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Article: Computational design of an apoptogenic protein that binds BCL-xL and MCL-1 simultaneously and potently

Kim, Seonghoon / Park, Hee-Sung / Oh, Byung-Ha

Computational and Structural Biotechnology Journal. 2022, v. 20

2022

Abstract: One of the hallmarks of cancer cells is their ability to evade apoptosis, which confers survival advantages and resistance to anti-cancer drugs. Cancers often exhibit overexpression of anti-apoptotic BCL-2 proteins, the loss of which triggers apoptosis. ... ...

Abstract	One of the hallmarks of cancer cells is their ability to evade apoptosis, which confers survival advantages and resistance to anti-cancer drugs. Cancers often exhibit overexpression of anti-apoptotic BCL-2 proteins, the loss of which triggers apoptosis. In particular, the inhibition of both BCL-xL and MCL-1, but neither one individually, synergistically enhances apoptotic cell death. Here, we report computational design to produce a protein that inhibits both BCL-xL and MCL-1 simultaneously. To a reported artificial three-helix bundle whose second helix was designed to bind MCL-1, we added a fourth helix and designed it to bind BCL-xL. After structural validation of the design and further structure-based sequence design, we produced a dual-binding protein that interacts with both BCL-xL and MCL-1 with apparent dissociation constants of 820 pM and 196 pM, respectively. Expression of this dual binder in a subset of cancer cells induced apoptotic cell death at levels significantly higher than those induced by the pro-apoptotic BIM protein. With a genetic fusion of a mitochondria-targeting sequence or the BH3 sequence of BIM, the activity of the dual binder was enhanced even further. These data suggest that targeted delivery of this dual binder alone or as a part of a modular protein to cancers in the form of protein, mRNA, or DNA may be an effective way to induce cancer cell apoptosis.
Keywords	DNA ; apoptosis ; biotechnology ; dissociation ; neoplasm cells
Language	English
Size	p. 3019-3029.
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	2694435-2
ISSN	2001-0370
ISSN	2001-0370
DOI	10.1016/j.csbj.2022.06.021
Database	NAL-Catalogue (AGRICOLA)

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Article: Computational design of an apoptogenic protein that binds BCL-xL and MCL-1 simultaneously and potently.

Kim, Seonghoon / Park, Hee-Sung / Oh, Byung-Ha

Computational and structural biotechnology journal

2022 Volume 20, Page(s) 3019–3029

Abstract	One of the hallmarks of cancer cells is their ability to evade apoptosis, which confers survival advantages and resistance to anti-cancer drugs. Cancers often exhibit overexpression of anti-apoptotic BCL-2 proteins, the loss of which triggers apoptosis. In particular, the inhibition of both BCL-xL and MCL-1, but neither one individually, synergistically enhances apoptotic cell death. Here, we report computational design to produce a protein that inhibits both BCL-xL and MCL-1 simultaneously. To a reported artificial three-helix bundle whose second helix was designed to bind MCL-1, we added a fourth helix and designed it to bind BCL-xL. After structural validation of the design and further structure-based sequence design, we produced a dual-binding protein that interacts with both BCL-xL and MCL-1 with apparent dissociation constants of 820 pM and 196 pM, respectively. Expression of this dual binder in a subset of cancer cells induced apoptotic cell death at levels significantly higher than those induced by the pro-apoptotic BIM protein. With a genetic fusion of a mitochondria-targeting sequence or the BH3 sequence of BIM, the activity of the dual binder was enhanced even further. These data suggest that targeted delivery of this dual binder alone or as a part of a modular protein to cancers in the form of protein, mRNA, or DNA may be an effective way to induce cancer cell apoptosis.
Language	English
Publishing date	2022-06-14
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2694435-2
ISSN	2001-0370
ISSN	2001-0370
DOI	10.1016/j.csbj.2022.06.021
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Article ; Online: Crystal structure of PYCH_01220 from Pyrococcus yayanosii potentially involved in binding nucleic acid.

Noh, Haemin / Jeon, Jae-Hyun / Kim, Yeon-Gil / Oh, Byung-Ha

Proteins

2020 Volume 89, Issue 4, Page(s) 468–472

Abstract: We report the crystal structure of PYCH_01220, a hypothetical protein in Pyrococcus yayanosii CH1. This protein is composed of two domains, named Domain A and Domain B. While Domain B is not significantly homologous to known protein structures, Domain A ... ...

Abstract	We report the crystal structure of PYCH_01220, a hypothetical protein in Pyrococcus yayanosii CH1. This protein is composed of two domains, named Domain A and Domain B. While Domain B is not significantly homologous to known protein structures, Domain A is structurally analogous to the C-terminal ribonuclease domain of Escherichia coli colicin D. Domain A has a positively charged surface patch rendered by 13 basic residues, eight arginine or lysine residues of which are evolutionarily conserved. Electrophoretic mobility shift assays showed that PYCH_01220 binds to DNA, and charge-inversion mutations on this patch negatively affect the DNA binding, suggesting that the function of PYCH_01220 might involve nucleic acid-binding via the positively charged patch.
MeSH term(s)	Archaeal Proteins/chemistry ; Archaeal Proteins/metabolism ; Crystallography, X-Ray ; DNA/chemistry ; DNA/metabolism ; Escherichia coli Proteins/chemistry ; Models, Molecular ; Protein Binding ; Protein Domains ; Pyrococcus/chemistry
Chemical Substances	Archaeal Proteins ; Escherichia coli Proteins ; colicin D immunity protein, E coli ; DNA (9007-49-2)
Language	English
Publishing date	2020-12-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	806683-8
ISSN	1097-0134 ; 0887-3585
ISSN (online)	1097-0134
ISSN	0887-3585
DOI	10.1002/prot.26029
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Article ; Online: Structural basis for the broad and potent cross-reactivity of an N501Y-centric antibody against sarbecoviruses.

Jeong, Bo-Seong / Jeon, Joon Young / Lai, Chih-Jen / Yun, Hye-Yeoung / Jung, Jae U / Oh, Byung-Ha

Frontiers in immunology

2022 Volume 13, Page(s) 1049867

Abstract: More than 80% of SARS-CoV-2 variants, including Alpha and Omicron, contain an N501Y mutation in the receptor-binding domain (RBD) of the spike protein. The N501Y change is an adaptive mutation enabling tighter interaction with the human ACE2 receptor. We ...

Abstract	More than 80% of SARS-CoV-2 variants, including Alpha and Omicron, contain an N501Y mutation in the receptor-binding domain (RBD) of the spike protein. The N501Y change is an adaptive mutation enabling tighter interaction with the human ACE2 receptor. We have developed a broadly neutralizing antibody (nAb), D27LEY, whose binding affinity was intentionally optimized for Y501. This N501Y-centric antibody not only interacts with the Y501-containing RBDs of SARS-CoV-2 variants, including Omicron, with pico- or subnanomolar binding affinity, but also binds tightly to the RBDs with a different amino acid at residue 501. The crystal structure of the Fab fragment of D27LEY bound to the RBD of the Alpha variant reveals that the Y501-containing loop adopts a ribbon-like topology and serves as a small but major epitope in which Y501 is a part of extensive intermolecular interactions. A hydrophobic cleft on the most conserved surface of the RBD core serves as another major binding epitope. These data explain the broad and potent cross-reactivity of this N501Y-centric antibody, and suggest that a vaccine antigenic component composed of the RBD core and a part of receptor-binding motif (RBM) containing tyrosine at residue 501 might elicit broad and potent humoral responses across sarbecoviruses.
MeSH term(s)	Humans ; SARS-CoV-2 ; COVID-19 ; Antibodies ; Epitopes
Chemical Substances	Antibodies ; Epitopes
Language	English
Publishing date	2022-11-17
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.1049867
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Article ; Online: Reversible modification of mitochondrial ADP/ATP translocases by paired

Kubori, Tomoko / Lee, Junyup / Kim, Hyunmin / Yamazaki, Kohei / Nishikawa, Masanari / Kitao, Tomoe / Oh, Byung-Ha / Nagai, Hiroki

Proceedings of the National Academy of Sciences of the United States of America

2022 Volume 119, Issue 23, Page(s) e2122872119

Abstract: Adenosine diphosphate (ADP) ribosylation is a reversible posttranslational modification involved in the regulation of numerous cellular processes. Prototype ADP ribosyltransferases (ARTs) from many pathogenic bacteria are known to function as toxins, ... ...

Abstract	Adenosine diphosphate (ADP) ribosylation is a reversible posttranslational modification involved in the regulation of numerous cellular processes. Prototype ADP ribosyltransferases (ARTs) from many pathogenic bacteria are known to function as toxins, while other bacterial ARTs have just recently emerged. Recent studies have shown that bacteria also possess enzymes that function as poly-ADP ribose (ADPr) glycohydrolases (PARGs), which reverse poly-ADP ribosylation. However, how bacteria manipulate host target proteins by coordinated reactions of ARTs and ADPr hydrolases (ARHs) remains elusive. The intracellular bacterial pathogen Legionella pneumophila, the causative agent of Legionnaires’ disease, transports a large array of effector proteins via the Dot/Icm type IV secretion system to host cells. The effector proteins, which mostly function as enzymes, modulate host cellular processes for the bacteria’s benefit. In this study, we identified a pair of L. pneumophila effector proteins, Lpg0080 and Lpg0081, which function as an ART and an ARH, respectively. The two proteins were shown to coordinately modulate mitochondrial ADP/adenosine triphosphate (ATP) translocases (ANTs) by their enzymatic activities to conjugate ADPr to, and remove it from, a key arginine residue. The crystal structures of Lpg0081 and the Lpg0081:ADPr complex indicated that Lpg0081 is a macroD-type ARH with a noncanonical macrodomain, whose folding topology is strikingly distinct from that of the canonical macrodomain that is ubiquitously found in eukaryotic PARGs and ARHs. Our results illustrate that L. pneumophila has acquired an effector pair that coordinately manipulate mitochondrial activity via reversible chemical modification of ANTs.
MeSH term(s)	Adenosine Diphosphate ; Adenosine Triphosphate ; Bacterial Proteins ; Legionella ; Legionella pneumophila ; Mitochondria/physiology ; Mitochondrial ADP, ATP Translocases
Chemical Substances	Bacterial Proteins ; Adenosine Diphosphate (61D2G4IYVH) ; Adenosine Triphosphate (8L70Q75FXE) ; Mitochondrial ADP, ATP Translocases (9068-80-8)
Language	English
Publishing date	2022-06-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2122872119
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Zs.A 1148: Show issues

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Article: Dimeric architecture of maltodextrin glucosidase (MalZ) provides insights into the substrate recognition and hydrolysis mechanism

Ahn, Woo-Chan / An, Yan / Song, Kyung-Mo / Park, Kwang-Hyun / Lee, Su-jin / Oh, Byung-Ha / Park, Jong-Tae / Woo, Eui-Jeon

Biochemical and biophysical research communications. 2022 Jan. 01, v. 586

2022

Abstract: Maltodextrin glucosidase (MalZ) is a key enzyme in the maltose utilization pathway in Escherichia coli that liberates glucose from the reducing end of the short malto-oligosaccharides. Unlike other enzymes in the GH13_21 subfamily, the hydrolytic ... ...

Abstract	Maltodextrin glucosidase (MalZ) is a key enzyme in the maltose utilization pathway in Escherichia coli that liberates glucose from the reducing end of the short malto-oligosaccharides. Unlike other enzymes in the GH13_21 subfamily, the hydrolytic activity of MalZ is limited to maltodextrin rather than long starch substrates, forming various transglycosylation products in α-1,3, α-1,4 or α-1,6 linkages. The mechanism for the substrate binding and hydrolysis of this enzyme is not well understood yet. Here, we present the dimeric crystal structure of MalZ, with the N-domain generating a unique substrate binding groove. The N-domain bears CBM34 architecture and forms a part of the active site in the catalytic domain of the adjacent molecule. The groove found between the N-domain and catalytic domain from the adjacent molecule, shapes active sites suitable for short malto-oligosaccharides, but hinders long stretches of oligosaccharides. The conserved residue of E44 protrudes at subsite +2, elucidating the hydrolysis pattern of the substrate by the glucose unit from the reducing end. The structural analysis provides a molecular basis for the substrate specificity and the enzymatic property, and has potential industrial application for protein engineering.
Keywords	Escherichia coli ; active sites ; crystal structure ; enzymes ; glucose ; glycosylation ; hydrolysis ; industrial applications ; maltodextrins ; maltose ; research ; starch ; substrate specificity
Language	English
Dates of publication	2022-0101
Size	p. 49-54.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	205723-2
ISSN	0006-291X ; 0006-291X
ISSN (online)	0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2021.11.070
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Article ; Online: Noncovalent antibody catenation on a target surface greatly increases the antigen-binding avidity.

Song, Jinyeop / Jeong, Bo-Seong / Kim, Seong-Woo / Im, Seong-Bin / Kim, Seonghoon / Lai, Chih-Jen / Cho, Wonki / Jung, Jae U / Ahn, Myung-Ju / Oh, Byung-Ha

eLife

2023 Volume 12

Abstract: Immunoglobulin G (IgG) antibodies are widely used for diagnosis and therapy. Given the unique dimeric structure of IgG, we hypothesized that, by genetically fusing a homodimeric protein (catenator) to the C-terminus of IgG, reversible catenation of ... ...

Abstract	Immunoglobulin G (IgG) antibodies are widely used for diagnosis and therapy. Given the unique dimeric structure of IgG, we hypothesized that, by genetically fusing a homodimeric protein (catenator) to the C-terminus of IgG, reversible catenation of antibody molecules could be induced on a surface where target antigen molecules are abundant, and that it could be an effective way to greatly enhance the antigen-binding avidity. A thermodynamic simulation showed that quite low homodimerization affinity of a catenator,
MeSH term(s)	Antibody Affinity ; Immunoglobulin G ; Antigens
Chemical Substances	Immunoglobulin G ; Antigens
Language	English
Publishing date	2023-05-30
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.81646
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Article ; Online: Dimeric architecture of maltodextrin glucosidase (MalZ) provides insights into the substrate recognition and hydrolysis mechanism.

Ahn, Woo-Chan / An, Yan / Song, Kyung-Mo / Park, Kwang-Hyun / Lee, Su-Jin / Oh, Byung-Ha / Park, Jong-Tae / Woo, Eui-Jeon

Biochemical and biophysical research communications

2021 Volume 586, Page(s) 49–54

Abstract	Maltodextrin glucosidase (MalZ) is a key enzyme in the maltose utilization pathway in Escherichia coli that liberates glucose from the reducing end of the short malto-oligosaccharides. Unlike other enzymes in the GH13_21 subfamily, the hydrolytic activity of MalZ is limited to maltodextrin rather than long starch substrates, forming various transglycosylation products in α-1,3, α-1,4 or α-1,6 linkages. The mechanism for the substrate binding and hydrolysis of this enzyme is not well understood yet. Here, we present the dimeric crystal structure of MalZ, with the N-domain generating a unique substrate binding groove. The N-domain bears CBM34 architecture and forms a part of the active site in the catalytic domain of the adjacent molecule. The groove found between the N-domain and catalytic domain from the adjacent molecule, shapes active sites suitable for short malto-oligosaccharides, but hinders long stretches of oligosaccharides. The conserved residue of E44 protrudes at subsite +2, elucidating the hydrolysis pattern of the substrate by the glucose unit from the reducing end. The structural analysis provides a molecular basis for the substrate specificity and the enzymatic property, and has potential industrial application for protein engineering.
MeSH term(s)	Biocatalysis ; Catalytic Domain ; Cloning, Molecular ; Crystallography, X-Ray ; Escherichia coli/enzymology ; Escherichia coli/genetics ; Escherichia coli Proteins/chemistry ; Escherichia coli Proteins/genetics ; Escherichia coli Proteins/metabolism ; Gene Expression ; Genetic Vectors/chemistry ; Genetic Vectors/metabolism ; Glucose/chemistry ; Glucose/metabolism ; Glycoside Hydrolases/chemistry ; Glycoside Hydrolases/genetics ; Glycoside Hydrolases/metabolism ; Hydrolysis ; Models, Molecular ; Polysaccharides/chemistry ; Polysaccharides/metabolism ; Protein Binding ; Protein Conformation, alpha-Helical ; Protein Conformation, beta-Strand ; Protein Interaction Domains and Motifs ; Protein Multimerization ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Substrate Specificity
Chemical Substances	Escherichia coli Proteins ; Polysaccharides ; Recombinant Proteins ; maltodextrin (7CVR7L4A2D) ; Glycoside Hydrolases (EC 3.2.1.-) ; malZ protein, E coli (EC 3.2.1.20) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2021-11-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	205723-2
ISSN	1090-2104 ; 0006-291X ; 0006-291X
ISSN (online)	1090-2104 ; 0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2021.11.070
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Zs.A 116: Show issues

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Article: Functional role of a novel algicidal compound produced by Pseudoruegeria sp. M32A2M on the harmful algae Alexandrium catenella

Ko, So-Ra / Jeong, Yujin / Cho, Sang-Hyeok / Lee, Eunju / Jeong, Bo-Seong / Baek, Seung Ho / Oh, Byung-Ha / Ahn, Chi-Yong / Oh, Hee-Mock / Cho, Byung-Kwan / Cho, Suhyung

Chemosphere. 2022 Aug., v. 300

2022

Abstract: A marine phytoplankton dinoflagellate, Alexandrium sp. is known to cause worldwide harmful algal blooms, resulting in paralytic shellfish poisoning. In this study, we isolated a novel compound secreted by the marine bacterium Pseudoruegeria sp. M32A2M, ... ...

Abstract	A marine phytoplankton dinoflagellate, Alexandrium sp. is known to cause worldwide harmful algal blooms, resulting in paralytic shellfish poisoning. In this study, we isolated a novel compound secreted by the marine bacterium Pseudoruegeria sp. M32A2M, and showed that it displays algicidal activity against A. catenella (group I). The molecular structure of the compound was analyzed by using ¹H nuclear magnetic resonance (NMR), ¹³C NMR, and gas chromatography-mass spectrometry, which revealed that the compound was a diketopiperazine, cyclo[Ala-Gly]. Cyclo[Ala-Gly] induced a rapid decrease in the active chlorophyll a content and maximal quantum yield of photosystem II, leading to membrane disintegration after 24 h of its treatment. It showed the highest algicidal effect against diketopiperazines and also showed specific algicidal activities against several dinoflagellate species, but not for diatom species. In particular, cyclo[Ala-Gly] caused the transcriptional downregulation of the photosynthesis-related membrane complex in A. catenella, but not in the diatom Chaetoceros simplex. Based on structural modeling, we elucidated that cyclo[Ala-Gly] has a structure similar to that of plastoquinone, which transfers electrons by binding to the photosystem II core proteins PsbA and PsbD. This suggests a novel role for cyclo[Ala-Gly] as a potential inhibitor of photosynthesis.
Keywords	Alexandrium catenella ; Bacillariophyceae ; Chaetoceros ; algicides ; aquatic bacteria ; chemical structure ; chlorophyll ; diketopiperazines ; gas chromatography-mass spectrometry ; nuclear magnetic resonance spectroscopy ; phytoplankton ; plastoquinones ; poisonous algae ; shellfish ; transcription (genetics)
Language	English
Dates of publication	2022-08
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	120089-6
ISSN	1879-1298 ; 0045-6535 ; 0366-7111
ISSN (online)	1879-1298
ISSN	0045-6535 ; 0366-7111
DOI	10.1016/j.chemosphere.2022.134535
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Zs.A 2540: Show issues

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Article ; Online: Computational design of a neutralizing antibody with picomolar binding affinity for all concerning SARS-CoV-2 variants.

Jeong, Bo-Seong / Cha, Jeong Seok / Hwang, Insu / Kim, Uijin / Adolf-Bryfogle, Jared / Coventry, Brian / Cho, Hyun-Soo / Kim, Kyun-Do / Oh, Byung-Ha

mAbs

2022 Volume 14, Issue 1, Page(s) 2021601

Abstract: Coronavirus disease 2019, caused by SARS-CoV-2, remains an on-going pandemic, partly due to the emergence of variant viruses that can "break-through" the protection of the current vaccines and neutralizing antibodies (nAbs), highlighting the needs for ... ...

Abstract	Coronavirus disease 2019, caused by SARS-CoV-2, remains an on-going pandemic, partly due to the emergence of variant viruses that can "break-through" the protection of the current vaccines and neutralizing antibodies (nAbs), highlighting the needs for broadly nAbs and next-generation vaccines. We report an antibody that exhibits breadth and potency in binding the receptor-binding domain (RBD) of the virus spike glycoprotein across SARS coronaviruses. Initially, a lead antibody was computationally discovered and crystallographically validated that binds to a highly conserved surface of the RBD of wild-type SARS-CoV-2. Subsequently, through experimental affinity enhancement and computational affinity maturation, it was further developed to bind the RBD of all concerning SARS-CoV-2 variants, SARS-CoV-1 and pangolin coronavirus with pico-molar binding affinities, consistently exhibited strong neutralization activity against wild-type SARS-CoV-2 and the Alpha and Delta variants. These results identify a vulnerable target site on coronaviruses for development of pan-sarbecovirus nAbs and vaccines.
MeSH term(s)	Angiotensin-Converting Enzyme 2/chemistry ; Angiotensin-Converting Enzyme 2/metabolism ; Antibodies, Viral/genetics ; Antibodies, Viral/immunology ; Antibodies, Viral/metabolism ; Antibody Affinity ; Antibody Specificity ; Antigen-Antibody Reactions ; Antigens, Viral/chemistry ; Antigens, Viral/genetics ; Antigens, Viral/immunology ; Broadly Neutralizing Antibodies/genetics ; Broadly Neutralizing Antibodies/immunology ; Broadly Neutralizing Antibodies/metabolism ; COVID-19/immunology ; Crystallography, X-Ray ; Epitopes/chemistry ; Epitopes/immunology ; Humans ; Immunoglobulin Fragments/immunology ; Molecular Docking Simulation ; Monte Carlo Method ; Neutralization Tests ; Peptide Fragments/chemistry ; Peptide Fragments/metabolism ; Protein Domains ; Recombinant Fusion Proteins/genetics ; Recombinant Fusion Proteins/immunology ; Recombinant Fusion Proteins/metabolism ; SARS-CoV-2/genetics ; SARS-CoV-2/immunology ; Spike Glycoprotein, Coronavirus/chemistry ; Spike Glycoprotein, Coronavirus/genetics ; Spike Glycoprotein, Coronavirus/immunology
Chemical Substances	Antibodies, Viral ; Antigens, Viral ; Broadly Neutralizing Antibodies ; Epitopes ; Immunoglobulin Fragments ; Peptide Fragments ; Recombinant Fusion Proteins ; Spike Glycoprotein, Coronavirus ; immunoglobulin Fv ; spike protein, SARS-CoV-2 ; ACE2 protein, human (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
Language	English
Publishing date	2022-01-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2537838-7
ISSN	1942-0870 ; 1942-0870
ISSN (online)	1942-0870
ISSN	1942-0870
DOI	10.1080/19420862.2021.2021601
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