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Article ; Online: Divergent effects of calcineurin Aβ on regulatory and conventional T-cell homeostasis.

Doetschman, Thomas / Sholl, Allyson / Chen, Hwu dau rw / Gard, Connie / Hildeman, David A / Bommireddy, Ramireddy

2011 Volume 138, Issue 3, Page(s) 321–330

Abstract: Calcineurin (CN) is a phosphatase that activates nuclear factor of activated T cells (NFAT ... Further, as Cnab(-/-) mice age, they exhibit spontaneous T-cell activation and enhanced production ... of proinflammatory cytokines (IL-4, IL-6, and IFNγ). FOXP3(+) T(reg) cells were significantly decreased in Cnab ...

Abstract	Calcineurin (CN) is a phosphatase that activates nuclear factor of activated T cells (NFAT). While the CN inhibitors cyclosporine A (CsA) and tacrolimus (FK506) can prevent graft rejection, they also cause inflammatory diseases. We investigated the role of calcineurin using mice deficient in the CN catalytic subunit Aβ (CNAβ). Cnab(-/-) mice exhibit defective thymocyte maturation, splenomegaly and hepatomegaly. Further, as Cnab(-/-) mice age, they exhibit spontaneous T-cell activation and enhanced production of proinflammatory cytokines (IL-4, IL-6, and IFNγ). FOXP3(+) T(reg) cells were significantly decreased in Cnab(-/-) mice likely contributing to increased T-cell activation. Interestingly, we found that CNAβ is critical for promotion of BCL-2 expression in FOXP3(+) T(reg) and for permitting TGFβ signaling, as TGFβ induces FOXP3 in control but not in Cnab(-/-) T-cells. Together, these data suggest that CNAβ is important for the production and maintenance of T(reg) cells and to ensure mature T-cell quiescence.
MeSH term(s)	Animals ; Calcineurin/genetics ; Calcineurin/immunology ; Cytokines/biosynthesis ; Cytokines/immunology ; Forkhead Transcription Factors/immunology ; Hepatomegaly/immunology ; Hepatomegaly/metabolism ; Homeostasis/immunology ; Lymphocyte Activation/immunology ; Mice ; Mice, Mutant Strains ; Proto-Oncogene Proteins c-bcl-2/biosynthesis ; Proto-Oncogene Proteins c-bcl-2/immunology ; Signal Transduction/immunology ; Splenomegaly/immunology ; Splenomegaly/metabolism ; T-Lymphocytes, Regulatory/immunology ; T-Lymphocytes, Regulatory/metabolism ; Transforming Growth Factor beta/immunology
Chemical Substances	Cytokines ; Forkhead Transcription Factors ; Foxp3 protein, mouse ; Proto-Oncogene Proteins c-bcl-2 ; Transforming Growth Factor beta ; Calcineurin (EC 3.1.3.16) ; protein phosphatase 3, catalytic subunit, beta isoform, mouse (EC 3.1.3.16)
Language	English
Publishing date	2011-01-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1459903-x
ISSN	1521-7035 ; 1521-6616
ISSN (online)	1521-7035
ISSN	1521-6616
DOI	10.1016/j.clim.2010.12.020
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Zs.A 880: Show issues

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Article: TGF-beta, T-cell tolerance and anti-CD3 therapy.

Bommireddy, Ramireddy / Doetschman, Thomas

Trends in molecular medicine

2003 Volume 10, Issue 1, Page(s) 3–9

MeSH term(s)	Animals ; Antibodies/therapeutic use ; Autoimmune Diseases/therapy ; CD3 Complex/immunology ; Calcium/pharmacology ; Humans ; Hypersensitivity, Immediate/prevention & control ; Immune Tolerance ; Lymphocyte Activation ; Mice ; Mice, Inbred NOD ; T-Lymphocytes/immunology ; Transforming Growth Factor beta/physiology ; Transforming Growth Factor beta1
Chemical Substances	Antibodies ; CD3 Complex ; TGFB1 protein, human ; Tgfb1 protein, mouse ; Transforming Growth Factor beta ; Transforming Growth Factor beta1 ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2003-05-05
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2036490-8
ISSN	1471-499X ; 1471-4914
ISSN (online)	1471-499X
ISSN	1471-4914
DOI	10.1016/j.molmed.2003.11.007
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Article: Self-antigen recognition by TGF beta1-deficient T cells causes their activation and systemic inflammation.

Bommireddy, Ramireddy / Pathak, Leena J / Martin, Jennifer / Ormsby, Ilona / Engle, Sandra J / Boivin, Gregory P / Babcock, George F / Eriksson, Anna U / Singh, Ram R / Doetschman, Thomas

Laboratory investigation; a journal of technical methods and pathology

2006 Volume 86, Issue 10, Page(s) 1008–1019

Abstract: ... by self-antigen (self-Ag)-specific autoreactive T cells, or whether it is caused by antigen independent ... spontaneous hyperactivation of T cells, we have generated Tgfb1(-/-) and Tgfb1(-/-) Rag1(-/-) mice expressing ... develop a milder inflammation than do Tgfb1(-/-) mice, and their T cells display a less activated ...

Abstract	To investigate whether the multifocal inflammatory disease in TGFbeta1-deficient mice is caused by self-antigen (self-Ag)-specific autoreactive T cells, or whether it is caused by antigen independent, spontaneous hyperactivation of T cells, we have generated Tgfb1(-/-) and Tgfb1(-/-) Rag1(-/-) mice expressing the chicken OVA-specific TCR transgene (DO11.10). On a Rag1-sufficient background, Tgfb1(-/-) DO11.10 mice develop a milder inflammation than do Tgfb1(-/-) mice, and their T cells display a less activated phenotype. The lower level of activation correlates with the expression of hybrid TCR (transgenic TCRbeta and endogenous TCRalpha), which could recognize self-Ag and undergo activation. In the complete absence of self-Ag recognition (Tgfb1(-/-) DO11.10 Rag1(-/-) mice) inflammation and T-cell activation are eliminated, demonstrating that self-Ag recognition is required for the hyper-responsiveness of TGFbeta1-deficient T cells. Thus, TGFbeta1 is required for the prevention of autoimmune disease through its ability to control the activation of autoreactive T cells to self-Ag.
MeSH term(s)	Animals ; Autoantigens/immunology ; Autoimmunity/immunology ; Inflammation/immunology ; Inflammation/pathology ; Mice ; Mice, Knockout ; Mice, Transgenic ; T-Lymphocytes/immunology ; Transforming Growth Factor beta1/immunology
Chemical Substances	Autoantigens ; Transforming Growth Factor beta1
Language	English
Publishing date	2006-07-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80178-1
ISSN	1530-0307 ; 0023-6837
ISSN (online)	1530-0307
ISSN	0023-6837
DOI	10.1038/labinvest.3700460
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Article: Loss of heterozygosity and point mutation at Aprt locus in T cells and fibroblasts of Pms2-/- mice.

Shao, Changshun / Yin, Moying / Deng, Li / Stambrook, Peter J / Doetschman, Thomas / Tischfield, Jay A

Oncogene

2002 Volume 21, Issue 18, Page(s) 2840–2845

Abstract: ... of in vivo genomic integrity in somatic cells, we characterized Aprt mutations in T cells and fibroblasts ... of 129 x C3H Pms2-/-Aprt+/- mice. The spontaneous frequency of DAP-resistant T ... of the DAP(r) mutant clones in Pms2+/+ mice, was predominant in the mutant T cell clones from Pms2-/- mice ...

Abstract	Mice null for the Pms2 mismatch repair (MMR) gene exhibit a predisposition to lymphoma, microsatellite repeat instability, and failure of spermatogenesis. To study the role of Pms2 in the maintenance of in vivo genomic integrity in somatic cells, we characterized Aprt mutations in T cells and fibroblasts of 129 x C3H Pms2-/-Aprt+/- mice. The spontaneous frequency of DAP-resistant T lymphocytes, as a consequence of APRT-deficiency, was increased threefold. Point mutation, which accounted for less than 20% of the DAP(r) mutant clones in Pms2+/+ mice, was predominant in the mutant T cell clones from Pms2-/- mice. These point mutations were predominantly TA to CG transitions. Fibroblasts of Pms2-/- mice exhibited only a modest increase in the frequency of clones with point mutations, such that mitotic recombination was still the primary cause of APRT deficiency. Thus, the mutator phenotype as a consequence of PMS2 deficiency is tissue-dependent, which may be related to the tissue-specific tumor proneness of Pms2-/- mice.
MeSH term(s)	Adenine Phosphoribosyltransferase/genetics ; Adenosine Triphosphatases/genetics ; Adenosine Triphosphatases/physiology ; Animals ; Base Pair Mismatch ; Base Sequence ; DNA Repair Enzymes ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/physiology ; Female ; Fibroblasts/enzymology ; Hypoxanthine Phosphoribosyltransferase/genetics ; Loss of Heterozygosity/genetics ; Male ; Mice ; Mice, Inbred C3H ; Mice, Inbred C57BL ; Mice, Knockout ; Mismatch Repair Endonuclease PMS2 ; Molecular Sequence Data ; Neoplasm Proteins/genetics ; Neoplasm Proteins/physiology ; Point Mutation ; T-Lymphocytes/enzymology
Chemical Substances	DNA-Binding Proteins ; Neoplasm Proteins ; Adenine Phosphoribosyltransferase (EC 2.4.2.7) ; Hypoxanthine Phosphoribosyltransferase (EC 2.4.2.8) ; Adenosine Triphosphatases (EC 3.6.1.-) ; Pms2 protein, mouse (EC 3.6.1.-) ; Mismatch Repair Endonuclease PMS2 (EC 3.6.1.3) ; DNA Repair Enzymes (EC 6.5.1.-)
Language	English
Publishing date	2002-04-25
Publishing country	England
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	639046-8
ISSN	1476-5594 ; 0950-9232
ISSN (online)	1476-5594
ISSN	0950-9232
DOI	10.1038/sj.onc.1205358
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Zs.A 2218: Show issues

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Article: Elimination of both CD4+ and CD8+ T cells but not B cells eliminates inflammation and prolongs the survival of TGFbeta1-deficient mice.

Bommireddy, Ramireddy / Engle, Sandra J / Ormsby, Ilona / Boivin, Gregory P / Babcock, George F / Doetschman, Thomas

Cellular immunology

2004 Volume 232, Issue 1-2, Page(s) 96–104

Abstract: ... combination with Scid or Rag null alleles. Here, we show that elimination of T but not B cells is sufficient ... of TGFbeta1. TGFbeta1 deficiency leads to activation of CD8+ T cells as suggested by down-modulation of CD8 ... even in the absence of CD4+ T cells. This study provides evidence that both CD4+ and CD8+ T ...

Abstract	Transforming growth factor beta1 (TGFbeta1) is a potent negative immunoregulatory molecule. We have previously shown that the autoimmune-mediated weaning-age lethality of Tgfb1-/- mice is reversed upon genetic combination with Scid or Rag null alleles. Here, we show that elimination of T but not B cells is sufficient for the reversal, but elimination of either CD4+ or CD8+ cells is not. Although elimination of B cells does not rescue TGFbeta1-deficient animals from autoimmunity, B cells are hyperresponsive to LPS in the absence of TGFbeta1. TGFbeta1 deficiency leads to activation of CD8+ T cells as suggested by down-modulation of CD8 even in the absence of CD4+ T cells. This study provides evidence that both CD4+ and CD8+ T cells, but not B cells, have the ability to cause inflammation in the absence of TGFbeta1. However, though TGFbeta1-deficient B cells are hyperresponsive to stimulation, alone they are not sufficient to cause inflammation.
MeSH term(s)	Animals ; B-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/immunology ; Inflammation/genetics ; Inflammation/immunology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Nude ; Phenotype ; Spleen/immunology ; Survival Rate ; Transforming Growth Factor beta/deficiency ; Transforming Growth Factor beta/genetics ; Transforming Growth Factor beta/immunology ; Transforming Growth Factor beta1
Chemical Substances	Tgfb1 protein, mouse ; Transforming Growth Factor beta ; Transforming Growth Factor beta1
Language	English
Publishing date	2004-11
Publishing country	Netherlands
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	80094-6
ISSN	1090-2163 ; 0008-8749
ISSN (online)	1090-2163
ISSN	0008-8749
DOI	10.1016/j.cellimm.2005.02.004
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Article ; Online: FGF receptor inhibitor BGJ398 partially rescues osteoarthritis-like phenotype in older high molecular weight FGF2 transgenic mice via multiple mechanisms.

Hurley, Marja M / Coffin, J Douglas / Doetschman, Thomas / Valera, Christina / Clarke, Kai / Xiao, Liping

Scientific reports

2022 Volume 12, Issue 1, Page(s) 15968

Abstract: We have used Basic Fibroblast Growth Factor (FGF2) transgenic mice as experimental models for human X-linked hypophosphatemia (XLH)-related degenerative osteoarthritis (OA) to investigate the pathogenesis of the disease and to test potential ... ...

Abstract	We have used Basic Fibroblast Growth Factor (FGF2) transgenic mice as experimental models for human X-linked hypophosphatemia (XLH)-related degenerative osteoarthritis (OA) to investigate the pathogenesis of the disease and to test potential pharmacotherapies for treatment. This study tested the efficacy of BJG398, a small molecule fibroblast growth factor receptor tyrosine kinase (FGFRTK) inhibitor, to rescue the knee joint osteoarthritis phenotype in High Molecular Weight fibroblast growth factor 2 transgenic (HMWTgFGF2) mice. BJG398 was administered in vivo to 8-month-old female HMWTgFGF2 mice for six weeks. Histomorphometry, immunohistochemistry and micro-CT were used to examine the knee joints in BGJ398-treated and control mice. We assessed: Fibroblast Growth Factor 23 (FGF23) expression and FGFR1 activity; Matrix metalloproteinase 13 (MMP13) and Aggrecanase2 (ADAMTS5) expression; then signaling by SMAD1/5/8-pSMAD6, pERK1/2 and Runt-related transcription factor 2 (RUNX2). Using PrimePCR arrays, we identified a contributing role for major target genes in the TGFB/BMP2 signaling pathway that were regulated by BGJ398. BGJ398 inhibited HMWFGF2/FGF23-induced increase in bone morphogenic protein receptor-1, bone morphogenic protein-2 and 4 and Serine peptidase inhibitor, clade E, member 1. The results from Micro-CT and histology show BGJ398 treatment rescued the OA changes in subchondral bone and knee articular cartilage of HMWTgFGF2 mice. The gene expression and signal transduction results provide convincing evidence that HMWFGF2 generates OA through FGFRTK with characteristic downstream signaling that defines OA, namely: increased FGF23-FGFR1 activity with BMP-BMPR, activation of pSMAD1/5/8-RUNX2 and pERK signaling pathways, then upregulation of MMP13 and ADAMTS5 to degrade matrix. BGJ398 treatment effectively reversed these OA molecular phenotypes, providing further evidence that the OA generated by HMWFGF2 in the transgenic mice is FGFR-mediated and phenocopies the OA found in the Hyp mouse homolog of XLH with a spontaneous mutation in the Phex (phosphate regulating endopeptidase on the X chromosome) gene and human XLH-OA. Overall, the results obtained here explain how the pleotropic effects of FGF2 emanate from the different functions of HMW protein isoforms for cartilage and bone homeostasis, and the pathogenesis of XLH-degenerative osteoarthropathy. BGJ398 inhibits HMWFGF2-induced osteoarthritis via multiple mechanisms. These results provided important scientific evidence for the potential application of BGJ398 as a therapeutic agent for osteoarthritis in XLH.
MeSH term(s)	Animals ; Core Binding Factor Alpha 1 Subunit/genetics ; Familial Hypophosphatemic Rickets/genetics ; Female ; Fibroblast Growth Factor 2/genetics ; Matrix Metalloproteinase 13/genetics ; Mice ; Mice, Transgenic ; Molecular Weight ; Osteoarthritis/drug therapy ; Osteoarthritis/genetics ; Osteoarthritis/metabolism ; Phenotype ; Phenylurea Compounds ; Protease Inhibitors ; Protein Isoforms/metabolism ; Pyrimidines ; Serine/genetics
Chemical Substances	Core Binding Factor Alpha 1 Subunit ; Phenylurea Compounds ; Protease Inhibitors ; Protein Isoforms ; Pyrimidines ; Fibroblast Growth Factor 2 (103107-01-3) ; Serine (452VLY9402) ; infigratinib (A4055ME1VK) ; Matrix Metalloproteinase 13 (EC 3.4.24.-)
Language	English
Publishing date	2022-09-24
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-022-20269-6
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Article ; Online: Gene Editing With CRISPR/Cas9 RNA-Directed Nuclease.

Doetschman, Thomas / Georgieva, Teodora

Circulation research

2017 Volume 120, Issue 5, Page(s) 876–894

Abstract: Genetic engineering of model organisms and cultured cells has for decades provided important insights into the mechanisms underlying cardiovascular development and disease. In the past few years the development of several nuclease systems has broadened ... ...

Abstract	Genetic engineering of model organisms and cultured cells has for decades provided important insights into the mechanisms underlying cardiovascular development and disease. In the past few years the development of several nuclease systems has broadened the range of model/cell systems that can be engineered. Of these, the CRISPR (clustered regularly interspersed short palindromic repeats)/Cas9 (CRISPR-associated protein 9) system has become the favorite for its ease of application. Here we will review this RNA-guided nuclease system for gene editing with respect to its usefulness for cardiovascular studies and with an eye toward potential therapy. Studies on its off-target activity, along with approaches to minimize this activity will be given. The advantages of gene editing versus gene targeting in embryonic stem cells, including the breadth of species and cell types to which it is applicable, will be discussed. We will also cover its use in iPSC for research and possible therapeutic purposes; and we will review its use in muscular dystrophy studies where considerable progress has been made toward dystrophin correction in mice. The CRISPR/Ca9s system is also being used for high-throughput screening of genes, gene regulatory regions, and long noncoding RNAs. In addition, the CRISPR system is being used for nongene-editing purposes such as activation and inhibition of gene expression, as well as for fluorescence tagging of chromosomal regions and individual mRNAs to track their cellular location. Finally, an approach to circumvent the inability of post-mitotic cells to support homologous recombination-based gene editing will be presented. In conclusion, applications of the CRISPR/Cas system are expanding at a breath-taking pace and are revolutionizing approaches to gain a better understanding of human diseases.
MeSH term(s)	Animals ; CRISPR-Cas Systems/genetics ; Clustered Regularly Interspaced Short Palindromic Repeats/genetics ; Gene Editing/methods ; Gene Editing/trends ; Genetic Therapy/methods ; Genetic Therapy/trends ; Humans ; Induced Pluripotent Stem Cells/physiology ; Induced Pluripotent Stem Cells/transplantation ; Muscular Dystrophies/genetics ; Muscular Dystrophies/therapy ; Ribonucleases/genetics
Chemical Substances	Ribonucleases (EC 3.1.-)
Language	English
Publishing date	2017-03-03
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	80100-8
ISSN	1524-4571 ; 0009-7330 ; 0931-6876
ISSN (online)	1524-4571
ISSN	0009-7330 ; 0931-6876
DOI	10.1161/CIRCRESAHA.116.309727
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Ui IV Zs.70: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Ui IV Zs.60: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)

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Article ; Online: GI GEMs: genetically engineered mouse models of gastrointestinal disease.

Doetschman, Thomas

Gastroenterology

2010 Volume 140, Issue 2, Page(s) 380–385.e2

MeSH term(s)	Animals ; Disease Models, Animal ; Embryonic Stem Cells/metabolism ; Gastrointestinal Neoplasms/genetics ; Gene Targeting ; Genetic Engineering ; Humans ; Inflammatory Bowel Diseases/genetics ; Mice ; Mice, Transgenic
Language	English
Publishing date	2010-12-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	80112-4
ISSN	1528-0012 ; 0016-5085
ISSN (online)	1528-0012
ISSN	0016-5085
DOI	10.1053/j.gastro.2010.12.013
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Article: Influence of genetic background on genetically engineered mouse phenotypes.

Doetschman, Thomas

Methods in molecular biology (Clifton, N.J.)

2009 Volume 530, Page(s) 423–433

Abstract: The history of mouse genetics, which involves the study of strain-dependent phenotype variability, makes it clear that the genetic background onto which a gene-targeted allele is placed can cause considerable variation in genetically engineered mouse ( ... ...

Abstract	The history of mouse genetics, which involves the study of strain-dependent phenotype variability, makes it clear that the genetic background onto which a gene-targeted allele is placed can cause considerable variation in genetically engineered mouse (GEM) phenotype. This variation can present itself as completely different phenotypes, as variations in penetrance of phenotype, or as variable expressivity of phenotype. In this chapter we provide examples from gene-targeting literature showing each of these types of phenotype variation. We discuss ways in which modifier genes can affect the phenotype of a mouse with a mutant gene, and we give examples of modifier locus identification. We also review approaches to minimize gene polymorphism and flanking gene differences between experimental animals, and between them and their controls. In addition, we discuss the advantages and disadvantages of performing the first analysis of a knockout mouse on a mixed genetic background. We conclude that a mixed background provides the quickest preview of possible strain-dependent phenotypes (1 , 2). Finally, we review recent approaches to improving genetic diversity by generating new inbred strains that encompass a broader range of alleles within the mouse species.
MeSH term(s)	Animals ; Genetic Engineering/methods ; Genetic Variation ; Mice ; Mice, Inbred Strains ; Penetrance ; Phenotype
Language	English
Publishing date	2009-03-06
Publishing country	United States
Document type	Journal Article ; Review
ISSN	1064-3745
ISSN	1064-3745
DOI	10.1007/978-1-59745-471-1_23
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Article ; Online: Acute Elution of TGFβ2 Affects the Smooth Muscle Cells in a Compliance-Matched Vascular Graft.

Furdella, Kenneth J / Higuchi, Shinichi / Kim, Kang / Doetschman, Tom / Wagner, William R / Vande Geest, Jonathan P

Tissue engineering. Part A

2022 Volume 28, Issue 13-14, Page(s) 640–650

Abstract: Transforming growth factor beta 2 (TGFβ2) is a pleiotropic growth factor that plays a vital role in smooth muscle cell (SMC) function. Our ... ...

Abstract	Transforming growth factor beta 2 (TGFβ2) is a pleiotropic growth factor that plays a vital role in smooth muscle cell (SMC) function. Our prior
MeSH term(s)	Animals ; Blood Vessel Prosthesis ; Collagen/metabolism ; Myocytes, Smooth Muscle/drug effects ; Myocytes, Smooth Muscle/metabolism ; Rats ; Rats, Sprague-Dawley ; Transforming Growth Factor beta2/administration & dosage ; Transforming Growth Factor beta2/pharmacology
Chemical Substances	Transforming Growth Factor beta2 ; Collagen (9007-34-5)
Language	English
Publishing date	2022-06-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2420582-5
ISSN	1937-335X ; 1937-3341
ISSN (online)	1937-335X
ISSN	1937-3341
DOI	10.1089/ten.TEA.2021.0161
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