ИМИТАЦИОННОЕ МОДЕЛИРОВАНИЕВ СТОХАСТИЧЕСКОЙ ЗАДАЧЕ УПРАВЛЕНИЯ ЗАПАСАМИ

The article is devoted to popular and important approach to optimization of stock management systems, which is based on costs minimization with account of uncertainties. The simulation and optimization mathematical model of decision-making for management of a trading company is described in the article.Статья посвящена актуальному сегодня подходу к оптимизации систем управления запасами, основанному на минимизации издержек с учетом неопределенности. В статье описана имита- ционно-оптимизационная математическая модель принятия решений по вопросам управления деятельностью торговой компании

Itt1p, a novel protein inhibiting translation termination in Saccharomyces cerevisiae

BACKGROUND: Termination of translation in eukaryotes is controlled by two interacting polypeptide chain release factors, eRFl and eRF3. eRFl recognizes nonsense codons UAA, UAG and UGA, while eRF3 stimulates polypeptide release from the ribosome in a GTP- and eRFl – dependent manner. Recent studies has shown that proteins interacting with these release factors can modulate the efficiency of nonsense codon readthrough. RESULTS: We have isolated a nonessential yeast gene, which causes suppression of nonsense mutations, being in a multicopy state. This gene encodes a protein designated Itt1p, possessing a zinc finger domain characteristic of the TRIAD proteins of higher eukaryotes. Overexpression of Itt1p decreases the efficiency of translation termination, resulting in the readthrough of all three types of nonsense codons. Itt1p interacts in vitro with both eRFl and eRF3. Overexpression of eRFl, but not of eRF3, abolishes the nonsense suppressor effect of overexpressed Itt1p. CONCLUSIONS: The data obtained demonstrate that Itt1p can modulate the efficiency of translation termination in yeast. This protein possesses a zinc finger domain characteristic of the TRIAD proteins of higher eukaryotes, and this is a first observation of such protein being involved in translation

Natural Phaeosphaeride A Derivatives Overcome Drug Resistance of Tumor Cells and Modulate Signaling Pathways

n the present study, natural phaeosphaeride A (PPA) derivatives are synthesized. Anti-tumor studies are carried out on the PC3, K562, HCT-116, THP-1, MCF-7, A549, NCI-H929, Jurkat, and RPMI8226 tumor cell lines, and on the human embryonic kidney (HEK293) cell line. All the compounds synthesized turned out to have better efficacy than PPA towards the tumor cell lines listed. Among them, three compounds exhibited an ability to overcome the drug resistance of tumor cells associated with the overexpression of the P-glycoprotein by modulating the work of this transporter. Luminex xMAP technology was used to assess the effect of five synthesized compounds on the activation of intracellular kinase cascades in A431 cells. MILLIPLEX MAP Multi-Pathway Magnetic Bead 9-Plex was used, which allowed for the simultaneous detection of the following nine phosphorylated protein markers of the main intracellular signaling pathways: a universal transcription factor that controls the expression of immune-response genes, apoptosis and cell cycle NFκB (pS536); cAMP-dependent transcription factor (CREB (pS133); mitogen-activated kinase p38 (pT180/pY182); stress-activated protein kinase JNK (pT183/pY185); ribosomal SK; transcription factors STAT3 (pS727) and STAT5A/B (pY694/699); protein kinase B (Akt) (pS473); and kinase regulated by extracellular signals ERK1/2 (pT185/pY187). The effect of various concentrations of PPA derivatives on the cell culture was studied using xCelligence RTCA equipment. The compounds were found to modulate JNK, ERK1/2, and p38 signaling pathways. The set of activated kinase cascades suggests that oxidative stress is the main probable mechanism of the toxic action of PPA derivatives

Er,Yb:ReGa3(BO3)4 (Re = Y, Gd) laser crystals

Phase relationships in the ErxYbyY1-x-yGa3(BO3)4-Bi2O3-B2O3-(Y,Er,Yb)2O3–Ga2O3 and ErxYbyGd1-x-yGa3(BO3)4-Bi2O3-B2O3-(Gd,Er,Yb)2O3 – Ga2O3 (x = 0.02, y = 0.11 at.%) system were studied in the temperature range from 1000 to 900 оС. Multicomponent melt Bi2O3-Ga2O3-B2O3-(Y,Gd)2O3 were used as reasonable fluxes for high-temperature solution growth of ErxYbyR1-x-yGa3(BO3)4 (R = Y, Gd) spontaneous crystals. The segregation coefficients of Yb and Er impurities in the obtained crystals are determined. The unit cell parameters for the grown crystals were studied, also showing the micromorphology characteristics of the crystals. The luminescence kinetics were investigated, and the lifetimes of the 4I13/2 energy level of Er3+ ions for Er,Yb:ReGa3(BO3)4 crystals were determined

Экспрессия белков цитоскелета – цитокератинов и бета-III тубулина в клетках культур меланомы человека из коллекции НМИЦ онкологии им. Н. Н. Блохина

Introduction. Despite advances in the treatment of melanoma, the results of therapy cannot be considered satisfactory, and the search for new drugs and effective combinations of medicine continues. The drugs are being developed aimed at reducing the metastatic tumor potential – migrastatics. The targets of the drugs can be cytoskeletal proteins of tumor cells – cytokeratin (CK) intermediate filaments and microtubule protein beta-III tubulin (TUBB3).Aim. To estimate of the CK and TUBB3 expression in melanoma cell lines to form an informative in vitro cell model for screening and studying migrastatics.Materials and methods. The molecular phenotype of 21 human melanoma cell lines from the collection of N. N. Blokhin National Medical Research Center of Oncology, and 18 of which were isolated from tumor metastases in the lymph nodes, soft tissues or subcutaneously. The level of TUBB3 expression and de novo expression of CKs in vimentin-expressing cells (CK + Vim) were assessed by an immunofluorescent method and flow cytometry.Results. Beta-III tubulin expression was detected in all cultures studied, de novo expression of CKs was found in 20 / 21 lines. The exception was primary uveal melanoma 92-1, that did not express CK + Vim. Both parameters significantly differed between the cells of the studied panel: CK + Vim co-expression – from 0 to 91 %, TUBB3 – from 18 to 86 %. No correlation was found between the expression level of TUBB3 and CK + Vim (Pearson’s correlation coefficient r = 0.11; p = 0.65). Three groups of the cell lines with different ratio of TUBB3 expression and CK + Vim co-expression were identified: 1) similar level of expression of both markers; 2) the level of co-expression of CK + Vim more or less high than the index for TUBB3; 3) the level of TUBB3 expression more or less high than the index for CK + Vim co-expression.Conclusion. A panel of 21 human melanoma cell lines was formed with quantitatively estimated expression of cytoske-letal proteins responsible for the migration activity of tumor cells – CKs and TUBB3. Groups of the lines with different expression ratio of the markers can be used for screening and preclinical evaluation potential migrastatics that reduce the metastatic potential of melanoma and may reduce resistance to taxanes.Введение. Несмотря на достижения в лечении меланомы, результаты терапии нельзя признать удовлетворительными, и поиск новых препаратов и эффективных комбинаций лекарств продолжается. Разрабатываются препараты, направленные на снижение метастатического потенциала опухолей, – миграстатики. Точкой приложения этой группы препаратов могут являться белки цитоскелета опухолевой клетки, к которым относятся промежуточные филаменты – цитокератины (Цк) и белок микротрубочек бета-III тубулин (TUBB3).Цель исследования – формирование панели культур клеток меланомы с охарактеризованной экспрессией Цк и TUBB3 для создания информативной клеточной модели in vitro для скрининга и изучения миграстатиков.Материалы и методы. Исследован молекулярный фенотип 21 культуры клеток меланомы из коллекции клеточных линий ФГБУ «Национальный медицинский исследовательский центр онкологии им. Н. Н. Блохина» Минздрава России, из которых 18 культур получены из метастазов опухоли в лимфатические узлы, мягкие ткани или подкожно. Оценка уровня экспрессии TUBB3 и de novo экспрессии Цк в клетках, экспрессирующих виментин (Вим) (Цк + Вим), проведена иммунофлуоресцентным методом, ассоциированным с проточной цитометрией.Результаты. экспрессия TUBB3 выявлена во всех исследованных культурах, de novo экспрессия Цк – в 20 из 21 культуры. Исключение составила первичная увеальная меланома 92-1, не экспрессирующая Цк + Вим. Оба показателя значительно различались между клетками исследованной панели: коэкспрессия Цк + Вим – от 0 до 91 %, TUBB3 – от 18 до 86 %. корреляции между уровнями экспрессии TUBB3 и Цк + Вим не выявлено (коэффициент корреляции пирсона r = 0,11; p = 0,65). Выделены 3 группы культур клеток с разным соотношением уровня экспрессии TUBB3 и коэкспрессии Цк + Вим: 1) сходный уровень показателей экспрессии маркеров; 2) уровень коэкспрессии Цк + Вим в большей или меньшей степени превышает показатель для TUBB3; 3) уровень экспрессии TUBB3 в разной степени превышает показатель коэкспрессии Цк + Вим.Заключение. Сформирована панель из 21 культуры клеток меланомы человека, в которых количественно охарактеризована экспрессия Цк и TUBB3 – белков цитоскелета, ответственных за миграционную активность опухолевых клеток. Группы культур с разным соотношением показателей экспрессии этих маркеров могут быть использованы для скрининга и доклинической оценки потенциальных миграстатиков, которые уменьшают метастатический потенциал меланомы и могут снижать резистентность к таксанам

SIMULATION MODELING IN THE STOCHASTIC PROBLEM OF STOCK MANAGEMENT

The article is devoted to popular and important approach to optimization of stock management systems, which is based on costs minimization with account of uncertainties. The simulation and optimization mathematical model of decision-making for management of a trading company is described in the article

A73

Human epidermal growth factor receptor-2 (HER2/nue) is overexpressed in breast cancer. It has been shown that HER2-targeted therapies have radically changed the outcome of HER2-positive breast cancer patients. The aim of this study was to develop the technique for preparation of recombinant anti-HER2/neu antibody from plants and to provide with the basic characteristics of the HER2/neu oncoprotein. Materials and Methods: We have designed and synthesized viral vectors to transform Agrobacterium tumifaciens affinity, ion exchange and gel filtration chromatography were used to purify the antibody. The quality of the substance was confirmed by SDS–PAGE and ELISA. The biological activity was tested by immunofluorescent analysis. Results: Antibodies were purified by affinity and ion exchange chromatography from the Agrobacterium tumifaciens leaves extracts. Gel filtration chromatography was used for final purification of the protein. Immunocytochemical staining was performed to test the functional activity of the plant-made antibodies. Here we also show that plant-made antibodies bind to HER2/neu receptors on the surface of human SK-BR-3 breast cancer cells as effectively as the diagnostic antibody A0485 (DAKO, Denmark). Flow cytometry analysis was used for quantitative estimation of recombinant anti-HER2/neu antibodies: from 75.7% to 98.3% cells bound the plant-made antibodies. The same data were obtained with trastuzumab. Conclusion: Based on the data obtained, we conclude that plant-made antibodies inhibit HER2/neu+ breast cancer cell proliferation. Additional experiments are required to prove that trastuzumab and plant-made antibodies share full identity in their biological activity