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In vitro models of the developing brain such as three-dimensional brain organoids offer an unprecedented opportunity to study aspects of human brain development and disease. However, the cells generated within organoids and the extent to which they recapitulate the regional complexity, cellular diversity and circuit functionality of the brain remain undefined. Here we analyse gene expression in over 80,000 individual cells isolated from 31 human brain organoids. We find that organoids can generate a broad diversity of cells, which are related to endogenous classes, including cells from the cerebral cortex and the retina. Organoids could be developed over extended periods (more than 9 months), allowing for the establishment of relatively mature features, including the formation of dendritic spines and spontaneously active neuronal networks. Finally, neuronal activity within organoids could be controlled using light stimulation of photosensitive cells, which may offer a way to probe the functionality of human neuronal circuits using physiological sensory stimuli. Long-term cultures of human brain organoids display a high degree of cellular diversity, mature spontaneous neuronal networks and are sensitive to light. Enlightening organoids Three-dimensional cellular models of the human brain, or organoids, enable the in vitro study of cerebral development and disease, but exactly which cells are generated and how much of the brain's complexity they recreate is undefined. To investigate in depth the nature of cells in human cerebral organoids differentiated from pluripotent stem cells, Paola Arlotta and colleagues carried out droplet-based single-cell expression analysis on cells isolated from over 30 organoids at developmental stages ranging from 3 to 9 months and beyond. They identify a wide diversity of neurons and progenitors and show that the more mature organoids formed dendritic spines as well as electrically active networks, which responded to light stimulation. The authors suggest that organoids may facilitate the study of circuit function using physiological sensory mechanisms. Elsewhere in this issue, Sergiu Paşca and colleagues show that re-assembling ventral and dorsal forebrain spheroids obtained separately in vitro allows the migration of human interneurons and the formation of functional synapses.

Recent developments in serial-section electron microscopy allow the efficient generation of very large image data sets but analyzing such data poses challenges for software tools. Here we introduce Volume Annotation and Segmentation Tool (VAST), a freely available utility program for generating and editing annotations and segmentations of large volumetric image (voxel) data sets. It provides a simple yet powerful user interface for real-time exploration and analysis of large data sets even in the Petabyte range.

An animal’s nervous system changes as its body grows from birth to adulthood and its behaviours mature 1 – 8 . The form and extent of circuit remodelling across the connectome is unknown 3 , 9 – 15 . Here we used serial-section electron microscopy to reconstruct the full brain of eight isogenic Caenorhabditis elegans individuals across postnatal stages to investigate how it changes with age. The overall geometry of the brain is preserved from birth to adulthood, but substantial changes in chemical synaptic connectivity emerge on this consistent scaffold. Comparing connectomes between individuals reveals substantial differences in connectivity that make each brain partly unique. Comparing connectomes across maturation reveals consistent wiring changes between different neurons. These changes alter the strength of existing connections and create new connections. Collective changes in the network alter information processing. During development, the central decision-making circuitry is maintained, whereas sensory and motor pathways substantially remodel. With age, the brain becomes progressively more feedforward and discernibly modular. Thus developmental connectomics reveals principles that underlie brain maturation. Serial-section electron microscopy is used to reconstruct the full brain connectome of eight individual Caenorhabditis elegans at various stages of development, providing insight into the principles underlying brain maturation.

Myelin is a defining feature of the vertebrate nervous system. Variability in the thickness of the myelin envelope is a structural feature affecting the conduction of neuronal signals. Conversely, the distribution of myelinated tracts along the length of axons has been assumed to be uniform. Here, we traced high-throughput electron microscopy reconstructions of single axons of pyramidal neurons in the mouse neocortex and built high-resolution maps of myelination. We find that individual neurons have distinct longitudinal distribution of myelin. Neurons in the superficial layers displayed the most diversified profiles, including a new pattern where myelinated segments are interspersed with long, unmyelinated tracts. Our data indicate that the profile of longitudinal distribution of myelin is an integral feature of neuronal identity and may have evolved as a strategy to modulate long-distance communication in the neocortex.

We provide evidence that increased political influence, arising from CIA interventions during the Cold War, was used to create a larger foreign market for American products. Following CIA interventions, imports from the US increased dramatically, while total exports to the US were unaffected. The surge in imports was concentrated in industries in which the US had a comparative disadvantage, not a comparative advantage. Our analysis is able to rule out decreased trade costs, changing political ideology, and an increase in US loans and grants as alternative explanations. We provide evidence that the increased imports arose through direct purchases of American products by foreign governments.

Cell survival after oxidative DNA damage requires signaling, repair and transcriptional events often enabled by nucleosome displacement, exchange or removal by chromatin remodeling enzymes. Here, we show that Chromodomain Helicase DNA-binding protein 6 (CHD6), distinct to other CHD enzymes, is stabilized during oxidative stress via reduced degradation. CHD6 relocates rapidly to DNA damage in a manner dependent upon oxidative lesions and a conserved N-terminal poly(ADP-ribose)-dependent recruitment motif, with later retention requiring the double chromodomain and central core. CHD6 ablation increases reactive oxygen species persistence and impairs anti-oxidant transcriptional responses, leading to elevated DNA breakage and poly(ADP-ribose) induction that cannot be rescued by catalytic or double chromodomain mutants. Despite no overt epigenetic or DNA repair abnormalities, CHD6 loss leads to impaired cell survival after chronic oxidative stress, abnormal chromatin relaxation, amplified DNA damage signaling and checkpoint hypersensitivity. We suggest that CHD6 is a key regulator of the oxidative DNA damage response. Oxidative DNA damage is associated with nucleosome respacing and transcriptional changes requiring chromatin remodeling enzymes. Here, the authors reveal that the CHD6 remodeler is a DNA damage response factor that relocates to damaged sites and promotes cell survival following oxidative damage.

•Large, high-resolution 3D EM data of human superficial white matter was segmented.•Segmentation results using deep learning were highly accurate.•128,285 myelinated axons were delineated, with 2102 longer than 100 μm.•Local variations in diameter (beading) and direction (undulation) were observed.•Axons had inner diameters ∼0.5 µm, outer diameters ∼1 µm, and g-ratios ∼0.5. Short-range association fibers located in the superficial white matter play an important role in mediating higher-order cognitive function in humans. Detailed morphological characterization of short-range association fibers at the microscopic level promises to yield important insights into the axonal features driving cortico-cortical connectivity in the human brain yet has been difficult to achieve to date due to the challenges of imaging at nanometer-scale resolution over large tissue volumes. This work presents results from multi-beam scanning electron microscopy (EM) data acquired at 4 × 4 × 33 nm3 resolution in a volume of human superficial white matter measuring 200 × 200 × 112 μm3, leveraging automated analysis methods. Myelin and myelinated axons were automatically segmented using deep convolutional neural networks (CNNs), assisted by transfer learning and dropout regularization techniques. A total of 128,285 myelinated axons were segmented, of which 70,321 and 2102 were longer than 10 and 100 μm, respectively. Marked local variations in diameter (i.e., beading) and direction (i.e., undulation) were observed along the length of individual axons. Myelinated axons longer than 10 μm had inner diameters around 0.5 µm, outer diameters around 1 µm, and g-ratios around 0.5. This work fills a gap in knowledge of axonal morphometry in the superficial white matter and provides a large 3D human EM dataset and accurate segmentation results for a variety of future studies in different fields.

Ataxia-telangiectasia mutated (ATM) is a serine/threonine protein kinase with a master regulatory function in the DNA damage response. In this role, ATM commands a complex biochemical network that signals the presence of oxidative DNA damage, including the dangerous DNA double-strand break, and facilitates subsequent repair. Here, we review the current state of knowledge regarding ATM-dependent chromatin remodelling and epigenomic alterations that are required to maintain genomic integrity in the presence of DNA double-strand breaks and/or oxidative stress. We will focus particularly on the roles of ATM in adjusting nucleosome spacing at sites of unresolved DNA double-strand breaks within complex chromatin environments, and the impact of ATM on preserving the health of cells within the mammalian central nervous system. This article is part of the themed issue ‘Chromatin modifiers and remodellers in DNA repair and signalling’.

The first phase of the Human Connectome Project pioneered advances in MRI technology for mapping the macroscopic structural connections of the living human brain through the engineering of a whole-body human MRI scanner equipped with maximum gradient strength of 300 mT/m, the highest ever achieved for human imaging. While this instrument has made important contributions to the understanding of macroscale connectional topology, it has also demonstrated the potential of dedicated high-gradient performance scanners to provide unparalleled in vivo assessment of neural tissue microstructure. Building on the initial groundwork laid by the original Connectome scanner, we have now embarked on an international, multi-site effort to build the next-generation human 3T Connectome scanner (Connectome 2.0) optimized for the study of neural tissue microstructure and connectional anatomy across multiple length scales. In order to maximize the resolution of this in vivo microscope for studies of the living human brain, we will push the diffusion resolution limit to unprecedented levels by (1) nearly doubling the current maximum gradient strength from 300 mT/m to 500 mT/m and tripling the maximum slew rate from 200 T/m/s to 600 T/m/s through the design of a one-of-a-kind head gradient coil optimized to minimize peripheral nerve stimulation; (2) developing high-sensitivity multi-channel radiofrequency receive coils for in vivo and ex vivo human brain imaging; (3) incorporating dynamic field monitoring to minimize image distortions and artifacts; (4) developing new pulse sequences to integrate the strongest diffusion encoding and highest spatial resolution ever achieved in the living human brain; and (5) calibrating the measurements obtained from this next-generation instrument through systematic validation of diffusion microstructural metrics in high-fidelity phantoms and ex vivo brain tissue at progressively finer scales with accompanying diffusion simulations in histology-based micro-geometries. We envision creating the ultimate diffusion MRI instrument capable of capturing the complex multi-scale organization of the living human brain – from the microscopic scale needed to probe cellular geometry, heterogeneity and plasticity, to the mesoscopic scale for quantifying the distinctions in cortical structure and connectivity that define cyto- and myeloarchitectonic boundaries, to improvements in estimates of macroscopic connectivity.

Introduction: Emergency department (ED) use varies by age, sex, race, ethnicity, language preference, and payor type. Most studies comparing ED use by patients with English vs non-English preference (ELP/NELP) have used racially aggregated data, potentially masking differences across population subgroups. In this study we aimed to disaggregate the associations of race, ethnicity, language preference, and Medicaid coverage with ED utilization. Methods: We used cross-sectional study electronic health record data for 2,047,105 Kaiser Permanente Northern California members who were 25 - 85 years of age in January 2019 and had been continuous health plan members during 2018 - 2019. We tabulated the percentages of adults in seven racial and ethnic groups (White, Black, Hispanic, Chinese, Filipino, Vietnamese, South Asian) within three age groups (25 - 44, 45 - 64, 65 - 85) who had ≥1 ED visit in 2019. Modified log-Poisson regression was used to examine racial, ethnic, and language preference differences after adjusting for demographic and Medicaid status covariates. Results: The study population was 51.8% White, 53.2% female, 9.6% NELP, and 6.2% Medicaid-insured. Overall, 18% had ≥ 1 ED visit. Compared with White adults, Black and Hispanic adults were more likely and Chinese, Vietnamese, and South Asian adults were less likely to have ≥ 1 ED visit. After adjusting for all covariates, NELP adults 25 - 64 years of age were 10% less likely to have had an ED visit. However, while NELP was associated with a 10-20% lower ED visit prevalence among Hispanic, Filipino, Chinese, and Vietnamese adults 25 - 64, the prevalence was 10% higher among White and South Asian adults 45 - 64 and Filipino and South Asian adults aged 65 - 85. Adults with Medicaid coverage aged 25 - 64 were twice as likely and adults aged 65 - 85 were 50% more likely to have had ≥ 1 ED visit. Conclusion: This study of a US adult health-plan membership found several significant differences in ED use across racial, ethnic, and language subgroups and a higher prevalence of ED use by Medicaid-covered adults ≤ 65 years of age in most racial and ethnic groups. Our findings highlight the importance of using disaggregated data, particularly for Asian ethnic groups, when comparing ED use in different populations. Further research is needed to identify similarities and differences in social, personal, and policy factors driving ED use in diverse adult populations to better inform population-specific health interventions.