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Target localization intervention and prognosis evaluation for an individual with mild cognitive impairment 轻度认知障碍患者的靶向定位干预和预后评估
Pub Date : 2023-08-22 DOI: 10.1002/brx2.25
Weiping Wang, Haiyan Zhao, Chang He, Yuanbo Cui, Zhen Wang, Alexander Hramov, Ping Luan, Xiong Luo, Jipeng Ouyang, Kurths Jürgen

Currently, no specific treatments are available for Alzheimer's disease (AD). Mild cognitive impairment (MCI), the preclinical stage of AD, has a high possibility of reversing symptoms through neural regulation. A state dynamics model for single brain regions was developed to simulate blood oxygen level-dependent signals in a patient with early mild cognitive impairment. Subsequently, the analysis of functional connections was used to comprehensively consider multiple complex network centralities to locate the intervention targets, and a multiple brain region collaborative control scheme was designed. Finally, the reliability and effectiveness of the intervention were verified at the brain region and subnetwork levels. This technique provides a basis for future clinical diagnosis and treatment of AD and MCI.

目前,还没有针对阿尔茨海默病(AD)的特定治疗方法。轻度认知障碍(MCI)是AD的临床前阶段,通过神经调节逆转症状的可能性很高。开发了一个单脑区域的状态动力学模型,以模拟早期轻度认知障碍患者的血氧水平依赖性信号。随后,利用功能连接分析,综合考虑多个复杂网络中心来定位干预目标,并设计了多脑区协同控制方案。最后,在大脑区域和子网络层面验证了干预的可靠性和有效性。该技术为未来AD和MCI的临床诊断和治疗提供了基础。
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引用次数: 1
Heart–brain team approach of acute myocardial infarction complicating acute stroke: Evidencing the knowledge gap 急性心肌梗死并发急性脑卒中的心脑团队方法:认识差距的证据
Pub Date : 2023-08-15 DOI: 10.1002/brx2.28
Na Li, Xin Tian, Yongzheng Guo

Acute myocardial infarction (AMI) occurs in 1.6%–2.1% of patients with acute stroke.1 Primary percutaneous coronary intervention (PCI) and antithrombotic therapy, which improve cardiovascular outcomes in patients with AMI, may elevate the risks of hemorrhagic stroke in the acute phase of stroke.2 How to manage the ischemic and bleeding risks in patients with AMI complicating acute stroke (AMI-CAS) is challenging in clinics. Therapeutics for AMI-CAS should be well-balanced by collaborating with cardiologists and neurologists. The institute in the present study has a structure to provide a heart–brain team approach,3 which was defined as cardiac catheterization and antithrombotic therapies, according to the status and severity of an acute stroke and the patient's condition.

In this issue of the Journal of the American Heart Association, Suzuki et al.4 described different clinical characteristics, coronary revascularization and antithrombotic therapies and cardiovascular and major bleeding outcomes of patients with AMI-CAS. These findings were based on a retrospective cohort study using data from the National Cerebral and Cardiovascular Center (Suita, Japan) between 1 January 2007, and 30 September 2020 and included 2393 consecutive patients with AMI. Of these patients, those with takotsubo cardiomyopathy (n = 3) were excluded. The primary outcome was defined as a composite of major adverse cerebral/cardiovascular events (MACCEs), which included cardiac-cause death, nonfatal myocardial infarction, and nonfatal stroke. The authors reported a few attractive findings. Firstly, AMI-CAS was identified in 1.6% (39/2390) of study participants in the current study. The characteristics of AMI-CAS tend to be women (46.2% vs. 26.2%; P = 0.005), chronic kidney disease (71.8% vs. 47.0%; P = 0.002), atrial fibrillation (38.5% vs. 9.8%; P < 0.001) and stroke (33.3% vs. 11.1%; P < 0.001). In 39 patients with AMI-CAS, 37 patients (37/39 = 94.9%) and 2 patients (2/39 = 5.1%) were diagnosed as having an ischemic stroke or hemorrhagic stroke, respectively. 69.2% and 10.3% of them were attributable to cardioembolic and atherosclerotic causes, respectively. AMI occurred within 3 days from the onset of acute stroke in 59.0% of patients with AMI-CAS, and the median duration of AMI from the onset of acute stroke was 2 days (interquartile range, 0–8 days). Secondly, medical procedures were conducted with a diverse frequency between AMI-CAS patients and AMI patients without acute stroke. Primary PCI (43.6% vs. 84.7%; p < 0.001), stent implantation (30.8% vs. 77.9%; p < 0.001) and dual-antithrombotic therapy (38.5% vs. 85.7%) were less frequently received in AMI-CAS, whereas thrombectomy (7.7% vs. 1.4%; p = 0.02) was higher than AMI patients without acute stroke. Additionally, angiotensin-converting

急性心肌梗死(AMI)发生在1.6%-2.1%的急性中风患者中。1初级经皮冠状动脉介入治疗(PCI)和抗血栓治疗可改善AMI患者的心血管预后,在脑卒中急性期,可能会增加出血性脑卒中的风险。2如何管理AMI并发急性脑卒中(AMI-CAS)患者的缺血性和出血风险在临床上具有挑战性。AMI-CAS的治疗应该通过与心脏病专家和神经科医生合作来很好地平衡。本研究中的研究所根据急性中风的状态和严重程度以及患者的病情,提供了一种心脑团队方法,3该方法被定义为心导管插入术和抗血栓疗法。在本期《美国心脏协会杂志》上,Suzuki等人4描述了AMI-CAS患者的不同临床特征、冠状动脉血运重建和抗血栓治疗以及心血管和大出血结果。这些发现基于一项回顾性队列研究,该研究使用了2007年1月1日至2020年9月30日期间国家脑心血管中心(日本佐田)的数据,包括2393名连续的AMI患者。在这些患者中,排除了患有takotsubo心肌病的患者(n=3)。主要转归被定义为主要不良脑/心血管事件(MACCE)的组合,包括心脏原因死亡、非致命性心肌梗死和非致命性中风。作者报告了一些有吸引力的发现。首先,在当前研究中,1.6%(39/2390)的研究参与者中发现了AMI-CAS。AMI-CAS的特征往往是女性(46.2%对26.2%;P=0.005)、慢性肾脏疾病(71.8%对47.0%;P=0.002)、心房颤动(38.5%对9.8%;P&lt;0.001)和中风(33.3%对11.1%;P&&lt;0.001)。在39名AMI-CAS患者中,37名患者(37/39=94.9%)和2名患者(2/39=5.1%)被诊断为缺血性中风或出血性中风,分别地其中69.2%和10.3%分别归因于心脏栓塞和动脉粥样硬化原因。在59.0%的AMI-CAS患者中,AMI发生在急性卒中发作后3天内,急性卒中发作时AMI的中位持续时间为2天(四分位间距,0-8天)。其次,在AMI-CAS患者和无急性卒中的AMI患者之间进行不同频率的医疗程序。原发性PCI(43.6%对84.7%;p<0.001)、支架植入(30.8%对77.9%;p<0.01)和双重抗血栓治疗(38.5%对85.7%)在AMI-CAS中的接受频率较低,而血栓切除术(7.7%对1.4%;p=0.02)高于无急性卒中的AMI患者。此外,血管紧张素转化酶抑制剂、血管紧张素II受体阻滞剂(59.0%对77.8%;p=0.005)和他汀类药物(48.7%对82.3%;p=005)在AMI-CAS患者中的使用显著减少。最后一点在观察期内(中位数为2.4年[四分位间距,1.1-4.4年]),AMI-CAS发生MACCE(95%CI,1.99-6.05;P&lt;0.001)和大出血事件(95%CI(1.34-8.10;P=0.009)的可能性高于其他组出血事件(HR,2.67[95%CI,1.03-6.93];P=0.04)。心-脑团队方法是一个协作平台,有助于多学科决策过程和患者参与。它还为教育和评估AMI-CAS患者的医疗保健提供了机会。然而,在接受心脑重症监护的AMI-CAS患者中,心脑团队方法被用于降低MACCE的风险,冠状动脉血运重建和抗血栓治疗仍然存在困难。同样,一篇综述5总结了在线2021亚太心脑血管峰会提出的指导方针和共识声明,其中强调了涉及神经病学、心脏病学和血液学的心血管疾病多学科临床决策的重要性。未来的研究迫切需要阐明AMI-CAS的更精细化管理。作者提供的数据强调了心脑团队方法在AMI-CAS中的重要性,这为以下研究方向提供了参考。与任何观察性研究一样,也有一些局限性,其中大多数是作者指出的。首先,在这项回顾性、单中心、观察性研究中,纳入了相对较少的日本AMI-CAS患者。因为阻塞性和出血性中风的发生频率存在种族差异。 其次,从2007年到2020年,本研究中的心血管和出血结果受到冠状动脉血运重建、抗血栓和降脂治疗可变指南的影响。第三,在本研究中,常规治疗的效果与心脑团队方法相比是不存在的。最后,在不同医生的管理和医疗经验的情况下,不可避免地会产生选择偏差。未来的研究需要进行一项多中心和大样本研究,以进一步阐明指导性心血管干预措施对出血风险的影响,确定心脑团队方法的益处,并研究中风和心血管事件之间时间相关性的潜在机制。尽管存在局限性,但应鼓励作者对文献的贡献。由于他们证实了心脑团队是管理AMI-CAS患者的一种促进方法。这强调了在进行冠状动脉血运重建和抗血栓治疗时评估出血风险的重要性。最后,Suzuki等人的论文。提供了一个重要知识差距的证据,迫切需要进一步的研究来帮助临床医生为AMI-CAS患者的心脑团队治疗做出个性化的治疗决策。李:概念化;书写——原始草稿。辛天:概念化,写作——评&amp;编辑。郭永正:概念化;写作——复习;编辑。作者声明没有利益冲突。
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引用次数: 0
Nanomedicines for Alzheimer's disease: Therapies based on pathological mechanisms 纳米药物治疗阿尔茨海默病:基于病理机制的治疗
Pub Date : 2023-07-28 DOI: 10.1002/brx2.27
Guowang Cheng, Aihua Xie, Zhao Yan, Xiaozhen Zhu, Yafang Song, Tongkai Chen

Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide. Because of the complex pathogenesis of AD and the unique location of AD lesions, effective clinical treatment strategies for this disease remain elusive. However, the development of nanotechnology has allowed a new era of AD treatment to emerge. AD nanomedicines are products of interdisciplinary research that enable high precision and targeted delivery. Additionally, they can specifically regulate various pathogenic factors. This review focuses on nanomedicines based on the pathological mechanisms of AD that can target AD lesions. We also discuss the precise regulatory effects of nanomedicines (including the nanomaterials themselves) on pathogenic proteins, neuroinflammatory molecules, and other pathogenic factors. We summarize the clinical trials that have examined new AD drugs, highlighting the development of new nanomedicines and the progress in their clinical translation. Nanotechnology-based AD treatment is a nascent field, and a complete cure is distant at present; therefore, we also elaborate on the shortcomings of current AD nanomedicines. Finally, we discuss the prospects to guide the future development of AD nanomedicines.

阿尔茨海默病(AD)是世界范围内最常见的神经退行性疾病。由于AD的发病机制复杂,病变位置独特,因此该疾病的有效临床治疗策略仍然难以捉摸。然而,纳米技术的发展使AD治疗的新时代出现了。AD纳米药物是跨学科研究的产物,能够实现高精度和靶向递送。此外,它们还可以特异性调节各种致病因素。这篇综述的重点是基于AD病理机制的纳米药物,这些药物可以靶向AD病变。我们还讨论了纳米药物(包括纳米材料本身)对致病蛋白、神经炎症分子和其他致病因素的精确调节作用。我们总结了检测新型AD药物的临床试验,重点介绍了新型纳米药物的开发及其临床转化的进展。基于纳米技术的AD治疗是一个新兴领域,目前完全治愈还很遥远;因此,我们也阐述了目前AD纳米药物的不足。最后,对AD纳米药物的发展前景进行了展望。
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引用次数: 3
Tribo-ferro-optoelectronic neuromorphic transistor of α-In2Se3 α-In2Se3的三铁光电子神经形态晶体管
Pub Date : 2023-07-18 DOI: 10.1002/brx2.24
Zhenyu Feng, Jinran Yu, Yichen Wei, Yifei Wang, Bobo Tian, Yonghai Li, Liuqi Cheng, Zhong Lin Wang, Qijun Sun

Inspired by biological neural networks, the fabrication of artificial neuromorphic systems with multimodal perception capacity shows promises in overcoming the “von Neumann bottleneck” and takes advantage of the efficient perception and computation of diverse types of signals. Here, we combine a triboelectric nanogenerator with an α-phase indium selenide (α-In2Se3) optoelectronic synaptic transistor to construct a tribo-ferro-optoelectronic artificial neuromorphic device with multimodal plasticity. Based on the excellent ferroelectric and optoelectronic characteristics of the α-In2Se3 channel, typical synaptic behaviors (e.g., pair-pulse facilitation and short-term/long-term plasticity) are successfully simulated in response to the synergistic effect of mechanical and optical stimuli. The interaction of mechanical displacement and light illumination enables heterosynaptic plasticity and spatiotemporal dynamic logic. Furthermore, multiple Boolean logical functions and associative learning behaviors are successfully implemented using the paired stimuli of displacement pulses and light pulses. The proposed tribo-ferro-optoelectronic artificial neuromorphic devices have great potential for application in interactive neural networks and next-generation artificial intelligence.

受生物神经网络的启发,具有多模式感知能力的人工神经形态系统的制造有望克服“冯·诺依曼瓶颈”,并利用对不同类型信号的有效感知和计算。在这里,我们将摩擦电纳米发电机与α相硒化铟(α-In2Se3)光电突触晶体管相结合,构建了一种具有多峰可塑性的摩擦铁光电人工神经形态装置。基于α-In2Se3通道优异的铁电和光电特性,成功模拟了典型的突触行为(如对脉冲促进和短期/长期可塑性),以响应机械和光学刺激的协同效应。机械位移和光照的相互作用使异突触具有可塑性和时空动态逻辑。此外,利用位移脉冲和光脉冲的配对刺激,成功地实现了多个布尔逻辑函数和联想学习行为。所提出的摩擦铁光电人工神经形态装置在交互式神经网络和下一代人工智能中具有巨大的应用潜力。
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引用次数: 0
Potential roles of transformers in brain tumor diagnosis and treatment 变压器在脑肿瘤诊断和治疗中的潜在作用
Pub Date : 2023-07-13 DOI: 10.1002/brx2.23
Yu-Long Lan, Shuang Zou, Bing Qin, Xiangdong Zhu

Brain tumor (BT) is one of many malignancies that have substantially enhanced global human morbidity and mortality rates. Early detection and characterization of glioma are essential for effective preventive strategies. Currently, the use of Transformers, a deep learning model for BT diagnosis and treatment, is attracting significant attention. The transformer self-attention mechanism automatically learns the associations between input data for efficient processing and analysis. Research indicates that Transformers could play an essential role in the BT segmentation of magnetic resonance imaging (MRI) images, the MRI and histopathology-based grading of brain cancer, BT molecular expression prediction, the classification of primary brain metastasis sites, voxel-level dose and BT radiotherapy outcome prediction, synergistic prediction, and the pathway deconvolution of drug combinations. In this review, the feasibility, accuracy, and applicability of various algorithms are systematically analyzed and their prospects are discussed. Overall, this review aimed to discuss and provide an overview of the increasing applications of Transformers in real-time BT detection and therapy, indicating their broad prospects and potential. In the future, Transformers are expected to be increasingly used for the diagnosis and subsequent treatment of BT because of the continuous development and improvement of Transformer-based deep learning technology. However, more work is required to investigate their properties for anomaly detection, medical image classification, network design development, and application to other medical data.

脑肿瘤(BT)是显著提高全球人类发病率和死亡率的许多恶性肿瘤之一。神经胶质瘤的早期发现和表征对于有效的预防策略至关重要。目前,变压器这一用于BT诊断和治疗的深度学习模型的使用正引起人们的极大关注。转换器自注意机制自动学习输入数据之间的关联,以进行有效的处理和分析。研究表明,Transformers可以在磁共振成像(MRI)图像的BT分割、基于MRI和组织病理学的脑癌症分级、BT分子表达预测、原发性脑转移部位的分类、体素水平剂量和BT放疗结果预测、协同预测、,以及药物组合的通路去卷积。在这篇综述中,系统地分析了各种算法的可行性、准确性和适用性,并讨论了它们的前景。总之,这篇综述旨在讨论并概述变压器在实时BT检测和治疗中日益增长的应用,表明其广阔的前景和潜力。未来,由于基于Transformer的深度学习技术的不断发展和改进,Transformer有望越来越多地用于BT的诊断和后续治疗。然而,还需要更多的工作来研究它们的特性,用于异常检测、医学图像分类、网络设计开发以及应用于其他医学数据。
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引用次数: 1
Functional magnetic resonance imaging study of children's brain development in phonological processing and speeded naming 儿童大脑语音处理和快速命名发育的功能磁共振成像研究
Pub Date : 2023-07-10 DOI: 10.1002/brx2.20
Zeyu Song, Zhenqi Jiang, Yingwei Fan, Liang Lu, Zhao Zhang, Yifei Wang, Yu Chen, Lifei Liu, Xiaoying Tang, Hanjun Li

The brain structure and language skills of children are understood to be in a phase of rapid development and are especially represented by key phonological-semantic expressions that actively develop with age. In the present study, resting-state functional magnetic resonance imaging data from 85 healthy children were retrospectively analyzed. Correlations of the phonological processing and speeded naming of specific brain regions of interest with age were assessed using the fractional amplitude of low-frequency fluctuations (fALFF), degree centrality (DC), regional homogeneity (ReHo), and chain mediation effect analysis. Our results suggest that the developmental stages of children's posterior cingulate gyrus (PCC) and right inferior frontal gyrus (IFG) mediate language development in children. Additionally, the functional similarity of the bilateral IFG triangular part was noted during development as was the stronger activation and higher local and whole-brain connectivity of the left IFG triangular part. Moreover, the PCC displayed stronger activation and higher local connectivity in the same period. Our data suggest that the development of the PCC and right IFG and the similarity of bilateral IFG function are important imaging markers of phonological processing and speeded naming in children and that the PCC and IFG show a more comprehensive development with age.

儿童的大脑结构和语言技能被认为处于快速发展阶段,尤其是随着年龄的增长而积极发展的关键语音语义表达。在本研究中,回顾性分析了85名健康儿童的静息状态功能磁共振成像数据。使用低频波动的分数幅度(fALFF)、程度中心性(DC)、区域同质性(ReHo)和连锁中介效应分析来评估感兴趣的特定大脑区域的语音处理和加速命名与年龄的相关性。我们的研究结果表明,儿童后扣带回(PCC)和右额下回(IFG)的发育阶段介导了儿童的语言发育。此外,在发育过程中注意到双侧IFG三角形部分的功能相似性,左侧IFG三角部分的激活更强,局部和全脑连接更高。此外,PCC在同一时期表现出更强的激活和更高的本地连接性。我们的数据表明,PCC和右IFG的发育以及双侧IFG功能的相似性是儿童语音处理和快速命名的重要成像标志,并且PCC和IFG随着年龄的增长表现出更全面的发展。
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引用次数: 0
Revolutionary delivery system enables precise protein transportation 革命性的递送系统实现精确的蛋白质运输
Pub Date : 2023-06-29 DOI: 10.1002/brx2.21
Qian Zhang, Kun Zhang

The capacity to transport customized proteins into certain cell types has enormous implications for life science research and disease therapy. However, challenges associated with cell targeting and protein transportation through cellular membranes still exist, necessitating the creation of complex systems that can continuously carry payload proteins into cells.1. In gene editing especially, achieving accurate targeted delivery is an intricate problem that warrants addressing. Endosymbiotic bacteria have developed complex delivery systems that enable them to interact with the host organism,2 wherein secreted contractile injection systems (CISs), which are analogous to bacteriophage tails, can be harnessed as nanodevices.3. These macromolecular complexes consist of a solid tubular structure encompassed in a compressible sheath that is attached to a baseplate and sharpened by a spike protein. It is hypothesized that payloads are packed into the lumen of the inner tube behind the spike, which upon recognition by the target cell are pushed into the target cell through the membrane via sheath contraction.4

Inspired by previous reports regarding CISs, recently, a team led by Professor Feng Zhang at the Broad Institute developed a redesigned protein delivery system; the corresponding results have been published in Nature.5 Therein, extracellular contractile injection systems (eCISs), syringe-like nanomachines mimicking bacteriophage tails that can transport payloads independently and extracellularly, served as a new tool to solve a long-standing problem, that is, how to deliver therapeutic molecules to specific types of human cells precisely and efficiently (Figure 1). The structural composition of eCISs originating from the Photorhabdus virulence cassette (PVC) is such that the tail fibers on the outside of one end recognize specific receptors on the cell surface and anchor to host cells; thus, in their study, the researchers speculated that modifying the structure of these tail fibers may enable them to recognize different cells. Given that the action and targeting mechanisms of eCISs in human cells remain a mystery, the team used AlphaFold, an artificial intelligence protein design platform that can predict protein structures from amino acid sequences, to redesign the injector of PVC to shift the targeting objective from insect cells to human cells. Cellular studies demonstrated that after modification, the syringe, carrying a variety of protein cargoes, could detect human and mouse cells. Further research on protein delivery to cultivated cells was carried out, and the modified PVC was proved to exhibit specific targeting toward epidermal growth factor receptor (EGFR) after genetic engineering.

The most promising application of the precise delivery based on such PVC-derived eCISs is the specific targetin

因此,在该系统应用于人类治疗之前,eCIS在体内的安全性和有效性是未来需要解决的最重要问题之一。通过开发一种灵活的重新设计系统,在广泛的应用中输送蛋白质,与eCIS相关的革命性工作可能会为人类癌症治疗和基因治疗带来更多灵感。钱章:写作——原稿。张昆:《写作——综述》;编辑。作者声明没有利益冲突。
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引用次数: 0
SPEAC-seq: A new method to investigate astrocyte-microglia crosstalk SPEAC seq:一种研究星形胶质细胞-小胶质细胞串扰的新方法
Pub Date : 2023-06-28 DOI: 10.1002/brx2.22
Yao Tang, Fuchen Liu

Multicellular organisms rely on cellular communication to function. Numerous biological activities depend on the dynamic communication networks created by cellular communication. In neuroinflammation, crosstalk between astrocytes and microglia plays a crucial role. Aberrant interactions between these two sub-types of glial cells have been implicated in several neuroimmunological diseases, such as multiple sclerosis (MS)—a chronic inflammatory disorder of the central nervous system (CNS)—and its preclinical model, experimental autoimmune encephalomyelitis (EAE).1 As is known, specific cell signaling pathways are activated by receptors via selective detection and interaction with signal molecules (ligands). This results in the conversion of these molecules into intracellular messages. Accordingly, analysis of ligand-receptor pair interactions forms the basis for understanding cell behavior.2 However, current methods fail to establish causal links between cellular interactions and molecular states. Furthermore, despite the CRISPR-Cas9 system serving as a powerful tool for gene identification, there are noted limitations relating to high-throughput co-culture and screening of the perturbation of single cells.3 Recently, Professor Francisco J. Quintana's team developed a novel technique to identify forward genetic screens of cell–cell interaction mechanisms, which they call systematic perturbation of encapsulated associated cells followed by sequencing (SPEAC-seq). It combines CRISPR-Cas9 perturbations, co-culture of cells in droplets, and fluorescence-activated droplet sorting based on microfluidics (Figure 1).4

The researchers established a preliminary microfluidic platform for studying cell-cell interactions. Firstly, a microfluidic co-flow system using two aqueous suspensions (one for each cell type) and oil was used to generate picoliter water-in-oil droplets containing cell pairs. For subsequent studies of cellular interactions, detection and selection were performed using a custom three-color optical system and dielectrophoretic microfluidic sorter. Next, the study was extended to cell pairs to determine if the cues generated by one cell were sufficient to alter the cellular state of cells co-cultured in the same droplet. Multiple labeling using a fluorescent dye with cell permeability was used for spiking and detection of cell pairs in the droplets. Results showed the upregulation of EGFP expression in NF-κB-labeled astrocytes paired with activated macrophages, as initially detected in isolated reporter cell pairs and following optimization of droplet sorting parameters. The above indicates that the researchers have successfully established an oil-in-droplet-based co-culture system. Subsequently, based on the microdroplet co-culture system combined with CRISPR-Cas9 perturbations, SPEAC-seq was developed as a forward genetic screening platfo

多细胞生物依靠细胞通讯来发挥作用。许多生物活动依赖于由细胞通信创建的动态通信网络。在神经炎症中,星形胶质细胞和小胶质细胞之间的相互作用起着至关重要的作用。这两种亚型神经胶质细胞之间的异常相互作用与几种神经免疫学疾病有关,如多发性硬化症(MS)——一种中枢神经系统的慢性炎症性疾病——及其临床前模型——实验性自身免疫性脑脊髓炎(EAE)。1众所周知,受体通过选择性检测和与信号分子(配体)的相互作用激活特定的细胞信号通路。这导致这些分子转化为细胞内信息。因此,配体-受体对相互作用的分析构成了理解细胞行为的基础。2然而,目前的方法未能建立细胞相互作用和分子状态之间的因果关系。此外,尽管CRISPR-Cas9系统是基因鉴定的有力工具,但在高通量共培养和单细胞扰动筛选方面存在显著的局限性。3最近,Francisco J.Quintana教授的团队开发了一种新技术,用于鉴定细胞-细胞相互作用机制的正向遗传筛选,他们称之为封装的相关细胞的系统扰动,随后进行测序(SPEAC seq)。它结合了CRISPR-Cas9扰动、液滴中细胞的共培养和基于微流体的荧光激活液滴分选(图1)。4研究人员建立了一个用于研究细胞-细胞相互作用的初步微流体平台。首先,使用两种水悬浮液(每种细胞类型一种)和油的微流体共流系统来产生含有细胞对的微升油包水液滴。对于随后的细胞相互作用研究,使用定制的三色光学系统和介电泳微流体分类器进行检测和选择。接下来,该研究扩展到细胞对,以确定一个细胞产生的线索是否足以改变在同一液滴中共同培养的细胞的细胞状态。使用具有细胞渗透性的荧光染料进行多重标记用于液滴中细胞对的加标和检测。结果显示,在NF-κB标记的星形胶质细胞与活化的巨噬细胞配对中,EGFP表达上调,最初在分离的报告细胞对中检测到,并在液滴分选参数优化后检测到。以上表明,研究人员已经成功建立了一个基于液滴油的共培养系统。随后,基于微滴共培养系统和CRISPR-Cas9扰动,SPEAC-seq被开发为一个用于调节细胞-细胞相互作用的正向遗传筛选平台。通过这种方法,鉴定了小胶质细胞产生的参与抑制星形胶质细胞NF-κB活化的因子或蛋白质。为了研究参与调节细胞-细胞通讯途径的候选蛋白,研究人员确定了四种候选生长因子(Areg、Nrtn、Fgl1和Pnoc),它们由小胶质细胞表达,并通过星形胶质细胞表达的四种独立受体(Egfr、Lag3、Gfra2、Oprl1)发出信号。为了进一步评估SPEAC-seq揭示的每个候选途径在炎症中的调节作用,应用了细胞类型特异性的体内扰动seq方法。在EAE模型中,靶向Egfr导致IL-1β/TNFα信号传导的最强激活,促进与EAE和MS相关的NF-κB驱动的星形胶质细胞反应。SPEAC-seq鉴定的Egfr配体是编码两调节蛋白的Areg。因此,小胶质细胞分泌的Areg通过Egfr受体抑制星形胶质细胞的促炎反应。研究人员随后通过诱导EAE小胶质细胞中Areg的表达来研究中枢神经系统病理学。IL-33已被鉴定为EAE的抑制剂和Areg表达的诱导剂。IL-33也是组织损伤后细胞释放的一种危言耸听的物质。5为了确定IL-33是否调节Areg介导的小胶质细胞-星形胶质细胞相互作用,研究人员重新分析了之前的测序数据集。这表明星形胶质细胞触发的IL-33信号转导是Areg+小胶质细胞的上游调节因子。这些发现表明,星形胶质细胞产生的IL-33在小胶质细胞中诱导Areg表达,进而作用于星形胶质细胞以抑制疾病促进反应。阐明细胞相互作用背后的机制可能会发现中枢神经系统疾病的潜在治疗靶点。因此,上述平台具有许多潜在的应用。此外,它使研究人员能够研究中枢神经系统中任何两种类型的细胞(例如,神经元星形胶质细胞、神经元小胶质细胞、星形胶质细胞小胶质细胞等)之间的相互作用。 ),允许在细胞-细胞通信中对配体-受体对相互作用进行高通量和系统鉴定。以前,已经创建了许多方法,并在受体和配体的研究中广泛使用。然而,它们严重依赖已建立的数据库。此外,由于目前用于研究细胞连接的大多数方法都涉及基因分析,因此在蛋白质水平上对配体-受体结合复合物的理解仍然有限。未来,SPEAC序列可能与遗传操作或多组学相结合,如表观基因组、转录组、蛋白质组和/或代谢组分析,以确定可以改变细胞-细胞相互作用的治疗方法。或者,它可以与抗体或小分子条形码文库结合,以确定细胞-细胞通信的治疗调节因子。因此,SPEAC seq可能具有巨大的价值,并提供广泛的潜在应用。姚棠:写作——原稿。刘:《写作——评论》;编辑。作者声明没有利益冲突。
{"title":"SPEAC-seq: A new method to investigate astrocyte-microglia crosstalk","authors":"Yao Tang,&nbsp;Fuchen Liu","doi":"10.1002/brx2.22","DOIUrl":"https://doi.org/10.1002/brx2.22","url":null,"abstract":"<p>Multicellular organisms rely on cellular communication to function. Numerous biological activities depend on the dynamic communication networks created by cellular communication. In neuroinflammation, crosstalk between astrocytes and microglia plays a crucial role. Aberrant interactions between these two sub-types of glial cells have been implicated in several neuroimmunological diseases, such as multiple sclerosis (MS)—a chronic inflammatory disorder of the central nervous system (CNS)—and its preclinical model, experimental autoimmune encephalomyelitis (EAE).<span><sup>1</sup></span> As is known, specific cell signaling pathways are activated by receptors via selective detection and interaction with signal molecules (ligands). This results in the conversion of these molecules into intracellular messages. Accordingly, analysis of ligand-receptor pair interactions forms the basis for understanding cell behavior.<span><sup>2</sup></span> However, current methods fail to establish causal links between cellular interactions and molecular states. Furthermore, despite the CRISPR-Cas9 system serving as a powerful tool for gene identification, there are noted limitations relating to high-throughput co-culture and screening of the perturbation of single cells.<span><sup>3</sup></span> Recently, Professor Francisco J. Quintana's team developed a novel technique to identify forward genetic screens of cell–cell interaction mechanisms, which they call systematic perturbation of encapsulated associated cells followed by sequencing (SPEAC-seq). It combines CRISPR-Cas9 perturbations, co-culture of cells in droplets, and fluorescence-activated droplet sorting based on microfluidics (Figure 1).<span><sup>4</sup></span></p><p>The researchers established a preliminary microfluidic platform for studying cell-cell interactions. Firstly, a microfluidic co-flow system using two aqueous suspensions (one for each cell type) and oil was used to generate picoliter water-in-oil droplets containing cell pairs. For subsequent studies of cellular interactions, detection and selection were performed using a custom three-color optical system and dielectrophoretic microfluidic sorter. Next, the study was extended to cell pairs to determine if the cues generated by one cell were sufficient to alter the cellular state of cells co-cultured in the same droplet. Multiple labeling using a fluorescent dye with cell permeability was used for spiking and detection of cell pairs in the droplets. Results showed the upregulation of EGFP expression in NF-κB-labeled astrocytes paired with activated macrophages, as initially detected in isolated reporter cell pairs and following optimization of droplet sorting parameters. The above indicates that the researchers have successfully established an oil-in-droplet-based co-culture system. Subsequently, based on the microdroplet co-culture system combined with CRISPR-Cas9 perturbations, SPEAC-seq was developed as a forward genetic screening platfo","PeriodicalId":94303,"journal":{"name":"Brain-X","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/brx2.22","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50146616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A new mechanism of consciousness recovery from anesthesia regulated by K+-Cl– cotransporter KCC2 K+-Cl协同转运蛋白KCC2调节麻醉后意识恢复的新机制
Pub Date : 2023-06-01 DOI: 10.1002/brx2.19
Jinwei Zhang

Neuroscience faces a puzzle in understanding the mechanism of general anesthesia. In the past, it was widely believed that recovery from anesthesia was a passive process caused by the breakdown of anesthetic agents. However, recent studies have challenged this view. For instance, activating specific neural circuits can promote the recovery of consciousness,1 indicating that these circuits is related to consciousness recovery and could play a crucial role in promoting it. However, prior to the recent work of Hu et al.,2 research had not yet examined the core of consciousness recovery.

Hu et al. presented findings indicating that consciousness recovery is an active, not passive, process.3 So-called passive recovery is merely an easily observable, intuitive, and superficial phenomenon and is not the essence of consciousness recovery. The authors used a combination of the traditional righting reflex test and a newly established scale to assess the level of consciousness in animals during the loss of consciousness following anesthetic administration. In mice, the administration of propofol, pentobarbital, or ketamine via intraperitoneal injection resulted in loss of the righting reflex (LORR) within 1 min and a righting reflex score of less than 3 within 15–20 min. The authors defined the state of mice with a consciousness score of less than 3 as the minimal response state (MRS) (Figure 1A). They then found that the active process of consciousness recovery is driven by inherent dynamics within the brain, initiated by a neurochemical reaction triggered by the ubiquitin degradation of the K+-Cl cotransporter-2 (KCC2), mediated by ubiquitin ligase Fbxl4 (F-box and leucine-rich repeat protein 4), in the ventral posteromedial nucleus (VPM) of the thalamus. Interestingly, the total amount of KCC2 (tKCC2) was observed to decrease from the awake state to MRS and increase from MRS to the recovery of the righting reflex (RRR), and with opposite changes in the amount of KCC2 Thr1007 phosphorylation (pKCC2) in the thalamus and hypothalamus (Figure 1B). The decreased tKCC2 and increased pKCC2 during MRS resulted in lower KCC2 activity, leading to elevated intraneuronal Cl levels [Cl] i . This facilitated γ-aminobutyric acid (GABA)-driven Cl output, which in turn led to GABAA receptor-mediated depolarization in VPM neurons (Figure 1C). Further in vitro experiments have shown that the interaction between KCC2 and Fbxl4 depends on the phosphorylation of KCC2 at Thr1007, which plays a critical role in the ubiquitination of KCC2 during propofol anesthesia. As a result, VPM neurons are disinhibited through GABAA receptor-mediated signaling, which accelerates the recovery of excitability and consciousness arousal.

Hu et al. discovered that ubiquitin degradati

神经科学在理解全身麻醉的机制方面面临着一个难题。过去,人们普遍认为,从麻醉中恢复是一个由麻醉剂分解引起的被动过程。然而,最近的研究对这一观点提出了质疑。例如,激活特定的神经回路可以促进意识的恢复,1表明这些回路与意识恢复有关,并可能在促进意识恢复中发挥关键作用。然而,在Hu等人最近的工作之前。,2项研究尚未检验意识恢复的核心。胡等。研究结果表明,意识恢复是一个主动而非被动的过程。3所谓的被动恢复只是一种容易观察、直观和肤浅的现象,并不是意识恢复的本质。作者使用传统的翻正反射测试和新建立的量表相结合的方法来评估动物在麻醉后意识丧失期间的意识水平。在小鼠中,通过腹膜内注射丙泊酚、戊巴比妥或氯胺酮导致1分钟内翻正反射(LORR)丧失,15-20分钟内翻右反射得分低于3。作者将意识评分低于3的小鼠的状态定义为最小反应状态(MRS)(图1A)。然后,他们发现意识恢复的主动过程是由大脑内固有的动力学驱动的,由丘脑腹后内侧核(VPM)中的泛素连接酶Fbxl4(F-box和富含亮氨酸的重复蛋白4)介导的K+-Cl−协同转运蛋白2(KCC2)的泛素降解引发的神经化学反应引发。有趣的是,观察到KCC2的总量(tKCC2)从清醒状态减少到MRS,从MRS增加到翻正反射(RRR)的恢复,丘脑和下丘脑中KCC2 Thr1007磷酸化(pKCC2)的量发生相反的变化(图1B)。MRS期间tKCC2的减少和pKCC2的增加导致KCC2活性降低,导致神经内Cl−水平[Cl−]i升高。这促进了γ-氨基丁酸(GABA)驱动的Cl−输出,进而导致VPM神经元中GABAA受体介导的去极化(图1C)。进一步的体外实验表明,KCC2和Fbxl4之间的相互作用取决于KCC2在Thr1007的磷酸化,Thr1007在丙泊酚麻醉期间KCC2的泛素化中起着关键作用。因此,VPM神经元通过GABAA受体介导的信号传导被解除抑制,从而加速兴奋性和意识觉醒的恢复。胡等。发现KCC2的泛素降解及其在VPM脑区Thr1007位点的磷酸化是主动意识恢复的关键机制,进一步延长了意识的丧失并加剧了麻醉效果。KCC2拮抗剂可以阻断这种作用,这表明一种有前景的治疗方法。这种机制独立于全身麻醉剂的药理学特性和分子靶标,包括众所周知的靶标,如N-甲基-D-天冬氨酸(NMDA)和GABAA受体。KCC2泛素降解诱导的VPM神经元的去抑制可以触发高度敏感的局部神经网络的形成,这些网络之间具有高质量的通信链路,从而导致神经回路的重建。胡等研究结果为复杂医疗病例中恢复意识的潜在方法提供了一个新的视角。他们研究了包括丙泊酚在内的四种麻醉剂,发现了一种共同的意识恢复机制。值得注意的是,靶向不同于丙泊酚的途径的氯胺酮也通过这种机制发挥作用。他们的研究还表明,泛素对KCC2的降解和随后的事件可能导致麻醉性癫痫。然而,有必要进行进一步的调查,以确定这些发现对人类的适用性。研究WNK-SPAK/OSR1信号通路在丙泊酚麻醉后意识主动恢复中的作用可能是值得的,因为它是KCC2 Thr1007磷酸化的主要上游通路。3总的来说,探索与重新连接神经网络有关的神经和分子底物可以深入了解意识的本质。张金伟:写作——初稿;写作——复习&;编辑。提交人声明没有利益冲突。
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引用次数: 1
The oscillating mystery: The effects of forty-hertz entrainment in treating Alzheimer's disease 振荡之谜:40赫兹夹带在治疗阿尔茨海默病中的作用
Pub Date : 2023-05-30 DOI: 10.1002/brx2.14
Chuanliang Han

Imagine standing at crossroads unable to find your way home or gazing into the eyes of your loved one without remembering their name. For some, this is not merely imagination but the reality of Alzheimer's disease (AD). AD is a neurodegenerative disease that predominantly affects the elderly and stands as the leading cause of dementia. However, its etiology and pathogenesis remain poorly understood. One hallmark of AD is the accumulation of abnormal proteins in the brain, including amyloid-beta (Aβ) and tau. These proteins can disrupt the normal functioning of neurons and lead to their eventual death.

Since 2016, a series of studies1 have demonstrated that 40-Hz stimulation effectively improves the cognitive abilities of AD model mice. This improvement is attributed to the reduction of accumulated amyloid-β (Aβ) proteins and the enhancement of microglial function, both of which are associated with the disease. However, these findings have been challenged by recent research2 conducted by Prof. Buzsáki and published in Nature Neuroscience. In this study, the research team utilized two AD mouse models, specifically APP/PS1 and 5xFAD, to explore the effects of both acute and chronic 40-Hz light stimulation on Aβ, microglia, and gamma oscillations. Firstly, they discovered that 40-Hz light stimulation had no effect on the level of Aβ deposition or the morphology of microglia, whether tested in vitro or in vivo. Subsequently, they demonstrated that the entrainment does not activate native gamma oscillations in the targeted brain regions (visual cortex, hippocampus, and entorhinal cortex). Furthermore, they observed that 40-Hz light stimulation induced aversion and avoidance behavior in mice. This was evident from the duration the mice spent in the compartment with 40-Hz light compared to the one with continuous light. Given the absence of experiments assessing cognitive functions before and after 40-Hz entrainment, the observed inconsistencies in pathological changes in AD following acute or chronic exposure should be considered with caution. For example, the inability to replicate the beneficial effects of flickering light stimulation on Aβ and microglia may be attributed to variations in the experimental parameters. Although both animal models and human subjects have shown improvements in cognitive functions (such as memory) after 40-Hz entrainment, the underlying mechanisms driving these changes remain elusive. Nevertheless, this study successfully eliminated one potential mechanism for reducing AD symptoms—namely, the entrainment of natural gamma-band oscillations. The search for alternative mechanisms continues.

Given the notable behavioral improvement resulting from 40-Hz stimulation, it is indisputable that the underlying mechanism must have a significant association with gamma-band activity (30–100 Hz). The broad frequency band comprises multiple sub-gamma oscillations, each

想象一下,站在十字路口找不到回家的路,或者凝视着你所爱的人的眼睛却不记得他们的名字。对一些人来说,这不仅仅是想象,而是阿尔茨海默病(AD)的现实。AD是一种主要影响老年人的神经退行性疾病,是痴呆症的主要原因。然而,其病因和发病机制仍知之甚少。AD的一个标志是大脑中异常蛋白质的积累,包括淀粉样蛋白β(Aβ)和tau。这些蛋白质会破坏神经元的正常功能,最终导致神经元死亡。自2016年以来,一系列研究1表明,40Hz的刺激有效提高了AD模型小鼠的认知能力。这种改善归因于积累的淀粉样蛋白-β(Aβ)蛋白的减少和小胶质细胞功能的增强,这两者都与该疾病有关。然而,这些发现受到了Buzsáki教授最近进行的研究2的挑战,该研究发表在《自然神经科学》杂志上。在这项研究中,研究团队使用了两种AD小鼠模型,特别是APP/PS1和5xFAD,来探索急性和慢性40Hz光刺激对Aβ、小胶质细胞和伽马振荡的影响。首先,他们发现,无论是在体外还是体内测试,40Hz的光刺激对Aβ沉积水平或小胶质细胞的形态都没有影响。随后,他们证明了夹带不会激活目标大脑区域(视觉皮层、海马体和内嗅皮层)的固有伽马振荡。此外,他们观察到40赫兹的光刺激诱导了小鼠的厌恶和回避行为。这一点从小鼠在具有40Hz光的隔间中度过的时间与具有连续光的隔间相比是显而易见的。鉴于缺乏评估40 Hz夹带前后认知功能的实验,应谨慎考虑急性或慢性暴露后AD病理变化的不一致性。例如,无法复制闪烁光刺激对Aβ和小胶质细胞的有益影响可能归因于实验参数的变化。尽管动物模型和人类受试者在40赫兹的刺激后都表现出认知功能(如记忆)的改善,但驱动这些变化的潜在机制仍然难以捉摸。然而,这项研究成功地消除了减少AD症状的一个潜在机制,即自然伽马带振荡的夹带。寻找替代机制的工作仍在继续。考虑到40赫兹刺激导致的显著行为改善,无可争议的是,潜在机制一定与伽马能带活动(30–100赫兹)有显著关联。宽频带包括多个亚伽马振荡,每个亚伽马振荡起着不同的作用。Buzsáki教授实验室的另一项研究3直接证明了不同的伽马节律在认知功能中的作用,特别是在学习方面。在空间学习过程中,发现高频伽马振荡使内侧内嗅皮层(MEC)和齿状回(DG)同步,从而夹带颗粒细胞。相反,在进行对象学习时,观察到低频伽马振荡使外侧内嗅皮层(LEC)和DG同步。同年发表的另一项研究4强化了多重伽马振荡的理论,每种振荡都扮演着不同的角色。然而,这一次,研究的重点是视觉系统,特别是初级视觉皮层(V1)和LGN,而不是边缘系统。这些不同的伽马振荡似乎能够同时携带不同的空间频率信息,证明了大脑中的多路复用现象。多重伽马节律的假设可能为夹带刺激提供未来的见解(图1)。虽然伽马振荡可能不能从根本上治愈阿尔茨海默氏症,但它们似乎有助于保持记忆功能。5需要进行额外的研究,以确定诱导可穿过整个大脑的内部伽马波的最佳目标。鉴于许多尚未解决的问题,进一步研究AD治疗中40 Hz夹带的神经机制至关重要。一个重要的问题是,不同类型和过程的AD是否会从相同的夹带方法中同等受益。不同的实验条件,包括使用不同的实验设备和光类型,会对争议产生怎样的影响,也存在不确定性。此外,40Hz刺激的潜在副作用,如诱发癫痫的风险,仍不清楚。 总之,尽管目前对夹带的使用存在分歧,但了解潜在机制的努力仍在继续。正如新物种出现在不同生态系统的边界上一样,新的科学见解也出现在不同学科的交叉点上。我们必须有敏锐的洞察力来认识到这些新出现的机会,并准备说服其他人相信它们的潜力。韩:概念化;融资收购;写作——初稿;写作-复习&amp;编辑。提交人声明没有利益冲突。
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