Int J Mol Sci

The placenta is a key organ for fetal and brain development. Its epigenome can be regarded as a biochemical record of the prenatal environment and a potential mechanism of its association with the future health of the fetus. We investigated associations between placental DNA methylation levels and child behavioral and emotional difficulties, assessed at 3 years of age using the Strengths and Difficulties Questionnaire (SDQ) in 441 mother-child dyads from the EDEN cohort. Hypothesis-driven and exploratory analyses (on differentially methylated probes (EWAS) and regions (DMR)) were adjusted for confounders, technical factors, and cell composition estimates, corrected for multiple comparisons, and stratified by child sex. Hypothesis-driven analyses showed an association of cg26703534 () with emotional symptoms, and exploratory analyses identified two probes, cg09126090 (intergenic region) and cg10305789 (), as negatively associated with peer relationship problems, as well as 33 DMRs, mostly positively associated with at least one of the SDQ subscales. Among girls, most associations were seen with emotional difficulties, whereas in boys, DMRs were as much associated with emotional than behavioral difficulties. This study provides the first evidence of associations between placental DNA methylation and child behavioral and emotional difficulties. Our results suggest sex-specific associations and might provide new insights into the mechanisms of neurodevelopment.Exposition prénatale au tabac et à la pollution atmosphérique et effets sur la santé respiratoire et le neurodévelopment de l'enfant: rôle de la méthylation placentaireHorizon 2020 research and innovation programm

Fine-Tuning Roles of Endogenous Brain-Derived Neurotrophic Factor, TrkB and Sortilin in Colorectal Cancer Cell Survival

International audienceBACKGROUND: Neurotrophin receptors were initially identified in neural cells. They were recently detected in some cancers in association with invasiveness, but the function of these tyrosine kinase receptors was not previously investigated in colorectal cancer (CRC) cells. METHODS AND FINDINGS: We report herein that human CRC cell lines synthesize the neural growth factor Brain-derived neurotrophic factor (BDNF) under stress conditions (serum starvation). In parallel, CRC cells expressed high- (TrkB) and low-affinity (p75(NTR)) receptors at the plasma membrane, whereas TrkA and TrkC, two other high affinity receptors for NGF and NT-3, respectively, were undetectable. We demonstrate that BDNF induced cell proliferation and had an anti-apoptotic effect mediated through TrkB, as assessed by K252a, a Trk pharmacologic inhibitor. It suppressed both cell proliferation and survival of CRC cells that do not express TrkA nor TrkC. In parallel to the increase of BDNF secretion, sortilin, a protein acting as a neurotrophin transporter as well as a co-receptor for p75(NTR), was increased in the cytoplasm of primary and metastatic CRC cells, which suggests that sortilin could regulate neurotrophin transport in these cells. However, pro-BDNF, also detected in CRC cells, was co-expressed with p75(NTR) at the cell membrane and co-localized with sortilin. In contrast to BDNF, exogenous pro-BDNF induced CRC apoptosis, which suggests that a counterbalance mechanism is involved in the control of CRC cell survival, through sortilin as the co-receptor for p75(NTR), the high affinity receptor for pro-neurotrophins. Likewise, we show that BDNF and TrkB transcripts (and not p75(NTR)) are overexpressed in the patients' tumors by comparison with their adjacent normal tissues, notably in advanced stages of CRC. CONCLUSION: Taken together, these results highlight that BDNF and TrkB are essential for CRC cell growth and survival in vitro and in tumors. This autocrine loop could be of major importance to define new targeted therapies

Computational Study of the Human Dystrophin Repeats: Interaction Properties and Molecular Dynamics

Dystrophin is a large protein involved in the rare genetic disease Duchenne muscular dystrophy (DMD). It functions as a mechanical linker between the cytoskeleton and the sarcolemma, and is able to resist shear stresses during muscle activity. In all, 75% of the dystrophin molecule consists of a large central rod domain made up of 24 repeat units that share high structural homology with spectrin-like repeats. However, in the absence of any high-resolution structure of these repeats, the molecular basis of dystrophin central domain's functions has not yet been deciphered. In this context, we have performed a computational study of the whole dystrophin central rod domain based on the rational homology modeling of successive and overlapping tandem repeats and the analysis of their surface properties. Each tandem repeat has very specific surface properties that make it unique. However, the repeats share enough electrostatic-surface similarities to be grouped into four separate clusters. Molecular dynamics simulations of four representative tandem repeats reveal specific flexibility or bending properties depending on the repeat sequence. We thus suggest that the dystrophin central rod domain is constituted of seven biologically relevant sub-domains. Our results provide evidence for the role of the dystrophin central rod domain as a scaffold platform with a wide range of surface features and biophysical properties allowing it to interact with its various known partners such as proteins and membrane lipids. This new integrative view is strongly supported by the previous experimental works that investigated the isolated domains and the observed heterogeneity of the severity of dystrophin related pathologies, especially Becker muscular dystrophy

Myeloid progenitor cluster formation drives emergency and leukaemic myelopoiesis

Although many aspects of blood production are well understood, the spatial organization of myeloid differentiation in the bone marrow remains unknown. Here we use imaging to track granulocyte/macrophage progenitor (GMP) behaviour in mice during emergency and leukaemic myelopoiesis. In the steady state, we find individual GMPs scattered throughout the bone marrow. During regeneration, we observe expanding GMP patches forming defined GMP clusters, which, in turn, locally differentiate into granulocytes. The timed release of important bone marrow niche signals (SCF, IL-1β, G-CSF, TGFβ and CXCL4) and activation of an inducible $\textit{Irf8}$ and β-catenin progenitor self-renewal network control the transient formation of regenerating GMP clusters. In leukaemia, we show that GMP clusters are constantly produced owing to persistent activation of the self-renewal network and a lack of termination cytokines that normally restore haematopoietic stem-cell quiescence. Our results uncover a previously unrecognized dynamic behaviour of GMPs $\textit{in situ}$, which tunes emergency myelopoiesis and is hijacked in leukaemia.This work was supported by NIH K01DK098315 award to E.M.P.; a Bloodwise and CRUK program grants and Wellcome Trust funding to the Cambridge Stem Cell Institute to B.G.; and NIH R01HL092471, R01HL111266 and P30DK063720 grants, Rita Allen Scholar Award and Leukemia Lymphoma Society Scholar Award to E.P

Epigenetic Alterations of Maternal Tobacco Smoking during Pregnancy: A Narrative Review

International audienceIn utero exposure to maternal tobacco smoking is the leading cause of birth complications in addition to being associated with later impairment in child’s development. Epigenetic alterations, such as DNA methylation (DNAm), miRNAs expression, and histone modifications, belong to possible underlying mechanisms linking maternal tobacco smoking during pregnancy and adverse birth outcomes and later child’s development. The aims of this review were to provide an update on (1) the main results of epidemiological studies on the impact of in utero exposure to maternal tobacco smoking on epigenetic mechanisms, and (2) the technical issues and methods used in such studies. In contrast with miRNA and histone modifications, DNAm has been the most extensively studied epigenetic mechanism with regard to in utero exposure to maternal tobacco smoking. Most studies relied on cord blood and children’s blood, but placenta is increasingly recognized as a powerful tool, especially for markers of pregnancy exposures. Some recent studies suggest reversibility in DNAm in certain genomic regions as well as memory of smoking exposure in DNAm in other regions, upon smoking cessation before or during pregnancy. Furthermore, reversibility could be more pronounced in miRNA expression compared to DNAm. Increasing evidence based on longitudinal data shows that maternal smoking-associated DNAm changes persist during childhood. In this review, we also discuss some issues related to cell heterogeneity as well as downstream statistical analyses used to relate maternal tobacco smoking during pregnancy and epigenetics. The epigenetic effects of maternal smoking during pregnancy have been among the most widely investigated in the epigenetic epidemiology field. However, there are still huge gaps to fill in, including on the impact on miRNA expression and histone modifications to get a better view of the whole epigenetic machinery. The consistency of maternal tobacco smoking effects across epigenetic marks and across tissues will also provide crucial information for future studies. Advancement in bioinformatic and biostatistics approaches is key to develop a comprehensive analysis of these biological systems

Physical activity during pregnancy and postpartum depression: Systematic review and meta-analysis

International audienceBackground: It is still largely unknown whether physical activity (PA) during pregnancy may be useful to avert subsequent postpartum depression (PPD). We conducted a systematic review and meta-analysis to determine the preventive effects of PA during pregnancy on PPD.Methods: A systematic review of English and non-English articles was conducted using CINAHL, Cochrane Controlled Trials Register, PsycINFO, MEDLINE, SportDiscuss and Web of Science databases. Studies which tested the effect of any type of PA measured during pregnancy on depression or depressive symptoms in the first year postpartum were included. Relevant articles were extracted independently by 2 authors using predefined data fields, including study quality indicators. The protocol was registered on PROSPERO (CRD42018087086).Results: Twenty one studies, fit our selection criteria. Among them, seventeen studies were included in the meta-analysis, representing 93 676 women. Robust Variance Estimation random-effects meta-analysis indicated a significant reduction in postpartum depression scores (Overall SMD = -0.22 [95% CI −0.42 to −0.01], p = 0.04; I2 = 86.4%) for women physically active during pregnancy relative to those who were not active. This association was reinforced in intervention studies (SMD = −0.58 [9% CI −1.09 to −0.08]).Limitations: Overall meta-analysis showed important heterogeneity in PA assessment, suggesting the existence of potential moderators such as intensity, frequency, trimester of pregnancy or type of physical activity practiced.Conclusions: PA during pregnancy appears to reduce the risk of PPD symptoms. High quality studies addressing the role of PA in the perinatal period and its impact on new mother's mental health remain necessary

Does liberalisation of cannabis policy influence levels of use in adolescents and young adults? A systematic review and meta-analysis.

OBJECTIVES: To examine the effect of cannabis policy liberalisation (decriminalisation and legalisation) levels of use in adolescents and young adults. DESIGN: Systematic review and meta-analysis. Included studies were conducted among individuals younger than 25 years and quantitatively assessing consequences of cannabis policy change. We excluded articles: (A) exclusively based on participants older than 25 years; (B) only reporting changes in perceptions of cannabis use; (C) not including at least two measures of cannabis use; (D) not including quantitative data; and (E) reviews, letters, opinions and policy papers. PubMed, PsycINFO, Embase and Web of Science were searched through 1 March 2018. DATA EXTRACTION AND SYNTHESIS: Two independent readers reviewed the eligibility of titles and abstracts and read eligible articles, and four authors assessed the risk of bias (Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies). Extracted data were meta-analysed. The protocol was registered with PROSPERO. RESULTS: 3438 records were identified via search terms and four via citation lists; 2312 were retained after removal of duplicates, 99 were assessed for eligibility and 41 were included in our systematic review. 13 articles examined cannabis decriminalisation, 20 examined legalisation for medical purposes and 8 examined legalisation for recreational purposes. Findings regarding the consequences of cannabis decriminalisation or legalisation for medical purposes were too heterogeneous to be meta-analysed. Our systematic review and meta-analysis suggest a small increase in cannabis use among adolescents and young adults following legalisation of cannabis for recreational purposes (standardised mean difference of 0.03, 95% CI -0.01 to -0.07). Nevertheless, studies characterised by a very low/low risk of bias showed no evidence of changes in cannabis use following policy modifications. CONCLUSIONS: Cannabis policy liberalisation does not appear to result in significant changes in youths' use, with the possible exception of legalisation for recreational purposes that requires monitoring

Subclinical psychosis in adult migrants and ethnic minorities: systematic review and meta-analysis

International audienceBackground It is well established that migration and ethnic minority status are risk factors for psychotic disorders. Recent studies have aimed to determine if they are also associated with subclinical psychosis (psychotic-like experiences and schizotypal traits). Aims We aimed to determine to what extent migrant and ethnic minority groups are associated with higher risk of subclinical psychosis. Method We conducted a systematic review, using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, and examined findings by ethnicity, migrant status, outcomes of subclinical psychosis and host country. A meta-analysis was carried out with robust variance estimation where possible, to handle statistically dependent effect size estimates. Results We included 28 studies (19 studies on psychotic-like experiences and 9 studies on schizotypal traits) and found that ethnicity, but not migrant status, was associated with current and lifetime psychotic-like experiences. In the narrative analysis, we observed the effect of psychosocial risk factors on this association: Black ethnicity groups showed consistent increased prevalence of current and lifetime psychotic-like experiences compared with the reference population across countries. Conclusions More generalisable and standardised cohort studies of psychotic-like experiences and schizotypal traits in relation to migration/ethnicity are necessary to examine the effects of exposures and outcomes in different contexts, and to understand the underlying mechanisms of the association between subclinical psychosis and migrant and ethnic minority status. Declaration of interest None

Informal and formal social support during pregnancy and joint maternal and paternal postnatal depression: Data from the French representative ELFE cohort study

Article first published online: April 18, 2020; Issue published: August 1, 202

Maternal tobacco smoking during pregnancy and children’s emotional and behavioural trajectories : The EDEN mother-child birth cohort study

International audienceIntroduction: The nature of the relationship between maternal tobacco smoking during pregnancy and the occurrence of children’s behavioural problems is still a matter of controversy. We tested this association using data collected among a sample of pregnant women and their offspring followed from birth to early adolescence (age 12 years), accounting for multiple parent, child, and family characteristics.Methods : Data come from 1424 mother-child pairs participating in the EDEN mother-child cohort in France. Using repeated measures (3, 5.5, 8 and 11.5 years) of the mother-reported Strengths and Difficulties Questionnaire, we estimated trajectories of children’s emotional and behavioural difficulties. Two aspects of maternal smoking were studied: the timing (non-smoker, smoking during the periconceptional period or throughout pregnancy) and the level of use (cigarettes/day) during the first trimester of pregnancy. Robust Poisson regression models controlled for confounding factors including maternal mental health and socioeconomic characteristics using propensity scores with the overlap weighting technique.Results: Contrary to bivariate analyses, in propensity score-controlled regression models, maternal smoking throughout pregnancy was no longer significantly associated with offspring emotional or behavioural difficulties. Maternal heavy smoking (≥10cigarettes/day) remained significantly associated with intermediate levels of conduct problems (RR 1.25 95%CI 1.19-1.31)Conclusion: The association between maternal smoking in pregnancy and offspring emotional and behavioural difficulties appears to be largely explained by women’s other characteristics. However, maternal heavy smoking appears to be related to offspring behavioural difficulties beyond the role of confounding characteristics