Vol 4, No 1 (2012)


Letter from the Editors

Acta Naturae -.



Acta Naturae. 2012;4(1):1-1
pages 1-1 views

Guidelines for Authors

Acta Naturae -.


Actae Naturae publishes experimental articles and reviews, as well as articles on topical issues, short reviews, and reports on the subjects of basic and applied life sciences and biotechnology. The journal is published by the Park Media publishing house in both Russian and English. The journal Acta Naturae is on the list of the leading periodicals of the Higher Attestation Commission of the Russian Ministry of Education and Science.

Acta Naturae. 2012;4(1):107-108
pages 107-108 views


Molecular Mechanisms of Induced Pluripotency

Muchkaeva I.A., Dashinimaev E.B., Terskikh V.V., Sukhanov Y.V., Vasiliev A.V.


In this review the distinct aspects of somatic cell reprogramming are discussed. The molecular mechanisms of generation of induced pluripotent stem (iPS) cells from somatic cells via the introduction of transcription factors into adult somatic cells are considered. Particular attention is focused on the generation of iPS cells without genome modifications via the introduction of the mRNA of transcription factors or the use of small molecules. Furthermore, the strategy of direct reprogramming of somatic cells omitting the generation of iPS cells is considered. The data concerning the differences between ES and iPS cells and the problem of epigenetic memory are also discussed. In conclusion, the possibility of using iPS cells in regenerative medicine is considered.

Acta Naturae. 2012;4(1):12-22
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Regulation of Immunity via Multipotent Mesenchymal Stromal Cells

Rubtsov Y.P., Suzdaltseva Y.G., Goryunov K.V., Kalinina N.I., Sysoeva V.Y., Tkachuk V.A.


Immune cells responsible for inflammation development are involved in tissue damage caused by wounding and various pathologies. Control of immune cell activation could be of significant benefit for regenerative medicine and the treatment of patients with autoimmune and degenerative diseases. It is a proven fact that MCSs (multipotent mesenchymal stromal cells) are capable of suppressing immune responses via the inhibition of dendritic cell maturation and via the restraining of the T, B, and NK cell function in the course of autoimmune diseases and various forms of inflammation. MSCs can be isolated easily from almost every type of tissue or organ and subsequently expanded in vitro. These cells are self-renewable and can be differentiated into various cell types of mesenchymal lineage. The current review contains a collection and critical analysis of data regarding the molecular mechanisms responsible for cross-talk between immune cells and MSCs. Some of these mechanisms can be used for the development of new practical approaches for the treatment of autoimmune diseases.

Acta Naturae. 2012;4(1):23-31
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Research Articles

Analogues of Artificial Human Box C/D Small Nucleolar RNA As Regulators of Alternative Splicing of a pre-mRNA Target

Stepanov G.A., Semenov D.V., Kuligina E.V., Koval O.A., Rabinov I.V., Kit Y.Y., Richter V.A.


Small nucleolar RNAs (snoRNAs) play a key role in ribosomal RNA (rRNA) biogenesis. Box C/D snoRNAs guide the site-specific 2’-O-ribose methylation of nucleotides in rRNAs and small nuclear RNAs (snRNAs). A number of box C/D snoRNAs and their fragments have recently been reported to regulate post-transcriptional modifications and the alternative splicing of pre-mRNA. Artificial analogues of U24 snoRNAs directed to nucleotides in 28S and 18S rRNAs, as well as pre-mRNAs and mature mRNAs of human heat shock cognate protein (hsc70), were designed and synthesized in this study. It was found that after the transfection of MCF-7 human cells with artificial box C/D RNAs in complex with lipofectamine, snoRNA analogues penetrated into cells and accumulated in the cytoplasm and nucleus. It was demonstrated that the transfection of cultured human cells with artificial box C/D snoRNA targeted to pre-mRNAs induce partial splicing impairments. It was found that transfection with artificial snoRNAs directed to 18S and 28S rRNA nucleotides, significant for ribosome functioning, induce a decrease in MCF-7 cell viability.

Acta Naturae. 2012;4(1):32-41
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Risk of HIV Infection and Lethality Are Decreased in CCR5del32 Heterozygotes: Focus Nosocomial Infection Study and Meta-analysis

Borinskaya S.A., Kozhekbaeva Z.M., Zalesov A.V., Olseeva E.V., Maksimov A.R., Kutsev S.I., Garaev M.M., Rubanovich A.V., Yankovsky N.K.


CCR5del32 Homozygous deletion in the chemokine receptor R5 gene provides almost complete protection to individuals against HIV infection. However, data relating to the protective effect for CCR5del32 heterozygous individuals have been contradictory. The frequency of the CCR5del32 allele in population control cohorts was compared with that of a group of children (27 Kalmyks and 50 Russians) infected by G-subtype HIV-1 in a nosocomial outbreak. The frequency of the CCR5del32 allele was shown to be lower among the infected children in comparison with that of the control group; however, the difference was small and statistically insignificant. Similar results were obtained in a number of earlier studies. The insignificance of the small differences could be a result of one of two reasons. (i) The fact that there is no protective effect of the heterozygous state, and that the phenomenon depends only on the fluctuation of allele frequencies. In this case, there would be no differences even if the infected cohort is enlarged. (ii)The protective effect of the heterozygous state is real; however, the size of the studied cohort is insufficient to demonstrate it. In order to discern between these two reasons, a meta-analysis of data from 25 published articles (a total of 5,963 HIV-infected individuals and 5,048 individuals in the control group, including the authors’ own data) was undertaken. A conclusion was drawn from the meta-analysis that the CCR5del32 allele protects individuals against the HIV infection even in a heterozygous state (OR=1.22, 95%CI=1.10-1.36). The risk of HIV infection for CCR5 wt/del32 heterozygotes was lower by at least 13% as compared to that for wild type CCR5 wt/wt homozygotes. Prior to this study, no data of the type or any conclusions had been published for Caucasians. The mortality rate in the 15 years following the infection was found to be approximately 40% lower for CCR5del32 heterozygotes in comparison with that for the wild type homozygotes in the studied group. The size of the studied group was insufficient to claim difference validity (OR=2.0; p= 0.705), even though the effect quantitatively matched the published data. The features of the meta-analysis influencing the threshold level and the statistical validity of the effects are being discussed. The level of the CCR5del32 protective effect on the chances to be infected with HIV and on the outcome of the HIV infection was assessed for various ethnic groups.

Acta Naturae. 2012;4(1):42-52
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The Genetic Diversity and Structure of Linkage Disequilibrium of the MTHFR Gene in Populations of Northern Eurasia

Trifonova E.A., Eremina E.R., Urnov F.D., Stepanov V.A.


The structure of the haplotypes and linkage disequilibrium (LD) of the methylenetetrahydrofolate reductase gene (MTHFR) in 9 population groups from Northern Eurasia and populations of the international HapMap project was investigated in the present study. The data suggest that the architecture of LD in the human genome is largely determined by the evolutionary history of populations; however, the results of phylogenetic and haplotype analyses seems to suggest that in fact there may be a common “old” mechanism for the formation of certain patterns of LD. Variability in the structure of LD and the level of diversity of MTHFR haplotypes cause a certain set of tagSNPs with an established prognostic significance for each population. In our opinion, the results obtained in the present study are of considerable interest for understanding multiple genetic phenomena: namely, the association of interpopulation differences in the patterns of LD with structures possessing a genetic susceptibility to complex diseases, and the functional significance of the pleiotropic MTHFR gene effect. Summarizing the results of this study, a conclusion can be made that the genetic variability analysis with emphasis on the structure of LD in human populations is a powerful tool that can make a significant contribution to such areas of biomedical science as human evolutionary biology, functional genomics, genetics of complex diseases, and pharmacogenomics.

Acta Naturae. 2012;4(1):53-69
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Hansenula Polymorpha TERT: A Telomerase Catalytic Subunit Isolated in Recombinant Form with Limited Reverse Transcriptase Activity

Smekalova E.M., Petrova O.A., Zvereva M.I., Dontsova O.A.


Telomerase is a ribonucleoprotein, the main function of which is to synthesize telomeres, i.e. repetitive sequences which are localized at the ends of eukaryotic chromosomes. Telomerase maintains the stability of the genome in eukaryotic cells by replicating chromosomal ends. The structural and functional investigation of the telomerase complex is significantly restricted due to difficulties connected with the isolation of its main catalytic subunit in recombinant form. Herein, we describe a method developed for the isolation of the recombinant telomerase reverse transcriptase from thermotolerant yeast Hansenula polymorpha. A functional test performed for the isolated protein and the RNA/DNA duplex, simulating the interaction of telomerase RNA and telomere, reveals that the isolated catalytic subunit of telomerase possesses limited reverse transcriptase activity.

Acta Naturae. 2012;4(1):70-73
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Conformational Differences between Active Angiotensins and Their Inactive Precursors

Solopova O.N., Pozdnyakova L.P., Varlamov N.E., Bokov M.N., Morozkina E.V., Yagudin Т.А., Sveshnikov P.G.


The peptide conformation in the context of a protein polypeptide chain is influenced by proximal amino acid residues. However, the mechanisms of this interference remain poorly understood. We studied the conformation of angiotensins 1, 2 and 3, which are produced naturally in a sequential fashion from a precursor protein angiotensinogen and contain an identical peptide core structure. Using the example of angiotensins 1, 2 and 3, it was shown that similar amino acid sequences may have significant conformational differences in various molecules. In order to assess the conformational changes, we developed a panel of high-affinity mouse monoclonal antibodies against angiotensins 1, 2 and 3 and studied their cross-reactivity in indirect and competitive ELISAs. It was found that the conformations of inactive angiotensin1 and the corresponding fragment of angiotensinogen are similar; the same is true for the conformations of active angiotensins 2 and 3, whereas the conformations of homologous fragments in the active and inactive angiotensins differ significantly.

Acta Naturae. 2012;4(1):74-77
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Monitoring of the Zeta Potential of Human Cells upon Reduction in Their Viability and Interaction with Polymers

Bondar O.V., Saifullina D.V., Shakhmaeva I.I., Mavlyutova I.I., Abdullin T.I.


The dynamic light scattering (DLS) technique was applied in order to assess the zeta potential of the plasma membrane of human cells. At pH 7.4, the cell zeta potential for different types of cells showed variations over a wide range and was equal to -19.4 ± 0.8 mV for HeLa cells and -31.8 ± 1.1 mV for erythrocytes. The difference could presumably be attributed to the differences in the biochemical composition of the cell plasma membrane. As a result of the heating of HeLa cells, the zeta potential shifted towards more negative voltages by 4.2 mV. An increase in the zeta potential correlated with an increase in the content of phosphatidylserine on the cell surface, which is considered to be an early marker of apoptosis. The DLS technique was also used to study the interactions between the cells and membranotropic polymers, such as polycations and nonionogenic Pluronic L121.

Acta Naturae. 2012;4(1):78-81
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Targeted Therapy: A New Approach for the Treatment of Locally Advanced Oropharyngeal Cancer

Velsher L.Z., Kosmynin A.A., Byakhov M.Y., Duditskaya T.K., Reshetov D.N.


Presented herein is a clinical study comprising 48 patients (42 men and 6 women) of working age (40-70 years), all of whom are suffering from locally advanced oropharyngeal cancer. A modern approach is applied to treat these patients, i.e., neoadjuvant targeted therapy, taking into account the biological profile of the tumor. The use of gefitinib causes an antitumor effect in 90.5% of cases as opposed to 56.5% when no drug is applied.

Acta Naturae. 2012;4(1):82-85
pages 82-85 views

Cytotoxic and Immunochemical Properties of Viscumin Encapsulated in Polylactide Microparticles

Kolotova E.S., Egorova S.G., Ramonova A.A., Bogorodski S.E., Popov V.K., Agapov I.I., Kirpichnikov M.P.


Biodegradable polylactide microparticles with encapsulated cytotoxic protein viscumin were obtained via the ultrasound-assisted supercritical fluid technique. The size of the microparticles was 10-50 μМ, as shown by electron microscopy. The time course of viscumin release from microparticles was studied using an immunoenzyme test system with anti-viscumin monoclonal antibodies. It was found that 99.91% of the cytotoxic protein was incorporated into polymer microparticles. Only 0.08% of the initially encapsulated viscumin was released from the microparticles following incubation for 120 h in a phosphate-buffered saline at neutral pH. Importantly, the method of ultrasonic dry supercritical fluid encapsulation failed to alter both the cytotoxic potency and the immunochemical properties of the encapsulated viscumin. Thus, this procedure can be used to generate biodegradable polylactide microparticles with encapsulated bioactive substances.

Acta Naturae. 2012;4(1):101-106
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Stable Expression of Recombinant Factor VIII in CHO Cells Using Methotrexate-Driven Transgene Amplification

Orlova N.A., Kovnir S.V., Vorobiev I.I., Yuriev A.S., Gabibov A.G., Vorobiev A.I.


Prophylaxis and treatment of inherited clotting disorder hemophilia A requires regular administration of factor VIII. Recombinant factor VIII, which is produced in CHO or BHK cells, is equivalent to the plasma derived one and is prevalent in current clinical practice in developed countries. Development of a biosimilar recombinant FVIII requires the creation of a highly productive clonal cell line and generation of monoclonal antibodies suitable for affinity purification of the product. Methotrexate-driven transgene amplification of genetic cassettes that code full-length and truncated variants of FVIII under the control of the CMV promoter was studied. It was shown that the expression level of the truncated variant of FVIII is 6.5 times higher than that of the full-length molecule. The transgene amplification procedure was sufficient for a twofold increase of the expression level in the transfected cells pool and subsequent selection of the clonal line, stably producing truncated FVIII at the level of 0.52 IU/ml during cultivation in a chemically defined protein-free culture medium. Four generated mouse monoclonal antibodies toward the heavy chain of FVIII were found suitable for binding the truncated variant of FVIII directly from the conditioned medium and elution of the FVIII with a more than 85% yield and normal pro-coagulant activity. The producer cell line and monoclonal antibodies obtained are sufficient for the development of upstream and downstream processes of biosimilar FVIII production. Generation of more productive cell lines by the use of stronger, nonviral promoters and shorter cDNA of FVIII will be the subject of further studies.

Acta Naturae. 2012;4(1):93-100
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Correction of Long-Lasting Negative Effects of Neonatal Isolation in White Rats Using Semax

Volodina M.A., Sebentsova E.A., Glazova N.Y., Manchenko D.M., Inozemtseva L.S., Dolotov O.V., Andreeva L.A., Levitskaya N.G., Kamensky A.A., Myasoedov N.F.


Adverse experience during the early postnatal period induces negative alterations in physiological and neurobiological functions, resulting in long-term disorder in animal behavior. The aim of the present work was to study the long-lasting effects of chronic neonatal stress in white rats and to estimate the possibility of their correction using Semax, an analogue of ACTH fragment (4-10). Early neonatal isolation was used as a model of early-life stress. Rat pups were separated from their mothers and littermates for 5 h daily during postnatal days 1-14. The pups of the control group were left undisturbed with the dams. Half of the rats subjected to neonatal isolation received an intranasal injection of Semax at a dose of 50 μg/kg daily, from postnatal day 15 until day 28. The other animals received intranasal vehicle injections daily at the same time points. It was shown that neonatal isolation leads to a delay in physical development, metabolic disturbances, and a decrease in the corticosterone stress response in white rats. These changes were observed during the first two months of life. Semax administration weakened the influence of neonatal isolation on the animals, body weight , reduced metabolic dysfunction, and led to an increase in stress-induced corticosterone release to the control values. So the chronic intranasal administration of Semax after termination of the neonatal isolation procedure diminishes the negative effects of neonatal stress.

Acta Naturae. 2012;4(1):86-92
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The 110th Anniversary of Academician Alexander Evseevich Braunstein

Demidkina T.V.



Acta Naturae. 2012;4(1):6-8
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V. Richter: "The low toxicity and originality of the pharmaceutical agent are its major advantages"

Richter V.A.


There is no question that the government needs to provide vigorous financial support to Russian researchers looking to design new drugs. A different question is to what extent should the government participate in the financing and at
what point should industrial investors join in?

Acta Naturae. 2012;4(1):9-11
pages 9-11 views

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