Mobile genetic elements from the maternal microbiome shape infant gut microbial assembly and metabolism.

The perinatal period represents a critical window for cognitive and immune system development, promoted by maternal and infant gut microbiomes and their metabolites. Here, we tracked the co-development of microbiomes and metabolomes from late pregnancy to 1 year of age using longitudinal multi-omics data from a cohort of 70 mother-infant dyads. We discovered large-scale mother-to-infant interspecies transfer of mobile genetic elements, frequently involving genes associated with diet-related adaptations. Infant gut metabolomes were less diverse than maternal but featured hundreds of unique metabolites and microbe-metabolite associations not detected in mothers. Metabolomes and serum cytokine signatures of infants who received regular-but not extensively hydrolyzed-formula were distinct from those of exclusively breastfed infants. Taken together, our integrative analysis expands the concept of vertical transmission of the gut microbiome and provides original insights into the development of maternal and infant microbiomes and metabolomes during late pregnancy and early life.

Cell-Type-Specific Alternative Splicing Governs Cell Fate in the Developing Cerebral Cortex.

Alternative splicing is prevalent in the mammalian brain. To interrogate the functional role of alternative splicing in neural development, we analyzed purified neural progenitor cells (NPCs) and neurons from developing cerebral cortices, revealing hundreds of differentially spliced exons that preferentially alter key protein domains-especially in cytoskeletal proteins-and can harbor disease-causing mutations. We show that Ptbp1 and Rbfox proteins antagonistically govern the NPC-to-neuron transition by regulating neuron-specific exons. Whereas Ptbp1 maintains apical progenitors partly through suppressing a poison exon of Flna in NPCs, Rbfox proteins promote neuronal differentiation by switching Ninein from a centrosomal splice form in NPCs to a non-centrosomal isoform in neurons. We further uncover an intronic human mutation within a PTBP1-binding site that disrupts normal skipping of the FLNA poison exon in NPCs and causes a brain-specific malformation. Our study indicates that dynamic control of alternative splicing governs cell fate in cerebral cortical development.

Alternative splicing events as peripheral biomarkers for motor learning deficit caused by adverse prenatal environments.

Severity of neurobehavioral deficits in children born from adverse pregnancies, such as maternal alcohol consumption and diabetes, does not always correlate with the adversity's duration and intensity. Therefore, biological signatures for accurate prediction of the severity of neurobehavioral deficits, and robust tools for reliable identification of such biomarkers, have an urgent clinical need. Here, we demonstrate that significant changes in the alternative splicing (AS) pattern of offspring lymphocyte RNA can function as accurate peripheral biomarkers for motor learning deficits in mouse models of prenatal alcohol exposure (PAE) and offspring of mother with diabetes (OMD). An aptly trained deep-learning model identified 29 AS events common to PAE and OMD as superior predictors of motor learning deficits than AS events specific to PAE or OMD. Shapley-value analysis, a game-theory algorithm, deciphered the trained deep-learning model's learnt associations between its input, AS events, and output, motor learning performance. Shapley values of the deep-learning model's input identified the relative contribution of the 29 common AS events to the motor learning deficit. Gene ontology and predictive structure-function analyses, using Alphafold2 algorithm, supported existing evidence on the critical roles of these molecules in early brain development and function. The direction of most AS events was opposite in PAE and OMD, potentially from differential expression of RNA binding proteins in PAE and OMD. Altogether, this study posits that AS of lymphocyte RNA is a rich resource, and deep-learning is an effective tool, for discovery of peripheral biomarkers of neurobehavioral deficits in children of diverse adverse pregnancies.

The role of mitosis in generating fitness heterogeneity.

Cancer cells have heterogeneous fitness, and this heterogeneity stems from genetic and epigenetic sources. Here, we sought to assess the contribution of asymmetric mitosis (AM) and time on the variability of fitness in sister cells. Around one quarter of sisters had differences in fitness, assessed as the intermitotic time (IMT), from 330 to 510 min. Phenotypes related to fitness, such as ERK activity (herein referring to ERK1 and ERK2, also known as MAPK3 and MAPK1, respectively), DNA damage and nuclear morphological phenotypes were also asymmetric at mitosis or turned asymmetric over the course of the cell cycle. The ERK activity of mother cell was found to influence the ERK activity and the IMT of the daughter cells, and cells with ERK asymmetry at mitosis produced more offspring with AMs, suggesting heritability of the AM phenotype for ERK activity. Our findings demonstrate how variabilities in sister cells can be generated, contributing to the phenotype heterogeneities in tumor cells.

Congenital Syphilis: a Review of Global Epidemiology.

In 2007, the World Health Organization (WHO) launched a global health initiative for the elimination of mother-to-child transmission (MTCT) of syphilis. This condition is highly preventable through antenatal identification of syphilis infection and treatment with penicillin during pregnancy. This review summarizes the global status of MTCT of syphilis and concludes that this condition remains a significant issue worldwide. There are large variations in case rates by region, with the highest numbers of cases in the African and Eastern Mediterranean regions, where there are also the least data available. There are also pockets of high-incidence areas within the other regions. Although the general trend is of decreasing rates over time, there are concerning indications of consistently increasing congenital syphilis cases in some areas, particularly in areas which have previously had very low case numbers. A concerted effort will be required to achieve the 2007 WHO goal of worldwide elimination of MTCT of syphilis in the near future.

Differential requirements for the Eps15 homology domain proteins EHD4 and EHD2 in the regulation of mammalian ciliogenesis.

The endocytic protein EHD1 controls primary ciliogenesis by facilitating fusion of the ciliary vesicle and by removal of CP110 from the mother centriole. EHD3, the closest EHD1 paralog, has a similar regulatory role, but initial evidence suggested that the other two more distal paralogs, EHD2 and EHD4 may be dispensable for ciliogenesis. Herein, we define a novel role for EHD4, but not EHD2, in regulating primary ciliogenesis. To better understand the mechanisms and differential functions of the EHD proteins in ciliogenesis, we first demonstrated a requirement for EHD1 ATP-binding to promote ciliogenesis. We then identified two sequence motifs that are entirely conserved between EH domains of EHD1, EHD3 and EHD4, but display key amino acid differences within the EHD2 EH domain. Substitution of either P446 or E470 in EHD1 with the aligning S451 or W475 residues from EHD2 was sufficient to prevent rescue of ciliogenesis in EHD1-depleted cells upon reintroduction of EHD1. Overall, our data enhance the current understanding of the EHD paralogs in ciliogenesis, demonstrate a need for ATP-binding and identify conserved sequences in the EH domains of EHD1, EHD3 and EHD4 that regulate EHD1 binding to proteins and its ability to rescue ciliogenesis in EHD1-depleted cells.

Patterns of perinatal polyunsaturated fatty acid status and associated dietary or candidate-genetic factors.

Perinatal exposure to omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) can be characterized through biomarkers in maternal or cord blood or breast milk. Objectives were to describe perinatal PUFA status combining multiple biofluids and to investigate how it was influenced by dietary intake during pregnancy and maternal FADS and ELOVL gene polymorphisms. This study involved 1,901 mother-child pairs from the EDEN cohort, with PUFA levels measured in maternal and cord erythrocytes, and colostrum. Maternal dietary PUFA intake during the last trimester was derived from a food frequency questionnaire. Twelve single-nucleotide polymorphisms in FADS and ELOVL genes were genotyped from maternal DNA. Principal component analysis incorporating PUFA levels from the three biofluids identified patterns of perinatal PUFA status. Spearman's correlations explored associations between patterns and PUFA dietary intake, and linear regression models examined pattern associations with FADS or ELOVL haplotypes. Five patterns were retained: "High omega-3 LC-PUFAs, low omega-6 LC-PUFAs"; "Omega-6 LC-PUFAs"; "Colostrum LC-PUFAs"; "Omega-6 precursor (LA) and DGLA"; "Omega-6 precursor and colostrum ALA". Maternal omega-3 LC-PUFA intakes were correlated with "High omega-3 LC-PUFAs, low omega-6 LC-PUFAs" (r(DHA) = 0.33) and "Omega-6 LC-PUFAs" (r(DHA) = -0.19) patterns. Strong associations were found between FADS haplotypes and PUFA patterns except for "High omega-3 LC-PUFAs, low omega-6 LC-PUFAs". Lack of genetic association with the "High omega-3 LC-PUFAs, low omega-6 LC-PUFAs" pattern, highly correlated with maternal omega-3 LC-PUFA intake, emphasizes the importance of adequate omega-3 LC-PUFA intake during pregnancy and lactation. This study offers a more comprehensive assessment of perinatal PUFA status and its determinants.

Tenofovir Alafenamide versus Tenofovir Disoproxil Fumarate for Preventing Vertical Transmission in Chronic Hepatitis B Mothers: A Systematic Review and Meta-Analysis.

OBJECTIVE: International guidelines recommend maternal tenofovir disoproxil fumarate (TDF) therapy accompanied by infant immunoprophylaxis to prevent HBV mother-to-child transmission (MTCT) in highly viremic mothers. However, pooled analyses for tenofovir alafenamide (TAF) effects and comparisons between the two regimens are lacking. DESIGN: In this meta-analysis, pairs of independent reviewers performed multiple database searches from inception to March 31, 2024, and extracted data from cohort studies and RCTs in highly viremic mothers. The outcomes of interest were the reduction of MTCT and safety in the TDF-treated, TAF-treated, and control groups. RESULTS: We included 31 studies with 2,588 highly viremic mothers receiving TDF, 280 receiving TAF, and 1,600 receiving no treatment. Compared to the control, TDF therapy reduced the MTCT rate in infants aged 6-12 months (risk ratio: 0.10, 95% confidence interval 0.07-0.16). Pairwise meta-analysis between TAF and TDF revealed similar effects on reducing MTCT (risk ratio: 1.09, 95% confidence interval 0.16-7.61). Network meta-analysis showed the equal efficacy of the two regimens in reducing MTCT (risk ratio: 1.09, 95% confidence interval 0.15-7.65). The surface under the cumulative ranking curve revealed TDF as the best regimen compared with TAF (probability ranking: 0.77 vs. 0.72), while receiving a placebo during pregnancy had the lowest efficacy (probability ranking 0.01). There were no safety concerns for mothers and infants in all regimens. CONCLUSION: Compared to placebo or no treatment, maternal TDF and TAF prophylaxis are equally effective and without safety concerns in reducing MTCT in highly viremic mothers.

Optimization of Mother-to-Child Hepatitis B Virus Prevention Program: Integration of Maternal Screening and Infant Post-vaccination Serologic Testing.

BACKGROUND: Evaluation of the impact on mother-to-child transmission (MTCT) of a HBV-prevention program that incorporates maternal antiviral prophylaxis is hindered by the limited availability of real-world data. METHODS: This study analyzed data on maternal HBV screening, neonatal immunization, and post-vaccination serologic testing (PVST) for HBsAg among at-risk infants born to HBV carrier mothers from the National Immunization Information System during 01/01/2008-31/12/2022. Through linkage with the National Health Insurance Database, information of maternal antiviral therapy was obtained. Multivariate logistic regression was performed to explore MTCT risk in relation to infant-mother characteristics and prevention strategies. RESULTS: Totally, 2,460,218 deliveries with maternal HBV status were screened. Between 2008 and 2022, the annual HBsAg and HBeAg seropositivity rates among native pregnant women aged 15-49 years decreased from 12.2% to 2.6% and from 2.7% to 0.4%, respectively (p for both trends < 0.0001). Among the 22,859 at-risk infants undergoing PVST, the MTCT rates differed between infants born to HBsAg-positive/HBeAg-negative and HBeAg-positive mothers (0.75% and 6.33%, respectively; p < 0.001). The MTCT rate was 1.72% (11/641) for infants born to HBeAg-positive mothers with antiviral prophylaxis. MTCT risk increased with maternal HBeAg-positivity (OR 9.29, 6.79-12.73) and decreased with maternal antiviral prophylaxis (OR 0.28, 0.16-0.49). For infants with maternal HBeAg-positivity, MTCT risk was associated with mothers born in the immunization era (OR 1.40, 1.17-1.67). CONCLUSIONS: MTCT was related to maternal HBeAg-positivity and effectively prevented by maternal prophylaxis in the immunized population. At-risk infants born to maternal vaccinated cohorts might possibly pose further risk.

A comparison of wavelet-based action potential detection from the NeuroAmp and the Iowa Bioengineering Nerve Traffic Analysis system.

Microneurographic recordings of muscle sympathetic nerve activity (MSNA) reflect postganglionic sympathetic axonal activity directed toward the skeletal muscle vasculature. Recordings are typically evaluated for spontaneous bursts of MSNA; however, the filtering and integration of raw neurograms to obtain multiunit bursts conceals the underlying c-fiber discharge behavior. The continuous wavelet transform with matched mother wavelet has permitted the assessment of action potential discharge patterns, but this approach uses a mother wavelet optimized for an amplifier that is no longer commercially available (University of Iowa Bioengineering Nerve Traffic Analysis System; Iowa NTA). The aim of this project was to determine the morphology and action potential detection performance of mother wavelets created from the commercially available NeuroAmp (ADinstruments), from distinct laboratories, compared with a mother wavelet generated from the Iowa NTA. Four optimized mother wavelets were generated in a two-phase iterative process from independent datasets, collected by separate laboratories (one Iowa NTA, three NeuroAmp). Action potential extraction performance of each mother wavelet was compared for each of the NeuroAmp-based datasets. The total number of detected action potentials was not significantly different across wavelets. However, the predictive value of action potential detection was reduced when the Iowa NTA wavelet was used to detect action potentials in NeuroAmp data, but not different across NeuroAmp wavelets. To standardize approaches, we recommend a NeuroAmp-optimized mother wavelet be used for the evaluation of sympathetic action potential discharge behavior when microneurographic data are collected with this system.NEW & NOTEWORTHY The morphology of custom mother wavelets produced across laboratories using the NeuroAmp was highly similar, but distinct from the University of Iowa Bioengineering Nerve Traffic Analysis System. Although the number of action potentials detected was similar between collection systems and mother wavelets, the predictive value differed. Our data suggest action potential analysis using the continuous wavelet transform requires a mother wavelet optimized for the collection system.

Prenatal exposure to benzodiazepine and z-hypnotics and fifth-grade scholastic skills - emulating target trials using data from the Norwegian Mother, Father and Child Cohort Study.

Evidence is limited regarding the effect of prenatal benzodiazepine and z-hypnotic exposure and long-term neurodevelopment in childhood. The objective of this study was to investigate the effects of initiating benzodiazepine or z-hypnotic treatment in early, mid and late pregnancy on fifth-grade numeracy and literacy scholastic skills in children, by emulating three target trials. The trials are identical except for the timing of enrollment and the number of eligible individuals. Eligibility to the trials required a history of anxiety and/or depression prior to pregnancy. We used data from the Norwegian Mother, Father and Child Cohort Study, linked to the Medical Birth Registry of Norway, to emulate the trials. We adjusted for baseline covariates that were available at time 0 for each trial by inverse probability of treatment weighting using the propensity score. The findings of this study did not show any effect of mothers' initiation of treatment with benzodiazepines or z-hypnotics in early, mid or late pregnancy on the children's 5th grade test scores in numeracy and literacy. The study results provide reassurance for patients in need of benzodiazepines and z-hypnotics during pregnancy; however, these findings need to be interpreted with caution due to low study power in some of the analyses.

Investigating mother-child inter-brain synchrony in a naturalistic paradigm: A functional near infrared spectroscopy (fNIRS) hyperscanning study.

Successful social interactions between mothers and children are hypothesised to play a significant role in a child's social, cognitive and language development. Earlier research has confirmed, through structured experimental paradigms, that these interactions could be underpinned by coordinated neural activity. Nevertheless, the extent of neural synchrony during real-life, ecologically valid interactions between mothers and their children remains largely unexplored. In this study, we investigated mother-child inter-brain synchrony using a naturalistic free-play paradigm. We also examined the relationship between neural synchrony, verbal communication patterns and personality traits to further understand the underpinnings of brain synchrony. Twelve children aged between 3 and 5 years old and their mothers participated in this study. Neural synchrony in mother-child dyads were measured bilaterally over frontal and temporal areas using functional Near Infra-red Spectroscopy (fNIRS) whilst the dyads were asked to play with child-friendly toys together (interactive condition) and separately (independent condition). Communication patterns were captured via video recordings and conversational turns were coded. Compared to the independent condition, mother-child dyads showed increased neural synchrony in the interactive condition across the prefrontal cortex and temporo-parietal junction. There was no significant relationship found between neural synchrony and turn-taking and between neural synchrony and the personality traits of each member of the dyad. Overall, we demonstrate the feasibility of measuring inter-brain synchrony between mothers and children in a naturalistic environment. These findings can inform future study designs to assess inter-brain synchrony between parents and pre-lingual children and/or children with communication needs.

Interbrain substrates of role switching during mother-child interaction.

Mother-child interaction is highly dynamic and reciprocal. Switching roles in these back-and-forth interactions serves as a crucial feature of reciprocal behaviors while the underlying neural entrainment is still not well-studied. Here, we designed a role-controlled cooperative task with dual EEG recording to explore how differently two brains interact when mothers and children hold different roles. When children were actors and mothers were observers, mother-child interbrain synchrony emerged primarily within the theta oscillations and the frontal lobe, which highly correlated with children's attachment to their mothers (self-reported by mothers). When their roles were reversed, this synchrony was shifted to the alpha oscillations and the central area and associated with mothers' perception of their relationship with their children. The results suggested an observer-actor neural alignment within the actor's oscillations, which was related to the actor-toward-observer emotional bonding. Our findings contribute to the understanding of how interbrain synchrony is established and dynamically changed during mother-child reciprocal interaction.

Role of HBsAg levels in guiding hepatitis B virus prophylaxis in pregnancy: Insights from a multi-ethnic cohort.

Pregnant mothers with chronic hepatitis B infection (CHB) need peri-partum antiviral prophylaxis (PAP) to reduce the risk of mother-to-child-transmission. Currently, PAP is recommended in those with high viral load (VL) that is, HBV DNA >200,000 IU/mL. Quantitative hepatitis B surface antigen (qHBsAg) >10,000 IU/mL, a cut-off derived primarily from hepatitis B e-antigen (HBeAg) positive antenatal cohorts in Chinese populations, is advocated as a surrogate marker of VL for guiding PAP. We investigated the utility of qHBsAg to predict high-VL in a multi-ethnic urban cohort with CHB. A consecutive cohort of women with CHB was identified from Barts Health NHS Trust databases in the United Kingdom. We included women with paired HBV DNA and qHBsAg during pregnancy. Women already on antiviral at conception were excluded. A total of 769 pregnancies in 678 CHB pregnant mothers (median age 31 years-old, 8.6% HBeAg+) were included. At median gestational age of 15.3 weeks, HBV DNA was 336 (IQR 44-2998) IU/mL, with 65 (8.5%) being high-VL. Serum qHBsAg was most useful in Black/Black-British/Caribbean/African (AUROC 0.946) with 100% sensitivity and 80.6% specificity to predict high-VL; but it performed less well for other ethnicities: Asian (AUROC 0.877), White (AUROC 0.797) and mixed ethnicities (AUROC 0.742). In conclusion, for settings where healthcare resources are not limited, HBV DNA remains the optimal marker to identify highly viraemic pregnancies for guiding PAP. For resource-limited settings where the prevailing cost is treatment, serum qHBsAg can be used in Black/Black British/Caribbean/African sub-cohorts, but not for other ethnicities.

Early or late menarche is associated with reduced fecundability in the Norwegian Mother, Father and Child Cohort Study.

STUDY QUESTION: Is age at menarche associated with fecundability? SUMMARY ANSWER: Both early (<11 years) and late (>15 years) menarche is associated with decreased fecundability. WHAT IS KNOWN ALREADY: Previous studies on age at menarche and fecundability have been inconclusive. Women with early or late menarche are at increased risks of gynaecological and autoimmune diseases that may affect their ability to conceive. STUDY DESIGN, SIZE, DURATION: We conducted a retrospective cohort study including 67 613 pregnant women, participating in the Norwegian Mother, Father and Child Cohort Study between 1999 and 2008, with self-reported information on age at menarche and time to pregnancy. We included planned pregnancies that were conceived either naturally or with the help of assisted reproductive technologies. PARTICIPANTS/MATERIALS, SETTING, METHODS: We calculated fecundability ratios (FRs) with 95% CIs representing the cycle-specific probability of conception by categories of age at menarche. FRs were adjusted for participants' pre-pregnancy body mass index, highest completed or ongoing education level, and age at initiation of trying to conceive. MAIN RESULTS AND THE ROLE OF CHANCE: We observed a 7% lower probability of conceiving during any given menstrual cycle up to 12 cycles in women with early or late menarche. Among women with menarche >15 years, the adjusted FR was 0.93 (95% CI: 0.90-0.97), and among women with menarche <11 years, the adjusted FR was 0.93 (95% CI: 0.89-0.99), when compared to women with menarche between 12 and 14 years. LIMITATIONS, REASONS FOR CAUTION: The study-population consisted of women pregnant in their second trimester, excluding those with persistent infertility. Recall of age at menarche and time to pregnancy may be inaccurate. WIDER IMPLICATIONS OF THE FINDINGS: Both early (<11 years) and late (>15 years) menarche was associated with decreased fecundability. Women experiencing early menarche or late menarche may be counselled accordingly. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Norwegian Institute of Public Health, Oslo, Norway, and by Telemark Hospital Trust, Porsgrunn, Norway and was partly supported by the Research Council of Norway through its centres of excellence funding scheme (project number 262700) and the Research Council of Norway (project no. 320656). The project was co-funded by the European Union (ERC, BIOSFER, 101071773). Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or the European Research Council. Neither the European Union nor the granting authority can be held responsible for them. M.C.M. has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement no. 947684). The authors report no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Polycomb proteins RING1A/B promote H2A monoubiquitination to regulate female gametophyte development in Arabidopsis.

A functional female gametophyte is the basis of successful sexual reproduction in flowering plants. During female gametophyte development, the megaspore mother cell (MMC), which differentiates from a single subepidermal somatic cell in the nucellus, undergoes meiosis to produce four megaspores; only the one at the chalazal end, referred to as the functional megaspore (FM), then undergoes three rounds of mitosis and develops into a mature embryo sac. Here, we report that RING1A and RING1B (RING1A/B), two functionally redundant Polycomb proteins in Arabidopsis, are critical for female gametophyte development. Mutations of RING1A/B resulted in defects in the specification of the MMC and the FM, and in the subsequent mitosis of the FM, thereby leading to aborted ovules. Detailed analysis revealed that several genes essential for female gametophyte development were ectopically expressed in the ring1a ring1b mutant, including Argonaute (AGO) family genes and critical transcription factors. Furthermore, RING1A/B bound to some of these genes to promote H2A monoubiquitination (H2Aub). Taken together, our study shows that RING1A/B promote H2Aub modification at key genes for female gametophyte development, suppressing their expression to ensure that the development progresses correctly.

Specific antibody responses to Qß-displayed Plasmodium falciparum-derived UB05 and MSP3 proteins in mother-neonate couples.

Malaria blood-stage parasite is a critical pathogenic stage responsible for serious adverse outcomes in pregnant women and their neonates. Immunoglobulin G (IgG) antibody responses specific to various asexual blood-stage antigens were well reported in non-pregnant individuals. However, little is still known during placental malaria. To assess the antibody responses specific to Plasmodium falciparum-derived MSP3 and UB05 malaria vaccine candidates in mother-neonate couples, mother's peripheral blood and neonate's cord blood samples were collected at delivery. After malaria diagnostic, plasma levels of IgG and IgG subclass responses specific to UB05, MSP3 and UB05-MSP3 were determined using ELISA. As outcomes, both mothers and neonates had significantly higher IgG responses to UB05 and UB05-MSP3 compared to anti-MSP3 IgG (p < 0.05), irrespective of malaria status. Significant negative correlations were observed between IgG levels specific to the three antigens and parasitaemia (p < 0.01). Anti-UB05 and anti-UB05-MSP3 IgG levels in neonates showed a significant positive correlation with the corresponding mothers' antibodies (rs = 0.25 with p = 0.04; rs = 0.31 with p = 0.01, respectively). UB05MSP3-specific IgG3 and IgG1 subclass responses were significantly higher than the IgG4 subclass (p < 0.01). The neonates IgG1 and IgG3 levels positively correlated with the corresponding antibody subclasses of mothers. These findings suggest an association between UB05 and UB05-MSP3-specific antibody responses and malaria control during pregnancy. Maternal-foetal transfer of MSP3 and UB05-specific IgG occurs during pregnancy, suggesting the interest in the future malaria vaccination strategies in pregnant women to generate early protective immunity in baby against malaria.

The X-factor in ART: does the use of assisted reproductive technologies influence DNA methylation on the X chromosome?

BACKGROUND: Assisted reproductive technologies (ART) may perturb DNA methylation (DNAm) in early embryonic development. Although a handful of epigenome-wide association studies of ART have been published, none have investigated CpGs on the X chromosome. To bridge this knowledge gap, we leveraged one of the largest collections of mother-father-newborn trios of ART and non-ART (natural) conceptions to date to investigate sex-specific DNAm differences on the X chromosome. The discovery cohort consisted of 982 ART and 963 non-ART trios from the Norwegian Mother, Father, and Child Cohort Study (MoBa). To verify our results from the MoBa cohort, we used an external cohort of 149 ART and 58 non-ART neonates from the Australian 'Clinical review of the Health of adults conceived following Assisted Reproductive Technologies' (CHART) study. The Illumina EPIC array was used to measure DNAm in both datasets. In the MoBa cohort, we performed a set of X-chromosome-wide association studies ('XWASs' hereafter) to search for sex-specific DNAm differences between ART and non-ART newborns. We tested several models to investigate the influence of various confounders, including parental DNAm. We also searched for differentially methylated regions (DMRs) and regions of co-methylation flanking the most significant CpGs. Additionally, we ran an analogous model to our main model on the external CHART dataset. RESULTS: In the MoBa cohort, we found more differentially methylated CpGs and DMRs in girls than boys. Most of the associations persisted after controlling for parental DNAm and other confounders. Many of the significant CpGs and DMRs were in gene-promoter regions, and several of the genes linked to these CpGs are expressed in tissues relevant for both ART and sex (testis, placenta, and fallopian tube). We found no support for parental DNAm-dependent features as an explanation for the observed associations in the newborns. The most significant CpG in the boys-only analysis was in UBE2DNL, which is expressed in testes but with unknown function. The most significant CpGs in the girls-only analysis were in EIF2S3 and AMOT. These three loci also displayed differential DNAm in the CHART cohort. CONCLUSIONS: Genes that co-localized with the significant CpGs and DMRs associated with ART are implicated in several key biological processes (e.g., neurodevelopment) and disorders (e.g., intellectual disability and autism). These connections are particularly compelling in light of previous findings indicating that neurodevelopmental outcomes differ in ART-conceived children compared to those naturally conceived.

Mother-infant interaction and infant development in women at risk of postpartum psychosis with and without a postpartum relapse.

BACKGROUND: This study aimed to investigate mother-infant interaction and infant development in women at-risk of postpartum psychosis (PP), with and without a postpartum relapse. METHODS: 103 women (and their offspring) were included, 43 at-risk-of-PP because of a diagnosis of bipolar disorder, schizoaffective disorder or previous PP, and 60 with no current/previous mental illness or family history of PP. Of the at-risk women, 18 developed a psychiatric relapse within 4 weeks after delivery (AR-unwell), while 25 remained symptom-free (AR-well). Mother-infant interaction was assessed using the CARE-Index at 8 weeks' and 12 months' postpartum and infant development using the Bayley-III at 12 months' postpartum. RESULTS: Women at-risk-of-PP as a group, regardless of whether they developed a psychiatric relapse within 4 weeks after delivery, had less synchronous mother-infant interactions and had infants with less optimal cognitive, language, motor and socio-emotional development than healthy controls. In particular, boys of at-risk women had the lowest scores in cognitive, language and motor development and in mother-infant interaction, while girls of the at-risk women had the lowest scores in socio-emotional development. The synchrony in the dyad predicted infant cognitive and language development. There was no evidence for a difference in mother-infant interaction nor in infant development between the AR-unwell and AR-well groups. CONCLUSIONS: These results suggest that, while there is a lack of evidence that an early postpartum relapse in women at-risk-of-PP could represent a risk for the infant per se, maternal risk for PP may be associated with less optimal mother-infant interaction and infant development.

Within-individual relationships between mother-to-infant bonding and postpartum depressive symptoms: a longitudinal study.

BACKGROUND: Although the importance of the dynamic intra-individual relationship between mother-to-infant bonding and postpartum depressive symptoms has been widely recognized, the complex interplay between them is not well understood. Furthermore, the potential role of prenatal depressive symptoms and infant temperament in this relationship remains unclear. This study aims to examine the bidirectional influence of mother-to-infant bonding on postpartum depressive symptoms within individuals and to elucidate whether prenatal depressive symptoms and infant temperament would influence deviations from stable individual states. METHODS: Longitudinal data were collected from 433 women in early pregnancy. Of these, 360 participants completed the main questionnaires measuring impaired mother-to-infant bonding and postpartum depressive symptoms at least once during the postpartum period. Data were collected at early and late pregnancy and several postpartum time points: shortly after birth and at one, four, ten, and 18 months postpartum. We also assessed prenatal depressive symptoms and infant temperament. A random-intercept cross-lagged panel model was used. RESULTS: Within-individual variability in mother-to-infant bonding, especially anger and rejection, significantly predicted subsequent postpartum depressive symptoms. However, the inverse relationship was not significant. Additionally, prenatal depressive symptoms and difficult infant temperament were associated with greater within-individual variability in impaired mother-to-infant bonding and postpartum depressive symptoms. CONCLUSIONS: The present study demonstrated that the within-individual relationship between mother-to-infant bonding and postpartum depressive symptoms is likely non-bidirectional. The significance of the findings is underscored by the potential for interventions aimed at improving mother-to-infant bonding to alleviate postpartum depressive symptoms, suggesting avenues for future research and practice.