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let-7 microRNA precursor

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let-7 microRNA precursor
Predicted secondary structure and sequence conservation of let-7
Identifiers
Symbollet-7
RfamRF00027
miRBaseMI0000001
miRBase familyMIPF0000002
Other data
RNA typeGene; miRNA
Domain(s)Eukaryota
GOGO:0035195 GO:0035068
SOSO:0001244
PDB structuresPDBe

The Let-7 microRNA precursor was identified from a study of developmental timing in C. elegans,[1] and was later shown to be part of a much larger class of non-coding RNAs termed microRNAs.[2] miR-98 microRNA precursor from human is a let-7 family member. Let-7 miRNAs have now been predicted or experimentally confirmed in a wide range of species (MIPF0000002[3]). miRNAs are initially transcribed in long transcripts (up to several hundred nucleotides) called primary miRNAs (pri-miRNAs), which are processed in the nucleus by Drosha and Pasha to hairpin structures of about 70 nucleotide. These precursors (pre-miRNAs) are exported to the cytoplasm by exportin5, where they are subsequently processed by the enzyme Dicer to a ~22 nucleotide mature miRNA. The involvement of Dicer in miRNA processing demonstrates a relationship with the phenomenon of RNA interference.

Genomic Locations

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In human genome, the cluster let-7a-1/let-7f-1/let-7d is inside the region B at 9q22.3, with the defining marker D9S280-D9S1809. One minimal LOH (loss of heterozygosity) region, between loci D11S1345-D11S1316, contains the cluster miR-125b1/let-7a-2/miR-100. The cluster miR-99a/let-7c/miR-125b-2 is in a 21p11.1 region of HD (homozygous deletions). The cluster let-7g/miR-135-1 is in region 3 at 3p21.1-p21.2.[4]

The let-7 family

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The lethal-7 (let-7) gene was first discovered in the nematode as a key developmental regulator and became one of the first two known microRNAs (the other one is lin-4).[5] Soon, let-7 was found in fruit fly, and identified as the first known human miRNA by a BLAST (basic local alignment search tool) research.[6] The mature form of let-7 family members is highly conserved across species.

In C.elegans

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In C.elegans, the let-7 family consists of genes encoding nine miRNAs sharing the same seed sequence.[7] Among them, let-7, mir-84, mir-48 and mir-241 are involved in C.elegans heterochronic pathway, sequentially controlling developmental timing of larva transitions.[8] Most animals with loss-of-function let-7 mutation burst through their vulvas and die, and therefore the mutant is lethal (let).[5] The mutants of other let-7 family members have a radio-resistant phenotype in vulval cells, which may be related to their ability to repress RAS.[9]

In Drosophila

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There is only one single let-7 gene in the Drosophila genome, which has the identical mature sequence to the one in C.elegans.[10] The role of let-7 has been demonstrated in regulating the timing of neuromuscular junction formation in the abdomen and cell-cycle in the wing.[11] Furthermore, the expression of pri-, pre- and mature let-7 have the same rhythmic pattern with the hormone pulse before each cuticular molt in Drosophila.[12]

In vertebrates

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The let-7 family has a lot more members in vertebrates than in C.elegans and Drosophila.[10] The sequences, expression timing, as well as genomic clustering of these miRNAs members are all conserved across species.[13] The direct role of let-7 family in vertebrate development has not been clearly shown as in less complex organisms, yet the expression pattern of let-7 family is indeed temporally regulated during developmental processes.[14] Functionally, let-7 has been shown in early vertebrates to control the differentiation of mesoderm and ectoderm.[15] Given that the expression levels of let-7 members are significantly low in human cancers and cancer stem cells,[16] the major function of let-7 genes may be to promote terminal differentiation in development and tumor suppression.

Regulation of expression

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Although the levels of mature let-7 members are undetectable in undifferentiated cells, the primary transcripts and the hairpin precursors of let-7 are present in these cells.[17] It indicates that the mature let-7 miRNAs may be regulated in a post-transcriptional manner.

By pluripotency promoting factor LIN28

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As one of the genes involved in (but not essential for) induced pluripotent stem (iPS) cell reprogramming,[18] LIN28 expression is reciprocal to that of mature let-7.[19] LIN28 selectively binds the primary and precursor forms of let-7, and inhibits the processing of pri-let-7 to form the hairpin precursor.[20] This binding is facilitated by the conserved loop sequence of primary let-7 family members and RNA-binding domains of LIN28 proteins.[21] Lin-28 uses two zinc knuckle domains to recognize the NGNNG motif in the let-7 precursors,[22] while the Cold-shock domain, connected by a flexible linker, binds to a closed loop in the precursors.[23] On the other hand, let-7 miRNAs in mammals have been shown to regulate LIN28,[24] which implies that let-7 might enhance its own level by repressing LIN28, its negative regulator.[25]

In autoregulatory loop with MYC

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Expression of let-7 members is controlled by MYC binding to their promoters. The levels of let-7 have been reported to decrease in models of MYC-mediated tumorigenesis, and to increase when MYC is inhibited by chemicals.[26] In a twist, there are let-7-binding sites in MYC 3' untranslated region(UTR) according to bioinformatic analysis, and let-7 overexpression in cell culture decreased MYC mRNA levels.[27] Therefore, there is a double-negative feedback loop between MYC and let-7. Furthermore, let-7 could lead to IMP1(/insulin-like growth factor II mRNA-binding protein) depletion, which destabilizes MYC mRNA, thus forming an indirect regulatory pathway.[28]

Targets of let-7

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Oncogenes: RAS, HMGA2

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Let-7 has been demonstrated to be a direct regulator of RAS expression in human cells[29] All the three RAS genes in human, K-, N-, and H-, have the predicted let-7 binding sequences in their 3'UTRs. In lung cancer patient samples, expression of RAS and let-7 showed reciprocal pattern, which has low let-7 and high RAS in cancerous cells, and high let-7 and low RAS in normal cells. Another oncogene, high mobility group A2 (HMGA2), has also been identified as a target of let-7. Let-7 directly inhibits HMGA2 by binding to its 3'UTR.[30] Removal of let-7 binding site by 3'UTR deletion cause overexpression of HMGA2 and formation of tumor.

Cell cycle, proliferation, and apoptosis regulators

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Microarray analyses revealed many genes regulating cell cycle and cell proliferation that are responsive to alteration of let-7 levels, including cyclin A2, CDC34, Aurora A and B kinases (STK6 and STK12), E2F5, and CDK8, among others.[29] Subsequent experiments confirmed the direct effects of some of these genes, such as CDC25A and CDK6.[31] Let-7 also inhibits several components of DNA replication machinery, transcription factors, even some tumor suppressor genes and checkpoint regulators.[29] Apoptosis is regulated by let-7 as well, through Casp3, Bcl2, Map3k1 and Cdk5 modulation.[32]

Immunity

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Let-7 has been implicated in post-transcriptional control of innate immune responses to pathogenic agents. Macrophages stimulated with live bacteria or purified microbial components down-regulate the expression of several members of the let-7 microRNA family to relieve repression of immune-modulatory cytokines IL-6 and IL-10.[33][34] Let-7 has also been implicated in the negative regulation of TLR4, the major immune receptor of microbial lipopolysaccharide and down-regulation of let-7 both upon microbial and protozoan infection might elevate TLR4 signalling and expression.[35][36] Let-7 has furthermore been reported to regulate the production of cytokine IL-13 by T lymphocytes during allergic airway inflammation thus linking this microRNA to adaptive immunity as well.[37] Down-modulation of let-7 negative regulator Lin28b in human T lymphocytes is believed to accrue during early neonate development to reprogram the immune system towards defense.[38]

Potential clinical use in cancer

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Given the prominent phenotype of cell overproliferation and undifferentiation by let-7 loss-of-function in nematodes, and the role of its targets on cell destiny determination, let-7 is closely associated with human cancer and acts as a tumor suppressor.

Diagnosis

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Numerous reports have shown that the expression levels of let-7 are frequently low and the chromosomal clusters of let-7 are often deleted in many cancers.[4] Let-7 is expressed at higher levels in more differentiated tumors, which also have lower levels of activated oncogenes such as RAS and HMGA2. Therefore, expression levels of let-7 could be prognostic markers in several cancers associated with differentiation stages.[39] In lung cancer, for example, reduced expression of let-7 is significantly correlated with reduced postoperative survival.[40] The expression of let-7b and let-7g microRNAs are significantly associated with overall survival in 1262 breast cancer patients.[41]

Therapy

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Let-7 is also a very attractive potential therapeutic that can prevent tumorigenesis and angiogenesis, typically in cancers that underexpress let-7.[42] Lung cancer, for instance, has several key oncogenic mutations including p53, RAS and MYC, some of which may directly correlate with the reduced expression of let-7, and may be repressed by introduction of let-7.[40] Intranasal administration of let-7 has already been found effective in reducing tumor growth in a transgenic mouse model of lung cancer.[43] Similar restoration of let-7 was also shown to inhibit cell proliferation in breast, colon and hepatic cancers, lymphoma, and uterine leiomyoma.[44]

References

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  1. ^ Rougvie AE (September 2001). "Control of developmental timing in animals". Nature Reviews. Genetics. 2 (9): 690–701. doi:10.1038/35088566. PMID 11533718. S2CID 44335211.
  2. ^ Ambros V (December 2001). "microRNAs: tiny regulators with great potential". Cell. 107 (7): 823–826. doi:10.1016/S0092-8674(01)00616-X. PMID 11779458.
  3. ^ MIPF0000002
  4. ^ a b Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S, et al. (March 2004). "Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers". Proceedings of the National Academy of Sciences of the United States of America. 101 (9): 2999–3004. Bibcode:2004PNAS..101.2999C. doi:10.1073/pnas.0307323101. PMC 365734. PMID 14973191.
  5. ^ a b Reinhart BJ, Slack FJ, Basson M, Pasquinelli AE, Bettinger JC, Rougvie AE, et al. (February 2000). "The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans". Nature. 403 (6772): 901–906. Bibcode:2000Natur.403..901R. doi:10.1038/35002607. PMID 10706289. S2CID 4384503.
  6. ^ Pasquinelli AE, Reinhart BJ, Slack F, Martindale MQ, Kuroda MI, Maller B, et al. (November 2000). "Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA". Nature. 408 (6808): 86–89. Bibcode:2000Natur.408...86P. doi:10.1038/35040556. PMID 11081512. S2CID 4401732.
  7. ^ Lim LP, Lau NC, Weinstein EG, Abdelhakim A, Yekta S, Rhoades MW, et al. (April 2003). "The microRNAs of Caenorhabditis elegans". Genes & Development. 17 (8): 991–1008. doi:10.1101/gad.1074403. PMC 196042. PMID 12672692.
  8. ^ Moss EG (June 2007). "Heterochronic genes and the nature of developmental time". Current Biology. 17 (11): R425–R434. Bibcode:2007CBio...17.R425M. doi:10.1016/j.cub.2007.03.043. PMID 17550772.
  9. ^ Weidhaas JB, Babar I, Nallur SM, Trang P, Roush S, Boehm M, et al. (December 2007). "MicroRNAs as potential agents to alter resistance to cytotoxic anticancer therapy". Cancer Research. 67 (23): 11111–11116. doi:10.1158/0008-5472.CAN-07-2858. PMC 6070379. PMID 18056433.
  10. ^ a b Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschl T (October 2001). "Identification of novel genes coding for small expressed RNAs". Science. 294 (5543): 853–858. Bibcode:2001Sci...294..853L. doi:10.1126/science.1064921. hdl:11858/00-001M-0000-0012-F65F-2. PMID 11679670. S2CID 18101169.
  11. ^ Caygill EE, Johnston LA (July 2008). "Temporal regulation of metamorphic processes in Drosophila by the let-7 and miR-125 heterochronic microRNAs". Current Biology. 18 (13): 943–950. Bibcode:2008CBio...18..943C. doi:10.1016/j.cub.2008.06.020. PMC 2736146. PMID 18571409.
  12. ^ Thummel CS (October 2001). "Molecular mechanisms of developmental timing in C. elegans and Drosophila". Developmental Cell. 1 (4): 453–465. doi:10.1016/S1534-5807(01)00060-0. PMID 11703937.
  13. ^ Rodriguez A, Griffiths-Jones S, Ashurst JL, Bradley A (October 2004). "Identification of mammalian microRNA host genes and transcription units". Genome Research. 14 (10A): 1902–1910. doi:10.1101/gr.2722704. PMC 524413. PMID 15364901.
  14. ^ Kloosterman WP, Plasterk RH (October 2006). "The diverse functions of microRNAs in animal development and disease". Developmental Cell. 11 (4): 441–450. doi:10.1016/j.devcel.2006.09.009. PMID 17011485.
  15. ^ Colas AR, McKeithan WL, Cunningham TJ, Bushway PJ, Garmire LX, Duester G, et al. (December 2012). "Whole-genome microRNA screening identifies let-7 and mir-18 as regulators of germ layer formation during early embryogenesis". Genes & Development. 26 (23): 2567–2579. doi:10.1101/gad.200758.112. PMC 3521625. PMID 23152446.
  16. ^ Esquela-Kerscher A, Slack FJ (April 2006). "Oncomirs - microRNAs with a role in cancer". Nature Reviews. Cancer. 6 (4): 259–269. doi:10.1038/nrc1840. PMID 16557279. S2CID 10620165.
  17. ^ Thomson JM, Newman M, Parker JS, Morin-Kensicki EM, Wright T, Hammond SM (August 2006). "Extensive post-transcriptional regulation of microRNAs and its implications for cancer". Genes & Development. 20 (16): 2202–2207. doi:10.1101/gad.1444406. PMC 1553203. PMID 16882971.
  18. ^ Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, et al. (December 2007). "Induced pluripotent stem cell lines derived from human somatic cells". Science. 318 (5858): 1917–1920. Bibcode:2007Sci...318.1917Y. doi:10.1126/science.1151526. PMID 18029452. S2CID 86129154.
  19. ^ Viswanathan SR, Daley GQ, Gregory RI (April 2008). "Selective blockade of microRNA processing by Lin28". Science. 320 (5872): 97–100. Bibcode:2008Sci...320...97V. doi:10.1126/science.1154040. PMC 3368499. PMID 18292307.
  20. ^ Newman MA, Thomson JM, Hammond SM (August 2008). "Lin-28 interaction with the Let-7 precursor loop mediates regulated microRNA processing". RNA. 14 (8): 1539–1549. doi:10.1261/rna.1155108. PMC 2491462. PMID 18566191.
  21. ^ Piskounova E, Viswanathan SR, Janas M, LaPierre RJ, Daley GQ, Sliz P, Gregory RI (August 2008). "Determinants of microRNA processing inhibition by the developmentally regulated RNA-binding protein Lin28". The Journal of Biological Chemistry. 283 (31): 21310–21314. doi:10.1074/jbc.C800108200. PMID 18550544.
  22. ^ Loughlin FE, Gebert LF, Towbin H, Brunschweiger A, Hall J, Allain FH (December 2011). "Structural basis of pre-let-7 miRNA recognition by the zinc knuckles of pluripotency factor Lin28". Nature Structural & Molecular Biology. 19 (1): 84–89. doi:10.1038/nsmb.2202. PMID 22157959. S2CID 2201304.
  23. ^ Nam Y, Chen C, Gregory RI, Chou JJ, Sliz P (November 2011). "Molecular basis for interaction of let-7 microRNAs with Lin28". Cell. 147 (5): 1080–1091. doi:10.1016/j.cell.2011.10.020. PMC 3277843. PMID 22078496.
  24. ^ Moss EG, Tang L (June 2003). "Conservation of the heterochronic regulator Lin-28, its developmental expression and microRNA complementary sites". Developmental Biology. 258 (2): 432–442. doi:10.1016/S0012-1606(03)00126-X. PMID 12798299.
  25. ^ Ali PS, Ghoshdastider U, Hoffmann J, Brutschy B, Filipek S (November 2012). "Recognition of the let-7g miRNA precursor by human Lin28B". FEBS Letters. 586 (22): 3986–3990. Bibcode:2012FEBSL.586.3986S. doi:10.1016/j.febslet.2012.09.034. PMID 23063642. S2CID 28899778.
  26. ^ Chang TC, Yu D, Lee YS, Wentzel EA, Arking DE, West KM, et al. (January 2008). "Widespread microRNA repression by Myc contributes to tumorigenesis". Nature Genetics. 40 (1): 43–50. doi:10.1038/ng.2007.30. PMC 2628762. PMID 18066065.
  27. ^ Koscianska E, Baev V, Skreka K, Oikonomaki K, Rusinov V, Tabler M, Kalantidis K (September 2007). "Prediction and preliminary validation of oncogene regulation by miRNAs". BMC Molecular Biology. 8: 79. doi:10.1186/1471-2199-8-79. PMC 2096627. PMID 17877811.
  28. ^ Ioannidis P, Mahaira LG, Perez SA, Gritzapis AD, Sotiropoulou PA, Kavalakis GJ, et al. (May 2005). "CRD-BP/IMP1 expression characterizes cord blood CD34+ stem cells and affects c-myc and IGF-II expression in MCF-7 cancer cells". The Journal of Biological Chemistry. 280 (20): 20086–20093. doi:10.1074/jbc.M410036200. PMID 15769738.
  29. ^ a b c Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R, Cheng A, et al. (March 2005). "RAS is regulated by the let-7 microRNA family". Cell. 120 (5): 635–647. doi:10.1016/j.cell.2005.01.014. PMID 15766527.
  30. ^ Mayr C, Hemann MT, Bartel DP (March 2007). "Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation". Science. 315 (5818): 1576–1579. Bibcode:2007Sci...315.1576M. doi:10.1126/science.1137999. PMC 2556962. PMID 17322030.
  31. ^ Johnson CD, Esquela-Kerscher A, Stefani G, Byrom M, Kelnar K, Ovcharenko D, et al. (August 2007). "The let-7 microRNA represses cell proliferation pathways in human cells". Cancer Research. 67 (16): 7713–7722. doi:10.1158/0008-5472.CAN-07-1083. PMID 17699775.
  32. ^ He YJ, Guo L, D ZH. (2009) Let-7 and mir-24 in uvb-induced apoptosis [Chinese]. Zhonghua Fang She Yi Xue Yu Fang Hu Za Zhi. 29, 234–6.
  33. ^ Schulte LN, Eulalio A, Mollenkopf HJ, Reinhardt R, Vogel J (May 2011). "Analysis of the host microRNA response to Salmonella uncovers the control of major cytokines by the let-7 family". The EMBO Journal. 30 (10): 1977–1989. doi:10.1038/emboj.2011.94. PMC 3098495. PMID 21468030.
  34. ^ Liu Y, Chen Q, Song Y, Lai L, Wang J, Yu H, et al. (June 2011). "MicroRNA-98 negatively regulates IL-10 production and endotoxin tolerance in macrophages after LPS stimulation". FEBS Letters. 585 (12): 1963–1968. Bibcode:2011FEBSL.585.1963L. doi:10.1016/j.febslet.2011.05.029. PMID 21609717. S2CID 2416276.
  35. ^ Hu G, Zhou R, Liu J, Gong AY, Eischeid AN, Dittman JW, Chen XM (August 2009). "MicroRNA-98 and let-7 confer cholangiocyte expression of cytokine-inducible Src homology 2-containing protein in response to microbial challenge". Journal of Immunology. 183 (3): 1617–1624. doi:10.4049/jimmunol.0804362. PMC 2906382. PMID 19592657.
  36. ^ Androulidaki A, Iliopoulos D, Arranz A, Doxaki C, Schworer S, Zacharioudaki V, et al. (August 2009). "The kinase Akt1 controls macrophage response to lipopolysaccharide by regulating microRNAs". Immunity. 31 (2): 220–231. doi:10.1016/j.immuni.2009.06.024. PMC 2865583. PMID 19699171.
  37. ^ Kumar M, Ahmad T, Sharma A, Mabalirajan U, Kulshreshtha A, Agrawal A, Ghosh B (November 2011). "Let-7 microRNA-mediated regulation of IL-13 and allergic airway inflammation". The Journal of Allergy and Clinical Immunology. 128 (5): 1077–1085. doi:10.1016/j.jaci.2011.04.034. PMID 21616524.
  38. ^ Yuan J, Nguyen CK, Liu X, Kanellopoulou C, Muljo SA (March 2012). "Lin28b reprograms adult bone marrow hematopoietic progenitors to mediate fetal-like lymphopoiesis". Science. 335 (6073): 1195–1200. Bibcode:2012Sci...335.1195Y. doi:10.1126/science.1216557. PMC 3471381. PMID 22345399.
  39. ^ Shell S, Park SM, Radjabi AR, Schickel R, Kistner EO, Jewell DA, et al. (July 2007). "Let-7 expression defines two differentiation stages of cancer". Proceedings of the National Academy of Sciences of the United States of America. 104 (27): 11400–11405. Bibcode:2007PNAS..10411400S. doi:10.1073/pnas.0704372104. PMC 2040910. PMID 17600087.
  40. ^ a b Takamizawa J, Konishi H, Yanagisawa K, Tomida S, Osada H, Endoh H, et al. (June 2004). "Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival". Cancer Research. 64 (11): 3753–3756. doi:10.1158/0008-5472.CAN-04-0637. PMID 15172979.
  41. ^ Lánczky A, Nagy Á, Bottai G, Munkácsy G, Szabó A, Santarpia L, Győrffy B (December 2016). "miRpower: a web-tool to validate survival-associated miRNAs utilizing expression data from 2178 breast cancer patients". Breast Cancer Research and Treatment. 160 (3): 439–446. doi:10.1007/s10549-016-4013-7. PMID 27744485. S2CID 11165696.
  42. ^ Kuehbacher A, Urbich C, Zeiher AM, Dimmeler S (July 2007). "Role of Dicer and Drosha for endothelial microRNA expression and angiogenesis". Circulation Research. 101 (1): 59–68. doi:10.1161/CIRCRESAHA.107.153916. PMID 17540974.
  43. ^ Esquela-Kerscher A, Trang P, Wiggins JF, Patrawala L, Cheng A, Ford L, et al. (March 2008). "The let-7 microRNA reduces tumor growth in mouse models of lung cancer". Cell Cycle. 7 (6): 759–764. doi:10.4161/cc.7.6.5834. PMID 18344688.
  44. ^ Barh D, Malhotra R, Ravi B, Sindhurani P (February 2010). "MicroRNA let-7: an emerging next-generation cancer therapeutic". Current Oncology. 17 (1): 70–80. doi:10.3747/co.v17i1.356. PMC 2826782. PMID 20179807.

Further reading

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