Fetal liver blood flow distribution: role in human developmental strategy to prioritize fat deposition versus brain development

Among primates, human neonates have the largest brains but also the highest proportion of body fat. If placental nutrient supply is limited, the fetus faces a dilemma: should resources be allocated to brain growth, or to fat deposition for use as a potential postnatal energy reserve? We hypothesised that resolving this dilemma operates at the level of umbilical blood distribution entering the fetal liver. In 381 uncomplicated pregnancies in third trimester, we measured blood flow perfusing the fetal liver, or bypassing it via the ductus venosus to supply the brain and heart using ultrasound techniques. Across the range of fetal growth and independent of the mother's adiposity and parity, greater liver blood flow was associated with greater offspring fat mass measured by dual-energy X-ray absorptiometry, both in the infant at birth (r = 0.43, P<0.001) and at age 4 years (r = 0.16, P = 0.02). In contrast, smaller placentas less able to meet fetal demand for essential nutrients were associated with a brain-sparing flow pattern (r = 0.17, p = 0.02). This flow pattern was also associated with a higher degree of shunting through ductus venosus (P = 0.04). We propose that humans evolved a developmental strategy to prioritize nutrient allocation for prenatal fat deposition when the supply of conditionally essential nutrients requiring hepatic inter-conversion is limited, switching resource allocation to favour the brain if the supply of essential nutrients is limited. Facilitated placental transfer mechanisms for glucose and other nutrients evolved in environments less affluent than those now prevalent in developed populations, and we propose that in circumstances of maternal adiposity and nutrient excess these mechanisms now also lead to prenatal fat deposition. Prenatal developmental influences play important roles in the human propensity to deposit fa

Structure of the hexameric HerA ATPase reveals a mechanism of translocation-coupled DNA-end processing in archaea.

The HerA ATPase cooperates with the NurA nuclease and the Mre11-Rad50 complex for the repair of double-strand DNA breaks in thermophilic archaea. Here we extend our structural knowledge of this minimal end-resection apparatus by presenting the first crystal structure of hexameric HerA. The full-length structure visualizes at atomic resolution the N-terminal HerA-ATP synthase domain and a conserved C-terminal extension, which acts as a physical brace between adjacent protomers. The brace also interacts in trans with nucleotide-binding residues of the neighbouring subunit. Our observations support a model in which the coaxial interaction of the HerA ring with the toroidal NurA dimer generates a continuous channel traversing the complex. HerA-driven translocation would propel the DNA towards the narrow annulus of NurA, leading to duplex melting and nucleolytic digestion. This system differs substantially from the bacterial end-resection paradigms. Our findings suggest a novel mode of DNA-end processing by this integrated archaeal helicase-nuclease machine.The SAXS data collection was supported by funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under BioStruct-X (grant agreement N°283570). Research in the N.P.R. laboratory is funded by the Medical Research Council [Career Development Award G0701443]. Research in the L.P. laboratory is funded by a Wellcome Trust Senior Fellowship Award in Basic Biomedical Sciences [grant number 08279/Z/07/Z]. Work in the L.P. and N.P.R. laboratories is also supported by an Isaac Newton Trust Research Grant, and S.M.B. is supported by a BBSRC Doctoral Training Grant.This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/ncomms650

Influences on the diet quality of pre-school children:importance of maternal psychological characteristics

OBJECTIVE: To test the hypothesis that maternal psychological profiles relate to children's quality of diet. DESIGN: Cross-sectional study. Mothers provided information on their health-related psychological factors and aspects of their child's mealtime environment. Children's diet quality was assessed using an FFQ from which weekly intakes of foods and a diet Z-score were calculated. A high score described children with a better quality diet. Cluster analysis was performed to assess grouping of mothers based on psychological factors. Mealtime characteristics, describing how often children ate while sitting at a table or in front of the television, their frequency of takeaway food consumption, maternal covert control and food security, and children's quality of diet were examined, according to mothers' cluster membership. SUBJECTS: Mother-child pairs (n 324) in the Southampton Initiative for Health. Children were aged 2-5 years. SETTING: Hampshire, UK. RESULTS: Two main clusters were identified. Mothers in cluster 1 had significantly higher scores for all psychological factors than mothers in cluster 2 (all P < 0.001). Clusters were termed 'more resilient' and 'less resilient', respectively. Children of mothers in the less resilient cluster ate meals sitting at a table less often (P = 0.03) and watched more television (P = 0.01). These children had significantly poorer-quality diets (β = -0.61, 95% CI -0.82, -0.40, P ≤ 0.001). This association was attenuated, but remained significant after controlling for confounding factors that included maternal education and home/mealtime characteristics (P = 0.006). CONCLUSIONS: The study suggests that mothers should be offered psychological support as part of interventions to improve children's quality of diet

Linear and Non-linear associations between vitamin D and grip strength: a Mendelian Randomisation study in UK Biobank

BACKGROUND: Low vitamin D status is a widespread phenomenon. Similarly, muscle weakness, often indicated by low grip strength, is another public health concern; however, the vitamin D-grip strength relationship is equivocal. It is important to understand whether variation in vitamin D status causally influences muscle strength to elucidate whether supplementation may help prevent/treat muscle weakness. METHODS: UK Biobank participants, aged 37-73 years, with valid data on Vitamin D status (circulating 25-hydroxyvitamin D (25(OH)D) concentration) and maximum grip strength were included (N=368,890). We examined sex-specific cross-sectional associations between 25(OH)D and grip strength. Using Mendelian randomisation (MR), we estimated the strength of the 25(OH)D-grip strength associations using genetic instruments for 25(OH)D as our exposure. Crucially, because potential effects of vitamin D supplementation on strength could vary by underlying 25(OH)D status, we allowed for non-linear relationships between 25(OH)D and strength in all analyses. RESULTS: Mean(SD) of 25(OH)D was 50(21)nmol/L in males and females. In cross-sectional analyses there was evidence of non-linear associations between 25(OH)D and strength: e.g., compared to males with 50nmol/L circulating 25(OH)D, males with 75nmol/L had 0.36kg (0.31,0.40) stronger grip; males with 25nmol/L had 1.01kg (95% CI: 0.93,1.08) weaker grip. In MR analyses, linear and non-linear models fitted the data similarly well: e.g., 25nmol/L higher circulating 25(OH)D in males was associated with 0.25kg (-0.05,0.55) greater grip (regardless of initial 25(OH)D status). Results were similar, albeit weaker, for females. CONCLUSIONS: Using two different methods to triangulate evidence, our findings suggest moderate to small causal links between circulating 25(OH)D and grip strength

The association between maternal-child physical activity levels at the transition to formal schooling: cross-sectional and prospective data from the Southampton Women's Survey.

BACKGROUND: Physical activity decreases through childhood, adolescence and into adulthood: parents of young children are particularly inactive, potentially negatively impacting their children's activity levels. This study aimed to determine the association between objectively measured maternal and 6-year-old children's physical activity; explore how this association differed by demographic and temporal factors; and identify change during the transition to school (from age 4-6). METHODS: Data were from the UK Southampton Women's Survey. Physical activity of 530 6-year-olds and their mothers was measured concurrently using accelerometry for ≤7 days. Cross-sectionally, two-level mixed-effects linear regression was used to model the association between maternal-child daily activity behaviour at age 6 [minutes sedentary (SED); in moderate-to-vigorous physical activity (MVPA)]. Interactions with demographic factors and time of the week were tested; how the association differed across the day was also explored. Change in the association between maternal-child physical activity (from age 4-6) was assessed in a subset (n = 170) [outcomes: SED, MVPA and light physical activity (LPA)]. RESULTS: Mother-child daily activity levels were positively associated (SED: β = 0.23 [0.20, 0.26] minutes/day; MVPA: 0.53 [0.43, 0.64] minutes/day). The association was stronger at weekends (vs. weekdays) (interaction term: SED: βi = 0.07 [0.02, 0.12]; MVPA: 0.44 [0.24, 0.64]). For SED, the association was stronger for those children with older siblings (vs. none); for MVPA, a stronger association was observed for those who had both younger and older siblings (vs. none) and a weaker relationship existed in spring compared to winter. Longitudinally, the association between mother-child activity levels did not change for SED and LPA. At age 6 (vs. age 4) the association between mother-child MVPA was weaker across the whole day (βi: - 0.16 [- 0.31, - 0.01]), but remained similar at both ages between 3 and 11 pm. CONCLUSIONS: More active mothers have more active 6-year-olds; this association was similar for boys and girls but differed by time of week, season and by age of siblings at home. Longitudinally, the association weakened for MVPA between 4 and 6 years, likely reflecting the differing activities children engage in during school hours and increased independence. Family-based physical activity remains an important element of children's activity behaviour regardless of age. This could be exploited in interventions to increase physical activity within families.This work was conducted by the Medical Research Council [Unit Programme number MC_UU_12015/3 and MC_UU_12015/7] and the Centre for Diet and Activity Research (CEDAR), a UKCRC Public Health Research Centre of Excellence. Funding from the British Heart Foundation, Cancer Research UK, Economic and Social Research Council, Medical Research Council, the National Institute for Health Research, and the Wellcome Trust, under the auspices of the UK Clinical Research Collaboration, is gratefully acknowledged (CEDAR grant numbers: ES/G007462/1; 087636/Z/08/Z; MR/K023187/1). The work of CC, KMG, NCH, HMI and SMR was supported by funding from the Medical Research Council, British Heart Foundation, the Arthritis Research UK, National Osteoporosis Society, International Osteoporosis Foundation, Cohen Trust, the European Union Seventh Framework Programme (FP7/2007-2013) EarlyNutrition project under grant agreement 289346, NIHR Southampton Biomedical Research Centre, and National Institute of Health Research Musculoskeletal Biomedical Research Unit, Oxford. KH is funded by the Wellcome Trust (107337/Z/15/Z)

Arachidonic acid and DHA status in pregnant women is not associated with cognitive performance of their children at 4 or 6–7 years

Arachidonic acid (ARA) and DHA, supplied primarily from the mother, are required for early development of the central nervous system. Thus, variations in maternal ARA or DHA status may modify neurocognitive development. We investigated the relationship between maternal ARA and DHA status in early (11·7 weeks) or late (34·5 weeks) pregnancy on neurocognitive function at the age of 4 years or 6–7 years in 724 mother–child pairs from the Southampton Women’s Survey cohort. Plasma phosphatidylcholine fatty acid composition was measured in early and late pregnancy. ARA concentration in early pregnancy predicted 13 % of the variation in ARA concentration in late pregnancy (β=0·36, P&lt;0·001). DHA concentration in early pregnancy predicted 21 % of the variation in DHA concentration in late pregnancy (β=0·46, P&lt;0·001). Children’s cognitive function at the age of 4 years was assessed by the Wechsler Preschool and Primary Scale of Intelligence and at the age of 6–7 years by the Wechsler Abbreviated Scale of Intelligence. Executive function at the age of 6–7 years was assessed using elements of the Cambridge Neuropsychological Test Automated Battery. Neither DHA nor ARA concentrations in early or late pregnancy were associated significantly with neurocognitive function in children at the age of 4 years or the age of 6–7 years. These findings suggest that ARA and DHA status during pregnancy in the range found in this cohort are unlikely to have major influences on neurocognitive function in healthy children.</p

Milk intake across adulthood and muscle strength decline from mid- to late life: the MRC National Survey of Health and Development

Milk is a source of several nutrients which may be beneficial for skeletal muscle. Evidence that links lower milk intake with declines in muscle strength from midlife to old age is lacking. We used data from the MRC NSHD to test sex-specific associations between milk consumption from age 36 to 60-64 years, low grip strength (GS) or probable sarcopenia, and GS decline from age 53 to 69 years. We included 1340 men and 1383 women with at least one measure of both milk intake and GS. Milk intake was recorded in 5-day food diaries (ages 36, 43, 53 and 60-64), and grand mean of total, reduced-fat and full-fat milk each categorised in thirds (T1 (lowest) to T3 (highest), g/day). GS was assessed at ages 53, 60-64, and 69, and probable sarcopenia classified at age 69. We employed logistic regression to examine the odds of probable sarcopenia, and multilevel models to investigate decline in GS in relation to milk intake thirds. Compared with T1, only T2 (58.7-145.2g/day) of reduced-fat milk was associated with lower odds of sex-specific low GS at age 69 (OR (95% CI): 0.59 (0.37, 0.94), p=0.03). In multilevel models, only T3 of total milk (≥237.5g/day) was associated with stronger GS in midlife in men (β (95% CI) = 1.82 (0.18, 3.45)kg, p=0.03) compared with T1 (≤152.0g/day), but not with GS decline over time. A higher milk intake across adulthood may promote muscle strength in midlife in men. Its role in muscle health in late life needs further examination

Maternal serum retinol and B-carotene concentrations and neonatal bone mineralisation: Results from the Southampton Women's Survey cohort

Background: studies in older adults and animals have suggested contrasting relations between bone health and different vitamin A compounds. To our knowledge, the associations between maternal vitamin A status and offspring bone development have not previously been elucidated.Objective: we examined the associations between maternal serum retinol and ?-carotene concentrations during late pregnancy and offspring bone mineralization assessed at birth with the use of dual-energy X-ray absorptiometry.Design: in the Southampton Women’s Survey mother-offspring birth cohort, maternal health, lifestyle, and diet were assessed prepregnancy and at 11 and 34 wk of gestation. In late pregnancy, maternal serum retinol and ?-carotene concentrations were measured. Offspring total body bone mineral density (BMD), bone mineral content (BMC), and bone area (BA) were measured within 2 wk after birth.Results: in total, 520 and 446 mother-offspring pairs had measurements of maternal serum retinol and ?-carotene, respectively. Higher maternal serum retinol in late pregnancy was associated with lower offspring total body BMC (? = ?0.10 SD/SD; 95% CI: ?0.19, ?0.02; P = 0.020) and BA (? = ?0.12 SD/SD; 95% CI: ?0.20, ?0.03; P = 0.009) but not BMD. Conversely, higher maternal serum ?-carotene concentrations in late pregnancy were associated with greater total body BMC (? = 0.12 SD/SD; 95% CI: 0.02, 0.21; P = 0.016) and BA (? = 0.12 SD/SD; 95% CI: 0.03, 0.22; P = 0.010) but not BMD.Conclusions: maternal serum retinol and ?-carotene concentrations had differing associations with offspring bone size and growth at birth: retinol was negatively associated with these measurements, whereas ?-carotene was positively associated. These findings highlight the need for further investigation of the effects of maternal retinol and carotenoid status on offspring bone developmen