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Improved anti-proliferative effect of doxorubicin-containing polymer nanoparticles upon surface modification with cationic groups. 用阳离子基团修饰含阿霉素聚合物纳米颗粒表面,提高其抗增殖效果。
Pub Date : 2012-12-28 DOI: 10.1039/C2JM35420A
Sai Archana Krovi, Elden P Swindell, Thomas V O'Halloran, Sonbinh T Nguyen

Polymer nanoparticles (PNPs) possessing a high density of drug payload have been successfully stabilized against aggregation in biological buffers after amine modification, which renders these PNPs positively charged. The resulting charge-stabilized PNPs retain their original narrow particle size distributions and well-defined spherical morphologies. This stabilization allows these PNPs to have an improved anti-proliferative effect on MDA-MB-231-Br human breast cancer cells compared to non-functionalized PNPs. As a non-cytotoxic control, similar surface-modified PNPs containing cholesterol in place of doxorubicin did not inhibit cell proliferation, indicating that the induced cytotoxic response was solely due to the doxorubicin release from the PNPs.

具有高密度药物负载的聚合物纳米粒子(PNPs)在胺修饰后成功地稳定了在生物缓冲液中的聚集,这使得这些PNPs带正电荷。所得到的电荷稳定PNPs保留了其原始的窄粒度分布和明确的球形形貌。与非功能化PNPs相比,这种稳定性使得这些PNPs对MDA-MB-231-Br人乳腺癌细胞具有更好的抗增殖作用。作为非细胞毒性对照,含有胆固醇代替阿霉素的类似表面修饰的PNPs没有抑制细胞增殖,这表明诱导的细胞毒性反应仅仅是由于PNPs释放了阿霉素。
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引用次数: 10
Anisotropic nanocrystal arrays organized on protein lattices formed by recombinant clathrin fragments. 在重组网格蛋白片段形成的蛋白质晶格上组织的各向异性纳米晶体阵列。
Pub Date : 2012-12-28 DOI: 10.1039/C2JM35019J
Nancy Hom, Kinjal R Mehta, Tsengming Chou, Amy B Foraker, Frances M Brodsky, Kent Kirshenbaum, Jin K Montclare

Recombinant clathrin protein fragments form assemblies that template gold nanocrystals in an array across the latticed surface. The nanocrystals exhibit unusual anisotropic morphologies with long range ordering, both of which are dependent upon the presence of a hexahistidine tag on the clathrin heavy chain fragments.

重组网格蛋白片段形成组装体,在网格表面以阵列形式模板化金纳米晶体。纳米晶体表现出不同寻常的各向异性形貌,具有长范围有序性,这两者都取决于网格蛋白重链片段上六组氨酸标签的存在。
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引用次数: 9
The effect of mineral coating morphology on mesenchymal stem cell attachment and expansion. 矿物包覆形态对间充质干细胞附着和扩增的影响。
Pub Date : 2012-12-28 DOI: 10.1039/C2JM33354F
Siyoung Choi, William L Murphy

Previous studies have demonstrated the influence of calcium phosphate (CaP) mineral coating characteristics on cell attachment, proliferation, and differentiation. However, the wide range of mineral properties that can potentially influence cell behavior calls for an efficient platform to screen for the effects of specific mineral properties. To address this need, we have developed an efficient well-plate format to probe for the effects of mineral coating properties on stem cell behavior. Specifically, here we systematically controlled mineral coating morphology by modulating ion concentrations in modified simulated body fluids (mSBF) during mineral nucleation and growth. We found that mineral micro-morphology could be gradually changed from spherulitic, to plate-like, to net-like depending on [Ca2+] and [PO43-] in mSBF solutions, while other mineral properties (Ca/P ratio, crystallinity, dissolution rate) remained constant. Differences in mineral morphology resulted in significant differences in stem cell attachment and expansion in vitro. These findings suggest that an enhanced throughput mineral coating format may be useful to identify mineral coating properties for optimal stem cell attachment and expansion, which may ultimately permit efficient intraoperative seeding of patient derived stem cells.

先前的研究已经证明了磷酸钙(CaP)矿物包被特性对细胞附着、增殖和分化的影响。然而,可能影响细胞行为的各种矿物性质需要一个有效的平台来筛选特定矿物性质的影响。为了满足这一需求,我们开发了一种高效的孔板格式来探测矿物涂层特性对干细胞行为的影响。具体来说,在这里,我们系统地控制矿物涂层形态通过调节离子浓度在修饰模拟体液(mSBF)在矿物成核和生长。我们发现矿物的微观形态可以根据[Ca2+]和[PO43-]在mSBF溶液中逐渐从球粒状转变为板状,再转变为网状,而其他矿物性质(Ca/P比,结晶度,溶解速率)保持不变。矿物形态的差异导致干细胞在体外的附着和扩增有显著差异。这些发现表明,增强通量的矿物涂层形式可能有助于确定最佳干细胞附着和扩增的矿物涂层特性,这可能最终允许术中有效地播种患者来源的干细胞。
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引用次数: 22
Location-tuned relaxivity in Gd-doped mesoporous silica nanoparticles. 钆掺杂介孔二氧化硅纳米颗粒的位置调谐弛豫度。
Pub Date : 2012-10-16 DOI: 10.1039/C2JM35116A
Jason J Davis, Wen-Yen Huang, Gemma-Louise Davies

In tuning the sub-particle localisation of Gd(III) binding macrocycles within a mesoporous scaffold, nanoparticle contrast agents of unprecedented relaxivity and low Gd(III) loadings can be realised.

在调节介孔支架内Gd(III)结合大环的亚粒子定位时,可以实现具有前所未有的弛豫性和低Gd(III)负载的纳米颗粒造影剂。
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引用次数: 51
Reversible Swelling of Chitosan and Quaternary Ammonium Modified Chitosan Brush Layers: Effect of pH and Counter Anion Size and Functionality. 壳聚糖和季铵改性壳聚糖刷层的可逆膨胀:pH 值及阴离子大小和功能性的影响
Pub Date : 2012-10-07 DOI: 10.1039/C2JM34316A
Hyun-Su Lee, Michael Q Yee, Yonaton Y Eckmann, Noreen J Hickok, David M Eckmann, Russell J Composto

This study investigates the swelling of grafted polycationic brushes as a function of pH and anion type. The brushes are chitosan (CH) and chitosans with 27% and 51% degree of substitution (DS) of quaternary ammonium salt, denoted as CH-Q(25) and CH-Q(50), respectively. The water content and swelling behaviors are monitored using in situ quartz-crystal microbalance with dissipation (QCM-D). The pH varies from ~3.5 to 8.5, and the counter anion types include chloride, acetate, and citrate. At fixed pH, the water content and brush swelling increase as the DS increases. Whereas the CH-Q(50) brush layer shows symmetric swelling with a minimum near pH = 4.5, the swelling of CH and CH-Q(25) is relatively constant as pH decreases from 8.2 to 5.5, and then begins to increase near pH 4. These studies indicate that the symmetric swelling of CH-Q(50) is likely attributed to increasing protonation of primary amines for pH values below pH 6.5 and the quaternary ammonium salts above pH 6.5. At pH 4, the swelling of the CH brush increases upon exchanging the smaller chloridewith a bulkier acetate anion, which is less effective at screening intra/inter molecular repulsion. In contrast, upon exchanging the acetate with trifunctional citrate, CH and CH-Q(25) brushes collapse by 53 and 42%, respectively, because the citrate forms ionic cross-links. To test antibacterial properties, silicon oxide, CH and CH-Q(50) brush layers are exposed to 10(7)-10(8) cfu/ml of S. aureus for two days at 37 °C and exposed to stepped shear stresses in 2 min intervals. Whereas an S. aureus biofilm adheres strongly to silicon oxide and CH for stresses up to 12 dyne/cm(2), biofilms on CH-Q(50) detach at a relatively low shear stress, 1.5 dyne/cm(2). Due to their high degree of swelling that can be tuned via pH, counterion size and type, chitosan and quaternary modified chitosans have potential as responsive coatings for applications including MEMS/NEMS devices and drug eluting implants.

本研究探讨了接枝聚阳离子刷的溶胀与 pH 值和阴离子类型的关系。这些刷子是壳聚糖(CH)和季铵盐取代度(DS)分别为 27% 和 51% 的壳聚糖,分别称为 CH-Q(25) 和 CH-Q(50)。使用带耗散的原位石英晶体微天平(QCM-D)对含水量和溶胀行为进行了监测。pH 值从 ~3.5 到 8.5 不等,反阴离子类型包括氯化物、醋酸盐和柠檬酸盐。在固定的 pH 值下,随着 DS 的增加,含水量和刷肿胀也随之增加。这些研究表明,CH-Q(50) 刷层的对称溶胀可能是由于在 pH 值低于 6.5 时,伯胺的质子化作用增强,而在 pH 值高于 6.5 时,季铵盐的质子化作用增强。在 pH 值为 4 时,当较小的氯离子与体积较大的醋酸阴离子交换时,CH 刷的膨胀会增加,因为醋酸阴离子在分子内/分子间排斥的屏蔽作用较弱。相反,当用三官能团柠檬酸盐交换醋酸盐时,CH 和 CH-Q(25)刷分别塌陷 53% 和 42%,这是因为柠檬酸盐形成了离子交联。为了测试抗菌性能,氧化硅、CH 和 CH-Q(50)刷层在 37 °C、10(7)-10(8) cfu/ml 金黄色葡萄球菌的作用下暴露两天,并每隔 2 分钟暴露于阶梯剪切应力下。金黄色葡萄球菌生物膜可在高达 12 dyne/cm(2) 的应力下牢固地粘附在氧化硅和 CH 上,而 CH-Q(50)上的生物膜则会在相对较低的剪切应力(1.5 dyne/cm(2))下脱离。壳聚糖和季化合物修饰壳聚糖具有很高的溶胀度,可通过 pH 值、反离子大小和类型进行调节,因此具有作为响应涂层的潜力,可应用于 MEMS/NEMS 设备和药物洗脱植入物。
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引用次数: 0
Photoreactive elastin-like proteins for use as versatile bioactive materials and surface coatings. 用作多功能生物活性材料和表面涂层的光活性弹性蛋白。
Pub Date : 2012-10-07 DOI: 10.1039/C2JM31768K
Jordan Raphel, Andreina Parisi-Amon, Sarah Heilshorn

Photocrosslinkable, protein-engineered biomaterials combine a rapid, controllable, cytocompatible crosslinking method with a modular design strategy to create a new family of bioactive materials. These materials have a wide range of biomedical applications, including the development of bioactive implant coatings, drug delivery vehicles, and tissue engineering scaffolds. We present the successful functionalization of a bioactive elastin-like protein with photoreactive diazirine moieties. Scalable synthesis is achieved using a standard recombinant protein expression host followed by site-specific modification of lysine residues with a heterobifunctional N-hydroxysuccinimide ester-diazirine crosslinker. The resulting biomaterial is demonstrated to be processable by spin coating, drop casting, soft lithographic patterning, and mold casting to fabricate a variety of two- and three-dimensional photocrosslinked biomaterials with length scales spanning the nanometer to millimeter range. Protein thin films proved to be highly stable over a three-week period. Cell-adhesive functional domains incorporated into the engineered protein materials were shown to remain active post-photo-processing. Human adipose-derived stem cells achieved faster rates of cell adhesion and larger spread areas on thin films of the engineered protein compared to control substrates. The ease and scalability of material production, processing versatility, and modular bioactive functionality make this recombinantly engineered protein an ideal candidate for the development of novel biomaterial coatings, films, and scaffolds.

可光照交联蛋白质工程生物材料将快速、可控、细胞兼容的交联方法与模块化设计策略相结合,创造出一系列新型生物活性材料。这些材料具有广泛的生物医学应用前景,包括开发生物活性植入涂层、药物输送载体和组织工程支架。我们介绍了一种具有生物活性的弹性蛋白与光活性重氮吖啶分子的成功功能化。利用标准重组蛋白表达宿主实现了可扩展的合成,然后用一种异双功能 N-羟基琥珀酰亚胺酯-重氮交联剂对赖氨酸残基进行了特定位点修饰。实验证明,由此产生的生物材料可以通过旋涂、滴注、软光刻制图和铸模等方法进行加工,从而制造出各种二维和三维光交联生物材料,其长度范围从纳米到毫米不等。事实证明,蛋白质薄膜在三周内高度稳定。在光处理后,加入工程蛋白质材料的细胞粘附功能域仍能保持活性。与对照基底相比,人体脂肪干细胞在工程蛋白质薄膜上的细胞粘附率更快,铺展面积更大。材料生产的简易性和可扩展性、加工的多功能性以及模块化生物活性功能使这种重组工程蛋白成为开发新型生物材料涂层、薄膜和支架的理想候选材料。
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引用次数: 0
Biocompatible, pH-sensitive AB(2) Miktoarm Polymer-Based Polymersomes: Preparation, Characterization, and Acidic pH-Activated Nanostructural Transformation. 生物相容性,ph敏感的AB(2) Miktoarm聚合物基聚合体:制备,表征和酸性ph激活的纳米结构转化。
Pub Date : 2012-09-28 DOI: 10.1039/C2JM33750A
Haiqing Yin, Han Chang Kang, Kang Moo Huh, You Han Bae

Motivated by the limitations of liposomal drug delivery systems, we designed a novel histidine-based AB(2)-miktoarm polymer (mPEG-b-(polyHis)(2)) equipped with a phospholipid-mimic structure, low cytotoxicity, and pH-sensitivity. Using "core-first" click chemistry and ring-opening polymerization, mPEG(2kDa)-b-(polyHis(29kDa))(2) was successfully synthesized with a narrow molecular weight distribution (1.14). In borate buffer (pH 9), the miktoarm polymer self-assembled to form a nano-sized polymersome with a hydrodynamic radius of 70.2 nm and a very narrow size polydispersity (0.05). At 4.2 µmol/mg polymer, mPEG(2kDa)-b-(polyHis(29kDa))(2) strongly buffered against acidification in the endolysosomal pH range and exhibited low cytotoxicity on a 5 d exposure. Below pH 7.4 the polymersome transitioned to cylindrical micelles, spherical micelles, and finally unimers as the pH was decreased. The pH-induced structural transition of mPEG(2kDa)-b-(polyHis(29kDa))(2) nanostructures may be caused by the increasing hydrophilic weight fraction of mPEG(2kDa)-b-(polyHis(29kDa))(2) and can help to disrupt the endosomal membrane through proton buffering and membrane fusion of mPEG(2kDa)-b-(polyHis(29kDa))(2). In addition, a hydrophilic model dye, 5(6)-carboxyfluorescein encapsulated into the aqueous lumen of the polymersome showed a slow, sustained release at pH 7.4 but greatly accelerated release below pH 6.8, indicating a desirable pH sensitivity of the system in the range of endosomal pH. Therefore, this polymersome that is based on a biocompatible histidine-based miktoarm polymer and undergoes acid-induced transformations could serve as a drug delivery vehicle for chemical and biological drugs.

由于脂质体给药系统的局限性,我们设计了一种新的基于组氨酸的AB(2)-miktoarm聚合物(mPEG-b-(polyHis)(2)),具有磷脂模拟结构,低细胞毒性和ph敏感性。利用“核优先”点击化学和开环聚合,成功合成了分子量分布较窄(1.14)的mPEG(2kDa)-b-(polyHis(29kDa))(2)。在硼酸盐缓冲液(pH为9)中,mitoarm聚合物自组装形成纳米级聚合物,其水动力半径为70.2 nm,尺寸多分散性非常窄(0.05)。在4.2µmol/mg聚合物下,mPEG(2kDa)-b-(polyHis(29kDa))(2)在内溶酶体pH范围内强烈缓冲酸化,并在暴露5 d后表现出低细胞毒性。当pH值低于7.4时,随着pH值的降低,聚合体转变为圆柱形胶束、球形胶束和单体。ph诱导的mPEG(2kDa)-b-(polyHis(29kDa))(2)纳米结构的结构转变可能是由mPEG(2kDa)-b-(polyHis(29kDa)))(2)的亲水重量分数增加引起的,并且可以通过mPEG(2kDa)-b-(polyHis(29kDa))的质子缓冲和膜融合来破坏内体膜(2)。此外,包裹在聚合物水腔内的亲水性模型染料5(6)-羧基荧光素在pH 7.4时缓释,但在pH 6.8以下释放速度大大加快,表明该系统在内体pH范围内具有理想的pH敏感性。因此,这种基于生物相容性组氨酸基mitoarm聚合物并经历酸诱导转化的聚合物可以作为化学和生物药物的药物递送载体。
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引用次数: 50
Modelling human embryoid body cell adhesion to a combinatorial library of polymer surfaces. 模拟人类胚状体细胞粘附到组合库的聚合物表面。
Pub Date : 2012-09-18 DOI: 10.1039/C2JM34782B
V Chandana Epa, Jing Yang, Ying Mei, Andrew L Hook, Robert Langer, Daniel G Anderson, Martyn C Davies, Morgan R Alexander, David A Winkler

Designing materials to control biology is an intense focus of biomaterials and regenerative medicine research. Discovering and designing materials with appropriate biological compatibility or active control of cells and tissues is being increasingly undertaken using high throughput synthesis and assessment methods. We report a relatively simple but powerful machine-learning method of generating models that link microscopic or molecular properties of polymers or other materials to their biological effects. We illustrate the potential of these methods by developing the first robust, predictive, quantitative, and purely computational models of adhesion of human embryonic stem cell embryoid bodies (hEB) to the surfaces of a 496-member polymer micro array library.

设计控制生物学的材料是生物材料和再生医学研究的一个热点。使用高通量合成和评估方法,发现和设计具有适当生物相容性或对细胞和组织有活性控制的材料正在越来越多地进行。我们报告了一种相对简单但功能强大的机器学习方法,用于生成将聚合物或其他材料的微观或分子特性与其生物效应联系起来的模型。我们通过开发人类胚胎干细胞胚状体(hEB)与496个聚合物微阵列文库表面粘附的第一个稳健、预测、定量和纯计算模型来说明这些方法的潜力。
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引用次数: 41
Microfabricated photocrosslinkable polyelectrolyte-complex of chitosan and methacrylated gellan gum. 微制光交联聚电解质-壳聚糖和甲基丙烯酸结冷胶复合物。
Pub Date : 2012-09-07 DOI: 10.1039/C2JM31374J
Daniela F Coutinho, Shilpa Sant, Mojdeh Shakiba, Ben Wang, Manuela E Gomes, Nuno M Neves, Rui L Reis, Ali Khademhosseini

Chitosan (CHT) based polyelectrolyte complexes (PECs) have been receiving great attention for tissue engineering approaches. These hydrogels are held together by ionic forces and can be disrupted by changes in physiological conditions. In this study, we present a new class of CHT-based PEC hydrogels amenable to stabilization by chemical crosslinking. The photocrosslinkable anionic methacrylated gellan gum (MeGG) was complexed with cationic CHT and exposed to light, forming a PEC hydrogel. The chemical characterization of the photocrosslinkable PEC hydrogel by Fourier transform infrared spectroscopy (FTIR) revealed absorption peaks specific to the raw polymers. A significantly higher swelling ratio was observed for the PEC hydrogel with higher CHT content. The molecular interactions between both polysaccharides were evaluated chemically and microscopically, indicating the diffusion of CHT to the interior of the hydrogel. We hypothesized that the addition of MeGG to CHT solution first leads to a membrane formation around MeGG. Then, migration of CHT inside the MeGG hydrogel occurs to balance the electrostatic charges. The photocrosslinkable feature of MeGG further allowed the formation of cell-laden microscale hydrogel units with different shapes and sizes. Overall, this system is potentially useful for a variety of applications including the replication of microscale features of tissues for modular tissue engineering.

壳聚糖(CHT)基聚电解质复合物(PECs)在组织工程领域受到广泛关注。这些水凝胶通过离子力保持在一起,并可能因生理条件的变化而被破坏。在这项研究中,我们提出了一类新的基于cht的PEC水凝胶,可以通过化学交联来稳定。将可光交联的阴离子甲基丙烯酸化结冷胶(MeGG)与阳离子CHT络合并暴露在光下,形成PEC水凝胶。利用傅里叶变换红外光谱(FTIR)对光交联PEC水凝胶进行了化学表征,揭示了原料聚合物特有的吸收峰。高CHT含量的PEC水凝胶溶胀率显著提高。两种多糖之间的分子相互作用进行了化学和显微评价,表明CHT扩散到水凝胶内部。我们假设将MeGG加入到CHT溶液中首先导致MeGG周围形成膜。然后,CHT在MeGG水凝胶内部发生迁移,以平衡静电荷。MeGG的光交联特性进一步允许形成具有不同形状和大小的细胞负载微尺度水凝胶单元。总的来说,该系统对各种应用都有潜在的用处,包括用于模块化组织工程的组织微观特征的复制。
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引用次数: 43
Biomimetic supported lipid bilayers with high cholesterol content formed by α-helical peptide-induced vesicle fusion. α螺旋肽诱导囊泡融合形成的高胆固醇含量仿生支撑脂质双分子层。
Pub Date : 2012-08-28 DOI: 10.1039/C2JM32016A
Gregory J Hardy, Rahul Nayak, S Munir Alam, Joseph G Shapter, Frank Heinrich, Stefan Zauscher

In this study, we present a technique to create a complex, high cholesterol-containing supported lipid bilayers (SLBs) using α-helical (AH) peptide-induced vesicle fusion. Vesicles consisting of POPC : POPE : POPS : SM : Chol (9.35 : 19.25 : 8.25 : 18.15 : 45.00) were used to form a SLB that models the native composition of the human immunodeficiency virus-1 (HIV-1) lipid envelope. In the absence of AH peptides, these biomimetic vesicles fail to form a complete SLB. We verified and characterized AH peptide-induced vesicle fusion by quartz crystal microbalance with dissipation monitoring, neutron reflectivity, and atomic force microscopy. Successful SLB formation entailed a characteristic frequency shift of -35.4 ± 2.0 Hz and a change in dissipation energy of 1.91 ± 0.52 × 10-6. Neutron reflectivity measurements determined the SLB thickness to be 49.9 +1.9-1.5 Å, and showed the SLB to be 100 +0.0-0.1% complete and void of residual AH peptide after washing. Atomic force microscopy imaging confirmed complete SLB formation and revealed three distinct domains with no visible defects. This vesicle fusion technique gives researchers access to a complex SLB composition with high cholesterol content and thus the ability to better recapitulate the native HIV-1 lipid membrane.

在本研究中,我们介绍了一种利用α-螺旋(AH)肽诱导的囊泡融合技术来创建复杂的高胆固醇支撑脂质双分子层(SLB)的技术。由 POPC : POPE : POPS : SM : Chol (9.35 : 19.25 : 8.25 : 18.15 : 45.00) 组成的囊泡被用来形成模拟人类免疫缺陷病毒-1(HIV-1)脂质包膜原生成分的支撑脂质双层膜(SLB)。在缺乏 AH 肽的情况下,这些仿生囊泡无法形成完整的 SLB。我们通过石英晶体微天平耗散监测、中子反射和原子力显微镜验证并鉴定了AH肽诱导的囊泡融合。SLB的成功形成需要-35.4 ± 2.0 Hz的特征频率偏移和1.91 ± 0.52 × 10-6的耗散能量变化。中子反射率测量确定 SLB 厚度为 49.9 +1.9-1.5 Å,并显示 SLB 的完整度为 100 +0.0-0.1%,且在清洗后没有残留的 AH 肽。原子力显微镜成像证实了 SLB 的完整形成,并显示出三个不同的畴,没有明显的缺陷。这种囊泡融合技术使研究人员能够获得高胆固醇含量的复杂SLB成分,从而能够更好地再现原生HIV-1脂膜。
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引用次数: 0
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Journal of Materials Chemistry
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