The development of the central nervous system (CNS) relies on precisely orchestrated gene expression regulation. Dysregulation of both genetic and environmental factors can affect proper CNS ...development and results in neurological diseases. Recent studies have shown that similar to protein coding genes, noncoding RNA molecules have a significant impact on normal CNS development and on causes and progression of human neurological disorders. In this review, we have highlighted discoveries of functions of noncoding RNAs, in particular microRNAs and long noncoding RNAs, in neural development and neurological diseases. Emerging evidence has shown that microRNAs play an essential role in many aspects of neural development, such as proliferation of neural stem cells and progenitors, neuronal differentiation, maturation, and synaptogenesis. Misregulation of microRNAs is associated with some mental disorders and neurodegeneration diseases. In addition, long noncoding RNAs are found to play a role in neural development by regulating the expression of protein coding genes. Therefore, examining noncoding RNA-mediated gene regulations has revealed novel mechanisms of neural development and provided new insights into the etiology of human neurological diseases.
Brain tumors are among the most lethal and devastating cancers. Their study is limited by genetic heterogeneity and the incompleteness of available laboratory models. Three-dimensional organoid ...culture models offer innovative possibilities for the modeling of human disease. Here we establish a 3D in vitro model called a neoplastic cerebral organoid (neoCOR), in which we recapitulate brain tumorigenesis by introducing oncogenic mutations in cerebral organoids via transposon- and CRISPR-Cas9-mediated mutagenesis. By screening clinically relevant mutations identified in cancer genome projects, we defined mutation combinations that result in glioblastoma-like and central nervous system primitive neuroectodermal tumor (CNS-PNET)-like neoplasms. We demonstrate that neoCORs are suitable for use in investigations of aspects of tumor biology such as invasiveness, and for evaluation of drug effects in the context of specific DNA aberrations. NeoCORs will provide a valuable complement to the current basic and preclinical models used to study brain tumor biology.
Cerebral organoids recapitulate human brain development at a considerable level of detail, even in the absence of externally added signaling factors. The patterning events driving this ...self‐organization are currently unknown. Here, we examine the developmental and differentiative capacity of cerebral organoids. Focusing on forebrain regions, we demonstrate the presence of a variety of discrete ventral and dorsal regions. Clearing and subsequent 3D reconstruction of entire organoids reveal that many of these regions are interconnected, suggesting that the entire range of dorso‐ventral identities can be generated within continuous neuroepithelia. Consistent with this, we demonstrate the presence of forebrain organizing centers that express secreted growth factors, which may be involved in dorso‐ventral patterning within organoids. Furthermore, we demonstrate the timed generation of neurons with mature morphologies, as well as the subsequent generation of astrocytes and oligodendrocytes. Our work provides the methodology and quality criteria for phenotypic analysis of brain organoids and shows that the spatial and temporal patterning events governing human brain development can be recapitulated in vitro.
Synopsis
Cerebral organoids develop differentiated areas of discrete brain region identities without the addition of exogenous patterning signals.
Cerebral organoids contain structures reminiscent of two forebrain organizing centers, cortical hem, and pallial–subpallial boundary, which may specify organoid regional identities.
Analysis of cerebral organoid 3D structure reveals a high degree of interconnectivity within organoid tissues.
Cerebral organoids generate different neuronal subtypes with mature morphologies in a timed manner.
Cerebral organoids are capable of forming astrocytes and oligodendrocytes.
Cerebral organoids have the intrinsic propensity to develop into differentiated brain tissue with regions of discrete identities in the absence of exogenously added patterning signals.
Human brain organoids cultured from human pluripotent stem cells provide a promising platform for recapitulating histological features of the human brain and for neural disorder modeling. However, ...unlike animal models, brain organoids lack a reproducible topographic organization, which limits their application in modeling the complex biology, such as the interaction between different brain regions. To overcome these drawbacks of current technologies, brain organoids have been pre-patterned into specific brain regions and fused to form an assembloid that represents reproducible models recapitulating more complex biological processes of human brain development and neurological diseases. This approach has been applied to model interneuron migration, neuronal projections, tumor invasion, oligodendrogenesis, forebrain axis establishment, and vascularization of brain organoids. In this review, we will summarize the usage of this technology to understand the fundamental biology undergoing human brain development and disorders.
Proper growth of the mammalian cerebral cortex is crucial for normal brain functions and is controlled by precise gene-expression regulation. Here, we show that microRNA-7 (miR-7) is highly expressed ...in cortical neural progenitors and describe miR-7 sponge transgenic mice in which miR-7-silencing activity is specifically knocked down in the embryonic cortex. Blocking miR-7 function causes microcephaly-like brain defects due to reduced intermediate progenitor (IP) production and apoptosis. Upregulation of miR-7 target genes, including those implicated in the p53 pathway, such as Ak1 and Cdkn1a (p21), is responsible for abnormalities in neural progenitors. Furthermore, ectopic expression of Ak1 or p21 and specific blockade of miR-7 binding sites in target genes using protectors in vivo induce similarly reduced IP production. Using conditional miRNA sponge transgenic approaches, we uncovered an unexpected role for miR-7 in cortical growth through its interactions with genes in the p53 pathway.
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•The miR-7 sponge is sufficient to block silencing activity of three miR-7 precursors•Cortical-specific miR-7 sponge transgenic mice show microcephaly-like brain defects•Expansion and survival of cortical intermediate progenitors require miR-7 function•miR-7 modifies expression levels of genes in the p53 pathway in the embryonic cortex
Proper brain size is crucial for cognitive functions in mice and humans. The molecular mechanisms that regulate cortical growth are not well understood. In this study, Pollock et al. generated conditional microRNA sponge transgenic mice. They show that miR-7 regulates the expansion and survival of intermediate progenitors and cortical size by modifying genes in the p53 pathway. This study identifies a new mechanism that controls cortical growth and is regulated by microRNAs and the p53 pathway.
During development of the embryonic neocortex, tightly regulated expansion of neural stem cells (NSCs) and their transition to intermediate progenitors (IPs) are critical for normal cortical ...formation and function. Molecular mechanisms that regulate NSC expansion and transition remain unclear. Here, we demonstrate that the microRNA (miRNA) miR-17-92 cluster is required for maintaining proper populations of cortical radial glial cells (RGCs) and IPs through repression of Pten and Tbr2 protein. Knockout of miR-17-92 and its paralogs specifically in the developing neocortex restricts NSC proliferation, suppresses RGC expansion, and promotes transition of RGCs to IPs. Moreover, Pten and Tbr2 protectors specifically block silencing activities of endogenous miR-17-92 and control proper numbers of RGCs and IPs in vivo. Our results demonstrate a critical role for miRNAs in promoting NSC proliferation and modulating the cell-fate decision of generating distinct neural progenitors in the developing neocortex.
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•The miR-17-92 cluster is expressed in the cortical ventricular zone•Knockout of miR-17-92 suppresses expansion of cortical neural stem cells•Transition of intermediate progenitors is controlled by miR-17-92•miR-17-92 regulates neural stem cell development by targeting Pten and Tbr2
Proper expansion of neural stem cells (NSCs) and progenitors determines brain size and controls brain functions. Here, Sun and colleagues show that microRNA miR-17-92 promotes NSC proliferation and radial glial cell expansion and suppresses transition of intermediate progenitors in the developing mouse cerebral cortex. miR-17-92 specifies the proper proportion of distinct cortical neural progenitors by targeting Pten and Tbr2. The findings expand known mechanisms of NSC expansion and neural progenitor specification in the developing brain.
Highlights • miRNAs are small noncoding RNAs that normally silence target gene expression. • Many miRNAs have enriched expression in the central nervous system. • miRNAs are required for ...proliferation and differentiation of neural stem cells. • Neuronal subtypes are specified by miRNAs by suppressing specific target genes. • Networks of miRNA-target are critical in cell fate determination of neurons and glia.
Bit rate is one of the important criterions for digital video quality. With some video tools, however, video bit rate can be easily increased without improving the video quality at all. In such a ...case, a claimed high bit rate video would actually have poor visual quality if it is up-converted from an original lower bit rate version. Therefore, exposing fake bit rate videos becomes an important issue for digital video forensics. To the best of our knowledge, although some methods have been proposed for exposing fake bit rate MPEG-2 videos, no relative work has been reported to further estimate their original bit rates. In this paper, we first analyze the statistical artifacts of these fake bit rate videos, including the requantization artifacts based on the first-digit law in the DCT frequency domain (12-D) and the changes of the structural similarity indexes between the query video and its sequential bit rate down-converted versions in the spatial domain (4-D), and then we propose a compact yet very effective 16-D feature vector for exposing fake bit rate videos and further estimating their original bit rates. The extensive experiments evaluated on hundreds of video sequences with four different resolutions and two typical compression schemes (i.e., MPEG-2 and H.264/AVC) have shown the effectiveness of the proposed method compared with the existing relative ones.
Abstract Molecular pathways mediating systemic inflammation entering the brain parenchyma to induce sepsis-associated encephalopathy (SAE) remain elusive. Here, we report that in mice during the ...first 6 hours of peripheral lipopolysaccharide (LPS)-evoked systemic inflammation (6 hpi), the plasma level of adenosine quickly increased and enhanced the tone of central extracellular adenosine which then provoked neuroinflammation by triggering early astrocyte reactivity. Specific ablation of astrocytic Gi protein-coupled A1 adenosine receptors (A1ARs) prevented this early reactivity and reduced the levels of inflammatory factors (e.g., CCL2, CCL5, and CXCL1) in astrocytes, thereby alleviating microglial reaction, ameliorating blood-brain barrier disruption, peripheral immune cell infiltration, neuronal dysfunction, and depression-like behaviour in the mice. Chemogenetic stimulation of Gi signaling in A1AR-deficent astrocytes at 2 and 4 hpi of LPS injection could restore neuroinflammation and depression-like behaviour, highlighting astrocytes rather than microglia as early drivers of neuroinflammation. Our results identify early astrocyte reactivity towards peripheral and central levels of adenosine as an important pathway driving SAE and highlight the potential of targeting A1ARs for therapeutic intervention.
Nowadays, it remains a major challenge to efficiently compress encrypted images. In this paper, we propose a novel encryption-then-compression (ETC) scheme to enhance the performance of lossy ...compression on encrypted gray images through heuristic optimization of bitplane allocation. Specifically, in compressing an encrypted image, we take a bitplane as a basic compression unit and formulate the lossy compression task as an optimization problem that maximizes the peak signal-to-noise ratio (PSNR) subject to a given compression ratio. We then develop a heuristic strategy of bitplane allocation to approximately solve this optimization problem, which leverages the asymmetric characteristics of different bitplanes. In particular, an encrypted image is divided into four sub-images. Among them, one sub-image is reserved, while the most significant bitplanes (MSBs) of the other sub-images are selected successively, and so are the second, third, etc., MSBs until a given compression ratio is met. As there exist clear statistical correlations within a bitplane and between adjacent bitplanes, where bitplane denotes those belonging to the first three MSBs, we further use the low-density parity-check (LDPC) code to compress these bitplanes according to the ETC framework. In reconstructing the original image, we first deploy the joint LDPC decoding, decryption, and Markov random field (MRF) exploitation to recover the chosen bitplanes belonging to the first three MSBs in a lossless way, and then apply content-adaptive interpolation to further obtain missing bitplanes and thus discarded pixels, which is symmetric to the encrypted image compression process. Experimental simulation results show that the proposed scheme achieves desirable visual quality of reconstructed images and remarkably outperforms the state-of-the-art ETC methods, which indicates the feasibility and effectiveness of the proposed scheme.
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