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Cerebral organoids—3D cultures of human cerebral tissue derived from pluripotent stem cells—have emerged as models of human cortical development. However, the extent to which in vitro organoid systems recapitulate neural progenitor cell proliferation and neuronal differentiation programs observed in vivo remains unclear. Here we use single-cell RNA sequencing (scRNA-seq) to dissect and compare cell composition and progenitor-to-neuron lineage relationships in human cerebral organoids and fetal neocortex. Covariation network analysis using the fetal neocortex data reveals known and previously unidentified interactions among genes central to neural progenitor proliferation and neuronal differentiation. In the organoid, we detect diverse progenitors and differentiated cell types of neuronal and mesenchymal lineages and identify cells that derived from regions resembling the fetal neocortex. We find that these organoid cortical cells use gene expression programs remarkably similar to those of the fetal tissue to organize into cerebral cortex-like regions. Our comparison of in vivo and in vitro cortical single-cell transcriptomes illuminates the genetic features underlying human cortical development that can be studied in organoid cultures.

The expansion of the neocortex during mammalian brain evolution results primarily from an increase in neural progenitor cell divisions in its two principal germinal zones during development, the ventricular zone (VZ) and the subventricular zone (SVZ). Using mRNA sequencing, we analyzed the transcriptomes of fetal human and embryonic mouse VZ, SVZ, and cortical plate. In mouse, the transcriptome of the SVZ was more similar to that of the cortical plate than that of the VZ, whereas in human the opposite was the case, with the inner and outer SVZ being highly related to each other despite their cytoarchitectonic differences. We describe sets of genes that are up-or down-regulated in each germinal zone. These data suggest that cell adhesion and cell-extracellular matrix interactions promote the proliferation and self-renewal of neural progenitors in the developing human neocortex. Notably, relevant extracellular matrix-associated genes include distinct sets of collagens, laminins, proteoglycans, and integrins, along with specific sets of growth factors and morphogens. Our data establish a basis for identifying novel cell-type markers and open up avenues to unravel the molecular basis of neocortex expansion during evolution.

Human neocortex expansion likely contributed to the remarkable cognitive abilities of humans. This expansion is thought to primarily reflect differences in proliferation versus differentiation of neural progenitors during cortical development. Here, we have searched for such differences by analysing cerebral organoids from human and chimpanzees using immunohistofluorescence, live imaging, and single-cell transcriptomics. We find that the cytoarchitecture, cell type composition, and neurogenic gene expression programs of humans and chimpanzees are remarkably similar. Notably, however, live imaging of apical progenitor mitosis uncovered a lengthening of prometaphase-metaphase in humans compared to chimpanzees that is specific to proliferating progenitors and not observed in non-neural cells. Consistent with this, the small set of genes more highly expressed in human apical progenitors points to increased proliferative capacity, and the proportion of neurogenic basal progenitors is lower in humans. These subtle differences in cortical progenitors between humans and chimpanzees may have consequences for human neocortex evolution. The human brain is about three times as big as the brain of our closest living relative, the chimpanzee. Moreover, a part of the brain called the cerebral cortex – which plays a key role in memory, attention, awareness and thought – contains twice as many cells in humans as the same region in chimpanzees. Networks of brain cells in the cerebral cortex also behave differently in the two species. How these species differences arise is not clear, but it likely occurs in the earliest phases of development when brain stem and progenitor cells divide and give rise to cerebral cortex cells in the growing brain. To study the earliest stages of brain development, researchers often use human brain cells grown in the laboratory. Under the right conditions, cells collected from adult humans and other animals can be reprogrammed to behave like brain stem cells. Recently, researchers have been able to use these reprogrammed cells to make tissue that resembles the brain in petri dishes, known as brain organoids. Mora-Bermúdez, Badsha, Kanton, Camp et al. have now analysed brain organoids grown from reprogrammed human, chimpanzee and orangutan cells. The experiments showed that the human and chimpanzee brain organoids were remarkably similar in many ways including in the mix of cell types and in how these cells were arranged. Mora-Bermúdez et al. then used live microscopy to show that progenitor cells that form the human cerebral cortex spend around 50% more time in a stage of the cell division process called metaphase compared to the same cells from chimpanzees or orangutans. Metaphase is the part of the division process when the cell makes sure that structures called chromosomes, which carry the cell’s DNA, can be separated and distributed equally between the two daughter cells. Mora-Bermúdez et al. also found that progenitor cells more likely to become neurons sooner had a shorter metaphase than progenitor cells more likely to remain proliferating as stem cells for longer. This suggests that a longer metaphase may be a feature of brain stem cells. Further studies are now needed to find out how the length of time these progenitor cells spend in metaphase affects how chimpanzee and human brains develop; and whether this can help explain why the human brain is so much larger.

Abstract Besides being one of the mechanisms responsible for ventilator-induced lung injury, atelectasis also seems to aggravate the course of experimental pneumonia. In this study, we examined the effect of reducing the degree of atelectasis by natural modified surfactant and/or open lung ventilation on bacterial growth and translocation in a piglet model of Group B streptococcal pneumonia. After creating surfactant deficiency by whole lung lavage, intratracheal instillation of bacteria induced severe pneumonia with bacterial translocation into the blood stream, resulting in a mortality rate of almost 80%. Treatment with 300 mg/kg of exogenous surfactant before instillation of streptococci attenuated both bacterial growth and translocation and prevented clinical deterioration. This goal was also achieved by reversing atelectasis in lavaged animals via open lung ventilation. Combining both exogenous surfactant and open lung ventilation prevented bacterial translocation completely, comparable to Group B streptococci instillation into healthy animals. We conclude that exogenous surfactant and open lung ventilation attenuate bacterial growth and translocation in experimental pneumonia and that this attenuation is at least in part mediated by a reduction in atelectasis. These findings suggest that minimizing alveolar collapse by exogenous surfactant and open lung ventilation may reduce the risk of pneumonia and subsequent sepsis in ventilated patients.

A previous study in piglets with experimental pneumonia showed that reducing atelectasis by means of open lung ventilation attenuated bacterial translocation compared to conventional ventilation settings. This study examined the effect of open lung ventilation with higher than necessary positive end-expiratory pressures (PEEP) on bacterial translocation. Prospective animal study in a university-affiliated research laboratory. Thirty piglets. Animals were surfactant-depleted by whole-lung lavage and infected with group B streptococci. Thereafter the animals were ventilated for 5 h according to either a conventional ventilation strategy, open lung strategy, or open lung/high-PEEP strategy. Blood samples for blood gas analysis and blood bacterial counts were taken every hour. After 5 h of ventilation surviving animals were killed, and lung colony forming units and lung mechanics parameters were determined. All animals in both open lung groups survived but only 30% of those in the conventional ventilation group. Open lung ventilation resulted in significantly less bacterial translocation than either conventional or high-PEEP ventilation. Lung function in the conventional ventilated group was significantly less than in the two open lung groups. The lowest level of bacterial translocation was observed during optimal ventilation (open lung) which was achieved by using individually tailored settings. Deviation to either side can be harmful, as shown by the increased bacterial translocation during conventional and high-PEEP ventilation.

Abstract In acute respiratory distress syndrome patients, protective ventilation strategies reduce mortality and proinflammatory mediator levels. It has been suggested that some of the side effects of mechanical ventilation are caused by the excessive release of mediators capable of causing pulmonary inflammation and tissue destruction (biotrauma). Selective inhibition of this process might be used to minimize the side effects of artificial mechanical ventilation. This study was designed to identify the cell types and specific signaling mechanisms that are activated by ventilation with increased pressure/volume (overventilation). In isolated perfused mouse lungs, overventilation caused nuclear translocation of nuclear factor-κB (NF-κB) and enhanced expression of interleukin-6 mRNA in alveolar macrophages and alveolar epithelial type II cells. The phosphoinositide 3-OH kinase inhibitor Ly294002 prevented nuclear translocation of NF-κB and the subsequent release of interleukin-6 and macrophage inflammatory protein–2α in overventilated but not in endotoxic lungs. Similar results were obtained in rats in vivo, where Ly294002 prevented NF-κB activation by overventilation but not by endotoxin. These findings show that alveolar macrophages and alveolar epithelial type II cells contribute to the ventilation-induced release of proinflammatory mediators and that selective inhibition of this process is possible without inhibiting the activation of NF-κB by endotoxin.

Evolutionary expansion of the human neocortex reflects increased amplification of basal progenitors in the subventricular zone, producing more neurons during fetal corticogenesis. In this work, we analyze the transcriptomes of distinct progenitor subpopulations isolated by a cell polarity–based approach from developing mouse and human neocortex. We identify 56 genes preferentially expressed in human apical and basal radial glia that lack mouse orthologs. Among these, ARHGAP11B has the highest degree of radial glia–specific expression. ARHGAP11B arose from partial duplication of ARHGAP11A (which encodes a Rho guanosine triphosphatase–activating protein) on the human lineage after separation from the chimpanzee lineage. Expression of ARHGAP11B in embryonic mouse neocortex promotes basal progenitor generation and self-renewal and can increase cortical plate area and induce gyrification. Hence, ARHGAP11B may have contributed to evolutionary expansion of human neocortex.

Objective: To describe the first trimester diagnosis of agenesis of the corpus callosum (ACC). Methods: The midbrain and falx cerebri were examined in stored images of the midsagittal view of the fetal brain at 11 +0 –13 +6 weeks’ gestation from 15 fetuses with ACC and 500 normal controls. The midbrain diameter and falx diameter were measured and their ratio was calculated. The values in fetuses with ACC and normal controls were compared. Results: In the control group, the midbrain and falx diameters increased significantly with crown-rump length (CRL) from respective mean values of 5.1 and 6.9 mm at CRL of 45–6.9 mm and 12.1 mm at CRL of 84 mm. In the ACC group the midbrain diameter was above the 95th percentile of the control group in 8 (53.3%) cases, the falx diameter was below the 5th percentile in 6 (40.0%) cases and the midbrain diameter-to-falx diameter ratio was above the 95th percentile in 13 (86.7%) cases. Conclusions: In the midsagittal view of the fetal brain at 11–13 weeks, the majority of fetuses with ACC have measurable abnormalities in the midbrain and falx area of the brain.

Objective: It was the aim of this study to investigate the pregnancy characteristics that influence the measured concentrations of maternal serum-free β-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A) at 9 +0 –13 +6 weeks’ gestation. Methods: In singleton pregnancies attending for routine care, serum-free β-hCG and PAPP-A were measured at 9 +0 –13 +6 weeks’ gestation and fetal nuchal translucency was measured at 11 +0 –13 +6 weeks. The population included 27,908 chromosomally normal and 104 trisomy 21 pregnancies. Multiple regression analysis was used to examine the pregnancy characteristics that have a significant effect on the measured concentrations of free β-hCG and PAPP-A. We also examined the impact of incorporating temporal effects on performance of screening for trisomy 21. Results: Serum-free β-hCG and PAPP-A concentrations were significantly affected by gestational age, maternal weight, racial origin, parity, preexisting diabetes mellitus type 2, smoking and conception by in vitro fertilization. There was a significant gestational age-dependent effect of Afro-Caribbean race on PAPP-A levels (p = 0.0005), with a weekly increase of 4.9% (95% CI 2.1–7.8). Conclusions: Serum-free β-hCG and PAPP-A concentrations at 9 +0 –13 +6 weeks’ gestation are affected by several pregnancy characteristics and the effect of Afro-Caribbean race on PAPP-A increases with gestational age.

Introduction: Idiopathic dilatation of the right atrium (IDRA) is a rare abnormality usually detected by chance at any time between antenatal and adult life. It is defined as isolated enlargement of the right atrium in the absence of other cardiac lesions causing right atrial dilatation. IDRA can be associated with atrial arrhythmia and systemic embolism. The clinical presentation shows high variability ranging from the lack of any symptoms up to cardiac failure. Methods/Results: We describe 2 children with antenatally diagnosed IDRA, the intrauterine course in 1 case, the postnatal management and its long-term follow-up. There has been no need for surgical intervention so far because of the lack of arrhythmias and no further progression of right atrial diameters. Thrombus formation in the right atrium, which is a potential risk for pulmonary embolism, led us to initiate anticoagulation in our cases to prevent such complications. Furthermore, we suggest one possible pathomechanism of congenital right atrial dilatation. Conclusion: Optimal management of severe IDRA depends on the individual case. Long-term follow-up of these patients is necessary to monitor a possible further progression of right atrial size and occurrence of arrhythmias. As a possible pathomechanism, a functional partial anomalous pulmonary venous insertion may imitate a structural abnormal pulmonary vein connection in some idiopathic cases of congenital right atrial dilatation.