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SARS-CoV-2 infects human brain organoids causing cell death and loss of synapses that can be rescued by treatment with Sofosbuvir.
The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19), which was rapidly declared a pandemic by the World Health Organization (WHO). Early clinical symptomatology focused mainly on respiratory illnesses. However, a variety of neurological manifestations in both adults and newborns are now well-documented. To experimentally determine whether SARS-CoV-2 could replicate in and affect human brain cells, we infected iPSC-derived human brain organoids. Here, we show that SARS-CoV-2 can productively replicate and promote death of neural cells, including cortical neurons. This phenotype was accompanied by loss of excitatory synapses in neurons. Notably, we found that the U.S. Food and Drug Administration (FDA)-approved antiviral Sofosbuvir was able to inhibit SARS-CoV-2 replication and rescued these neuronal alterations in infected brain organoids. Given the urgent need for readily available antivirals, these results provide a cellular basis supporting repurposed antivirals as a strategic treatment to alleviate neurocytological defects that may underlie COVID-19- related neurological symptoms.
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[Features of the ultrastructure of the brain tissue of Meriones unguiculatus after cerebral ischemia and postischemic recirculation].
The authors studied the ultrastructure of the brain tissue in "symptom negative" clawed jirds (M. unguiculatus) in the presence of permanent and transient circulatory ischemia caused by ligation of the right common carotid artery and by a 3-minute occlusion of the left common carotid artery which was unattended by any clinical manifestations signifying cerebral ischemia. The formation of oedema and dystrophic changes in the right hemisphere differed from that in the left one. Permanent ischemia was associated with the typical picture of hypoxic damage to the neural tissue with the development of cytotoxic oedema. Transient ischemia was predominantly characterized by an impairment of the blood-brain barrier with the development of marked vasogenic oedema. The study made it possible to closely follow the differences in the formation of an early stage of brain damage in permanent and transient ischemia and to establish the possibility of the damaging effect of blood recirculation in the hemisphere previously affected with ischemia.
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Visualization of incrementally learned projection trajectories for longitudinal data.
Longitudinal studies that continuously generate data enable the capture of temporal variations in experimentally observed parameters, facilitating the interpretation of results in a time-aware manner. We propose IL-VIS (incrementally learned visualizer), a new machine learning pipeline that incrementally learns and visualizes a progression trajectory representing the longitudinal changes in longitudinal studies. At each sampling time point in an experiment, IL-VIS generates a snapshot of the longitudinal process on the data observed thus far, a new feature that is beyond the reach of classical static models. We first verify the utility and correctness of IL-VIS using simulated data, for which the true progression trajectories are known. We find that it accurately captures and visualizes the trends and (dis)similarities between high-dimensional progression trajectories. We then apply IL-VIS to longitudinal multi-electrode array data from brain cortical organoids when exposed to different levels of quinolinic acid, a metabolite contributing to many neuroinflammatory diseases including Alzheimer's disease, and its blocking antibody. We uncover valuable insights into the organoids' electrophysiological maturation and response patterns over time under these conditions.
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FLAM-seq: full-length mRNA sequencing reveals principles of poly(A) tail length control.
Although messenger RNAs are key molecules for understanding life, until now, no method has existed to determine the full-length sequence of endogenous mRNAs including their poly(A) tails. Moreover, although non-A nucleotides can be incorporated in poly(A) tails, there also exists no method to accurately sequence them. Here, we present full-length poly(A) and mRNA sequencing (FLAM-seq), a rapid and simple method for high-quality sequencing of entire mRNAs. We report a complementary DNA library preparation method coupled to single-molecule sequencing to perform FLAM-seq. Using human cell lines, brain organoids and Caenorhabditis elegans we show that FLAM-seq delivers high-quality full-length mRNA sequences for thousands of different genes per sample. We find that 3' untranslated region length is correlated with poly(A) tail length, that alternative polyadenylation sites and alternative promoters for the same gene are linked to different tail lengths, and that tails contain a substantial number of cytosines.
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Thalamus-cortex interactions drive cell type-specific cortical development in human pluripotent stem cell-derived assembloids.
The thalamus is pivotal for the development and function of neural circuits in the cerebral cortex. However, how thalamus-cortex interactions influence human cortical development remains unknown primarily because of the inaccessibility of the human embryonic brain. Here, we demonstrate thalamus-dependent gene expression, circuit organization, and neural activity during corticogenesis using human thalamocortical assembloids (hThCAs). Human cortical (hCOs) and thalamic organoids derived from induced pluripotent stem cells exhibited region-specific gene expression and spontaneous neuronal activity. Upon the fusion of these organoids, hThCAs reconstructed reciprocal thalamus-cortex axonal projections and synaptic connections. Transcriptomic analysis revealed thalamus-dependent acceleration of cortical maturation, with upregulation of programs linked to axon development, subplate/cortical plate identity, and activity-regulated genes. Histological analysis showed expanded progenitor pools and increased deep-layer neurons within hThCAs. Wide-field Ca2+ imaging demonstrated that wave-like activity originated in the thalamic region and propagated to the cortical region. Furthermore, two-photon Ca2+ imaging of cortical neurons revealed that synchronous activity emerged exclusively in pyramidal tract neurons and corticothalamic neurons, whereas intratelencephalic neurons remain asynchronous, highlighting cell type-specific circuit integration within hThCAs. These synchronized events were absent in isolated hCOs or in cortico-cortical assembloids, underscoring the specificity of thalamic input. Our findings suggest that diffusible thalamic cues broadly enhance progenitor expansion, while long-range thalamic input organizes cell type-specific synchronous activity. This study demonstrates the thalamus-dependent acquisition of mature cortical phenotypes in a cell type-specific manner in hThCAs, establishing developmental mechanisms linking regional interactions and cell type-specific circuit specification.
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Ciprofloxacin exposure impairs neurogenesis and E/I balance in human cortical organoids.
Ciprofloxacin (CPFX) is a widely used broad-spectrum fluoroquinolone antibiotic. Although its neurotoxic potential in the mature brain has been recognized, its impact on the developing human nervous system remains largely unexplored. Given that the developing brain exhibits heightened vulnerability to environmental and pharmacological insults, we investigated the developmental neurotoxicity of CPFX using human cortical organoids (hCOs) that recapitulate key features of early cortical development. In this study, chronic low-dose CPFX exposure over two weeks induces significant mitochondrial dysfunction, characterized by excessive ROS production and decreased mitochondrial membrane potential (MMP). These mitochondrial impairments were accompanied by alterations in cortical development and disruptions in GABAergic network formation. Mechanistically, CPFX exposure significantly downregulated Forkhead box G1 (FOXG1) expression in hCOs. Molecular docking simulations suggested an interaction of CPFX with the functional domain of FOXG1. Furthermore, FOXG1 knockdown in primary mouse neurons mimicked CPFX-induced mitochondrial hyperactivity and metabolic dysregulation. Microelectrode array analyses revealed aberrant neuronal firing patterns consistent with an epileptiform phenotype. Importantly, aspirin significantly alleviated CPFX-induced mitochondrial dysfunction, restored ATP and ROS levels, and stabilized neuronal electrophysiological activity in primary neurons, underscoring its potential as a therapeutic intervention. Overall, CPFX induces a broad neuropathological phenotype and impair both mitochondrial function and neurogenesis in hCOs, potentially through a mechanism mediated by FOXG1 disruption. These findings offer novel insights into CPFX-induced neurotoxicity and imply FOXG1 as a promising intervention target.
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Brain ultrastructure in Reye's disease. II. Acute injury and recovery processes in three children.
Acute and recovery biopsies of three patients with Reye's Disease are described. Pleomorphic changes of neuronal mitochondria were identified in all of the acute biopsies, similar in appearance to the characteristic alterations of hepatic mitochondria. Distinctive myelin bleb formation may be directly attributable to the mitochondrial injury. The mitochondrial lesion is reversible. There is morphologic evidence for regeneration and repair of myelin; but the presence of myelin ovoids at long intervals after recovery indicates a loss of some myelinated fibers. The neuronal mitochondrial changes, pleomorphism with matrix expansion, and myelin bleb formation, reflect a specific biochemical injury be attributable to ischemic injury secondary to brain edema.
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Cycloleucine-induced vacuolation of myelin is associated with inhibition of protein methylation.
Chickens injected with cycloleucine developed vacuolation of myelin similar to that seen in humans with vitamin B12 deficiency. Cycloleucine, an inhibitor of the formation of S-adenosylmethionine, decreased the incorporation of methyl groups into methylarginine in myelin basic protein in vivo. The need for methylcobalamin for the conversion of homocysteine to methionine and the requirement that myelin basic protein may be methylated, offer a rational explanation for the myelin lesions observed in cases of vitamin B12 deficiency where there is increasing evidence that methyl-, rather than adenosylcobalamin is required to prevent dysmyelination.
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Single-cell epigenomics reveals mechanisms of human cortical development.
During mammalian development, differences in chromatin state coincide with cellular differentiation and reflect changes in the gene regulatory landscape1. In the developing brain, cell fate specification and topographic identity are important for defining cell identity2 and confer selective vulnerabilities to neurodevelopmental disorders3. Here, to identify cell-type-specific chromatin accessibility patterns in the developing human brain, we used a single-cell assay for transposase accessibility by sequencing (scATAC-seq) in primary tissue samples from the human forebrain. We applied unbiased analyses to identify genomic loci that undergo extensive cell-type- and brain-region-specific changes in accessibility during neurogenesis, and an integrative analysis to predict cell-type-specific candidate regulatory elements. We found that cerebral organoids recapitulate most putative cell-type-specific enhancer accessibility patterns but lack many cell-type-specific open chromatin regions that are found in vivo. Systematic comparison of chromatin accessibility across brain regions revealed unexpected diversity among neural progenitor cells in the cerebral cortex and implicated retinoic acid signalling in the specification of neuronal lineage identity in the prefrontal cortex. Together, our results reveal the important contribution of chromatin state to the emerging patterns of cell type diversity and cell fate specification and provide a blueprint for evaluating the fidelity and robustness of cerebral organoids as a model for cortical development.
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Ultrastructural and biochemical studies of the brain and other organs in rats after chronic ethanol administration. I. Electronmicroscopic investigations of the morphologic elements of the blood-brain barrier in the rat after ethanol intoxication.
The aim in view was to establish whether chronic administration of ethanol causes ultrastructura changes in the brain of rats, particularly in the structures through which alcohol penetrates to the brain, that is the cerebral cortex capillaries. The experiments were performed with 5 Wistar rats, three of which received ethanol according to RATCLIFFE'S model for 8 weeks in increasing concentrations from 2.5 to 25 per cent. Two rats served as control. In the endothelium of some capillaries of the brain cortex in the rats ingesting ethanol an enlargement of the cell nuclei was observed. The number of mitochondria in the cytoplasm and of micropinocytic vesicles was found to increase, and proliferation of the smooth endoplasmic reticulum and Golgi system were noted. Considerable oedema was observed in the astrocytic processes surrounding the vessels, with the presence of numerous mitochondria of abnormal shape and huge size. Oedema of perivascular astrocytic processes and enhanced pinocytosis seem to indicate an increased permeability of the blood-brain barrier as the result of the toxic effect of ethanol.