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Downregulating human leucocyte antigens on mesenchymal stromal cells by epigenetically repressing a β2-microglobulin super-enhancer 通过表观遗传抑制β2-微球蛋白超级增强子来下调间充质基质细胞上的人类白细胞抗原
IF 28.1 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-10-21 DOI: 10.1038/s41551-024-01264-w
Fei Wang, Ran Li, Jing Yi Xu, Xiaoxia Bai, Ying Wang, Xu Ri Chen, Chen Pan, Shen Chen, Ke Zhou, Boon Chin Heng, Xuewei Wu, Wei Guo, Zhe Song, Shu Cheng Jin, Jing Zhou, Xiao Hui Zou, Hong Wei Ouyang, Hua Liu

Immune rejection caused by mismatches in human leucocyte antigens (HLAs) remains a major obstacle to the success of allogeneic cell therapies. Current strategies for the generation of ‘universal’ immune-compatible cells, particularly the editing of HLA class I (HLA-I) genes or the modulation of proteins that inhibit natural killer cells, often result in genomic instability or cellular cytotoxicity. Here we show that a β2-microglobulin super-enhancer (B2M-SE) that is responsive to interferon-γ is a critical regulator of the expression of HLA-I on mesenchymal stromal cells (MSCs). Targeted epigenetic repression of B2M-SE in MSCs reduced the surface expression of HLA-I below the threshold required to activate allogenic T cells while maintaining levels sufficient to evade cytotoxicity mediated by natural killer cells. In a humanized mouse model, the epigenetically edited MSCs demonstrated improved survival by evading the immune system, allowing them to exert enhanced therapeutic effects on LPS-induced acute lung injury. Targeted epigenetic repression of B2M-SE may facilitate the development of off-the-shelf cell sources for allogeneic cell therapy.

人类白细胞抗原(HLA)不匹配引起的免疫排斥仍是异体细胞疗法取得成功的主要障碍。目前生成 "通用 "免疫相容细胞的策略,特别是编辑 HLA I 类(HLA-I)基因或调节抑制自然杀伤细胞的蛋白质,往往会导致基因组不稳定或细胞毒性。在这里,我们发现对干扰素-γ有反应的β2-微球蛋白超级增强子(B2M-SE)是间充质基质细胞(MSCs)上HLA-I表达的关键调节因子。间充质干细胞中 B2M-SE 的靶向表观遗传抑制可将 HLA-I 的表面表达降低到激活异源 T 细胞所需的阈值以下,同时保持足够的水平以规避自然杀伤细胞介导的细胞毒性。在人源化小鼠模型中,经过表观遗传学编辑的间充质干细胞通过逃避免疫系统而提高了存活率,从而使它们对 LPS 诱导的急性肺损伤发挥了更强的治疗效果。对B2M-SE进行靶向表观遗传学抑制可能有助于开发用于异体细胞治疗的现成细胞来源。
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引用次数: 0
Overcoming immune hurdles to implant longevity 克服免疫障碍,延长植入物寿命
IF 26.8 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-10-17 DOI: 10.1038/s41551-024-01276-6
The design of implanted biomaterials and devices should involve strategies for the prevention of inflammation and fibrosis that enhance the functional lifespan of the implants.
植入式生物材料和设备的设计应包括预防炎症和纤维化的策略,以延长植入物的功能寿命。
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引用次数: 0
Targeting overexpressed antigens in glioblastoma via CAR T cells with computationally designed high-affinity protein binders 利用通过计算设计的高亲和力蛋白结合剂,通过 CAR T 细胞靶向胶质母细胞瘤中的过表达抗原
IF 28.1 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-10-17 DOI: 10.1038/s41551-024-01258-8
Zhen Xia, Qihan Jin, Zhilin Long, Yexuan He, Fuyi Liu, Chengfang Sun, Jinyang Liao, Chun Wang, Chentong Wang, Jian Zheng, Weixi Zhao, Tianxin Zhang, Jeremy N. Rich, Yongdeng Zhang, Longxing Cao, Qi Xie

Chimeric antigen receptor (CAR) T cells targeting receptors on tumour cells have had limited success in patients with glioblastoma. Here we report the development and therapeutic performance of CAR constructs leveraging protein binders computationally designed de novo to have high affinity for the epidermal growth factor receptor (EGFR) or the tumour-associated antigen CD276, which are overexpressed in glioblastoma. With respect to T cells with a CAR using an antibody-derived single-chain variable fragment as antigen-binding domain, the designed binders on CAR T cells promoted the proliferation of the cells, the secretion of cytotoxic cytokines and their resistance to cell exhaustion, and improved antitumour performance in vitro and in vivo. Moreover, CARs with the binders exhibited higher surface expression and greater resistance to degradation, as indicated by bulk and single-cell transcriptional profiling of the cells. The de novo design of binding domains for specific tumour antigens may potentiate the antitumour efficacy of CAR T cell therapies for other solid cancers.

以肿瘤细胞上的受体为靶点的嵌合抗原受体(CAR)T细胞在胶质母细胞瘤患者中的疗效有限。在这里,我们报告了利用通过计算重新设计的蛋白结合体的 CAR 构建物的开发和治疗效果,这种结合体对表皮生长因子受体(EGFR)或肿瘤相关抗原 CD276 具有高亲和力,而表皮生长因子受体或肿瘤相关抗原 CD276 在胶质母细胞瘤中过度表达。对于使用抗体衍生的单链可变片段作为抗原结合域的CAR T细胞,CAR T细胞上设计的结合剂促进了细胞的增殖、细胞毒性细胞因子的分泌和细胞衰竭的抵抗力,并提高了体外和体内的抗肿瘤性能。此外,细胞的大量和单细胞转录谱分析表明,带有结合域的 CAR 具有更高的表面表达能力和更强的抗降解能力。重新设计特定肿瘤抗原的结合域可能会增强CAR T细胞疗法对其他实体瘤的抗肿瘤疗效。
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引用次数: 0
Systemically injected oxygen within rapidly dissolving microbubbles improves the outcomes of severe hypoxaemia in swine 在快速溶解的微气泡内全身注射氧气可改善猪严重低氧血症的治疗效果
IF 26.8 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-10-17 DOI: 10.1038/s41551-024-01266-8
Julia Garcia Mancebo, Kristen Sack, Jay Hartford, Saffron Dominguez, Michelle Balcarcel-Monzon, Elizabeth Chartier, Tien Nguyen, Alexis R. Cole, Francesca Sperotto, David M. Harrild, Brian D. Polizzotti, Allen D. Everett, Alan B. Packard, Jason Dearling, Arthur G. Nedder, Simon Warfield, Edward Yang, Hart G. W. Lidov, John N. Kheir, Yifeng Peng
Acute respiratory failure can cause profound hypoxaemia that leads to organ injury or death within minutes. When conventional interventions are ineffective, the intravenous administration of oxygen can rescue patients from severe hypoxaemia, but at the risk of microvascular obstruction and of toxicity of the carrier material. Here we describe polymeric microbubbles as carriers of high volumes of oxygen (350–500 ml of oxygen per litre of foam) that are stable in storage yet quickly dissolve following intravenous injection, reverting to their soluble and excretable molecular constituents. In swine with profound hypoxaemia owing to acute and temporary (12 min) upper-airway obstruction, the microbubble-mediated delivery of oxygen led to: the maintenance of critical oxygenation, lowered burdens of cardiac arrest, improved survival, and substantially improved neurologic and kidney function in surviving animals. Our findings underscore the importance of maintaining a critical threshold of oxygenation and the promise of injectable oxygen as a viable therapy in acute and temporary hypoxaemic crises. The intravenous injection of oxygen via polymeric microbubbles that are stable in storage yet quickly dissolve following intravenous injection led to the maintenance of critical oxygenation and to improved survival in swine with profound hypoxaemia.
急性呼吸衰竭可导致严重低氧血症,并在数分钟内导致器官损伤或死亡。当常规干预措施无效时,静脉注射氧气可将患者从严重的低氧血症中解救出来,但存在微血管阻塞和载体材料中毒的风险。在这里,我们描述了聚合物微气泡作为大容量氧气(每升泡沫中含有 350-500 毫升氧气)的载体,它在储存过程中非常稳定,但在静脉注射后会迅速溶解,恢复成可溶解和可排泄的分子成分。在因急性和暂时性(12 分钟)上气道阻塞而出现严重低氧血症的猪身上,微气泡介导的氧气输送可:维持临界氧饱和度、降低心脏骤停的负担、提高存活率以及显著改善存活动物的神经和肾功能。我们的研究结果强调了维持临界氧合阈值的重要性,以及注射氧作为急性和暂时性低氧血症危机的可行疗法的前景。
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引用次数: 0
Interpretable discovery of patterns in tabular data via spatially semantic topographic maps 通过空间语义地形图在表格数据中发现可解释的模式
IF 28.1 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-10-15 DOI: 10.1038/s41551-024-01268-6
Rui Yan, Md Tauhidual Islam, Lei Xing

Tabular data—rows of samples and columns of sample features—are ubiquitously used across disciplines. Yet the tabular representation makes it difficult to discover underlying associations in the data and thus hinders their analysis and the discovery of useful patterns. Here we report a broadly applicable strategy for unravelling intertwined relationships in tabular data by reconfiguring each data sample into a spatially semantic 2D topographic map, which we refer to as TabMap. A TabMap preserves the original feature values as pixel intensities, with the relationships among the features spatially encoded in the map (the strength of two inter-related features correlates with their distance on the map). TabMap makes it possible to apply 2D convolutional neural networks to extract association patterns in the data to aid data analysis, and offers interpretability by ranking features according to importance. We show the superior predictive performance of TabMap by applying it to 12 datasets across a wide range of biomedical applications, including disease diagnosis, human activity recognition, microbial identification and the analysis of quantitative structure–activity relationships.

表格数据--样本的行和样本特征的列--在各学科中普遍使用。然而,表格表示法难以发现数据中的潜在关联,从而阻碍了对数据的分析和有用模式的发现。在这里,我们报告了一种广泛适用的策略,通过将每个数据样本重新配置为具有空间语义的二维地形图(我们称之为 TabMap),来揭示表格数据中错综复杂的关系。TabMap 将原始特征值保留为像素强度,并在地图中对特征之间的关系进行空间编码(两个相互关联的特征的强度与它们在地图上的距离相关)。TabMap 可以应用二维卷积神经网络来提取数据中的关联模式,以帮助数据分析,并根据重要性对特征进行排序,从而提供可解释性。我们将 TabMap 应用于 12 个数据集,展示了它在疾病诊断、人类活动识别、微生物鉴定和定量结构-活性关系分析等广泛生物医学应用领域的卓越预测性能。
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引用次数: 0
Synthetic chest X-ray images from text prompts 根据文字提示合成胸部 X 光图像
IF 28.1 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-10-07 DOI: 10.1038/s41551-024-01261-z
Daniel Truhn, Jakob Nikolas Kather
A latent diffusion model pre-trained on pairs of natural images and text descriptors can be adapted to generate realistic chest radiographs that are controlled by free-form medical text prompts.
在自然图像和文本描述符对上预先训练的潜在扩散模型可用于生成由自由格式医学文本提示控制的逼真胸片。
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引用次数: 0
Immunometabolic cues recompose and reprogram the microenvironment around implanted biomaterials 免疫代谢线索对植入生物材料周围的微环境进行重组和重编程
IF 26.8 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-10-04 DOI: 10.1038/s41551-024-01260-0
Chima V. Maduka, Axel D. Schmitter-Sánchez, Ashley V. Makela, Evran Ural, Katlin B. Stivers, Hunter Pope, Maxwell M. Kuhnert, Oluwatosin M. Habeeb, Anthony Tundo, Mohammed Alhaj, Artem Kiselev, Shoue Chen, Alexis Donneys, Wade P. Winton, Jenelle Stauff, Peter J. H. Scott, Andrew J. Olive, Kurt D. Hankenson, Ramani Narayan, Sangbum Park, Jennifer H. Elisseeff, Christopher H. Contag
Circulating monocytes infiltrate and coordinate immune responses in tissues surrounding implanted biomaterials and in other inflamed tissues. Here we show that immunometabolic cues in the biomaterial microenvironment govern the trafficking of immune cells, including neutrophils and monocytes, in a manner dependent on the chemokine receptor 2 (CCR2) and the C-X3-C motif chemokine receptor 1 (CX3CR1). This affects the composition and activation states of macrophage and dendritic cell populations, ultimately orchestrating the relative composition of pro-inflammatory, transitory and anti-inflammatory CCR2+, CX3CR1+ and CCR2+ CX3CR1+ immune cell populations. In amorphous polylactide implants, modifying immunometabolism by glycolytic inhibition drives a pro-regenerative microenvironment principally by myeloid cells. In crystalline polylactide implants, together with arginase-1-expressing myeloid cells, T helper 2 cells and γδ+ T cells producing interleukin-4 substantially contribute to shaping the metabolically reprogrammed pro-regenerative microenvironment. Our findings inform the premise that local metabolic states regulate inflammatory processes in the biomaterial microenvironment. Immunometabolic cues surrounding implanted biomaterials govern the trafficking of subsets of neutrophils, monocytes and other immune cells, and determine the relative composition of pro-inflammatory and anti-inflammatory immune cell populations.
循环中的单核细胞在植入的生物材料周围组织和其他发炎组织中浸润并协调免疫反应。在这里,我们展示了生物材料微环境中的免疫代谢线索以一种依赖于趋化因子受体 2(CCR2)和 C-X3-C motif 趋化因子受体 1(CX3CR1)的方式控制着包括中性粒细胞和单核细胞在内的免疫细胞的迁移。这会影响巨噬细胞和树突状细胞群的组成和活化状态,最终协调促炎性、暂时性和抗炎性 CCR2+、CX3CR1+ 和 CCR2+ CX3CR1+ 免疫细胞群的相对组成。在无定形聚乳酸植入物中,通过抑制糖酵解来改变免疫代谢,从而主要通过髓系细胞来推动有利于再生的微环境。在结晶聚乳酸植入物中,T辅助2细胞和产生白细胞介素-4的γδ+ T细胞与表达精氨酸酶-1的髓系细胞一起,为塑造代谢重编程的促再生微环境做出了重大贡献。我们的研究结果证明了一个前提,即局部代谢状态可调节生物材料微环境中的炎症过程。
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引用次数: 0
Amine headgroups in ionizable lipids drive immune responses to lipid nanoparticles by binding to the receptors TLR4 and CD1d 可离子化脂质中的胺头基通过与 TLR4 和 CD1d 受体结合驱动对纳米脂质颗粒的免疫反应
IF 26.8 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-10-03 DOI: 10.1038/s41551-024-01256-w
Namit Chaudhary, Lisa N. Kasiewicz, Alexandra N. Newby, Mariah L. Arral, Saigopalakrishna S. Yerneni, Jilian R. Melamed, Samuel T. LoPresti, Katherine C. Fein, Daria M. Strelkova Petersen, Sushant Kumar, Rahul Purwar, Kathryn A. Whitehead
Lipid nanoparticles (LNPs) are the most clinically advanced delivery vehicle for RNA therapeutics, partly because of established lipid structure–activity relationships focused on formulation potency. Yet such knowledge has not extended to LNP immunogenicity. Here we show that the innate and adaptive immune responses elicited by LNPs are linked to their ionizable lipid chemistry. Specifically, we show that the amine headgroups in ionizable lipids drive LNP immunogenicity by binding to Toll-like receptor 4 and CD1d and by promoting lipid-raft formation. Immunogenic LNPs favour a type-1 T-helper-cell-biased immune response marked by increases in the immunoglobulins IgG2c and IgG1 and in the pro-inflammatory cytokines tumour necrosis factor, interferon γ and the interleukins IL-6 and IL-2. Notably, the inflammatory signals originating from these receptors inhibit the production of anti-poly(ethylene glycol) IgM antibodies, preventing the often-observed loss of efficacy in the LNP-mediated delivery of siRNA and mRNA. Moreover, we identified computational methods for the prediction of the structure-dependent innate and adaptive responses of LNPs. Our findings may help accelerate the discovery of well-tolerated ionizable lipids suitable for repeated dosing. Amine headgroups in ionizable lipids drive the immunogenicity of lipid nanoparticles by binding to Toll-like receptor 4 and CD1d and by promoting lipid-raft formation.
脂质纳米颗粒(LNPs)是临床上最先进的 RNA 治疗药物递送载体,部分原因是脂质结构与活性的关系已经确立,重点在于配方的有效性。然而,这些知识尚未扩展到 LNP 的免疫原性。在这里,我们证明了 LNPs 引起的先天性和适应性免疫反应与其可电离的脂质化学性质有关。具体来说,我们发现可离子化脂质中的胺头基通过与 Toll 样受体 4 和 CD1d 结合以及促进脂质移植物的形成来驱动 LNP 的免疫原性。免疫原性 LNP 有利于 1 型 T 辅助细胞为主的免疫反应,其特征是免疫球蛋白 IgG2c 和 IgG1 以及促炎细胞因子肿瘤坏死因子、干扰素 γ 和白细胞介素 IL-6 和 IL-2 的增加。值得注意的是,来自这些受体的炎症信号抑制了抗聚乙二醇 IgM 抗体的产生,从而避免了在 LNP 介导的 siRNA 和 mRNA 传输过程中经常出现的功效损失。此外,我们还找到了预测 LNPs 结构依赖性先天反应和适应性反应的计算方法。我们的发现可能有助于加快发现耐受性良好、适合重复给药的可电离脂质。
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引用次数: 0
Accurate prediction of disease-risk factors from volumetric medical scans by a deep vision model pre-trained with 2D scans 用二维扫描预训练的深度视觉模型从体积医学扫描中准确预测疾病风险因素
IF 28.1 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-10-01 DOI: 10.1038/s41551-024-01257-9
Oren Avram, Berkin Durmus, Nadav Rakocz, Giulia Corradetti, Ulzee An, Muneeswar G. Nittala, Prerit Terway, Akos Rudas, Zeyuan Johnson Chen, Yu Wakatsuki, Kazutaka Hirabayashi, Swetha Velaga, Liran Tiosano, Federico Corvi, Aditya Verma, Ayesha Karamat, Sophiana Lindenberg, Deniz Oncel, Louay Almidani, Victoria Hull, Sohaib Fasih-Ahmad, Houri Esmaeilkhanian, Maxime Cannesson, Charles C. Wykoff, Elior Rahmani, Corey W. Arnold, Bolei Zhou, Noah Zaitlen, Ilan Gronau, Sriram Sankararaman, Jeffrey N. Chiang, Srinivas R. Sadda, Eran Halperin

The application of machine learning to tasks involving volumetric biomedical imaging is constrained by the limited availability of annotated datasets of three-dimensional (3D) scans for model training. Here we report a deep-learning model pre-trained on 2D scans (for which annotated data are relatively abundant) that accurately predicts disease-risk factors from 3D medical-scan modalities. The model, which we named SLIViT (for ‘slice integration by vision transformer’), preprocesses a given volumetric scan into 2D images, extracts their feature map and integrates it into a single prediction. We evaluated the model in eight different learning tasks, including classification and regression for six datasets involving four volumetric imaging modalities (computed tomography, magnetic resonance imaging, optical coherence tomography and ultrasound). SLIViT consistently outperformed domain-specific state-of-the-art models and was typically as accurate as clinical specialists who had spent considerable time manually annotating the analysed scans. Automating diagnosis tasks involving volumetric scans may save valuable clinician hours, reduce data acquisition costs and duration, and help expedite medical research and clinical applications.

由于用于模型训练的三维(3D)扫描注释数据集有限,机器学习在涉及容积生物医学成像任务中的应用受到限制。在此,我们报告了一种在二维扫描(注释数据相对丰富)上预先训练的深度学习模型,该模型能从三维医学扫描模式中准确预测疾病风险因素。我们将该模型命名为 SLIViT(意为 "通过视觉转换器进行切片整合"),它将给定的容积扫描预处理为二维图像,提取其特征图,并将其整合为一个预测结果。我们在八个不同的学习任务中对该模型进行了评估,包括涉及四种容积成像模式(计算机断层扫描、磁共振成像、光学相干断层扫描和超声波)的六个数据集的分类和回归。SLIViT 的表现始终优于特定领域的最先进模型,其准确性通常不亚于花费大量时间手动标注分析扫描结果的临床专家。将涉及容积扫描的诊断任务自动化,可以节省临床医生的宝贵时间,降低数据采集成本,缩短数据采集时间,并有助于加快医学研究和临床应用。
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引用次数: 0
A fast all-optical 3D photoacoustic scanner for clinical vascular imaging 用于临床血管成像的快速全光三维光声扫描仪
IF 28.1 1区 医学 Q1 ENGINEERING, BIOMEDICAL Pub Date : 2024-09-30 DOI: 10.1038/s41551-024-01247-x
N. T. Huynh, E. Zhang, O. Francies, F. Kuklis, T. Allen, J. Zhu, O. Abeyakoon, F. Lucka, M. Betcke, J. Jaros, S. Arridge, B. Cox, A. A. Plumb, P. Beard

The clinical assessment of microvascular pathologies (in diabetes and in inflammatory skin diseases, for example) requires the visualization of superficial vascular anatomy. Photoacoustic tomography (PAT) scanners based on an all-optical Fabry–Perot ultrasound sensor can provide highly detailed 3D microvascular images, but minutes-long acquisition times have precluded their clinical use. Here we show that scan times can be reduced to a few seconds and even hundreds of milliseconds by parallelizing the optical architecture of the sensor readout, by using excitation lasers with high pulse-repetition frequencies and by exploiting compressed sensing. A PAT scanner with such fast acquisition minimizes motion-related artefacts and allows for the volumetric visualization of individual arterioles, venules, venous valves and millimetre-scale arteries and veins to depths approaching 15 mm, as well as for dynamic 3D images of time-varying tissue perfusion and other haemodynamic events. In exploratory case studies, we used the scanner to visualize and quantify microvascular changes associated with peripheral vascular disease, skin inflammation and rheumatoid arthritis. Fast all-optical PAT may prove useful in cardiovascular medicine, oncology, dermatology and rheumatology.

微血管病变(例如糖尿病和炎症性皮肤病)的临床评估需要表层血管解剖的可视化。基于全光学法布里-珀罗超声传感器的光声层析(PAT)扫描仪可以提供非常详细的三维微血管图像,但长达几分钟的采集时间使其无法用于临床。在这里,我们展示了通过并行化传感器读出的光学结构、使用高脉冲重复频率的激发激光器以及利用压缩传感技术,扫描时间可以缩短到几秒甚至几百毫秒。具有这种快速采集功能的 PAT 扫描仪能最大限度地减少与运动相关的伪影,并能对单个动脉血管、静脉、静脉瓣膜和毫米级的动脉和静脉(深度接近 15 毫米)进行容积可视化,以及对随时间变化的组织灌注和其他血流动力学事件进行动态三维成像。在探索性案例研究中,我们使用该扫描仪对与外周血管疾病、皮肤炎症和类风湿性关节炎相关的微血管变化进行了可视化和量化。快速全光 PAT 可能会在心血管医学、肿瘤学、皮肤病学和风湿病学领域大有用武之地。
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引用次数: 0
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