Including supramaximal verification reduced uncertainty in VO2peak response rate.

Many reports describe using a supramaximal verification phase-exercising at a power output higher than the highest power output recorded during an incremental cardiopulmonary test-to validate VO2max. The impact of verification phases on estimating the proportion of individuals who increased VO2peak in response to high-intensity interval training (HIIT) remains an underexplored area in the individual response literature. This analysis investigated the influence of same-day and separate-day verification phases during repeated measurements (incremental tests-INCR1 and INCR2; incremental tests + supramaximal verification phases-INCR1+ and INCR2+) of VO2peak on typical error (TE) and the proportion of individuals classified as responders (i.e., the response rate) following 4 weeks of HIIT (n = 25) or a no-exercise control period (n = 9). Incorporation of supramaximal verification consistently reduced the standard deviation of individual response, TE, and confidence interval (CI) widths. However, variances were statistically similar across all groups (p > 0.05). Response rates increased when incorporating either one (INCR1 to INCR1+; 24%-48%, p = 0.07) or two (INCR2 to INCR2+; 28%-48%, p = 0.063) supramaximal verification phases. However, response rates remained unchanged when either zero-based thresholds or smallest worthwhile difference response thresholds were used (50% and 90% CIs, all p > 0.05). Supramaximal verification phases reduced random variability in VO2peak response to HIIT. Compared with separate-day testing (INCR2 and INCR2+), the incorporation of a same-day verification (INCR1+) reduced CI widths the most. Researchers should consider using a same-day verification phase to reduce uncertainty and better estimate VO2peak response rate to HIIT.

Systematic investigation of imprinted gene expression and enrichment in the mouse brain explored at single-cell resolution.

BACKGROUND: Although a number of imprinted genes are known to be highly expressed in the brain, and in certain brain regions in particular, whether they are truly over-represented in the brain has never been formally tested. Using thirteen single-cell RNA sequencing datasets we systematically investigated imprinted gene over-representation at the organ, brain region, and cell-specific levels. RESULTS: We established that imprinted genes are indeed over-represented in the adult brain, and in neurons particularly compared to other brain cell-types. We then examined brain-wide datasets to test enrichment within distinct brain regions and neuron subpopulations and demonstrated over-representation of imprinted genes in the hypothalamus, ventral midbrain, pons and medulla. Finally, using datasets focusing on these regions of enrichment, we identified hypothalamic neuroendocrine populations and the monoaminergic hindbrain neurons as specific hotspots of imprinted gene expression. CONCLUSIONS: These analyses provide the first robust assessment of the neural systems on which imprinted genes converge. Moreover, the unbiased approach, with each analysis informed by the findings of the previous level, permits highly informed inferences about the functions on which imprinted gene expression converges. Our findings indicate the neuronal regulation of motivated behaviours such as feeding and sleep, alongside the regulation of pituitary function, as functional hotspots for imprinting. This adds statistical rigour to prior assumptions and provides testable predictions for novel neural and behavioural phenotypes associated with specific genes and imprinted gene networks. In turn, this work sheds further light on the potential evolutionary drivers of genomic imprinting in the brain.

Prevalence and predictors of poor mental health among pregnant women in Wales using a cross-sectional survey.

OBJECTIVES: To assess the prevalence of self-reported mental health problems in a cohort of women in early pregnancy. To describe the relationship between poor mental health and sociodemographic characteristics, self-efficacy and support networks. To assess if participants were representative of the local antenatal population. RESEARCH DESIGN AND SETTING: The UK government has pledged money to provide more support for women with perinatal mental health issues. Understanding the prevalence and predicting women who may need support will inform clinical practice. This paper reports part of the larger 'Mothers Mood Study', which explored women's and midwives' experience of mild to moderate perinatal mental health issues and service provision. Routinely collected population level data were analysed and a smaller cross-sectional survey design used to assess predictors of poor mental health in early pregnancy in one health board in Wales. PARTICIPANTS: Routinely collected data were extracted for all women who registered for maternity care between May 2017 and May 2018 (n = 6312) from the electronic maternity information system (pregnant population). Over a three month period 302 of these women completed a questionnaire at the antenatal clinic after an ultrasound scan (participants). Eligible women were aged ≥18 years, with sufficient spoken and written English to complete the questionnaire and a viable pregnancy of ≤18 weeks' gestation. The questionnaire collected data on sociodemographic status, self-efficacy and support networks, self-reported mental health problems. Current anxiety and depression were assessed using the General Anxiety Disorders Assessment and Edinburgh Postnatal Depression Scale. FINDINGS: Among the pregnant population 23% (n = 1490) disclosed a mental health problem during routine questioning with anxiety and depression being the most common conditions. Participants completing the detailed questionnaire were similar in age and parity to the pregnant population with similar levels of depression (15.6%; n = 15.6 v 17.3%, n = 1092). Edinburgh Postnatal Depression Scale and General Anxiety Disorder 7 scores identified 8% with symptoms of anxiety (n = 25) or depression (n = 26) and a further 24.2% (n = 73) with symptoms of mild anxiety and 25.2% (n = 76) with mild depression. Low self-efficacy (OR 1.27, 95% CI 1.12-1.45), a previous mental health problem (OR 3.95, 95% CI 1.37-11.33) and low support from family (OR 1.13, 95% CI 1.00-1.27) were found to be associated with early pregnancy anxiety and/or depression. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Around one in five women who register for maternity care may have a mental health problem. Mild to moderate anxiety and depression are common in early pregnancy. Services need to improve for women who do not currently meet the threshold for referral to perinatal mental health services. Assessment and active monitoring of mental health is recommended, in particular for pregnant women with risk factors including a history of previous mental health difficulties, poor family support or low self-efficacy.

Impacts of depression subcase and case on all-cause mortality in older people: The findings from the multi-centre community-based cohort study in China.

OBJECTIVES: It is unclear whether and to what extent depression subcases and cases in older age were associated with all-cause mortality. Little is known about gender differences in the associations. We assess these in older Chinese. METHODS: We examined a random sample of 6124 participants aged ≥60 years across five provinces in China. They were interviewed using a standard method of the GMS-AGECAT to diagnose depression subcase and case and record sociodemographic and disease risk factors at baseline, and to follow up their vital status. We employed Cox regression models to determine all-cause mortality in relation to depression subcases and cases, with adjustment for important variables, including social support and co-morbidities. RESULTS: Over the 10-year follow-up, 928 deaths occurred. Compared to those without depression at baseline, participants with depression subcase (n = 196) and case (n = 264) had increased risk of mortality; adjusted hazard ratios (HRs) were 1.46 (95% CI 1.07-2.00) and 1.45 (1.10-1.91). The adjusted HRs in men were 1.15 (0.72-1.81) and 1.85 (1.22-2.81), and in women 1.87 (1.22-2.87) and 1.22 (0.83-1.77) respectively. In participants aged ≥65 years, the adjusted HRs were 1.12 (0.68-1.84) and 1.99 (1.28-3.10) in men, and 2.06 (1.32-2.24) and 1.41 (0.94-2.10) in women. Increased HR in depression subcases was higher in women than man (ratio of HRs was 1.84, p = 0.034). CONCLUSIONS: Older people with depression subcase could have increased all-cause mortality to a similar extent to those with depression case. More attention should be paid to subcases of depression in women to tackle gender inequalities and improve survival.

Risk factors for excessive gestational weight gain in a UK population: a biopsychosocial model approach.

BACKGROUND: Gestational weight gain (GWG) can have implications for the health of both mother and child. However, the contributing factors remain unclear. Despite the advantages of using a biopsychosocial approach, this approach has not been applied to study GWG in the UK. This study aimed to investigate the risk factors of excessive GWG in a UK population, employing a biopsychosocial model. METHODS: This study utilised data from the longitudinal Grown in Wales (GiW) cohort, which recruited women in late pregnancy in South Wales. Specifically, data was collected from midwife recorded notes and an extensive questionnaire completed prior to an elective caesarean section (ELCS) delivery. GWG was categorised according to Institute of Medicine (IOM) guidelines. The analysis was undertaken for 275 participants. RESULTS: In this population 56.0% of women had excessive GWG. Increased prenatal depression symptoms (Exp(B)=1.10, p=.019) and an overweight (Exp(B)=4.16, p<.001) or obese (Exp(B)=4.20, p=.010) pre-pregnancy BMI, consuming alcohol in pregnancy (Exp(B)=.37, p=.005) and an income of less than £18,000 (Exp(B)=.24, p=.043) and £25-43,000 (Exp(B)=.25, p=.002) were associated with excessive GWG. CONCLUSION: GWG is complex and influenced by a range of biopsychosocial factors, with the high prevalence of excessive weight gain in this population a cause for concern. Women in the UK may benefit from a revised approach toward GWG within the National Health Service (NHS), such as tracking weight gain throughout pregnancy. Additionally, this research provides evidence for potential targets for future interventions, and potentially at-risk populations to target, to improve GWG outcomes.

The placental programming hypothesis: Placental endocrine insufficiency and the co-occurrence of low birth weight and maternal mood disorders.

Polypeptide hormones and steroid hormones, either expressed by the placenta or dependant on the placenta for their synthesis, are key to driving adaptations in the mother during pregnancy that support growth in utero. These adaptations include changes in maternal behaviour that take place in pregnancy and after the birth to ensure that offspring receive appropriate care and nutrition. Placentally-derived hormones implicated in the programming of maternal caregiving in rodents include prolactin-related hormones and steroid hormones. Neuromodulators produced by the placenta may act directly on the fetus to support brain development. A number of imprinted genes function antagonistically in the placenta to regulate the development of key placental endocrine lineages expressing these hormones. Gain-in-expression of the normally maternally expressed gene Phlda2 or loss-of-function of the normally paternally expressed gene Peg3 results in fewer endocrine cells in the placenta, and pups are born low birth weight. Importantly, wild type dams carrying these genetically altered pups display alterations in their behaviour with decreased focus on nurturing (Phlda2) or heightened anxiety (Peg3). These same genes may regulate placental hormones in human pregnancies, with the potential to influence birth weight and maternal mood. Consequently, the aberrant expression of imprinted genes in the placenta may underlie the reported co-occurrence of low birth weight with maternal prenatal depression.

Prenatal symptoms of anxiety and depression associated with sex differences in both maternal perceptions of one year old infant temperament and researcher observed infant characteristics.

BACKGROUND: Sex differences in the behaviour of children exposed to prenatal maternal depression and anxiety have been reported. This study compared depression and anxiety symptoms reported by mothers at term with maternal perceptions of one year old male and female infant temperament and with researcher observed infant characteristics, identifying differences for males and females with both approaches. METHODS: Infant behaviour and temperament was assessed via maternally completed questionnaires including Infant Behavioural Questionnaire Revised - Short form and by researcher administered subcomponents of Laboratory Temperament Assessment Battery and Bayley Scales of Infant Development III. RESULTS: For female infants, higher prenatal scores for depression and anxiety were associated with maternal perceptions of lower bonding, higher aggression and negativity, and lower soothability (n = 67 mother-infant dyads). In the laboratory assessment, intensity of escape was the only female infant factor significantly associated with maternal mood (n = 41). For male infants, there was minimal association between prenatal mood scores and maternal perceptions (n = 46) whereas in the laboratory assessment (n = 35) depression scores were associated with expressive language, facial interest and facial fear while anxiety scores were associated with expressive and receptive language, parent behaviour and facial fear. LIMITATIONS: Findings may be restricted to a single ethnicity or mode of delivery. Fewer infants attended the infant assessment. A laboratory setting may mask symptomatology in females. CONCLUSIONS: Atypical maternal perceptions may present a barrier to the early identification of male infants impacted by maternal depression and anxiety.

Patterns of floral nectar standing crops allow plants to manipulate their pollinators.

'Pollination syndromes' involving floral nectar have eluded satisfactory evolutionary explanation. For example, floral nectars for vertebrate-pollinated plants average low sugar concentrations, while such animals prefer high concentrations, perplexing pollination biologists and arousing recent controversy. Such relationships should result from evolutionary games, with plants and pollinators adopting Evolutionarily Stable Strategies, and nectar manipulating rather than attracting pollinators. Plant potential to manipulate pollinators depends on relationships between neighbouring flowers within plants, for all nectar attributes, but this has not been investigated. We measured nectar volume, concentration and sugar composition for open flowers on naturally-growing Blandfordia grandiflora plants, presenting classic bird-pollinated plant syndrome. To evaluate potential pollinator manipulation through nectar, we analysed relationships between neighbouring flowers for nectar volume, concentration, proportion sucrose, log(fructose/glucose), and sugar weight. To evaluate potential attraction of repeat-visits to flowers or plants through nectar, we compared attributes between successive days. Nearby flowers were positively correlated for all attributes, except log(fructose/glucose) as fructose≈glucose. Most relationships between nectar attributes for flowers and plants on successive days were non-significant. Nectar-feeding pollinators should therefore decide whether to visit another flower on a plant, based on all attributes of nectar just-obtained, enabling plants to manipulate pollinators through adjusting nectar. Plants are unlikely to attract repeat pollinator-visits through nectar production. Floral nectar evolution is conceptually straightforward but empirically challenging. A mutant plant deviating from the population in attributes of nectar-production per flower would manipulate, rather than attract, nectar-feeding pollinators, altering pollen transfer, hence reproduction. However, links between floral nectar and plant fitness present empirical difficulties.

Imprinted genes influencing the quality of maternal care.

In mammals successful rearing imposes a cost on later reproductive fitness specifically on the mother creating the potential for parental conflict. Loss of function of three imprinted genes in the dam results in deficits in maternal care suggesting that, like maternal nutrients, maternal care is a resource over which the parental genomes are in conflict. The induction of maternal care is a complex, highly regulated process and it is unsurprising that many gene disruptions and environmental adversities result in maternal care deficits. However, recent compelling evidence for a more purposeful imprinting phenomenon comes from observing alterations in the mother's behaviour when expression of the imprinted genes Phlda2 and Peg3 has been manipulated solely in the offspring. This explicit demonstration that imprinted genes expressed in the offspring influence maternal behaviour lends significant weight to the hypothesis that maternal care is a resource that has been manipulated by the paternal genome.

Maternal care boosted by paternal imprinting in mammals.

In mammals, mothers are the primary caregiver, programmed, in part, by hormones produced during pregnancy. High-quality maternal care is essential for the survival and lifelong health of offspring. We previously showed that the paternally silenced imprinted gene pleckstrin homology-like domain family A member 2 (Phlda2) functions to negatively regulate a single lineage in the mouse placenta called the spongiotrophoblast, a major source of hormones in pregnancy. Consequently, the offspring's Phlda2 gene dosage may influence the quality of care provided by the mother. Here, we show that wild-type (WT) female mice exposed to offspring with three different doses of the maternally expressed Phlda2 gene-two active alleles, one active allele (the extant state), and loss of function-show changes in the maternal hypothalamus and hippocampus during pregnancy, regions important for maternal-care behaviour. After birth, WT dams exposed in utero to offspring with the highest Phlda2 dose exhibit decreased nursing and grooming of pups and increased focus on nest building. Conversely, 'paternalised' dams, exposed to the lowest Phlda2 dose, showed increased nurturing of their pups, increased self-directed behaviour, and a decreased focus on nest building, behaviour that was robustly maintained in the absence of genetically modified pups. This work raises the intriguing possibility that imprinting of Phlda2 contributed to increased maternal care during the evolution of mammals.

Dopaminergic and behavioural changes in a loss-of-imprinting model of Cdkn1c.

The imprinted gene Cdkn1c is expressed exclusively from the maternally inherited allele as a consequences of epigenetic regulation. Cdkn1c exemplifies many of the functional characteristics of imprinted genes, playing a role in foetal growth and placental development. However, Cdkn1c also plays an important role in the brain, being key to the appropriate proliferation and differentiation of midbrain dopaminergic neurons. Using a transgenic model (Cdkn1cBACx1 ) with a twofold elevation in Cdkn1c expression that mimics loss-of-imprinting, we show that increased expression of Cdkn1c in the brain gives rise to neurobiological and behavioural changes indicative of a functionally altered dopaminergic system. Cdkn1cBACX1 mice displayed altered expression of dopamine system-related genes, increased tyrosine hydroxylase (Th) staining and increased tissue content of dopamine in the striatum. In addition, Cdkn1cBACx1 animals were hypersensitive to amphetamine as showed by c-fos expression in the nucleus accumbens. Cdkn1cBACX1 mice had significant changes in behaviours that are dependent on the mesolimbic dopaminergic system. Specifically, increased motivation for palatable food stuffs, as indexed on a progressive ratio task. In addition, Cdkn1cBACX1 mice displayed enhanced social dominance. These data show, for the first time, the consequence of elevated Cdkn1c expression on dopamine-related behaviours highlighting the importance of correct dosage of this imprinted gene in the brain. This work has significant relevance for deepening our understanding of the epigenetic factors that can shape neurobiology and behaviour.

Loss of offspring Peg3 reduces neonatal ultrasonic vocalizations and increases maternal anxiety in wild-type mothers.

Depression and anxiety are the most common mental health conditions during pregnancy and can impair the normal development of mother-infant interactions. These adversities are associated with low birth weight and increased risk of behavioural disorders in children. We recently reported reduced expression of the imprinted gene PATERNALLY EXPRESSED GENE 3 (PEG3) in placenta of human infants born to depressed mothers. Expression of Peg3 in the brain has previously been linked maternal behaviour in rodents, at least in some studies, with mutant dams neglecting their pups. However, in our human study decreased expression was in the placenta derived from the fetus. Here, we examined maternal behaviour in response to reduced expression of Peg3 in the feto-placental unit. Prenatally we found novelty reactivity was altered in wild-type females carrying litters with a null mutation in Peg3. This behavioural alteration was short-lived and there were no significant differences the transcriptomes of either the maternal hypothalamus or hippocampus at E16.5. In contrast, while maternal gross maternal care was intact postnatally, the exposed dams were significantly slower to retrieve their pups and displayed a marked increase in anxiety. We also observed a significant reduction in the isolation-induced ultrasonic vocalizations (USVs) emitted by mutant pups separated from their mothers. USVs are a form of communication known to elicit maternal care suggesting Peg3 mutant pups drive the deficit in maternal behaviour. These data support the hypothesis that reduced placental PEG3 in human pregnancies occurs as a consequence of prenatal depression but leaves scope for feto-placental Peg3 dosage, during gestation, influencing aspects of maternal behaviour.

Telomere length heterogeneity in placenta revealed with high-resolution telomere length analysis.

INTRODUCTION: Telomeres, are composed of tandem repeat sequences located at the ends of chromosomes and are required to maintain genomic stability. Telomeres can become shorter due to cell division and specific lifestyle factors. Critically shortened telomeres are linked to cellular dysfunction, senescence and aging. A number of studies have used low resolution techniques to assess telomere length in the placenta. In this study, we applied Single Telomere Length Analysis (STELA) which provides high-resolution chromosome specific telomere length profiles to ask whether we could obtain more detailed information on the length of individual telomeres in the placenta. METHODS: Term placentas (37-42 weeks) were collected from women delivering at University Hospital of Wales or Royal Gwent Hospital within 2 h of delivery. Multiple telomere-length distributions were determined using STELA. Intraplacental variation of telomere length was analysed (N = 5). Telomere length distributions were compared between labouring (N = 10) and non-labouring (N = 11) participants. Finally, telomere length was compared between female (N = 17) and male (N = 20) placenta. RESULTS: There were no significant influences of sampling site, mode of delivery or foetal sex on the telomere-length distributions obtained. The mean telomere length was 7.7 kb ranging from 5.0 kb to 11.7 kb across all samples (N = 42) and longer compared with other human tissues at birth. STELA also revealed considerable telomere length heterogeneity within samples. CONCLUSIONS: We have shown that STELA can be used to study telomere length homeostasis in the placenta regardless of sampling site, mode of delivery and foetal sex. Moreover, as each amplicon is derived from a single telomeric molecule, from a single cell, STELA can reveal the full detail of telomere-length distributions, including telomeres within the length ranges observed in senescent cells. STELA thus provides a new tool to interrogate the relationship between telomere length and pregnancy complications linked to placental dysfunction.

Long-term variation in concentrations and mass loads in a semi-arid watershed influenced by historic mercury mining and urban pollutant sources.

Urban watersheds are significantly anthropogenically-altered landscapes. Most previous studies cover relatively short periods, without addressing concentrations, loads, and yields in relation to annual climate fluctuations, and datasets on Ag, Se, PBDEs, and PCDD/Fs are rare. Intensive storm-focused sampling and continuous turbidity monitoring were employed to quantify pollution at two locations in the Guadalupe River (California, USA). At a downstream location, we determined loads of suspended sediment (SS) for 14yrs., mercury (HgT), PCBs, and total organic carbon (TOC) (8yrs), total methylmercury (MeHgT) (6yrs), nutrients, and trace elements including Ag and Se (3yrs), DDTs, chlordanes, dieldrin, and PBDEs (2yrs), and PCDD/Fs (1yr). At an upstream location, we determined loads of SS for 4yrs. and HgT, MeHgT, PCBs and PCDD/Fs for 1yr. These data were compared to previous studies, climatically adjusted, and used to critically assess the use of small datasets for estimating annual average conditions. Concentrations and yields in the Guadalupe River appear to be atypical for total phosphorus, DDTs, dieldrin, HgT, MeHgT, Cr, Ni, and possibly Se due to local conditions. Other pollutants appear to be similar to other urban systems. On average, wet season flow varied by 6.5-fold and flow-weighted mean (FWM) concentrations varied 4.4-fold, with an average 7.1-fold difference between minimum and maximum annual loads. Loads for an average runoff year for each pollutant were usually less than the best estimate of long-term average. The arithmetic average of multiple years of load data or a FWM concentration combined with mean annual flow was also usually below the best estimate of long-term average load. Mean annual loads using sampled years were also less than the best estimate of long-term average by a mean of 2.2-fold. Climatic adjustment techniques are needed for computing estimates of long-term average annual loads.

Distribution of natural and anthropogenic radionuclides in northwest Mediterranean coastal sediments.

The distribution of radionuclides in NW Mediterranean coastal sediments, and the processes controlling their abundance were investigated in three cores taken near the island of Porquerolles and one offshore Monaco. The sediments collected near Porquerolles were strongly anoxic due to diagenetic processes involved in the decomposition of organic matter, whereas they transitioned from oxic to anoxic at a depth of 4 cm beneath the seawater interface at Monaco. Organic carbon (OC) was more abundant in sediments at Porquerolles (by about a factor of 3-5) than at Monaco and elsewhere in the coastal NW Mediterranean. Sediment cores collected NE of Porquerolles also possessed elevated uranium concentrations that correlated with high OC content and strong reducing conditions. The 239,240Pu and 241Am activities in surficial sediments ranged from 1 to 5.7 Bq kg-1 and 0.3 to 1 Bq kg-1, respectively, while the 137Cs activity ranged from 0.3 to 6.2 Bq kg-1. The mean activity ratios of 241Am/239,240Pu and 238Pu/239,240Pu in Porquerolles and Monaco sediments were similar to the global fallout ratios. Sediment inventories of global fallout 239,240Pu (430-800 Bq m-2) and 241Am (150-285 Bq m-2) were by about a factor of 5-10 higher at Porquerolles, whereas the inventory of 137Cs (430-1000 Bq m-2) was substantially lower at the investigated stations than have been reported elsewhere at similar latitudes. Specific local conditions characterised by high OC sediment loads due to the growth and mortality of Posidonia oceanica have been responsible for deposition of large amounts of seagrass tissues at the NE corner of Porquerolles, which have had a profound effect on the distribution of radionuclides in the sediments.

Birth size, risk factors across life and cognition in late life: protocol of prospective longitudinal follow-up of the MYNAH (MYsore studies of Natal effects on Ageing and Health) cohort.

INTRODUCTION: For late-life neurocognitive disorders, as for other late-life chronic diseases, much recent interest has focused on the possible relevance of Developmental Origins of Health and Disease (DOHaD). Programming by undernutrition in utero, followed by overnutrition in adult life may lead to an increased risk, possibly mediated through cardiovascular and metabolic pathways. This study will specifically examine, if lower birth weight is associated with poorer cognitive functioning in late life in a south Indian population. METHODS AND ANALYSIS: From 1934 onwards, the birth weight, length and head circumference of all babies born in the CSI Holdsworth Memorial Hospital, Mysore, India, were recorded in obstetric notes. Approximately 800 men and women from the Mysore Birth Records Cohort aged above 55 years, and a reliable informant for each, will be asked to participate in a single cross-sectional baseline assessment for cognitive function, mental health and cardiometabolic disorders. Participants will be assessed for hypertension, type-2 diabetes and coronary heart disease, nutritional status, health behaviours and lifestyles, family living arrangements, economic status, social support and social networks. Additional investigations include blood tests (for diabetes, insulin resistance, dyslipidaemia, anaemia, vitamin B12 and folate deficiency, hyperhomocysteinemia, renal impairment, thyroid disease and Apolipoprotein E genotype), anthropometry, ECG, blood pressure, spirometry and body composition (bioimpedance). We will develop an analysis plan, first using traditional univariate and multivariable analytical paradigms with independent, dependent and mediating/confounding/interacting variables to test the main hypotheses. ETHICS AND DISSEMINATION: This study has been approved by the research ethics committee of CSI Holdsworth Memorial Hospital. The findings will be disseminated locally and at international meetings, and will be published in open access peer reviewed journals.

Maternal prenatal depression is associated with decreased placental expression of the imprinted gene PEG3.

BACKGROUND: Maternal prenatal stress during pregnancy is associated with fetal growth restriction and adverse neurodevelopmental outcomes, which may be mediated by impaired placental function. Imprinted genes control fetal growth, placental development, adult behaviour (including maternal behaviour) and placental lactogen production. This study examined whether maternal prenatal depression was associated with aberrant placental expression of the imprinted genes paternally expressed gene 3 (PEG3), paternally expressed gene 10 (PEG10), pleckstrin homology-like domain family a member 2 (PHLDA2) and cyclin-dependent kinase inhibitor 1C (CDKN1C), and resulting impaired placental human placental lactogen (hPL) expression. METHOD: A diagnosis of depression during pregnancy was recorded from Manchester cohort participants' medical notes (n = 75). Queen Charlotte's (n = 40) and My Baby and Me study (MBAM) (n = 81) cohort participants completed the Edinburgh Postnatal Depression Scale self-rating psychometric questionnaire. Villous trophoblast tissue samples were analysed for gene expression. RESULTS: In a pilot study, diagnosed depression during pregnancy was associated with a significant reduction in placental PEG3 expression (41%, p = 0.02). In two further independent cohorts, the Queen Charlotte's and MBAM cohorts, placental PEG3 expression was also inversely associated with maternal depression scores, an association that was significant in male but not female placentas. Finally, hPL expression was significantly decreased in women with clinically diagnosed depression (44%, p < 0.05) and in those with high depression scores (31% and 21%, respectively). CONCLUSIONS: This study provides the first evidence that maternal prenatal depression is associated with changes in the placental expression of PEG3, co-incident with decreased expression of hPL. This aberrant placental gene expression could provide a possible mechanistic explanation for the co-occurrence of maternal depression, fetal growth restriction, impaired maternal behaviour and poorer offspring outcomes.

Increased dosage of the imprinted Ascl2 gene restrains two key endocrine lineages of the mouse Placenta.

Imprinted genes are expressed primarily from one parental allele by virtue of a germ line epigenetic process. Achaete-scute complex homolog 2 (Ascl2 aka Mash2) is a maternally expressed imprinted gene that plays a key role in placental and intestinal development. Loss-of-function of Ascl2 results in an expansion of the parietal trophoblast giant cell (P-TGC) lineage, an almost complete loss of Trophoblast specific protein alpha (Tpbpa) positive cells in the ectoplacental cone and embryonic failure by E10.5. Tpbpa expression marks the progenitors of some P-TGCs, two additional trophoblast giant cell lineages (spiral artery and canal), the spongiotrophoblast and the glycogen cell lineage. Using a transgenic model, here we show that elevated expression of Ascl2 reduced the number of P-TGC cells by 40%. Elevated Ascl2 also resulted in a marked loss of the spongiotrophoblast and a substantial mislocalisation of glycogen cells into the labyrinth. In addition, Ascl2-Tg placenta contained considerably more placental glycogen than wild type. Glycogen cells are normally located within the junctional zone in close contact with spongiotrophoblast cells, before migrating through the P-TGC layer into the maternal decidua late in gestation where their stores of glycogen are released. The failure of glycogen cells to release their stores of glycogen may explain both the inappropriate accumulation of glycogen and fetal growth restriction observed late in gestation in this model. In addition, using in a genetic cross we provide evidence that Ascl2 requires the activity of a second maternally expressed imprinted gene, Pleckstrin homology-like domain, family a, member 2 (Phlda2) to limit the expansion of the spongiotrophoblast. This "belts and braces" approach demonstrates the importance of genomic imprinting in regulating the size of the placental endocrine compartment for optimal placental development and fetal growth.

A Role for the Placenta in Programming Maternal Mood and Childhood Behavioural Disorders.

Substantial data demonstrate that the early-life environment, including in utero, plays a key role in later life disease. In particular, maternal stress during pregnancy has been linked to adverse behavioural and emotional outcomes in children. Data from human cohort studies and experimental animal models suggest that modulation of the developing epigenome in the foetus by maternal stress may contribute to the foetal programming of disease. Here, we summarise insights gained from recent studies that may advance our understanding of the role of the placenta in mediating the association between maternal mood disorders and offspring outcomes. First, the placenta provides a record of exposures during pregnancy, as indicated by changes in the placental trancriptome and epigenome. Second, prenatal maternal mood may alter placental function to adversely impact foetal and child development. Finally, we discuss the less well established but interesting possibility that altered placental function, more specifically changes in placental hormones, may adversely affect maternal mood and later maternal behaviour, which can also have consequence for offspring well-being.