Stereotypic Immune System Development in Newborn Children.

Epidemiological data suggest that early life exposures are key determinants of immune-mediated disease later in life. Young children are also particularly susceptible to infections, warranting more analyses of immune system development early in life. Such analyses mostly have been performed in mouse models or human cord blood samples, but these cannot account for the complex environmental exposures influencing human newborns after birth. Here, we performed longitudinal analyses in 100 newborn children, sampled up to 4 times during their first 3 months of life. From 100 µL of blood, we analyze the development of 58 immune cell populations by mass cytometry and 267 plasma proteins by immunoassays, uncovering drastic changes not predictable from cord blood measurements but following a stereotypic pattern. Preterm and term children differ at birth but converge onto a shared trajectory, seemingly driven by microbial interactions and hampered by early gut bacterial dysbiosis.

Disease Model of GATA4 Mutation Reveals Transcription Factor Cooperativity in Human Cardiogenesis.

Mutation of highly conserved residues in transcription factors may affect protein-protein or protein-DNA interactions, leading to gene network dysregulation and human disease. Human mutations in GATA4, a cardiogenic transcription factor, cause cardiac septal defects and cardiomyopathy. Here, iPS-derived cardiomyocytes from subjects with a heterozygous GATA4-G296S missense mutation showed impaired contractility, calcium handling, and metabolic activity. In human cardiomyocytes, GATA4 broadly co-occupied cardiac enhancers with TBX5, another transcription factor that causes septal defects when mutated. The GATA4-G296S mutation disrupted TBX5 recruitment, particularly to cardiac super-enhancers, concomitant with dysregulation of genes related to the phenotypic abnormalities, including cardiac septation. Conversely, the GATA4-G296S mutation led to failure of GATA4 and TBX5-mediated repression at non-cardiac genes and enhanced open chromatin states at endothelial/endocardial promoters. These results reveal how disease-causing missense mutations can disrupt transcriptional cooperativity, leading to aberrant chromatin states and cellular dysfunction, including those related to morphogenetic defects.

Canary in the Coal Mine? Male Infertility as a Marker of Overall Health.

Male factor infertility is a common problem. Evidence is emerging regarding the spectrum of systemic disease and illness harbored by infertile men who otherwise appear healthy. In this review, we present evidence that infertile men have poor overall health and increased morbidity and mortality, increased rates of both genitourinary and non-genitourinary malignancy, and greater risks of systemic disease. The review also highlights numerous genetic conditions associated with male infertility as well as emerging translational evidence of genitourinary birth defects and their impact on male infertility. Finally, parallels to the overall health of infertile women are presented. This review highlights the importance of a comprehensive health evaluation of men who present for an infertility assessment.

Interferons and Proinflammatory Cytokines in Pregnancy and Fetal Development.

Successful pregnancy requires carefully-coordinated communications between the mother and fetus. Immune cells and cytokine signaling pathways participate as mediators of these communications to promote healthy pregnancy. At the same time, certain infections or inflammatory conditions in pregnant mothers cause severe disease and have detrimental impacts on the developing fetus. In this review, we examine evidence for the role of maternal and fetal immune responses affecting pregnancy and fetal development, both under homeostasis and following infection. We discuss immune responses that are necessary to promote healthy pregnancy and those that lead to congenital disorders and pregnancy complications, with a particular emphasis on the role of interferons and cytokines. Understanding the contributions of the immune system in pregnancy and fetal development provides important insights into the pathogenesis underlying maternal and fetal diseases and sheds insights on possible targets for therapy.

Estimates of early outbreak-specific SARS-CoV-2 epidemiological parameters from genomic data.

We estimate the basic reproductive number and case counts for 15 distinct Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreaks, distributed across 11 populations (10 countries and one cruise ship), based solely on phylodynamic analyses of genomic data. Our results indicate that, prior to significant public health interventions, the reproductive numbers for 10 (out of 15) of these outbreaks are similar, with median posterior estimates ranging between 1.4 and 2.8. These estimates provide a view which is complementary to that provided by those based on traditional line listing data. The genomic-based view is arguably less susceptible to biases resulting from differences in testing protocols, testing intensity, and import of cases into the community of interest. In the analyses reported here, the genomic data primarily provide information regarding which samples belong to a particular outbreak. We observe that once these outbreaks are identified, the sampling dates carry the majority of the information regarding the reproductive number. Finally, we provide genome-based estimates of the cumulative number of infections for each outbreak. For 7 out of 11 of the populations studied, the number of confirmed cases is much bigger than the cumulative number of infections estimated from the sequence data, a possible explanation being the presence of unsequenced outbreaks in these populations.

Disruption of DNA methylation-mediated cranial neural crest proliferation and differentiation causes orofacial clefts in mice.

Orofacial clefts of the lip and palate are widely recognized to result from complex gene-environment interactions, but inadequate understanding of environmental risk factors has stymied development of prevention strategies. We interrogated the role of DNA methylation, an environmentally malleable epigenetic mechanism, in orofacial development. Expression of the key DNA methyltransferase enzyme DNMT1 was detected throughout palate morphogenesis in the epithelium and underlying cranial neural crest cell (cNCC) mesenchyme, a highly proliferative multipotent stem cell population that forms orofacial connective tissue. Genetic and pharmacologic manipulations of DNMT activity were then applied to define the tissue- and timing-dependent requirement of DNA methylation in orofacial development. cNCC-specific Dnmt1 inactivation targeting initial palate outgrowth resulted in OFCs, while later targeting during palatal shelf elevation and elongation did not. Conditional Dnmt1 deletion reduced cNCC proliferation and subsequent differentiation trajectory, resulting in attenuated outgrowth of the palatal shelves and altered development of cNCC-derived skeletal elements. Finally, we found that the cellular mechanisms of cleft pathogenesis observed in vivo can be recapitulated by pharmacologically reducing DNA methylation in multipotent cNCCs cultured in vitro. These findings demonstrate that DNA methylation is a crucial epigenetic regulator of cNCC biology, define a critical period of development in which its disruption directly causes OFCs, and provide opportunities to identify environmental influences that contribute to OFC risk.

The Angiosperm Terrestrial Revolution buffered ants against extinction.

With ~14,000 extant species, ants are ubiquitous and of tremendous ecological importance. They have undergone remarkable diversification throughout their evolutionary history. However, the drivers of their diversity dynamics are not well quantified or understood. Previous phylogenetic analyses have suggested patterns of diversity dynamics associated with the Angiosperm Terrestrial Revolution (ATR), but these studies have overlooked valuable information from the fossil record. To address this gap, we conducted a comprehensive analysis using a large dataset that includes both the ant fossil record (~24,000 individual occurrences) and neontological data (~14,000 occurrences), and tested four hypotheses proposed for ant diversification: co-diversification, competitive extinction, hyper-specialization, and buffered extinction. Taking into account biases in the fossil record, we found three distinct diversification periods (the latest Cretaceous, Eocene, and Oligo-Miocene) and one extinction period (Late Cretaceous). The competitive extinction hypothesis between stem and crown ants is not supported. Instead, we found support for the co-diversification, buffered extinction, and hyper-specialization hypotheses. The environmental changes of the ATR, mediated by the angiosperm radiation, likely played a critical role in buffering ants against extinction and favoring their diversification by providing new ecological niches, such as forest litter and arboreal nesting sites, and additional resources. We also hypothesize that the decline and extinction of stem ants during the Late Cretaceous was due to their hyper-specialized morphology, which limited their ability to expand their dietary niche in changing environments. This study highlights the importance of a holistic approach when studying the interplay between past environments and the evolutionary trajectories of organisms.

Antiracism and positive intergenerational (infant) outcomes: A county-level examination of low birth weight and infant mortality.

Racism is associated with negative intergenerational (infant) outcomes. That is, racism, both perceived and structural, is linked to critical, immediate, and long-term health factors such as low birth weight and infant mortality. Antiracism-resistance to racism such as support for the Black Lives Matter (BLM) movement-has been linked to positive emotional, subjective, and mental health outcomes among adults and adolescents. To theoretically build on and integrate such past findings, the present research asked whether such advantageous health correlations might extend intergenerationally to infant outcomes? It examined a theoretical/correlational process model in which mental and physical health indicators might be indirectly related to associations between antiracism and infant health outcomes. Analyses assessed county-level data that measured BLM support (indexed as volume of BLM marches) and infant outcomes from 2014 to 2020. As predicted, in the tested model, BLM support was negatively correlated with 1) low birth weight (Ncounties = 1,445) and 2) mortalities (Ncounties = 409) among African American infants. Given salient, intergroup, policy debates tied to antiracism, the present research also examined associations among White Americans. In the tested model, BLM marches were not meaningfully related to rates of low birth weight among White American infants (Ncounties = 2,930). However, BLM support was negatively related to mortalities among White American infants (Ncounties = 862). Analyses controlled for structural indicators of income inequality, implicit/explicit bias, voting behavior, prior low birth weight/infant mortality rates, and demographic characteristics. Theory/applied implications of antiracism being linked to nonnegative and positive infant health associations tied to both marginalized and dominant social groups are discussed.

Human white matter myelinates faster in utero than ex utero.

The formation of myelin, the fatty sheath that insulates nerve fibers, is critical for healthy brain function. A fundamental open question is what impact being born has on myelin growth. To address this, we evaluated a large (n = 300) cross-sectional sample of newborns from the Developing Human Connectome Project (dHCP). First, we developed software for the automated identification of 20 white matter bundles in individual newborns that is well suited for large samples. Next, we fit linear models that quantify how T1w/T2w (a myelin-sensitive imaging contrast) changes over time at each point along the bundles. We found faster growth of T1w/T2w along the lengths of all bundles before birth than right after birth. Further, in a separate longitudinal sample of preterm infants (N = 34), we found lower T1w/T2w than in full-term peers measured at the same age. By applying the linear models fit on the cross-section sample to the longitudinal sample of preterm infants, we find that their delay in T1w/T2w growth is well explained by the amount of time they spent developing in utero and ex utero. These results suggest that white matter myelinates faster in utero than ex utero. The reduced rate of myelin growth after birth, in turn, explains lower myelin content in individuals born preterm and could account for long-term cognitive, neurological, and developmental consequences of preterm birth. We hypothesize that closely matching the environment of infants born preterm to what they would have experienced in the womb may reduce delays in myelin growth and hence improve developmental outcomes.

Rapidly changing speciation and extinction rates can be inferred in spite of nonidentifiability.

The birth-death model is commonly used to infer speciation and extinction rates by fitting the model to phylogenetic trees with exclusively extant taxa. Recently, it was demonstrated that speciation and extinction rates are not identifiable if the rates are allowed to vary freely over time. The group of birth-death models that have the same likelihood is called a congruence class, and there is no statistical evidence to favor one model over the other. This issue has led researchers to question if and what patterns can reliably be inferred from phylogenies of only extant taxa and whether time-variable birth-death models should be fitted at all. We explore the congruence class in the context of several empirical phylogenies as well as hypothetical scenarios. For these empirical phylogenies, we assume that we inferred the true congruence class. Thus, our conclusions apply to any empirical phylogeny for which we robustly inferred the true congruence class. When we summarize shared patterns in the congruence class, we show that strong directional trends in speciation and extinction rates are shared among most models. Therefore, we conclude that the inference of strong directional trends is robust. Conversely, estimates of constant rates or gentle slopes are not robust and must be treated with caution. Interestingly, the space of valid speciation rates is narrower and more limited in contrast to extinction rates, which are less constrained. These results provide further evidence and insights that speciation rates can be estimated more reliably than extinction rates.

Plasticity of thalamocortical axons is regulated by serotonin levels modulated by preterm birth.

Sensory inputs are conveyed to distinct primary areas of the neocortex through specific thalamocortical axons (TCA). While TCA have the ability to reorient postnatally to rescue embryonic mistargeting and target proper modality-specific areas, how this remarkable adaptive process is regulated remains largely unknown. Here, using a mutant mouse model with a shifted TCA trajectory during embryogenesis, we demonstrated that TCA rewiring occurs during a short postnatal time window, preceded by a prenatal apoptosis of thalamic neurons-two processes that together lead to the formation of properly innervated albeit reduced primary sensory areas. We furthermore showed that preterm birth, through serotonin modulation, impairs early postnatal TCA plasticity, as well as the subsequent delineation of cortical area boundary. Our study defines a birth and serotonin-sensitive period that enables concerted adaptations of TCA to primary cortical areas with major implications for our understanding of brain wiring in physiological and preterm conditions.

Fetal inflammatory response at the fetomaternal interface: A requirement for labor at term and preterm.

Human parturition at term and preterm is an inflammatory process synchronously executed by both fetomaternal tissues to transition them from a quiescent state t an active state of labor to ensure delivery. The initiators of the inflammatory signaling mechanism can be both maternal and fetal. The placental (fetal)-maternal immune and endocrine mediated homeostatic imbalances and inflammation are well reported. However, the fetal inflammatory response (FIR) theories initiated by the fetal membranes (amniochorion) at the choriodecidual interface are not well established. Although immune cell migration, activation, and production of proparturition cytokines to the fetal membranes are reported, cellular level events that can generate a unique set of inflammation are not well discussed. This review discusses derangements to fetal membrane cells (physiologically and pathologically at term and preterm, respectively) in response to both endogenous and exogenous factors to generate inflammatory signals. In addition, the mechanisms of inflammatory signal propagation (fetal signaling of parturition) and how these signals cause immune imbalances at the choriodecidual interface are discussed. In addition to maternal inflammation, this review projects FIR as an additional mediator of inflammatory overload required to promote parturition.

Predictors of Inflammation-Mediated Preterm Birth.

Preterm birth remains a worldwide health concern due to ongoing challenges in prediction and prevention. Current predictors are limited by poor performance, need for invasive sampling, and an inability to identify patients in a timely fashion to allow for effective intervention. The multiple etiologies of preterm birth often have an inflammatory component. Thus, a deeper understanding of the inflammatory mechanisms involved in preterm birth may provide opportunities to identify new predictors of preterm birth. This review will discuss the multiple etiologies of preterm birth, their links to inflammation, current predictors available, and new directions for the field.

The fetal lineage is susceptible to Zika virus infection within days of fertilization.

Adults contracting Zika virus (ZIKV) typically exhibit mild symptoms, yet ZIKV infection of pregnant individuals can cause miscarriage or birth defects in their offspring. Many studies have focused on maternal-to-fetal ZIKV transmission via blood and placenta. Notably, however, ZIKV is also transmitted sexually, raising the possibility that ZIKV could infect the embryo shortly after fertilization, long before the placenta is established. Here, we evaluate the consequences of ZIKV infection in mouse embryos during the first few days of embryogenesis. We show that divergent strains of ZIKV can infect the fetal lineage and can cause developmental arrest, raising concern for the developmental consequences of sexual ZIKV transmission. This article has an associated 'The people behind the papers' interview.

Maternal B cell signaling orchestrates fetal development in mice.

B cell participation in early embryo/fetal development and the underlying molecular pathways have not been explored. To understand whether maternal B cell absence or impaired signaling interferes with placental and fetal growth, we paired CD19-deficient (CD19-/-) mice, females with B cell-specific MyD88 (BMyD88-/-) or IL10 (BIL10-/-) deficiency as well as wild-type and MyD88-/- controls on C57Bl/6 background with BALB/c males. Pregnancies were followed by ultrasound and Doppler measurements. Implantation number was reduced in BMyD88-/- and MyD88-/- mice. Loss of MyD88 or B cell-specific deletion of MyD88 or IL10 resulted in decreased implantation areas at gestational day (gd) 5, gd8 and gd10, accompanied by reduced placental thickness, diameter and areas at gd10. Uterine artery resistance was enhanced in BIL10-/- dams at gd10. Challenge with 0.4 mg lipopolysaccharide/kg bodyweight at gd16 revealed that BMyD88-/-, BIL10-/- and CD19-/- mothers delivered preterm, whereas controls maintained their pregnancy. B cell-specific MyD88 and IL10 expression is essential for appropriate in utero development. IL10+B cells are involved in uterine blood flow regulation during pregnancy. Finally, B cell-specific CD19, MyD88 and IL10 expression influences susceptibility towards preterm birth.

Statistical methods for assessing the effects of de novo variants on birth defects.

With the development of next-generation sequencing technology, de novo variants (DNVs) with deleterious effects can be identified and investigated for their effects on birth defects such as congenital heart disease (CHD). However, statistical power is still limited for such studies because of the small sample size due to the high cost of recruiting and sequencing samples and the low occurrence of DNVs. DNV analysis is further complicated by genetic heterogeneity across diseased individuals. Therefore, it is critical to jointly analyze DNVs with other types of genomic/biological information to improve statistical power to identify genes associated with birth defects. In this review, we discuss the general workflow, recent developments in statistical methods, and future directions for DNV analysis.

The Limits of the Constant-rate Birth-Death Prior for Phylogenetic Tree Topology Inference.

Birth-death models are stochastic processes describing speciation and extinction through time and across taxa and are widely used in biology for inference of evolutionary timescales. Previous research has highlighted how the expected trees under the constant-rate birth-death (crBD) model tend to differ from empirical trees, for example, with respect to the amount of phylogenetic imbalance. However, our understanding of how trees differ between the crBD model and the signal in empirical data remains incomplete. In this Point of View, we aim to expose the degree to which the crBD model differs from empirically inferred phylogenies and test the limits of the model in practice. Using a wide range of topology indices to compare crBD expectations against a comprehensive dataset of 1189 empirically estimated trees, we confirm that crBD model trees frequently differ topologically compared with empirical trees. To place this in the context of standard practice in the field, we conducted a meta-analysis for a subset of the empirical studies. When comparing studies that used Bayesian methods and crBD priors with those that used other non-crBD priors and non-Bayesian methods (i.e., maximum likelihood methods), we do not find any significant differences in tree topology inferences. To scrutinize this finding for the case of highly imbalanced trees, we selected the 100 trees with the greatest imbalance from our dataset, simulated sequence data for these tree topologies under various evolutionary rates, and re-inferred the trees under maximum likelihood and using the crBD model in a Bayesian setting. We find that when the substitution rate is low, the crBD prior results in overly balanced trees, but the tendency is negligible when substitution rates are sufficiently high. Overall, our findings demonstrate the general robustness of crBD priors across a broad range of phylogenetic inference scenarios but also highlight that empirically observed phylogenetic imbalance is highly improbable under the crBD model, leading to systematic bias in data sets with limited information content.

Birth Weight, Childhood and Young Adult Overweight, and the Risk of Coronary Heart Disease in Men.

BACKGROUND: Low birth weight is a known risk factor for adult coronary heart disease (CHD), but the additional effect of weight development during childhood and early adult life has not been studied. METHODS: We included 35 659 men born 1945 to 1961 from the population-based BMI Epidemiology Study Gothenburg, with data available on birthweight, BMI in childhood (8 years), and BMI in young adulthood (20 years). Information on CHD diagnoses was retrieved from national registers. We used Cox proportional hazards regression to estimate hazard ratios and 95% CIs for the risk of early and late CHD (before and after 58.4 years of age, respectively). RESULTS: During follow-up, a total of 3380 cases of CHD (fatal and nonfatal) were registered. Birth weight was inversely associated with the risk of both early (hazard ratio, 0.88 per SD increase [95% CI, 0.84-0.92]) and late (hazard ratio, 0.94 per SD increase [95% CI, 0.90-0.98]) CHD, independently of BMI at 8 years and BMI change during puberty. In a model including birth weight (below or above the median) together with overweight at 8 and 20 years, only birth weight and young adult overweight, but not overweight in childhood, were significantly associated with the risk of CHD. A birth weight below the median, followed by overweight at 20 years of age was associated with a more than doubled risk of early CHD (hazard ratio, 2.29 [95% CI, 1.86-2.81]), compared with the reference (birth weight above the median and normal weight at 20 years of age). This excess risk was even more pronounced for a birthweight below 2.5 kg. CONCLUSIONS: We demonstrate that low birth weight and young adult overweight are important developmental markers of risk for adult CHD. These findings motivate a life course perspective for prevention and risk assessment of adult CHD.

CD8+ T cells in fetal membranes display a unique phenotype, and their activation is involved in the pathophysiology of spontaneous preterm birth.

Preterm labor/birth is the leading cause of perinatal mortality and morbidity worldwide. Previous studies demonstrated that T cells were crucial for maintaining maternal-fetal immune tolerance during the first trimester of pregnancy; however, their phenotypes and functions in labor and delivery remain largely unknown. We recruited three cohorts of women at delivery for T-cell immunophenotyping in the placentas, fetal membranes, umbilical cord blood, and maternal peripheral blood. Our data showed a differential enrichment of T cells during the third trimester of human pregnancy, with CD4+ T cells being more observable within the umbilical cord blood, whereas CD8+ T cells became relatively more abundant in fetal membranes. CD4+ and CD8+ T cells derived from fetal membranes were dominated by effector memory T cells and exhibited extensive expression of activation markers but decreased expression of homing receptor. In comparison with term births, fetal membrane CD8+ T cells, especially the central memory subset, were significantly increased in frequency and showed more profound activation in spontaneous preterm birth patients. Finally, using an allogeneic mouse model, we found that T-cell-activation-induced preterm birth could be alleviated by the depletion of CD8+ T but not CD4+ T cells in vivo. Collectively, we showed that CD8+ T cells in fetal membranes displayed a unique phenotype, and their activation was involved in the pathophysiology of spontaneous preterm birth, which provides novel insights into the immune mechanisms of preterm birth and potential targets for the prevention of this syndrome. © 2023 The Pathological Society of Great Britain and Ireland.

Cortical growth from infancy to adolescence in preterm and term-born children.

Early life experiences can exert a significant influence on cortical and cognitive development. Very preterm birth exposes infants to several adverse environmental factors during hospital admission, which affect cortical architecture. However, the subsequent consequence of very preterm birth on cortical growth from infancy to adolescence has never been defined; despite knowledge of critical periods during childhood for establishment of cortical networks. Our aims were to: chart typical longitudinal cortical development and sex differences in cortical development from birth to adolescence in healthy term-born children; estimate differences in cortical development between children born at term and very preterm; and estimate differences in cortical development between children with normal and impaired cognition in adolescence. This longitudinal cohort study included children born at term (≥37 weeks' gestation) and very preterm (<30 weeks' gestation) with MRI scans at ages 0, 7 and 13 years (n = 66 term-born participants comprising 34 with one scan, 18 with two scans and 14 with three scans; n = 201 very preterm participants comprising 56 with one scan, 88 with two scans and 57 with three scans). Cognitive assessments were performed at age 13 years. Cortical surface reconstruction and parcellation were performed with state-of-the-art, equivalent MRI analysis pipelines for all time points, resulting in longitudinal cortical volume, surface area and thickness measurements for 62 cortical regions. Developmental trajectories for each region were modelled in term-born children, contrasted between children born at term and very preterm, and contrasted between all children with normal and impaired cognition. In typically developing term-born children, we documented anticipated patterns of rapidly increasing cortical volume, area and thickness in early childhood, followed by more subtle changes in later childhood, with smaller cortical size in females than males. In contrast, children born very preterm exhibited increasingly reduced cortical volumes, relative to term-born children, particularly during ages 0-7 years in temporal cortical regions. This reduction in cortical volume in children born very preterm was largely driven by increasingly reduced cortical thickness rather than area. This resulted in amplified cortical volume and thickness reductions by age 13 years in individuals born very preterm. Alterations in cortical thickness development were found in children with impaired language and memory. This study shows that the neurobiological impact of very preterm birth on cortical growth is amplified from infancy to adolescence. These data further inform the long-lasting impact on cortical development from very preterm birth, providing broader insights into neurodevelopmental consequences of early life experiences.