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The modern era of research in immunology is characterized by an unprecedented level of detail about structural characteristics of the immune system and the regulation of activities of its numerous components, which function together as a whole distributed-parameter system. Mathematical modeling provides an analytical tool to describe, analyze, and predict the dynamics of immune responses by applying a reductionist approach. In modern systems immunology and mathematical immunology as a new interdisciplinary field, a great challenge is to formulate the mathematical models of the human immune system that reflect the level achieved in understanding its structure and describe the processes that sustain its function. To this end, a systematic development of multiscale mathematical models has to be advanced. An appropriate methodology should consider (1) the intracellular processes of immune cell fate regulation, (2) the population dynamics of immune cells in various organs, and (3) systemic immunophysiological processes in the whole host organism. Main studies aimed at modeling the intracellular regulatory networks are reviewed in the context of multiscale mathematical modelling. The processes considered determine the regulation of the immune cell fate, including activation, division, differentiation, apoptosis, and migration. Because of the complexity and high dimensionality of the regulatory networks, identifying the parsimonious descriptions of signaling pathways and regulatory loops is a pressing problem of modern mathematical immunology.

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AIM: Comparative study of tight junctions and ultrastructure alterations of enterocytes of mucous membranes of jejunum of rats under the effect of lipopolysaccharides and cholera toxin. MATERIALS AND METHODS: Lipopolysaccharides (Sigma-Aldrich, Germany) and cholera toxin (Sigma-Aldrich, Germany) were used. The study was carried out in Wistar line rats. Effect of lipopolysaccharides and cholera toxin on epitheliocytes was carried out by a method of withdrawal of segments of rat jejunum and their incubation with the specified substances. Comparative analysis of ultrathin sections of enterocytes of jejunum of rats and tight junctions between them was carried out in control and under the effect of lipopolysaccharides and cholera toxin. RESULTS: Effect of lipopolysaccharides on ultrastructure of enterocytes of rat jejunum manifested in the change of cell form as a result of increase of intercellular space without destruction of tight junctions. Disappearance of desmosomes, increase of nuclei and more pronounced ER were noted in some epitheliocytes. Effect of cholerogen on epitheliocytes of mucous membrane of rat jejunum by a number of signs is similar to the effect of lipopolysaccharides, that manifested in an alteration of ultrastructure of cell, the form of those also transformed as a result of an increase of intercellular space, this process was not accompanied by destruction of tight junctions. Disappearance of folding of the lateral region of plasmatic membrane of cells and a reduction of a number of microvilli was observed under the effect of cholera toxin. CONCLUSION: A similar character of effect of lipopolysaccharides and cholera toxins on ultrastructure of cells and region of tight junctions of enterocytes of rat jejunum was detected, both substances caused an increase of intercellular space without the destruction of tight junctions.

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AIM: Study the effect of microgravitation on the formation of Lactobacillusplantarum 8PA-3 bacterial biofilms in the conditions of space flight. MATERIALS AND METHODS: Information on the ef- fect of microgravitation on the development of biofilms was obtained during study of L. plantarum 8PA-3 probiotic lactobacilli in special equipment in the process of execution of space experiments in the Russian segment of the International Space Station. Comparative analysis of growth of plankton and biofilm forms of cells developing in the conditions of space flight and surface conditions was carried out by microbiologic and electron-microscopy methods using scanning and transmission electron microscopy. RESULTS: Accelerated dynamics of formation of L. plantarum 8PA-3 lactobacilli biofim on the surface polymer substrate was shown for the first time during the space experiment. Microbiological anfalysis of the bacterial culture has also confirmed the accelerated growth of L.plantarum 8PA-3 under microgravitation compared with surface conditions. Ultrastructure of plankton form of L. plantarum 8PA-3 taking part in formation of biofilms inconditions ofmicrogravitationwas detected for the first time inthe space experiment. CONCLUSION: Data on comparative electron-microscopic analysis obtained in space experiments are important for scientific justification of the effect of icrogravitation on bacterial communities developig as biofilms - the most natural form of existence of microorganisms. The results obtained could be taken into consideration during creation of novel antibacterial means and disinfectants as well as methods of treatment of surfaces of modules of piloted space complexes that could allow to clarify methods of effective prophylaxis of biofilm spread which pose a risk of health of the crew and normal functioning of equipment in the International Space Station.

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AIM: Detection of bactericidal effect of pulse-periodic corona discharge (PPCD) on cells and biofilms of Escherichia coli M17. MATERIALS AND METHODS: A gas-discharge device was created based on PPCD in air with power supply parameters: amplitude values of voltage of 30 - 60 kV, pulse repetition rate of 250 - 400 kHz. Ultrastructure changes in cells and biofilms of E. coli M17, affected by PPCD, generated in air, were studied by typical methods of transmission electron microscopy. RESULTS: Disturbances of integrity of surface and abyssal structures of biofilms, as well as changes of morphological properties of E. coli M17 cells, characteristic for sub-lethal heat impact, were detected. Destructive changes of bacterial cells were developed by formation of focal disturbance of cytoplasmic membrane, extension of periplasmic space, formation of globular structures, characteristic for heat effect, and destruction of cytoplasm. CONCLUSION: Bactericidal effect of PPCD on E. coli M17 cells as part of biofilms was shown. Destructive morphological changes in cells and biofilms of E. coli M17 after the effect of PPCD were detected for the first time on electron-microscopic level.

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Analysis of summarized data obtained by us on ultrastructure of microbial biofilms of opportunistic bacteria is presented. A complex ultrathin organization of lactobacilli, enterobacteria, staphylococci and enterococci biofilms discovered during electron microscopy is described. The presence of surface film and polysaccharide matrix that determine increased resistance of intrabiofilm bacteria against the effect of protective immune factors of the organism and etiotropic preparations is demonstrated in all the studied comminutes. A varied response of bacterial cells contained in the biofilm during antagonistic effect of symbiont probiotic bacteria was discovered.

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Data on antimicrobial peptides (AMP) of lactobacilli, mechanism of their damagin effect, chemical nature and genetic control are presented. Regardless of the source of isolation AMP of lactobacilli except reuterin are peptides with low molecular weight (4 - 6 kDa), differ from each other by chemical structure, sensitivity to temperature, effect of various enzymes, active at neutral or more frequently low pH. Especially important are mechanisms ensuring fine regulation of phenotypic expression of bacteriocin synthesis and formation of immunity against their effect. Activity and most importantly the level of their production depend on the conditions in which these bacteria are present and are controlled by a three-component regulation system. This system includes signal peptide (pheromone), sensory histidine kinase, regulator protein activating transcription. Resistance of the producer to the effect of its own bacteriocin is ensured by the so called immunity protein. AMP of lactobacilli are able to influence septoformation, peptidoglycan and protein synthesis, affect cytoplasmic membranes causing their destabilization. Stages of this damaging effect are described: interaction of effector peptides with the membrane of the sensitive cell, positioning of the peptide in the region of connection with protein receptor, submerging into the core of the spiral structure membranes with the formation of a pore and exhaustion of ATP pool leading to cell death. Protection from AMP is determined by specific proteins blocking pore formation in the membrane by direct binding of damaging molecules or their receptors. Perspectives of further studies of the role of antimicrobial peptides of lactobacilli are discussed.

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AIM: Determination of morpho-physiological changes in cells of a lactobacillus industry strain suppressed by antagonistically active clinical cultures of Staphylococcus aureus. MATERIALS AND METHODS: 5 clinical strains of Staphylococcus aureus detected among 42 strains isolated previously in atopic dermatitis were used. Bacteria of the industry strain Lactobacillus plantarum 8PA-3 that synthesize bacteriocin-like inhibitory substances (BLIS) were used as target-cells. Suppression of growth of lactobacilli cells by staphylococci was performed on modified agar nutrient medium MRS by delayed antagonism method. Ultrastructure changes in lactobacilli cells exposed to staphylococci BLIS were studied by various methods of transmission electron microscopy. RESULTS: Destructive changes (exfoliation of small layered fragments of peptidoglycan layers) were detected in the cell walls of lactobacilli suppressed by staphylococci BLIS, and rearrangement of ultrathin structure of their cytoplasm with the destruction of protein-ribosomal complex was noticed. CONCLUSION; Clinical S. aureus strains that produce BLIS, suppress antagonistic activity of lactobacilli were revealed, and morpho-physiological changes in lactobacilli target-cells damaged by BLIS were detected. Local damage of cell components manifested by the destruction of cytoplasm and formation of "cell shadows".

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AIM: Bacteriological and electron microscopic study of skin of healthy persons and patients with atopic dermatitis (AD). MATERIALS AND METHODS: Fifteen patients (7 males and 8 females aged 17-53 years) with lichenoid form of AD treated in dermatovenerologic outpatient clinics were compared with group of virtually healthy 10 persons of the same age. Comparative study of skin and electron microscopic evaluation of ultrathin sections from affected areas of the skin were performed in all participants. Main representatives of resident and facultative groups of microbiota were counted. RESULTS: Differences in microbial spectrum and level of physiological activity of microorganisms colonizing skin surface of healthy persons and patients with AD were revealed. Unlike microbes on healhy skin, the microorganisms colonizing skin of the patients with AD were characterized by profound polymorphism of cells. Widening of population spectrum of opportunistic microorganisms belonging to genuses Staphylococcus, Corynebacterium, and Candida was accompanied by manifestation of destructive changes of the skin of patients with AD. Electron microscopic evaluation of skin of patients with AD showed that bacterial cells located predominantly in upper layers of epidermis. Major number of microorganisms colonized corneal layer and located between friable skin squama. CONCLUSION: Changes of skin microbiota with marked pathomorphologic changes of keratinocytes were observed in patients with AD that necessary to consider during basic therapy of this disease.

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AIM: To study morpho-physiologic characteristics of clinical biofilm-forming strains of Staphylococcus aureus and S. epidermidis suppressed by metabolites of lactobacilli, which produce bacteriocin-like substances. MATERIALS AND METHODS: Two clinical biofilm-forming strains of S. aureus and one strain of S. epidermidis were used. Strains Lactobacillus plantarum L3 and L. fermentum 97 were used as producers of bactericidal metabolites. Ability of staphylococci to form biofilms was studied after their growth during 18 h at 37 degrees C in beef-extract broth with subsequent registration of biofilms attached to walls and bottom of polystyrene plate and stained by 0.1% alcohol solution of crystal violet. Ultrastructural changes in target cells were visualized by electron microscopy. RESULTS: Suppressive effect of lactobacilli metabolites on formation of biofilms by staphylococci was established. Ultrasructural changes, which characterize disorganization of vital processes such as mitosis, synthesis of DNA and peptidoglycan layer, were revealed in target cells. Formation and detachment of peptidoglycan globules from cell wall surface externally were noted. CONCLUSION: Metabolites of lactobacilli are able to suppress formation of biofilms and induce ultrastructural changes in S. aureus and S. epidermidis, which lead to their destruction.

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AIM: To assess sorption properties of Spherocelle beads consisting of particles of macroporous celiulose with various charges in relation to bacterial cells of manufacturing probiotic strains from different taxonomic groups. MATERIALS AND METHODS: The following manufacturing strains: Bifidobacterium bifidum 1, Lactobacillus plantarum 8PA-3 and Escherichia coli M-17, as well as 3 variants of Spherocelles' matrix: neutral, with positive and negative charges, were used. RESULTS: Spherocelle globules DEAE with a positive charge of the matrix were successively used for designing of immobilized probiotic preparations. Efficacy of sorbent is determined by sorption of > or =1000 viable cells as well as bacterial metabolites interacting in conditions of sorbent-regulated pH on each globule with diameter 100-180 microm. It provides, on the one hand, prolonged viability of probiotic bacteria in culture fluid within 6 months and, on the other hand, optimal pharmacokinetics of preparation due to gradual desorption of metabolites from sorbent globules. CONCLUSION: Sorbent Spherocell DEAE is biocompatible with cells of manufacturing strains of lactobacilli, bifidobacteria and E. coli and recommended for designing of immobilized probiotics.

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Kidney function and some mechanisms of its regulation were studied in 161 premature babies. The renin-angiotensin-aldosterone system was found to play a certain role in controlling the water-electrolyte balance in premature infants. The incidence of pronounced and latent renal failure in infants with posthypoxia lesions of the central nervous system (CNS) of varying degrees was demonstrated. The informative value of calculation parameters of partial kidney functions as the early diagnostic criteria in pronounced and latent renal failure is confirmed. A role that the revealed posthypoxia hypermyoglobinemia might possibly play in the pathogenesis of acute renal failure in premature infants is discussed.

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