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Singh, Pardeep
Publications (10 of 18) Show all publications
Sarkar, S., Singh, P., Edin, S., Wendt, O. F. & Almqvist, F. (2024). Synthesis of three-dimensional ring fused heterocycles by a selective [4 + 2] cycloaddition between bicyclic thiazolo 2-pyridones and arynes. Journal of Organic Chemistry, 89(1), 731-739
Open this publication in new window or tab >>Synthesis of three-dimensional ring fused heterocycles by a selective [4 + 2] cycloaddition between bicyclic thiazolo 2-pyridones and arynes
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2024 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 89, no 1, p. 731-739Article in journal (Refereed) Published
Abstract [en]

A selective [4 + 2] cycloaddition reaction of thiazolo-2-pyridones with arynes has been demonstrated. The developed protocol allows rapid access to highly functionalized, structurally complex thiazolo-fused bridged isoquinolones in high yields, which are susceptible to further late-stage functionalization.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2024
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-219753 (URN)10.1021/acs.joc.3c01957 (DOI)001137559200001 ()38093677 (PubMedID)2-s2.0-85180992605 (Scopus ID)
Funder
NIH (National Institutes of Health), R01AI134847-01A1NIH (National Institutes of Health), 1U19AI157797-01Familjen Erling-Perssons Stiftelse, P20-00473Swedish Research Council, 2018-04589Swedish Research Council, 2021-05040JThe Kempe Foundations, SMK-1755
Available from: 2024-01-22 Created: 2024-01-22 Last updated: 2024-01-22Bibliographically approved
Tükenmez, H., Singh, P., Sarkar, S., Çakır, M., Oliveira, A. H., Lindgren, C., . . . Johansson, J. (2023). A highly substituted ring-fused 2-pyridone compound targeting PrfA and the efflux regulator BrtA in listeria monocytogenes [Letter to the editor]. mBio, 14(3), Article ID e0044923.
Open this publication in new window or tab >>A highly substituted ring-fused 2-pyridone compound targeting PrfA and the efflux regulator BrtA in listeria monocytogenes
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2023 (English)In: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 14, no 3, article id e0044923Article in journal, Letter (Refereed) Published
Abstract [en]

Listeria monocytogenes is a facultative Gram-positive bacterium that causes listeriosis, a severe foodborne disease. We previously discovered that ring-fused 2-pyridone compounds can decrease virulence factor expression in Listeria by binding and inactivating the PrfA virulence activator. In this study, we tested PS900, a highly substituted 2-pyridone that was recently discovered to be bactericidal to other Gram-positive pathogenic bacteria, such as Staphylococcus aureus and Enterococcus faecalis. We show that PS900 can interact with PrfA and reduce the expression of virulence factors. Unlike previous ring-fused 2-pyridones shown to inactivate PrfA, PS900 had an additional antibacterial activity and was found to potentiate sensitivity toward cholic acid. Two PS900-tolerant mutants able to grow in the presence of PS900 carried mutations in the brtA gene, encoding the BrtA repressor. In wild-type (WT) bacteria, cholic acid binds and inactivates BrtA, thereby alleviating the expression of the multidrug transporter MdrT. Interestingly, we found that PS900 also binds to BrtA and that this interaction causes BrtA to dissociate from its binding site in front of the mdrT gene. In addition, we observed that PS900 potentiated the effect of different osmolytes. We suggest that the increased potency of cholic acid and osmolytes to kill bacteria in the presence of PS900 is due to the ability of the latter to inhibit general efflux, through a yet-unknown mechanism. Our data indicate that thiazolino 2-pyridones constitute an attractive scaffold when designing new types of antibacterial agents.

IMPORTANCE: Bacteria resistant to one or several antibiotics are a very large problem, threatening not only treatment of infections but also surgery and cancer treatments. Thus, new types of antibacterial drugs are desperately needed. In this work, we show that a new generation of substituted ring-fused 2-pyridones not only inhibit Listeria monocytogenes virulence gene expression, presumably by inactivating the PrfA virulence regulator, but also potentiate the bactericidal effects of cholic acid and different osmolytes. We identified a multidrug repressor as a second target of 2-pyridones. The repressor–2-pyridone interaction displaces the repressor from DNA, thus increasing the expression of a multidrug transporter. In addition, our data suggest that the new class of ring-fused 2-pyridones are efficient efflux inhibitors, possibly explaining why the simultaneous addition of 2-pyridones together with cholic acid or osmolytes is detrimental for the bacterium. This work proves conclusively that 2-pyridones constitute a promising scaffold to build on for future antibacterial drug design.

Place, publisher, year, edition, pages
American Society for Microbiology, 2023
Keywords
2-pyridones, BrtA, Listeria monocytogenes, PrfA, antibacterial, antibiotic
National Category
Biochemistry and Molecular Biology Microbiology in the medical area Organic Chemistry
Research subject
molecular cell biology
Identifiers
urn:nbn:se:umu:diva-214132 (URN)10.1128/mbio.00449-23 (DOI)000975886700001 ()37120759 (PubMedID)2-s2.0-85172894238 (Scopus ID)
Funder
Familjen Erling-Perssons StiftelseNIH (National Institutes of Health), RO1AI134847-01A1NIH (National Institutes of Health), 1IU19AI157797-01Olle Engkvists stiftelseVinnova, 2019-05491Swedish Research Council, 2020-02005Swedish Research Council, 2018-04589Swedish Research Council, 202105040J
Available from: 2023-09-05 Created: 2023-09-05 Last updated: 2023-10-13Bibliographically approved
Nye, T. M., Tükenmez, H., Singh, P., Flores-Mireles, A. L., Obernuefemann, C. L. .., Pinkner, J. S., . . . Hultgren, S. J. (2022). Ring-fused 2-pyridones effective against multidrug-resistant Gram-positive pathogens and synergistic with standard-of-care antibiotics. Proceedings of the National Academy of Sciences of the United States of America, 119(43), Article ID e2210912119.
Open this publication in new window or tab >>Ring-fused 2-pyridones effective against multidrug-resistant Gram-positive pathogens and synergistic with standard-of-care antibiotics
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2022 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 119, no 43, article id e2210912119Article in journal (Refereed) Published
Abstract [en]

The alarming rise of multidrug-resistant Gram-positive bacteria has precipitated a healthcare crisis, necessitating the development of new antimicrobial therapies. Here we describe a new class of antibiotics based on a ring-fused 2-pyridone backbone, which are active against vancomycin-resistant enterococci (VRE), a serious threat as classified by the Centers for Disease Control and Prevention, and other multidrug-resistant Gram-positive bacteria. Ring-fused 2-pyridone antibiotics have bacteriostatic activity against actively dividing exponential phase enterococcal cells and bactericidal activity against nondividing stationary phase enterococcal cells. The molecular mechanism of drug-induced killing of stationary phase cells mimics aspects of fratricide observed in enterococcal biofilms, where both are mediated by the Atn autolysin and the GelE protease. In addition, combinations of sublethal concentrations of ring-fused 2-pyridones and standard-of-care antibiotics, such as vancomycin, were found to synergize to kill clinical strains of VRE. Furthermore, a broad range of antibiotic resistant Gram-positive pathogens, including those responsible for the increasing incidence of antibiotic resistant healthcare-associated infections, are susceptible to this new class of 2-pyridone antibiotics. Given the broad antibacterial activities of ring-fused 2-pyridone compounds against Gram-positive (GmP) bacteria we term these compounds GmPcides, which hold promise in combating the rising tide of antibiotic resistant Gram-positive pathogens.

Place, publisher, year, edition, pages
PNAS, 2022
Keywords
antibiotic resistance, antibiotic synergy, multidrug-resistant pathogens, VRE
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-201191 (URN)10.1073/pnas.2210912119 (DOI)36252016 (PubMedID)2-s2.0-85141283133 (Scopus ID)
Funder
NIH (National Institutes of Health), 1U19AI157797-01NIH (National Institutes of Health), R01AI134847-01A1NIH (National Institutes of Health), R01DK128805NIH (National Institutes of Health), RO1DK51406NIH (National Institutes of Health), T32AI007172Swedish Research Council, 2018-04589Swedish Research Council, 2021-05040JThe Kempe Foundations, SMK-1755
Available from: 2023-01-05 Created: 2023-01-05 Last updated: 2023-08-25Bibliographically approved
Núñez-Otero, C., Bahnan, W., Vielfort, K., Silver, J., Singh, P., Elbir, H., . . . Gylfe, Å. (2021). A 2-pyridone amide inhibitor of transcriptional activity in Chlamydia trachomatis. Antimicrobial Agents and Chemotherapy, 65(5), Article ID e01826-20.
Open this publication in new window or tab >>A 2-pyridone amide inhibitor of transcriptional activity in Chlamydia trachomatis
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2021 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 65, no 5, article id e01826-20Article in journal (Refereed) Published
Abstract [en]

Chlamydia trachomatis is a strict intracellular bacterium that causes sexually transmitted infections and eye infections that can lead to lifelong sequelae. Treatment options are limited to broad-spectrum antibiotics that disturb the commensal flora and contribute to selection of antibiotic-resistant bacteria. Hence, development of novel drugs that specifically target C. trachomatis would be beneficial. 2-Pyridone amides are potent and specific inhibitors of Chlamydia infectivity. The first-generation compound KSK120 inhibits the developmental cycle of Chlamydia, resulting in reduced infectivity of progeny bacteria. Here, we show that the improved, highly potent second-generation 2-pyridone amide KSK213 allowed normal growth and development of C. trachomatis, and the effect was only observable upon reinfection of new cells. Progeny elementary bodies (EBs) produced in the presence of KSK213 were unable to activate transcription of essential genes in early development and did not differentiate into the replicative form, the reticulate body (RB). The effect was specific to C. trachomatis since KSK213 was inactive in the closely related animal pathogen Chlamydia muridarum and in Chlamydia caviae. The molecular target of KSK213 may thus be different in C. trachomatis or nonessential in C. muridarum and C. caviae. Resistance to KSK213 was mediated by a combination of amino acid substitutions in both DEAD/DEAH RNA helicase and RNase III, which may indicate inhibition of the transcriptional machinery as the mode of action. 2-Pyridone amides provide a novel antibacterial strategy and starting points for development of highly specific drugs for C. trachomatis infections.

Place, publisher, year, edition, pages
American Society for Microbiology, 2021
Keywords
Chlamydia trachomatis, antibacterial agents, intracellular bacteria, mode of action, virulence inhibitors
National Category
Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-174665 (URN)10.1128/AAC.01826-20 (DOI)000641612600035 ()2-s2.0-85105036198 (Scopus ID)
Note

Originally included in thesis in manuscript form.

Available from: 2020-08-31 Created: 2020-08-31 Last updated: 2023-09-05Bibliographically approved
Cairns, A. G., Sarkar, S., Singh, P., Larsson, A. & Almqvist, F. (2021). An efficient and scalable synthesis of thiazolo ring fused 2-pyridones using flow chemistry. ARKIVOC, 2020(7), 365-378
Open this publication in new window or tab >>An efficient and scalable synthesis of thiazolo ring fused 2-pyridones using flow chemistry
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2021 (English)In: ARKIVOC, ISSN 1551-7004, E-ISSN 1551-7012, Vol. 2020, no 7, p. 365-378Article in journal (Refereed) Published
Abstract [en]

Thiazolino ring fused 2-pyridones are a valuable scaffold with varied and substitution dependent biological activity, accessed primarily by an acyl ketene-imine cycloaddition and rearrangement. Although powerful, some aspects of this chemistry such as the requirement for excess starting material and the production of gas can make larger scale synthesis challenging. Here we describe the development, application and scaling of a continuous flow process allowing larger scale synthesis, with better handling of hazards and more reliable scaling. Optimisation and control of conditions allows for a more efficient synthesis, with a lower equivalence of the acyl ketene precursor required.

Place, publisher, year, edition, pages
Arkat, 2021
Keywords
Acyl ketene, Design of experiments, Flow chemistry, Heterocycle, Pyridone, Thiazolo
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-181828 (URN)10.24820/ARK.5550190.P011.445 (DOI)000746840700002 ()2-s2.0-85102694748 (Scopus ID)
Available from: 2021-04-06 Created: 2021-04-06 Last updated: 2023-09-05Bibliographically approved
Bharate, J. B., Ådén, J., Gharibyan, A., Adolfsson, D. E., Jayaweera, S. W., Singh, P., . . . Almqvist, F. (2021). K2S2O8-mediated coupling of 6-amino-7-aminomethyl-thiazolino-pyridones with aldehydes to construct amyloid affecting pyrimidine-fused thiazolino-2-pyridones. Organic and biomolecular chemistry, 19(44), 9758-9772
Open this publication in new window or tab >>K2S2O8-mediated coupling of 6-amino-7-aminomethyl-thiazolino-pyridones with aldehydes to construct amyloid affecting pyrimidine-fused thiazolino-2-pyridones
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2021 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 19, no 44, p. 9758-9772Article in journal (Refereed) Published
Abstract [en]

We herein present the synthesis of diversely functionalized pyrimidine fused thiazolino-2-pyridones via K2S2O8-mediated oxidative coupling of 6-amino-7-(aminomethyl)-thiazolino-2-pyridones with aldehydes. The developed protocol is mild, has wide substrate scope, and does not require transition metal catalyst or base. Some of the synthesized compounds have an ability to inhibit the formation of Amyloid-β fibrils associated with Alzheimer's disease, while others bind to mature amyloid-β and α-synuclein fibrils.

Place, publisher, year, edition, pages
The Royal Society of Chemistry, 2021
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-189516 (URN)10.1039/D1OB01580J (DOI)000714122800001 ()34730163 (PubMedID)2-s2.0-85120001225 (Scopus ID)
Funder
Swedish Research Council, 2017-02339; 2017-00695; 2018-04589Knut and Alice Wallenberg Foundation, 2013.0031Göran Gustafsson Foundation for Research in Natural Sciences and MedicineSwedish Foundation for Strategic Research, SB12-0070NIH (National Institutes of Health), (R01AI134847-01A1
Available from: 2021-11-15 Created: 2021-11-15 Last updated: 2023-08-09Bibliographically approved
Tyagi, M., Adolfsson, D. E., Singh, P., Ådén, J., Jayaweera, S. W., Gharibyan, A., . . . Almqvist, F. (2021). Tandem Ring Opening/Intramolecular [2 + 2] Cycloaddition Reaction for the Synthesis of Cyclobutane Fused Thiazolino-2-Pyridones. Journal of Organic Chemistry, 86(23), 16582-16592
Open this publication in new window or tab >>Tandem Ring Opening/Intramolecular [2 + 2] Cycloaddition Reaction for the Synthesis of Cyclobutane Fused Thiazolino-2-Pyridones
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2021 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 86, no 23, p. 16582-16592Article in journal (Refereed) Published
Abstract [en]

Reaction of thiazoline fused 2-pyridones with alkyl halides in the presence of cesium carbonate opens the thiazoline ring via S-alkylation and generates N-alkenyl functionalized 2-pyridones. In the reaction with propargyl bromide, the thiazoline ring opens and subsequently closes via a [2 + 2] cycloaddition between an in situ generated allene and the α,β-unsaturated methyl ester. This method enabled the synthesis of a variety of cyclobutane fused thiazolino-2-pyridones, of which a few analogues inhibit amyloid β1–40 fibril formation. Furthermore, other analogues were able to bind mature α-synuclein and amyloid β1−40 fibrils. Several thiazoline fused 2-pyridones with biological activity tolerate this transformation, which in addition provides an exocyclic alkene as a potential handle for tuning bioactivity.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2021
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-189656 (URN)10.1021/acs.joc.1c01875 (DOI)000752848600030 ()34767366 (PubMedID)2-s2.0-85119436020 (Scopus ID)
Funder
Swedish Research Council, 2017-02339Swedish Research Council, 2017-00695Swedish Research Council, 2018-04589Knut and Alice Wallenberg Foundation, 2013.0031Göran Gustafsson Foundation for Research in Natural Sciences and MedicineThe Kempe Foundations, SMK-1755Swedish Foundation for Strategic Research , SB12-0070NIH (National Institute of Health), (R01AI134847-01A1Familjen Erling-Perssons Stiftelse
Available from: 2021-11-18 Created: 2021-11-18 Last updated: 2023-09-05Bibliographically approved
Adolfsson, D. E., Tyagi, M., Singh, P., Deuschmann, A., Ådén, J., Gharibyan, A., . . . Almqvist, F. (2020). Intramolecular Povarov Reactions for the Synthesis of Chromenopyridine fused 2-Pyridone Polyheterocycles Binding to α-Synuclein and Amyloid-β fibrils. Journal of Organic Chemistry, 85(21), 14174-14189
Open this publication in new window or tab >>Intramolecular Povarov Reactions for the Synthesis of Chromenopyridine fused 2-Pyridone Polyheterocycles Binding to α-Synuclein and Amyloid-β fibrils
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2020 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 85, no 21, p. 14174-14189Article in journal (Other academic) Published
Abstract [en]

A BF3×OEt2 catalyzed intramolecular Povarov reaction was used to synthesize a library of 15 chromenopyridine fused thiazolino-2-pyridone peptidomimetics. The reaction works with a range of O-alkylated salicylaldehydes and amino functionalized thiazolino-2-pyridones, to generate polyheterocycles with diverse substitution. The synthesized compounds were screened for their ability to bind α-synuclein and amyloid β fibrils in vitro. Analogs substituted with a nitro group bind to mature amyloid fibrils, and the activity moreover depends on the positioning of this functional group.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2020
Keywords
Nanofibers, Column chromatography, Peptides and proteins, Mixtures, Alkyls
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-174531 (URN)10.1021/acs.joc.0c01699 (DOI)000589941700068 ()2-s2.0-85095859796 (Scopus ID)
Funder
Swedish Research Council, 2017-02339Swedish Research Council, 2017-00695Swedish Research Council, 2018-04589Knut and Alice Wallenberg Foundation, KAW 2013.0031Göran Gustafsson Foundation for Research in Natural Sciences and MedicineThe Kempe Foundations, SMK-1755Swedish Foundation for Strategic Research , SB12-0070NIH (National Institute of Health), R01AI134847-01A1
Note

Previously included in thesis in manuscript form.

Available from: 2020-08-26 Created: 2020-08-26 Last updated: 2023-03-24Bibliographically approved
Kulén, M., Núñez-Otero, C., Cairns, A. G., Silver, J., Lindgren, A. E. G., Andersson, E. K., . . . Almqvist, F. (2019). Methyl sulfonamide substituents improve the pharmacokinetic properties of bicyclic 2-pyridone based Chlamydia trachomatis inhibitors. MedChemComm, 10(11), 1966-1987
Open this publication in new window or tab >>Methyl sulfonamide substituents improve the pharmacokinetic properties of bicyclic 2-pyridone based Chlamydia trachomatis inhibitors
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2019 (English)In: MedChemComm, ISSN 2040-2503, E-ISSN 2040-2511, Vol. 10, no 11, p. 1966-1987Article in journal (Refereed) Published
Abstract [en]

Chlamydia trachomatis infections are a global health problem and new approaches to treat C. trachomatis with drugs of high specificity would be valuable. A library of substituted ring fused 2-pyridones has been synthesized and evaluated for their ability to attenuate C. trachomatis infectivity. In vivo pharmacokinetic studies were performed, with the best candidates demonstrating that a C8-methylsulfonamide substituent improved pharmacokinetic properties important for oral administration. C8-Methyl sulfonamide analogue 30 inhibited C. trachomatis infectivity in low micromolar concentrations. Further pharmacokinetic evaluation at an oral dose of 10 mg kg(-1) showed an apparent bioavailability of 41%, compared to C8-cyclopropyl and -methoxy analogues which had negligible oral uptake. In vitro ADME (absorption, distribution, metabolism and excretion) testing of solubility and Caco-2 cell permeability revealed that both solubility and permeability is greatly improved with the C8-methyl sulfonamide 30, effectively moving it from BCS (Biopharmaceutical Classification System) class IV to II.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2019
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:umu:diva-166479 (URN)10.1039/c9md00405j (DOI)000498725400013 ()2-s2.0-85075072755 (Scopus ID)
Funder
Swedish Cancer SocietyKnut and Alice Wallenberg FoundationGöran Gustafsson Foundation for Research in Natural Sciences and MedicineThe Kempe FoundationsSwedish Foundation for Strategic Research
Available from: 2020-01-02 Created: 2020-01-02 Last updated: 2023-08-25Bibliographically approved
Singh, P., Adolfsson, D. E., Ådén, J., Cairns, A. G., Bartens, C., Brännström, K., . . . Almqvist, F. (2019). Pyridine-Fused 2-Pyridones via Povarov and A3 Reactions: Rapid Generation of Highly Functionalized Tricyclic Heterocycles Capable of Amyloid Fibril Binding. Journal of Organic Chemistry, 84(7), 3887-3903
Open this publication in new window or tab >>Pyridine-Fused 2-Pyridones via Povarov and A3 Reactions: Rapid Generation of Highly Functionalized Tricyclic Heterocycles Capable of Amyloid Fibril Binding
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2019 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 84, no 7, p. 3887-3903Article in journal (Refereed) Published
Abstract [en]

We here describe the use of three-component reactions to synthesize tricyclic pyridine ring-fused 2-pyridones. The developed protocols have a wide substrate scope and allow for the installation of diverse chemical functionalities on the tricyclic central fragment. Several of these pyridine-fused rigid polyheterocycles are shown to bind to Aβ and α-synuclein fibrils, which are associated with neurodegenerative diseases.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2019
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-157464 (URN)10.1021/acs.joc.8b03015 (DOI)000464250800014 ()30862161 (PubMedID)2-s2.0-85063365828 (Scopus ID)
Funder
Swedish Research Council, 2014-04673Swedish Research Council, 2018-04589Knut and Alice Wallenberg Foundation, KAW 2013.0031The Kempe Foundations, SMK-1755Swedish Foundation for Strategic Research , SB12-0070
Available from: 2019-03-21 Created: 2019-03-21 Last updated: 2023-03-24Bibliographically approved
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