PlantRegMap/PlantTFDB v5.0
Plant Transcription Factor Database
Transcription Factor Information
Basic Information | Signature Domain | Sequence | 
Basic Information? help Back to Top
TF ID AT1G63650.1
Common NameAtEGL3, ATMYC-2, BHLH2, EGL1, EGL3, EN30, F24D7.16, MYC146
Taxonomic ID
Taxonomic Lineage
cellular organisms; Eukaryota; Viridiplantae; Streptophyta; Streptophytina; Embryophyta; Tracheophyta; Euphyllophyta; Spermatophyta; Magnoliophyta; Mesangiospermae; eudicotyledons; Gunneridae; Pentapetalae; rosids; malvids; Brassicales; Brassicaceae; Camelineae; Arabidopsis
Family bHLH
Protein Properties Length: 596aa    MW: 66620 Da    PI: 4.8068
Description bHLH family protein
Gene Model
Gene Model ID Type Source Coding Sequence
AT1G63650.1genomeTAIRView CDS
Signature Domain? help Back to Top
Signature Domain
No. Domain Score E-value Start End HMM Start HMM End
          HLH   4 ahnerErrRRdriNsafeeLrellPk.askapskKlsKaeiLekAveYIksLq 55 
                  +h   E++RR+++N++f +Lr+++P+ +      K +K++iL  ++eY+++Lq
                  79999*********************66......******************9 PP

Protein Features ? help Back to Top
3D Structure
Database Entry ID E-value Start End InterPro ID Description
PfamPF142152.5E-5413202IPR025610Transcription factor MYC/MYB N-terminal
PROSITE profilePS5088816.869401450IPR011598Myc-type, basic helix-loop-helix (bHLH) domain
CDDcd000832.52E-15405455No hitNo description
PfamPF000106.5E-12405451IPR011598Myc-type, basic helix-loop-helix (bHLH) domain
SuperFamilySSF474593.4E-18405468IPR011598Myc-type, basic helix-loop-helix (bHLH) domain
Gene3DG3DSA:, basic helix-loop-helix (bHLH) domain
SMARTSM003537.7E-17407456IPR011598Myc-type, basic helix-loop-helix (bHLH) domain
Gene Ontology ? help Back to Top
GO Term GO Category GO Description
GO:0006355Biological Processregulation of transcription, DNA-templated
GO:0007275Biological Processmulticellular organism development
GO:0009957Biological Processepidermal cell fate specification
GO:0005634Cellular Componentnucleus
GO:0003677Molecular FunctionDNA binding
GO:0003700Molecular Functiontranscription factor activity, sequence-specific DNA binding
GO:0005515Molecular Functionprotein binding
GO:0046983Molecular Functionprotein dimerization activity
Plant Ontology ? help Back to Top
PO Term PO Category PO Description
PO:0000037anatomyshoot apex
PO:0006036anatomyroot epidermis
PO:0006504anatomyleaf trichome
PO:0009006anatomyshoot system
PO:0009009anatomyplant embryo
PO:0009025anatomyvascular leaf
PO:0009052anatomyflower pedicel
PO:0025022anatomycollective leaf structure
PO:0001078developmental stageplant embryo cotyledonary stage
PO:0001081developmental stagemature plant embryo stage
PO:0001185developmental stageplant embryo globular stage
PO:0004507developmental stageplant embryo bilateral stage
PO:0007039developmental stageleaf trichome development stage
PO:0007611developmental stagepetal differentiation and expansion stage
PO:0007616developmental stageflowering stage
Sequence ? help Back to Top
Protein Sequence    Length: 596 aa     Download sequence    Send to blast
3D Structure ? help Back to Top
PDB ID Evalue Query Start Query End Hit Start Hit End Description
4rqw_A9e-16112027192Transcription factor MYC3
4rqw_B9e-16112027192Transcription factor MYC3
4rs9_A9e-16112027192Transcription factor MYC3
4yz6_A9e-16112027192Transcription factor MYC3
Search in ModeBase
Nucleic Localization Signal ? help Back to Top
No. Start End Sequence
Expression -- UniGene ? help Back to Top
UniGene ID E-value Expressed in
At.250240.0flower| seed
Expression -- Microarray ? help Back to Top
Source ID E-value
Expression AtlasAT1G63650-
Expression -- Description ? help Back to Top
Source Description
UniprotDEVELOPMENTAL STAGE: Localized in trichome developing region of leaves, prior to trichome initiation. Levels increase in initiating and young trichome cells, but dropped in the pavement cells between trichomes. Disappears in mature trichomes. {ECO:0000269|PubMed:12917293}.
UniprotTISSUE SPECIFICITY: Ubiquitous with higher levels in buds and flowers. Specifically localized in developing root hair cells. Expressed in epidermal root hair cells (trichoblasts) and moves to root hairless cells (atrichoblasts) by a cell-to-cell movement through plasmodesmata (at protein level). {ECO:0000269|PubMed:12956536, ECO:0000269|PubMed:14627722, ECO:0000269|PubMed:15590742}.
Functional Description ? help Back to Top
Source Description
TAIRMutant has reduced trichomes, anthocyanin, and seed coat mucilage and abnormally patterned stomates. Encodes a bHLH Transcription Factor 1. The protein is functionally redundant with GL3 and TT8 and interacts with TTG1, the myb proteins GL1, PAP1 and 2, CPC and TRY, and it will form heterodimers with GL3. Expression in N (non-hair cell forming) cell layers is negatively regulated by WER. Expression in H cells (hair cell forming) is promoted by CPC/TRY.
UniProtTranscription activator, when associated with MYB75/PAP1, MYB90/PAP2 or TT2. Involved in epidermal cell fate specification. Regulates negatively stomata formation but promotes trichome formation. Together with MYB66/WER, promotes the formation of non-hair cells in root epidermis cells in the N position. Whereas together with CPC, promotes the formation of hair cells in root epidermis cells in the H position by inhibiting non-hair cell formation. Seems also to play a role in the activation of anthocyanin biosynthesis, probably together with MYB75/PAP1. Involved in seed mucilage production. Activates the transcription of GL2. {ECO:0000269|PubMed:12917293, ECO:0000269|PubMed:12956536, ECO:0000269|PubMed:14627722, ECO:0000269|PubMed:15361138, ECO:0000269|PubMed:15590742}.
Function -- GeneRIF ? help Back to Top
  1. GL3 and EGL3 participate in an intercellular regulatory circuit that controls cell patterning in the Arabidopsis root epidermis [EGL3]
    [PMID: 15590742]
  2. Anthocyanins accumulate in both wild type and egl3, but not in gl3 loss-of-function mutants when depleted of nitrogen.
    [PMID: 19621239]
  3. EGL3 activity is under proteasome-dependent proteolysis control.
    [PMID: 23373825]
  4. Localization of CPC in the nucleus requires the H-cell-expressed ENHANCER OF GLABRA3 (EGL3).
    [PMID: 23832626]
  5. WER expressed ubiquitously in the root induced GL2 expression only in the root epidermis, whereas co-expression of WER and EGL3 induced GL2 expression in the corresponding tissues.
    [PMID: 26408906]
  6. the C-terminal domain of the bHLH members (GLABRA3 [GL3], ENHANCER OF GLABRA3 [EGL3] and TRANSPARENT TESTA8 [TT8]) interacted with JAZs.
    [PMID: 29293407]
Cis-element ? help Back to Top
Regulation -- Description ? help Back to Top
Source Description
UniProtINDUCTION: By UV treatment. Negatively regulated by MYB66/WER, GL3 and BHLH2 in the developing non-hair cells, and positively regulated by CPC and TRY in the developing hair cells. {ECO:0000269|PubMed:12679534, ECO:0000269|PubMed:15590742}.
Regulation -- PlantRegMap ? help Back to Top
Source Upstream Regulator Target Gene
Regulation -- ATRM (Manually Curated Upstream Regulators) ? help Back to Top
Source Upstream Regulator (A: Activate/R: Repress)
ATRM AT1G71030 (R), AT2G46410 (A), AT5G07100 (R)
Regulation -- ATRM (Manually Curated Target Genes) ? help Back to Top
Source Target Gene (A: Activate/R: Repress)
ATRM AT1G01380(A), AT1G71030(A), AT1G79840(A), AT2G23550(A), AT2G23580(A), AT2G37260(A), AT2G46410(A), AT4G01060(A), AT4G09820(A), AT4G22880(R), AT5G08640(R), AT5G13930(R), AT5G53200(A)
Regulation -- Hormone ? help Back to Top
Source Hormone
AHDJasmonic acid
Interaction -- BIND ? help Back to Top
Source Intact With Description
BINDAT1G63650EGL3 interacts with another molecule of EGL3 to form a dimer.
BINDAT1G66370EGL3 interacts with MYB113.
BINDAT1G66380EGL3 interacts with MYB114.
BINDAT1G66390EGL3 interacts with PAP2.
Interaction ? help Back to Top
Source Intact With
BioGRIDAT1G63650, AT1G66370, AT1G66380, AT1G66390
IntActSearch Q9CAD0
Phenotype -- Mutation ? help Back to Top
Source ID
T-DNA ExpressAT1G63650
Annotation -- Nucleotide ? help Back to Top
Source Hit ID E-value Description
GenBankAF2516870.0AF251687.1 Arabidopsis thaliana putative transcription factor BHLH2 (BHLH2) mRNA, complete cds.
Annotation -- Protein ? help Back to Top
Source Hit ID E-value Description
RefseqNP_001185302.10.0basic helix-loop-helix (bHLH) DNA-binding superfamily protein
RefseqNP_176552.10.0basic helix-loop-helix (bHLH) DNA-binding superfamily protein
RefseqNP_974080.10.0basic helix-loop-helix (bHLH) DNA-binding superfamily protein
SwissprotQ9CAD00.0EGL1_ARATH; Transcription factor EGL1
TrEMBLC0SV140.0C0SV14_ARATH; Uncharacterized protein At1g63650 (Fragment)
STRINGAT1G63650.30.0(Arabidopsis thaliana)
Orthologous Group ? help Back to Top
LineageOrthologous Group IDTaxa NumberGene Number
Representative plantOGRP24471429
Publications ? help Back to Top
  1. Riechmann JL, et al.
    Arabidopsis transcription factors: genome-wide comparative analysis among eukaryotes.
    Science, 2000. 290(5499): p. 2105-10
  2. Sawa S
    Overexpression of the AtmybL2 gene represses trichome development in Arabidopsis.
    DNA Res., 2002. 9(2): p. 31-4
  3. Heim MA, et al.
    The basic helix-loop-helix transcription factor family in plants: a genome-wide study of protein structure and functional diversity.
    Mol. Biol. Evol., 2003. 20(5): p. 735-47
  4. Toledo-Ortiz G,Huq E,Quail PH
    The Arabidopsis basic/helix-loop-helix transcription factor family.
    Plant Cell, 2003. 15(8): p. 1749-70
  5. Zhang F,Gonzalez A,Zhao M,Payne CT,Lloyd A
    A network of redundant bHLH proteins functions in all TTG1-dependent pathways of Arabidopsis.
    Development, 2003. 130(20): p. 4859-69
  6. Ramsay NA,Walker AR,Mooney M,Gray JC
    Two basic-helix-loop-helix genes (MYC-146 and GL3) from Arabidopsis can activate anthocyanin biosynthesis in a white-flowered Matthiola incana mutant.
    Plant Mol. Biol., 2003. 52(3): p. 679-88
  7. Bernhardt C, et al.
    The bHLH genes GLABRA3 (GL3) and ENHANCER OF GLABRA3 (EGL3) specify epidermal cell fate in the Arabidopsis root.
    Development, 2003. 130(26): p. 6431-9
  8. Zimmermann IM,Heim MA,Weisshaar B,Uhrig JF
    Comprehensive identification of Arabidopsis thaliana MYB transcription factors interacting with R/B-like BHLH proteins.
    Plant J., 2004. 40(1): p. 22-34
  9. Montiel G,Gantet P,Jay-Allemand C,Breton C
    Transcription factor networks. Pathways to the knowledge of root development.
    Plant Physiol., 2004. 136(3): p. 3478-85
  10. Bernhardt C,Zhao M,Gonzalez A,Lloyd A,Schiefelbein J
    The bHLH genes GL3 and EGL3 participate in an intercellular regulatory circuit that controls cell patterning in the Arabidopsis root epidermis.
    Development, 2005. 132(2): p. 291-8
  11. Broun P
    Transcriptional control of flavonoid biosynthesis: a complex network of conserved regulators involved in multiple aspects of differentiation in Arabidopsis.
    Curr. Opin. Plant Biol., 2005. 8(3): p. 272-9
  12. Serna L
    Epidermal cell patterning and differentiation throughout the apical-basal axis of the seedling.
    J. Exp. Bot., 2005. 56(418): p. 1983-9
  13. Xu CR, et al.
    Histone acetylation affects expression of cellular patterning genes in the Arabidopsis root epidermis.
    Proc. Natl. Acad. Sci. U.S.A., 2005. 102(40): p. 14469-74
  14. Kurata T, et al.
    Cell-to-cell movement of the CAPRICE protein in Arabidopsis root epidermal cell differentiation.
    Development, 2005. 132(24): p. 5387-98
  15. Dolan L
    Positional information and mobile transcriptional regulators determine cell pattern in the Arabidopsis root epidermis.
    J. Exp. Bot., 2006. 57(1): p. 51-4
  16. Baudry A,Caboche M,Lepiniec L
    TT8 controls its own expression in a feedback regulation involving TTG1 and homologous MYB and bHLH factors, allowing a strong and cell-specific accumulation of flavonoids in Arabidopsis thaliana.
    Plant J., 2006. 46(5): p. 768-79
  17. Kwak SH,Schiefelbein J
    The role of the SCRAMBLED receptor-like kinase in patterning the Arabidopsis root epidermis.
    Dev. Biol., 2007. 302(1): p. 118-31
  18. Chen ZH,Nimmo GA,Jenkins GI,Nimmo HG
    BHLH32 modulates several biochemical and morphological processes that respond to Pi starvation in Arabidopsis.
    Biochem. J., 2007. 405(1): p. 191-8
  19. Wang S,Chang Y,Guo J,Chen JG
    Arabidopsis Ovate Family Protein 1 is a transcriptional repressor that suppresses cell elongation.
    Plant J., 2007. 50(5): p. 858-72
  20. Dombrecht B, et al.
    MYC2 differentially modulates diverse jasmonate-dependent functions in Arabidopsis.
    Plant Cell, 2007. 19(7): p. 2225-45
  21. Tominaga R,Iwata M,Okada K,Wada T
    Functional analysis of the epidermal-specific MYB genes CAPRICE and WEREWOLF in Arabidopsis.
    Plant Cell, 2007. 19(7): p. 2264-77
  22. Cominelli E, et al.
    Expression analysis of anthocyanin regulatory genes in response to different light qualities in Arabidopsis thaliana.
    J. Plant Physiol., 2008. 165(8): p. 886-94
  23. Ishida T, et al.
    Arabidopsis TRANSPARENT TESTA GLABRA2 is directly regulated by R2R3 MYB transcription factors and is involved in regulation of GLABRA2 transcription in epidermal differentiation.
    Plant Cell, 2007. 19(8): p. 2531-43
  24. Morohashi K, et al.
    Participation of the Arabidopsis bHLH factor GL3 in trichome initiation regulatory events.
    Plant Physiol., 2007. 145(3): p. 736-46
  25. Gonzalez A,Zhao M,Leavitt JM,Lloyd AM
    Regulation of the anthocyanin biosynthetic pathway by the TTG1/bHLH/Myb transcriptional complex in Arabidopsis seedlings.
    Plant J., 2008. 53(5): p. 814-27
  26. Wang Y, et al.
    Salt-induced plasticity of root hair development is caused by ion disequilibrium in Arabidopsis thaliana.
    J. Plant Res., 2008. 121(1): p. 87-96
  27. Zhao M,Morohashi K,Hatlestad G,Grotewold E,Lloyd A
    The TTG1-bHLH-MYB complex controls trichome cell fate and patterning through direct targeting of regulatory loci.
    Development, 2008. 135(11): p. 1991-9
  28. Dubos C, et al.
    MYBL2 is a new regulator of flavonoid biosynthesis in Arabidopsis thaliana.
    Plant J., 2008. 55(6): p. 940-53
  29. Wang S, et al.
    Comprehensive analysis of single-repeat R3 MYB proteins in epidermal cell patterning and their transcriptional regulation in Arabidopsis.
    BMC Plant Biol., 2008. 8: p. 81
  30. Gao Y, et al.
    SAD2 in Arabidopsis functions in trichome initiation through mediating GL3 function and regulating GL1, TTG1 and GL2 expression.
    J Integr Plant Biol, 2008. 50(7): p. 906-17
  31. Ben
    Interlinked nonlinear subnetworks underlie the formation of robust cellular patterns in Arabidopsis epidermis: a dynamic spatial model.
    BMC Syst Biol, 2008. 2: p. 98
  32. Li SF, et al.
    The Arabidopsis MYB5 transcription factor regulates mucilage synthesis, seed coat development, and trichome morphogenesis.
    Plant Cell, 2009. 21(1): p. 72-89
  33. Wester K, et al.
    Functional diversity of R3 single-repeat genes in trichome development.
    Development, 2009. 136(9): p. 1487-96
  34. Kang YH, et al.
    The MYB23 gene provides a positive feedback loop for cell fate specification in the Arabidopsis root epidermis.
    Plant Cell, 2009. 21(4): p. 1080-94
  35. Arsovski AA,Villota MM,Rowland O,Subramaniam R,Western TL
    MUM ENHANCERS are important for seed coat mucilage production and mucilage secretory cell differentiation in Arabidopsis thaliana.
    J. Exp. Bot., 2009. 60(9): p. 2601-12
  36. Feyissa DN,Løvdal T,Olsen KM,Slimestad R,Lillo C
    The endogenous GL3, but not EGL3, gene is necessary for anthocyanin accumulation as induced by nitrogen depletion in Arabidopsis rosette stage leaves.
    Planta, 2009. 230(4): p. 747-54
  37. Marks MD,Wenger JP,Gilding E,Jilk R,Dixon RA
    Transcriptome analysis of Arabidopsis wild-type and gl3-sst sim trichomes identifies four additional genes required for trichome development.
    Mol Plant, 2009. 2(4): p. 803-22
  38. Skinner MK,Rawls A,Wilson-Rawls J,Roalson EH
    Basic helix-loop-helix transcription factor gene family phylogenetics and nomenclature.
    Differentiation, 2010. 80(1): p. 1-8
  39. Qi T, et al.
    The Jasmonate-ZIM-domain proteins interact with the WD-Repeat/bHLH/MYB complexes to regulate Jasmonate-mediated anthocyanin accumulation and trichome initiation in Arabidopsis thaliana.
    Plant Cell, 2011. 23(5): p. 1795-814
  40. Appelhagen I, et al.
    Leucoanthocyanidin Dioxygenase in Arabidopsis thaliana: characterization of mutant alleles and regulation by MYB-BHLH-TTG1 transcription factor complexes.
    Gene, 2011. 484(1-2): p. 61-8
  41. Song SK, et al.
    Cell fate in the Arabidopsis root epidermis is determined by competition between WEREWOLF and CAPRICE.
    Plant Physiol., 2011. 157(3): p. 1196-208
  42. Balkunde R,Bouyer D,H
    Nuclear trapping by GL3 controls intercellular transport and redistribution of TTG1 protein in Arabidopsis.
    Development, 2011. 138(22): p. 5039-48
  43. Gan L,Xia K,Chen JG,Wang S
    Functional characterization of TRICHOMELESS2, a new single-repeat R3 MYB transcription factor in the regulation of trichome patterning in Arabidopsis.
    BMC Plant Biol., 2011. 11: p. 176
  44. Tominaga-Wada R,Iwata M,Nukumizu Y,Sano R,Wada T
    A full-length R-like basic-helix-loop-helix transcription factor is required for anthocyanin upregulation whereas the N-terminal region regulates epidermal hair formation.
    Plant Sci., 2012. 183: p. 115-22
  45. Zhao H, et al.
    A single amino acid substitution in IIIf subfamily of basic helix-loop-helix transcription factor AtMYC1 leads to trichome and root hair patterning defects by abolishing its interaction with partner proteins in Arabidopsis.
    J. Biol. Chem., 2012. 287(17): p. 14109-21
  46. Chiu LW,Li L
    Characterization of the regulatory network of BoMYB2 in controlling anthocyanin biosynthesis in purple cauliflower.
    Planta, 2012. 236(4): p. 1153-64
  47. Tominaga-Wada R,Nukumizu Y,Sato S,Wada T
    Control of plant trichome and root-hair development by a tomato (Solanum lycopersicum) R3 MYB transcription factor.
    PLoS ONE, 2013. 8(1): p. e54019
  48. Patra B,Pattanaik S,Yuan L
    Ubiquitin protein ligase 3 mediates the proteasomal degradation of GLABROUS 3 and ENHANCER OF GLABROUS 3, regulators of trichome development and flavonoid biosynthesis in Arabidopsis.
    Plant J., 2013. 74(3): p. 435-47
  49. Nukumizu Y,Wada T,Tominaga-Wada R
    Tomato (Solanum lycopersicum) homologs of TRIPTYCHON (SlTRY) and GLABRA3 (SlGL3) are involved in anthocyanin accumulation.
    Plant Signal Behav, 2013. 8(7): p. e24575
  50. Qi T,Song S,Xie D
    Modified bimolecular fluorescence complementation assay to study the inhibition of transcription complex formation by JAZ proteins.
    Methods Mol. Biol., 2013. 1011: p. 187-97
  51. Kang YH,Song SK,Schiefelbein J,Lee MM
    Nuclear trapping controls the position-dependent localization of CAPRICE in the root epidermis of Arabidopsis.
    Plant Physiol., 2013. 163(1): p. 193-204
  52. Liu Z,Shi MZ,Xie DY
    Regulation of anthocyanin biosynthesis in Arabidopsis thaliana red pap1-D cells metabolically programmed by auxins.
    Planta, 2014. 239(4): p. 765-81
  53. Qi T, et al.
    Arabidopsis DELLA and JAZ proteins bind the WD-repeat/bHLH/MYB complex to modulate gibberellin and jasmonate signaling synergy.
    Plant Cell, 2014. 26(3): p. 1118-33
  54. Nayidu NK, et al.
    Comparison of five major trichome regulatory genes in Brassica villosa with orthologues within the Brassicaceae.
    PLoS ONE, 2014. 9(4): p. e95877
  55. Cheng Y, et al.
    Brassinosteroids control root epidermal cell fate via direct regulation of a MYB-bHLH-WD40 complex by GSK3-like kinases.
    Elife, 2018.
  56. Ranocha P,Francoz E,Burlat V,Dunand C
    Expression of PRX36, PMEI6 and SBT1.7 is controlled by complex transcription factor regulatory networks for proper seed coat mucilage extrusion.
    Plant Signal Behav, 2014. 9(11): p. e977734
  57. Nemie-Feyissa D,Heidari B,Blaise M,Lillo C
    Analysis of interactions between heterologously produced bHLH and MYB proteins that regulate anthocyanin biosynthesis: quantitative interaction kinetics by Microscale Thermophoresis.
    Phytochemistry, 2015. 111: p. 21-6
  58. Jin J, et al.
    An Arabidopsis Transcriptional Regulatory Map Reveals Distinct Functional and Evolutionary Features of Novel Transcription Factors.
    Mol. Biol. Evol., 2015. 32(7): p. 1767-73
  59. Song SK,Kwak SH,Chang SC,Schiefelbein J,Lee MM
    WEREWOLF and ENHANCER of GLABRA3 are interdependent regulators of the spatial expression pattern of GLABRA2 in Arabidopsis.
    Biochem. Biophys. Res. Commun., 2015. 467(1): p. 94-100
  60. Kwak SH,Song SK,Lee MM,Schiefelbein J
    TORNADO1 regulates root epidermal patterning through the WEREWOLF pathway in Arabidopsis thaliana.
    Plant Signal Behav, 2015. 10(12): p. e1103407
  61. Dai X, et al.
    A single amino acid substitution in the R3 domain of GLABRA1 leads to inhibition of trichome formation in Arabidopsis without affecting its interaction with GLABRA3.
    Plant Cell Environ., 2016. 39(4): p. 897-907
  62. Friede A, et al.
    The Second Intron Is Essential for the Transcriptional Control of the Arabidopsis thaliana GLABRA3 Gene in Leaves.
    Front Plant Sci, 2017. 8: p. 1382
  63. Feng K, et al.
    An R2R3-MYB transcription factor, OjMYB1, functions in anthocyanin biosynthesis in Oenanthe javanica.
    Planta, 2018. 247(2): p. 301-315
  64. Wen J, et al.
    The C-terminal domains of Arabidopsis GL3/EGL3/TT8 interact with JAZ proteins and mediate dimeric interactions.
    Plant Signal Behav, 2018. 13(1): p. e1422460