[How Histone Deacetylase 3 Controls Hepcidin Expression and Hepatitis C Virus Replication].

The key role of histone deacetylases (HDAC) in the regulation of the cellular response to infection with the hepatitis C virus (HCV) was first demonstrated in 2008. When studying the metabolism of iron in the liver tissues of patients with chronic hepatitis C, the authors found that the expression of the hepcidin gene (HAMP), a hormone regulator of iron export, is markedly reduced in hepatocytes under conditions of oxidative stress caused by viral infection. HDAC were involved in the regulation of hepcidin expression through the control of acetylation level of histones and transcription factors, primarily STAT3, associated with the HAMP promoter. The purpose of this review was to summarize current data on the functioning of the HCV-HDAC3-STAT3-HAMP regulatory circuit as an example of a well-characterized interaction between the virus and the epigenetic apparatus of the host cell.

Selective inhibitor of histone deacetylase 6 (tubastatin A) suppresses proliferation of hepatitis C virus replicon in culture of human hepatocytes.

Acetylation of α-tubulin was studied in cultures of human hepatocytes under the influence of selective inhibitors of histone deacetylases HDAC6 and SIRT-2 - tubastatin A and 2-(3-phenethoxyphenylamino)benzamide, respectively. It was found that in hepatocyte cell line HepG2 acetylated α-tubulin is accumulated preferentially on inhibition of HDAC6 but not of SIRT-2. Under the same conditions, no acetylation of α-tubulin was observed in hepatocyte cell line Huh7. However, the inhibition of HDAC6 with tubastatin A led to hyperacetylation of α-tubulin and simultaneously to decrease in viral RNA concentration in hepatocyte cell line Huh7-luc/neo, which supports propagation of the full genome replicon of hepatitis C virus. The correlation between these two processes points to HDAC6 as a promising cellular target for therapy of hepatitis C.

[A new approach to analysis of participation of oxidative processes in regulation of metabolism in animal tissues].

A new approach to the analysis of the oxidative processes participated in regulation of metabolism in norm and the assessment of the biological consequences under the action of damaging factors of different nature and intensity for animal groups is suggested using the analysis of interrelations between the different parameters of the physicochemical regulatory system of the lipid peroxidation in tissues of the laboratory mice (the phospholipid composition, amounts of the oxidation products in lipids). by changes of the scale and direction of interrelations between the reciprocal parameters of the lipid peroxidation system in norm.

[New synthesis of highly selective inhibitor of histone deacetylase 6--N-hydroxy-4-(2-methyl-1,2,3,4-tetrahydro-pyrido[4,3b]indol-5-ylmethyl)benzamide--Tubastatin A].

A four-stage synthesis of highly selective inhibitor of histone deacetylase 6--Tubastatin A was carried out. Convenient and safety reaction conditions were used throughout the synthesis.

[Significance of the initial state of the murine liver for the development of consequences after the combined action of the factors of different nature].

The search of the most significant parameters of the liver initial state of mice Balb/c (males) for the development of the biological consequences under a combined action of the Tween-80 (0.3% solution) in the 10% solution of the aqueous acetone and X-rays at the doses of 4 and 5 Gy during one month after exposure was performed by means of the software program for the experimental data analysis. The study has shown both the absence of the same correlation relationships and the existence of two groups of relationships in terms of the coefficient correlation values under the alteration of the X-ray dose. The assumption has been made about different mechanisms underlying regulation of the biochemical process in the murine liver after the combined action of low-toxicity chemical agents at low doses and X-rays irradiation at sublethal doses, whose contribution to the development of effects of different factors depends on the radiation dose.

[Change of the lipid parameters in the murine liver during one month after low intensity X-ray exposure at low doses].

Parameters of the physicochemical regulatory system of lipid peroxidation in the liver of white outbred mice (females) were studied before and during one month after X-ray exposure at the doses less than 1.5 mGy in the autumn and spring-summer seasons. The initial value of parameters is found to exert the most substantial influence on the liver relative mass, the phosphatidylcholine and lysoform relative content in the liver phospholipids of mice. The reliable diminution and the substantial influence of the dose rate dynamics during irradiation are revealed for the molar ratio of [sterols]/[phospholipids], the phosphatidylcholine/phosphatidylethanolamine ratio and the ratio of sums of the more easily oxidizable to the more poorly oxidizable fractions ofphospolipids. The experimental data testify to the complicated nonlinear character of the biological effects of X-irradiation at low doses.

[Surface active properties of isobornylphenols in systems with different degrees of complexity].

Interrelations between the structure of the semi-synthetic phenolic antioxidants -- isobornylphenols and their surface active properties were studied in the chemical (the lecithin aggregation in hexane) and biological (the incubation with the blood erythrocytes) model systems. It has been shown that all studied compounds are able to affect the lecithin aggregation in hexane: the share of the main fraction of the L micelles decreases with increasing the share of particles of greater size. The effect substantially depends on hindered OH group and the presence of the intramolecular hydrogen bond in molecule. The cytotoxic properties of isobornylphenols (the concentration is 100 M) are predominantly due to the molecule structure. The interrelation between the aggregate size of the main fraction of L in the presence of the studied compounds and the discocyte share during mice blood erythrocyte incubation in their presence for 4 h is revealed. Thus, this provides the possibility to assume that the ability of the different biological active substances to affect the lecithin aggregation in non-polar solvent could be used as a model system for the initial assessment of their surface active properties.

[Effect of physicochemical properties of murine liver lipids on the interrelation between the parameters of their composition].

The effect of properties of liver lipids on the interrelation between the contents of different lipid fractions has been studied on nine groups of intact SHK female mice. To reveal interrelations, lipids were divided into four groups depending on their antioxidative activity, prooxidant properties, antiperoxide activity, and the content of peroxide in lipids. The data obtained indicate that the physicochemical properties of lipids affect the biosynthesis and degradation of phospholipids, which plays a significant role in the origination of consequences under the action of unfavourable factors on biological objects having the different intensity of oxidative processes.

[Influence of the lipid characteristics on the age changes of the interrelation in the metabolic regulatory system of the laboratory murine tissues].

The age changes of the lipid physicochemical characteristics in tissues of the laboratory mice were studied. The reliable age changes of the phospholipid composition in the liver and brain of outbreed mice were revealed. The conclusion was done about the influence of the physicochemical characteristics of lipids on the regulation of the biochemical processes in the animal organism. This is necessary to remember by the analysis of the age changes in the murine tissues and the investigation of the aging mechanism.

Mountain birch under multiple stressors--heavy metal-resistant populations co-resistant to biotic stress but maladapted to abiotic stress.

Stress adaptations often include a trade-off of weakened performance in nonlocal conditions, resulting in divergent selection, and potentially, genetic differentiation and evolutionary adaptation. Results of a two-phase (greenhouse and field) common garden experiment demonstrated adaptation of mountain birch (Betula pubescens subsp. czerepanovii) populations from industrially polluted areas of the Kola Peninsula, north-western Russia, to heavy metals (HM), whereas no adaptations to wind or drought stress were detected in populations from wind-exposed sites. HM-adapted seedlings were maladapted to drought but less palatable (co-resistant) to insect herbivores, even under background HM concentrations. The absence of adaptations to harsh microclimate and the generally high adaptive potential of mountain birch, a critical forest forming tree in subarctic Europe, need to be accounted for in models predicting consequences of human-driven environmental changes, including the projected climate change.

RNA-dependent RNA polymerase of hepatitis C virus: study on inhibition by alpha,gamma-diketo acid derivatives.

It is supposed that alpha,gamma-diketo acids (DKAs) inhibit the activity of hepatitis C virus RNA-dependent RNA polymerase (RdRP HCV) via chelation of catalytic magnesium ions in the active center of the enzyme. However, DKAs display noncompetitive mode of inhibition with respect to NTP substrate, which contradicts the proposed mechanism. We have examined the NTP substrate entry channel and the active site of RdRP HCV for their possible interaction with DKAs. The substitutions R48A, K51A, and R222A greatly facilitated RdRP inhibition by DKAs and simultaneously increased K(m) values for UTP substrate. Interestingly, C223A was the only one of a number of substitutions that decreased K(m)(UTP) but facilitated the inhibitory action of DKAs. The findings allowed us to model an enzyme-inhibitor complex. According to the proposed model, DKAs introduce an additional Mg2+ ion into the active site of the enzyme at a stage of phosphodiester bond formation, which results in displacement of the NTP substrate triphosphate moiety to a catalytically inactive binding mode. This mechanism, in contrast to the currently adopted one, explains the noncompetitive mode of inhibition.

Mycorrhizal colonisation of mountain birch (Betula pubescens ssp. czerepanovii) along three environmental gradients: does life in harsh environments alter plant-fungal relationships?

Environmental stress affects ectomycorrhizal communities (ECM), but it is not known how general the detected ECM responses are. We investigated ECM fungi on roots of mountain birch, Betula pubescens subsp. czerepanovii (Orlova) Hämet-Ahti, along three environmental gradients, two natural (altitude, seashore) and one human-induced (pollution), within the Kola Peninsula, NW Russia. Chlorophyll fluorescence of birch leaves indicated no environmental stress even in the conditions that were presumed most stressful in terms of abiotic environment, where the biomass and population density of birches were strongly reduced. Although neither overall ECM colonisation nor root fungal biomass showed stress-related patterns, colonisation by Cenococcum geophilum tended to decrease with abiotic stress. ECM morphotype diversity declined with abiotic stress, and along altitudinal gradient this decline was related to an increase in proportion of morphotypes with high fungal biomass. Polycormic birches had higher ECM colonisation than monocormic birches at high stress sites only. ECM morphotype diversity increased with foliar nitrogen concentration at low stress sites, but not at high stress sites. Birches with higher chlorophyll fluorescence had lower chitin concentration in their roots (indicating lower proportion of fungal structures) at high stress sites only. Our results suggest that at high stress sites (1) mechanical shelter created by polycormic trees may favour ECM fungi and (2) mountain birches maintain lower ECM diversity than at low stress sites.

[Changes in the lipid peroxidation systems in tissues from various rodent species during aging].

The comparative investigation of parameters of the physicochemical regulatory system of the lipid peroxidation (LPO) in liver, spleen and blood components of laboratory rodents of 5 strains and species was carried out. The interrelation between the LPO intensity and the cell-free DNA content in the blood plasma of mice has been shown. The absence of the same type and direct changes of the LPO regulatory system parameters during aging was shown. This is due to modifying effect of those factors as season, the lipid evalability by antioxidants, the species and sex of rodent, diet on the lipid exchange.

[The influence of damage factors of the different nature on the lipid composition in the mice liver].

The combined effect of the X-rays at the dose of 4 and 5 Gy and the Tween 80 (the 0.3% solution) in the 10% solution of the water acetone on the lipid composition in the mice Balb/c liver is studied after 1 month. It is revealed that the disturbance of the linear dependence of "biological effect-dose" is due to the enhancement of the action of the acute X-rays with sublethal doses after the preliminary administration of the low toxic chemical agents at low doses on the lipid composition of the mice liver. The decrease of differences in the scale of the correlation between the generalized phospholipid composition parameters in the mice liver after combined action of the chemical and physical factors is shown. The interrelation between the mice Balb/c survival and the ratio of the general phospholipid fractions of the lipid liver in the age control groups is found.

[Interconnection of parameters of regulation system of lipid peroxidation and of morphophysiological parameters of mouse liver].

A complex analysis of seasonal fluctuations of the mean group parameters of the system of regulation of lipid peroxidation has been performed in liver of Balb/c mice. Association of lipid characteristics and morphophysiological parameters is studied in the Balb/c mouse liver. An interconnection is revealed between the liver index and the amount of lysoforms of phospholipids, the scale and character of the interconnection differing essentially depending on proportion of phosphatidylcholine in mouse liver phospholipids.

[Influence of the characteristics of lipids on the regulation of biochemical processes in animal liver and blood].

It has been established experimentally that the character and the scale of interrelations between various parameters of the phospholipid composition and their group-average values depend significantly on the characteristics of lipids (the antioxidative activity, quantity of peroxides, and antiperoxide activity) of animal liver and blood erythrocytes. It was shown that a single injection of low-toxicity Tween 80 and acetone at low doses modifies the intensity of lipid peroxidation in the liver and changes the physicochemical properties of lipids, and the interrelations between the parameters that are coordinated in norm, thereby causing the disturbance of biochemical functions of the liver.

Combined effects of environmental disturbance and climate warming on insect herbivory in mountain birch in subarctic forests: Results of 26-year monitoring.

Both pollution and climate affect insect-plant interactions, but the combined effects of these two abiotic drivers of global change on insect herbivory remain almost unexplored. From 1991 to 2016, we monitored the population densities of 25 species or species groups of insects feeding on mountain birch (Betula pubescens ssp. czerepanovii) in 29 sites and recorded leaf damage by insects in 21 sites in subarctic forests around the nickel-copper smelter at Monchegorsk, north-western Russia. The leaf-eating insects demonstrated variable, and sometimes opposite, responses to pollution-induced forest disturbance and to climate variations. Consequently, we did not discover any general trend in herbivory along the disturbance gradient. Densities of eight species/species groups correlated with environmental disturbance, but these correlations weakened from 1991 to 2016, presumably due to the fivefold decrease in emissions of sulphur dioxide and heavy metals from the smelter. The densities of externally feeding defoliators decreased from 1991 to 2016 and the densities of leafminers increased, while the leaf roller densities remained unchanged. Consequently, no overall temporal trend in the abundance of birch-feeding insects emerged despite a 2-3°C elevation in spring temperatures. Damage to birch leaves by insects decreased during the observation period in heavily disturbed forests, did not change in moderately disturbed forests and tended to increase in pristine forests. The temporal stability of insect-plant interactions, quantified by the inverse of the coefficient of among-year variations of herbivore population densities and of birch foliar damage, showed a negative correlation with forest disturbance. We conclude that climate differently affects insect herbivory in heavily stressed versus pristine forests, and that herbivorous insects demonstrate diverse responses to environmental disturbance and climate variations. This diversity of responses, in combination with the decreased stability of insect-plant interactions, increases the uncertainty in predictions on the impacts of global change on forest damage by insects.

[Etiology of pulmonary diseases in children in Khabarovsk Region].

Microflora of upper respiratory tract in 658 children aged 1 month - 17 years hospitalized with acute pneumonia (AP), acute bronchitis (AB), recurrent obstructive bronchitis (ROB), malformation of lungs (ML) and broncho-alveolar dysplasia (BALD) were studied. Carriage rates of Streptococcus pneumoniae (up to 95%) and Haemophilus influenzae (up to 89%) in 240 children attending daycare centers and schools were determined. Etiology of infectious process was ascertained in 40% of cases. S. pneumoniae was isolated in 45% of acute cases (AP and AB) and in 25% of chronic cases (BALD). H. influenzae was isolated in 8 - 12% of acute cases and in 32% of chronic cases. In 23 - 29% of all cases of pulmonary pathology in children persistence of Enterococcus faecium was determined. There were 13 different serotypes among isolated pneumococci. In patients with pneumonia the rate of detection of S. pneumoniae and H. influenzae DNA fragments by PCR was significantly higher compared with rate of their isolation from sputum.

[Pseudoreplication, chatter, and the international nature of science: a response to D.V. Tatarnikov].

The commentary by Tatarnikov (2005) on the design and analysis of manipulative experiments in ecology represents an obvious danger to readers with poor knowledge of modern statistics due to its erroneous interpretation of pseudoreplication and statistical independence. Here we offer clarification of those concepts--and related ones such as experimental unit and evaluation unit--by reference to studies cited by Tatarnikov (2005). We stress the necessity of learning from the accumulated experience of the international scientific community in order not to repeat the errors found in earlier publications that have already been analyzed and widely written about. (An Englisch translation of the full article is available as a pdf-file from either or the authors.)

Abundance and diversity of human-biting flies (Diptera: Ceratopogonidae, Culicidae, Tabanidae, Simuliidae) around a nickel-copper smelter at Monchegorsk, northwestern Russia.

In the summers of 2001 and 2002, we quantitatively sampled human-biting flies in twelve sites located 1.6 to 63 km from a large copper-nickel smelter at Monchegorsk on the Kola Peninsula, Russia. We collected 429 specimens of three species of Ceratopogonidae, 92 specimens of seven species of Culicidae, 76 specimens of seven species of Tabanidae, and 4,788 specimens of 19 species of Simuliidae. Culicoides chiropterus was for the first time reported from the Kola Peninsula. Catches of Culicidae and Simuliidae decreased near the smelter, presumably due to the combined action of toxicity of pollutants, pollution-induced forest damage, and decline in vertebrate density. An abundance of Ceratopogonidae and Tabanidae, the size of the most common black fly species, Simulium pusillum, and the diversity of all families did not change along the pollution gradient.