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\"Embryologist Magdalena Zernicka-Goetz has spent two decades unraveling the mysteries of fetal development. By studying embryonic mouse cells, she witnessed the embryo's ability to rid itself of abnormal cells as it prepared for implantation in the womb. When Zernicka-Goetz became pregnant at 44, she received a call that took her by surprise: a sample test of the cells in her own placenta indicated that the fetus had trisomy-2, a disastrous extra copy of the second chromosome, which increased the risk of miscarriage or serious birth defects. It seemed likely that the best choice was to have an abortion. But the plasticity of the embryonic mouse cells in her studies gave her hope; if mouse cells were able to course correct, then perhaps human cells were capable of similar resiliency. Six months later, she gave birth to a healthy baby boy, and the experience inspired her to begin a series of studies to test this hypothesis. Her subsequent experiments with early human embryos and artificial 'three parent' embryos were not only groundbreaking; they also proved that embryotic cells could be artificially nurtured through the trials and tribulations of their early development. To say that her work is controversial would be an understatement, but as Zernicka-Goetz notes, harm can arise as much from doing nothing as from taking risks. And with profound implications for stem cell research, infertility treatment, prenatal diagnostic testing, immunotherapy, and genetic engineering, not to mention women's reproductive health, the stakes have never been higher\"-- Provided by publisher.

New animal models of Zika virus (ZIKV) infection are imperative to accelerating efforts to treat or prevent disease in humans. Adams Waldorf et al . now report that ZIKV infection of a pregnant female pigtailed macaque caused brain lesions in the developing fetus, suggesting that this model may be useful for understanding ZIKV-associated congenital abnormalities in humans. We describe the development of fetal brain lesions after Zika virus (ZIKV) inoculation in a pregnant pigtail macaque. Periventricular lesions developed within 10 d and evolved asymmetrically in the occipital–parietal lobes. Fetal autopsy revealed ZIKV in the brain and significant cerebral white matter hypoplasia, periventricular white matter gliosis, and axonal and ependymal injury. Our observation of ZIKV-associated fetal brain lesions in a nonhuman primate provides a model for therapeutic evaluation.

In this paper we present a computer aided detection (CAD) system for automated measurement of the fetal head circumference (HC) in 2D ultrasound images for all trimesters of the pregnancy. The HC can be used to estimate the gestational age and monitor growth of the fetus. Automated HC assessment could be valuable in developing countries, where there is a severe shortage of trained sonographers. The CAD system consists of two steps: First, Haar-like features were computed from the ultrasound images to train a random forest classifier to locate the fetal skull. Secondly, the HC was extracted using Hough transform, dynamic programming and an ellipse fit. The CAD system was trained on 999 images and validated on an independent test set of 335 images from all trimesters. The test set was manually annotated by an experienced sonographer and a medical researcher. The reference gestational age (GA) was estimated using the crown-rump length measurement (CRL). The mean difference between the reference GA and the GA estimated by the experienced sonographer was 0.8 ± 2.6, -0.0 ± 4.6 and 1.9 ± 11.0 days for the first, second and third trimester, respectively. The mean difference between the reference GA and the GA estimated by the medical researcher was 1.6 ± 2.7, 2.0 ± 4.8 and 3.9 ± 13.7 days. The mean difference between the reference GA and the GA estimated by the CAD system was 0.6 ± 4.3, 0.4 ± 4.7 and 2.5 ± 12.4 days. The results show that the CAD system performs comparable to an experienced sonographer. The presented system shows similar or superior results compared to systems published in literature. This is the first automated system for HC assessment evaluated on a large test set which contained data of all trimesters of the pregnancy.

Mucosal immunity develops in the human fetal intestine by 11–14 weeks of gestation, yet whether viable microbes exist in utero and interact with the intestinal immune system is unknown. Bacteria-like morphology was identified in pockets of human fetal meconium at mid-gestation by scanning electron microscopy ( n  = 4), and a sparse bacterial signal was detected by 16S rRNA sequencing ( n  = 40 of 50) compared to environmental controls ( n  = 87). Eighteen taxa were enriched in fetal meconium, with Micrococcaceae ( n  = 9) and Lactobacillus ( n  = 6) the most abundant. Fetal intestines dominated by Micrococcaceae exhibited distinct patterns of T cell composition and epithelial transcription. Fetal Micrococcus luteus , isolated only in the presence of monocytes, grew on placental hormones, remained viable within antigen presenting cells, limited inflammation ex vivo and possessed genomic features linked with survival in the fetus. Thus, viable bacteria are highly limited in the fetal intestine at mid-gestation, although strains with immunomodulatory capacity are detected in subsets of specimens. Microscopy and 16S rRNA sequencing suggest that there is a limited bacterial presence in the human fetal intestine, with one enriched Micrococcus species exhibiting immunomodulatory activity ex vivo.

The anatomical and functional architecture of the human brain is mainly determined by prenatal transcriptional processes. We describe an anatomically comprehensive atlas of the mid-gestational human brain, including de novo reference atlases, in situ hybridization, ultra-high-resolution magnetic resonance imaging (MRI) and microarray analysis on highly discrete laser-microdissected brain regions. In developing cerebral cortex, transcriptional differences are found between different proliferative and post-mitotic layers, wherein laminar signatures reflect cellular composition and developmental processes. Cytoarchitectural differences between human and mouse have molecular correlates, including species differences in gene expression in subplate, although surprisingly we find minimal differences between the inner and outer subventricular zones even though the outer zone is expanded in humans. Both germinal and post-mitotic cortical layers exhibit fronto-temporal gradients, with particular enrichment in the frontal lobe. Finally, many neurodevelopmental disorder and human-evolution-related genes show patterned expression, potentially underlying unique features of human cortical formation. These data provide a rich, freely-accessible resource for understanding human brain development. A spatially resolved transcriptional atlas of the mid-gestational developing human brain has been created using laser-capture microdissection and microarray technology, providing a comprehensive reference resource which also enables new hypotheses about the nature of human brain evolution and the origins of neurodevelopmental disorders. New whole-brain mapping resources With President Barack Obama's BRAIN (Brain Research through Advancing Innovative Neurotechnologies) initiative now entering year two, this issue of Nature presents two landmark papers that mobilize 'big science' resources to the cause. Hongkui Zeng and colleagues present the first brain-wide, mesoscale connectome for a mammalian species — the laboratory mouse — based on cell-type-specific tracing of axonal projections. The wiring diagram of a complete nervous system has long been available for a small roundworm, but neuronal connectivity data for larger animals has been patchy until now. The new three-dimensional Allen Mouse Brain Connectivity Atlas is a whole-brain connectivity matrix that will provide insights into how brain regions communicate. Much of the data generated in this project will be of relevance to investigations of neural networks in humans and should help to further our understanding of human brain connectivity and its involvement in brain disorders. In a separate report Ed Lein and colleagues present a transcriptional atlas of the mid-gestational human brain at high spatial resolution, based on laser microdissection and DNA microarray technology. The structure and function of the human brain is largely determined by prenatal transcriptional processes that initiate gene expression, but our understanding of the developing brain has been limited. The new data set reveals transcriptional signatures for developmental processes associated with the massive expansion of neocortex during human evolution, and suggests new cortical germinal zones or postmitotic neurons as sites of dynamic expression for many genes associated with neurological or psychiatric disorders.

Fetal structural anomalies, which are detected by ultrasonography, have a range of genetic causes, including chromosomal aneuploidy, copy number variations (CNVs; which are detectable by chromosomal microarrays), and pathogenic sequence variants in developmental genes. Testing for aneuploidy and CNVs is routine during the investigation of fetal structural anomalies, but there is little information on the clinical usefulness of genome-wide next-generation sequencing in the prenatal setting. We therefore aimed to evaluate the proportion of fetuses with structural abnormalities that had identifiable variants in genes associated with developmental disorders when assessed with whole-exome sequencing (WES). In this prospective cohort study, two groups in Birmingham and London recruited patients from 34 fetal medicine units in England and Scotland. We used whole-exome sequencing (WES) to evaluate the presence of genetic variants in developmental disorder genes (diagnostic genetic variants) in a cohort of fetuses with structural anomalies and samples from their parents, after exclusion of aneuploidy and large CNVs. Women were eligible for inclusion if they were undergoing invasive testing for identified nuchal translucency or structural anomalies in their fetus, as detected by ultrasound after 11 weeks of gestation. The partners of these women also had to consent to participate. Sequencing results were interpreted with a targeted virtual gene panel for developmental disorders that comprised 1628 genes. Genetic results related to fetal structural anomaly phenotypes were then validated and reported postnatally. The primary endpoint, which was assessed in all fetuses, was the detection of diagnostic genetic variants considered to have caused the fetal developmental anomaly. The cohort was recruited between Oct 22, 2014, and June 29, 2017, and clinical data were collected until March 31, 2018. After exclusion of fetuses with aneuploidy and CNVs, 610 fetuses with structural anomalies and 1202 matched parental samples (analysed as 596 fetus-parental trios, including two sets of twins, and 14 fetus-parent dyads) were analysed by WES. After bioinformatic filtering and prioritisation according to allele frequency and effect on protein and inheritance pattern, 321 genetic variants (representing 255 potential diagnoses) were selected as potentially pathogenic genetic variants (diagnostic genetic variants), and these variants were reviewed by a multidisciplinary clinical review panel. A diagnostic genetic variant was identified in 52 (8·5%; 95% CI 6·4–11·0) of 610 fetuses assessed and an additional 24 (3·9%) fetuses had a variant of uncertain significance that had potential clinical usefulness. Detection of diagnostic genetic variants enabled us to distinguish between syndromic and non-syndromic fetal anomalies (eg, congenital heart disease only vs a syndrome with congenital heart disease and learning disability). Diagnostic genetic variants were present in 22 (15·4%) of 143 fetuses with multisystem anomalies (ie, more than one fetal structural anomaly), nine (11·1%) of 81 fetuses with cardiac anomalies, and ten (15·4%) of 65 fetuses with skeletal anomalies; these phenotypes were most commonly associated with diagnostic variants. However, diagnostic genetic variants were least common in fetuses with isolated increased nuchal translucency (≥4·0 mm) in the first trimester (in three [3·2%] of 93 fetuses). WES facilitates genetic diagnosis of fetal structural anomalies, which enables more accurate predictions of fetal prognosis and risk of recurrence in future pregnancies. However, the overall detection of diagnostic genetic variants in a prospectively ascertained cohort with a broad range of fetal structural anomalies is lower than that suggested by previous smaller-scale studies of fewer phenotypes. WES improved the identification of genetic disorders in fetuses with structural abnormalities; however, before clinical implementation, careful consideration should be given to case selection to maximise clinical usefulness. UK Department of Health and Social Care and The Wellcome Trust.

Background The maternal microbiota affects the development of the offspring by microbial metabolites translocating to the fetus. To reveal the spectrum of these molecular mediators of the earliest host-microbe interactions, we compared placenta, fetal intestine and brain from germ-free (GF) and specific pathogen free (SPF) mouse dams by non-targeted metabolic profiling. Results One hundred one annotated metabolites and altogether 3680 molecular features were present in significantly different amounts in the placenta and/or fetal organs of GF and SPF mice. More than half of these were more abundant in the SPF organs, suggesting their microbial origin or a metabolic response of the host to the presence of microbes. The clearest separation was observed in the placenta, but most of the molecular features showed significantly different levels also in the fetal intestine and/or brain. Metabolites that were detected in lower amounts in the GF fetal organs included 5-aminovaleric acid betaine, trimethylamine N-oxide, catechol-O-sulphate, hippuric and pipecolic acid. Derivatives of the amino acid tryptophan, such as kynurenine, 3-indolepropionic acid and hydroxyindoleacetic acid, were also less abundant in the absence of microbiota. Ninety-nine molecular features were detected only in the SPF mice. We also observed several molecular features which were more abundant in the GF mice, possibly representing precursors of microbial metabolites or indicators of a metabolic response to the absence of microbiota. Conclusions The maternal microbiota has a profound impact on the fetal metabolome. Our observations suggest the existence of a multitude of yet unidentified microbially modified metabolites which pass through the placenta into the fetus and potentially influence fetal development.

To determine the origin of adult tissue-resident macrophages, a mouse lineage tracing study has revealed that these cells derive from erythro-myeloid progenitors in the yolk sac that are distinct from fetal and adult haematopoietic stem cells. The origin of adult myeloid cells The developmental origin of tissue-resident macrophage progenitors and their contribution to macrophages in fetal and adult organs relative to bone marrow macrophages are still unclear. Using lineage tracing, Elisa Gomez Perdiguero et al . identify a population of yolk-sac-derived progenitors — distinct from fetal and adult haematopoetic stem cells — that gives rise to erythrocytes, macrophages, granulocytes and monocytes in the young mouse fetus, and to the vast majority of adult tissue-resident macrophages. Most haematopoietic cells renew from adult haematopoietic stem cells (HSCs) 1 , 2 , 3 , however, macrophages in adult tissues can self-maintain independently of HSCs 4 , 5 , 6 , 7 . Progenitors with macrophage potential in vitro have been described in the yolk sac before emergence of HSCs 8 , 9 , 10 , 11 , 12 , 13 , and fetal macrophages 13 , 14 , 15 can develop independently of Myb 4 , a transcription factor required for HSC 16 , and can persist in adult tissues 4 , 17 , 18 . Nevertheless, the origin of adult macrophages and the qualitative and quantitative contributions of HSC and putative non-HSC-derived progenitors are still unclear 19 . Here we show in mice that the vast majority of adult tissue-resident macrophages in liver (Kupffer cells), brain (microglia), epidermis (Langerhans cells) and lung (alveolar macrophages) originate from a Tie2 + (also known as Tek ) cellular pathway generating Csf1r + erythro-myeloid progenitors (EMPs) distinct from HSCs. EMPs develop in the yolk sac at embryonic day (E) 8.5, migrate and colonize the nascent fetal liver before E10.5, and give rise to fetal erythrocytes, macrophages, granulocytes and monocytes until at least E16.5. Subsequently, HSC-derived cells replace erythrocytes, granulocytes and monocytes. Kupffer cells, microglia and Langerhans cells are only marginally replaced in one-year-old mice, whereas alveolar macrophages may be progressively replaced in ageing mice. Our fate-mapping experiments identify, in the fetal liver, a sequence of yolk sac EMP-derived and HSC-derived haematopoiesis, and identify yolk sac EMPs as a common origin for tissue macrophages.

Context.— The placenta is an important component in understanding the fetal response to intrauterine Zika virus infection, but the pathologic changes in this organ remain largely unknown. Hofbauer cells are fetal-derived macrophages normally present in the chorionic villous stroma. They have been implicated in a variety of physiological and pathologic processes, in particular involving infectious agents. Objectives.— To characterize the fetal and maternal responses and viral localization in the placenta following Zika virus transmission to an 11 weeks' gestation fetus. The clinical course was notable for prolonged viremia in the mother and extensive neuronal necrosis in the fetus. The fetus was delivered at 21 weeks' gestation after pregnancy termination. Design.— The placenta was evaluated by using immunohistochemistry for inflammatory cells (macrophages/monocytes [Hofbauer cells], B and T lymphocytes) and proliferating cells, and an RNA probe to Zika virus. The fetal brain and the placenta were previously found to be positive for Zika virus RNA by reverse transcription–polymerase chain reaction. Results.— The placenta demonstrated prominently enlarged, hydropic chorionic villi with hyperplasia and focal proliferation of Hofbauer cells. The degree of Hofbauer cell hyperplasia gave an exaggerated immature appearance to the villi. No acute or chronic villitis, villous necrosis, remote necroinflammatory abnormalities, chorioamnionitis, funisitis, or hemorrhages were present. An RNA probe to Zika virus was positive in villous stromal cells, presumably Hofbauer cells. Conclusions.— Zika virus placental infection induces proliferation and prominent hyperplasia of Hofbauer cells in the chorionic villi but does not elicit villous necrosis or a maternal or fetal lymphoplasmacellular or acute inflammatory cell reaction.

Many observational studies and some randomized trials demonstrate how fetal growth can be influenced by environmental insults (for example, maternal infections) 1 and preventive interventions (for example, multiple-micronutrient supplementation) 2 that can have a long-lasting effect on health, growth, neurodevelopment and even educational attainment and income in adulthood 3 . In a cohort of pregnant women ( n  = 3,598), followed-up between 2012 and 2019 at six sites worldwide 4 , we studied the associations between ultrasound-derived fetal cranial growth trajectories, measured longitudinally from <14 weeks’ gestation, against international standards 5 , 6 , and growth and neurodevelopment up to 2 years of age 7 , 8 . We identified five trajectories associated with specific neurodevelopmental, behavioral, visual and growth outcomes, independent of fetal abdominal growth, postnatal morbidity and anthropometric measures at birth and age 2. The trajectories, which changed within a 20–25-week gestational age window, were associated with brain development at 2 years of age according to a mirror (positive/negative) pattern, mostly focused on maturation of cognitive, language and visual skills. Further research should explore the potential for preventive interventions in pregnancy to improve infant neurodevelopmental outcomes before the critical window of opportunity that precedes the divergence of growth at 20–25 weeks’ gestation. This study of a cohort of over 3,500 pregnant women in six different populations worldwide identifies specific fetal cranial growth trajectories, measured by serial ultrasound scans early in gestation, that are related to postnatal growth and neurodevelopment up to the key milestone age of 2 years.