JID innovations : skin science from molecules to population health最新文献

Corrigendum to ‘Proteomic Profiling of CCCA Reveals Role of Humoral Immune Response Pathway and Metabolic Dysregulation’ JID Innovations, Volume 4, Issue 3, May 2024, 100263 CCCA的蛋白质组学分析揭示了体液免疫反应途径和代谢失调的作用》的更正，《JID创新》，第4卷第3期，2024年5月，100263页

JID innovations : skin science from molecules to population health

Pub Date : 2024-11-01 DOI: 10.1016/j.xjidi.2024.100312

引用次数: 0

Identification of Associations with Dermatologic Diseases through a Focused GWAS of the UK Biobank 通过英国生物库的重点基因组研究确定皮肤病的相关性

JID innovations : skin science from molecules to population health

Pub Date : 2024-10-26 DOI: 10.1016/j.xjidi.2024.100322

Jason C. Klein , Ruchika Mahapatra , Gary C. Hon , Richard C. Wang

The UK Biobank includes genotype information for about 500,000 patients for over 7000 phenotypes. However, owing to multiple testing correction for approximately 200 billion tests, many clinically and statistically significant associations remain unappreciated. We perform a focused analysis of the UK Biobank for 13 dermatologic conditions, including malignant melanoma, melanoma in situ, squamous cell carcinoma, basal cell carcinoma, actinic keratosis, seborrheic keratosis, psoriasis, lichen planus, systemic lupus erythematosus, hyperhidrosis, pilonidal cyst, sebaceous cyst, and lipoma. We identify 447 sentinel variants, which are enriched for protein-coding variants and an elevated combined annotation-dependent depletion (CADD) score compared with background variants. Through gene ontology enrichment analysis, we identify known pathways involved in melanoma, actinic keratoses, and squamous cell carcinoma and uncover additional pathways. We also uncover 5 protein-coding variants, which, to our knowledge, have not been previously reported, including LRP3 for lipomas, PLCD1 for sebaceous cysts, EIF3CL for lichen planus, TTK for pilonidal cysts, and MAPK15 for systemic lupus erythematosus.

英国生物库包括约 50 万名患者 7000 多种表型的基因型信息。然而，由于对约 2,000 亿次检测进行了多重检测校正，许多具有临床和统计学意义的关联仍未得到重视。我们对英国生物库中的 13 种皮肤病进行了重点分析，包括恶性黑色素瘤、原位黑色素瘤、鳞状细胞癌、基底细胞癌、光化性角化病、脂溢性角化病、银屑病、扁平苔藓、系统性红斑狼疮、多汗症、皮样囊肿、皮脂腺囊肿和脂肪瘤。我们发现了 447 个哨点变异，这些变异富含蛋白质编码变异，与背景变异相比，综合注释依赖性损耗（CADD）得分较高。通过基因本体富集分析，我们确定了涉及黑色素瘤、光化性角化病和鳞状细胞癌的已知通路，并发现了其他通路。我们还发现了 5 种蛋白质编码变异，据我们所知，这些变异以前从未报道过，其中包括脂肪瘤的 LRP3、皮脂腺囊肿的 PLCD1、扁平苔藓的 EIF3CL、朝天鼻囊肿的 TTK 和系统性红斑狼疮的 MAPK15。

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引用次数: 0

From Plant to Patient: A Historical Perspective and Review of Selected Medicinal Plants in Dermatology 从植物到病人：皮肤病学中的部分药用植物的历史视角与回顾

JID innovations : skin science from molecules to population health

Pub Date : 2024-10-25 DOI: 10.1016/j.xjidi.2024.100321

Aygun Israyilova , Tsvetomira Zhivkova Peykova , Ben Kittleson , Paul Caleb Sprowl , Taha Osman Mohammed , Cassandra L. Quave

Skin conditions are a common health concern faced by patients of all ages. For thousands of years, plants have been used to treat various skin conditions, including acne, vitiligo, and psoriasis, to name a few. Today, with increasing patient preference for natural therapies, modern medicine is now more than ever incorporating age-old knowledge of herbal remedies useful in treating skin conditions into modern-day treatments. This review covers various plant-derived therapeutics (polyphenon E [sincatechins], psoralen, salicylic acid, anthralin, podophyllotoxin, and Filsuvez [birch triterpenes, oleogel-S10]) that have demonstrated scientific evidence of clinical efficacy for dermatologic disorders. The discovery, composition, history of use, and current uses in dermatology are summarized for each botanical ingredient.

皮肤病是各个年龄段的患者都会面临的常见健康问题。几千年来，植物一直被用来治疗各种皮肤病，包括痤疮、白癜风和银屑病等等。如今，随着患者对自然疗法的偏爱与日俱增，现代医学比以往任何时候都更加重视将古老的草药治疗皮肤病的知识融入到现代治疗中。本综述涵盖了各种植物提取的疗法（多酚 E [sincatechins]、补骨脂素、水杨酸、蒽林、荚叶菌素和 Filsuvez [birch triterpenes, oleogel-S10]），这些疗法已被科学证明对皮肤病具有临床疗效。本文概述了每种植物成分的发现、组成、使用历史和目前在皮肤病学中的用途。

引用次数: 0

Spatial Transcriptomics in Inflammatory Skin Diseases Using GeoMx Digital Spatial Profiling: A Practical Guide for Applications in Dermatology 利用 GeoMx 数字空间剖析技术研究炎症性皮肤病的空间转录组学：皮肤病学应用实用指南

JID innovations : skin science from molecules to population health

Pub Date : 2024-09-27 DOI: 10.1016/j.xjidi.2024.100317

Christina Cho , Nazgol-Sadat Haddadi , Michal Kidacki , Gavitt A. Woodard , Saeed Shakiba , Ümmügülsüm Yıldız-Altay , Jillian M. Richmond , Matthew D. Vesely

The spatial organization of the skin is critical for its function. In particular, the skin immune microenvironment is arranged spatially and temporally, such that imbalances in the immune milieu are indicative of disease. Spatial transcriptomic platforms are helping to provide additional insights into aberrant inflammation in tissues that are not captured by tissue processing required for single-cell RNA sequencing. In this paper, we discuss a technical and user experience overview of NanoString's GeoMx Digital Spatial Profiler to perform in-depth spatial analysis of the transcriptome in inflammatory skin diseases. Our objective is to provide potential pitfalls and methods to optimize RNA capture that are not readily available in the manufacturer’s guidelines. We use concrete examples from our experiments to demonstrate these strategies in inflammatory skin diseases, including psoriasis, lichen planus, and discoid lupus erythematosus. Overall, we hope to illustrate the potential of digital spatial profiling to dissect skin disease pathogenesis in a spatially resolved manner and provide a framework for other skin biology investigators using digital spatial profiling.

皮肤的空间组织对其功能至关重要。特别是，皮肤免疫微环境在空间和时间上都有安排，因此免疫环境的失衡是疾病的征兆。空间转录组平台有助于深入了解单细胞 RNA 测序所需的组织处理无法捕获的组织中的异常炎症。在本文中，我们将讨论 NanoString 的 GeoMx 数字空间分析仪的技术和用户体验概览，该分析仪可对炎症性皮肤病的转录组进行深入的空间分析。我们的目标是提供制造商指南中没有的潜在隐患和优化 RNA 捕获的方法。我们将利用实验中的具体实例来展示这些策略在炎症性皮肤病（包括银屑病、扁平苔藓和盘状红斑狼疮）中的应用。总之，我们希望说明数字空间轮廓分析在以空间分辨的方式剖析皮肤病发病机制方面的潜力，并为其他使用数字空间轮廓分析的皮肤生物学研究人员提供一个框架。

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引用次数: 0

Skin & Digital: The 2023 Startups/Innovators 皮肤与数字2023 年初创企业/创新者

JID innovations : skin science from molecules to population health

Pub Date : 2024-09-19 DOI: 10.1016/j.xjidi.2024.100316

Dominique du Crest , Philipp Wustrow , Oliver Worsley , Barbara Geusens , Omar Badri , Monisha Madhumita , Art Papier , Alexander Zink , Merete Hædersdal , Lilit Garibyan

引用次数: 0

Advances in Microengineered Platforms for Skin Research 微工程皮肤研究平台的进展

JID innovations : skin science from molecules to population health

Pub Date : 2024-09-18 DOI: 10.1016/j.xjidi.2024.100315

Sireesh Kumar Teertam , Vijayasaradhi Setaluri , Jose M. Ayuso

The skin plays a critical role in human physiology, acting both as a barrier to environmental insults and as a window to environmental stimuli. Disruption of this homeostasis leads to numerous skin disorders. Human and animal skin differ significantly, limiting the translational potential of animal-based investigations to advance therapeutics to human skin diseases. Hence, there is a critical need for physiologically relevant human skin models to explore novel treatment strategies. Recent advances in microfluidic technologies now allow design and generation of organ-on-chip devices that mimic critical features of tissue architecture. Skin-on-a-chip and microfluidic platforms hold promise as useful models for diverse dermatology applications. Compared with traditional in vitro models, microfluidic platforms offer improved control of fluid flow, which in turn allows precise manipulation of cell and molecular distribution. These properties enable the generation of multilayered in vitro models that mimic human skin structure while simultaneously offering superior control over nutrient and drug distribution. Researchers have used microfluidic platforms for a variety of applications in skin research, including epidermal–dermal cellular crosstalk, cell migration, mechanobiology, microbiome–immune response interactions, vascular biology, and wound healing. In this review, we comprehensively review state-of-the-art microfluidic models for skin research. We discuss the challenges and promise of current skin-on-a-chip technologies and provide a roadmap for future research in this active field.

皮肤在人体生理中起着至关重要的作用，它既是抵御环境伤害的屏障，也是接受环境刺激的窗口。这种平衡状态的破坏会导致许多皮肤疾病。人类和动物的皮肤差异很大，这限制了以动物为基础的研究在促进人类皮肤病治疗方面的转化潜力。因此，亟需与生理相关的人类皮肤模型来探索新的治疗策略。微流体技术的最新进展现在可以设计和生成模拟组织结构关键特征的片上器官装置。片上皮肤和微流控平台有望成为各种皮肤病学应用的有用模型。与传统的体外模型相比，微流体平台能更好地控制流体流动，进而精确控制细胞和分子的分布。这些特性使多层体外模型得以产生，在模仿人体皮肤结构的同时，还能对营养物质和药物的分布进行出色的控制。研究人员已将微流控平台用于皮肤研究的多种应用，包括表皮-真皮细胞串联、细胞迁移、机械生物学、微生物-免疫反应相互作用、血管生物学和伤口愈合。在这篇综述中，我们全面回顾了最先进的皮肤研究微流控模型。我们讨论了当前片上皮肤技术所面临的挑战和前景，并为这一活跃领域的未来研究提供了路线图。

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引用次数: 0

Transcriptomic Analyses Predict Enhanced Metabolic Activity and Therapeutic Potential of mTOR Inhibitors in Acne-Prone Skin 转录组分析预测了 mTOR 抑制剂在痤疮皮肤中增强的代谢活性和治疗潜力

JID innovations : skin science from molecules to population health

Pub Date : 2024-09-07 DOI: 10.1016/j.xjidi.2024.100306

Mackenzie L. Sennett , George W. Agak , Diane M. Thiboutot , Amanda M. Nelson

Current acne therapies center on preventing new lesions in patients with acne. These therapies were historically found to be beneficial yet were chosen without knowledge of the specific changes in the skin that favor lesion development. A major challenge in developing new treatments is the incomplete understanding of nonlesional (NL), acne-prone skin’s molecular characteristics. To address this, we compared RNA-sequencing data from NL skin of 49 patients with acne (denoted as NL acne [NLA]) with those from 19 healthy controls with no acne history. We found 77 differentially expressed genes in NLA (log fold change > 1; P < .05), including genes associated with innate immunity and epidermal barrier function. Notably, KRT6C, KRT16, S100A8, S100A9, and lactotransferrin were upregulated, and LCE4A, LCE6A, and CTSE were downregulated. Gene set enrichment analysis revealed that metabolic pathways were enriched in NLA skin, whereas keratinization was negatively enriched. To identify compounds that could shift the gene expression signature of NLA skin toward healthy control skin, we performed connectivity mapping with the Library of Integrated Network-Based Signatures. We identified 187 compounds, particularly mTOR inhibitors, that could potentially normalize the gene expression profile of acne-prone skin to that of healthy skin. Our findings indicate that NLA skin has distinct differences in epidermal differentiation, cellular metabolism, and innate immunity that may promote lesion formation and suggest that mTOR inhibitors could restore NLA skin toward a healthier state, potentially reversing the predisposition to lesion development.

目前的痤疮疗法主要是防止痤疮患者出现新的皮损。这些疗法历来被认为是有益的，但在选择这些疗法时，人们并不了解有利于皮损发展的皮肤的具体变化。开发新疗法面临的一大挑战是对非皮损性（NL）痤疮易发皮肤分子特征的不完全了解。为了解决这个问题，我们比较了 49 名痤疮患者（简称为 NL 型痤疮 [NLA]）的 NL 型皮肤与 19 名无痤疮史的健康对照者的 RNA 序列数据。我们在 NLA 中发现了 77 个差异表达基因（对数折叠变化为 1；P 为 0.05），其中包括与先天免疫和表皮屏障功能相关的基因。值得注意的是，KRT6C、KRT16、S100A8、S100A9 和乳转铁蛋白被上调，而 LCE4A、LCE6A 和 CTSE 被下调。基因组富集分析表明，新陈代谢途径在 NLA 皮肤中富集，而角质化则呈负富集。为了找出能使 NLA 皮肤的基因表达特征向健康对照皮肤转变的化合物，我们利用基于综合网络特征库进行了连接图谱分析。我们发现了 187 种化合物，尤其是 mTOR 抑制剂，它们有可能使痤疮皮肤的基因表达谱正常化，与健康皮肤的基因表达谱一致。我们的研究结果表明，NLA 皮肤在表皮分化、细胞代谢和先天性免疫方面存在明显差异，这些差异可能会促进皮损的形成。

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引用次数: 0

Long-Term Safety and Efficacy of Lenabasum, a Cannabinoid Receptor Type 2 Agonist, in Patients with Dermatomyositis with Refractory Skin Disease: Follow-Up Data from a 3-Year Open-Label Extension Study 大麻素受体 2 型激动剂 Lenabasum 对患有难治性皮肤病的皮肌炎患者的长期安全性和疗效：一项为期 3 年的开放标签扩展研究的随访数据

JID innovations : skin science from molecules to population health

Pub Date : 2024-09-05 DOI: 10.1016/j.xjidi.2024.100311

Caroline J. Stone , Geeta Ahuja , Lais Lopes Almeida Gomes , Joy Poroye , Daniella Forman Faden , Lillian Xie , Rui Feng , Barbara White , Victoria P. Werth

Background

Dermatomyositis (DM) is a rare autoimmune condition involving skin manifestations often resistant to standard treatments such as immunosuppressants and antimalarials. Biopsies show elevated inflammatory cells such as CD4+ T cells, dendritic cells, and cytokines. Lenabasum, a selective cannabinoid receptor 2 agonist, has demonstrated significant benefits in treating autoimmune skin diseases. Objectives: This study utilizes data from the open-label extension (OLE) phase of the lenabasum phase 2 trial and additional post-OLE follow-up data. Key aims include evaluating the drug’s long-term effectiveness and assessing disease manifestation recurrence. Methods: The phase 2 lenabasum trial enrolled patients with treatment-resistant, skin-predominant DM. The OLE consisted of a 3-year period during which 20 patients were on the drug for the entire duration, with assessments every 8 weeks to evaluate drug safety and efficacy. Subsequently, a follow-up retrospective chart review was performed on patients who completed the OLE as well as on control subjects with DM who did not participate in the lenabasum trial. Results: By week 68, patients exhibited reductions in Cutaneous Dermatomyositis Disease Area and Severity Index activity score (−21.8), Patient Skin Activity Visual Analog Scale (−3.0), and Skindex-29 (−28.0) from OLE baseline. After OLE, 58.3% maintained stable disease, significantly higher than controls (P = .035), with 41.7% not experiencing flares compared with 91.6% of controls. In addition, 50% of patients reported sustained pruritus improvement. Conclusions: Data from OLE and subsequent follow-up periods demonstrate lenabasum’s efficacy in maintaining disease stability, reducing flares, and improving DM symptoms, suggesting that it is a promising option for patients with treatment-resistant skin-predominant DM. Trial Registration: This study was registered at clinicaltrials.gov, with NCT02466243. Study registration was first submitted on June 2, 2015.

背景皮肌炎（Dermatomyositis，DM）是一种罕见的自身免疫性疾病，患者的皮肤表现往往对免疫抑制剂和抗疟药等标准疗法产生抗药性。活组织检查显示 CD4+ T 细胞、树突状细胞和细胞因子等炎症细胞升高。莱那巴苏姆是一种选择性大麻素受体 2 激动剂，在治疗自身免疫性皮肤病方面有显著疗效。研究目的本研究利用来那巴苏姆二期试验开放标签延长（OLE）阶段的数据以及开放标签延长后的额外随访数据。主要目的包括评估该药物的长期疗效和疾病复发情况。研究方法来那巴苏姆2期试验招募了耐药的皮肤型DM患者。OLE为期3年，20名患者全程用药，每8周进行一次评估，以评价药物的安全性和有效性。随后，我们对完成OLE的患者以及未参加来那巴苏试验的DM对照组患者进行了随访回顾性病历审查。结果显示到第68周时，患者的皮肤皮肌炎疾病面积和严重程度指数活动评分（-21.8）、患者皮肤活动视觉模拟量表（-3.0）和Skindex-29（-28.0）与OLE基线相比均有所下降。OLE后，58.3%的患者病情保持稳定，明显高于对照组（P = 0.035），41.7%的患者没有复发，而对照组的这一比例为91.6%。此外，50% 的患者报告瘙痒症状持续改善。结论：来自OLE和后续随访期的数据表明来那巴苏在维持病情稳定、减少复发和改善DM症状方面具有疗效，这表明它是皮肤为主的DM耐药患者的一个很有前景的选择。试验注册：该研究已在 clinicaltrials.gov 注册，注册号为 NCT02466243。研究注册于2015年6月2日首次提交。

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引用次数: 0

Type 2 Cytokine–Dependent Skin Barrier Regulation in Personalized 2-Dimensional and 3-Dimensional Skin Models of Atopic Dermatitis: A Pilot Study 特应性皮炎个性化二维和三维皮肤模型中的 2 型细胞因子依赖性皮肤屏障调节：试点研究

JID innovations : skin science from molecules to population health

Pub Date : 2024-08-30 DOI: 10.1016/j.xjidi.2024.100309

Hila Emmert , Franziska Rademacher , Matthias Hübenthal , Regine Gläser , Hanne Norsgaard , Stephan Weidinger , Jürgen Harder

Keratinocytes (KCs) from healthy donors stimulated with type 2 cytokines are often used to experimentally study atopic dermatitis (AD) inflammatory responses. Owing to potential intrinsic alterations, it seems favorable to use KCs from patients with AD. KCs isolated from hair follicles offer a noninvasive approach to investigate AD-derived KCs. To evaluate whether such AD-derived KCs are suitable to mimic AD inflammatory responses, we compared hair follicle–derived KCs from healthy donors with those from patients with AD in a type 2 cytokine environment. Stimulation of AD-derived KCs with IL-4 and IL-13 induced higher expression changes of AD-associated markers than that of healthy KCs. The combination of IL-4 and IL-13 generally induced highest expression changes, but IL-13 alone also induced significant changes of AD-specific markers. Similar to the 2-dimensional cultures, IL-4/IL-13 stimulation of 3-dimensional skin models generated with AD-derived KCs modulated the expression of several AD-relevant factors. Whole-transcriptome analysis revealed that IL-4 and IL-13 acted similarly on these 3-dimensional skin models. Histologically, IL-13 alone and in combination with IL-4 increased epidermal spongiosis, a histological hallmark of AD skin. Taken together, our pilot study suggests that hair follicle–derived KCs from patients with AD represent a useful model system to study AD-related inflammation in a personalized in vitro model.

用 2 型细胞因子刺激健康供体的角质形成细胞（KCs）通常被用于特应性皮炎（AD）炎症反应的实验研究。由于潜在的内在改变，使用特应性皮炎患者的角质形成细胞似乎更为有利。从毛囊中分离出的 KC 为研究 AD 衍生的 KC 提供了一种非侵入性的方法。为了评估这种 AD 衍生的 KCs 是否适合模拟 AD 的炎症反应，我们比较了在 2 型细胞因子环境中来自健康供体的毛囊衍生 KCs 和来自 AD 患者的毛囊衍生 KCs。与健康KCs相比，用IL-4和IL-13刺激AD衍生KCs会诱发更高的AD相关标记物表达变化。一般来说，IL-4和IL-13的组合能诱导最高的表达变化，但单独使用IL-13也能诱导AD特异性标记物的显著变化。与二维培养相似，IL-4/IL-13刺激由AD衍生KCs生成的三维皮肤模型也会调节多种AD相关因子的表达。全转录组分析表明，IL-4和IL-13对这些三维皮肤模型的作用类似。从组织学角度看，IL-13单独或与IL-4联合使用都会增加表皮海绵状增生，这是AD皮肤的组织学特征。综上所述，我们的试验性研究表明，来自AD患者的毛囊衍生KC是在个性化体外模型中研究AD相关炎症的有用模型系统。

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引用次数: 0

Keratinocyte Integrin α3β1 Promotes Efficient Healing of Wound Epidermis 角质细胞整合素 α3β1 促进伤口表皮的有效愈合

JID innovations : skin science from molecules to population health

Pub Date : 2024-08-29 DOI: 10.1016/j.xjidi.2024.100310

Sanjana Dhulipalla , Giesse Albeche Duarte , Lei Wu , Mathieu R. DiPersio , John M. Lamar , C. Michael DiPersio , Whitney M. Longmate

To date, studies of the role for epidermal integrin α3β1 in cutaneous wound re-epithelialization have produced conflicting results: wound studies in skin from global α3-null neonatal mice have implicated the integrin in promoting timely wound re-epithelialization, whereas studies in adult mice with constitutive, epidermal-specific α3β1 deletion have not. The objective of this study was to utilize a model of inducible α3β1 deletion in the epidermis to clarify the role of α3β1 in the healing of adult wounds. We utilized the recently developed transgenic K14^Cre-ERT::α3^flx/flx mice (ie, inducible α3 epidermal knockout), permitting us to delete floxed Itga3 alleles (α3^flx/flx) from epidermis just prior to wounding with topical treatment of 4-hydroxytamoxifen. This allows for the elucidation of α3β1-dependent wound healing in adult skin, free from compensatory mechanisms that may occur after embryonic deletion of epidermal α3β1 in the widely used constitutive α3β1-knockout mouse. We found that re-epithelializing wound gaps are larger in inducible α3 epidermal knockout mice than in control mice, indicating delayed healing, and that epidermal integrin α3β1 promotes healing of wounds, at least in part by enhancing keratinocyte proliferation. This work provides essential rationale for future studies to investigate integrin α3β1 as a therapeutic target to facilitate wound healing.

迄今为止，有关表皮整合素α3β1在皮肤伤口再上皮化中的作用的研究得出了相互矛盾的结果：对全基因α3缺失的新生小鼠皮肤伤口的研究表明，整合素能促进伤口及时再上皮化，而对组成型表皮特异性α3β1缺失的成年小鼠的研究则没有发现这种作用。本研究的目的是利用表皮中可诱导的α3β1缺失模型来阐明α3β1在成人伤口愈合中的作用。我们利用最近开发的转基因K14Cre-ERT::α3flx/flx小鼠（即诱导性α3表皮基因敲除），在使用4-羟基他莫昔芬局部处理伤口之前，从表皮中删除浮性Itga3等位基因（α3flx/flx）。这样就可以阐明成年皮肤中α3β1依赖性伤口愈合的情况，而不需要考虑广泛使用的组成型α3β1基因敲除小鼠胚胎期缺失表皮α3β1后可能出现的代偿机制。我们发现，诱导性α3表皮基因敲除小鼠的伤口再表皮化间隙比对照小鼠大，表明伤口愈合延迟，表皮整合素α3β1至少部分通过增强角质形成细胞的增殖来促进伤口愈合。这项工作为今后研究将整合素α3β1作为促进伤口愈合的治疗靶点提供了重要依据。

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引用次数: 0