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Eriksson, E. K., Agmo Hernandez, V. & Edwards, K. (2018). Effect of ubiquinone-10 on the stability of biomimetic membranes of relevance for the inner mitochondrial membrane.. Biochimica et Biophysica Acta - Biomembranes, 1860(5), 1205-1215
Open this publication in new window or tab >>Effect of ubiquinone-10 on the stability of biomimetic membranes of relevance for the inner mitochondrial membrane.
2018 (English)In: Biochimica et Biophysica Acta - Biomembranes, ISSN 0005-2736, E-ISSN 1879-2642, Vol. 1860, no 5, p. 1205-1215Article in journal (Refereed) Published
Abstract [en]

Ubiquinone-10 (Q10) plays a pivotal role as electron-carrier in the mitochondrial respiratory chain, and is also well known for its powerful antioxidant properties. Recent findings suggest moreover that Q10 could have an important membrane stabilizing function. In line with this, we showed in a previous study that Q10 decreases the permeability to carboxyfluorescein (CF) and increases the mechanical strength of 1-palmitoyl-2-oleyl-sn-glycero-phosphocholine (POPC) membranes. In the current study we report on the effects exerted by Q10 in membranes having a more complex lipid composition designed to mimic that of the inner mitochondrial membrane (IMM). Results from DPH fluorescence anisotropy and permeability measurements, as well as investigations probing the interaction of liposomes with silica surfaces, corroborate a membrane stabilizing effect of Q10 also in the IMM-mimicking membranes. Comparative investigations examining the effect of Q10 and the polyisoprenoid alcohol solanesol on the IMM model and on membranes composed of individual IMM components suggest, moreover, that Q10 improves the membrane barrier properties via different mechanisms depending on the lipid composition of the membrane. Thus, whereas Q10's inhibitory effect on CF release from pure POPC membranes appears to be directly and solely related to Q10's lipid ordering and condensing effect, a mechanism linked to Q10's ability to amplify intrinsic curvature elastic stress dominates in case of membranes containing high proportions of palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE).

Keywords
Biomimetic membranes, Coenzyme Q10, Liposomes, Membrane stability, Solanesol
National Category
Biophysics
Identifiers
urn:nbn:se:uu:diva-353473 (URN)10.1016/j.bbamem.2018.02.015 (DOI)000435057700029 ()29470946 (PubMedID)
Funder
Swedish Research Council, 2016-03464Swedish Cancer Society, 17 0566
Available from: 2018-06-13 Created: 2018-06-13 Last updated: 2018-09-23Bibliographically approved
Boge, L., Västberg, A., Umerska, A., Bysell, H., Eriksson, J., Edwards, K., . . . Andersson, M. (2018). Freeze-dried and re-hydrated liquid crystalline nanoparticles stabilized with disaccharides for drug-delivery of the plectasin derivative AP114 antimicrobial peptide. Journal of Colloid and Interface Science, 522, 126-135
Open this publication in new window or tab >>Freeze-dried and re-hydrated liquid crystalline nanoparticles stabilized with disaccharides for drug-delivery of the plectasin derivative AP114 antimicrobial peptide
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2018 (English)In: Journal of Colloid and Interface Science, ISSN 0021-9797, E-ISSN 1095-7103, Vol. 522, p. 126-135Article in journal (Refereed) Published
Abstract [en]

Liquid crystalline nanoparticles (LCNPs), e.g. cubosomes and hexosomes, are receiving more and more attraction as drug delivery vehicles. Dry powder formulation that forms LCNPs upon hydration can be advantageous to make new routes of administration accessible. In this work, we investigate use of three disaccharides (lactose, trehalose and sucrose) as protective matrices for glycerol monooleate based LCNP forming powders produced by freeze-drying. Phase behavior, particle size and size distributions at the different preparation steps were monitored by small angle x-ray scattering (SAXS) and dynamic light scattering (DLS). Particle appearance was imaged by cryogenic transmission electron microscopy (cryo-TEM). Moreover, the therapeutic relevant antimicrobial peptide AP114 (plectasin derivative) was incorporated in the formulations. Peptide encapsulation and release as well as in vitro antibacterial effect were investigated. Results showed that all freeze-dried powders did form particles with liquid crystalline structure upon hydration. However, a phase transition from the bicontinuous cubic Pn3m to the reversed hexagonal was observed, as a consequence of sugar addition and the freeze-drying procedure. Data indicates that trehalose is the preferred choice of lyo-protectant in order to maintain a mono-modal particle size distribution. In addition, antimicrobial activity of AP114-containing formulations was found to be highest for the formulation containing trehalose. The release kinetics of AP114 from the nanoparticles was strongly affected by the dimensions of the hexagonal phase. Larger dimension of the hexagonal phase, significantly improved the release of AP114 and antimicrobial activity of the formulation.

Keywords
AP114, Antimicrobial peptide, Cubosome, Freeze-drying, Glycerol monooleate, Hexosome, Liquid crystal, Plectasin
National Category
Physical Chemistry
Identifiers
urn:nbn:se:uu:diva-353471 (URN)10.1016/j.jcis.2018.03.062 (DOI)000431100000015 ()29587194 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 604182
Available from: 2018-06-13 Created: 2018-06-13 Last updated: 2018-07-25Bibliographically approved
Kumar, A., Terakosolphan, W., Hassoun, M., Vandera, K.-K., Novicky, A., Harvey, R., . . . Forbes, B. (2017). A Biocompatible Synthetic Lung Fluid Based on Human Respiratory Tract Lining Fluid Composition.. Pharmaceutical research, 34(12), 2454-2465
Open this publication in new window or tab >>A Biocompatible Synthetic Lung Fluid Based on Human Respiratory Tract Lining Fluid Composition.
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2017 (English)In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 34, no 12, p. 2454-2465Article in journal (Refereed) Published
Abstract [en]

PURPOSE: To characterise a biorelevant simulated lung fluid (SLF) based on the composition of human respiratory tract lining fluid. SLF was compared to other media which have been utilized as lung fluid simulants in terms of fluid structure, biocompatibility and performance in inhalation biopharmaceutical assays.

METHODS: The structure of SLF was investigated using cryo-transmission electron microscopy, photon correlation spectroscopy and Langmuir isotherms. Biocompatibility with A549 alveolar epithelial cells was determined by MTT assay, morphometric observations and transcriptomic analysis. Biopharmaceutical applicability was evaluated by measuring the solubility and dissolution of beclomethasone dipropionate (BDP) and fluticasone propionate (FP), in SLF.

RESULTS: SLF exhibited a colloidal structure, possessing vesicles similar in nature to those found in lung fluid extracts. No adverse effect on A549 cells was apparent after exposure to the SLF for 24 h, although some metabolic changes were identified consistent with the change of culture medium to a more lung-like composition. The solubility and dissolution of BDP and FP in SLF were enhanced compared to Gamble's solution.

CONCLUSION: The SLF reported herein constitutes a biorelevant synthetic simulant which is suitable to study biopharmaceutical properties of inhalation medicines such as those being proposed for an inhaled biopharmaceutics classification system.

Keywords
aerosol, beclomethasone dipropionate, biopharmaceutics, dissolution, fluticasone propionate, inhalation, solubility
National Category
Physical Chemistry
Identifiers
urn:nbn:se:uu:diva-327975 (URN)10.1007/s11095-017-2169-4 (DOI)000418390000002 ()28560698 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, INFRA-2010-262,163GlaxoSmithKline (GSK)
Available from: 2017-08-14 Created: 2017-08-14 Last updated: 2018-02-05Bibliographically approved
Wehbe, M., Malhotra, A., Anantha, M., Roosendaal, J., Leung, A. W., Plackett, D., . . . Bally, M. B. (2017). A simple passive equilibration method for loading carboplatin into pre-formed liposomes incubated with ethanol as a temperature dependent permeability enhancer.. Journal of Controlled Release, 252, 50-61
Open this publication in new window or tab >>A simple passive equilibration method for loading carboplatin into pre-formed liposomes incubated with ethanol as a temperature dependent permeability enhancer.
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2017 (English)In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 252, p. 50-61Article in journal (Refereed) Published
Abstract [en]

A passive equilibration method which relies on addition of candidate drugs to pre-formed liposomes is described as an alternative method for preparing liposome encapsulated drugs. The method is simple, rapid and applicable to liposomes prepared with high (45mol%) or low (<20mol%) levels of cholesterol. Passive equilibration is performed in 4-steps: (i) formation of liposomes, (ii) addition of the candidate drug to the liposomes in combination with a permeability enhancing agent, (iii) incubation at a temperature that facilitates diffusion of the added compound across the lipid bilayer, and (iv) quenching the enhanced membrane permeability by reduction in temperature and/or removal of the permeabilization enhancer. The method is fully exemplified here using ethanol as the permeabilization enhancer and carboplatin (CBDCA) as the drug candidate. It is demonstrated that ethanol can be added to liposomes prepared with 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and Cholesterol (Chol) (55:45mol ratio) in amounts up to 30% (v/v) with no change in liposome size, even when incubated at temperatures>60°C. Super-saturated solutions of CBDCA (40mg/mL) can be prepared at 70°C and these are stable in the presence of ethanol even when the temperature is reduced to <30°C. maximum CBDCA encapsulation is achieved within 1h after the CBDCA solution is added to pre-formed DSPC/Chol liposomes in the presence of 30% (v/v) ethanol at 60°C. When the pre-formed liposomes are mixed with ethanol (30% v/v) at or below 40°C, the encapsulation efficiency is reduced by an order of magnitude. The method was also applied to liposomes prepared from other compositions include a cholesterol free formulations (containing 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[carboxy(polyethylene glycol)-2000] (DSPE-PEG2000)) and a low Chol (<20mol%) formulations prepared with the distearoyl-sn-glycero-3-phospho-(1'-rac-glycerol) DSPG)). The cytotoxic activity of CBDCA was unaffected when prepared in this manner and two of the resultant formulations exhibited good stability in vitro and in vivo. The cytotoxic activity of CBDCA was unaffected when prepared in this manner and the resultant formulations exhibited good stability in vitro and in vivo. Pharmacokinetics studies in CD-1 mice indicated that the resulting formulations increased the circulation half life of the associated CBDCA significantly (AUC0-24h of CBDCA=0.016μg·hr/mL; AUC0-24h of the DSPC/Chol CBDCA formulation=1014.0μg·hr/mL and AUC0-24h of the DSPC/DSPG/Chol CBDCA formulation=583.96μg·hr/mL). Preliminary efficacy studies in Rag-2M mice with established subcutaneous H1975 and U-251 tumors suggest that the therapeutic activity of CBDCA is improved when administered in liposomal formulations. The encapsulation method described here has not been disclosed previously and will have broad applications to drugs that would normally be encapsulated during liposome manufacturing.

Keywords
Cancer, Carboplatin, Cholesterol, DSPC, DSPE-PEG, DSPG, Drug delivery, Drug loading, Ethanol, Glioblastoma, Liposomes, Nanoparticle, Passive equilibration, Passive loading
National Category
Physical Chemistry
Identifiers
urn:nbn:se:uu:diva-327977 (URN)10.1016/j.jconrel.2017.03.010 (DOI)000403562800004 ()28286316 (PubMedID)
Available from: 2017-08-14 Created: 2017-08-14 Last updated: 2017-10-19Bibliographically approved
Boge, L., Umerska, A., Matougui, N., Bysell, H., Ringstad, L., Davoudi, M., . . . Andersson, M. (2017). Cubosomes post-loaded with antimicrobial peptides: characterization, bactericidal effect and proteolytic stability.. International Journal of Pharmaceutics, 526(1-2), 400-412
Open this publication in new window or tab >>Cubosomes post-loaded with antimicrobial peptides: characterization, bactericidal effect and proteolytic stability.
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2017 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 526, no 1-2, p. 400-412Article in journal (Refereed) Published
Abstract [en]

Novel antibiotics, such as antimicrobial peptides (AMPs), have recently attended more and more attraction. In this work, dispersed cubic liquid crystalline gel (cubosomes) was used as drug delivery vehicles for three AMPs (AP114, DPK-060 and LL-37). Association of peptides onto cubosomes was studied at two cubosome/peptide ratios using high performance liquid chromatography, ζ-potential and circular dichroism measurements. AMPs impact on the cubosome structure was investigated using small angle x-ray scattering and cryogenic transmission electron microscopy. The antimicrobial effect of the AMP loaded cubosomes was studied in vitro by minimum inhibitory concentration and time-kill assays. Proteolytic protection was investigated by incubating the formulations with two elastases and the antimicrobial effect after proteolysis was studied using radial diffusion assay. Different association efficacy onto the cubosomes was observed among the AMPs, with LL-37 showing greatest association (>60%). AP114 loaded cubosomes displayed a preserved antimicrobial effect, whereas for LL-37 the broad spectrum bacterial killing was reduced to only comprise Gram-negative bacteria. Interestingly, DPK-060 loaded cubosomes showed a slight enhanced effect against S. aureus and E. coli strains. Moreover, the cubosomes were found to protect LL-37 from proteolytic degradation, resulting in a significantly better bactericidal effect after being subjected to elastase, compared to unformulated peptide.

Keywords
Amp, Antimicrobial peptide, Cubosome, Glycerol monooleate, Liquid crystalline nanoparticle, Proteolysis
National Category
Physical Chemistry
Identifiers
urn:nbn:se:uu:diva-327973 (URN)10.1016/j.ijpharm.2017.04.082 (DOI)000404491400038 ()28476579 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 604182
Available from: 2017-08-14 Created: 2017-08-14 Last updated: 2017-10-10Bibliographically approved
Kumar, A., Bicer, E. M., Pfeffer, P., Monopoli, M. P., Dawson, K. A., Eriksson, J., . . . Mudway, I. (2017). Differences in the coronal proteome acquired by particles depositing in the lungs of asthmatic versus healthy humans. Nanomedicine: Nanotechnology, Biology and Medicine, 13(8), 2517-2521, Article ID S1549-9634(17)30115-6.
Open this publication in new window or tab >>Differences in the coronal proteome acquired by particles depositing in the lungs of asthmatic versus healthy humans
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2017 (English)In: Nanomedicine: Nanotechnology, Biology and Medicine, ISSN 1549-9634, E-ISSN 1549-9642, Vol. 13, no 8, p. 2517-2521, article id S1549-9634(17)30115-6Article in journal (Refereed) Published
Abstract [en]

Most inhaled nanomedicines in development are for the treatment of lung disease, yet little is known about their interaction with the respiratory tract lining fluids (RTLFs). Here we combined the use of nano-silica, as a protein concentrator, with label-free snapshot proteomics (LC-MS/MS; key findings confirmed by ELISA) to generate a quantitative profile of the RTLF proteome and provided insight into the evolved corona; information that may be used in future to improve drug targeting to the lungs by inhaled medicines. The asthmatic coronal proteome displayed a reduced contribution of surfactant proteins (SP-A and B) and a higher contribution of α1-antitrypsin. Pathway analysis suggested that asthmatic RTLFs may also be deficient in proteins related to metal handling (e.g. lactoferrin). This study demonstrates how the composition of the corona acquired by inhaled nanoparticles is modified in asthma and suggests depressed mucosal immunity even in mild airway disease.

National Category
Physical Chemistry Respiratory Medicine and Allergy Nano Technology
Identifiers
urn:nbn:se:uu:diva-327974 (URN)10.1016/j.nano.2017.06.008 (DOI)000414301400013 ()28647590 (PubMedID)
Funder
Swedish Heart Lung Foundation
Available from: 2017-08-14 Created: 2017-08-14 Last updated: 2018-02-05Bibliographically approved
Kovachev, P. S., Banerjee, D., Rangel, L. P., Eriksson, J., Pedrote, M. M., Martins-Dinis, M. M., . . . Sanyal, S. (2017). Distinct modulatory role of RNA in the aggregation of the tumor suppressor protein p53 core domain.. Journal of Biological Chemistry, 292(22), 9345-9357
Open this publication in new window or tab >>Distinct modulatory role of RNA in the aggregation of the tumor suppressor protein p53 core domain.
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2017 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 292, no 22, p. 9345-9357Article in journal (Refereed) Published
Abstract [en]

Inactivation of the tumor suppressor protein p53 by mutagenesis, chemical modification, protein-protein interaction, or aggregation has been associated with different human cancers. Although DNA is the typical substrate of p53, numerous studies have reported p53 interactions with RNA. Here, we have examined the effects of RNA of varied sequence, length, and origin on the mechanism of aggregation of the core domain of p53 (p53C) using light scattering, intrinsic fluorescence, transmission electron microscopy, thioflavin-T binding, seeding, and immunoblot assays. Our results are the first to demonstrate that RNA can modulate the aggregation of p53C and full-length p53. We found bimodal behavior of RNA in p53C aggregation. A low RNA:protein ratio (∼1:50) facilitates the accumulation of large amorphous aggregates of p53C. By contrast, at a high RNA:protein ratio (≥1:8), the amorphous aggregation of p53C is clearly suppressed. Instead, amyloid p53C oligomers are formed that can act as seeds nucleating de novo aggregation of p53C. We propose that structured RNAs prevent p53C aggregation through surface interaction and play a significant role in the regulation of the tumor suppressor protein.

Place, publisher, year, edition, pages
American Society for Biochemistry and Molecular Biology, 2017
Keywords
RNA, amyloid, domain V of 23S rRNA, fluorescence, kinetics, p53, p53C, prion, protein aggregation, protein folding
National Category
Cell Biology
Identifiers
urn:nbn:se:uu:diva-327976 (URN)10.1074/jbc.M116.762096 (DOI)000402538900028 ()28420731 (PubMedID)
Available from: 2017-08-14 Created: 2017-08-14 Last updated: 2018-01-14
Ahlgren, S., Fondell, A., Gedda, L. & Edwards, K. (2017). EGF-targeting lipodisks for specific delivery of poorly water-soluble anticancer agents to tumour cells. RSC Advances, 7(36), 22178-22186
Open this publication in new window or tab >>EGF-targeting lipodisks for specific delivery of poorly water-soluble anticancer agents to tumour cells
2017 (English)In: RSC Advances, ISSN 2046-2069, E-ISSN 2046-2069, Vol. 7, no 36, p. 22178-22186Article in journal (Refereed) Published
Abstract [en]

Concerns regarding poor aqueous solubility, high toxicity and lack of specificity impede the translation of many hydrophobic anticancer agents into safe and effective anticancer drugs. The application of colloidal drug delivery systems, and in particular the use of lipid-based nanocarriers, has been identified as a promising means to overcome these issues. PEG-stabilized lipid nanodisks (lipodisks) have lately emerged as a novel type of biocompatible, nontoxic and adaptable drug nanocarrier. In this study we have explored the potential of lipodisks as a platform for formulation and tumour targeted delivery of hydrophobic anticancer agents. Using curcumin as a model compound, we show that lipodisks can be loaded with substantial amounts of hydrophobic drugs (curcumin/lipid molar ratio 0.15). We demonstrate moreover that by deliberate choice of preparation protocols the lipodisks can be provided with relevant amounts of targeting proteins, such as epidermal growth factor (EGF). Data from in vitro cell studies verify that such EGF-decorated curcumin-loaded lipodisks are capable of EGF-receptor specific targeting of human A-431 tumour cells, and strongly suggest that the interaction between the lipodisks and the tumour cells results in receptor-mediated internalization of the disks and their cargo.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2017
National Category
Analytical Chemistry
Identifiers
urn:nbn:se:uu:diva-323680 (URN)10.1039/c7ra04059h (DOI)000400157700020 ()
Available from: 2017-06-08 Created: 2017-06-08 Last updated: 2017-11-29Bibliographically approved
Ahlgren, S., Reijmar, K. & Edwards, K. (2017). Targeting lipodisks enable selective delivery of anticancer peptides to tumor cells. Nanomedicine: Nanotechnology, Biology and Medicine, 13(7), 2325-2328
Open this publication in new window or tab >>Targeting lipodisks enable selective delivery of anticancer peptides to tumor cells
2017 (English)In: Nanomedicine: Nanotechnology, Biology and Medicine, ISSN 1549-9634, E-ISSN 1549-9642, Vol. 13, no 7, p. 2325-2328Article in journal (Refereed) Published
Abstract [en]

Issues concerning non-specificity, degradation and hemolysis severely hamper the development of membranolytic amphiphilic peptides into safe and efficient anticancer agents. To increase the therapeutic potential, we have previously developed a strategy based on formulation of the peptides in biocompatible nanosized lipodisks. Studies using melittin as model peptide show that the proteolytic degradation and hemolytic effect of the peptide are substantially reduced upon loading in lipodisks. Here, we explored the possibilities to increase the specificity and boost the cytotoxicity of melittin to tumor cells by use of targeting lipodisk. We demonstrate that small (~20 nm) EGF-targeted lipodisks can be produced and loaded with substantial amounts of peptide (lipid/peptide molar ratio >7) by means of a simple and straightforward preparation protocol. In vitro cell studies confirm specific binding of the peptide-loaded disks to tumor cells and suggest that cellular internalization of the disks results in a significantly improved cell-killing effect.

Keywords
EGFR, Melittin, Nanocarrier, PEG-stabilized lipid disk, Selective targeting
National Category
Physical Chemistry
Identifiers
urn:nbn:se:uu:diva-327972 (URN)10.1016/j.nano.2017.06.020 (DOI)000411954200023 ()28712916 (PubMedID)
Available from: 2017-08-14 Created: 2017-08-14 Last updated: 2018-01-31
Reijmar, K., Edwards, K., Andersson, K. & Agmo Hernández, V. (2016). Characterizing and controlling the loading and release of cationic amphiphilic peptides onto and from PEG-stabilized lipodisks. Langmuir, 32(46), 12091-12099
Open this publication in new window or tab >>Characterizing and controlling the loading and release of cationic amphiphilic peptides onto and from PEG-stabilized lipodisks
2016 (English)In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 32, no 46, p. 12091-12099Article in journal (Refereed) Published
Abstract [en]

Recent studies have identified PEG-stabilized lipid nanodisks (lipodisks) as promising carriers for cationic amphiphilic peptides with antimicrobial and anticancer activity. Using fluorimetric and nanogravimetric methods, we have in this work characterized the parameters describing and controlling the binding of three selected peptides (melittin, LL37, and magainin 2) onto lipodisks. It was found that the affinity of melittin for lipodisks is independent of the disk size and rim charge. On the other hand, the number of binding sites is strongly dependent on both parameters, with the highest loading being obtained for small disks with a negatively charged rim. An optimized composition of the lipodisks was utilized to study the loading of antimicrobial peptides magainin 2 and human LL37. It was observed that although magainin 2 can be loaded in large amounts, it is released very fast upon dilution, which limits future therapeutic applications. In contrast, LL37 can be loaded at relevant concentrations and the formulation is stable. This opens up for applications of LL37-loaded lipodisks as antibiotics and in anticancer treatments.

National Category
Physical Chemistry
Identifiers
urn:nbn:se:uu:diva-305377 (URN)10.1021/acs.langmuir.6b03012 (DOI)000388914400012 ()
Funder
Swedish Cancer Society
Available from: 2016-10-17 Created: 2016-10-17 Last updated: 2017-11-29Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-0674-2219

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