PlantTFDB - Plant Transcription Factor Database @ CBI, PKU

PlantRegMap/PlantTFDB v5.0

Plant Transcription Factor Database

Transcription Factor Information

Basic Information | Signature Domain | Sequence |

Basic Information? help Back to Top

TF ID

AT4G36930.1

Common Name

AP22.25, BHLH24, C7A10.430, EN99, SPT

Organism

Arabidopsis thaliana

Taxonomic ID

3702

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: 373aa MW: 40297.6 Da PI: 6.837

Description

bHLH family protein

Gene Model

Gene Model ID	Type	Source	Coding Sequence
AT4G36930.1	genome	TAIR	View CDS

Signature Domain? help Back to Top

No.	Domain	Score	E-value	Start	End	HMM Start	HMM End
1	HLH	50.8	3e-16	201	247	4	55
HHHHHHHHHHHHHHHHHHHHHCTSCCC...TTS-STCHHHHHHHHHHHHHHH CS HLH 4 ahnerErrRRdriNsafeeLrellPkaskapskKlsKaeiLekAveYIksLq 55 hn E+rRR+riN+++ L++l+P++ K +Ka++L +A+eY+k+Lq AT4G36930.1 201 VHNLSEKRRRSRINEKMKALQSLIPNS-----NKTDKASMLDEAIEYLKQLQ 247 6***********************7.....5****************9 PP

Protein Features ? help Back to Top

Database	Entry ID	E-value	Start	End	InterPro ID	Description
SuperFamily	SSF47459	5.5E-20	195	257	IPR011598	Myc-type, basic helix-loop-helix (bHLH) domain
PROSITE profile	PS50888	18.063	197	246	IPR011598	Myc-type, basic helix-loop-helix (bHLH) domain
Gene3D	G3DSA:4.10.280.10	4.2E-19	198	257	IPR011598	Myc-type, basic helix-loop-helix (bHLH) domain
CDD	cd00083	1.05E-16	200	251	No hit	No description
Pfam	PF00010	1.0E-13	201	247	IPR011598	Myc-type, basic helix-loop-helix (bHLH) domain
SMART	SM00353	4.0E-18	203	252	IPR011598	Myc-type, basic helix-loop-helix (bHLH) domain

Gene Ontology ? help Back to Top
GO Term	GO Category	GO Description
GO:0006355	Biological Process	regulation of transcription, DNA-templated
GO:0007623	Biological Process	circadian rhythm
GO:0009409	Biological Process	response to cold
GO:0010114	Biological Process	response to red light
GO:0010154	Biological Process	fruit development
GO:0010187	Biological Process	negative regulation of seed germination
GO:0048440	Biological Process	carpel development
GO:0005634	Cellular Component	nucleus
GO:0003677	Molecular Function	DNA binding
GO:0003700	Molecular Function	transcription factor activity, sequence-specific DNA binding
GO:0005515	Molecular Function	protein binding
GO:0046983	Molecular Function	protein dimerization activity

Plant Ontology ? help Back to Top
PO Term	PO Category	PO Description
PO:0000013	anatomy	cauline leaf
PO:0000037	anatomy	shoot apex
PO:0000230	anatomy	inflorescence meristem
PO:0000293	anatomy	guard cell
PO:0008019	anatomy	leaf lamina base
PO:0009005	anatomy	root
PO:0009006	anatomy	shoot system
PO:0009009	anatomy	plant embryo
PO:0009010	anatomy	seed
PO:0009025	anatomy	vascular leaf
PO:0009029	anatomy	stamen
PO:0009030	anatomy	carpel
PO:0009031	anatomy	sepal
PO:0009032	anatomy	petal
PO:0009046	anatomy	flower
PO:0009047	anatomy	stem
PO:0009052	anatomy	flower pedicel
PO:0020030	anatomy	cotyledon
PO:0020038	anatomy	petiole
PO:0020100	anatomy	hypocotyl
PO:0020137	anatomy	leaf apex
PO:0025022	anatomy	collective leaf structure
PO:0025281	anatomy	pollen
PO:0001054	developmental stage	vascular leaf senescent stage
PO:0001078	developmental stage	plant embryo cotyledonary stage
PO:0001081	developmental stage	mature plant embryo stage
PO:0001185	developmental stage	plant embryo globular stage
PO:0004507	developmental stage	plant embryo bilateral stage
PO:0007064	developmental stage	LP.12 twelve leaves visible stage
PO:0007095	developmental stage	LP.08 eight leaves visible stage
PO:0007098	developmental stage	LP.02 two leaves visible stage
PO:0007103	developmental stage	LP.10 ten leaves visible stage
PO:0007115	developmental stage	LP.04 four leaves visible stage
PO:0007123	developmental stage	LP.06 six leaves visible stage
PO:0007611	developmental stage	petal differentiation and expansion stage
PO:0007616	developmental stage	flowering stage
PO:0025374	developmental stage	seed dormant stage

Sequence ? help Back to Top
Protein Sequence Length: 373 aa Download sequence Send to blast
MISQREEREE KKQRVMGDKK LISSSSSSSV YDTRINHHLH HPPSSSDEIS QFLRHIFDRS 60 SPLPSYYSPA TTTTTASLIG VHGSGDPHAD NSRSLVSHHP PSDSVLMSKR VGDFSEVLIG 120 GGSGSAAACF GFSGGGNNNN VQGNSSGTRV SSSSVGASGN ETDEYDCESE EGGEAVVDEA 180 PSSKSGPSSR SSSKRCRAAE VHNLSEKRRR SRINEKMKAL QSLIPNSNKT DKASMLDEAI 240 EYLKQLQLQV QMLTMRNGIN LHPLCLPGTT LHPLQLSQIR PPEATNDPLL NHTNQFASTS 300 NAPEMINTVA SSYALEPSIR SHFGPFPLLT SPVEMSREGG LTHPRLNIGH SNANITGEQA 360 LFDGQPDLKD RIT

Sequence ? help Back to Top

Protein Sequence Length: 373 aa Download sequence Send to blast

MISQREEREE KKQRVMGDKK LISSSSSSSV YDTRINHHLH HPPSSSDEIS QFLRHIFDRS  60
SPLPSYYSPA TTTTTASLIG VHGSGDPHAD NSRSLVSHHP PSDSVLMSKR VGDFSEVLIG  120
GGSGSAAACF GFSGGGNNNN VQGNSSGTRV SSSSVGASGN ETDEYDCESE EGGEAVVDEA  180
PSSKSGPSSR SSSKRCRAAE VHNLSEKRRR SRINEKMKAL QSLIPNSNKT DKASMLDEAI  240
EYLKQLQLQV QMLTMRNGIN LHPLCLPGTT LHPLQLSQIR PPEATNDPLL NHTNQFASTS  300
NAPEMINTVA SSYALEPSIR SHFGPFPLLT SPVEMSREGG LTHPRLNIGH SNANITGEQA  360
LFDGQPDLKD RIT

Expression -- UniGene ? help Back to Top
UniGene ID	E-value	Expressed in
At.4639	0.0	seed

Expression -- Microarray ? help Back to Top
Source	ID	E-value
Genevisible	246212_at	0.0
Expression Atlas	AT4G36930	-
AtGenExpress	AT4G36930	-
ATTED-II	AT4G36930	-

Expression -- Description ? help Back to Top
Source	Description
Uniprot	DEVELOPMENTAL STAGE: During flower initiation, expressed in the peripheral zone of the shoot apical meristem. Confined to the anlagen of successive flower buds yet to arise. Later expressed in abaxial and adaxial sepal primordia, but not in sepals. When sepals initiate, localized in the region interior to them. Within the gynoecium, detected in the initiating and developing medial regions, and then in the developing septum and stigma. SPT expression also occurs in sub-regions of developing ovules, and in the wall and dehiscence zone of the maturing fruit. As the petals develop, becomes restricted to the adaxial epidermis. In stamen expression increase in the vicinity of the archesporial cells and in cells undergoing divisions to produce sporogenous and secondary parietal cells of the anther locules. Expressed in the tapetum and microspore mother cells until the initiation of meiosis. Also detected in stomium and filaments. {ECO:0000269\|PubMed:11245574}.
Uniprot	TISSUE SPECIFICITY: Expressed in lateral root caps, young leaves, stipules, maturing pith cells of the stem, differentiating vascular cells, shoot apical meristems and flowers. {ECO:0000269\|PubMed:11245574}.

Functional Description ? help Back to Top
Source	Description
TAIR	Encodes a transcription factor of the bHLH protein family. Mutants have abnormal, unfused carpels and reduced seed dormancy.
UniProt	Transcription factor that plays a role in floral organogenesis. Promotes the growth of carpel margins and of pollen tract tissues derived from them. {ECO:0000269\|PubMed:10225997, ECO:0000269\|Ref.8}.

Function -- GeneRIF ? help Back to Top
SPATULA is a light-stable repressor of seed germination and mediates the germination response to temperature. [PMID: 16303558] conserved acidic domain is essential for carpel function, supported by conserved amphipathic helix [PMID: 18315540] SPT is necessary in limiting leaf size without dramatically affecting leaf shape by restricting the size of the meristematic region in leaf primordia independently of the AN3-AtGRF5 pathway. [PMID: 20040585] Study show that IND may directly regulate SPT expression through variant E-box. [PMID: 20176890] SPT integrates time of day and temperature signaling to control vegetative growth rate. [PMID: 20705468] Data show that phytochrome B regulates gynoecium formation in association with the transcription factor SPATULA. [PMID: 21364315] SPT acts in an analogous manner to the gibberellin-dependent DELLAs, REPRESSOR OF GA1-3 and GIBBERELLIC ACID INSENSITIVE, which restrain cotyledon expansion alongside SPT. [PMID: 21478445] Over-expression of ALCATRAZ can partially compensate for a loss of SPT function, and over-expression of SPT can fully compensate for loss of ALCATRAZ function. [PMID: 21801252] SPT and IND at least partially mediate their joint functions in gynoecium and fruit development by controlling auxin distribution. [PMID: 21990939] SPT negatively regulates CUC1 and CUC2 expression in the apical part of the gynoecium. [PMID: 22514090] SPATULA (SPT) regulates gynoecium development by activating genes involved in shade avoidance. [PMID: 22851763] The data suggests that SPT plays a role in control of root growth, similar to its roles in above ground tissues. [PMID: 23280064] SPT is a growth repressor that acts to limit the size of meristems in response to environmental signals, perhaps by regulating auxin transport. [PMID: 23470719] SPT has opposite roles in setting seed dormancy in Landsberg erecta and Columbia Arabidopsis ecotypes [PMID: 23754415] cytokinin signaling, that can provide meristematic properties required for CMM activity and growth, is enabled by the transcription factor SPATULA (SPT). Meanwhile, cytokinin signaling is confined to the medial domain by the cytokinin response repressor (AHP6), and perhaps by ARR16 (a type-A ARR) as well, both present in the lateral domains (presumptive valves) of the developing gynoecia. [PMID: 28388635] These results indicate that SPT promotes the transition from vegetative stage to floral stage and it regulates this transition in a PHYB-dependent manner. [PMID: 29966653]

Binding Motif ? help Back to Top
Motif ID	Method	Source	Motif file
MP00035	PBM	25215497	Download

Cis-element ? help Back to Top
Source	Link
PlantRegMap	AT4G36930.1

Regulation -- Description ? help Back to Top
Source	Description
UniProt	INDUCTION: Down-regulated by the A class gene AP2 in the first whorl and by ARF3/ETT in gynoecium. {ECO:0000269\|PubMed:11245574}.

Regulation -- PlantRegMap ? help Back to Top
Source	Upstream Regulator	Target Gene
PlantRegMap	Retrieve	Retrieve

Regulation -- ATRM (Manually Curated Upstream Regulators) ? help Back to Top
Source	Upstream Regulator (A: Activate/R: Repress)
ATRM	AT2G33860 (R), AT4G00120 (A)

Regulation -- ATRM (Manually Curated Target Genes) ? help Back to Top
Source	Target Gene (A: Activate/R: Repress)
ATRM	AT1G15550(R), AT1G80340(R), AT4G36260(A)

Interaction ? help Back to Top
Source	Intact With
BioGRID	AT4G36930, AT5G67110
IntAct	Search Q9FUA4

Phenotype -- Mutation ? help Back to Top
Source	ID
T-DNA Express	AT4G36930

Annotation -- Nucleotide ? help Back to Top
Source	Hit ID	E-value	Description
GenBank	AF319540	0.0	AF319540.1 Arabidopsis thaliana SPATULA (SPT) mRNA, complete cds.
GenBank	AK229267	0.0	AK229267.1 Arabidopsis thaliana mRNA for putative bHLH transcription factor (AtbHLH024) / SPATULA (SPT), complete cds, clone: RAFL16-54-P05.
GenBank	BT026462	0.0	BT026462.1 Arabidopsis thaliana At4g36930 mRNA, complete cds.

Annotation -- Protein ? help Back to Top
Source	Hit ID	E-value	Description
Refseq	NP_568010.1	0.0	basic helix-loop-helix (bHLH) DNA-binding superfamily protein
Swissprot	Q9FUA4	0.0	SPT_ARATH; Transcription factor SPATULA
TrEMBL	A0A178UVX7	0.0	A0A178UVX7_ARATH; SPT
STRING	AT4G36930.1	0.0	(Arabidopsis thaliana)

Orthologous Group ? help Back to Top
Lineage	Orthologous Group ID	Taxa Number	Gene Number
Malvids	OGEM4199	27	54
Representative plant	OGRP258	16	128

Link Out ? help Back to Top
Phytozome	AT4G36930.1
Entrez Gene	829847
iHOP	AT4G36930
wikigenes	AT4G36930

Publications ? help Back to Top
Alvarez J,Smyth DR CRABS CLAW and SPATULA, two Arabidopsis genes that control carpel development in parallel with AGAMOUS. Development, 1999. 126(11): p. 2377-86 [PMID:10225997] Nemhauser JL,Feldman LJ,Zambryski PC Auxin and ETTIN in Arabidopsis gynoecium morphogenesis. Development, 2000. 127(18): p. 3877-88 [PMID:10952886] Riechmann JL, et al. Arabidopsis transcription factors: genome-wide comparative analysis among eukaryotes. Science, 2000. 290(5499): p. 2105-10 [PMID:11118137] Heisler MG,Atkinson A,Bylstra YH,Walsh R,Smyth DR SPATULA, a gene that controls development of carpel margin tissues in Arabidopsis, encodes a bHLH protein. Development, 2001. 128(7): p. 1089-98 [PMID:11245574] Kuusk S,Sohlberg JJ,Long JA,Fridborg I,Sundberg E STY1 and STY2 promote the formation of apical tissues during Arabidopsis gynoecium development. Development, 2002. 129(20): p. 4707-17 [PMID:12361963] 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 [PMID:12679534] Toledo-Ortiz G,Huq E,Quail PH The Arabidopsis basic/helix-loop-helix transcription factor family. Plant Cell, 2003. 15(8): p. 1749-70 [PMID:12897250] Nakayama N, et al. Gene trap lines define domains of gene regulation in Arabidopsis petals and stamens. Plant Cell, 2005. 17(9): p. 2486-506 [PMID:16055634] Penfield S, et al. Cold and light control seed germination through the bHLH transcription factor SPATULA. Curr. Biol., 2005. 15(22): p. 1998-2006 [PMID:16303558] Fahlgren N, et al. Regulation of AUXIN RESPONSE FACTOR3 by TAS3 ta-siRNA affects developmental timing and patterning in Arabidopsis. Curr. Biol., 2006. 16(9): p. 939-44 [PMID:16682356] Sohlberg JJ, et al. STY1 regulates auxin homeostasis and affects apical-basal patterning of the Arabidopsis gynoecium. Plant J., 2006. 47(1): p. 112-23 [PMID:16740145] Balanz Patterning the female side of Arabidopsis: the importance of hormones. J. Exp. Bot., 2006. 57(13): p. 3457-69 [PMID:17023565] Donohue K,Heschel MS,Chiang GC,Butler CM,Barua D Phytochrome mediates germination responses to multiple seasonal cues. Plant Cell Environ., 2007. 30(2): p. 202-12 [PMID:17238911] Finch-Savage WE,Cadman CS,Toorop PE,Lynn JR,Hilhorst HW Seed dormancy release in Arabidopsis Cvi by dry after-ripening, low temperature, nitrate and light shows common quantitative patterns of gene expression directed by environmentally specific sensing. Plant J., 2007. 51(1): p. 60-78 [PMID:17461781] Gremski K,Ditta G,Yanofsky MF The HECATE genes regulate female reproductive tract development in Arabidopsis thaliana. Development, 2007. 134(20): p. 3593-601 [PMID:17855426] Zentella R, et al. Global analysis of della direct targets in early gibberellin signaling in Arabidopsis. Plant Cell, 2007. 19(10): p. 3037-57 [PMID:17933900] Groszmann M,Paicu T,Smyth DR Functional domains of SPATULA, a bHLH transcription factor involved in carpel and fruit development in Arabidopsis. Plant J., 2008. 55(1): p. 40-52 [PMID:18315540] Holdsworth MJ,Bentsink L,Soppe WJ Molecular networks regulating Arabidopsis seed maturation, after-ripening, dormancy and germination. New Phytol., 2008. 179(1): p. 33-54 [PMID:18422904] Ståldal V,Sohlberg JJ,Eklund DM,Ljung K,Sundberg E Auxin can act independently of CRC, LUG, SEU, SPT and STY1 in style development but not apical-basal patterning of the Arabidopsis gynoecium. New Phytol., 2008. 180(4): p. 798-808 [PMID:18811619] Penfield S,Josse EM,Halliday KJ A role for an alternative splice variant of PIF6 in the control of Arabidopsis primary seed dormancy. Plant Mol. Biol., 2010. 73(1-2): p. 89-95 [PMID:19911288] Ichihashi Y,Horiguchi G,Gleissberg S,Tsukaya H The bHLH transcription factor SPATULA controls final leaf size in Arabidopsis thaliana. Plant Cell Physiol., 2010. 51(2): p. 252-61 [PMID:20040585] Gallego-Bartolomé J, et al. Transcriptional diversification and functional conservation between DELLA proteins in Arabidopsis. Mol. Biol. Evol., 2010. 27(6): p. 1247-56 [PMID:20093430] Groszmann M,Bylstra Y,Lampugnani ER,Smyth DR Regulation of tissue-specific expression of SPATULA, a bHLH gene involved in carpel development, seedling germination, and lateral organ growth in Arabidopsis. J. Exp. Bot., 2010. 61(5): p. 1495-508 [PMID:20176890] 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 [PMID:20219281] Sidaway-Lee K, et al. SPATULA links daytime temperature and plant growth rate. Curr. Biol., 2010. 20(16): p. 1493-7 [PMID:20705468] Tisza V,Kov Characterization of FaSPT, a SPATULA gene encoding a bHLH transcriptional factor from the non-climacteric strawberry fruit. Plant Physiol. Biochem., 2010 Oct-Nov. 48(10-11): p. 822-6 [PMID:20822914] Foreman J,White J,Graham I,Halliday K,Josse EM Shedding light on flower development: phytochrome B regulates gynoecium formation in association with the transcription factor SPATULA. Plant Signal Behav, 2011. 6(4): p. 471-6 [PMID:21364315] Josse EM, et al. A DELLA in disguise: SPATULA restrains the growth of the developing Arabidopsis seedling. Plant Cell, 2011. 23(4): p. 1337-51 [PMID:21478445] Li G, et al. Coordinated transcriptional regulation underlying the circadian clock in Arabidopsis. Nat. Cell Biol., 2011. 13(5): p. 616-22 [PMID:21499259] Groszmann M,Paicu T,Alvarez JP,Swain SM,Smyth DR SPATULA and ALCATRAZ, are partially redundant, functionally diverging bHLH genes required for Arabidopsis gynoecium and fruit development. Plant J., 2011. 68(5): p. 816-29 [PMID:21801252] Ichihashi Y, et al. Key proliferative activity in the junction between the leaf blade and leaf petiole of Arabidopsis. Plant Physiol., 2011. 157(3): p. 1151-62 [PMID:21880932] Girin T, et al. INDEHISCENT and SPATULA interact to specify carpel and valve margin tissue and thus promote seed dispersal in Arabidopsis. Plant Cell, 2011. 23(10): p. 3641-53 [PMID:21990939] Nahar MA,Ishida T,Smyth DR,Tasaka M,Aida M Interactions of CUP-SHAPED COTYLEDON and SPATULA genes control carpel margin development in Arabidopsis thaliana. Plant Cell Physiol., 2012. 53(6): p. 1134-43 [PMID:22514090] Reymond MC, et al. A light-regulated genetic module was recruited to carpel development in Arabidopsis following a structural change to SPATULA. Plant Cell, 2012. 24(7): p. 2812-25 [PMID:22851763] Fuentes S, et al. Fruit growth in Arabidopsis occurs via DELLA-dependent and DELLA-independent gibberellin responses. Plant Cell, 2012. 24(10): p. 3982-96 [PMID:23064323] Makkena S,Lamb RS The bHLH transcription factor SPATULA regulates root growth by controlling the size of the root meristem. BMC Plant Biol., 2013. 13: p. 1 [PMID:23280064] Efroni I, et al. Regulation of leaf maturation by chromatin-mediated modulation of cytokinin responses. Dev. Cell, 2013. 24(4): p. 438-45 [PMID:23449474] Makkena S,Lamb RS The bHLH transcription factor SPATULA is a key regulator of organ size in Arabidopsis thaliana. Plant Signal Behav, 2013. 8(5): p. e24140 [PMID:23470719] Footitt S,Huang Z,Clay HA,Mead A,Finch-Savage WE Temperature, light and nitrate sensing coordinate Arabidopsis seed dormancy cycling, resulting in winter and summer annual phenotypes. Plant J., 2013. 74(6): p. 1003-15 [PMID:23590427] Xing S, et al. SPL8 and miR156-targeted SPL genes redundantly regulate Arabidopsis gynoecium differential patterning. Plant J., 2013. 75(4): p. 566-77 [PMID:23621152] Vaistij FE, et al. Differential control of seed primary dormancy in Arabidopsis ecotypes by the transcription factor SPATULA. Proc. Natl. Acad. Sci. U.S.A., 2013. 110(26): p. 10866-71 [PMID:23754415] Lenser T,Thei Conservation of fruit dehiscence pathways between Lepidium campestre and Arabidopsis thaliana sheds light on the regulation of INDEHISCENT. Plant J., 2013. 76(4): p. 545-56 [PMID:24004048] Pabón-Mora N,Wong GK,Ambrose BA Evolution of fruit development genes in flowering plants. Front Plant Sci, 2014. 5: p. 300 [PMID:25018763] Moubayidin L,Ostergaard L Dynamic control of auxin distribution imposes a bilateral-to-radial symmetry switch during gynoecium development. Curr. Biol., 2014. 24(22): p. 2743-8 [PMID:25455035] 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] Pfannebecker KC,Lange M,Rupp O,Becker A Seed Plant-Specific Gene Lineages Involved in Carpel Development. Mol. Biol. Evol., 2017. 34(4): p. 925-942 [PMID:28087776] Zumajo-Cardona C,Ambrose BA,Pabón-Mora N Evolution of the SPATULA/ALCATRAZ gene lineage and expression analyses in the basal eudicot, Bocconia frutescens L. (Papaveraceae). Evodevo, 2017. 8: p. 5 [PMID:28331573] Reyes-Olalde JI, et al. The bHLH transcription factor SPATULA enables cytokinin signaling, and both activate auxin biosynthesis and transport genes at the medial domain of the gynoecium. PLoS Genet., 2017. 13(4): p. e1006726 [PMID:28388635] Wu M, et al. SPATULA regulates floral transition and photomorphogenesis in a PHYTOCHROME B-dependent manner in Arabidopsis. Biochem. Biophys. Res. Commun., 2018. 503(4): p. 2380-2385 [PMID:29966653]