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Evidence for the major role of PH4⍺EFB in the prolyl 4-hydroxylation of Drosophila collagen IV PH4 - EFB在果蝇胶原脯氨酰4-羟基化中主要作用的证据。
IF 4.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-09-12 DOI: 10.1016/j.matbio.2025.09.002
Yoshihiro Ishikawa , Melissa A. Toups , Marwan Elkrewi , Allison L. Zajac , Sally Horne-Badovinac , Yutaka Matsubayashi
Collagens are fundamental components of extracellular matrices, requiring precise intracellular post-translational modifications for proper function. Among the modifications, prolyl 4-hydroxylation is critical to stabilise the collagen triple helix. In humans, this reaction is mediated by collagen prolyl 4-hydroxylases (P4Hs). While humans possess three genes encoding these enzymes (P4H⍺s), Drosophila melanogaster harbour at least 26 candidates for collagen P4H⍺s despite its simple genome, and it is poorly understood which of them are actually working on collagen in the fly. In this study, we addressed this question by carrying out thorough bioinformatic and biochemical analyses. We demonstrate that among the 26 potential collagen P4H⍺s, PH4⍺EFB shares the highest homology with vertebrate collagen P4H⍺s. Furthermore, while collagen P4Hs and their substrates must exist in the same cells, our transcriptomic analyses at the tissue and single cell levels showed a global co-expression of PH4⍺EFB but not the other P4H⍺-related genes with the collagen IV genes. Moreover, expression of PH4⍺EFB during embryogenesis was found to precede that of collagen IV, presumably enabling efficient collagen modification by PH4⍺EFB. Finally, biochemical assays confirm that PH4⍺EFB binds collagen, supporting its direct role in collagen IV modification. Collectively, we identify PH4⍺EFB as the primary and potentially constitutive prolyl 4-hydroxylase responsible for collagen IV biosynthesis in Drosophila. Our findings highlight the remarkably simple nature of Drosophila collagen IV biosynthesis, which may serve as a blueprint for defining the minimal requirements for collagen engineering.
胶原是细胞外基质的基本组成部分,需要精确的细胞内翻译后修饰才能发挥正常功能。在这些修饰中,脯氨酰4-羟基化对稳定胶原蛋白三螺旋结构至关重要。在人类中,这种反应是由胶原脯氨酸4-羟化酶(P4Hs)介导的。虽然人类拥有三个编码这些酶的基因(P4H s),但黑胃果蝇尽管基因组简单,但至少有26个候选蛋白P4H s,而且人们对其中哪些基因实际上对果蝇的胶原蛋白起作用知之甚少。在这项研究中,我们通过进行彻底的生物信息学和生化分析来解决这个问题。我们发现在26种潜在的胶原蛋白P4H中,PH4与脊椎动物胶原蛋白P4H具有最高的同源性。此外,虽然胶原P4Hs及其底物必须存在于相同的细胞中,但我们在组织和单细胞水平上的转录组学分析显示,PH4 EFB与胶原IV基因共表达,而其他P4H相关基因则不表达。此外,在胚胎发生过程中发现PH4 EFB的表达先于胶原IV,推测PH4 EFB可以有效地修饰胶原。最后,生化分析证实PH4能与胶原结合,支持其在IV型胶原修饰中的直接作用。总的来说,我们确定PH4是果蝇中负责胶原IV生物合成的主要和潜在组成的脯氨酸4-羟化酶。我们的研究结果强调了果蝇胶原IV生物合成的非常简单的性质,这可能作为确定胶原工程最低要求的蓝图。
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引用次数: 0
Exploring basement membrane dynamics through cross-scale imaging, manipulation, and molecular mapping 通过跨尺度成像、操作和分子作图探索基底膜动力学。
IF 4.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-09-02 DOI: 10.1016/j.matbio.2025.09.001
Kohei Omachi, Hironobu Fujiwara
The basement membrane (BM), a specialized extracellular matrix (ECM), provides structural support for epithelial, endothelial, and other parenchymal cells. Once considered a static scaffold, the BM is now recognized as a dynamic and complex nanostructure composed of a diversity of molecules that actively regulate cell behavior and tissue organization. Its molecular composition, assembly, and remodeling are precisely controlled in a tissue- and stage-specific manner, contributing to the regulation of local and global mechanical properties and biochemical signaling. Understanding BM structure and function requires integrated approaches across biological scales—from nanoscale molecular interactions to tissue-level architecture. In this review, we highlight advances in three methodological areas: (1) imaging techniques that reveal BM nanostructure and dynamics, (2) manipulation strategies that uncover causal roles of BM components, and (3) omics-based approaches that map BM composition and cellular sources. Integrating these strategies enables the bridging of molecular events and organ-level functions, offering new insights into how the BM is involved in development, homeostasis, and disease progression. The aim of this review is to provide researchers with a comprehensive perspective on evolving tools for dissecting BM structure, dynamics, and function.
基底膜(BM)是一种特殊的细胞外基质(ECM),为上皮细胞、内皮细胞和其他实质细胞提供结构支持。BM曾经被认为是一个静态支架,现在被认为是一个动态和复杂的纳米结构,由多种分子组成,积极调节细胞行为和组织组织。它的分子组成、组装和重塑以组织和阶段特异性的方式精确控制,有助于调节局部和全局的机械特性和生化信号。了解BM的结构和功能需要跨生物尺度的综合方法-从纳米级分子相互作用到组织级结构。在这篇综述中,我们强调了三个方法学领域的进展:(1)揭示BM纳米结构和动力学的成像技术,(2)揭示BM成分因果作用的操作策略,以及(3)基于组学的方法,绘制BM成分和细胞来源。整合这些策略可以将分子事件和器官水平功能连接起来,为脑转移如何参与发育、体内平衡和疾病进展提供新的见解。这篇综述的目的是为研究人员提供一个全面的视角,以了解不断发展的工具来解剖脑基底膜的结构、动力学和功能。
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引用次数: 0
Laminin γ1 chain is essential for the cardiorespiratory and muscular systems 层粘连蛋白γ - 1链对心肺和肌肉系统至关重要
IF 4.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-08-23 DOI: 10.1016/j.matbio.2025.08.006
Kinga I. Gawlik , Deniz A. Bölükbas , Fatima Daoud , Niccolò Peruzzi , Ellinor Welinder , Trevor S. Wendt , Marycarmen Arévalo Martinez , Sinem Tas , Johan Holmberg , Nika Gvazava , Saema Ansar , Sebastian Albinsson , Darcy Wagner , Karl Swärd , Karin Tran-Lundmark , Madeleine Durbeej
Laminins are basement membrane components that regulate a plethora of biological processes. Despite decades of research, the exact roles of laminins in different tissues and in organogenesis remain to be elucidated. Here, we investigated the function of laminin γ1 chain in heart, lung and other tissues by generating a mouse that lacks laminin γ1 in cells expressing SM22α (Tagln) (LMγ1 flox/SM22α Cre mouse, referred to as LMγ1KO). Laminin γ1 deletion led to basement membrane disruption around cardiomyocytes, smooth muscle cells, alveolar cells and skeletal muscle. This, in turn, led to perinatal death of conditional LMγ1KO mice. Synchrotron-based imaging revealed developmental heart abnormalities: ventricular and atrioventricular septal defects. Lung tissue from embryos and newborns showed impaired alveolization and this defect was not reversed ex vivo. We also created adult inducible laminin γ1 knockout mice (iLMγ1KO) with targeted knockdown in all tissues, and they exhibited decreased contractility of smooth muscle in colonic and arterial tissue. Finally, both LMγ1KO neonates and iLMγ1KO adults displayed severe dystrophic features in skeletal muscle.
In summary, our study reveals novel roles for laminin γ1 chain and basement membranes in heart, lung, skeletal and smooth muscle. Compromising basement membranes around various cell types expressing SM22α during embryonic development did not impair early organogenesis of lung, heart and skeletal muscle, but rather disturbed late developmental events in these tissues. Our results could help to understand clinical implications for patients with laminin α2 chain mutations (muscular dystrophy) and laminin α4 mutations (cardiomyopathy), but also for patients with congenital heart disease and lung diseases.
层粘连蛋白是调节大量生物过程的基膜成分。尽管经过几十年的研究,层粘连蛋白在不同组织和器官发生中的确切作用仍有待阐明。在此,我们通过在表达SM22α (Tagln)的细胞中产生缺乏层粘连蛋白γ1的小鼠(LMγ1 flox/SM22α Cre小鼠,简称LMγ1KO)来研究层粘连蛋白γ1链在心脏、肺和其他组织中的功能。层粘连蛋白γ - 1缺失导致心肌细胞、平滑肌细胞、肺泡细胞和骨骼肌周围的基底膜破坏。这进而导致条件性LMγ1KO小鼠的围产期死亡。基于同步加速器的成像显示发育性心脏异常:心室和房室间隔缺损。胚胎和新生儿的肺组织显示肺泡化受损,这种缺陷在体外不能逆转。我们还建立了成年诱导型层粘连蛋白γ1敲除小鼠(iLMγ1KO),在所有组织中都有靶向敲除,它们在结肠和动脉组织中表现出平滑肌收缩性降低。最后,iLMγ1KO新生儿和iLMγ1KO成人都表现出严重的骨骼肌营养不良特征。
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引用次数: 0
Loss of col4a1 in zebrafish recapitulates the cerebrovascular phenotypes associated with monogenic cerebral small vessel disease 斑马鱼col4a1的缺失再现了与单基因脑血管疾病相关的脑血管表型
IF 4.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-08-20 DOI: 10.1016/j.matbio.2025.08.005
Daisy Flatman , Richard W Naylor , Siobhan Crilly , Isabel Carter , Aleksandr Mironov , Emmanuel Pinteaux , Stuart M. Allan , Rachel Lennon , Paul R. Kasher
Cerebral small vessel disease (cSVD) is a major cause of vascular dementia and stroke. Our understanding of cSVD pathophysiology is incomplete and our ability to treat patients is limited. Pathogenic variants in type IV collagen alpha 1 (COL4A1) cause a monogenic form of cSVD with variable age of onset, via disturbance of cerebrovascular basement membranes. Zebrafish larvae are a powerful model organism for studying cerebrovascular disease due to their optical clarity and applicability for live imaging. In this study, we characterised a zebrafish crispant model for loss-of-function COL4A1-associated cSVD that successfully recapitulates key disease features, including spontaneous intracerebral haemorrhage and cerebrovascular abnormalities. We also identified evidence for abnormal cerebrovascular basement membranes and elevated matrix metalloproteinase 9 (mmp9) transcription associated with loss of col4a1. Pharmacological inhibition of mmp9 was sufficient to ameliorate some cerebrovascular phenotypes. Finally, we describe the generation of a mutant line carrying a germline-transmissible 20 bp deletion in zebrafish col4a1 (col4a1Δ20) which is associated with cerebrovascular abnormalities, swimming defects and increased susceptibility to pharmacologically induced brain haemorrhages during larval stages. In adulthood, mutant col4a1Δ20 animals developed spontaneous brain haemorrhages that were observable in free-swimming fish. Overall, this study validates the use of zebrafish disease modelling for preclinical COL4A1-associated cSVD research and highlights its potential for further understanding disease pathophysiology and future drug discovery projects.
脑血管病(cSVD)是血管性痴呆和中风的主要原因。我们对cSVD病理生理的理解是不完整的,我们治疗患者的能力是有限的。IV型胶原α 1 (COL4A1)的致病性变异通过扰乱脑血管基底膜导致单基因型cSVD,其发病年龄不同。斑马鱼幼鱼由于其光学清晰度和活体成像的适用性,是研究脑血管疾病的有力模式生物。在这项研究中,我们对col4a1相关的功能丧失cSVD的斑马鱼脆化模型进行了表征,该模型成功地概括了关键的疾病特征,包括自发性脑出血和脑血管异常。我们还发现了与col4a1缺失相关的脑血管基底膜异常和基质金属蛋白酶9 (mmp9)转录升高的证据。药理抑制mmp9足以改善一些脑血管表型。最后,我们描述了斑马鱼col4a1 (col4a1Δ20)中携带可种系传播的20bp缺失的突变系的产生,该缺失与幼虫期脑血管异常、游泳缺陷和对药物诱导的脑出血的易感性增加有关。成年后,突变col4a1Δ20动物发生自发性脑出血,在自由游动的鱼类中也可以观察到。总的来说,本研究验证了斑马鱼疾病模型在临床前col4a1相关cSVD研究中的应用,并强调了其在进一步了解疾病病理生理和未来药物发现项目方面的潜力。
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引用次数: 0
Corrigendum to “Decorin deficiency promotes epithelial-mesenchymal transition and colon cancer metastasis” [Matrix Biology Volume 95 (2021)1-14] “Decorin缺乏促进上皮-间质转化和结肠癌转移”的勘误[基质生物学卷95(2021)1-14]。
IF 4.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-08-16 DOI: 10.1016/j.matbio.2025.08.002
Liping Mao , Jinxue Yang , Jiaxin Yue , Yang Chen , Hongrui Zhou , Dongdong Fan , Qiuhua Zhang , Simone Buraschi , Renato V. Iozzo , Xiuli Bi
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引用次数: 0
Basement membrane structure and function: Relating biology to mechanics 基膜结构与功能:生物学与力学的关系。
IF 4.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-08-14 DOI: 10.1016/j.matbio.2025.08.004
Andrea Page-McCaw , Nicholas Ferrell
Basement membranes are key mediators of many biological processes such as epithelial morphogenesis, kidney filtration, and muscle function among others. Basement membranes provide structural support to tissues so understanding their mechanical properties is important for determining how they contribute to tissue form and function. Further, basement membranes are altered in many diseases including cancer, diabetes, and fibrosis, and these changes may contribute to disease pathogenesis and progression. Understanding how basement membrane mechanics integrate with tissue function is the work of both biologists and engineers/material scientists, yet these disciplines have very different foundations. This review discusses basement membrane macromolecular structure with a view to illuminate how this structure confers basement membranes with unique mechanical properties adapted to resisting physiological stresses. The pathological implications of altered basement membrane mechanics are discussed in the context of different diseases. Additionally, we survey methods used to measure basement membrane mechanical properties, including atomic force microscopy, tensile stiffness assays, and non-quantitative assays such as cell bursting, assessing their strengths and limitations and their accessibility for different types of in vivo studies. We focus on explaining and illuminating the complexities of basement membrane material properties for biologists, and explaining the biological aspects for engineers, with the goal of making interdisciplinary science more accessible to experimentalists and readers.
基底膜是许多生物过程的关键介质,如上皮形态发生、肾脏过滤和肌肉功能等。基底膜为组织提供结构支持,因此了解其力学特性对于确定它们如何影响组织形态和功能非常重要。此外,基底膜在许多疾病中发生改变,包括癌症、糖尿病和纤维化,这些改变可能有助于疾病的发病和进展。了解基底膜力学如何与组织功能相结合是生物学家和工程师/材料科学家的工作,然而这些学科有非常不同的基础。本文讨论了基底膜的大分子结构,以阐明这种结构如何赋予基底膜以适应生理应力的独特力学性能。在不同疾病的背景下讨论了基底膜力学改变的病理意义。此外,我们调查了用于测量基底膜力学性能的方法,包括原子力显微镜、拉伸刚度分析和非定量分析(如细胞破裂),评估了它们的优势和局限性,以及它们在不同类型体内研究中的可及性。我们专注于为生物学家解释和阐明基底膜材料特性的复杂性,并为工程师解释生物学方面的问题,目的是使实验家和读者更容易理解跨学科科学。
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引用次数: 0
Retraction Notice for “Novel regulatory roles of small leucine-rich proteoglycans in remodeling of the uterine cervix in pregnancy” [Matrix Biology, Volume 105, January 2022, Pages 53-71] “富含亮氨酸的小蛋白聚糖在妊娠期子宫颈重塑中的新调控作用”的撤回通知[基质生物学,第105卷,2022年1月,53-71页]
IF 4.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-08-12 DOI: 10.1016/j.matbio.2025.08.001
Mariano Colon-Caraballo , Nicole Lee , Shanmugasundaram Nallasamy , Kristin Myers , David Hudson , Renato V. Iozzo , Mala Mahendroo
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引用次数: 0
Heparan sulfate N-deacetylase/N-sulfotransferase-1 regulates glioblastoma cell migration and invasion 硫酸乙酰肝素n -去乙酰化酶/ n -硫转移酶-1调控胶质母细胞瘤细胞的迁移和侵袭。
IF 4.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-08-10 DOI: 10.1016/j.matbio.2025.08.003
Argyris Spyrou , Ananya Roy , Anqi Xiong , Soumi Kundu , Xi Lu , Ylva Jansson , Anna Falk , Christoph Riethmüller , Burkhard Greve , Martin Götte , Xinqi Chen , Lena Kjellén , Karin Forsberg-Nilsson
The glioblastoma (GBM) microenvironment undergoes adaptations to support tumor progression, including a dysregulated extracellular matrix, with altered heparan sulfate (HS) proteoglycans. We investigated N-deacetylase/N-sulfotransferase-1 (NDST1) because NDSTs are initial modifying enzymes of HS biosynthesis and have key roles in designing the HS sulfation pattern. This, in turn governs interactions with growth factors and other biomolecules. We report that NDST1 expression is lower in GBM than in the normal brain, and that patient-derived GBM cells, grown under neural stem cell culture conditions have lower levels of HS than normal astrocytes. Overexpression of NDST1 in GBM cells with low inherent NDST1 levels stimulates cell migration, reduce cell adhesion, induce EMT markers and increase invasion. Conversely, when NDST1 levels were reduced by shRNA in GBM cells, that had higher baseline expression, we find that invasion is reduced, and instead, self-renewal capacity increases alongside elevated stem cell marker expression. Moreover, overexpression of NDST1 changes chromatin accessibility of gene regulatory regions with the capacity to affect transcription factor expression, and pathways that favors cell motility and invasion. Furthermore, NDST1 overexpression results in increased activation of several receptor tyrosine kinases. This study shows that low NDST1 levels support GBM cell stemness, whereas high NDST1 levels endow tumor cells with a motile cell phenotype. We therefore propose that NDST1 is important for regulation of the balance between proliferation and invasive properties in GBM cells.
胶质母细胞瘤(GBM)微环境经历适应以支持肿瘤进展,包括细胞外基质失调,硫酸肝素(HS)蛋白聚糖改变。我们研究了n -去乙酰化酶/ n -硫转移酶-1 (NDST1),因为NDST1是HS生物合成的初始修饰酶,在设计HS磺化模式中起关键作用。这反过来又控制着与生长因子和其他生物分子的相互作用。我们报道了NDST1在GBM中的表达低于正常大脑,并且在神经干细胞培养条件下生长的患者来源的GBM细胞的HS水平低于正常星形胶质细胞。NDST1在固有NDST1水平较低的GBM细胞中过表达,可刺激细胞迁移,降低细胞粘附,诱导EMT标志物,增加侵袭。相反,当具有较高基线表达的GBM细胞中的NDST1水平被shRNA降低时,我们发现侵袭减少,相反,自我更新能力随着干细胞标记物表达的升高而增加。此外,NDST1的过表达改变了基因调控区域的染色质可及性,从而影响转录因子的表达,以及有利于细胞运动和侵袭的途径。此外,NDST1过表达导致几种受体酪氨酸激酶的激活增加。该研究表明,低NDST1水平支持GBM细胞的干性,而高NDST1水平赋予肿瘤细胞运动细胞表型。因此,我们认为NDST1在GBM细胞增殖和侵袭特性之间的平衡调节中很重要。
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引用次数: 0
Basement membranes in lung development, disease, and repair 基底膜在肺发育、疾病和修复中的作用。
IF 4.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-07-28 DOI: 10.1016/j.matbio.2025.07.007
Matilda Thuringer , Roy Zent , Rachel Lennon , Erin J. Plosa
The primary function of the respiratory system is the exchange of oxygen and carbon dioxide across the alveolar-capillary barrier in the distal lung. This structure is composed of alveolar epithelial cells (type 1 and type 2) and capillary endothelial cells, separated by a thin, fused alveolar basement membrane. The developmental programming that creates this specialized niche is largely unexplored and the role of lung basement membranes in respiratory disease pathogenesis and repair remains an emerging field of study. Thus, in this review, we discuss the distribution, composition, and function of the alveolar basement membrane, as well as the other three lung basement membranes that support the airway epithelium, airway smooth muscles, and the endothelium of the macrovasculature in lung development and disease.
呼吸系统的主要功能是通过远端肺的肺泡-毛细血管屏障交换氧气和二氧化碳。该结构由肺泡上皮细胞(1型和2型)和毛细血管内皮细胞组成,由一层薄薄的融合肺泡基底膜隔开。创造这种特殊生态位的发育程序在很大程度上尚未被探索,肺基底膜在呼吸系统疾病发病机制和修复中的作用仍然是一个新兴的研究领域。因此,在这篇综述中,我们讨论了肺泡基底膜的分布、组成和功能,以及在肺发育和疾病中支持气道上皮、气道平滑肌和大血管内皮的其他三种肺基底膜。
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引用次数: 0
Collagen diversity in human skin: Aging, wound healing, and disorders 胶原蛋白在人类皮肤的多样性:老化,伤口愈合和疾病。
IF 4.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-07-25 DOI: 10.1016/j.matbio.2025.07.006
Mélanie Salamito , Valérie Haydont , Hervé Pageon , Florence Ruggiero , Sarah Girardeau-Hubert
Collagen is an essential skin protein, accounting for 75 % of the skin’s dry weight. The collagen superfamily encompasses a diverse group of proteins with a variety of structures that fulfil a wide range of functions. The half-life of collagen in the skin is generally estimated at 10 to 15 years; however, the expression pattern of the different types of skin collagen varies throughout life. Both intrinsic and extrinsic factors influence collagen turn-over within the different skin layers. In this review, we discuss current knowledge of the different types of collagen present in human skin, focusing on insights gained from research exploring the dynamic roles of these proteins in skin development, homeostasis including aging, collagen-linked pathologies, adaptability in response to stress, and wound healing-related processes and disorders. Specificities of skin diversity due to ancestral origin and gender will also be discussed.
胶原蛋白是一种重要的皮肤蛋白质,占皮肤干重的75%。胶原蛋白超家族包括一组具有多种结构的蛋白质,这些蛋白质具有广泛的功能。皮肤中胶原蛋白的半衰期一般估计为10至15年;然而,不同类型的皮肤胶原蛋白的表达模式在人的一生中是不同的。内在和外在因素都会影响不同皮肤层内的胶原蛋白周转。在这篇综述中,我们讨论了目前对人类皮肤中不同类型胶原蛋白的了解,重点介绍了这些蛋白质在皮肤发育、体内平衡(包括衰老)、胶原相关病理、应激适应性以及伤口愈合相关过程和疾病中的动态作用。由于祖先起源和性别的皮肤多样性的特殊性也将被讨论。
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引用次数: 0
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