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Abstract Quiescence, a hallmark of adult neural stem cells (NSCs), is required for maintaining the NSC pool to support life-long continuous neurogenesis in the adult dentate gyrus (DG). Whether long-lasting epigenetic modifications maintain NSC quiescence over the long term in the adult DG is not well-understood. Here we show that mice with haploinsufficiency of Setd1a, a schizophrenia risk gene encoding a histone H3K4 methyltransferase, develop an enlarged DG with more dentate granule cells after young adulthood. Deletion of Setd1a specifically in quiescent NSCs in the adult DG promotes their activation and neurogenesis, which is countered by inhibition of the histone demethylase LSD1. Mechanistically, RNA-sequencing and CUT & RUN analyses of cultured quiescent adult NSCs reveal Setd1a deletion-induced transcriptional changes and many Setd1a targets, among which down-regulation of Bhlhe40 promotes quiescent NSC activation in the adult DG in vivo. Together, our study reveals a Setd1a-dependent epigenetic mechanism that sustains NSC quiescence in the adult DG.

IntroductionFor many therapeutic drugs, including antiretroviral drugs used to treat people living with HIV-1 (PLWH), we have little data on the potential effects on the developing human brain due to limited access to tissue and historical constraints on the inclusion of pregnant populations in clinical trials. Human induced pluripotent stem cells (iPSCs) offer a new avenue to gain insight on how drugs may impact human cell types representative of the developing central nervous system. To prevent vertical transmission of HIV and promote the health of pregnant PLWH, antiretroviral therapy must be initiated and/or maintained throughout pregnancy. However, many antiretroviral drugs are approved for widespread use following clinical testing only in non-pregnant populations and there may be limited information on potential teratogenicity until pregnancy outcomes are evaluated. The integrase strand transfer inhibitor dolutegravir (DTG) is a frontline antiretroviral drug that is effective in viral suppression of HIV but was previously reported to be associated with a slight increase in the risk for neural tube defects in one study, although this has not been replicated in other cohorts.MethodsTo directly investigate the potential impact of DTG on human cortical neurogenesis, we measured the effects of daily drug exposure on the early stages of corticogenesis in a human iPSC-based forebrain organoid model. We quantified organoid size and structure and analyzed gene and protein expression to evaluate the impact of several doses of DTG on organoid development.ResultsWe observed deficits in organoid structure and impaired neurogenesis in DTG-treated organoids compared to vehicle-treated control organoids after 20 or 40 days in culture. Our highest dose of DTG (10 μM) resulted in significantly smaller organoids with a reduced density of neural rosette structures compared to vehicle-treated controls. Mechanistically, RNA-sequencing and immunohistological analysis suggests dysregulated amino acid transport and activation of the integrated stress response in the DTG-treated organoids, and functionally, a small molecule integrated stress response inhibitor (ISRIB) could partially rescue increased expression of proteins related to cell cycle regulation.DiscussionTogether, these results illustrate the potential for human iPSC-based strategies to reveal biological processes during neurogenesis that may be affected by therapeutic drugs and provide complementary data in relevant human cell types to augment preclinical investigations of drug safety during pregnancy.

Summary: Quiescent adult neural stem cells (NSCs) in the mammalian brain arise from proliferating NSCs during development. Beyond acquisition of quiescence, an adult NSC hallmark, little is known about the process, milestones, and mechanisms underlying the transition of developmental NSCs to an adult NSC state. Here, we performed targeted single-cell RNA-seq analysis to reveal the molecular cascade underlying NSC development in the early postnatal mouse dentate gyrus. We identified two sequential steps, first a transition to quiescence followed by further maturation, each of which involved distinct changes in metabolic gene expression. Direct metabolic analysis uncovered distinct milestones, including an autophagy burst before NSC quiescence acquisition and cellular reactive oxygen species level elevation along NSC maturation. Functionally, autophagy is important for the NSC transition to quiescence during early postnatal development. Together, our study reveals a multi-step process with defined milestones underlying establishment of the adult NSC pool in the mammalian brain.

Summary: Homoharringtonine (HHT), an alkaloid isolated from Cephalotaxus, is an effective anti-leukemia agent and exhibits inhibitory effects in various solid tumors. However, the impacts of HHT treatment on thyroid cancer (TC) remain unclear. Our findings demonstrated that HHT exhibited remarkable anti-TC activity that involved inhibiting cell proliferation, invasion, and migration, as well as inducing apoptosis. Proteomics analysis revealed that the expression of the tissue inhibitor of metalloproteinase 1 (TIMP1) was downregulated in TC cells after HHT treatment. TIMP1 overexpression promoted TC progression and partially reversed the anti-TC effects of HHT, while TIMP1 downregulation inhibited TC progression and enhanced the anti-TC effects of HHT. Furthermore, TIMP1 re-expression attenuated the enhancement of anti-TC effects of HHT induced by TIMP1 knockdown. Mechanistically, HHT exerted anti-TC effects by downregulating TIMP1 expression and then inactivating the FAK/PI3K/AKT signaling pathway. Taken together, our study demonstrated that HHT could inhibit TC progression by inhibiting the TIMP1/FAK/PI3K/AKT signaling pathway.

Ship detection is a crucial application of synthetic aperture radar (SAR). Most recent studies have relied on convolutional neural networks (CNNs). CNNs tend to struggle in gathering adequate contextual information through local receptive fields and are also susceptible to noise. Inshore scenes in SAR images are plagued by substantial background noise, so achieving high-accuracy ship detection of arbitrary orientations within complex scenes remains an ongoing challenge when relying solely on CNNs. To address the above challenges, this article presents an anchor-free method based on transformers and adaptive features, namely, SAD-Det, which can detect rotationally invariant ship targets with high average precision in SAR images. Specifically, a transformer-based backbone network called the ship spatial pooling pyramid vision transformer is proposed to enhance the long-range dependencies and obtain sufficient contextual information for ships in SAR images. In addition, a neck network called the adaptive feature pyramid network is designed to enhance the ability of ship feature adaptation by adding fusion factors to feature layers in SAR images. Finally, a head network called the deformable head is constructed to make the network more adaptable to the characteristics of ships by adaptively detecting the spatial sampling positions of the targets in SAR images. The effectiveness of the proposed method is verified by experiments on two publicly available datasets, i.e., SAR ship detection dataset and rotated ship detection dataset in SAR images. Compared with other arbitrarily oriented object detection methods, the proposed method achieves state-of-the-art detection performance.

Abstract Organoids are becoming increasingly relevant in biology and medicine for their physiological complexity and accuracy in modeling human disease. To fully assess their biological profile while preserving their spatial information, spatiotemporal imaging tools are warranted. While previously developed imaging techniques, such as four‐dimensional (4D) live imaging and light‐sheet imaging have yielded important clinical insights, these technologies lack the combination of cyclic and multiplexed analysis. To address these challenges, bioorthogonal click chemistry is applied to display the first demonstration of multiplexed cyclic imaging of live and fixed patient‐derived glioblastoma tumor organoids. This technology exploits bioorthogonal click chemistry to quench fluorescent signals from the surface and intracellular of labeled cells across multiple cycles, allowing for more accurate and efficient molecular profiling of their complex phenotypes. Herein, the versatility of this technology is demonstrated for the screening of glioblastoma markers in patient‐derived human glioblastoma organoids while conserving their viability. It is anticipated that the findings and applications of this work can be broadly translated into investigating physiological developments in other organoid systems.

Abstract Background Oxidation Resistance 1 (OXR1) gene is a highly conserved gene of the TLDc domain-containing family. OXR1 is involved in fundamental biological and cellular processes, including DNA damage response, antioxidant pathways, cell cycle, neuronal protection, and arginine methylation. In 2019, five patients from three families carrying four biallelic loss-of-function variants in OXR1 were reported to be associated with cerebellar atrophy. However, the impact of OXR1 on cellular functions and molecular mechanisms in the human brain is largely unknown. Notably, no human disease models are available to explore the pathological impact of OXR1 deficiency. Results We report a novel loss-of-function mutation in the TLDc domain of the human OXR1 gene, resulting in early-onset epilepsy, developmental delay, cognitive disabilities, and cerebellar atrophy. Patient lymphoblasts show impaired cell survival, proliferation, and hypersensitivity to oxidative stress. These phenotypes are rescued by TLDc domain replacement. We generate patient-derived induced pluripotent stem cells (iPSCs) revealing impaired neural differentiation along with dysregulation of genes essential for neurodevelopment. We identify that OXR1 influences histone arginine methylation by activating protein arginine methyltransferases (PRMTs), suggesting OXR1-dependent mechanisms regulating gene expression during neurodevelopment. We model the function of OXR1 in early human brain development using patient-derived brain organoids revealing that OXR1 contributes to the spatial–temporal regulation of histone arginine methylation in specific brain regions. Conclusions This study provides new insights into pathological features and molecular underpinnings associated with OXR1 deficiency in patients.

The integrated assessment of ecological quality in estuarine ecosystems holds significant importance for environmental management. Previous monitoring programs predominantly focused on environmental data, lacking a comprehensive quality assessment approach. To address this gap, this study aimed to integrate environmental factors with macrofaunal community information to evaluate the ecological quality status of the Yellow River Estuary. A total of 13 stations were routinely monitored in August for four consecutive years to collect environmental and biological data. Candidate indicators were screened based on variation coefficients, distribution ranges, and redundancy analysis, identifying 16 indicators belonging to three categories (i.e., seawater, sediment, and biology). The model fit and the interrelationship of the components were determined using structural equation modelling (SEM). The main results were as follows. (1) A total of 144 macrofaunal taxa, belonging to eight animal phyla and 98 families, were identified, with a dominance of Annelida (37.8%) and Mollusca (33.3%). The environmental variables most strongly correlated with the macrofaunal community were TOC, DO, Cd, and Md. (2) NO2 and heavy metals represented the two most direct factors of environmental pollution, while the factor load of biodiversity indices (H’, J, and D) was large in the biology category. (3) The evaluation results indicated that 78.85% of the total samples were between the average and upper levels of ecological quality, but only 7.69% of samples were at the “high” level. The framework system for the evaluation of ecological quality constructed in this study provides a theoretical and practical basis for the evaluation of the effectiveness of conservation management of the Yellow River Estuary.

Abstract Genetic variants in chromatin regulators are frequently found in neurodevelopmental disorders, but their effect in disease etiology is rarely determined. Here, we uncover and functionally define pathogenic variants in the chromatin modifier EZH1 as the cause of dominant and recessive neurodevelopmental disorders in 19 individuals. EZH1 encodes one of the two alternative histone H3 lysine 27 methyltransferases of the PRC2 complex. Unlike the other PRC2 subunits, which are involved in cancers and developmental syndromes, the implication of EZH1 in human development and disease is largely unknown. Using cellular and biochemical studies, we demonstrate that recessive variants impair EZH1 expression causing loss of function effects, while dominant variants are missense mutations that affect evolutionarily conserved aminoacids, likely impacting EZH1 structure or function. Accordingly, we found increased methyltransferase activity leading to gain of function of two EZH1 missense variants. Furthermore, we show that EZH1 is necessary and sufficient for differentiation of neural progenitor cells in the developing chick embryo neural tube. Finally, using human pluripotent stem cell-derived neural cultures and forebrain organoids, we demonstrate that EZH1 variants perturb cortical neuron differentiation. Overall, our work reveals a critical role of EZH1 in neurogenesis regulation and provides molecular diagnosis for previously undefined neurodevelopmental disorders.

Purpose: To determine whether thyroid-stimulating hormone level ≥ 30 mU/L is necessary for radioiodine (131I) remnant ablation (RRA) in patients with differentiated thyroid cancer (DTC), as well as its influencing factors and pre dictors. Methods: A total of 487 DTC patients were retrospectively enrolled in t his study. They were divided into two groups (TSH < 30 and ≥ 30 mU/L) and further divided into eight subgroups (0–

The Yellow River Estuary and its adjacent waters serve as crucial spawning, foraging, and nursery areas for marine organisms, possessing abundant biological resources. Monitoring fish communities provides a baseline for implementing the sustainable utilization of marine resources. In this study, data were collected from 15 spring surface and bottom sites and 17 summer surface sites using eDNA and trawl surveys. The results showed that 37, 40, and 35 fish species were detected using eDNA in the spring (surface and bottom) and summer (surface), respectively, with 38 fish species caught during summer trawling. The dominant species mainly belonged to Engraulidae of Clupeiformes in the spring and Gobiidae of Perciformes in the summer, characterized by smaller-sized, short-lived, and pelagic fish species. The summer surface communities exhibited higher diversity than the spring surface and bottom communities. NMDS analysis revealed a degree of seasonal differences in fish communities and that there may be a lack of vertical stratification in the spring communities. The pH and DO were identified as the key environmental factors affecting the fish community. Additionally, the combination of eDNA and trawl surveys was regarded as a superior survey method. Our study provides valuable information for understanding seasonal fish communities in the Yellow River Estuary and its adjacent waters, contributing to fishery resource management and conservation in the region.

Increasing evidence reinforces the essential function of RNA modifications in development and diseases, especially in the nervous system. RNA modifications impact various processes in the brain, including neurodevelopment, neurogenesis, neuroplasticity, learning and memory, neural regeneration, neurodegeneration, and brain tumorigenesis, leading to the emergence of a new field termed neuroepitranscriptomics. Deficiency in machineries modulating RNA modifications has been implicated in a range of brain disorders from microcephaly, intellectual disability, seizures, and psychiatric disorders to brain cancers such as glioblastoma. The inaugural NSAS Challenge Workshop on Brain Epitranscriptomics hosted in Crans-Montana, Switzerland in 2023 assembled a group of experts from the field, to discuss the current state of the field and provide novel translational perspectives. A summary of the discussions at the workshop is presented here to simulate broader engagement from the general neuroscience field.

Dopamine system dysfunction is implicated in adolescent-onset neuropsychiatric disorders. Although psychosis symptoms can be alleviated by antipsychotics, cognitive symptoms remain unresponsive and novel paradigms investigating the circuit substrates underlying cognitive deficits are critically needed. The frontal cortex and its dopaminergic input from the midbrain are implicated in cognitive functions and undergo maturational changes during adolescence. Here, we used mice carrying mutations in Arc or Disc1 to model mesofrontal dopamine circuit deficiencies and test circuit-based neurostimulation strategies to restore cognitive functions. We found that in a memory-guided spatial navigation task, frontal cortical neurons were activated coordinately at the decision-making point in wild-type but not Arc-/- mice. Chemogenetic stimulation of midbrain dopamine neurons or optogenetic stimulation of frontal cortical dopamine axons in a limited adolescent period consistently reversed genetic defects in mesofrontal innervation, task-coordinated neuronal activity, and memory-guided decision-making at adulthood. Furthermore, adolescent stimulation of dopamine neurons also reversed the same cognitive deficits in Disc1+/- mice. Our findings reveal common mesofrontal circuit alterations underlying the cognitive deficits caused by two different genes and demonstrate the feasibility of adolescent neurostimulation to reverse these circuit and behavioral deficits. These results may suggest developmental windows and circuit targets for treating cognitive deficits in neurodevelopmental disorders.

Summary: Human stem-cell-derived organoids represent a promising substrate for transplantation-based neural repair. Here, we describe a protocol for transplanting forebrain organoids into an injured adult rat visual cortex. This protocol includes surgical details for craniectomy, aspiration injury, organoid transplantation, and cranioplasty. This platform represents a valuable tool for investigating the efficacy of organoids as structured grafts for neural repair.For complete details on the use and execution of this protocol, please refer to Jgamadze et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Bulk or pooled epigenomic profiling in the heterogenous brain obscures cell-type-specificity and individual subject variability in gene regulation. Here the authors optimized a hybrid protocol, ICuRuS, to profile epigenetic features in neuronal subtypes from a single mouse.

Antigen heterogeneity that results in tumor antigenic escape is one of the major obstacles to successful chimeric antigen receptor (CAR) T cell therapies in solid tumors including glioblastoma multiforme (GBM). To address this issue and improve the efficacy of CAR T cell therapy for GBM, we developed an approach that combines CAR T cells with inhibitor of apoptosis protein (IAP) antagonists, a new class of small molecules that mediate the degradation of IAPs, to treat GBM. Here, we demonstrated that the IAP antagonist birinapant could sensitize GBM cell lines and patient-derived primary GBM organoids to apoptosis induced by CAR T cell-derived cytokines, such as tumor necrosis factor. Therefore, birinapant could enhance CAR T cell-mediated bystander death of antigen-negative GBM cells, thus preventing tumor antigenic escape in antigen-heterogeneous tumor models in vitro and in vivo. In addition, birinapant could promote the activation of NF-κB signaling pathways in antigen-stimulated CAR T cells, and with a birinapant-resistant tumor model we showed that birinapant had no deleterious effect on CAR T cell functions in vitro and in vivo. Overall, we demonstrated the potential of combining the IAP antagonist birinapant with CAR T cells as a novel and feasible approach to overcoming tumor antigen heterogeneity and enhancing CAR T cell therapy for GBM.

Lightweight ship detection is an important application of synthetic aperture radar (SAR). The prevailing trend in recent research involves employing a detection framework based on convolutional neural networks (CNNs) and horizontal bounding boxes (HBBs). However, CNNs with local receptive fields fall short in acquiring adequate contextual information and exhibit sensitivity to noise. Moreover, HBBs introduce significant interference from both the background and adjacent ships. To overcome these limitations, this paper proposes a lightweight transformer-based method for detecting arbitrarily oriented ships in SAR images, called LD-Det, which excels at promptly and accurately identifying rotating ship targets. First, light pyramid vision transformer (LightPVT) is introduced as a lightweight backbone network. Built upon PVT v2-B0-Li, it effectively captures the long-range dependencies of ships in SAR images. Subsequently, multi-scale deformable feature pyramid network (MDFPN) is constructed as a neck network, utilizing the multi-scale deformable convolution (MDC) module to adjust receptive field regions and extract ship features from SAR images more effectively. Lastly, shared deformable head (SDHead) is proposed as a head network, enhancing ship feature extraction with the combination of deformable convolution operations and a shared parameter structure design. Experimental evaluations on two publicly available datasets validate the efficacy of the proposed method. Notably, the proposed method achieves state-of-the-art detection performance when compared with other lightweight methods in detecting rotated targets.

In order to promote the development of the carbon sink fisheries and the construction of national parks in Changdao, this paper calculated the carbon sink data of marine bivalves and seaweeds in Changdao for the first time, comprehensively evaluated the carbon sink capacity of mariculture in Changdao and its influencing factors, and put forward countermeasures and suggestions. The results showed that mariculture in Changdao had a certain carbon sink capacity. The average carbon sink of shellfish cultured in Changdao from 2016 to 2020 was 29 400 tons, and the carbon sink of shellfish, especially scallop, was significantly higher than that of algae; the structure and yield of mariculture were the main factors affecting the carbon sink capacity of Changdao mariculture, and the yield of mariculture was also affected by the scale, environment and technology. In the future, the development of carbon sink fisheries in Changdao should further optimize mariculture structure, establish mariculture carbon sink accounting system, and formulate and implement related policies.

To promote the harmonious and sustainable development of mariculture and marine ecological environmental protection in China, this paper selected Chinese and English literature data from authoritative databases, composed and analyzed the research progress of aquaculture in marine protected areas based on CiteSpace software, and discussed it according to the actual situation. The results showed that the number of papers on aquaculture in marine protected areas was relatively small but showed a gradual increase, and recently the number of papers in English literature had exceeded that in Chinese literature. The high-frequency keywords in both Chinese and English literature included biodiversity, with the English literature focusing on climate change and biological community structure, and the Chinese literature focusing on landscape pattern and environmental pollution. Both Chinese and English literature paid high attention to the spatial distribution pattern of aquaculture in marine protected areas and its impact on endangered protected species. The English literature had begun to focus on the positive impact of aquaculture on the functional diversity of the ecological environment, while the Chinese literature was still mainly concerned with the negative impact. Aquaculture had both positive and negative impacts on the ecological environment of marine protected areas. Further scientific research should be conducted, along with the implementation of marine protected areas zoning management, development of green cultivation, and strengthening of top-level design.

Summary: Hippocampal place cells exhibit spatially modulated firing, or place fields, which can remap to encode changes in the environment or other variables. Unique among hippocampal subregions, the dentate gyrus (DG) has two excitatory populations of place cells, granule cells and mossy cells, which are among the least and most active spatially modulated cells in the hippocampus, respectively. Previous studies of remapping in the DG have drawn different conclusions about whether granule cells exhibit global remapping and contribute to the encoding of context specificity. By recording granule cells and mossy cells as mice foraged in different environments, we found that by most measures, both granule cells and mossy cells remapped robustly but through different mechanisms that are consistent with firing properties of each cell type. Our results resolve the ambiguity surrounding remapping in the DG and suggest that most spatially modulated granule cells contribute to orthogonal representations of distinct spatial contexts.

Neural transplantation represents a promising approach to repairing damaged brain circuitry. Cellular grafts have been shown to promote functional recovery through “bystander effects” and other indirect mechanisms. However, extensive brain lesions may require direct neuronal replacement to achieve meaningful restoration of function. While fetal cortical grafts have been shown to integrate with the host brain and appear to develop appropriate functional attributes, the significant ethical concerns and limited availability of this tissue severely hamper clinical translation. Induced pluripotent stem cell-derived cells and tissues represent a more readily scalable alternative. Significant progress has recently been made in developing protocols for generating a wide range of neural cell types in vitro. Here, we discuss recent progress in neural transplantation approaches for two conditions with distinct design needs: Parkinson’s disease and cortical injury. We discuss the current status and future application of injections of dopaminergic cells for the treatment of Parkinson’s disease as well as the use of structured grafts such as brain organoids for cortical repair.

Previous work has shown in iPSC derived neurons that synaptic impairments are associated with a 4bp DISC1 deletion. Here the authors demonstrate a role for the PDE4 signalling pathway in these synaptic impairments.

Identifying readers of epigenetic marks is a critical step for understanding the role of epigenetic marks in biology. Here, the authors applied DAPPL, an all-to-all approach to profile the interactions between TFs and epigenetic modified DNA libraries.

Hippocampal neurogenesis has typically been studied during embryonic development or in adulthood, promoting the perception of two distinct phenomena. We propose a perspective that hippocampal neurogenesis in the mammalian brain is one continuous, lifelong developmental process. We summarize the common features of hippocampal neurogenesis that are maintained across the lifespan, as well as dynamic age-dependent properties. We highlight that while the progression of hippocampal neurogenesis across the lifespan is conserved between mammalian species, the timing of this progression is species-dependent. Finally, we discuss some current challenges in the hippocampus neurogenesis field, and future research directions to address them, such as time course analysis across the lifespan, mechanisms regulating neurogenesis progression, and interspecies comparisons. We hope that this new perspective of hippocampal neurogenesis will prompt fresh insight into previous research and inspire new directions to advance the field to identify biologically significant ways to harness the endogenous capacity for neurogenesis in the hippocampus.

Human neurogenesis occurs mainly in embryonic, fetal, and neonatal stages and generates tremendously diverse neural cell types that constitute the human nervous system. Studies on human neurogenesis have been limited due to a lack of access to human embryonic and fetal tissues. Brain organoids derived from human pluripotent stem cells not only recapitulate major developmental processes during neurogenesis, but also exhibit human-specific features, thus providing an unprecedented opportunity to study human neurodevelopment. First, three-dimensional brain organoids resemble early human neurogenesis with diverse stem cell pools, including the presence of primate-enriched outer radial glia cells. Second, brain organoids recapitulate human neurogenesis at the cellular level, generating diverse neuronal cell types and forming stratified cortical layers. Third, brain organoids also capture gliogenesis with the presence of human-specific astrocytes. Fourth, combined with genome-editing technologies, brain organoids are promising models for investigating functions of human-specific genes at different stages of human neurogenesis. Finally, human organoids derived from patient iPSCs can recapitulate specific disease phenotypes, providing unique models for studying developmental brain disorders of genetic and environmental causes, and for mechanistic studies and drug screening. The aim of this review is to illustrate why brain organoids are good models to study various steps of human neurogenesis, with a focus on corticogenesis. We also discuss limitations of current brain organoid models and future improvements.

The regulation of gene expression underlies many forms of learning and behaviour in the mammalian brain. Carpenter et al. define a molecular mechanism whereby Nr4a1 activation leads to persistent changes in gene expression, chromatin and behaviour, in the context of cocaine abstinence.

Tumor heterogeneity is a key reason for therapeutic failure and tumor recurrence in glioblastoma (GBM). Our chimeric antigen receptor (CAR) T cell (2173 CAR T cells) clinical trial (NCT02209376) against epidermal growth factor receptor (EGFR) variant III (EGFRvIII) demonstrated successful trafficking of T cells across the blood–brain barrier into GBM active tumor sites. However, CAR T cell infiltration was associated only with a selective loss of EGFRvIII+ tumor, demonstrating little to no effect on EGFRvIII- tumor cells. Post-CAR T-treated tumor specimens showed continued presence of EGFR amplification and oncogenic EGFR extracellular domain (ECD) missense mutations, despite loss of EGFRvIII. To address tumor escape, we generated an EGFR-specific CAR by fusing monoclonal antibody (mAb) 806 to a 4-1BB co-stimulatory domain. The resulting construct was compared to 2173 CAR T cells in GBM, using in vitro and in vivo models. 806 CAR T cells specifically lysed tumor cells and secreted cytokines in response to amplified EGFR, EGFRvIII, and EGFR-ECD mutations in U87MG cells, GBM neurosphere-derived cell lines, and patient-derived GBM organoids. 806 CAR T cells did not lyse fetal brain astrocytes or primary keratinocytes to a significant degree. They also exhibited superior antitumor activity in vivo when compared to 2173 CAR T cells. The broad specificity of 806 CAR T cells to EGFR alterations gives us the potential to target multiple clones within a tumor and reduce opportunities for tumor escape via antigen loss.

Radioiodine remnant ablation (RRA) was previously demonstrated to be a safe and effective alternative to completion thyroidectomy for patients with differentiated thyroid cancer (DTC). However, its side effects have not been fully investigated, particularly in patients with lobectomy. We reported a young euthyroidal female who underwent RRA post lobectomy and lymph node dissection for papillary thyroid cancer, whose post-ablation 131I-whole-body scan accidentally showed diffuse radioiodine distribution on chest-mimicking pulmonary metastases. Immediately-added single-photon emission computed tomography/computed tomography (SPECT/CT), nevertheless, revealed a 131I-accumulating swollen left thyroid lobe and emerging pleural effusion, which relieved after short-term treatment with prednisone. In summary, acute pleural effusion ascribed to RRA-induced thoracic duct compression was reported for the first time. 131I-lobectomy-induced pleural effusion could be precisely diagnosed by SPECT/CT and efficiently manipulated via treating radiation thyroiditis with the short-term administration of corticosteroid.

The 2015 to 2016 outbreak of Zika virus (ZIKV) infections in the Americas coincided with a dramatic increase in neurodevelopmental abnormalities, including fetal microcephaly, in newborns born to infected women. In this study, we observed mitochondrial fragmentation and disrupted mitochondrial membrane potential after 24 h of ZIKV infection in human neural stem cells and the SNB-19 glioblastoma cell line. The severity of these changes correlated with the amount of ZIKV proteins expressed in infected cells. ZIKV infection also decreased the levels of mitofusin 2, which modulates mitochondria fusion. Mitochondrial division inhibitor 1 (Mdivi-1), a small molecule inhibiting mitochondria fission, ameliorated mitochondria disruptions and reduced cell death in ZIKV-infected cells. Collectively, this study suggests that abnormal mitochondrial fragmentation contributes to ZIKV-induced neuronal cell death; rebalancing mitochondrial dynamics of fission-fusion could be a therapeutic strategy for drug development to treat ZIKV-mediated neuronal apoptosis.

The blossoming field of epitranscriptomics has recently garnered attention across many fields by findings that chemical modifications on RNA have immense biological consequences. Methylation of nucleotides in RNA, including N6-methyladenosine (m6A), 2-O-dimethyladenosine (m6Am), N1-methyladenosine (m1A), 5-methylcytosine (m5C), and isomerization of uracil to pseudouridine (Ψ), have the potential to alter RNA processing events and contribute to developmental processes and different diseases. Though the abundance and roles of some RNA modifications remain contentious, the epitranscriptome is thought to be especially relevant in stem cell biology and neurobiology. In particular, m6A occurs at the highest levels in the brain and plays major roles in embryonic stem cell differentiation, brain development, and neurodevelopmental disorders. However, studies in these areas have reported conflicting results on epitranscriptomic regulation of stem cell pluripotency and mechanisms in neural development. In this review we provide an overview of the current understanding of several RNA modifications and disentangle the various findings on epitranscriptomic regulation of stem cell biology and neural development.

Summary: Although congenital infection by human cytomegalovirus (HCMV) is well recognized as a leading cause of neurodevelopmental defects, HCMV neuropathogenesis remains poorly understood. A major challenge for investigating HCMV-induced abnormal brain development is the strict CMV species specificity, which prevents the use of animal models to directly study brain defects caused by HCMV. We show that infection of human-induced pluripotent-stem-cell-derived brain organoids by a “clinical-like” HCMV strain results in reduced brain organoid growth, impaired formation of cortical layers, and abnormal calcium signaling and neural network activity. Moreover, we show that the impeded brain organoid development caused by HCMV can be prevented by neutralizing antibodies (NAbs) that recognize the HCMV pentamer complex. These results demonstrate in a three-dimensional cellular biosystem that HCMV can impair the development and function of the human brain and provide insights into the potential capacity of NAbs to mitigate brain defects resulted from HCMV infection.

As an active microwave remote sensing device, synthetic aperture radar (SAR) has been widely used in the field of marine surveillance. However, moving ships appear defocused in SAR images, which seriously affects the classification and identification of ships. Considering the three-dimensional (3-D) rotational motions (roll, pitch, and yaw) of the navigating ship, a novel method for refocusing moving ships in SAR images based on inverse synthetic aperture radar (ISAR) technique is proposed. First, a rectangular window is used to extract the defocused ship subimage. Next, the subimage is transformed into the ISAR equivalent echo domain, and the range migration and phase error caused by the identical movement of all ship scatterers are compensated. Then, the optimal imaging time can be selected by the maximum image contrast search method. Finally, the iterative adaptive approach (IAA) is used to obtain the image with high resolution. This method has satisfactory imaging performance in both azimuth resolution and image focus, and the amount of calculation is small due to the processing of subimages. Simulated data and Gaofen-3 real SAR data are used to verify the effectiveness of the proposed method.

Editorial summary Breakthroughs on many fronts have provided strong evidence to support synaptic dysfunction as a causal factor for neuropsychiatric diseases. Genetic studies have identified variants implicated in novel biological and synaptic pathways, and animal and patient-derived induced pluripotent stem cell-based models have allowed mechanistic investigations of synaptic dysfunction in pathological processes.

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and carries a dismal prognosis. The EGFR gene is among the most commonly deranged genes in GBM and thus an important therapeutic target. We report the case of a young female with heavily pretreated EGFR-mutated GBM, for whom we initiated osimertinib, an oral, third-generation tyrosine kinase inhibitor that irreversibly inhibits EGFR and has significant brain penetration. We then review some of the main challenges in targeting EGFR, including lack of central nervous system penetration with most tyrosine kinase inhibitors, molecular heterogeneity of GBM and the need for enhanced specificity for the EGFR mutations relevant in GBM.

https://doi.org/10.1038/s41467-021-23263-0

Road network is an important part of modern transportation. For the demands of accurate road information in practical applications such as urban planning and disaster assessment, we propose a multiscale method to extract road network from high-resolution synthetic aperture radar (SAR) images, which consists of three stages: potential road area segmentation, preliminary network generation, and road network refinement. Multiscale analysis is implemented using an image pyramid framework together with a fixed-size filter. First, a directional road detector is designed to highlight road targets in feature response maps. Subsequently, adaptive fusion is performed independently at each image scale, followed by a threshold method to produce potential road maps. Then, binary maps are decomposed according to the obtained direction information. For each connected component (CC), quality evaluation is conducted to further distinguish road segments and polynomial curve fitting is adopted as a thinning method. Multiscale information fusion is realized through the weighted sum of road curves. Finally, tensor voting and spatial regularization are employed to generate the final road network. Experiments on three TerraSAR images demonstrate the effectiveness of the proposed algorithm to extract road network completely and correctly.

ABSTRACT IMPACT: This study will provide the essential characterization of intrinsic neural activity in human brain organoids, both at the single cell and network levels, to harness for translational purposes. OBJECTIVES/GOALS: Brain organoids are 3D, stem cell-derived neural tissues that recapitulate neurodevelopment. However, to levy their full translational potential, a deeper understanding of their intrinsic neural activity is essential. Here, we present our preliminary analysis of maturing neural activity in human forebrain organoids. METHODS/STUDY POPULATION: Forebrain organoids were generated from human iPSC lines derived from healthy volunteers. Linear microelectrode probes were employed to record spontaneous electrical activity from day 77, 100, and 130 organoids. Single unit recordings were collected during hour-long recordings, involving baseline recordings followed by glutamatergic blockade. Subsequently, tetrodotoxin, was used to abolish action potential firing. Single units were identified via spike sorting, and the spatiotemporal evolution of baseline neural properties and network dynamics was characterized. RESULTS/ANTICIPATED RESULTS: Nine organoids were recorded successfully (n=3 per timepoint). A significant difference in number of units was seen across age groups (F (2,6) = 6.4178, p = 0.0323). Post hoc comparisons by the Tukey HSD test showed significantly more units in day 130 (51.67 ±14.15) than day 77 (16.33 ±14.98) organoids. Mean firing rates were significantly different in organoids based on age, with drug condition also trending toward significance (F (6,12) = 9.97; p = 0.0028 and p = 0.08 respectively). Post hoc comparisons showed a higher baseline firing rate in day 130 (0.99Hz ±0.30) organoids than their day 77 counterparts at baseline (0.31Hz ±0.066) and glutamate blockade (0.31Hz ±0.045). Preliminary network analysis showed no modularity or small-world features; however, these features are expected to emerge as organoids mature. DISCUSSION/SIGNIFICANCE OF FINDINGS: Initial analysis of brain organoid activity demonstrates changes in single unit properties as they mature. Additional work in this area, as well as further network analyses, will confer better sense of how to rationally utilize brain organoids for translational purposes.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-21726-y

Target detection on the sea-surface has always been a high-profile problem, and the detection of weak targets is one of the most difficult problems and the key issue under this problem. Traditional techniques, such as imaging, cannot effectively detect these types of targets, so researchers choose to start by mining the characteristics of the received echoes and other aspects for target detection. This paper proposes a false alarm rate (FAR) controllable deep forest model based on six-dimensional feature space for efficient and accurate detection of weak targets on the sea-surface. This is the first attempt at the deep forest model in this field. The validity of the model was verified on IPIX data, and the detection probability was compared with other proposed methods. Under the same FAR condition, the average detection accuracy rate of the proposed method could reach over 99.19%, which is 9.96% better than the results of the current most advanced method (K-NN FAR-controlled Detector). Experimental results show that multi-feature fusion and the use of a suitable detection framework have a positive effect on the detection of weak targets on the sea-surface.

The in vivo function of CRMP2 is unclear. Zhang et al. generate and characterize brain-specific Crmp2knockout mice. These mice show impairments in hippocampal neurogenesis, neuronal maturation and synaptic transmission, and exhibit schizophrenia-related behavioral deficits.

Dysregulation of microRNAs has been implicated in neurodevelopmental disorders, including schizophrenia. Here the authors show that the TLX-miR-219 cascade regulates the proliferation of neural stem cells during normal development, and this pathway is dysregulated in a schizophrenia iPSC model.

As a group, we met to discuss the current challenges for creating meaningful patient-specific in vitro models to study brain disorders. Although the convergence of findings between laboratories and patient cohorts provided us confidence and optimism that hiPSC-based platforms will inform future drug discovery efforts, a number of critical technical challenges remain. This opinion piece outlines our collective views on the current state of hiPSC-based disease modeling and discusses what we see to be the critical objectives that must be addressed collectively as a field.

Neocortical development has been extensively studied and therefore is the basis of our understanding of mammalian brain development. One fundamental principle of neocortical development is that neurogenesis and gliogenesis are temporally segregated processes. However, it is unclear how neurogenesis and gliogenesis are coordinated in non-neocortical regions of the cerebral cortex, such as the hippocampus, also known as the archicortex. Here, we show that the timing of neurogenesis and astrogenesis in the Cornu Ammonis (CA) 1 and CA3 regions of mouse hippocampus mirrors that of the neocortex; neurogenesis occurs embryonically, followed by astrogenesis during early postnatal development. In contrast, we find that neurogenesis in the dentate gyrus begins embryonically but is a protracted process which peaks neonatally and continues at low levels postnatally. As a result, astrogenesis, which occurs during early postnatal development, overlaps with the process of neurogenesis in the dentate gyrus. During all stages, neurogenesis overwhelms astrogenesis in the dentate gyrus. In addition, we find that the timing of peak astrogenesis varies by hippocampal subregion. Together, our results show differential timing and coordination of neurogenesis and astrogenesis in developing mouse hippocampal subregions and suggest that neurogenesis and gliogenesis occur simultaneously during dentate gyrus development, challenging the conventional principle that neurogenesis and gliogenesis are temporally separated processes.

Synthetic aperture radar (SAR) has become one of the most important means of information acquisition in today’s society and shows great potential in many fields. Target identification and classification of SAR images are also the focus of research. With the vigorous development of deep learning, many researchers apply this method to SAR target classification to obtain a more automatic process and more accurate results. In this paper, a novel deep forest model constructed by multi-grained cascade forest (gcForest), which is different from the traditional neural network (NN) model, is employed to classify ten types of SAR targets in the moving and stationary target acquisition and recognition (MSTAR) dataset. Considering that the targets of input images may be off-center and of different sizes in practical applications, two improved models based on varying weights by image features have been put forward, and both obtain better results. A series of experiments have been conducted to optimize model parameters, and final results with the MSTAR dataset illustrate that the two improved models are both superior to the original gcForest model. This is the first attempt to classify SAR targets using the non-NN model.

Weighting window functions are commonly used in Synthetic Aperture Radar (SAR) imaging to suppress the high Peak SideLobe Ratio (PSLR) at the price of probable Signal-to-Noise Ratio (SNR) loss and mainlobe widening. In this paper, based on the method of designing a mismatched filter, we have proposed a Quadratically Constrained Quadratic Program (QCQP) approach, which is a convex that can be solved efficiently, to optimize the weighting window function with both amplitude and phase, expecting to offer better imaging performance, especially on PSLR, SNR loss, and mainlobe width. According to this approach and its modified form, we are able to design window functions to optimize the PSLR or the SNR loss under different kinds of flexible and practical constraints. Compared to the ordinary real-valued and symmetric window functions, like the Taylor window, the designed window functions are complex-valued and can be asymmetric. By using Synthetic Aperture Radar (SAR) point target imaging simulation, we show that the optimized weighting window function can clearly show the weak target hidden in the sidelobes of the strong target.

The thalamus, a crucial regulator of cortical functions, is composed of many nuclei arranged in a spatially complex pattern. Thalamic neurogenesis occurs over a short period during mammalian embryonic development. These features have hampered the effort to understand how regionalization, cell divisions, and fate specification are coordinated and produce a wide array of nuclei that exhibit distinct patterns of gene expression and functions. Here, we performed in vivo clonal analysis to track the divisions of individual progenitor cells and spatial allocation of their progeny in the developing mouse thalamus. Quantitative analysis of clone compositions revealed evidence for sequential generation of distinct sets of thalamic nuclei based on the location of the founder progenitor cells. Furthermore, we identified intermediate progenitor cells that produced neurons populating more than one thalamic nuclei, indicating a prolonged specification of nuclear fate. Our study reveals an organizational principle that governs the spatial and temporal progression of cell divisions and fate specification and provides a framework for studying cellular heterogeneity and connectivity in the mammalian thalamus.

Adult neurogenesis occurs in the dentate gyrus in the mammalian hippocampus. These new neurons arise from neural precursor cells named radial glia-like cells, which are situated in the subgranular zone of the dentate gyrus. Here, we review the emerging topic of precursor heterogeneity in the adult subgranular zone. We also discuss how this heterogeneity may be established during development and focus on the embryonic origin of the dentate gyrus and radial glia-like stem cells. Finally, we discuss recently developed single-cell techniques, which we believe will be critical to comprehensively investigate adult neural stem cell origin and heterogeneity.