Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSXP1M3)

• DOT Name: N6-adenosine-methyltransferase catalytic subunit (METTL3)
• Synonyms: EC 2.1.1.348; Methyltransferase-like protein 3; hMETTL3; N6-adenosine-methyltransferase 70 kDa subunit; MT-A70
• Gene Name: METTL3
• Related Disease:
  Acute myelogenous leukaemia
  Bone osteosarcoma
  Hepatocellular carcinoma
  Leukemia
  Myeloid leukaemia
  Osteosarcoma
  Rheumatoid arthritis
  Acute lymphocytic leukaemia
  Adult glioblastoma
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Cardiac failure
  Childhood acute lymphoblastic leukemia
  Clear cell renal carcinoma
  Colorectal carcinoma
  Congestive heart failure
  Epithelial ovarian cancer
  Glioblastoma multiforme
  Glioma
  Immunodeficiency
  leukaemia
  Liver cancer
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Major depressive disorder
  Melanoma
  Metabolic disorder
  Metastatic malignant neoplasm
  Neoplasm
  Non-insulin dependent diabetes
  Obesity
  Osteoporosis
  Ovarian cancer
  Ovarian neoplasm
  Prostate cancer
  Prostate carcinoma
  Renal cell carcinoma
  Urinary bladder cancer
  Urinary bladder neoplasm
  Advanced cancer
  Non-small-cell lung cancer
  Osteoarthritis
  Gastric cancer
  Pancreatic cancer
  Stomach cancer
• UniProt ID: MTA70_HUMAN
• PDB ID: 5IL0 ; 5IL1 ; 5IL2 ; 5K7M ; 5K7U ; 5K7W ; 5L6D ; 5L6E ; 5TEY ; 5YZ9 ; 6TTP ; 6TTT ; 6TTV ; 6TTW ; 6TTX ; 6TU1 ; 6Y4G ; 7ACD ; 7NHG ; 7NHH ; 7NHI ; 7NHJ ; 7NHV ; 7NI7 ; 7NI8 ; 7NI9 ; 7NIA ; 7NID ; 7O08 ; 7O09 ; 7O0L ; 7O0M ; 7O0P ; 7O0Q ; 7O0R ; 7O27 ; 7O28 ; 7O29 ; 7O2E ; 7O2F ; 7O2H ; 7O2I ; 7O2X ; 7OED ; 7OEE ; 7OEF ; 7OEG ; 7OEH ; 7OEI ; 7OEJ ; 7OEK ; 7OEL ; 7OEM ; 7OQL ; 7OQO ; 7OQP ; 7RX6 ; 7RX7 ; 7RX8 ; 8BN8 ; 8PW8 ; 8PW9 ; 8PWA ; 8PWB
• EC Number: 2.1.1.348
• Pfam ID: PF05063
• Sequence:
  MSDTWSSIQAHKKQLDSLRERLQRRRKQDSGHLDLRNPEAALSPTFRSDSPVPTAPTSGG
  PKPSTASAVPELATDPELEKKLLHHLSDLALTLPTDAVSICLAISTPDAPATQDGVESLL
  QKFAAQELIEVKRGLLQDDAHPTLVTYADHSKLSAMMGAVAEKKGPGEVAGTVTGQKRRA
  EQDSTTVAAFASSLVSGLNSSASEPAKEPAKKSRKHAASDVDLEIESLLNQQSTKEQQSK
  KVSQEILELLNTTTAKEQSIVEKFRSRGRAQVQEFCDYGTKEECMKASDADRPCRKLHFR
  RIINKHTDESLGDCSFLNTCFHMDTCKYVHYEIDACMDSEAPGSKDHTPSQELALTQSVG
  GDSSADRLFPPQWICCDIRYLDVSILGKFAVVMADPPWDIHMELPYGTLTDDEMRRLNIP
  VLQDDGFLFLWVTGRAMELGRECLNLWGYERVDEIIWVKTNQLQRIIRTGRTGHWLNHGK
  EHCLVGVKGNPQGFNQGLDCDVIVAEVRSTSHKPDEIYGMIERLSPGTRKIELFGRPHNV
  QPNWITLGNQLDGIHLLDPDVVARFKQRYPDGIISKPKNL
• Function: The METTL3-METTL14 heterodimer forms a N6-methyltransferase complex that methylates adenosine residues at the N(6) position of some RNAs and regulates various processes such as the circadian clock, differentiation of embryonic and hematopoietic stem cells, cortical neurogenesis, response to DNA damage, differentiation of T-cells and primary miRNA processing. In the heterodimer formed with METTL14, METTL3 constitutes the catalytic core. N6-methyladenosine (m6A), which takes place at the 5'-[AG]GAC-3' consensus sites of some mRNAs, plays a role in mRNA stability, processing, translation efficiency and editing. M6A acts as a key regulator of mRNA stability: methylation is completed upon the release of mRNA into the nucleoplasm and promotes mRNA destabilization and degradation. In embryonic stem cells (ESCs), m6A methylation of mRNAs encoding key naive pluripotency-promoting transcripts results in transcript destabilization, promoting differentiation of ESCs. M6A regulates the length of the circadian clock: acts as an early pace-setter in the circadian loop by putting mRNA production on a fast-track for facilitating nuclear processing, thereby providing an early point of control in setting the dynamics of the feedback loop. M6A also regulates circadian regulation of hepatic lipid metabolism. M6A regulates spermatogonial differentiation and meiosis and is essential for male fertility and spermatogenesis. Also required for oogenesis. Involved in the response to DNA damage: in response to ultraviolet irradiation, METTL3 rapidly catalyzes the formation of m6A on poly(A) transcripts at DNA damage sites, leading to the recruitment of POLK to DNA damage sites. M6A is also required for T-cell homeostasis and differentiation: m6A methylation of transcripts of SOCS family members (SOCS1, SOCS3 and CISH) in naive T-cells promotes mRNA destabilization and degradation, promoting T-cell differentiation. Inhibits the type I interferon response by mediating m6A methylation of IFNB. M6A also takes place in other RNA molecules, such as primary miRNA (pri-miRNAs). Mediates m6A methylation of Xist RNA, thereby participating in random X inactivation: m6A methylation of Xist leads to target YTHDC1 reader on Xist and promote transcription repression activity of Xist. M6A also regulates cortical neurogenesis: m6A methylation of transcripts related to transcription factors, neural stem cells, the cell cycle and neuronal differentiation during brain development promotes their destabilization and decay, promoting differentiation of radial glial cells. METTL3 mediates methylation of pri-miRNAs, marking them for recognition and processing by DGCR8. Acts as a positive regulator of mRNA translation independently of the methyltransferase activity: promotes translation by interacting with the translation initiation machinery in the cytoplasm. Its overexpression in a number of cancer cells suggests that it may participate in cancer cell proliferation by promoting mRNA translation. During human coronorivus SARS-CoV-2 infection, adds m6A modifications in SARS-CoV-2 RNA leading to decreased RIGI binding and subsequently dampening the sensing and activation of innate immune responses.
• Tissue Specificity: Widely expressed at low level. Expressed in spleen, thymus, prostate, testis, ovary, small intestine, colon and peripheral blood leukocytes.
• Reactome Pathway: Processing of Capped Intron-Containing Pre-mRNA (R-HSA-72203)

Molecular Interaction Atlas (MIA) of This DOT

49 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Altered Expression	[1]
Bone osteosarcoma	DIST1004	Definitive	Biomarker	[2]
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[3]
Leukemia	DISNAKFL	Definitive	Biomarker	[1]
Myeloid leukaemia	DISMN944	Definitive	Biomarker	[1]
Osteosarcoma	DISLQ7E2	Definitive	Biomarker	[2]
Rheumatoid arthritis	DISTSB4J	Definitive	Altered Expression	[4]
Acute lymphocytic leukaemia	DISPX75S	Strong	Altered Expression	[5]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[6]
Bladder cancer	DISUHNM0	Strong	Biomarker	[7]
Breast cancer	DIS7DPX1	Strong	Biomarker	[8]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[8]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Altered Expression	[9]
Cardiac failure	DISDC067	Strong	Biomarker	[10]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Altered Expression	[5]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[11]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[12]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[10]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[13]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[6]
Glioma	DIS5RPEH	Strong	Biomarker	[14]
Immunodeficiency	DIS093I0	Strong	Altered Expression	[15]
leukaemia	DISS7D1V	Strong	Biomarker	[1]
Liver cancer	DISDE4BI	Strong	Altered Expression	[9]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[16]
Lung cancer	DISCM4YA	Strong	Altered Expression	[17]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[17]
Lung neoplasm	DISVARNB	Strong	Biomarker	[18]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[19]
Melanoma	DIS1RRCY	Strong	Altered Expression	[20]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[21]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[12]
Neoplasm	DISZKGEW	Strong	Posttranslational Modification	[8]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Altered Expression	[22]
Obesity	DIS47Y1K	Strong	Biomarker	[23]
Osteoporosis	DISF2JE0	Strong	Altered Expression	[24]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[13]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[13]
Prostate cancer	DISF190Y	Strong	Altered Expression	[25]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[25]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[11]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[7]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[7]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[18]
Non-small-cell lung cancer	DIS5Y6R9	moderate	Biomarker	[17]
Osteoarthritis	DIS05URM	moderate	Biomarker	[26]
Gastric cancer	DISXGOUK	Limited	Biomarker	[27]
Pancreatic cancer	DISJC981	Limited	Biomarker	[28]
Stomach cancer	DISKIJSX	Limited	Biomarker	[27]

15 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of N6-adenosine-methyltransferase catalytic subunit (METTL3).	[29]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of N6-adenosine-methyltransferase catalytic subunit (METTL3).	[30]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of N6-adenosine-methyltransferase catalytic subunit (METTL3).	[31]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of N6-adenosine-methyltransferase catalytic subunit (METTL3).	[32]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of N6-adenosine-methyltransferase catalytic subunit (METTL3).	[33]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of N6-adenosine-methyltransferase catalytic subunit (METTL3).	[34]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of N6-adenosine-methyltransferase catalytic subunit (METTL3).	[35]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of N6-adenosine-methyltransferase catalytic subunit (METTL3).	[36]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of N6-adenosine-methyltransferase catalytic subunit (METTL3).	[37]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of N6-adenosine-methyltransferase catalytic subunit (METTL3).	[38]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of N6-adenosine-methyltransferase catalytic subunit (METTL3).	[39]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of N6-adenosine-methyltransferase catalytic subunit (METTL3).	[40]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of N6-adenosine-methyltransferase catalytic subunit (METTL3).	[41]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of N6-adenosine-methyltransferase catalytic subunit (METTL3).	[43]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of N6-adenosine-methyltransferase catalytic subunit (METTL3).	[44]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of N6-adenosine-methyltransferase catalytic subunit (METTL3).	[42]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of N6-adenosine-methyltransferase catalytic subunit (METTL3).	[42]

References

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• [2] The m6A methyltransferase METTL3 promotes osteosarcoma progression by regulating the m6A level of LEF1.Biochem Biophys Res Commun. 2019 Aug 27;516(3):719-725. doi: 10.1016/j.bbrc.2019.06.128. Epub 2019 Jun 26.
• [3] Expression profiles and prognostic significance of RNA N6-methyladenosine-related genes in patients with hepatocellular carcinoma: evidence from independent datasets.Cancer Manag Res. 2019 May 1;11:3921-3931. doi: 10.2147/CMAR.S191565. eCollection 2019.
• [4] METTL3 Attenuates LPS-Induced Inflammatory Response in Macrophages via NF-B Signaling Pathway.Mediators Inflamm. 2019 Oct 24;2019:3120391. doi: 10.1155/2019/3120391. eCollection 2019.
• [5] The study of METTL3 and METTL14 expressions in childhood ETV6/RUNX1-positive acute lymphoblastic leukemia.Mol Genet Genomic Med. 2019 Oct;7(10):e00933. doi: 10.1002/mgg3.933. Epub 2019 Aug 20.
• [6] N(6)-Methyladenosine Modulates Nonsense-Mediated mRNA Decay in Human Glioblastoma.Cancer Res. 2019 Nov 15;79(22):5785-5798. doi: 10.1158/0008-5472.CAN-18-2868. Epub 2019 Sep 17.
• [7] Dynamic m(6)A mRNA methylation reveals the role of METTL3-m(6)A-CDCP1 signaling axis in chemical carcinogenesis.Oncogene. 2019 Jun;38(24):4755-4772. doi: 10.1038/s41388-019-0755-0. Epub 2019 Feb 22.
• [8] N6-methyladenosine METTL3 promotes the breast cancer progression via targeting Bcl-2.Gene. 2020 Jan 5;722:144076. doi: 10.1016/j.gene.2019.144076. Epub 2019 Aug 24.
• [9] RNA m(6)A methylation regulates the epithelial mesenchymal transition of cancer cells and translation of Snail.Nat Commun. 2019 May 6;10(1):2065. doi: 10.1038/s41467-019-09865-9.
• [10] The N(6)-Methyladenosine mRNA Methylase METTL3 Controls Cardiac Homeostasis and Hypertrophy.Circulation. 2019 Jan 22;139(4):533-545. doi: 10.1161/CIRCULATIONAHA.118.036146.
• [11] The M6A methyltransferase METTL3: acting as a tumor suppressor in renal cell carcinoma.Oncotarget. 2017 Oct 10;8(56):96103-96116. doi: 10.18632/oncotarget.21726. eCollection 2017 Nov 10.
• [12] Upregulated METTL3 promotes metastasis of colorectal Cancer via miR-1246/SPRED2/MAPK signaling pathway.J Exp Clin Cancer Res. 2019 Sep 6;38(1):393. doi: 10.1186/s13046-019-1408-4.
• [13] METTL3 promotes ovarian carcinoma growth and invasion through the regulation of AXL translation and epithelial to mesenchymal transition.Gynecol Oncol. 2018 Nov;151(2):356-365. doi: 10.1016/j.ygyno.2018.09.015. Epub 2018 Sep 21.
• [14] N?Methyladenosine Landscape of Glioma Stem-Like Cells: METTL3 Is Essential for the Expression of Actively Transcribed Genes and Sustenance of the Oncogenic Signaling.Genes (Basel). 2019 Feb 13;10(2):141. doi: 10.3390/genes10020141.
• [15] Promoter-bound METTL3 maintains myeloid leukaemia by m(6)A-dependent translation control.Nature. 2017 Dec 7;552(7683):126-131. doi: 10.1038/nature24678. Epub 2017 Nov 27.
• [16] The m(6)A Methyltransferase METTL3 Promotes Translation in Human Cancer Cells.Mol Cell. 2016 May 5;62(3):335-345. doi: 10.1016/j.molcel.2016.03.021. Epub 2016 Apr 21.
• [17] miR-600 inhibits lung cancer via downregulating the expression of METTL3.Cancer Manag Res. 2019 Feb 1;11:1177-1187. doi: 10.2147/CMAR.S181058. eCollection 2019.
• [18] mRNA circularization by METTL3-eIF3h enhances translation and promotes oncogenesis.Nature. 2018 Sep;561(7724):556-560. doi: 10.1038/s41586-018-0538-8. Epub 2018 Sep 19.
• [19] An association study of the m6A genes with major depressive disorder in Chinese Han population.J Affect Disord. 2015 Sep 1;183:279-86. doi: 10.1016/j.jad.2015.05.025. Epub 2015 May 21.
• [20] RNA m6A methyltransferase METTL3 regulates invasiveness of melanoma cells by matrix metallopeptidase 2.Melanoma Res. 2019 Aug;29(4):382-389. doi: 10.1097/CMR.0000000000000580.
• [21] The m(6)A methyltransferase Ime4 epitranscriptionally regulates triacylglycerol metabolism and vacuolar morphology in haploid yeast cells.J Biol Chem. 2017 Aug 18;292(33):13727-13744. doi: 10.1074/jbc.M117.783761. Epub 2017 Jun 27.
• [22] METTL3 inhibits hepatic insulin sensitivity via N6-methyladenosine modification of Fasn mRNA and promoting fatty acid metabolism.Biochem Biophys Res Commun. 2019 Oct 8;518(1):120-126. doi: 10.1016/j.bbrc.2019.08.018. Epub 2019 Aug 10.
• [23] The RNA Methyltransferase Complex of WTAP, METTL3, and METTL14 Regulates Mitotic Clonal Expansion in Adipogenesis.Mol Cell Biol. 2018 Jul 30;38(16):e00116-18. doi: 10.1128/MCB.00116-18. Print 2018 Aug 15.
• [24] Mettl3-mediated m(6)A RNA methylation regulates the fate of bone marrow mesenchymal stem cells and osteoporosis.Nat Commun. 2018 Nov 14;9(1):4772. doi: 10.1038/s41467-018-06898-4.
• [25] RNA m(6)A Methyltransferase METTL3 Promotes The Growth Of Prostate Cancer By Regulating Hedgehog Pathway.Onco Targets Ther. 2019 Nov 5;12:9143-9152. doi: 10.2147/OTT.S226796. eCollection 2019.
• [26] METTL3 promotes experimental osteoarthritis development by regulating inflammatory response and apoptosis in chondrocyte.Biochem Biophys Res Commun. 2019 Aug 13;516(1):22-27. doi: 10.1016/j.bbrc.2019.05.168. Epub 2019 Jun 8.
• [27] Dysregulated N6-methyladenosinemethylation writer METTL3 contributes to the proliferation and migration of gastric cancer.J Cell Physiol. 2020 Jan;235(1):548-562. doi: 10.1002/jcp.28994. Epub 2019 Jun 24.
• [28] The RNA m6A methyltransferase METTL3 promotes pancreatic cancer cell proliferation and invasion.Pathol Res Pract. 2019 Nov;215(11):152666. doi: 10.1016/j.prp.2019.152666. Epub 2019 Sep 24.
• [29] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [30] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [31] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [32] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [33] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [34] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [35] Role of N6-methyladenosine RNA modification in the imbalanced inflammatory homeostasis of arsenic-induced skin lesions. Environ Toxicol. 2022 Aug;37(8):1831-1839. doi: 10.1002/tox.23530. Epub 2022 Apr 1.
• [36] Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7653-8.
• [37] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [38] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [39] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [40] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [41] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [42] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [43] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [44] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.