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Publications (10 of 11) Show all publications
Deiana, M., Andrés Castán, J. M., Josse, P., Kahsay, A., Sánchez, D. P., Morice, K., . . . Sabouri, N. (2023). A new G-quadruplex-specific photosensitizer inducing genome instability in cancer cells by triggering oxidative DNA damage and impeding replication fork progression. Nucleic Acids Research, 51(12), 6264-6285
Open this publication in new window or tab >>A new G-quadruplex-specific photosensitizer inducing genome instability in cancer cells by triggering oxidative DNA damage and impeding replication fork progression
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2023 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 51, no 12, p. 6264-6285Article in journal (Refereed) Published
Abstract [en]

Photodynamic therapy (PDT) ideally relies on the administration, selective accumulation and photoactivation of a photosensitizer (PS) into diseased tissues. In this context, we report a new heavy-atom-free fluorescent G-quadruplex (G4) DNA-binding PS, named DBI. We reveal by fluorescence microscopy that DBI preferentially localizes in intraluminal vesicles (ILVs), precursors of exosomes, which are key components of cancer cell proliferation. Moreover, purified exosomal DNA was recognized by a G4-specific antibody, thus highlighting the presence of such G4-forming sequences in the vesicles. Despite the absence of fluorescence signal from DBI in nuclei, light-irradiated DBI-treated cells generated reactive oxygen species (ROS), triggering a 3-fold increase of nuclear G4 foci, slowing fork progression and elevated levels of both DNA base damage, 8-oxoguanine, and double-stranded DNA breaks. Consequently, DBI was found to exert significant phototoxic effects (at nanomolar scale) toward cancer cell lines and tumor organoids. Furthermore, in vivo testing reveals that photoactivation of DBI induces not only G4 formation and DNA damage but also apoptosis in zebrafish, specifically in the area where DBI had accumulated. Collectively, this approach shows significant promise for image-guided PDT.

Place, publisher, year, edition, pages
Oxford University Press, 2023
National Category
Biochemistry and Molecular Biology Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-212227 (URN)10.1093/nar/gkad365 (DOI)000988008500001 ()37191066 (PubMedID)2-s2.0-85164253573 (Scopus ID)
Funder
Swedish Cancer Society, 22 2380 PjSwedish Research Council, VR-MH 2021–02468Knut and Alice Wallenberg Foundation, KAW 2021-0173Swedish Cancer Society, 21 0302 PT 01 HWenner-Gren Foundations, UPD2020-0097Swedish Cancer Society, 20 0827 PjFCancerforskningsfonden i Norrland, LP 22-2312Cancerforskningsfonden i Norrland, LP20 1024 2257Cancerforskningsfonden i Norrland, LP 21–2298Swedish Research Council, 2017-01531Swedish Society of Medicine, SLS-890521Region Västerbotten, RV-930167Sjöberg FoundationKnut and Alice Wallenberg Foundation, KAW 2015.0114Marianne and Marcus Wallenberg Foundation, MMW 2020.0189Swedish Cancer Society, 20 1339 PjF
Available from: 2023-07-21 Created: 2023-07-21 Last updated: 2023-07-21Bibliographically 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
Jamroskovic, J., Deiana, M. & Sabouri, N. (2022). Probing the folding pathways of four-stranded intercalated cytosine-rich motifs at single base-pair resolution. Biochimie, 199, 81-91
Open this publication in new window or tab >>Probing the folding pathways of four-stranded intercalated cytosine-rich motifs at single base-pair resolution
2022 (English)In: Biochimie, ISSN 0300-9084, E-ISSN 1638-6183, Vol. 199, p. 81-91Article in journal (Refereed) Published
Abstract [en]

Cytosine-rich DNA can fold into four-stranded intercalated structures called i-motifs (iMs) under acidic conditions through the formation of hemi-protonated C:C+ base pairs. However, the folding and stability of iMs rely on many other factors that are not yet fully understood. Here, we combined biochemical and biophysical approaches to determine the factors influencing iM stability under a wide range of experimental conditions. By using high-resolution primer extension assays, circular dichroism, and absorption spectroscopies, we demonstrate that the stabilities of three different biologically relevant iMs are not dependent on molecular crowding agents. Instead, some of the crowding agents affected overall DNA synthesis. We also tested a range of small molecules to determine their effect on iM stabilization at physiological temperature and demonstrated that the G-quadruplex-specific molecule CX-5461 is also a promising candidate for selective iM stabilization. This work provides important insights into the requirements needed for different assays to accurately study iM stabilization, which will serve as important tools for understanding the contribution of iMs in cell regulation and their potential as therapeutic targets.

Place, publisher, year, edition, pages
Elsevier, 2022
Keywords
CX-5461, DNA replication, G-quadruplex DNA, High-resolution primer extension assay, I-motif DNA, pH
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-194635 (URN)10.1016/j.biochi.2022.04.007 (DOI)000800388200003 ()35452743 (PubMedID)2-s2.0-85129038456 (Scopus ID)
Funder
Swedish Research Council, 2021-02468Swedish Cancer Society, 2019/126Åke Wiberg Foundation, M20-0125Swedish Cancer Society, 21 0302 PT 01 H
Available from: 2022-05-12 Created: 2022-05-12 Last updated: 2023-09-05Bibliographically approved
Deiana, M., Josse, P., Dalinot, C., Osmolovskyi, A., Marqués, P. S., Castán, J. M., . . . Cabanetos, C. (2022). Site-selected thionated benzothioxanthene chromophores as heavy-atom-free small-molecule photosensitizers for photodynamic therapy. Communications Chemistry, 5, Article ID 142.
Open this publication in new window or tab >>Site-selected thionated benzothioxanthene chromophores as heavy-atom-free small-molecule photosensitizers for photodynamic therapy
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2022 (English)In: Communications Chemistry, E-ISSN 2399-3669, Vol. 5, article id 142Article in journal (Refereed) Published
Abstract [en]

Photodynamic therapy is a clinically approved anticancer modality that employs a light-activated agent (photosensitizer) to generate cytotoxic reactive oxygen species (ROS). There is therefore a growing interest for developing innovative photosensitizing agents with enhanced phototherapeutic performances. Herein, we report on a rational design synthetic procedure that converts the ultrabright benzothioxanthene imide (BTI) dye into three heavy-atom-free thionated compounds featuring close-to-unit singlet oxygen quantum yields. In contrast to the BTI, these thionated analogs display an almost fully quenched fluorescence emission, in agreement with the formation of highly populated triplet states. Indeed, the sequential thionation on the BTI scaffold induces torsion of its skeleton reducing the singlet-triplet energy gaps and enhancing the spin-orbit coupling. These potential PSs show potent cancer-cell ablation under light irradiation while remaining non-toxic under dark condition owing to a photo-cytotoxic mechanism that we believe simultaneously involves singlet oxygen and superoxide species, which could be both characterized in vitro. Our study demonstrates that this simple site-selected thionated platform is an effective strategy to convert conventional carbonyl-containing fluorophores into phototherapeutic agents for anticancer PDT.

Place, publisher, year, edition, pages
Springer Nature, 2022
National Category
Biophysics
Identifiers
urn:nbn:se:umu:diva-200995 (URN)10.1038/s42004-022-00752-x (DOI)000876981400002 ()2-s2.0-85140992916 (Scopus ID)
Funder
Swedish Cancer Society, 21 0302 PT 01 HSwedish Cancer Society, 2019/126Swedish Research Council, 2021-02468EU, Horizon 2020, 722651
Note

We acknowledge the Biochemical Imaging Center at Umeå University and the National Microscopy Infrastructure, NMI (VR-RFI 2019-00217) for providing assistance in microscopy.

Available from: 2022-11-17 Created: 2022-11-17 Last updated: 2022-11-17Bibliographically 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
Deiana, M., Mosser, M., Le Bahers, T., Dumont, E., Dudek, M., Denis-Quanquin, S., . . . Guy, L. (2021). Light-induced in situ chemical activation of a fluorescent probe for monitoring intracellular G-quadruplex structures. Nanoscale, 13(32), 13795-13808
Open this publication in new window or tab >>Light-induced in situ chemical activation of a fluorescent probe for monitoring intracellular G-quadruplex structures
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2021 (English)In: Nanoscale, ISSN 2040-3364, E-ISSN 2040-3372, Vol. 13, no 32, p. 13795-13808Article in journal (Refereed) Published
Abstract [en]

Light-activated functional materials capable of remote control over duplex and G-quadruplex (G4) nucleic acids formation at the cellular level are still very rare. Herein, we report on the photoinduced macrocyclisation of a helicenoid quinoline derivative of binaphthol that selectively provides easy access to an unprecedented class of extended heteroaromatic structures with remarkable photophysical and DNA/RNA binding properties. Thus, while the native bisquinoline precursor shows no DNA binding activity, the new in situ photochemically generated probe features high association constants to DNA and RNA G4s. The latter inhibits DNA synthesis by selectively stabilizing G4 structures associated with oncogenic promoters and telomere repeat units. Finally, the light sensitive compound is capable of in cellulo photoconversion, localizes primarily in the G4-rich sites of cancer cells, competes with a well-known G4 binder and shows a clear nuclear co-localization with the quadruplex specific antibody BG4. This work provides a benchmark for the future design and development of a brand-new generation of light-activated target-selective G4-binders.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2021
National Category
Biophysics Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-187087 (URN)10.1039/d1nr02855c (DOI)000680884100001 ()34477654 (PubMedID)2-s2.0-85113310558 (Scopus ID)
Funder
Swedish Research Council, 2018-02651Knut and Alice Wallenberg Foundation, KAW2015-0189Swedish Cancer Society, 2019/126
Note

Correction: Light-induced in situ chemicalactivation of a fluorescent probe for monitoringintracellular G-quadruplex structures. Nanoscale, 2023, 15, 388. DOI: 10.1039/d2nr90225g

Available from: 2021-09-03 Created: 2021-09-03 Last updated: 2022-12-29Bibliographically approved
Dudek, M., Deiana, M., Szkaradek, K., Janicki, M. J., Pokładek, Z., Góra, R. W. & Matczyszyn, K. (2021). Light-Induced Modulation of Chiral Functions in G-Quadruplex-Photochrome Systems. Journal of Physical Chemistry Letters, 12(39), 9436-9441
Open this publication in new window or tab >>Light-Induced Modulation of Chiral Functions in G-Quadruplex-Photochrome Systems
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2021 (English)In: Journal of Physical Chemistry Letters, ISSN 1948-7185, E-ISSN 1948-7185, Vol. 12, no 39, p. 9436-9441Article in journal (Refereed) Published
Abstract [en]

The design of artificially engineered chiral structures has received much attention, but the implementation of dynamic functions to modulate the chiroptical response of the systems is less explored. Here, we present a light-responsive G-quadruplex (G4)-based assembly in which chirality enrichment is induced, tuned, and fueled by molecular switches. In particular, the mirror-image dependence on photoactivated azo molecules, undergoing trans-to-cis isomerization, shows chiral recognition effects on the inherent flexibility and conformational diversity of DNA G4s having distinct handedness (right- and left-handed). Through a detailed experimental and computational analysis, we bring compelling evidence on the binding mode of the photochromes on G4s, and we rationalize the origin of the chirality effect that is associated with the complexation event.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2021
National Category
Theoretical Chemistry
Identifiers
urn:nbn:se:umu:diva-189197 (URN)10.1021/acs.jpclett.1c02207 (DOI)000707046300004 ()2-s2.0-85116661772 (Scopus ID)
Available from: 2021-11-10 Created: 2021-11-10 Last updated: 2021-11-10Bibliographically approved
Deiana, M., Chand, K., Jamroskovic, J., Obi, I., Chorell, E. & Sabouri, N. (2020). A Light‐up Logic Platform for Selective Recognition of Parallel G‐Quadruplex Structures via Disaggregation‐Induced Emission. Angewandte Chemie International Edition, 59(2), 896-902
Open this publication in new window or tab >>A Light‐up Logic Platform for Selective Recognition of Parallel G‐Quadruplex Structures via Disaggregation‐Induced Emission
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2020 (English)In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 59, no 2, p. 896-902Article in journal (Refereed) Published
Abstract [en]

The design of turn‐on dyes with optical signals sensitive to the formation of supramolecular structures provides fascinating and underexplored opportunities for G‐quadruplex (G4) DNA detection and characterization. Here, we show a new switching mechanism that relies on the recognition‐driven disaggregation (on‐signal) of an ultrabright coumarin‐quinazoline conjugate. The synthesized probe selectively lights‐up parallel G4 DNA structures via the disassembly of its supramolecular state, demonstrating outputs that are easily integrable into a label free molecular logic system. Finally, our molecule preferentially stains the G4‐rich nucleoli of cancer cells.

Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2020
Keywords
aggregation, biosensor, DNA, G-quadruplex, logic gate
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Medical Biochemistry
Identifiers
urn:nbn:se:umu:diva-164662 (URN)10.1002/anie.201912027 (DOI)000497789300001 ()31644837 (PubMedID)2-s2.0-85075533982 (Scopus ID)
Funder
Knut and Alice Wallenberg Foundation, KAW2015-0189Swedish Research Council, VR-NT 2017-05235Swedish Research Council, VR-MH 2018-02651The Kempe Foundations, SMK-1632
Available from: 2019-10-25 Created: 2019-10-25 Last updated: 2023-09-05Bibliographically approved
Deiana, M., Chand, K., Jamroskovic, J., Das, R. N., Obi, I., Chorell, E. & Sabouri, N. (2020). A Site-Specific Self-Assembled Light-up Rotor Probe for Selective Recognition and Stabilization of c-MYC G-Quadruplex DNA. Nanoscale, 12(24), 12950-12957
Open this publication in new window or tab >>A Site-Specific Self-Assembled Light-up Rotor Probe for Selective Recognition and Stabilization of c-MYC G-Quadruplex DNA
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2020 (English)In: Nanoscale, ISSN 2040-3364, E-ISSN 2040-3372, Vol. 12, no 24, p. 12950-12957Article in journal (Refereed) Published
Abstract [en]

Direct and unambiguous evidence of the formation of G-quadruplexes (G4s) in human cells have shown their implication in several key biological events and has emphasized their role as important targets for small-molecule cancer therapeutics. Here, we report on the first example of a self-assembled multitasking molecular-rotor G4-binder able to discriminate between an extensive panel of G4 and non-G4 structures and to selectively light-up (up to 105-fold), bind (nanomolar range), and stabilize the c-MYC promoter G4 DNA. In particular, association with the c-MYC G4 triggers the disassembly of its supramolecular state (disaggregation-induced emission, DIE) and induces geometrical restrictions (motion-induced change in emission, MICE) leading to a significant enhancement of its emission yield. Moreover, this optical reporter is able to selectively stabilize the c-MYC G4 and inhibit DNA synthesis. Finally, by using confocal laser-scanning microscopy (CLSM) we show the ability of this compound to localize primarily in the subnuclear G4-rich compartments of cancer cells. This work provides a benchmark for the future design and development of a new generation of smart sequence-selective supramolecular G4-binders that combine outstanding sensing and stability properties, to be utilized in anti-cancer therapy.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2020
National Category
Biochemistry and Molecular Biology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Organic Chemistry Physical Chemistry
Research subject
Biochemistry; Organic Chemistry; Physical Chemistry; cell research
Identifiers
urn:nbn:se:umu:diva-171513 (URN)10.1039/D0NR03404E (DOI)000545599900025 ()2-s2.0-85087110627 (Scopus ID)
Funder
Knut and Alice Wallenberg Foundation, KAW2015-0189Swedish Research Council, VR-NT 2017-05235Swedish Research Council, VR-MH 2018-02651The Kempe Foundations, SMK-1632
Available from: 2020-06-03 Created: 2020-06-03 Last updated: 2023-03-24Bibliographically approved
Jamroskovic, J., Doimo, M., Chand, K., Obi, I., Kumar, R., Brännström, K., . . . Sabouri, N. (2020). Quinazoline Ligands Induce Cancer Cell Death through Selective STAT3 Inhibition and G-Quadruplex Stabilization. Journal of the American Chemical Society, 142(6), 2876-2888
Open this publication in new window or tab >>Quinazoline Ligands Induce Cancer Cell Death through Selective STAT3 Inhibition and G-Quadruplex Stabilization
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2020 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 142, no 6, p. 2876-2888Article in journal (Refereed) Published
Abstract [en]

The signal transducer and activator of transcription 3 (STAT3) protein is a master regulator of most key hallmarks and enablers of cancer, including cell proliferation and the response to DNA damage. G-Quadruplex (G4) structures are four-stranded noncanonical DNA structures enriched at telomeres and oncogenes' promoters. In cancer cells, stabilization of G4 DNAs leads to replication stress and DNA damage accumulation and is therefore considered a promising target for oncotherapy. Here, we designed and synthesized novel quinazoline-based compounds that simultaneously and selectively affect these two well-recognized cancer targets, G4 DNA structures and the STAT3 protein. Using a combination of in vitro assays, NMR, and molecular dynamics simulations, we show that these small, uncharged compounds not only bind to the STAT3 protein but also stabilize G4 structures. In human cultured cells, the compounds inhibit phosphorylation-dependent activation of STAT3 without affecting the antiapoptotic factor STAT1 and cause increased formation of G4 structures, as revealed by the use of a G4 DNA-specific antibody. As a result, treated cells show slower DNA replication, DNA damage checkpoint activation, and an increased apoptotic rate. Importantly, cancer cells are more sensitive to these molecules compared to noncancerous cell lines. This is the first report of a promising class of compounds that not only targets the DNA damage cancer response machinery but also simultaneously inhibits the STAT3-induced cancer cell proliferation, demonstrating a novel approach in cancer therapy.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Atom and Molecular Physics and Optics
Identifiers
urn:nbn:se:umu:diva-169314 (URN)10.1021/jacs.9b11232 (DOI)000514255300025 ()31990532 (PubMedID)2-s2.0-85079045732 (Scopus ID)
Funder
Knut and Alice Wallenberg FoundationSwedish Research CouncilThe Kempe Foundations, SMK-1632Åke Wiberg FoundationSwedish Cancer SocietyVästerbotten County Council, VLL-643451Västerbotten County Council, VLL-832001EU, Horizon 2020, 751474
Available from: 2020-03-31 Created: 2020-03-31 Last updated: 2023-03-24Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-7815-4494

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