PlantTFDB
Plant Transcription Factor Database
v4.0
Previous version: v1.0, v2.0, v3.0
Transcription Factor Information
Basic Information | Signature Domain | Sequence | 
Basic Information? help Back to Top
TF ID AT2G38470.1
Common NameATWRKY33, T19C21.4, WRKY33
Organism
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 WRKY
Protein Properties Length: 519aa    MW: 57178.8 Da    PI: 7.8903
Description WRKY DNA-binding protein 33
Gene Model
Gene Model ID Type Source Coding Sequence
AT2G38470.1genomeTAIRView CDS
Signature Domain? help Back to Top
Signature Domain
No. Domain Score E-value Start End HMM Start HMM End
1WRKY104.65.5e-33184241260
                  --SS-EEEEEEE--TT-SS-EEEEEE-STT---EEEEEE-SSSTTEEEEEEES--SS-- CS
         WRKY   2 dDgynWrKYGqKevkgsefprsYYrCtsagCpvkkkversaedpkvveitYegeHnhek 60 
                  +DgynWrKYGqK+vkgse+prsYY+Ct+++Cp+kkkvers  +++++ei+Y+g+Hnh+k
  AT2G38470.1 184 EDGYNWRKYGQKQVKGSENPRSYYKCTFPNCPTKKKVERSL-EGQITEIVYKGSHNHPK 241
                  7****************************************.***************85 PP

2WRKY1054e-33361419159
                  ---SS-EEEEEEE--TT-SS-EEEEEE-STT---EEEEEE-SSSTTEEEEEEES--SS- CS
         WRKY   1 ldDgynWrKYGqKevkgsefprsYYrCtsagCpvkkkversaedpkvveitYegeHnhe 59 
                  ldDgy+WrKYGqK+vkg+++prsYY+Ct+ gCpv+k+ver+++d ++v++tYeg+Hnh+
  AT2G38470.1 361 LDDGYRWRKYGQKVVKGNPNPRSYYKCTTIGCPVRKHVERASHDMRAVITTYEGKHNHD 419
                  59********************************************************7 PP

Protein Features ? help Back to Top
3D Structure
Database Entry ID E-value Start End InterPro ID Description
Gene3DG3DSA:2.20.25.805.9E-28175242IPR003657WRKY domain
SMARTSM007742.3E-34183241IPR003657WRKY domain
SuperFamilySSF1182901.44E-24183242IPR003657WRKY domain
PfamPF031063.9E-25184240IPR003657WRKY domain
PROSITE profilePS5081122.905184242IPR003657WRKY domain
Gene3DG3DSA:2.20.25.806.5E-37346421IPR003657WRKY domain
SuperFamilySSF1182903.27E-29353421IPR003657WRKY domain
PROSITE profilePS5081138.434356421IPR003657WRKY domain
SMARTSM007741.8E-38361420IPR003657WRKY domain
PfamPF031062.0E-25362419IPR003657WRKY domain
Gene Ontology ? help Back to Top
GO Term GO Category GO Description
GO:0009409Biological Processresponse to cold
GO:0009414Biological Processresponse to water deprivation
GO:0009651Biological Processresponse to salt stress
GO:0009753Biological Processresponse to jasmonic acid
GO:0009788Biological Processnegative regulation of abscisic acid-activated signaling pathway
GO:0009938Biological Processnegative regulation of gibberellic acid mediated signaling pathway
GO:0010120Biological Processcamalexin biosynthetic process
GO:0010200Biological Processresponse to chitin
GO:0010508Biological Processpositive regulation of autophagy
GO:0042742Biological Processdefense response to bacterium
GO:0045893Biological Processpositive regulation of transcription, DNA-templated
GO:0050832Biological Processdefense response to fungus
GO:0070370Biological Processcellular heat acclimation
GO:0005634Cellular Componentnucleus
GO:0003700Molecular Functiontranscription factor activity, sequence-specific DNA binding
GO:0005515Molecular Functionprotein binding
GO:0043565Molecular Functionsequence-specific DNA binding
GO:0044212Molecular Functiontranscription regulatory region DNA binding
Plant Ontology ? help Back to Top
PO Term PO Category PO Description
PO:0000013anatomycauline leaf
PO:0000037anatomyshoot apex
PO:0000230anatomyinflorescence meristem
PO:0000293anatomyguard cell
PO:0008019anatomyleaf lamina base
PO:0009001anatomyfruit
PO:0009005anatomyroot
PO:0009009anatomyplant embryo
PO:0009010anatomyseed
PO:0009025anatomyvascular leaf
PO:0009029anatomystamen
PO:0009030anatomycarpel
PO:0009031anatomysepal
PO:0009032anatomypetal
PO:0009046anatomyflower
PO:0009047anatomystem
PO:0009052anatomyflower pedicel
PO:0020030anatomycotyledon
PO:0020038anatomypetiole
PO:0020100anatomyhypocotyl
PO:0020137anatomyleaf apex
PO:0025022anatomycollective leaf structure
PO:0025281anatomypollen
PO:0001054developmental stagevascular leaf senescent stage
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:0007064developmental stageLP.12 twelve leaves visible stage
PO:0007095developmental stageLP.08 eight leaves visible stage
PO:0007098developmental stageLP.02 two leaves visible stage
PO:0007103developmental stageLP.10 ten leaves visible stage
PO:0007115developmental stageLP.04 four leaves visible stage
PO:0007123developmental stageLP.06 six leaves visible stage
PO:0007611developmental stagepetal differentiation and expansion stage
PO:0007616developmental stageflowering stage
Sequence ? help Back to Top
Protein Sequence    Length: 519 aa     Download sequence    Send to blast
MAASFLTMDN SRTRQNMNGS ANWSQQSGRT STSSLEDLEI PKFRSFAPSS ISISPSLVSP  60
STCFSPSLFL DSPAFVSSSA NVLASPTTGA LITNVTNQKG INEGDKSNNN NFNLFDFSFH  120
TQSSGVSAPT TTTTTTTTTT TTNSSIFQSQ EQQKKNQSEQ WSQTETRPNN QAVSYNGREQ  180
RKGEDGYNWR KYGQKQVKGS ENPRSYYKCT FPNCPTKKKV ERSLEGQITE IVYKGSHNHP  240
KPQSTRRSSS SSSTFHSAVY NASLDHNRQA SSDQPNSNNS FHQSDSFGMQ QEDNTTSDSV  300
GDDEFEQGSS IVSRDEEDCG SEPEAKRWKG DNETNGGNGG GSKTVREPRI VVQTTSDIDI  360
LDDGYRWRKY GQKVVKGNPN PRSYYKCTTI GCPVRKHVER ASHDMRAVIT TYEGKHNHDV  420
PAARGSGYAT NRAPQDSSSV PIRPAAIAGH SNYTTSSQAP YTLQMLHNNN TNTGPFGYAM  480
NNNNNNSNLQ TQQNFVGGGF SRAKEEPNEE TSFFDSFMP
3D Structure ? help Back to Top
Structure
PDB ID Evalue Query Start Query End Hit Start Hit End Description
1wj2_A9e-38184422878Probable WRKY transcription factor 4
2lex_A9e-38184422878Probable WRKY transcription factor 4
Search in ModeBase
Expression -- UniGene ? help Back to Top
UniGene ID E-value Expressed in
At.131230.0leaf| root| seed
Expression -- Microarray ? help Back to Top
Source ID E-value
Genevisible267028_at0.0
Expression AtlasAT2G38470-
AtGenExpressAT2G38470-
ATTED-IIAT2G38470-
Expression -- Description ? help Back to Top
Source Description
UniprotTISSUE SPECIFICITY: Highly expressed in roots, leaves and flowers, and at lower levels in stems, siliques and seeds. {ECO:0000269|PubMed:18839316}.
Functional Description ? help Back to Top
Source Description
TAIRMember of the plant WRKY transcription factor family. Regulates the antagonistic relationship between defense pathways mediating responses to P. syringae and necrotrophic fungal pathogens. Located in nucleus. Involved in response to various abiotic stresses - especially salt stress.
UniProtTranscription factor. Interacts specifically with the W box (5'-TTGAC[CT]-3'), a frequently occurring elicitor-responsive cis-acting element. Involved in defense responses. Required for resistance to the necrotrophic fungal pathogen B.cinerea (PubMed:17059405, PubMed:21990940). Regulates the antagonistic relationship between defense pathways mediating responses to the bacterial pathogen P. syringae and the necrotrophic pathogen B.cinerea (PubMed:17059405). Required for the phytoalexin camalexin synthesis following infection with B.cinerea. Acts as positive regulator of the camalexin biosynthetic genes PAD3 (CYP71B15) and CYP71A13 by binding to their promoters (PubMed:21498677, PubMed:22392279). Acts downstream of MPK3 and MPK6 in reprogramming the expression of camalexin biosynthetic genes, which drives the metabolic flow to camalexin production (PubMed:21498677). Functions with WRKY25 as positive regulator of salt stress response and abscisic acid (ABA) signaling (PubMed:18839316). Functions with WRKY25 and WRKY26 as positive regulator of plant thermotolerance by partially participating in ethylene-response signal transduction pathway (PubMed:21336597). The DNA-binding activity of WRKY33 is increased by SIB1 and SIB2 (PubMed:21990940). {ECO:0000269|PubMed:18839316, ECO:0000269|PubMed:21336597, ECO:0000269|PubMed:21498677, ECO:0000269|PubMed:21990940, ECO:0000269|PubMed:22392279}.
Function -- GeneRIF ? help Back to Top
  1. Mmutations of WRKY33 gene encoding a WRKY transcription factor cause enhanced susceptibility to Botrytis cinerea and Alternaria brassicicola concomitant with reduced expression of the jasmonate-regulated plant defensin PDF1.2 gene.
    [PMID: 17059405]
  2. Study shows that a set of three WRKY-specific cis-acting DNA elements (W boxes) within the AtWRKY33 promoter is required for efficient pathogen- or PAMP-triggered gene activation.
    [PMID: 17427812]
  3. overexpression of WRKY25 or WRKY33 was sufficient to increase Arabidopsis NaCl tolerance, while increasing sensitivity to abscisic acid
    [PMID: 18839316]
  4. AtWRKY25 and AtWRKY26 were gradually induced during heat and cold treatments, whereas AtWRKY33 was suppressed by heat treatment and induced rapidly during cold stress.
    [PMID: 20709683]
  5. MKS1 function and subcellular location requires an intact N-terminus important for both MPK4 and WRKY33 interactions
    [PMID: 21203436]
  6. WRKY33 is required for MPK3/MPK6-induced camalexin biosynthesis.
    [PMID: 21498677]
  7. Dual-targeted SIB1 and SIB2 function as activators of WRKY33 in plant defense against necrotrophic pathogens.
    [PMID: 21990940]
  8. WRKY33 is a negative regulator of the salicylic acid pathway upon Botrytis cinerea infection.
    [PMID: 22392279]
  9. The WRKY33 proteins interact with VQ motif of SIB1 (SIGMA FACTOR-INTERACTING PROTEIN1) proteins through their C-terminal WRKY domains.
    [PMID: 22535423]
  10. direct binding of WRKY33 to the W-boxes in the promoters of ACS2 and ACS6 genes in vivo, suggesting that WRKY33 is directly involved in the activation of ACS2 and ACS6 expression downstream of MPK3/MPK6 cascade in response to pathogen invasion
    [PMID: 22761583]
  11. AtWRKY33 has an extended C-terminal domain (CTD) absent in its close homologue AtWRKY25. Both its CTD and the strong pathogen/stress-responsive expression of AtWRKY33 are necessary to complement the critical phenotypes of atwrky33.
    [PMID: 25969555]
  12. Loss-of-WRKY33 function resulted in elevated abscisic acid levels and genetic studies confirmed that WRKY33 acts upstream of NCED3/NCED5 to negatively regulate abscisic acid biosynthesis.
    [PMID: 26076231]
Binding Motif ? help Back to Top
Motif ID Method Source Motif file
MP00299DAP27203113Download
Motif logo
Cis-element ? help Back to Top
SourceLink
PlantRegMapAT2G38470.1
Regulation -- Description ? help Back to Top
Source Description
UniProtINDUCTION: By salt stress (PubMed:18839316). Induced by infection with the necrotrophic fungal pathogen B.cinerea (PubMed:17059405, PubMed:21498677, PubMed:21990940). Induced by infection with the bacterial pathogen P.syringae pv. tomato DC3000 (PubMed:17059405). {ECO:0000269|PubMed:17059405, ECO:0000269|PubMed:18839316, ECO:0000269|PubMed:21498677, ECO:0000269|PubMed:21990940}.
Regulation -- PlantRegMap ? help Back to Top
Source Upstream Regulator Target Gene
PlantRegMapRetrieveRetrieve
Regulation -- ATRM (Manually Curated Target Genes) ? help Back to Top
Source Target Gene (A: Activate/R: Repress)
ATRM AT1G06160(R), AT2G14610(R), AT3G12500(A), AT3G15210(R), AT3G23240(A), AT3G26830(A), AT3G52430(R), AT5G07100(A), AT5G60890(R)
Regulation -- Hormone ? help Back to Top
Source Hormone
AHDabscisic acid
Interaction ? help Back to Top
Source Intact With
IntActSearch Q8S8P5
Phenotype -- Disruption Phenotype ? help Back to Top
Source Description
UniProtDISRUPTION PHENOTYPE: No visible phenotype under normal growth conditions, but mutant plants are extremely susceptible to the necrotrophic fungal pathogen B.cinerea. {ECO:0000269|PubMed:17059405, ECO:0000269|PubMed:21990940}.
Phenotype -- Mutation ? help Back to Top
Source ID
T-DNA ExpressAT2G38470
Annotation -- Nucleotide ? help Back to Top
Source Hit ID E-value Description
GenBankBT0330300.0BT033030.1 Arabidopsis thaliana unknown protein (At2g38470) mRNA, complete cds.
GenBankAK2263010.0AK226301.1 Arabidopsis thaliana mRNA for putative WRKY-type DNA binding protein, complete cds, clone: RAFL05-11-J06.
Annotation -- Protein ? help Back to Top
Source Hit ID E-value Description
RefseqNP_181381.20.0putative WRKY transcription factor 33
SwissprotQ8S8P50.0WRK33_ARATH; Probable WRKY transcription factor 33
TrEMBLB3DNP20.0B3DNP2_ARATH; At2g38470
STRINGAT2G38470.10.0(Arabidopsis thaliana)
Orthologous Group ? help Back to Top
LineageOrthologous Group IDTaxa NumberGene Number
Representative plantOGRP1417875
MalvidsOGEM45832755
Publications ? help Back to Top
  1. Eulgem T,Rushton PJ,Robatzek S,Somssich IE
    The WRKY superfamily of plant transcription factors.
    Trends Plant Sci., 2000. 5(5): p. 199-206
    [PMID:10785665]
  2. Riechmann JL, et al.
    Arabidopsis transcription factors: genome-wide comparative analysis among eukaryotes.
    Science, 2000. 290(5499): p. 2105-10
    [PMID:11118137]
  3. Klok EJ, et al.
    Expression profile analysis of the low-oxygen response in Arabidopsis root cultures.
    Plant Cell, 2002. 14(10): p. 2481-94
    [PMID:12368499]
  4. Andreasson E, et al.
    The MAP kinase substrate MKS1 is a regulator of plant defense responses.
    EMBO J., 2005. 24(14): p. 2579-89
    [PMID:15990873]
  5. Zheng Z,Qamar SA,Chen Z,Mengiste T
    Arabidopsis WRKY33 transcription factor is required for resistance to necrotrophic fungal pathogens.
    Plant J., 2006. 48(4): p. 592-605
    [PMID:17059405]
  6. Lippok B, et al.
    Expression of AtWRKY33 encoding a pathogen- or PAMP-responsive WRKY transcription factor is regulated by a composite DNA motif containing W box elements.
    Mol. Plant Microbe Interact., 2007. 20(4): p. 420-9
    [PMID:17427812]
  7. Dombrecht B, et al.
    MYC2 differentially modulates diverse jasmonate-dependent functions in Arabidopsis.
    Plant Cell, 2007. 19(7): p. 2225-45
    [PMID:17616737]
  8. Libault M,Wan J,Czechowski T,Udvardi M,Stacey G
    Identification of 118 Arabidopsis transcription factor and 30 ubiquitin-ligase genes responding to chitin, a plant-defense elicitor.
    Mol. Plant Microbe Interact., 2007. 20(8): p. 900-11
    [PMID:17722694]
  9. Suza WP,Staswick PE
    The role of JAR1 in Jasmonoyl-L: -isoleucine production during Arabidopsis wound response.
    Planta, 2008. 227(6): p. 1221-32
    [PMID:18247047]
  10. Galon Y, et al.
    Calmodulin-binding transcription activator (CAMTA) 3 mediates biotic defense responses in Arabidopsis.
    FEBS Lett., 2008. 582(6): p. 943-8
    [PMID:18298954]
  11. Koornneef A,Pieterse CM
    Cross talk in defense signaling.
    Plant Physiol., 2008. 146(3): p. 839-44
    [PMID:18316638]
  12. Ascencio-Ib
    Global analysis of Arabidopsis gene expression uncovers a complex array of changes impacting pathogen response and cell cycle during geminivirus infection.
    Plant Physiol., 2008. 148(1): p. 436-54
    [PMID:18650403]
  13. Qiu JL, et al.
    Arabidopsis MAP kinase 4 regulates gene expression through transcription factor release in the nucleus.
    EMBO J., 2008. 27(16): p. 2214-21
    [PMID:18650934]
  14. Kim KC,Lai Z,Fan B,Chen Z
    Arabidopsis WRKY38 and WRKY62 transcription factors interact with histone deacetylase 19 in basal defense.
    Plant Cell, 2008. 20(9): p. 2357-71
    [PMID:18776063]
  15. Jiang Y,Deyholos MK
    Functional characterization of Arabidopsis NaCl-inducible WRKY25 and WRKY33 transcription factors in abiotic stresses.
    Plant Mol. Biol., 2009. 69(1-2): p. 91-105
    [PMID:18839316]
  16. Yamaguchi Y,Huffaker A,Bryan AC,Tax FE,Ryan CA
    PEPR2 is a second receptor for the Pep1 and Pep2 peptides and contributes to defense responses in Arabidopsis.
    Plant Cell, 2010. 22(2): p. 508-22
    [PMID:20179141]
  17. Wan J,Zhang S,Stacey G
    Activation of a mitogen-activated protein kinase pathway in Arabidopsis by chitin.
    Mol. Plant Pathol., 2004. 5(2): p. 125-35
    [PMID:20565589]
  18. Fu QT,Yu DQ
    [Expression profiles of AtWRKY25, AtWRKY26 and AtWRKY33 under abiotic stresses.].
    Yi Chuan, 2010. 32(8): p. 848-56
    [PMID:20709683]
  19. Qi Z, et al.
    Ca2+ signaling by plant Arabidopsis thaliana Pep peptides depends on AtPepR1, a receptor with guanylyl cyclase activity, and cGMP-activated Ca2+ channels.
    Proc. Natl. Acad. Sci. U.S.A., 2010. 107(49): p. 21193-8
    [PMID:21088220]
  20. Shin R,Jez JM,Basra A,Zhang B,Schachtman DP
    14-3-3 proteins fine-tune plant nutrient metabolism.
    FEBS Lett., 2011. 585(1): p. 143-7
    [PMID:21094157]
  21. Kishi-Kaboshi M,Takahashi A,Hirochika H
    MAMP-responsive MAPK cascades regulate phytoalexin biosynthesis.
    Plant Signal Behav, 2010. 5(12): p. 1653-6
    [PMID:21150304]
  22. Petersen K, et al.
    Arabidopsis MKS1 is involved in basal immunity and requires an intact N-terminal domain for proper function.
    PLoS ONE, 2010. 5(12): p. e14364
    [PMID:21203436]
  23. Li S,Fu Q,Chen L,Huang W,Yu D
    Arabidopsis thaliana WRKY25, WRKY26, and WRKY33 coordinate induction of plant thermotolerance.
    Planta, 2011. 233(6): p. 1237-52
    [PMID:21336597]
  24. Lai Z,Wang F,Zheng Z,Fan B,Chen Z
    A critical role of autophagy in plant resistance to necrotrophic fungal pathogens.
    Plant J., 2011. 66(6): p. 953-68
    [PMID:21395886]
  25. Mao G, et al.
    Phosphorylation of a WRKY transcription factor by two pathogen-responsive MAPKs drives phytoalexin biosynthesis in Arabidopsis.
    Plant Cell, 2011. 23(4): p. 1639-53
    [PMID:21498677]
  26. Fiil BK,Petersen M
    Constitutive expression of MKS1 confers susceptibility to Botrytis cinerea infection independent of PAD3 expression.
    Plant Signal Behav, 2011. 6(10): p. 1425-7
    [PMID:21900742]
  27. Lai Z, et al.
    Arabidopsis sigma factor binding proteins are activators of the WRKY33 transcription factor in plant defense.
    Plant Cell, 2011. 23(10): p. 3824-41
    [PMID:21990940]
  28. Birkenbihl RP,Diezel C,Somssich IE
    Arabidopsis WRKY33 is a key transcriptional regulator of hormonal and metabolic responses toward Botrytis cinerea infection.
    Plant Physiol., 2012. 159(1): p. 266-85
    [PMID:22392279]
  29. Maekawa S, et al.
    The Arabidopsis ubiquitin ligases ATL31 and ATL6 control the defense response as well as the carbon/nitrogen response.
    Plant Mol. Biol., 2012. 79(3): p. 217-27
    [PMID:22481162]
  30. Cheng Y, et al.
    Structural and functional analysis of VQ motif-containing proteins in Arabidopsis as interacting proteins of WRKY transcription factors.
    Plant Physiol., 2012. 159(2): p. 810-25
    [PMID:22535423]
  31. Li G, et al.
    Dual-level regulation of ACC synthase activity by MPK3/MPK6 cascade and its downstream WRKY transcription factor during ethylene induction in Arabidopsis.
    PLoS Genet., 2012. 8(6): p. e1002767
    [PMID:22761583]
  32. Nongbri PL, et al.
    Indole-3-acetaldoxime-derived compounds restrict root colonization in the beneficial interaction between Arabidopsis roots and the endophyte Piriformospora indica.
    Mol. Plant Microbe Interact., 2012. 25(9): p. 1186-97
    [PMID:22852809]
  33. Ma Y,Walker RK,Zhao Y,Berkowitz GA
    Linking ligand perception by PEPR pattern recognition receptors to cytosolic Ca2+ elevation and downstream immune signaling in plants.
    Proc. Natl. Acad. Sci. U.S.A., 2012. 109(48): p. 19852-7
    [PMID:23150556]
  34. Logemann E, et al.
    Functional dissection of the PROPEP2 and PROPEP3 promoters reveals the importance of WRKY factors in mediating microbe-associated molecular pattern-induced expression.
    New Phytol., 2013. 198(4): p. 1165-77
    [PMID:23496690]
  35. Dubois M, et al.
    Ethylene Response Factor6 acts as a central regulator of leaf growth under water-limiting conditions in Arabidopsis.
    Plant Physiol., 2013. 162(1): p. 319-32
    [PMID:23553636]
  36. Miao Y,Jiang J,Ren Y,Zhao Z
    The single-stranded DNA-binding protein WHIRLY1 represses WRKY53 expression and delays leaf senescence in a developmental stage-dependent manner in Arabidopsis.
    Plant Physiol., 2013. 163(2): p. 746-56
    [PMID:23922267]
  37. 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
    [PMID:25750178]
  38. Zhou J, et al.
    Characterization of the promoter and extended C-terminal domain of Arabidopsis WRKY33 and functional analysis of tomato WRKY33 homologues in plant stress responses.
    J. Exp. Bot., 2015. 66(15): p. 4567-83
    [PMID:25969555]
  39. Liu S,Kracher B,Ziegler J,Birkenbihl RP,Somssich IE
    Negative regulation of ABA signaling by WRKY33 is critical for Arabidopsis immunity towards Botrytis cinerea 2100.
    Elife, 2015. 4: p. e07295
    [PMID:26076231]