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Publications (10 of 63) Show all publications
Andréasson, M., Donzel, M., Abrahamsson, A., Berner, A., Doimo, M., Quiroga, A., . . . Chorell, E. (2024). Exploring the dispersion and electrostatic components in arene-arene interactions between ligands and G4 DNA to develop G4-ligands. Journal of Medicinal Chemistry, 67(3), 2202-2219
Open this publication in new window or tab >>Exploring the dispersion and electrostatic components in arene-arene interactions between ligands and G4 DNA to develop G4-ligands
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2024 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 67, no 3, p. 2202-2219Article in journal (Refereed) Published
Abstract [en]

G-Quadruplex (G4) DNA structures are important regulatory elements in central biological processes. Small molecules that selectively bind and stabilize G4 structures have therapeutic potential, and there are currently >1000 known G4 ligands. Despite this, only two G4 ligands ever made it to clinical trials. In this work, we synthesized several heterocyclic G4 ligands and studied their interactions with G4s (e.g., G4s from the c-MYC, c-KIT, and BCL-2 promoters) using biochemical assays. We further studied the effect of selected compounds on cell viability, the effect on the number of G4s in cells, and their pharmacokinetic properties. This identified potent G4 ligands with suitable properties and further revealed that the dispersion component in arene-arene interactions in combination with electron-deficient electrostatics is central for the ligand to bind with the G4 efficiently. The presented design strategy can be applied in the further development of G4-ligands with suitable properties to explore G4s as therapeutic targets.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2024
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:umu:diva-220319 (URN)10.1021/acs.jmedchem.3c02127 (DOI)38241609 (PubMedID)2-s2.0-85183093324 (Scopus ID)
Funder
The Kempe Foundations, JCK-3159The Kempe Foundations, SMK-1632Swedish Research Council, 2017-05235Swedish Research Council, 2021-04805Knut and Alice Wallenberg Foundation
Available from: 2024-02-13 Created: 2024-02-13 Last updated: 2024-02-13Bibliographically approved
Doimo, M., Chaudhari, N., Abrahamsson, S., L'Hôte, V., Nguyen, T. V. H., Berner, A., . . . Wanrooij, S. (2023). Enhanced mitochondrial G-quadruplex formation impedes replication fork progression leading to mtDNA loss in human cells. Nucleic Acids Research, 51(14), 7392-7408
Open this publication in new window or tab >>Enhanced mitochondrial G-quadruplex formation impedes replication fork progression leading to mtDNA loss in human cells
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2023 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 51, no 14, p. 7392-7408Article in journal (Refereed) Published
Abstract [en]

Mitochondrial DNA (mtDNA) replication stalling is considered an initial step in the formation of mtDNA deletions that associate with genetic inherited disorders and aging. However, the molecular details of how stalled replication forks lead to mtDNA deletions accumulation are still unclear. Mitochondrial DNA deletion breakpoints preferentially occur at sequence motifs predicted to form G-quadruplexes (G4s), four-stranded nucleic acid structures that can fold in guanine-rich regions. Whether mtDNA G4s form in vivo and their potential implication for mtDNA instability is still under debate. In here, we developed new tools to map G4s in the mtDNA of living cells. We engineered a G4-binding protein targeted to the mitochondrial matrix of a human cell line and established the mtG4-ChIP method, enabling the determination of mtDNA G4s under different cellular conditions. Our results are indicative of transient mtDNA G4 formation in human cells. We demonstrate that mtDNA-specific replication stalling increases formation of G4s, particularly in the major arc. Moreover, elevated levels of G4 block the progression of the mtDNA replication fork and cause mtDNA loss. We conclude that stalling of the mtDNA replisome enhances mtDNA G4 occurrence, and that G4s not resolved in a timely manner can have a negative impact on mtDNA integrity.

Place, publisher, year, edition, pages
Oxford University Press, 2023
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-214069 (URN)10.1093/nar/gkad535 (DOI)001030190900001 ()37351621 (PubMedID)2-s2.0-85168980694 (Scopus ID)
Funder
Knut and Alice Wallenberg FoundationSwedish Research Council, VR-MH 2018-0278Swedish Research Council, VR-NT 2017-05235The Kempe Foundations, SMK-1632Wenner-Gren FoundationsEU, Horizon 2020, 751474Swedish Foundation for Strategic Research, RIF14-0081
Available from: 2023-09-05 Created: 2023-09-05 Last updated: 2023-09-05Bibliographically approved
Berner, A., Das, R. N., Bhuma, N., Golebiewska, J., Abrahamsson, A., Andréasson, M., . . . Chorell, E. (2023). G4-ligand-conjugated oligonucleotides mediate selective binding and stabilization of individual G4 DNA structures. Journal of the American Chemical Society, 146(10), 6926-6935
Open this publication in new window or tab >>G4-ligand-conjugated oligonucleotides mediate selective binding and stabilization of individual G4 DNA structures
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2023 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 146, no 10, p. 6926-6935Article in journal (Refereed) Published
Abstract [en]

G-quadruplex (G4) DNA structures are prevalent secondary DNA structures implicated in fundamental cellular functions, such as replication and transcription. Furthermore, G4 structures are directly correlated to human diseases such as cancer and have been highlighted as promising therapeutic targets for their ability to regulate disease-causing genes, e.g., oncogenes. Small molecules that bind and stabilize these structures are thus valuable from a therapeutic perspective and helpful in studying the biological functions of the G4 structures. However, there are hundreds of thousands of G4 DNA motifs in the human genome, and a long-standing problem in the field is how to achieve specificity among these different G4 structures. Here, we developed a strategy to selectively target an individual G4 DNA structure. The strategy is based on a ligand that binds and stabilizes G4s without selectivity, conjugated to a guide oligonucleotide, that specifically directs the G4-Ligand-conjugated oligo (GL-O) to the single target G4 structure. By employing various biophysical and biochemical techniques, we show that the developed method enables the targeting of a unique, specific G4 structure without impacting other off-target G4 formations. Considering the vast amount of G4s in the human genome, this represents a promising strategy to study the presence and functions of individual G4s but may also hold potential as a future therapeutic modality.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2023
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-222294 (URN)10.1021/jacs.3c14408 (DOI)001179314400001 ()38430200 (PubMedID)2-s2.0-85186374110 (Scopus ID)
Funder
The Kempe Foundations, JCK-3159The Kempe Foundations, SMK-1632The Kempe Foundations, SMK21-0059Swedish Research Council, 2017-05235Swedish Research Council, 2021-04805Swedish Research Council, 2018-0278Cancerforskningsfonden i Norrland, AMP19-968Knut and Alice Wallenberg Foundation, SMK21-0059
Available from: 2024-03-20 Created: 2024-03-20 Last updated: 2024-03-20Bibliographically approved
Deiana, M., Chand, K., Chorell, E. & Sabouri, N. (2023). Parallel G-quadruplex DNA structures from nuclear and mitochondrial genomes trigger emission enhancement in a nonfluorescent nano-aggregated fluorine-boron-based dye. Journal of Physical Chemistry Letters, 14(7), 1862-1869
Open this publication in new window or tab >>Parallel G-quadruplex DNA structures from nuclear and mitochondrial genomes trigger emission enhancement in a nonfluorescent nano-aggregated fluorine-boron-based dye
2023 (English)In: Journal of Physical Chemistry Letters, ISSN 1948-7185, E-ISSN 1948-7185, Vol. 14, no 7, p. 1862-1869Article in journal (Refereed) Published
Abstract [en]

Molecular self-assembly is a powerful tool for the development of functional nanostructures with adaptive optical properties. However, in aqueous solution, the hydrophobic effects in the monomeric units often afford supramolecular architectures with typical side-by-side π-stacking arrangement with compromised emissive properties. Here, we report on the role of parallel DNA guanine quadruplexes (G4s) as supramolecular disaggregating-capture systems capable of coordinating a zwitterionic fluorine-boron-based dye and promoting activation of its fluorescence signal. The dye's high binding affinity for parallel G4s compared to nonparallel topologies leads to a selective disassembly of the dye's supramolecular state upon contact with parallel G4s. This results in a strong and selective disaggregation-induced emission that signals the presence of parallel G4s observable by the naked eye and inside cells. The molecular recognition strategy reported here will be useful for a multitude of affinity-based applications with potential in sensing and imaging systems.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2023
National Category
Physical Chemistry
Identifiers
urn:nbn:se:umu:diva-205385 (URN)10.1021/acs.jpclett.2c03301 (DOI)000936590300001 ()36779779 (PubMedID)2-s2.0-85148521026 (Scopus ID)
Available from: 2023-03-10 Created: 2023-03-10 Last updated: 2023-09-05Bibliographically approved
Bhuma, N., Chand, K., Andréasson, M., Mason, J. E., Das, R. N., Patel, A. K., . . . Chorell, E. (2023). The effect of side chain variations on quinazoline-pyrimidine G-quadruplex DNA ligands. European Journal of Medicinal Chemistry, 248, Article ID 115103.
Open this publication in new window or tab >>The effect of side chain variations on quinazoline-pyrimidine G-quadruplex DNA ligands
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2023 (English)In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 248, article id 115103Article in journal (Refereed) Published
Abstract [en]

G-quadruplex (G4) DNA structures are involved in central biological processes such as DNA replication and transcription. These DNA structures are enriched in promotor regions of oncogenes and are thus promising as novel gene silencing therapeutic targets that can be used to regulate expression of oncoproteins and in particular those that has proven hard to drug with conventional strategies. G4 DNA structures in general have a well-defined and hydrophobic binding area that also is very flat and featureless and there are ample examples of G4 ligands but their further progression towards drug development is limited. In this study, we use synthetic organic chemistry to equip a drug-like and low molecular weight central fragment with different side chains and evaluate how this affect the compound's selectivity and ability to bind and stabilize G4 DNA. Furthermore, we study the binding interactions of the compounds and connect the experimental observations with the compound's structural conformations and electrostatic potentials to understand the basis for the observed improvements. Finally, we evaluate the top candidates' ability to selectively reduce cancer cell growth in a 3D co-culture model of pancreatic cancer which show that this is a powerful approach to generate highly active and selective low molecular weight G4 ligands with a promising therapeutic window.

Place, publisher, year, edition, pages
Elsevier, 2023
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:umu:diva-202112 (URN)10.1016/j.ejmech.2023.115103 (DOI)000922160800001 ()2-s2.0-85146280645 (Scopus ID)
Funder
The Kempe Foundations, SMK-1632Swedish Research Council, 2017–05235Swedish Research Council, 2017- 01531The Swedish Medical Association, SLS-890521Region Västerbotten, RV-930167Knut and Alice Wallenberg FoundationMarianne and Marcus Wallenberg Foundation, 2020.0189Swedish Cancer Society, 20 1339 PjFCancerforskningsfonden i Norrland, LP 21–2298Cancerforskningsfonden i Norrland, LP 22–2332
Note

Originally included in thesis in manuscript form.

Available from: 2023-01-02 Created: 2023-01-02 Last updated: 2023-09-05Bibliographically approved
Prasad, B., Doimo, M., Andréasson, M., L'Hôte, V., Chorell, E. & Wanrooij, S. (2022). A complementary chemical probe approach towards customized studies of G-quadruplex DNA structures in live cells. Chemical Science, 13(8), 2347-2354
Open this publication in new window or tab >>A complementary chemical probe approach towards customized studies of G-quadruplex DNA structures in live cells
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2022 (English)In: Chemical Science, ISSN 2041-6520, E-ISSN 2041-6539, Vol. 13, no 8, p. 2347-2354Article in journal (Refereed) Published
Abstract [en]

G-quadruplex (G4) DNA structures are implicated in central biological processes and are considered promising therapeutic targets because of their links to human diseases such as cancer. However, functional details of how, when, and why G4 DNA structures form in vivo are largely missing leaving a knowledge gap that requires tailored chemical biology studies in relevant live-cell model systems. Towards this end, we developed a synthetic platform to generate complementary chemical probes centered around one of the most effective and selective G4 stabilizing compounds, Phen-DC3. We used a structure-based design and substantial synthetic devlopments to equip Phen-DC3 with an amine in a position that does not interfere with G4 interactions. We next used this reactive handle to conjugate a BODIPY fluorophore to Phen-DC3. This generated a fluorescent derivative with retained G4 selectivity, G4 stabilization, and cellular effect that revealed the localization and function of Phen-DC3 in human cells. To increase cellular uptake, a second chemical probe with a conjugated cell-penetrating peptide was prepared using the same amine-substituted Phen-DC3 derivative. The cell-penetrating peptide conjugation, while retaining G4 selectivity and stabilization, increased nuclear localization and cellular effects, showcasing the potential of this method to modulate and direct cellular uptake e.g. as delivery vehicles. The applied approach to generate multiple tailored biochemical tools based on the same core structure can thus be used to advance the studies of G4 biology to uncover molecular details and therapeutic approaches. This journal is

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2022
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-193064 (URN)10.1039/d1sc05816a (DOI)000751956900001 ()2-s2.0-85125772577 (Scopus ID)
Funder
Swedish Research Council, VR-NT 2017-05235The Kempe Foundations, SMK-1632Knut and Alice Wallenberg Foundation, VR-MH 2018-0278EU, Horizon 2020, 751474
Available from: 2022-03-21 Created: 2022-03-21 Last updated: 2023-03-24Bibliographically approved
Andréasson, M., Bhuma, N., Pemberton, N. & Chorell, E. (2022). Using Macrocyclic G-Quadruplex Ligands to Decipher the Interactions Between Small Molecules and G-Quadruplex DNA. Chemistry - A European Journal, 28(65), Article ID e202202020.
Open this publication in new window or tab >>Using Macrocyclic G-Quadruplex Ligands to Decipher the Interactions Between Small Molecules and G-Quadruplex DNA
2022 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 28, no 65, article id e202202020Article in journal (Refereed) Published
Abstract [en]

This study aims to deepen the knowledge of the current state of rational G4-ligand design through the design and synthesis of a novel set of compounds based on indoles, quinolines, and benzofurans and their comparisons with well-known G4-ligands. This resulted in novel synthetic methods and G4-ligands that bind and stabilize G4 DNA with high selectivity. Furthermore, the study corroborates previous studies on the design of G4-ligands and adds deeper explanations to why a) macrocycles offer advantages in terms of G4-binding and -selectivity, b) molecular pre-organization is of key importance in the development of strong novel binders, c) an electron-deficient aromatic core is essential to engage in strong arene-arene interactions with the G4-surface, and d) aliphatic amines can strengthen interactions indirectly through changing the arene electrostatic nature of the compound. Finally, fundamental physicochemical properties of selected G4-binders are evaluated, underscoring the complexity of aligning the properties required for efficient G4 binding and stabilization with feasible pharmacokinetic properties.

Place, publisher, year, edition, pages
John Wiley & Sons, 2022
Keywords
arene-arene interactions, G-quadruplex DNA, G4-ligand, macrocycle, molecular design
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-199908 (URN)10.1002/chem.202202020 (DOI)000855541300001 ()35997141 (PubMedID)2-s2.0-85138242355 (Scopus ID)
Funder
The Kempe Foundations, SMK‐1632Swedish Research Council, 2017‐05235
Note

This article also appears in: Society Volumes: Sweden.

Available from: 2022-10-04 Created: 2022-10-04 Last updated: 2023-01-02Bibliographically approved
Broman, K., Chorell, E., Holmboe, M. & Magkakis, K. (2022). Virtual Reality to visualise chemistry in higher education: Digital tools to enhance student learning. In: : . Paper presented at NU2022, Nätverk och utveckling, Stockholm/online, Sverige, 15-17 juni, 2022.
Open this publication in new window or tab >>Virtual Reality to visualise chemistry in higher education: Digital tools to enhance student learning
2022 (English)Conference paper, Oral presentation only (Refereed)
Abstract [en]

Visualisation of molecular representations is an important area within chemistry education that has been explored for a long time, from several different perspectives. In the 1950s, Linus Pauling and Robert Koltun defined the CPK-model, describing the colours of the different atoms used in wood or plastic ball-and-stick models, for example, the black carbon, the white hydrogen, and the red oxygen. These analogue ball-and-stick models (e.g., MolyMod) are still used both in schools and at universities to help students “see” chemistry in three dimensions (3D). Today, with digitalisation, new tools are available to represent and visualise chemistry(Bernholt, Broman, Siebert, & Parchmann, 2019). With these modern digital tools, there are less limitations in molecular size to represent molecules, and even large structures and reaction mechanisms can be explored (Won, Mocerino, Tang, Treagust, & Tasker, 2019). In our project, interventions applying Virtual Reality (VR) as the digital tool during organic chemistry workshops and tutorials, have been explored related to cognitive and affective learning.

VR gives students the possibility to practice spatial ability, i.e., to move between 2D and 3D. In textbooks, chemistry is presented in 2D using, for example, Lewis structures. However, in real life, chemistry is three-dimensional, and the move between 2D and 3D is something students, as novices, need to practice to understand why and how chemicals react. In our project, university students practice their spatial ability through the application of VR. This on-going project started in 2018, and different workshops and tutorials have been implemented in different chemistry courses for bachelor, master, and engineering students. As presented in previous recent research from Brown and colleagues (2021), our students were very positive, enthusiastic and engaged to work with VR to develop their spatial ability and to visualise chemistry. In the presentation, we will give examples on how students can improve their learning and interest with the use of VR to represent chemical structures.

National Category
Didactics
Research subject
didactics of chemistry
Identifiers
urn:nbn:se:umu:diva-196949 (URN)
Conference
NU2022, Nätverk och utveckling, Stockholm/online, Sverige, 15-17 juni, 2022
Available from: 2022-06-20 Created: 2022-06-20 Last updated: 2022-07-04Bibliographically approved
Broman, K., Chorell, E., Holmboe, M. & Magkakis, K. (2022). Virtual Reality: visualization of chemical structures to enhance student interest and learning. In: ECRICE 2022: chemistry teaching and learning in a global unified world: abstract book. Paper presented at ECRICE 2022, 15th European Conference on Research in Chemical Education: Chemistry Teaching and Learning in a Global Unified World, Reẖovot, Israel, July 11-13, 2022. Weizmann Institute of Science
Open this publication in new window or tab >>Virtual Reality: visualization of chemical structures to enhance student interest and learning
2022 (English)In: ECRICE 2022: chemistry teaching and learning in a global unified world: abstract book, Weizmann Institute of Science , 2022Conference paper, Oral presentation with published abstract (Refereed)
Abstract [en]

One of the fundamental aspects of chemistry learning is to visualize chemical structures. Through the application of Alex Johnstone's (1991) multilevel thought, the submicroscopic level is often a challenge for students, especially the shift between 2D and 3D, i.e., spatial thinking or spatial ability (Harle & Towns, 2011). With small molecules, plastic ball-and-stick models are commonly used, but on university level, the structures are often larger. By applying digital tools and techniques, as Virtual Reality (VR), there are less limitations in size to represent molecules, and even large structures and reaction mechanisms can be explored (Won et al., 2019). In a five-year design-based research project (Anderson & Shattuck, 2012), a collaboration between university chemistry teachers and a chemistry education researcher, has had an aim to develop university chemistry students' spatial thinking.

Students and teachers have, in workshops and tutorials, applied VR with both simple and more advanced tools, see figures 1 and 2. Empirical data has been collected using surveys, interviews, and observations. Standard ethical considerations have been considered throughout the whole project.

In this presentation, students' cognitive and affective learning related to spatial thinking will be discussed, as well as students', teachers', and researcher’s perspectives from the application of VR to visualize chemistry will be elaborated further. Implications for chemistry teaching at all levels will also be explored.

Place, publisher, year, edition, pages
Weizmann Institute of Science, 2022
National Category
Didactics
Research subject
didactics of chemistry
Identifiers
urn:nbn:se:umu:diva-198012 (URN)
Conference
ECRICE 2022, 15th European Conference on Research in Chemical Education: Chemistry Teaching and Learning in a Global Unified World, Reẖovot, Israel, July 11-13, 2022
Available from: 2022-07-12 Created: 2022-07-12 Last updated: 2023-05-31Bibliographically approved
Deiana, M., Obi, I., Andréasson, M., Tamilselvi, S., Chand, K., Chorell, E. & Sabouri, N. (2021). A Minimalistic Coumarin Turn-On Probe for Selective Recognition of Parallel G-Quadruplex DNA Structures. ACS Chemical Biology, 16(8), 1365-1376
Open this publication in new window or tab >>A Minimalistic Coumarin Turn-On Probe for Selective Recognition of Parallel G-Quadruplex DNA Structures
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2021 (English)In: ACS Chemical Biology, ISSN 1554-8929, E-ISSN 1554-8937, Vol. 16, no 8, p. 1365-1376Article in journal (Refereed) Published
Abstract [en]

G-quadruplex (G4) DNA structures are widespread in the human genome and are implicated in biologically important processes such as telomere maintenance, gene regulation, and DNA replication. Guanine-rich sequences with potential to form G4 structures are prevalent in the promoter regions of oncogenes, and G4 sites are now considered as attractive targets for anticancer therapies. However, there are very few reports of small “druglike” optical G4 reporters that are easily accessible through one-step synthesis and that are capable of discriminating between different G4 topologies. Here, we present a small water-soluble light-up fluorescent probe that features a minimalistic amidinocoumarin-based molecular scaffold that selectively targets parallel G4 structures over antiparallel and non-G4 structures. We showed that this biocompatible ligand is able to selectively stabilize the G4 template resulting in slower DNA synthesis. By tracking individual DNA molecules, we demonstrated that the G4-stabilizing ligand perturbs DNA replication in cancer cells, resulting in decreased cell viability. Moreover, the fast-cellular entry of the probe enabled detection of nucleolar G4 structures in living cells. Finally, insights gained from the structure–activity relationships of the probe suggest the basis for the recognition of parallel G4s, opening up new avenues for the design of new biocompatible G4-specific small molecules for G4-driven theranostic applications.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2021
National Category
Medicinal Chemistry Biochemistry and Molecular Biology Biophysics
Identifiers
urn:nbn:se:umu:diva-187118 (URN)10.1021/acschembio.1c00134 (DOI)000697396400009 ()34328300 (PubMedID)2-s2.0-85113337330 (Scopus ID)
Funder
The Kempe Foundations, SMK-1632Knut and Alice Wallenberg Foundation, KAW2015-0189Swedish Cancer Society, CAN 2019/126Swedish Research Council, 2017-05235Swedish Research Council, 2018-02651
Available from: 2021-09-01 Created: 2021-09-01 Last updated: 2023-03-23Bibliographically approved
Projects
Selectively targeting specific G-quadruplex DNA structures with small molecules to probe their biological functions and potential as drug targets [2017-05235_VR]; Umeå University
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-2523-1940

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