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1.
Nanoscale ; 14(26): 9286-9296, 2022 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-35649277

RESUMO

The alarming and prevailing antibiotic resistance crisis urgently calls for innovative "outside of the box" antibacterial agents, which can differ substantially from conventional antibiotics. In this context, we have established antibacterial candidates based on dynamic supramolecular dendrimer nanosystems self-assembled with amphiphilic dendrimers composed of a long hydrophobic alkyl chain and a small hydrophilic poly(amidoamine) dendron bearing distinct terminal functionalities. Remarkably, the amphiphilic dendrimer with amine terminals exhibited strong antibacterial activity against both Gram-positive and Gram-negative as well as drug-resistant bacteria, and prevented biofilm formation. Multidisciplinary studies combining experimental approaches and computer modelling together demonstrate that the dendrimer interacts and binds via electrostatic interactions with the bacterial membrane, where it becomes enriched and then dynamically self-assembles into supramolecular nanoassemblies for stronger and multivalent interactions. These, in turn, rapidly promote the insertion of the hydrophobic dendrimer tail into the bacterial membrane thereby inducing bacterial cell lysis and constituting powerful antibacterial activity. Our study presents a novel concept for creating nanotechnology-based antibacterial candidates via dynamic self-assembly and offers a new perspective for combatting recalcitrant bacterial infection.


Assuntos
Dendrímeros , Antibacterianos/química , Antibacterianos/farmacologia , Bactérias , Biofilmes , Dendrímeros/química , Dendrímeros/farmacologia , Testes de Sensibilidade Microbiana
2.
Nanoscale ; 13(25): 11289-11297, 2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34156049

RESUMO

Understanding of cobalt nanorods' (Co NRs) formation still remains challenging when it comes to enhancing their anisotropic properties applicable in magnetic or catalytic areas. Herein, we propose a mechanism for the morphological transition from spherical cobalt nanoparticles (NPs) to Co NRs over time (9 h) in a mixture of [CoCl(PPh3)3] and oleylamine (OAm). In the literature, we described how spherical Co NPs are synthesized via a disproportionation process. Based on in situ and pseudo in situ observations, two steps of this unique mechanism are characterized first by the dissolution of the spheres and then the regrowth in rods' shape in the presence of an OAm template. Furthermore, ex situ experiments show that these steps are the result of interdependent reactions occurring between Co NPs, cobalt(ii) and OAm. The latter plays numerous roles in this synthesis: as a surfactant, a disproportionation promoter, and a hydrogen source allowing the reduction of cobalt(ii) complexes; its ammonium salt derivative is involved in oxidative etching of Co NPs and it promotes the anisotropic growth in NRs. These coupling actions of reduction and etching generate two cobalt reservoirs of nuclei under thermodynamic conditions.

3.
ACS Nano ; 15(3): 4018-4033, 2021 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-32786209

RESUMO

We report on the shape, composition (from Pt95Zn5 to Pt77Zn23), and surface chemistry of Pt-Zn nanoparticles obtained by reduction of precursors M2+(acac)2- (M2+: Pt2+ and Zn2+) in oleylamine, which serves as both solvent and ligand. We show first that the addition of phenyl ether or benzyl ether determines the composition and shape of the nanoparticles, which point to an adsorbate-controlled synthesis. The organic (ligand)/inorganic (nanoparticles) interface is characterized on the structural and chemical level. We observe that the particles, after washing with ethanol, are coated with oleylamine and the oxidation products of the latter, namely, an aldimine and a nitrile. After exposure to air, the particles oxidize, covering themselves with a few monolayer thick ZnO film, which is certainly discontinuous when the particles are low in zinc. Pt-Zn particles are unstable and prone to losing Zn. We have strong indications that the driving force is the preferential oxidation of the less noble metal. Finally, we show that adsorption of CO on the surface of nanoparticles modifies the oxidation state of amine ligands and attribute it to the displacement of hydrogen adsorbed on Pt. All the structural and chemical information provided by the combination of electron microscopy and X-ray photoelectron spectroscopy allows us to give a fairly accurate picture of the surface of nanoparticles and to better understand why Pt-Zn alloys are efficient in certain electrocatalytic reactions such as the oxidation of methanol.

4.
Small ; 16(37): e2003290, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32794645

RESUMO

Bioimaging has revolutionized medicine by providing accurate information for disease diagnosis and treatment. Nanotechnology-based bioimaging is expected to further improve imaging sensitivity and specificity. In this context, supramolecular nanosystems based on self-assembly of amphiphilic dendrimers for single photon emission computed tomography (SPECT) bioimaging are developed. These dendrimers bear multiple In3+ radionuclides at their terminals as SPECT reporters. By replacing the macrocyclic 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid cage with the smaller 1,4,7-triazacyclononane-1,4,7-triacetic acid scaffold as the In3+ chelator, the corresponding dendrimer exhibits neutral In3+ -complex terminals in place of negatively charged In3+ -complex terminals. This negative-to-neutral surface charge alteration completely reverses the zeta-potential of the nanosystems from negative to positive. As a consequence, the resulting SPECT nanoprobe generates a highly sought-after biodistribution profile accompanied by a drastically reduced uptake in liver, leading to significantly improved tumor imaging. This finding contrasts with current literature reporting that positively charged nanoparticles have preferential accumulation in the liver. As such, this study provides new perspectives for improving the biodistribution of positively charged nanosystems for biomedical applications.


Assuntos
Dendrímeros , Nanopartículas , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton Único , Tomografia Computadorizada por Raios X
5.
Chem Commun (Camb) ; 56(2): 301-304, 2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31808472

RESUMO

Bioimaging has revolutionized modern medicine, and nanotechnology can offer further specific and sensitive imaging. We report here an amphiphilic dendrimer able to self-assemble into supramolecular nanomicelles for effective tumor detection using SPECT radioimaging. This highlights the promising potential of supramolecular dendrimer platforms for biomedical imaging.


Assuntos
Dendrímeros/química , Nanoestruturas/química , Tensoativos/química , Adenocarcinoma/diagnóstico por imagem , Animais , Linhagem Celular Tumoral , Quelantes/síntese química , Quelantes/química , Dendrímeros/síntese química , Compostos Heterocíclicos com 1 Anel/síntese química , Compostos Heterocíclicos com 1 Anel/química , Humanos , Índio , Radioisótopos de Índio , Camundongos , Micelas , Neoplasias Pancreáticas/diagnóstico por imagem , Radioisótopos , Tensoativos/síntese química , Tomografia Computadorizada de Emissão de Fóton Único/métodos
6.
Nanomedicine (Lond) ; 14(18): 2441-2458, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31456476

RESUMO

Aim: Alterations of microglia, the brain-resident macrophages, are associated with numerous brain pathologies. Genetic manipulation of microglia in diseases using small interfering RNA (siRNA) is hampered by the lack of safe and efficient siRNA delivery methods. We assessed the amphiphilic dendrimer (AD) for functional siRNA delivery and gene knockdown in primary microglia. Materials & methods: We characterized the ability of AD to form nanoparticles with siRNA, and studied their size, surface potential, cell uptake and gene silencing in rodent microglia. Results: AD effectively delivered siRNA to primary microglia and decreased target gene and protein expression, leading to transcriptomic changes without affecting basal microglial functions. Conclusion: The dendrimer AD promises to be an innocuous carrier for siRNA delivery into microglia.


Assuntos
Dendrímeros/química , Portadores de Fármacos/química , Interferência de RNA , RNA Interferente Pequeno/administração & dosagem , Tensoativos/química , Animais , Células Cultivadas , Camundongos Endogâmicos C57BL , Microglia/citologia , Microglia/metabolismo , RNA Interferente Pequeno/genética , Ratos Wistar
7.
J Am Chem Soc ; 140(47): 16264-16274, 2018 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-30346764

RESUMO

Small interfering RNA (siRNA) is emerging as a novel therapeutic for treating various diseases, provided a safe and efficient delivery is available. In particular, specific delivery to target cells is critical for achieving high therapeutic efficacy while reducing toxicity. Amphiphilic dendrimers are emerging as novel promising carriers for siRNA delivery by virtue of the combined multivalent cooperativity of dendrimers with the self-assembling property of lipid vectors. Here, we report a ballistic approach for targeted siRNA delivery to cancer cells using an amphiphilic dendrimer equipped with a dual targeting peptide bearing an RGDK warhead. According to the molecular design, the amphiphilic dendrimer was expected to deliver siRNA effectively, while the aim of the targeting peptide was to home in on tumors via interaction of its warhead with integrin and the neuropilin-1 receptor on cancer cells. Coating the positively charged siRNA/dendrimer delivery complex with the negatively charged segment of the targeting peptide via electrostatic interactions led to small and stable nanoparticles which were able to protect siRNA from degradation while maintaining the accessibility of RGDK for targeting cancer cells and preserving the ability of the siRNA to escape from endosomes. The targeted system had enhanced siRNA delivery, stronger gene silencing, and more potent anticancer activity compared to nontargeted or covalent dendrimer-based systems. In addition, neither acute toxicity nor induced inflammation was observed. Consequently, this delivery system constitutes a promising nonviral vector for targeted delivery and can be further developed to provide RNAi-based personalized medicine against cancer. Our study also gives new perspectives on the use of nanotechnology based on self-assembling dendrimers in various biomedical applications.


Assuntos
Antineoplásicos/uso terapêutico , Dendrímeros/química , Portadores de Fármacos/química , Neoplasias/terapia , Peptídeos/química , RNA Interferente Pequeno/uso terapêutico , Sequência de Aminoácidos , Animais , Antineoplásicos/farmacologia , Feminino , Inativação Gênica/efeitos dos fármacos , Proteínas de Choque Térmico HSP27/antagonistas & inibidores , Proteínas de Choque Térmico HSP27/genética , Proteínas de Choque Térmico , Humanos , Integrinas/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Chaperonas Moleculares , Nanopartículas/química , Neuropilina-1/metabolismo , Células PC-3 , Peptídeos/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia , Tensoativos/química , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Proc Natl Acad Sci U S A ; 115(45): 11454-11459, 2018 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-30348798

RESUMO

Bioimaging plays an important role in cancer diagnosis and treatment. However, imaging sensitivity and specificity still constitute key challenges. Nanotechnology-based imaging is particularly promising for overcoming these limitations because nanosized imaging agents can specifically home in on tumors via the "enhanced permeation and retention" (EPR) effect, thus resulting in enhanced imaging sensitivity and specificity. Here, we report an original nanosystem for positron emission tomography (PET) imaging based on an amphiphilic dendrimer, which bears multiple PET reporting units at the terminals. This dendrimer is able to self-assemble into small and uniform nanomicelles, which accumulate in tumors for effective PET imaging. Benefiting from the combined dendrimeric multivalence and EPR-mediated passive tumor targeting, this nanosystem demonstrates superior imaging sensitivity and specificity, with up to 14-fold increased PET signal ratios compared with the clinical gold reference 2-fluorodeoxyglucose ([18F]FDG). Most importantly, this dendrimer system can detect imaging-refractory low-glucose-uptake tumors that are otherwise undetectable using [18F]FDG. In addition, it is endowed with an excellent safety profile and favorable pharmacokinetics for PET imaging. Consequently, this dendrimer nanosystem constitutes an effective and promising approach for cancer imaging. Our study also demonstrates that nanotechnology based on self-assembling dendrimers provides a fresh perspective for biomedical imaging and cancer diagnosis.


Assuntos
Neoplasias do Colo/diagnóstico por imagem , Complexos de Coordenação/farmacocinética , Radioisótopos de Gálio/farmacocinética , Glioblastoma/diagnóstico por imagem , Neoplasias Pancreáticas/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Neoplasias da Próstata/diagnóstico por imagem , Animais , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , Meios de Contraste/química , Meios de Contraste/farmacocinética , Complexos de Coordenação/sangue , Complexos de Coordenação/química , Dendrímeros/química , Fluordesoxiglucose F18/química , Radioisótopos de Gálio/sangue , Radioisótopos de Gálio/química , Glioblastoma/patologia , Compostos Heterocíclicos/química , Compostos Heterocíclicos com 1 Anel , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Pancreáticas/patologia , Neoplasias da Próstata/patologia
9.
Mol Ther ; 26(1): 70-83, 2018 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-29241971

RESUMO

Metastasis is the cause of most (>90%) cancer deaths and currently lacks effective treatments. Approaches to understanding the biological process, unraveling the most effective molecular target(s), and implementing nanotechnology to increase the therapeutic index are expected to facilitate cancer therapy against metastasis. Here, we demonstrate the potential advantages of bringing these three approaches together through the rational design of a small interfering RNA (siRNA) that targets p70S6K in cancer stem cells (CSCs) in combination with dendrimer nanotechnology-based siRNA delivery. Our results demonstrated that the generation 6 (G6) poly(amidoamine) dendrimer can be used as a nanovector to effectively deliver p70S6K siRNA by forming uniform dendriplex nanoparticles that protect the siRNA from degradation. These nanoparticles were able to significantly knock down p70S6K in ovarian CSCs, leading to a marked reduction in CSC proliferation and expansion without obvious toxicity toward normal ovarian surface epithelial cells. Furthermore, treatment with the p70S6K siRNA/G6 dendriplexes substantially decreased mesothelial interaction, migration and invasion of CSCs in vitro, as well as tumor growth and metastasis in vivo. Collectively, these results suggest that p70S6K constitutes a promising therapeutic target, and the use of siRNA in combination with nanotechnology-based delivery may constitute a new approach for molecularly targeted cancer therapy to treat metastasis.


Assuntos
Dendrímeros , Técnicas de Transferência de Genes , Células-Tronco Neoplásicas/metabolismo , Neoplasias Ovarianas/genética , RNA Interferente Pequeno/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Animais , Adesão Celular , Movimento Celular/genética , Proliferação de Células , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Neoplasias Ovarianas/patologia , Interferência de RNA , Estabilidade de RNA , RNA Interferente Pequeno/administração & dosagem , Recidiva , Nanomedicina Teranóstica
10.
ACS Appl Mater Interfaces ; 9(1): 1029-1035, 2017 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-27957833

RESUMO

Self-assembly of supramolecular structures has become an attractive means to create new biologically inspired materials and interfaces. We report the first robust hybrid bilayer systems readily coassembled from amphiphilic dendrimers and a naturally occurring phospholipid. Both concentration and generation of the dendrimers have direct impacts on the biophysical properties of the coassemblies. Raising the dendrimer concentration increases the hybrid bilayer stability, while changes in the generation and the concentration of the embedded dendrimers impact the fluidity of the coassembled systems. Multivalent dendrimer amine terminals allow for nondestructive in situ derivatization, providing a convenient approach to decorate and modulate the local environment of the hybrid bilayer. The coassembly of lipid/dendrimer interfaces offers a unique platform for the creation of hybrid systems with modular and precisely controllable behavior for further applications in sensing and drug delivery.


Assuntos
Dendrímeros/química , Sistemas de Liberação de Medicamentos , Fosfolipídeos
11.
Small ; 12(27): 3667-76, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27244195

RESUMO

Self-assembly is a fundamental concept and a powerful approach in molecular science. However, creating functional materials with the desired properties through self-assembly remains challenging. In this work, through a combination of experimental and computational approaches, the self-assembly of small amphiphilic dendrons into nanosized supramolecular dendrimer micelles with a degree of structural definition similar to traditional covalent high-generation dendrimers is reported. It is demonstrated that, with the optimal balance of hydrophobicity and hydrophilicity, one of the self-assembled nanomicellar systems, totally devoid of toxic side effects, is able to deliver small interfering RNA and achieve effective gene silencing both in cells - including the highly refractory human hematopoietic CD34(+) stem cells - and in vivo, thus paving the way for future biomedical implementation. This work presents a case study of the concept of generating functional supramolecular dendrimers via self-assembly. The ability of carefully designed and gauged building blocks to assemble into supramolecular structures opens new perspectives on the design of self-assembling nanosystems for complex and functional applications.


Assuntos
Dendrímeros/química , Inativação Gênica/fisiologia , RNA Interferente Pequeno/química , Animais , Linhagem Celular Tumoral , Humanos , Interações Hidrofóbicas e Hidrofílicas , Masculino , Camundongos , Camundongos Nus , Micelas , Estrutura Molecular , Neoplasias da Próstata/genética , Neoplasias da Próstata/terapia , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Bioorg Med Chem Lett ; 26(15): 3770-3, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-27287371

RESUMO

Staphylococcus aureus, a Gram positive coccal bacterium is a major cause of nosocomial infection. We report the synthesis of new triphenylamine phosphonium ionic liquids which are able to self-assemble into multiwall nanoassemblies and to reveal a strong bactericidal activity (MIC=0.5mg/L) for Gram positive bacteria (including resistant strains) comparable to that of standard antibiotics. Time kill, metabolism and fluorescence confocal microscopy studies show a quasi-instantaneously penetration of the nanoassemblies inside the bacteria resulting of a rapid blocking (30min) of their proliferation. As confirmed by rezasurin reduction monitoring, these compounds strongly affect the bacterial metabolism and a Gram positive versus Gram negative selectivity is clearly observed. These fluorescent phosphonium ionic liquid might constitute a useful tool for both translocation studies and to tackle infectious diseases related to the field of implantology.


Assuntos
Aminas/farmacologia , Antibacterianos/farmacologia , Corantes Fluorescentes/farmacologia , Líquidos Iônicos/farmacologia , Compostos Organofosforados/farmacologia , Aminas/síntese química , Aminas/química , Antibacterianos/síntese química , Antibacterianos/química , Bactérias/citologia , Bactérias/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Líquidos Iônicos/síntese química , Líquidos Iônicos/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Compostos Organofosforados/síntese química , Compostos Organofosforados/química , Relação Estrutura-Atividade
13.
Angew Chem Int Ed Engl ; 53(44): 11822-7, 2014 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-25219970

RESUMO

siRNA delivery remains a major challenge in RNAi-based therapy. Here, we report for the first time that an amphiphilic dendrimer is able to self-assemble into adaptive supramolecular assemblies upon interaction with siRNA, and effectively delivers siRNAs to various cell lines, including human primary and stem cells, thereby outperforming the currently available nonviral vectors. In addition, this amphiphilic dendrimer is able to harness the advantageous features of both polymer and lipid vectors and hence promotes effective siRNA delivery. Our study demonstrates for the first time that dendrimer-based adaptive supramolecular assemblies represent novel and versatile means for functional siRNA delivery, heralding a new age of dendrimer-based self-assembled drug delivery in biomedical applications.


Assuntos
Dendrímeros/química , Inativação Gênica/imunologia , RNA Interferente Pequeno/imunologia , Humanos
14.
J Phys Chem Lett ; 5(12): 2126-30, 2014 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-26270503

RESUMO

The growth of Pt-Pd nanoparticles from organometallic precursors is studied in situ in real time by HRTEM in a graphene oxide liquid cell. The reduction of the metal precursors is induced by the electron beam. During the growth, the particles rearrange their internal structure to form faceted single crystals. The growth is compatible with the Lifshitz-Slyozov-Wagner (LSW) mechanism in the limiting case of a reaction-limited process. The same particles are also synthesized ex situ by using a chemical reducing agent and observed in HRTEM.

15.
Small ; 7(2): 235-41, 2011 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-21213388

RESUMO

The morphology of platinum nanoparticles synthesized using an organometallic approach from PtMe(2) (C(8) H(12) ) is influenced by the nature of the ligands used as stabilizing agents. The use of long alkyl chain amines leads to the formation of multipodal nanoparticles that transform into compact nano-objects, adopting cubic, truncated cubic, or cuboctahedral shapes. In contrast, the use of diamine ligands allows the growth of compact (111) arrowlike faces, forming polycrystalline nanoparticles of an overall desert-rose aspect. Different reaction parameters are studied ([ligand]/[metal] ratio, temperature, solvent identity) in order to optimize the various shapes.


Assuntos
Nanopartículas Metálicas/química , Platina/química , Nanopartículas Metálicas/ultraestrutura , Microscopia Eletrônica de Transmissão , Nanotecnologia
16.
Bioconjug Chem ; 21(6): 1062-9, 2010 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-20481514

RESUMO

Cationic nucleoside lipids (CNLs) derived from 5-nitroindole and 4-nitroimidazole bases were prepared from d-ribose by using a straightforward chemical synthesis. TEM experiments indicate that these amphiphilic molecules self-assemble to form supramolecular organizations in aqueous solutions. Electrophoresis and standard ethidium bromide (EB) fluorescence displacement assay shows that CNLs are able to bind siRNA. We demonstrated that both the nature of the universal bases and the stereochemistry of the anomeric position (alpha, beta) have an impact on the CNLs-siRNA complex formation. Correlations among chemical structure, stereochemistry, siRNA knockdown effect, and binding affinities for all the compounds were shown and analyzed with a simple molecular modeling study. The best binding affinities for siRNA were found for the beta anomer of the 5-nitroindole CNL which exhibits protein knockdown activity similar to the standard siPORT NeoFX positive control. It is noteworthy that no significant cytotoxicity at the tested concentration was observed for the novel CNLs.


Assuntos
Lipídeos/química , Nucleosídeos/química , RNA Interferente Pequeno/genética , Ribose/química , Transfecção/métodos , Sítios de Ligação , Cátions/química , Eletroforese , Etídio/química , Etídio/metabolismo , Indóis/química , Microscopia Eletrônica de Transmissão , Modelos Moleculares , Nitroimidazóis/química , RNA Interferente Pequeno/química , Espectrometria de Fluorescência
17.
Bioconjug Chem ; 20(2): 193-6, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19159294

RESUMO

Cationic nucleoside lipids based on a 3-nitropyrrole universal base were prepared from D-ribose using a straightforward chemical synthesis. Several studies including DLS, TEM, and ethidium bromide (EthBr) assay demonstrated that these amphiphilic molecules form supramolecular organizations of nanometer size in aqueous solutions and are able to bind nucleic acids. siRNA knockdown experiments were performed with these nucleolipids, and we observed protein knockdown activity similar to the siPORT NeoFX positive control. No significant cytotoxicity was found.


Assuntos
Lipídeos/química , Pirróis/química , Pirróis/metabolismo , RNA Interferente Pequeno/metabolismo , Ribonucleosídeos/química , Ribonucleosídeos/metabolismo , Transfecção/métodos , Animais , Linhagem Celular , Técnicas de Silenciamento de Genes , Humanos , Pirróis/toxicidade , Ribonucleosídeos/toxicidade
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