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1.
Biomacromolecules ; 18(7): 2214-2219, 2017 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-28605182

RESUMO

Pluronics F127 (P, PEG-PPG-PEG triblock copolymer) was coupled with diphenylalanine (FF) to prepare FF-end-capped Pluronics (FFPFF). With increasing temperature from 10 to 60 °C, the FFPFF self-assembled to vesicles in water. The unimer-to-vesicle transition accompanies endothermic enthalpy of 53.9 kcal/mol. Aqueous P and FFPFF solutions exhibited thermogelation in 15.0-24.0 wt %. The gel phase of FFPFF was stable up to 90 °C, whereas that of P turned into a sol again at 55-86 °C, indicating that end-capping with FF improved the gel stability against heat. In addition, the carboxylic acids of the FF end-groups can form coordination bonds with metal ions, and the gel modulus at 37 °C increased from 15-21 KPa (P) to 20-25 KPa (FFPFF) to 24-28 KPa (FFPFF-Zn), and the duration of gel against water-erosion increased from 24 h (P) to 60 h (FFPFF-Zn), leading to a useful biomaterial for sustained drug delivery. The FFPFF-Zn gels implanted in the rats' subcutaneous layer induced a mild inflammatory responses. Contrary to the previous end-capping of Pluronics by poly(lactic acid), polycarprolactone, carboxylic acid, and so on that weakened the gel stability, the diphenylalanine end-capping strengthened the stability of Pluronics gel against heat and water-erosion. This paper suggests that the control of polymer nanoassemblies directed by FF end-groups improves the mechanical properties and stability of the resulting thermogel and, thus, provides a useful drug delivery carrier with prolonged durability.


Assuntos
Micelas , Poloxâmero , Animais , Portadores de Fármacos/síntese química , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Géis , Poloxâmero/química , Poloxâmero/farmacologia , Ratos , Água
2.
Eur Arch Otorhinolaryngol ; 273(11): 3827-3834, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26994900

RESUMO

Surgical transplantation of parathyroid tissue into the forearm muscle is one of the most commonly used surgical techniques. While simple, the procedure suffers from drawbacks. This study evaluated the feasibility of thermoreversible gel as an injectable carrier for parathyroid autotransplantation. Polyethyleneglycol-polyalanine-co-phenylalanine (PEG-PAF) thermoreversible gel (sol form at 4 °C, gel form at 37 °C) were manufactured. Thirty-eight Sprague-Dawley rats were divided into two groups (19 control, C group; 19 experimental, P group). The parathyroid glands of rats were excised. Parathyroid tissues were transplanted into the muscle pocket in sternocleidomastoid muscle in the C group. In the P group, the tissues were injected into the same muscle mixed with 0.3 ml thermoreversible gel. The serum levels of parathyroid hormone (PTH), ionized calcium, and phosphorous were measured before surgical procedure, on 7, 21, 56, and 70 days after surgery. Histology and immunohistochemistry were performed. Preoperative median PTH level of the C and the P group were 60.80 and 43.85 pg/ml, respectively (p = 0.641). Seventy days after surgery, median PTH level was 32.8 and 25.61 pg/ml, respectively. On day 70, the PTH level was restored by 54 % in the C group and 56 % in the P group compared to the preoperative value (p = 0.620). There were no significant intergroup differences in the ionized calcium/phosphorous level. Histology and immunohistochemistry revealed the successful transplantation of parathyroid tissues into the muscles in both groups. In conclusion, the PEG-PAF-based thermoreversible gel is a good candidate carrier material for intramuscular parathyroid autotransplantation.


Assuntos
Glândulas Paratireoides/transplante , Alicerces Teciduais , Animais , Estudos de Viabilidade , Feminino , Géis , Humanos , Injeções Intramusculares , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo/sangue , Fenilalanina/química , Polietilenoglicóis/química , Ratos , Ratos Sprague-Dawley , Transplante Autólogo
3.
ACS Appl Mater Interfaces ; 8(8): 5160-9, 2016 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-26844684

RESUMO

As two-dimensional (2D) nanomaterials, graphene (G) and graphene oxide (GO) have evolved into new platforms for biomedical research as biosensors, imaging agents, and drug delivery carriers. In particular, the unique surface properties of GO can be an important tool in modulating cellular behavior and various biological sequences. Here, we report that a composite system of graphene oxide/polypeptide thermogel (GO/P), prepared by temperature-sensitive sol-to-gel transition of a GO-suspended poly(ethylene glycol)-poly(L-alanine) (PEG-PA) aqueous solution significantly enhances the expression of adipogenic biomarkers, including PPAR-γ, CEBP-α, LPL, AP2, ELOVL3, and HSL, compared to both a pure hydrogel system and a composite system of G/P, graphene-incorporated hydrogel. We prove that insulin, an adipogenic differentiation factor, preferentially adhered to GO, is supplied to the incorporated stem cells in a sustained manner over the three-dimensional (3D) cell culture period. On the other hand, insulin is partially denatured in the presence of G and interferes with the adipogenic differentiation of the stem cells. The study suggests that a 2D/3D composite system is a promising platform as a 3D cell culture matrix, where the surface properties of 2D materials in modulating the fates of the stem cells are effectively transcribed in a 3D culture system.


Assuntos
Adipogenia/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Grafite/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Engenharia Tecidual , Alanina/química , Técnicas de Cultura de Células , Portadores de Fármacos/química , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Grafite/química , Humanos , Óxidos/química , Tonsila Palatina/citologia , Peptídeos/química , Polietilenoglicóis/química
4.
Biomacromolecules ; 17(3): 1075-82, 2016 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-26909543

RESUMO

There are four EF-hand polypeptides in calmodulin, a natural ubiquitous calcium binding protein that activates the enzymes involved in Ca(2+)-mediated signal transduction. An EF-hand polypeptide has six carboxylate functional groups in the middle loop region between two rigid polypeptides. In this study, a calcium binding polymer (CBP) with a structure of poly(L-alanine)-poly(L-alanine-co-L-glutamic acid)-poly(ethylene glycol)-poly(L-alanine-co-L-glutamic acid)-poly(L-alanine) (PA-PAE-PEG-PAE-PA; A11.1-A3.4E3.2-EG40.1-A3.4E3.2-A11.1) was synthesized by mimicking the EF-hand polypeptide. The 6-7 carboxylate functional groups from PAE are expected to form a binding site for Ca(2+). As the Ca(2+) bound to CBP, small changes in the circular dichroism spectra and (13)C NMR spectra were observed, indicating that Ca(2+) binding to CBP induced changes in the conformation of CBP. The binding constant of CBP to Ca(2+) was investigated by using the competitive binding of 2,2',2″,2‴-{ethane-1,2-diylbis[oxy(4-bromo-2,1-phenylene)nitrilo]} tetraacetic acid (5,5-Br2-BAPTA). The binding constant obtained with a CaLigator program by least-squares fitting of the absorbance profile as a function of Ca(2+) concentration was 5.1 × 10(5) M(-1), which was similar to that of calmodulin. The selectivity of CBP for metal ion binding was compared among Ca(2+), Cu(2+), and Zn(2+). The binding constant was obtained through a similar competitive binding study with murexide. The binding constants for Ca(2+), Cu(2+), and Zn(2+) were 7.0 × 10(5), 4.2 × 10(5), and 1.7 × 10(5) M(-1), respectively, indicating 2-4-fold higher selectivity of CBP for Ca(2+) compared to Cu(2+) and Zn(2+). The CBP has selectivity for Ca(2+), and binding affinity for Ca(2+) was similar to the biological Ca(2+) binding motif of calmodulin.


Assuntos
Cálcio/metabolismo , Motivos EF Hand , Peptídeos/química , Sítios de Ligação , Calmodulina/química , Calmodulina/metabolismo , Cobre/metabolismo , Peptídeos/síntese química , Peptídeos/metabolismo , Ligação Proteica , Zinco/metabolismo
5.
Biomacromolecules ; 16(12): 3853-62, 2015 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-26551029

RESUMO

Zwitterionic polymers have been investigated as surface-coating materials due to their low protein adsorption properties, which reduce immunogenicity, biofouling, and bacterial adsorption of coated materials. Most zwitterionic polymers, reported so far, are based on (meth)acrylate polymers which can induce toxicity by residual monomers or amines produced by degradation. Here, we report a new zwitterionic polymer consisting of phosphorylcholine (PC) and biocompatible poly(propylene glycol) (PPG) as a new thermogelling material. The PC-PPG-PC polymer aqueous solution undergoes unique multiple sol-gel transitions as the temperature increases. A heat-induced unimer-to-micelle transition, changes in ionic interactions, and dehydration of PPG are involved in the sol-gel transitions. Based on the broad gel window and low protein adsorption properties, the PC-PPG-PC thermogel is proved for sustained delivery of protein drugs and stem cells over 1 week.


Assuntos
Acrilatos/química , Materiais Biocompatíveis/síntese química , Preparações de Ação Retardada/síntese química , Fosforilcolina/química , Polímeros/química , Propilenoglicóis/química , Animais , Materiais Biocompatíveis/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Criança , Preparações de Ação Retardada/farmacologia , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Feminino , Géis , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Insulina/química , Insulina/farmacologia , Masculino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Tonsila Palatina/citologia , Tonsila Palatina/efeitos dos fármacos , Transição de Fase , Polimerização , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley , Temperatura
6.
Biomacromolecules ; 16(5): 1461-9, 2015 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-25849077

RESUMO

Poly(ethylene glycol)-poly(l-alanine-co-l-phenyl alanine) diblock copolymers (PEG-PAF) of 2000-990 Da (P2K) and 5000-2530 Da (P5K) with the different molecular weights of PEGs, but having a similar molecular weight ratio of hydrophobic block to hydrophilic block were synthesized to compare their solution behavior and corresponding protein drug release profiles from their in situ formed thermogels. The PEG-PAF aqueous solutions underwent heat-induced sol-to-gel transition in a concentration range of 18.0-24.0 wt % and 8.0-12.0 wt % for P2K and P5K, respectively. P5K formed bigger micelles than P2K, of a broad distribution, whereas the PAF blocks of P5K developed richer in α-helix than those of P2K in the core of the micelles. As the temperature increased, the micelles underwent dehydration of the PEG, which led to the aggregation of micelles, while the secondary structure of PAF was slightly affected during the sol-to-gel transition. The P5K exhibited higher tendency to aggregate and formed a tighter gel than P2K. Upon injection into the subcutaneous layer of rats, both polymer aqueous solutions formed a biocompatible gel with typical mild inflammatory tissue responses. Recombinant human growth hormone (rhGH) maintained its stability without forming any aggregates in both sol (4 °C) and gel (37 °C) states of the PEG-PAFs. Even though P2K and P5K have a similar molecular weight ratio of hydrophobic block to hydrophilic block, the P5K system exhibited a reduced initial burst release, improved bioavailability, and prolonged therapeutic duration of the rhGH, compared to the P2K system. The current research suggests that a drug release profile is a complex function of self-assembling carriers and incorporated drugs, and thus, a promising protein delivery system could be designed by adjusting the molecular parameters of a thermogel.


Assuntos
Alanina/química , Sistemas de Liberação de Medicamentos , Hormônio do Crescimento/química , Fenilalanina/química , Polietilenoglicóis/química , Animais , Hormônio do Crescimento/genética , Hormônio do Crescimento/uso terapêutico , Humanos , Micelas , Transição de Fase , Polietilenoglicóis/uso terapêutico , Polímeros/química , Polímeros/uso terapêutico , Agregados Proteicos , Ratos , Soluções/química , Temperatura , Água/química
7.
J Mater Chem B ; 3(17): 3525-3530, 2015 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-32262236

RESUMO

Temperature sensitive nanogels prepared from ionic complexes of positively charged poly(ethylene glycol)-poly(l-lysine)-poly(l-alanine) (PEG-PK-PA) and negatively charged hyaluronic acid (HA) were investigated as intracellular delivery vehicles of a biomacromolecular drug of fluorescein isothiocyanate conjugated bovine serum albumin (FITC-BSA). By varying the weight ratio of the polymer to hyaluronic acid from 100/0 to 19/81, the zeta potential of the nanogel could be controlled from +47 mV (100/0), 0 mV (67/33), and -47 mV (35/65). In particular, the nanogels prepared from 67/33 exhibited 0 mV, and the size was reversibly changed from 220 nm at 20 °C to 160 nm at 37 °C with a narrow size distribution. The internalization of the FITC-BSA loaded nanogel was significantly affected by the zeta potential. In particular, the nanogel with zero zeta potential was very effective in internalizing the model drug. The cells treated with chlorpromazine significantly reduced the internalization efficiency, suggesting that clathrin mediated endocytosis is the main mechanism of the internalization of the nanogel. Cytotoxicity measured by the MTT assay suggested that the PEG-PK-PA/HA ionic complex nanogel is significantly less cytotoxic than PEG-PK-PA itself. This paper suggests that (1) the PEG-PK-PA/HA nanogel could be tightened by heat-induced shrinkage, (2) the internalization efficiency of the nanocarrier could be controlled by modulating the size and zeta potential of the nanogel, and (3) cytotoxicity of the positively charged nanogel was significantly improved by the formation of the ionic complex with negatively charged hyaluronic acid.

8.
Macromol Biosci ; 15(4): 464-72, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25515203

RESUMO

Bone-marrow-derived mesenchymal stem cells (BMSCs) were cultured in three-dimensional (3D) scaffolds formed by temperature-sensitive sol-to-gel transition of BMSC-suspended poly(ethylene glycol)-poly(L-alanine) (PEG-PA) aqueous solutions. A commercialized thermogelling 3D scaffold of Matrigel™ was used for the comparative study. The cells maintained their spherical shapes in the PEG-PA thermogel, whereas fibrous cell morphologies were observed in the Matrigel™. Type II collagen and myogenic differentiation factor 1 were dominantly expressed in the PEG-PA thermogel. On the other hand, a significant extent of type III ß-tubulin was expressed in the Matrigel™ in addition to type II collagen and myogenic differentiation factor 1. After confirming the dominant chondrogenic differentiation of the BMSCs in the PEG-PA thermogel in in vitro study, in vivo study was performed for injectable tissue engineering application of the BMSCs/PEG-PA system. The cell-growing implant was formed in situ by subcutaneous injection of the BMSC-suspended PEG-PA aqueous solution to mice. In vivo study also proved the excellent expressions of chondrogenic biomarkers including collagen type II and sulfated glycosaminoglycan in the mouse model. This paper suggests that the PEG-PA thermogel is a very promising as a 3D culture matrix as well as an injectable tissue-engineering system for preferential chondrogenic differentiation of the BMSCs.


Assuntos
Diferenciação Celular , Técnicas In Vitro , Células-Tronco Mesenquimais/citologia , Engenharia Tecidual , Animais , Células da Medula Óssea/citologia , Proliferação de Células , Condrogênese , Colágeno/química , Combinação de Medicamentos , Laminina/química , Camundongos , Peptídeos/química , Polietilenoglicóis/química , Proteoglicanas/química , Alicerces Teciduais
9.
ACS Appl Mater Interfaces ; 6(19): 17034-43, 2014 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-25192309

RESUMO

Tonsil-derived mesenchymal stem cells (TMSCs) were investigated for hepatogenic differentiation in the 3D matrixes of poly(ethylene glycol)-b-poly(l-alanine) (PEG-L-PA) thermogel. The diblock polymer formed ß-sheet based fibrous nanoassemblies in water, and the aqueous polymer solution undergoes sol-to-gel transition as the temperature increases in a concentration range of 5.0-8.0 wt %. The cell-encapsulated 3D matrix was prepared by increasing the temperature of the cell-suspended PEG-L-PA aqueous solution (6.0 wt %) to 37 °C. The gel modulus at 37 °C was about 1000 Pa, which was similar to that of decellularized liver tissue. Cell proliferation, changes in cell morphology, hepatogenic biomarker expressions, and hepatocyte-specific biofunctions were compared for the following 3D culture systems: TMSC-encapsulated thermogels in the absence of hepatogenic growth factors (protocol M), TMSC-encapsulated thermogels where hepatogenic growth factors were supplied from the medium (protocol MGF), and TMSC-encapsulated thermogels where hepatogenic growth factors were coencapsulated with TMSCs during the sol-to-gel transition (protocol GGF). The spherical morphology and size of the encapsulated cells were maintained in the M system during the 3D culture period of 28 days, whereas the cells changed their morphology and significant aggregation of cells was observed in the MGF and GGF systems. The hepatocyte-specific biomarker expressions and metabolic functions were negligible for the M system. However, hepatogenic genes of albumin, cytokeratin 18 (CK-18), and hepatocyte nuclear factor 4α (HNF 4α) were significantly expressed in both MGF and GGF systems. In addition, production of albumin and α-fetoprotein was also significantly observed in both MGF and GGF systems. The uptake of cardiogreen and low-density lipoprotein, typical metabolic functions of hepatocytes, was apparent for MGF and GGF. The above data indicate that the 3D culture system of PEG-L-PA thermogels provides cytocompatible microenvironments for hepatogenic differentiation of TMSCs. In particular, the successful results of the GGF system suggest that the PEG-L-PA thermogel can be a promising injectable tissue engineering system for liver tissue regeneration after optimizing the aqueous formulation of TMSCs, hepatogenic growth factors, and other biochemicals.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Géis/farmacologia , Hepatócitos/citologia , Células-Tronco Mesenquimais/citologia , Tonsila Palatina/citologia , Peptídeos/farmacologia , Alicerces Teciduais/química , Adolescente , Técnicas de Cultura de Células , Endocitose , Hepatócitos/efeitos dos fármacos , Humanos , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Peptídeos/química , Polietilenoglicóis/química , Espectroscopia de Prótons por Ressonância Magnética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Soluções , Temperatura , Temperatura de Transição , Água/química
10.
Biomacromolecules ; 15(10): 3664-70, 2014 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-25178662

RESUMO

A poly(ethylene glycol)/poly(L-alanine) multiblock copolymer incorporating ethylene diamine tetraacetic acid ([PA-PEG-PA-EDTA(m)) was synthesized as an ion/temperature dual stimuli-sensitive polymer, where the effect of different metal ions (Cu(2+), Zn(2+), and Ca(2+)) on the thermogelation of the polymer aqueous solution was investigated. The dissociation constants between the metal ions and the multiblock copolymer were calculated to be 1.2 × 10(-7), 6.6 × 10(-6), and 1.2 × 10(-4) M for Cu(2+), Zn(2+), and Ca(2+), respectively, implying that the binding affinity of the multiblock copolymer for Cu(2+) is much greater than that for Zn(2+) or Ca(2+). Atomic force microscopy and dynamic light scattering of the multiblock copolymer containing metal ions suggested micelle formation at low temperature, which aggregated as the temperature increased. Circular dichroism spectra suggested that changes in the α-helical secondary structure of the multiblock copolymer were more pronounced by adding Cu(2+) than other metal ions. The thermogelation of the multiblock copolymer aqueous solution containing Cu(2+) was observed at a lower temperature, and the modulus of the gel was significantly higher than that of the system containing Ca(2+) or Zn(2+), in spite of the same concentration of the metal ions and their same ionic valence of +2. The above results suggested that strong ionic complexes between Cu(2+) and the multiblock copolymer not only affected the secondary structure of the polymer but also facilitated the thermogelation of the polymer aqueous solution through effective salt-bridge formation even in a millimolar range of the metal ion concentration. Therefore, binding affinity of metal ions for polymers should be considered first in designing an effective ion/temperature dual stimuli-sensitive polymer.


Assuntos
Íons/química , Metais/química , Peptídeos/química , Polímeros/química , Alanina/química , Micelas , Concentração Osmolar , Polietilenoglicóis/química , Temperatura
11.
Adv Healthc Mater ; 3(11): 1782-91, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24958187

RESUMO

Poly(ethylene glycol)-poly(L-alanine-co-L-phenyl alanine) (PEG-PAF) aqueous solutions undergo sol-to-gel transition as the temperature increases. The transition is driven by the micelle aggregation involving the partial dehydration of the PEG block and the partial increase in ß-sheet content of the PAF block. Tonsil-tissue-derived mesenchymal stem cells (TMSCs), a new stem cell resource, are encapsulated through the sol-to-gel transition of the TMSC-suspended PEG-PAF aqueous solutions. The encapsulated TMSCs are in vitro 3D cultured by using induction media supplemented with adipogenic, osteogenic, or chondrogenic factors, where the TMSCs preferentially undergo chondrogenesis with high expressions of type II collagen and sulfated glycosaminoglycan. As a feasibility study of the PEG-PAF thermogel for injectable tissue engineering, the TMSCs encapsulated in hydrogels are implanted in the subcutaneous layer of mice by injecting the TMSC suspended PEG-PAF aqueous solution. The in vivo studies also prove that TMSCs undergo chondrogenesis with high expression of the chondrogenic biomarkers. This study suggests that the TMSCs can be an excellent resource of MSCs, and the thermogelling PEG-PAF is a promising injectable tissue engineering scaffold, particularly for chondrogenic differentiation of the stem cells.


Assuntos
Técnicas de Cultura de Células/métodos , Hidrogéis/química , Células-Tronco Mesenquimais/fisiologia , Tonsila Palatina/fisiologia , Peptídeos/química , Polietilenoglicóis/química , Engenharia Tecidual/métodos , Adipogenia/fisiologia , Animais , Biomarcadores/metabolismo , Diferenciação Celular/fisiologia , Células Cultivadas , Condrogênese/fisiologia , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Micelas , Transição de Fase , Soluções/química
12.
Chem Soc Rev ; 41(14): 4860-83, 2012 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-22688789

RESUMO

Aqueous solutions that undergo sol-to-gel transition as the temperature increases have been extensively studied during the last decade. The material can be designed by controlling the hydrophilic and hydrophobic balance of the material. Basically, the molecular weight of the hydrophilic block and hydrophobic block of a compound should be fine-tuned from the synthetic point of view. In addition, stereochemistry, microsequence, topology, and nanostructures of the compound also affect the transition temperature, gel window, phase diagram, and modulus of the gel. From a practical point of view, biodegradability, biocompatibility, and interactions between the material and drug or cell should be considered in designing a thermogelling material. The interactions are particularly important in that they control drug release profile and initial burst release of the drug in the drug delivery system, and affect cell proliferation, differentiation, and biomarker expression in three-dimensional cell culture and tissue engineering application. This review provides an in-depth summary of the recent progress of thermogelling systems including polymers, low molecular compounds, and nanoemulsions. Their biomedical applications were also comparatively discussed. In addition, perspectives on future material design of a new thermogelling material and its application are suggested.


Assuntos
Tecnologia Biomédica/métodos , Géis , Temperatura , Animais , Técnicas de Cultura de Células , Portadores de Fármacos/química , Géis/química , Humanos , Engenharia Tecidual
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