fasting diverts metabolism to fatty acid oxidation, and the fasted response occurs much more rapidly in pregnant women than in non-pregnant women. The product of the imprinted DLK1 gene (delta-like homolog 1) is an endocrine signaling molecule that reaches a high concentration in the maternal circulation during late pregnancy. By using mouse models with deleted Dlk1, we show that the fetus is the source of maternal circulating DLK1. In the absence of fetally derived DLK1, the maternal fasting response is impaired. Furthermore, we found that maternal circulating DLK1 levels predict embryonic mass in mice and can differentiate healthy small-for-gestational-age (SGA) infants from pathologically small infants in a human cohort. Therefore, measurement of DLK1 concentration in maternal blood may be a valuable method for diagnosing human disorders associated with impaired DLK1 expression and to predict poor intrauterine growth and complications of pregnancy.M.A.M.C. was supported by a PhD studentship from the Cambridge Centre for Trophoblast Research. Research was supported by grants from the MRC (MR/J001597/1 and MR/L002345/1), the Medical College of Saint Bartholomew's Hospital Trust, a Wellcome Trust Investigator Award, EpigeneSys (FP7 Health-257082), EpiHealth (FP7 Health-278414), a Herchel Smith Fellowship (N.T.) and NIH grant RO1 DK89989. The contents are the authors' sole responsibility and do not necessarily represent official NIH views. We thank G. Burton for invaluable support, and M. Constância and I. Sandovici (University of Cambridge) for the Meox2-cre mice. We are extremely grateful to all of the participants in the Pregnancy Outcome Prediction study. This work was supported by the NIHR Cambridge Comprehensive Biomedical Research Centre (Women's Health theme) and project grants from the MRC (G1100221) and Sands (Stillbirth and Neonatal Death Charity). The study was also supported by GE Healthcare (donation of two Voluson i ultrasound systems for this study) and by the NIHR Cambridge Clinical Research Facility, where all research visits took place.This is the author accepted manuscript. The final version is available from Nature Publishing Group via https://doi.org/10.1038/ng.369

Untreated severe dental decay: a neglected determinant of low Body Mass Index in 12-year-old Filipino children

Contains fulltext : 98500.pdf (publisher's version ) (Open Access)BACKGROUND: Dental decay is the most common childhood disease worldwide and most of the decay remains untreated. In the Philippines caries levels are among the highest in the South East Asian region. Elementary school children suffer from high prevalence of stunting and underweight.The present study aimed to investigate the association between untreated dental decay and Body Mass Index (BMI) among 12-year-old Filipino children. METHODS: Data collection was part of the National Oral Health Survey, a representative cross-sectional study of 1951 11-13-year-old school children using a modified, stratified cluster sampling design based on population classifications of the Philippine National Statistics Office. Caries was scored according to WHO criteria (1997) and odontogenic infections using the PUFA index. Anthropometric measures were performed by trained nurses. Some socio-economic determinants were included as potential confounding factors. RESULTS: The overall prevalence of caries (DMFT + dmft > 0) was 82.3% (95%CI; 80.6%-84.0%). The overall prevalence of odontogenic infections due to caries (PUFA + pufa > 0) was 55.7% (95% CI; 53.5%-57.9%) The BMI of 27.1% (95%CI; 25.1%-29.1%) of children was below normal, 1% (95%CI; 0.5%-1.4%) had a BMI above normal. The regression coefficient between BMI and caries was highly significant (p 0) as compared to those without odontogenic infections had an increased risk of a below normal BMI (OR: 1.47; 95% CI: 1.19-1.80). CONCLUSIONS: This is the first-ever representative survey showing a significant association between caries and BMI and particularly between odontogenic infections and below normal BMI. An expanded model of hypothesised associations is presented that includes progressed forms of dental decay as a significant, yet largely neglected determinant of poor child development

Differential requirements for Tousled-like kinases 1 and 2 in mammalian development

The regulation of chromatin structure is critical for a wide range of essential cellular processes. The Tousled-like kinases, TLK1 and TLK2, regulate ASF1, a histone H3/H4 chaperone, and likely other substrates, and their activity has been implicated in transcription, DNA replication, DNA repair, RNA interference, cell cycle progression, viral latency, chromosome segregation and mitosis. However, little is known about the functions of TLK activity in vivo or the relative functions of the highly similar TLK1 and TLK2 in any cell type. To begin to address this, we have generated Tlk1- and Tlk2-deficient mice. We found that while TLK1 was dispensable for murine viability, TLK2 loss led to late embryonic lethality because of placental failure. TLK2 was required for normal trophoblast differentiation and the phosphorylation of ASF1 was reduced in placentas lacking TLK2. Conditional bypass of the placental phenotype allowed the generation of apparently healthy Tlk2-deficient mice, while only the depletion of both TLK1 and TLK2 led to extensive genomic instability, indicating that both activities contribute to genome maintenance. Our data identifies a specific role for TLK2 in placental function during mammalian development and suggests that TLK1 and TLK2 have largely redundant roles in genome maintenance