Biopolym. Cell. 2013; 29(4):283-294.
http://dx.doi.org/10.7124/bc.000823
Огляди
Регуляція мутагенезу екзогенними біологічними чинниками в евкаріотних клітинних системах
1Лукаш Л. Л.
  1. Інститут молекулярної біології і генетики НАН України
    Вул. Академіка Заболотного, 150, Київ, Україна, 03680

Abstract

Проаналізовано уявлення щодо природи мутацій і спонтанного мутаційного процесу, а також мутагенезу, індукованого екзогенними онковірусами, ДНК і білками-мітогенами. Екзогенні біологічні чинники індукують пошкодження ДНК регуляторно-інформаційним шляхом, діючи на системи підтримки генетичної стабільності. Молекулярні механізми мутацій такі самі, як і за спонтанного мутагенезу, але реалізуються за участі чужорідного генетичного матеріалу. Серед біогенних мутагенів виокремлюють онковіруси і мобільні генетичні елементи (МГЕ) як найсильніші дестабілізувальні фактори, що контролюють процес злоякісної трансформації соматичних клітин ссавців. Генетичне перепрограмування або зміна програм генної експресії при диференціюванні стовбурових клітин і клітин-попередників під впливом ростових факторів и цитокінів, ймовірно, також супроводжується мутаціями й рекомбінаціями.
Keywords: мутагенез, мутація, клітини евкаріотів, онковіруси, МГЕ, білок-мітоген
Повний текст: (PDF, англійською)

References

[1] Drake J. W. Looking backward on a century of mutation research Environ. Mol. Mutagen 1994 23, Suppl. 24:11–14.
[2] Ivanov V. I., Baryshnikov N. V., Bileva Dj. C., Dadali E. L., Konstantinova L. M., Kuznetsova O. V., Polyakov A. V. Genetics M: IKTs «AKADEMKNIGA», 2006 638 p.
[3] Gershenzon S. M., Aleksandrov Yu. A. Malyuta S. S. Mutagenic action of DNA and viruses at drosophila Kiev: Naukova dumka, 1975 160 p.
[4] Shapiro N. I., Marshak M. I., Varshaver N. B. Mutagenic effects of DNA-containing oncogenic viruses and malignant transformation of mammalian cells Cancer Genet. Cytogenet 1984 13, N 2:–167–179.
[5] Buzhiyevskaya T. I. Virus-induced mutagenesis Kiev: Naukova dumka,1984 134 p.
[6] Lukash LL, Buzhievskaya TI. Role of early viral genes in mutagenesis Biotechnology. Current progress Lancaster: Technomic Publ. Co. Inc., 1991:119–132.
[7] Lukash L. L. Destabilization of a cellular genome under the influence of an expression of early regulatory genes of oncoviruses Cytol. Genet 2002 36, N 2:66–68.
[8] Khesin RB. Genome instability. Moscow, Nauka, 1984; 472 p.
[9] Akif'ev A. P., Khudolii G. A. Mutagenesis and genetic homeostasis in higher organisms Vestn. Ross. Akad. Med. Nauk 1993 N 1:3–9.
[10] Zhimulev I. F. General and molecular genetics Novosibirsk: Sib. Univ. publ. house, 2003 480 p.
[11] Houle D., Kondrashov A. Mutation Evolutionary Genetics Oxford: Univ. press, 2006:32–48.
[12] Gershenson S. M., Alexandrov Yu. N. Molecular mechanisms of mutagenicity of DNA and other natural and synthetic polynucleotides Kiev: Naukova dumka, 1997 262 p.
[13] Gershenzon S. M., Aleksandrov Yu. M., Malyuta S. S., Buzhievskaya T. I., Karpova I. S., Larchenko K. A. Mutagenic action of nucleic acids and viruses Kyiv: Znannya, 1999 29 p.
[14] Grishanin A. K., Shekhovtsov A. K., Boikova T. V., Akif'ev A. P., Zhimulev I. F. Chromatin diminution at the border of the XX and XXI centuries Tsitologiia 2006 48, N 5:379–397.
[15] Feinberg A. P., Ohlsson R., Henikoff S. The epigenetic progenitor origin of human cancer Nat. Rev. Genet 2006 7, N 1 P. 21–33.
[16] Kolotova T. Yu., Volyansky A. Yu., Kuchma I. Yu. et al. Instability of a genome and epigenetic inheritance at eukaryotes Kharkiv: Oko, 2007 287 p.
[17] Rubtsov N. B., Borodin P. M. Evolution of chromosomes: from A to B and back Nature Magazine 2002 N 3:59–66.
[18] Akifyev A. P. Excess DNA – a genetic quadrature of a circle? Nature Magazine 2004 N 10:3–11.
[19] Shapiro N. I. Varshaver N. B. Rate of the spontaneous mutation process in mammalian somatic cells and several related questions Genetika 1976 12, N 7 P 132–149.
[20] Drake J. W. The distribution of rates of spontaneous mutations over viruses, prokaryotes and eukaryotes Ann. NY Acad. Sci 1999 870:100–107.
[21] Zhestyannikov V. D. DNA reparation and its biological value Leningrad: Nauka, 1979 286 p.
[22] Kholodna L. S. Imunology Kyiv: Vishcha shkola, 2007 271 p.
[23] Alekperov U. K. Antimutagenesis M: Nauka, 1984 100 p.
[24] Lukash L. L. Mutagenesis and antimutagenesis are contrary direciod processes determining the level of genetic variability and stability Biopolym. Cell 1998 14, N 6 P 500–511.
[25] Cherepenko E. I., Hovorun D. M. The updated picture of spontaneous mutagenesis could involve DNA bases tautomerism Biopolym. Cell 2007 23, N 3 P 155–166.
[26] Lukash L. L., Iatsishina A. P., Pidpala O. V., Vagina I. M, Kochubey T. P. Obtaining new lines of mouse stem cells and studying microenvironment influence on their karyotipic variability in vitro Physiology and Biochemistry of Cultural Plants 2006 38, N 2:144–152.
[27] Lukash L. L., Iatsishina A. P., Kushniruk V. O., Pidpala O. V. Reprogramming of human somatic adult cells in vitro Factors of experimental evolution of organisms Kiev: Logos, 2011 Vol. 11:493–498.
[28] Iatsyshyna A. P., Pidpala O. V., Kochubey T. P., Lukash L. L. Cytogenetical analysis of spontaneously immortalized mouse cell line Biopolym. Cell 2006 22, N 4:299–306.
[29] Akopyan G. R., Guleyuk N. L. Kushniruk V. O., Mikitenko D. M., Iatsishina A. P., Lukash L. L. Comparative analysis of karyotype of a new line of human cells in conditions of long time cultivation. 1. Ploidy of chromosomal set Tsitol. Genet. 2013 47, N 5:55–69.
[30] Iatsyshyna A. P., Lylo V. V., Pidpala O. V., Ruban T. P., Vagina I. M, Lukash L. L. The expression of O6-methylguanine-DNA methyltransferase in the spontaneously immortalized mouse cell line G1 and its sublines G1-OA and G1-T Biopolym. Cell 2007 23, N 3:250–254.
[31] Lylo V. V., Macewicz L. L., Kotsarenko E. V. et al. Activation of gene expression of the O6-methylguanine-DNA-transferase repair enzyme upon the influence of EMAP II cytokine in human cells in vitro Cytol. Genet 2011 45, N 6:373–378.
[32] Kotsarenko E. V., Lylo V. V., Macewicz L. L. et al. Change of an expression of MGMT gene for repair enzyme under the action of exogenous cytokies in human cells in vitro Cytol. Genet. 2013 47, N 4: 202-209.
[33] Zasukhina G. D. Reparation mechanisms of cells and environment problems M: Nauka, 1979 184 p.
[34] Genomics and World Health Geneva: WHO, 2002 241 p.
[35] Glasko V. I. Geneticaly modified organisms: from bacteria to the person Kiev: Ministery of Science and Education of Ukraine, 2002 210 p.
[36] Kordyum VA, Frolkis VV, Lukash LL, Shulzhenko VN, Shpilevaya SP, Kostetsky IE, Titok TG, Varsanova IS, Likhacheva LI, Irodov DM. Gene therapy of mass pathologies. Biopolym Cell. 1993; 9(4):63-104.
[37] Rumyantsev A. G. Maschan A. A. Transplantation of haemopoietic stem cells at children M: MIA, 2003 910 p.
[38] Lukash L. L. Biological mutagens: their influence on stability of eukaryotic cell systems Bull. Ukrainian Soc. Genetisists and Selectionists 2003 N 1:62–81.
[39] Lukash L. L., Buzhievskaya T. I., Varshaver N. B., Shapiro N. I. Oncogenic adenovirus as mutagen for chinese hamster cells in vitro Somatic. Cell. Genet 1981 7, N 2:133–146.
[40] Marengo C., Mbikay M., Weber I., Thirion J. P. Adenovirus-induced mutations at the hypoxanthine phosphoribosyltransferase locus of Chinese hamster cells J. Virol 1981 38, N 1 P. 184–190.
[41] Jenkins N. A., Copeland N. G., Taylor B. A., Lee B. K. Dilute (d) coat colour mutation of DBA/2J mice is associated with the site of integration of an ecotropic MuLV genome Nature 1981 293, N 5831:370–374.
[42] Varmus H. E., Quintrell N., Ortiz S. Retroviruses as mutagens: insertion and excision of a nontransforming provirus alter expression of a resident transforming provirus Cell 1981 25, N 1:23–36.
[43] Schlehofer J. R., Hausen H. Z. Induction of mutations within the host genome by partially inactivated herpes simplex virus type 1 Virology 1982 122, N 3:471–475.
[44] Pilon L., Langelier L., Royal A. Herpes simplex virus type 2 mutagenesis: characterization of mutants induced at the hprt locus of nonpermissive XC cells Mol. Cell. Biol 1986 6, N 8 P. 2977–2983.
[45] Gazaryan K. G. Microinjections of genes in zygotes and embryos: integration into a genome and genetic effects Uspekhi Sovremennoy Genetiki M.: Nauka, 1985 Vol. 13:75–88.
[46] Tarantul V. Z., Kuznetsova E. D. Gazaryan K. G. Characteristic of segments of transgenic animal genomes, adjacent to integrated sequences of foreign DNA Mol. Biol (Mosk) 1989 23, N 4:1036–1040.
[47] Gordon J. W. A foreign dihydrofolate reductase gene in transgenic mice acts as dominant mutation Mol. Cell. Biol 1986 6, N 6:2158–2167.
[48] Gabitova L. B., Nabirochkin S. D., Begetova T. V., Gazarian K. G. Induction of unstable mutations in Drosophila melanogaster by microinjections of oncogenic virus DNA into the embryo polar plasma. Prolonged genetic instability of mutations at the lobe locus Genetika 1991 27, N 4:617–624.
[49] Lukash L. L., Varshaver N. B., Buzhiyevskaya T. I., Shapiro N. I. The oncogene of BAV-3 as a mutagen J. Cell. Sci 1985 78:97–103.
[50] Sassone-Corsi P. Mutagenic activity of transforming genes Trends Genetics 1986 2:6.
[51] Manuilova E. S., Lukash L. L., Shapiro N. I. The action of the tumour promoter, TPA, on mutagenesis induced by different agents (UV light, chemical and viral mutagenesis) Mutat. Res 1987 179, N 2:231–236.
[52] Lukash L. L. Kovalenko O. A., Pidpala O. V. Influence of DNA fragments of adenovirus, containing early regulatory genes, on mutation process in mammalian cells in vitro Factors of experimental evolution of organisms Kiev: Agrarna nauka, 2003:85–90.
[53] Lukash L. L. Kovalenko O. A. Mapping of transforming and mutagen activity of adenoviruses Bull. Ukrainian Soc. Genetisists and Selectionists 2004 N 1:104–121.
[54] Durnam D. M., Smith P. P., Menninger J. C., McDougall J. K. The E1 region of human adenovirus type 12 determines the sites of virally induced chromosomal damage Cancer Cells 4: DNA tumor viruses / Eds M. Botchan et al New York: Cold Spring Harbor Lab. Press, 1986:349–354.
[55] Schramayr S., Caporossi D., Mak I., Jelinek T., Bacchetti S. Chromosomal damage induced by human adenovirus type 12 requires expression of the E1B 55-kilodalton viral protein J. Virol 1990 64, N 5:2090–2095.
[56] Zhao L. Y., Colosimo A. L., Liu Y., Wan Y., Liao D. Adenovirus E1B 55-kilodalton oncoprotein binds to Daxx and eliminates enhancement of p53-dependent transcription by Daxx J. Virol 2003 77, N 21:11809–11821.
[57] Shillitoe E. J., Zhang S., Wang G., Hwang C. B. Functions and proteins of herpes simplex virus type-1 that are involved in raising the mutation frequence of infected cells Virus Res 1993 27, N 3:239–251.
[58] Das C. M., Zhang S., Shillitoe E. J. Expression of the mutagenic peptide of herpes simplex virus type 1 in virus infected cells Virus Res 1994 34, N 2:97–114.
[59] Drize OB, Sokova OI, Nikashina EB, Shliankevich MA, Shapot VS. Possible role of the T antigen in inducing chromosome aberrations in SV40 virus-transformed cells. Tsitologiia. 1985;27(1):76-82.
[60] Baron H. M., Bobrisheva I. V., Varshaver N. B. The activated human c-Ha-ras-1 oncogene as a mutagen Cancer Genet. Cytogenet 1992 62, N 1:15–20.
[61] Bobrisheva I. V. Baron E. M. Varshaver N. B. The plasmid of pSVc-myc-1 induces gene mutations and chromosomal aberrations in cultivated Chinese hamster cells Cytol. Genet 1993 27, N 4:51–47.
[62] Bobrysheva I. V. Varshaver N. B. Characteristics of mutants induced by the c-Ha-ras1 oncogene and the nature of the oncogene's mutagenic action Genetika 1995 31, N 12:1598– 1604.
[63] Kovalenko O. O., Kostetskaia K. V., Lukash L. L. The influence of lectins of different origin on mutagenic process of mammalian somatic cells in vitro Biopolym. Cell 2006 22, N 1:33–37.
[64] Kovalenko O. O., Lukash L.L., Lukash S. I. Induction of gene mutations by lectins of different origin and cytokine EMAP II in somatic mammalian cells in vitro Biopolym. Cell 2007 23, N 5:410–415.
[65] Lukash L. L. Karpova I. S. Miroshnichenko O. S., Tikhonova T. N., Lylo V. V., Man'ko V. G., Sukhorada E. M., Golynskaia E. L.The effect of the lectin from Sambucus nigra inflorescences on spontaneous and alkylating agent-induced mutagenesis in mammalian somatic cells Tsitol. Genet 1997 31, N 5 P. 47–52.
[66] Kovalenko O. O., Lukash L. L. Antimutagenic effect of lectin and N-methyl-N'-nitro-N-nitrosoguanidine on induced mutagenesis in mammalian cells in vitro Cytol. Genet 2007 41, N 6:381–384.
[67] Travers A. DNA–protein interactions Amsterdam: Springer, 1993 180 p.
[68] Lukash L. L. Podolskaya S. V., Sukhorada H. M., Kostetskaya K. V., Kostetsky I. E., Varzanova I. S., Patskovsky Yu. V., Vavilina I. V., Deys S. V.The Influence of alkylating agent MNNG on mutagenic effect of exogeneous recombinant DNA Biopolym. Cell 1995 11, N 1:87–91.
[69] Lukash L. L. The regulation of a variability of somatic mammalian cell genome under the influence of exogeneous biological factors Biopolym. Cell 2004 20, N 1–2:93–105.
[70] Lukash L. L. Mutagenesis induced by integration processes and evolution of nuclear genome Biopolym. Cell 2007 23, N 3:172–182.
[71] Ageenko A. I. Oncogenes and carcinogenesis M.: Medicina, 1986 256 p.
[72] Shakhmuradov I. A., Kapitonov V. V., Kolchanov N. A., Omel'ianchuk L. V. Evolution of Alu repeats: dynamics of distribution in genome Genetika 1989 25, N 9:1682–1689.
[73] Lukash L. L. Shvachko L. P., Kostetskaya K. V. Mobile genetic elements in mutagenic process, recombination and malignization of human cells Biopolym. Cell 1996 12, N 2:7–19.
[74] Hoffmann J. S., Pillaire M. J., Garcia-Estefania D., Lapalu S., Villani G. In vitro bypass replication of the cisplatin-d(GpG) lesion by calf thymus DNA polymerase beta and human immunodeficiency virus type 1 reverse transcriptase is highly mutagenic J. Biol. Chem 1996 271, N 26:15386–15392.
[75] Krutyakov VM. Fidelity of DNA biosynthesis: proofreading role of mammalian autonomous 3'-5'-exonucleases. Usp Sovrem Biol. 1997; 117(6):660-7.
[76] Levin A. J. The adenovirus early proteins Curr. Top. Microbiol. and Immunol 1984 110:143–167.
[77] Huh J. J., Wolf J. K., Fightmaster D. L., Lotan R., Follen M. Transduction of adenovirus-mediated wild-type p53 after radiotherapy in human cervical cancer cells Gynecol. Oncol 2003 89, N 2:243–250.
[78] Dyachenko N. S., Nas I., Berenchi et al. Adenovirus, cell, organism Kiev: Naukova dumka, 1988 232 p.
[79] Filchenkov A.A. Stoika R. S. Apoptosis (physiological death of a cell) Kyiv: MP «VITUS», 1995 24 p.
[80] Macewicz L., Suchorada O. M., Lukash L. L. Influence of Sambucus nigra bark lectin on cell DNA under different in vitro conditions Cell Biol. Int 2005 29, N 1:29–32.
[81] Grooteclaes M., Deveraux Q., Hildebrand J., Zhang Q., Goodman R. H., Frisch S. M. C-terminal-binding protein corepresses epithelial and proapoptotic gene expression programs Proc. Natl Acad. Sci 2003 100, N 8:4568–4573.
[82] Matassa A. A., Kalkofen R. L., Carpenter L., Biden T. J., Reyland M. E. Inhibition of PKCalpha induces a PKCdelta-dependent apoptotic program in salivary epithelial cells Cell Death Differ 2003 10, N 3:269–277.
[83] Sinel'shchikova T. A., Chekova V. V., Zasukhina G. D. Mechanisms of impairment of DNA repair in human cells. Interferons stimulated DNA repair in xeroderma pigmentosum cells Genetika 1989 25, N 9:1658–1663.
[84] Pegg A. E., Dolan M. E., Moschel R. C. Structure, function, and inhibion of O6-alkylguanine-DNA-alkyltransferase Prog. Nucleic Acid Res. Mol. Biol 1995 51:167–223.
[85] Pegg A. E. Repair of O6-alkylguanine by alkyltransferases Mutat. Res 2000 462, N 2–3:83–100.
[86] Lukash L. L., Boldt J., Pegg A. E., Dolan M. E., Maher V. M., McCormick J. J. Effect of O6-alkylguanine-DNA-alkyltransferase on the frequency and spectrum of mutations induced by N-methyl-N'-nitro-N-nitrosoguanidine in the HPRT gene of diploid human fibroblasts Mutat. Res 1991 250, N 1–2 P. 397–409.
[87] Lukash L. L., Lylo V. V., Man'ko V. G., Terent'ev A. G. The increasing mutagenic effect of nitrosoguanidine under the influence of modified bases during inhibition of repair AGT enzyme in mammalian somatic cells in vitro Cytol. Genet 2002 36, N 3:38–41.
[88] McGregor W. G., Chen R. H., Lukash L. L., Maher V. M., McCormick J. J. Cell-cycle-dependent strand bias for UV-induced mutations in the transcribed strand of excision repair-proficient human fibroblasts but not in repair-deficient cells Mol. Cell Biol 1991 11, N 4:1927–1934.
[89] Lylo V. V., Piven' O. A., Serebriakova K. V., Matsevich L. L., Lukash L. L. The influence of lectins on some repair processes in mammalian cells in vitro Ukr. Biokhim. Zh 2008 80, N 6 P. 60–65.
[90] Christmann M., Verbeek B., Roos W. P., Kaina B. O6-methylguanine-DNA methyltransferase (MGMT) in normal tissues and tumors: enzyme activity, promoter methylation and immunohistochemistry Biochim. Biophys. Acta 2011 1816, N 2 P. 179–190.
[91] Iatsyshyna A. P. Current approaches to improve the anticancer chemotherapy with alkylating agents: state of the problem in world and Ukraine Biopolym. Cell 2012 28, N 2:83–92.
[92] Popov L. S., Gorbunova L. V., Varshaver N. B., Shapiro N. I. Integration of SV40 DNA into cell genome and viral mutgenesis Genetika 1986 22, N 9:2213–2219.
[93] Stabel S., Doerfler W., Friis R. R. Integration sites of adenovirus type 12 DNA in transformed hamster cells and hamster tumor cells J. Virol 1980 36, N 1:22–40.
[94] Doerfler W. Uptake, fixation and expression of foreign DNA in mammalian cells: the organization of integrated adenovirus DNA sequences Curr. Top. Microbiol. Immunol 1982 101:128–188.
[95] Kuhlmann I., Achten S., Rudolph R., Doerfler W. Tumor induction by human adenovirus type 12 in hamsters: loss of the viral genome from adenovirus type 12-induced tumor cells is compatible with tumor formation EMBO J 1982 1, N 1:79–86.
[96] Gahlman R., Doerfler W. Integration of viral DNA into the genome of the adenovirus type 2-transformed hamster cell line HE5 without loss or alteration of cellular nucleotides Nucleic Acids Res 1983 11, N 21:7347–7361.
[97] Kuhlmann I., Doerfler W. Loss of viral genomes from hamster tumor cells and nonrandom alterations in patterns of methylation of integrated adenovirus type 12 DNA J. Virol 1983 47, N 3:631–636.
[98] Schultz M., Doerfler W. Detection of cellular DNA at site of viral DNA insertion in the adenovirus type 12-induced mouse tumor CBA-12-1-T Nucleic Acids Res 1984 12, N 12 P. 4959– 4976.
[99] Pidpala O. V., Iatsishina A. P., Lukash L. L. Human mobile genetic elements: Structure, distribution and functional role Cytol. Genet 2008 42, N 6:420–430.
[100] Pidpala O. V., Iatsishina A. P., Lukash L. L. Potentional cis-elements ALUSP-repeat on the promotor of MGMT gene Factors of experimental evolution of organisms Kyiv: Logos, 2009 Vol. 7:43–47.
[101] Ratner V. A., Zabanov S. A., Kolesnikova O. V., Vasilyeva L. A. Induction of the mobile genetic element Dm-412 transtositions in the Drosophila genome by heat shock treatment Proc. Nat. Acad. Sci. USA 1992 89, N 12:5650–5654.
[102] Deininger P. L., Moran I. V., Batzer M. A., Kazazian H. H., Jr. Mobile elements and mammalian genome evolution Curr. Opin. Genet. Dev 2003 13, N 6:651–658.
[103] Edwards A., Voss H., Rice P. et al. Automated DNA sequencing of the human HPRT locus Genomics 1990 6, N 4:593–608.
[104] Lukash S. I., Lukash L. L., Zadorozhnyi V. F. Mathematical model of mutagenesis dynamics under the action of adenovirus DNA fragment Biopolym. Cell 1996 12, N 3:7–16.
[105] Lukash S. I., Lukash L. L. The influence of heterogeneity of somatic mammalian cell system on mutagenesis manifestation induced by transforming genes of adenovirus Biopolym. Cell 1996 12, N 6:25–35.
[106] Popov B. V. Introduction into the cell biology of stem cells Saint-Petersburg: SpezLit, 2010 319 p.
[107] Lukash L. L. Cell therapy of heart pathologies Biotechnology 2008 1, N 1:40–45.
[108] Shablyi V. A., Kuchma M. D., Onishchenko A. N., Lukash L. L., Lobintseva G. S. Cryoconservation of human placental tissue as source of hematopoietic progenitor cells and multipotent mesenchymal stromal cells Cell Transplantology and Tissue Engineering 2012 7, N 1:54–62.
[109] Piven O. O., Kostetskii I. E., Macewicz L. L., Kolomijec Y. M., Radice G. L., Lukash L. l. Requirement for N-cadherin-catenin complex in heart development Exp. Biol. Med. (Maywood) 2011 236, N 6:816–822.
[110] Cervantes R. B., Stringer J. R., Shao C., Tischfield J. A., Stambrook P. J. Embryonic stem cells and somatic cells differ in mutation frequency and type Proc. Natl Acad. Sci. USA 2002 99, N 6:3586–3590.
[111] Denisenko S. V., Daryi A. S., Kononenko M., Zerova-Lyubimova T. E. Genetics of reproduction Kyiv: Ferz TA, 2008 650 p.
[112] Kordium V. A. Mutations: what are they? Biopolym. Cell 2007 23, N 3:215–242.
[113] Cherepenko E. I. Molecular protection mechanisms of a cell and farmacotherapy Kiev: Naukova dumka, 2012 261 c.
[114] Breiden G. Matrix of consciousness Sofiya: Izd-vo Sofiya, 2008 255 p.