Safety assessment of food and feed from biotechnology-derived crops employing RNA-mediated gene regulation to achieve desired traits: A scientific review

Regulatory Toxicology and Pharmacology

Volumn 66, Issue 2, 2013, Pages 167-176

  Petrick, Jay S ^a   Brower Toland, Brent ^a   Jackson, Aimee L ^b   Kier, Larry D ^c  

^a MONSANTO COMPANY   (United States)

^b Jackson BioConsulting   (United States)

^c NONE   (United States)

Author keywords

Biotechnology derived plant; Comparative safety assessment; Food safety; Genetically modified; RNA interference; RNAi; SiRNA

Indexed keywords

DOUBLE STRANDED RNA; MICRORNA; OLIGONUCLEOTIDE; SMALL INTERFERING RNA;

ARTICLE; BEAN; CROP; CYTOKINE RESPONSE; DRUG ABSORPTION; DRUG CLEARANCE; DRUG DEGRADATION; DRUG DISTRIBUTION; DRUG EFFECT; DRUG HALF LIFE; DRUG METABOLISM; FOOD BIOTECHNOLOGY; FOOD INTAKE; FOOD SAFETY; GENE CONTROL; GENE SILENCING; HUMAN; HYDRODYNAMICS BASED TRANSFECTION; NONHUMAN; OLIGONUCLEOTIDE THERAPY; PAPAYA; PHENOTYPE; PLANT BREEDING; PLUM; POTATO; PRIORITY JOURNAL; PROTEIN ENGINEERING; PROTEIN EXPRESSION; RISK ASSESSMENT; RNA DEGRADATION; RNA INTERFERENCE; SINGLE DRUG DOSE; SOYBEAN; SQUASH; TOMATO;

EID: 84877335523     PISSN: 02732300     EISSN: 10960295     Source Type: Journal    
DOI: 10.1016/j.yrtph.2013.03.008     Document Type: Article

References (149)

1. Akhtar S. Oral delivery of siRNA and antisense oligonucleotides. J. Drug Target. 2009, 17:491-495.
2. Allen R.S., et al. RNAi-mediated replacement of morphine with the nonnarcotic alkaloid reticuline in opium poppy. Nat. Biotechnol. 2004, 22:1559-1566.
3. Alnylam Pharmaceuticals, 2013. ALN-VSP: Liver cancers. <> (accessed 10.01.13.). http://www.alnylam.com/Programs-and-Pipeline/Partner-Programs/Liver-Cancer.php.
4. Amarzguioui M., et al. Tolerance for mutations and chemical modifications in a siRNA. Nucleic Acids Res. 2003, 31:589-595.
5. Andersson M., et al. Targeted gene suppression by RNA interference: an efficient method for production of high-amylose potato lines. J. Biotechnol. 2006, 123:137-148.
6. Aouadi M., et al. Orally delivered siRNA targeting macrophage Map4k4 suppresses systemic inflammation. Nature 2009, 458:1180-1184.
7. Astwood J.D., et al. Stability of food allergens to digestion in vitro. Nat. Biotechnol. 1996, 14:1269-1273.
8. Atherton K.T. Safety assessment of genetically modified crops. Toxicology 2002, 181-182:421-426.
9. Bartel D.P. MicroRNAs: target recognition and regulatory functions. Cell 2009, 136:215-233.
10. Baum J.A., et al. Control of coleopteran insect pests through RNA interference. Nat. Biotechnol. 2007, 25:1322-1326.
11. Behlke M.A. Progress towards in vivo use of siRNAs. Mol. Ther. 2006, 13:644-670.
12. Boutla A., et al. Induction of RNA interference in Caenorhabditis elegans by RNAs derived from plants exhibiting post-transcriptional gene silencing. Nucleic Acids Res. 2002, 30:1688-1694.
13. Braasch D.A., et al. Biodistribution of phosphodiester and phosphorothioate siRNA. Bioorg. Med. Chem. Lett. 2004, 14:1139-1143.
14. Brodersen P., Voinnet O. The diversity of RNA silencing pathways in plants. Trends Genet. 2006, 22:268-280.
15. Brodersen P., et al. Widespread translational inhibition by plant miRNAs and siRNAs. Science 2008, 320:1185-1190.
16. Caplen N.J., et al. Specific inhibition of gene expression by small double-stranded RNAs in invertebrate and vertebrate systems. Proc. Natl. Acad. Sci. USA 2001, 98:9742-9747.
17. Carthew R.W., Sontheimer E.J. Origins and mechanisms of miRNAs and siRNAs. Cell 2009, 136:642-655.
18. Cellini F., et al. Unintended effects and their detection in genetically modified crops. Food Chem. Toxicol. 2004, 42:1089-1125.
19. Chau B.L., Lee K.A. Function and anatomy of plant siRNA pools derived from hairpin transgenes. Plant Methods 2007, 3:13.
20. Cock J.M., et al. Natural antisense transcripts of the S locus receptor kinase gene and related sequences in Brassica oleracea. Mol. Gen. Genet. 1997, 255:514-524.
21. Cockburn A. Assuring the safety of genetically modified (GM) foods: the importance of an holistic, integrative approach. J. Biotechnol. 2002, 98:79-106.
22. Codex Guideline for the Conduct of Food Safety Assessment of Foods Derived from Recombinant-DNA Plants (CAC/GL 45-2003), 7-26. Codex Alimentarius Commission, Joint FAO/WHO Food Standards Programme 2003, Food and Agriculture Organisation, Italy, Rome.
23. Della Vedova C.B., et al. The dominant inhibitory chalcone synthase allele C2-Idf (inhibitor diffuse) from Zea mays (L.) acts via an endogenous RNA silencing mechanism. Genetics 2005, 170:1989-2002.
24. Didiano D., Hobert O. Perfect seed pairing is not a generally reliable predictor for miRNA-target interactions. Nat. Struct. Mol. Biol. 2006, 13:849-851.
25. Doench J.G., Sharp P.A. Specificity of microRNA target selection in translational repression. Genes Dev. 2004, 18:504-511.
26. Dougherty W.G., et al. RNA-mediated virus resistance in transgenic plants: exploitation of a cellular pathway possibly involved in RNA degradation. Mol. Plant Microbe Interact. 1994, 7:544-552.
27. Du Q., et al. A systematic analysis of the silencing effects of an active siRNA at all single-nucleotide mismatched target sites. Nucleic Acids Res. 2005, 33:1671-1677.
28. Duxbury M.S., et al. Systemic siRNA-mediated gene silencing: a new approach to targeted therapy of cancer. Ann. Surg. 2004, 240:667-674. discussion 675-6.
29. Dykxhoorn D.M., et al. Killing the messenger: short RNAs that silence gene expression. Nat. Rev. Mol. Cell Biol. 2003, 4:457-467.
30. EC, 2003. Guidance document for the risk assessment of genetically modified plants and derived food and feed, prepared by the Joint Working Group on Novel Foods and GMOs, 6-7 March 2003. European Commission.
31. EFSA Opinion of the scientific panel on Genetically Modified Organisms on a request from the commission related to the notification (reference C/SE/96/3501) for the placing on the market of genetically modified potato EH92-527-1 with altered starch composition, for cultivation and production of starch, under Part C of Directive 2001/18/EC from BASF plant science. EFSA J. 2006, 323:1-20.
32. Elbashir S.M., et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 2001, 411:494-498.
33. Fabian M.R., et al. Regulation of mRNA translation and stability by microRNAs. Ann. Rev. Biochem. 2010, 79:351-379.
34. Fairbairn D.J., et al. Host-delivered RNAi: an effective strategy to silence genes in plant parasitic nematodes. Planta 2007, 226:1525-1533.
35. FAO/WHO, 1996. Biotechnology and Food Safety. Report of a Joint FAO/WHO Consultation. FAO/WHO.
36. FAO/WHO, 2000. Safety Aspects of Genetically Modified Foods of Plant Origin. Report of a Joint FAO/WHO Consultation. Geneva, Switzerland.
37. FDA Statement of policy: foods derived from new plant varieties. Fed. Regist. 1992, 57:22984-23005.
38. FDA, 1994. Biotechnology of Food. U.S. Food and Drug Administration Center for Food Safety and Nutrition.
39. Fire A., et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 1998, 391:806-811.
40. Flachowsky G., et al. Animal nutrition with feeds from genetically modified plants. Arch. Anim. Nutr. 2005, 59:1-40.
41. Frizzi A., Huang S. Tapping RNA silencing pathways for plant biotechnology. Plant Biotechnol. J. 2010, 8:655-677.
42. Fukuhara T., et al. Enigmatic double-stranded RNA in Japonica rice. Plant Mol. Biol. 1993, 21:1121-1130.
43. Ghildiyal M., et al. Endogenous siRNAs derived from transposons and mRNAs in Drosophila somatic cells. Science 2008, 320:1077-1081.
44. Gilmore I.R., et al. The design and exogenous delivery of siRNA for post-transcriptional gene silencing. J. Drug Target. 2004, 12:315-340.
45. Gordon K.H.J., Waterhouse P.M. RNAi for insect-proof plants. Nat. Biotechnol. 2007, 25:1231-1232.
46. Gould A.R., Francki R.I. Immunochemical detection of ds-RNA in healthy and virus-infected plants and specific detection of viral ds-RNA by hybridization to labelled complementary DNA. J. Virol. Methods. 1981, 2:277-286.
47. Grimson A., et al. MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol. Cell 2007, 27:91-105.
48. Guo H., et al. Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature 2010, 466:835-840.
49. Ha I., et al. A bulged lin-4/lin-14 RNA duplex is sufficient for Caenorhabditis elegans lin-14 temporal gradient formation. Genes Dev. 1996, 10:3041-3050.
50. Hamilton A.J., Baulcombe D.C. A species of small antisense RNA in posttranscriptional gene silencing in plants. Science 1999, 286:950-952.
51. Hammond S.M. Dicing and slicing: the core machinery of the RNA interference pathway. FEBS Lett. 2005, 579:5822-5829.
52. Harrigan G.G., et al. Natural variation in crop composition and the impact of transgenesis. Nat. Biotechnol. 2010, 28:402-404.
53. Haupenthal J., et al. Inhibition of RNAse A family enzymes prevents degradation and loss of silencing activity of siRNAs in serum. Biochem. Pharmacol. 2006, 71:702-710.
54. Heidel J.D., et al. Lack of interferon response in animals to naked siRNAs. Nat. Biotechnol. 2004, 22:1579-1582.
55. Heisel S.E., et al. Characterization of unique small RNA populations from rice grain. PLoS One 2008, 3:e2871.
56. Hemmings-Mieszczak M., Hohn T. A stable hairpin preceded by a short open reading frame promotes nonlinear ribosome migration on a synthetic mRNA leader. RNA 1999, 5:1149-1157.
57. Herman R.A., et al. Compositional assessment of transgenic crops: an idea whose time has passed?. Trends Biotechnol. 2009, 27:555-557.
58. Hollingworth R.M., et al. The safety of genetically modified foods produced through biotechnology. Toxicol. Sci. 2003, 71:2-8.
59. Houck J.C. The microdetermination of ribonuclease. Arch. Biochem. Biophys. 1958, 73:384-390.
60. Huang G., et al. Engineering broad root-knot resistance in transgenic plants by RNAi silencing of a conserved and essential root-knot nematode parasitism gene. Proc. Natl. Acad. Sci. USA 2006, 103:14302-14306.
61. Huntzinger E., Izaurralde E. Gene silencing by microRNAs: contributions of translational repression and mRNA decay. Nat. Rev. Genet. 2011, 12:99-110.
62. Huvenne H., Smagghe G. Mechanisms of dsRNA uptake in insects and potential of RNAi for pest control: a review. J. Insect Physiol. 2010, 56:227-235.
63. ILSI Nutritional and safety assessments of foods and feeds nutritionally improved through biotechnology: an executive summary. J. Food Science. 2004, 69:CRH62-CRH68.
64. Ivashuta S.I., et al. Endogenous small RNAs in grain: semi-quantification and sequence homology to human and animal genes. Food Chem. Toxicol. 2009, 47:353-360.
65. Jackson A.L., Linsley P.S. Recognizing and avoiding siRNA off-target effects for target identification and therapeutic application. Nat. Rev. Drug Discov. 2010, 9:57-67.
66. Jackson A.L., et al. Expression profiling reveals off-target gene regulation by RNAi. Nat. Biotechnol. 2003, 21:635-637.
67. Jackson A.L., et al. Position-specific chemical modification of siRNAs reduces "off-target" transcript silencing. RNA 2006, 12:1197-1205.
68. Jackson A.L., et al. Widespread siRNA "off-target" transcript silencing mediated by seed region sequence complementarity. RNA 2006, 12:1179-1187.
69. Jain K.K. Stability and delivery of RNA via the gastrointestinal tract. Curr. Drug Deliv. 2008, 5:27-31.
70. James C. Global status of commercialized biotech/GM crops: 2011 2011, International Service for the Acquisition of Agri-Biotech Applications, Ithaca, New York.
71. Jonas D.A., et al. Safety considerations of DNA in food. Ann. Nutr. Metab. 2001, 45:235-254.
72. Jones-Rhoades M.W., et al. MicroRNAs and their regulatory roles in plants. Annu. Rev. Plant Biol. 2006, 57:19-53.
73. Jose A.M., Hunter C.P. Transport of sequence-specific RNA interference information between cells. Annu. Rev. Genet. 2007, 41:305-330.
74. Judge A., MacLachlan I. Overcoming the innate immune response to small interfering RNA. Hum. Gene Ther. 2008, 19:111-124.
75. Khatsenko O., et al. Absorption of antisense oligonucleotides in rat intestine: effect of chemistry and length. Antisense Nucleic Acid Drug Dev. 2000, 10:35-44.
76. Konig A., et al. Assessment of the safety of foods derived from genetically modified (GM) crops. Food Chem. Toxicol. 2004, 42:1047-1088.
77. Kozak M. Circumstances and mechanisms of inhibition of translation by secondary structure in eucaryotic mRNAs. Mol. Cell. Biol. 1989, 9:5134-5142.
78. Krek A., et al. Combinatorial microRNA target predictions. Nat. Genet. 2005, 37:495-500.
79. Kusaba M., et al. Low glutelin content1: a dominant mutation that suppresses the glutelin multigene family via RNA silencing in rice. Plant Cell. 2003, 15:1455-1467.
80. Lares M.R., et al. RNAi and small interfering RNAs in human disease therapeutic applications. Trends Biotechnol. 2010, 28:570-579.
81. Lassek E., Montag A. Nucleic acid components in carbohydrate-rich food. Zeitschrift fur Lebensmittel-Untersuchung und -Forschung 1990, 190:17-21.
82. Layzer J.M., et al. In vivo activity of nuclease-resistant siRNAs. RNA 2004, 10:766-771.
83. Le L.Q., et al. Reduced allergenicity of tomato fruits harvested from Lyc e 1-silenced transgenic tomato plants. J. Allergy Clin. Immunol. 2006, 118:1176-1183.
84. Lewis D.L., Wolff J.A. Systemic siRNA delivery via hydrodynamic intravascular injection. Adv. Drug Deliv. Rev. 2007, 59:115-123.
85. Lewis B.P., et al. Prediction of mammalian microRNA targets. Cell 2003, 115:787-798.
86. Lewis B.P., et al. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 2005, 120:15-20.
87. Li L., Liu Y. Diverse small non-coding RNAs in RNA interference pathways. Methods Mol. Biol. 2011, 764:169-182.
88. Lingor P., et al. Transfection of "naked" siRNA results in endosomal uptake and metabolic impairment in cultured neurons. Biochem. Biophys. Res. Comm. 2004, 315:1126-1133.
89. Liu Q., et al. Dicer-like (DCL) proteins in plants. Funct. Integr. Genomics 2009, 9:277-286.
90. Loretz B., et al. Oral gene delivery: strategies to improve stability of pDNA towards intestinal digestion. J. Drug Target. 2006, 14:311-319.
91. Ma Z., et al. Cationic lipids enhance siRNA-mediated interferon response in mice. Biochem. Biophys. Res. Comm. 2005, 330:755-759.
92. Maeda I., et al. Large-scale analysis of gene function in Caenorhabditis elegans by high-throughput RNAi. Curr. Biol. 2001, 11:171-176.
93. Mallory A.C., Vaucheret H. Functions of microRNAs and related small RNAs in plants. Nat. Genet. 2006, 38(Suppl.):S31-S36.
94. Manjunath N., Dykxhoorn D.M. Advances in synthetic siRNA delivery. Discov. Med. 2010, 9:418-430.
95. Mao Y.B., et al. Silencing a cotton bollworm P450 monooxygenase gene by plant-mediated RNAi impairs larval tolerance of gossypol. Nat. Biotechnol. 2007, 25:1307-1313.
96. Martinez L.A., et al. Synthetic small inhibiting RNAs: efficient tools to inactivate oncogenic mutations and restore p53 pathways. Proc. Natl. Acad. Sci. USA 2002, 99:14849-14854.
97. McCarthy B.A., et al. RNA interference of IL-10 in leukemic B-1 cells. Cancer Immun. 2004, 4:6.
98. Molitoris B.A., et al. SiRNA targeted to p53 attenuates ischemic and cisplatin-induced acute kidney injury. J. Am. Soc. Nephrol. 2009, 20:1754-1764.
99. Moriyama H., et al. Stringently and developmentally regulated levels of a cytoplasmic double-stranded RNA and its high-efficiency transmission via egg and pollen in rice. Plant Mol. Biol. 1996, 31:713-719.
100. Napoli C., et al. Introduction of a chimeric chalcone synthase gene into Petunia results in reversible co-suppression of homologous genes in trans. Plant Cell 1990, 2:279-289.
101. Newmark P.A., et al. Ingestion of bacterially expressed double-stranded RNA inhibits gene expression in planarians. Proc. Natl. Acad. Sci. USA 2003, 100(Suppl 1):11861-11865.
102. Nguyen T., et al. RNAi therapeutics: an update on delivery. Curr. Opin. Mol. Ther. 2008, 10:158-167.
103. Nicklin P.L., et al. Pulmonary bioavailability of a phosphorothioate oligonucleotide (CGP 64128A): comparison with other delivery routes. Pharm. Res. 1998, 15:583-591.
104. OECD, 2001a. Consensus document on compositional considerations for new varieties of soybean: key food and feed nutrients and anti-nutrients. OECD. ENV/JM/MONO(2001) 15.
105. OECD, 2001b. Consensus document on key nutrient and key toxicants in low erucic acid rapeseed (canola). OECD. ENV/JM/MONO(2001) 13.
106. OECD, 2003. Considerations for the safety assessment of animal feedstuffs derived from genetically modified plants. OECD. ENV/JM/MONO(2003) 10.
107. OECD, 2005. An introduction to the biosafety consensus documents of OECD's working group for harmonisation in biotechnology. Series on harmonisation of regulatory oversight in biotechnology. 32.
108. OECD, 2002. Consensus Document on Compositional Considerations for New Varieties of Maize (Zea Mays): Key Food and Feed Nutrients, Anti-Nutrients and Secondary Plant Metabolites. (Organization for Economic Cooperation and Development, Paris, France) Series on the Safety of Novel Foods and Feeds, No. 6 ENV/JM/MONO(2002) 25.
109. Ogita S., et al. RNA interference: producing decaffeinated coffee plants. Nature 2003, 423:823.
110. O'Neill M.J., et al. Intestinal delivery of non-viral gene therapeutics: physiological barriers and preclinical models. Drug Discov. Today 2011, 16:203-218.
111. Osato N., et al. Antisense transcripts with rice full-length cDNAs. Genome Biol. 2003, 5:R5.
112. Pariza M.W., Johnson E.A. Evaluating the safety of microbial enzyme preparations used in food processing: update for a new century. Regul. Toxicol. Pharmacol. 2001, 33:173-186.
113. Park N.J., et al. Characterization of RNA in saliva. Clin. Chem. 2006, 52:988-994.
114. Parrott W., et al. Application of food and feed safety assessment principles to evaluate transgenic approaches to gene modulation in crops. Food Chem. Toxicol. 2010, 48:1773-1790.
115. Quark Pharmaceuticals, 2013. Quark Pharmaceuticals. <> Identifier NCT00802347 (accessed 10.01.13.). http://www.clinicaltrials.gov.
116. Redenbaugh K., et al. Safety Assessment of Genetically Engineered Fruits and Vegetables: A Case Study of the Flavr Savr (tm) Tomato 1992, CRC Press, Inc., Boca Raton, FL.
117. Regina A., et al. High-amylose wheat generated by RNA interference improves indices of large-bowel health in rats. Proc. Natl. Acad. Sci. USA 2006, 103:3546-3551.
118. Robbins M., et al. SiRNA and innate immunity. Oligonucleotides 2009, 19:89-102.
119. Rother S., Meister G. Small RNAs derived from longer non-coding RNAs. Biochimie 2011, 93:1905-1915.
120. Ryu M.H., et al. Differential regulation of hepatic gene expression by starvation versus refeeding following a high-sucrose or high-fat diet. Nutrition 2005, 21:543-552.
121. Sandy P., et al. Mammalian RNAi: a practical guide. Biotechniques 2005, 39:215-224.
122. Sioud M. On the delivery of small interfering RNAs into mammalian cells. Expert Opin. Drug Deliv. 2005, 2:639-651.
123. Sjoblad R.D., et al. Toxicological considerations for protein components of biological pesticide products. Regul. Toxicol. Pharmacol. 1992, 15:3-9.
124. Soutschek J., et al. Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs. Nature 2004, 432:173-178.
125. Tabara H., et al. RNAi in C. elegans: soaking in the genome sequence. Science 1998, 282:430-431.
126. Tay Y., et al. MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation. Nature 2008, 455:1124-1128.
127. Thompson J.D., et al. Toxicological and pharmacokinetic properties of chemically modified siRNAs targeting p53 RNA following intravenous administration. Nucleic Acid Ther. 2012, 22:255-264.
128. Tillman L.G., et al. Oral delivery of antisense oligonucleotides in man. J. Pharm. Sci. 2008, 97:225-236.
129. Timmons L., et al. Ingestion of bacterially expressed dsRNAs can produce specific and potent genetic interference in Caenorhabditis elegans. Gene 2001, 263:103-112.
130. Tomari Y., Zamore P.D. Perspective: machines for RNAi. Genes Dev. 2005, 19:517-529.
131. Tuteja J.H., et al. Tissue-specific gene silencing mediated by a naturally occurring chalcone synthase gene cluster in Glycine max. Plant Cell 2004, 16:819-835.
132. Urban-Klein B., et al. RNAi-mediated gene-targeting through systemic application of polyethylenimine (PEI)-complexed siRNA in vivo. Gene Ther. 2005, 12:461-466.
133. Vaishnaw A.K., et al. A status report on RNAi therapeutics. Silence 2010, 1:14.
134. Vazquez F. Arabidopsis endogenous small RNAs: highways and byways. Trends Plant Sci. 2006, 11:460-468.
135. Vazquez F., et al. Endogenous trans-acting siRNAs regulate the accumulation of Arabidopsis mRNAs. Mol. Cell 2004, 16:69-79.
136. Vella M.C., et al. The C. elegans microRNA let-7 binds to imperfect let-7 complementary sites from the lin-41 3'UTR. Genes Dev. 2004, 18:132-137.
137. Voinnet O. Non-cell autonomous RNA silencing. FEBS Lett. 2005, 579:5858-5871.
138. Wang J.F., et al. Identification of 20 microRNAs from Oryza sativa. Nucleic Acids Res. 2004, 32:1688-1695.
139. WHO GEMS/Food, 2013. Global Environment Monitoring System - Food Contamination Monitoring and Assessment Programme (GEMS/Food). <> (accessed 14.01.13.). http://www.who.int/foodsafety/chem/gems/en/.
140. Wiedenheft B., et al. RNA-guided genetic silencing systems in bacteria and archaea. Nature 2012, 482:331-338.
141. Yadav B.C., et al. Host-generated double stranded RNA induces RNAi in plant-parasitic nematodes and protects the host from infection. Mol. Biochem. Parasitol. 2006, 148:219-222.
142. Yoo B.C., et al. A systemic small RNA signaling system in plants. Plant Cell 2004, 16:1979-2000.
143. Zamore P., et al. RNAi: Double-stranded RNA directs the ATP-dependent cleavage of mRNA at 21 to 23 nucleotide intervals. Cell 2000, 101:25-33.
144. Zhang L., et al. Exogenous plant MIR168a specifically targets mammalian LDLRAP1: evidence of cross-kingdom regulation by microRNA. Cell Res. 2012, 22:107-126.
145. Zhang Y., et al. Purine-rich foods intake and recurrent gout attacks. Ann. Rheum. Dis. 2012, 71:1448-1453.
146. Zhang Y., et al. Analysis of plant-derived miRNAs in animal small RNA datasets. BMC Genomics 2012, 13:381.
147. Zhou J., et al. Stability in the composition equivalence of grain from insect-protected maize and seed from glyphosate-tolerant soybean to conventional counterparts over multiple seasons, locations, and breeding germplasms. J. Agric. Food Chem. 2011, 59:8822-8828.
148. Zhou X.H., et al. A 90-day toxicology study of high-amylose transgenic rice grain in Sprague-Dawley rats. Food Chem. Toxicol. 2011, 49:3112-3118.
149. Zhou X.H., et al. A three generation study with high-lysine transgenic rice in Sprague-Dawley rats. Food Chem. Toxicol. 2012, 50:1902-1910.