128 research outputs found

    Збройні сили Королівства Данії у військовій структурі Північноатлантичного Альянсу

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    Пугачова Д. В. Збройні сили Королівства Данії у військовій структурі Північноатлантичного Альянсу / Д. В. Пугачова // Людина, суспільство, політика: актуальні виклики сучасності: матеріали ІІ Міжнародної науково-практичної конференції (м. Одеса, 13-14 лютого 2015 р.) / НУ «ОЮА», Одеське відділення Міжнародної асоціації студентів політологічної науки, за заг. ред. Д. В. Яковлева – Одеса : НУ «ОЮА», 2015. – С. 137-139

    The use of intermediate inserts for CO 2 laser welding of steel AISI 321 and a Grade 2 titanium alloy

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    The paper studies the structure, chemical and phase compositions, hardness and strength of welded joints obtained in AISI 321 steel and Grade 2 titanium alloy sheets by CO 2 continuous laser with the use of intermediate Cu, Ni and Ag-Cu-Zn alloy inserts. It is demonstrated that the maximum strength of welded joints is achieved by the welding conditions enabling one to form multiphase structures with intermetallics in the material of a weld, rather than only those based on solid solutions. © 2018 Author(s)

    Regulation of the apoptotic genes in breast cancer cells by the transcription factor CTCF

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    CTCF is a highly conserved and ubiquitous transcription factor with versatile functions. We previously demonstrated that elevated protein levels of CTCF in breast cancer cells were associated with the specific anti-apoptotic function of CTCF. We used proteomics and microarray approaches to identify regulatory targets of CTCF specific for breast cancer cells. Among the CTCF identified targets were proteins involved in the control of apoptosis. A proapoptotic protein, Bax, negatively regulated by CTCF, was chosen for further investigation. Repression of the human Bax gene at the transcriptional level by CTCF in breast cancer cells was confirmed by real-time PCR. Two CTCF binding sites within the Bax promoter were identified by electrophoretic mobility shift assay and footprinting. In reporter assays, the Bax-luciferase reporter construct, containing CTCF-binding sites, was negatively regulated by CTCF. In vivo, CTCF occupied its binding sites in breast cancer cells and tissues, as confirmed by chromatin immunoprecipitation assay. Our findings suggest a possible mechanism of the specific CTCF anti-apoptotic function in breast cancer cells whereby CTCF is bound to the Bax promoter, resulting in repression of Bax and inhibition of apoptosis; depletion of CTCF leads to activation of Bax and apoptotic death. CTCF binding sites in the Bax promoter are unmethylated in all cells and tissues inspected. Therefore, specific CTCF interaction with the Bax promoter in breast cancer cells, and the functional outcome, may depend on a combination of epigenetic factors characteristic for these cells. Interestingly, CTCF appears to be a negative regulator of other proapoptotic genes (for example, Fas, Apaf-1, TP531NP1). Conversely, stimulating effects of CTCF on the anti-apoptotic genes (Bcl-2, Bag-3) have been observed. Taken together, these findings suggest that specific mechanisms have evolved in breast cancer cells to protect them from apoptosis; regulation of apoptotic genes by CTCF appears to be one of the resistance strategies

    Kruppel-like factor 4 signals through microRNA-206 to promote tumor initiation and cell survival

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    Tumor cell heterogeneity poses a major hurdle in the treatment of cancer. Mammary cancer stem-like cells (MaCSCs), or tumor-initiating cells, are highly tumorigenic sub-populations that have the potential to self-renew and to differentiate. These cells are clinically important, as they display therapeutic resistance and may contribute to treatment failure and recurrence, but the signaling axes relevant to the tumorigenic phenotype are poorly defined. The zinc-finger transcription factor Kruppel-like factor 4 (KLF4) is a pluripotency mediator that is enriched in MaCSCs. KLF4 promotes RAS-extracellular signal-regulated kinase pathway activity and tumor cell survival in triple-negative breast cancer (TNBC) cells. In this study, we found that both KLF4and a downstream effector, microRNA-206 (miR-206), are selectively enriched in the MaCSC fractions of cultured human TNBC cell lines, as well as in the aldehyde dehydrogenase-high MaCSC sub-population of cells derived from xenografted human mammary carcinomas. The suppression of endogenous KLF4 or miR-206 activities abrogated cell survival and in vivo tumor initiation, despite having only subtle effects on MaCSC abundance. Using a combinatorial approach that included in silico as well as loss- and gain-of-function in vitro assays, we identified miR-206-mediated repression of the pro-apoptotic molecules programmed cell death 4 (PDCD4) and connexin 43 (CX43/GJA1). Depletion of either of these two miR-206-regulated transcripts promoted resistance to anoikis, a prominent feature of CSCs, but did not consistently alter MaCSC abundance. Consistent with increased levels of miR-206 in MaCSCs, the expression of both PDCD4 and CX43 was suppressed in these cells relative to control cells. These results identify miR-206 as an effector of KLF4-mediated prosurvival signaling in MaCSCs through repression of PDCD4 and CX43. Consequently, our study suggests that a pluripotency factor exerts prosurvival signaling in MaCSCs, and that antagonism of KLF4-miR-206 signaling may selectively target the MaCSC niche in TNBC

    Опыт использования краткосрочных курсов химиотерапии в лечении туберкулеза с множественной лекарственной устойчивостью возбудителя у детей с разным ВИЧ-статусом

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    The objective: to study the time frames and efficacy of treatment for tuberculosis with confirmed and suspected multiple drug resistance (MDR) in children with different HIV status.Subjects and methods. The method of continuous sampling was used in the study which included 21 children with MDR tuberculosis, they all had been exposed to MDR TB and were treated in hospital. 3 children had concurrent HIV.Results. The duration of the intensive care phase in HIV negative children (19 people) made: 60 doses – 1 (5.3%) child, 90 doses – 11 (57.9%) children, 120 doses – 2 (10.5%) children, 180 doses – 3 (15.8%) children, 240 doses – 1 (4.3%) child. The duration of the continuation phase was the following: 120 doses – 1 (4.3%) child, 150 doses – 1 (5.3%) children, 180 doses – 12 (63.1%) children, 270 doses – 1 (5.3%) children, 320 doses – 3 (15.8%) children.The duration of the intensive phase of treatment in 3 children with concurrent MDR TB and HIV infection made 180 doses in 2 (66.6%) children and 240 doses in 1 (33.4%) child. The continuation phase included 180 doses in 2 (66.6%) children and 320 in 1 (33.4%) child respectively.Outcomes of the main course of chemotherapy were favorable in the majority of the cases - inflammatory changes resolved, focuses consolidated and fibrosis formed in the lung tissue.Conclusion. Should children have negative results of sputum tests, the treatment is prescribed based on the results of drug susceptibility tests of the index case. If limited tuberculous lesions are diagnosed, the duration of treatment of children with MDR can be shorter. The outcomes of short-course treatment in children with tuberculosis are favorable, changes in the lungs have resolved and thickened more frequently. In children with HIV infection, low adherence to HIV treatment in socially disadvantaged families requires long-term directly observed tuberculosis chemotherapy combined with antiretroviral therapy.Цель исследования: изучить сроки и эффективность лечения туберкулеза с установленной и предполагаемой множественной лекарственной устойчивостью (МЛУ) возбудителя у детей с разным ВИЧ-статусом.Материалы и методы. В исследование методом сплошной выборки включен 21 ребенок, больной туберкулезом с МЛУ (все из очагов МЛУ-туберкулеза) находившийся на стационарном лечении. У 3 детей имелось сочетание с ВИЧ-инфекцией.Результаты исследования. Длительность фазы интенсивной терапии у детей с ВИЧ-негативным статусом (19 детей) составила: 60 доз – 1 (5,3%) ребенок, 90 доз – 11 (57,9%) детей, 120 доз – 2 (10,5%) ребенка, 180 доз – 3 (15,8%) ребенка, 240 доз – 1 (4,3%) ребенок. Длительность фазы продолжения лечения: 120 доз у 1 (4,3%) ребенка, 150 доз у 1 (5,3%) ребенка, 180 доз у 12 (63,1%) детей, 270 доз у 1 (5,3%) ребенка, 320 доз у 3 (15,8%) детей.Длительность фазы интенсивной терапии у 3 детей при сочетании МЛУ-туберкулеза и ВИЧ-инфекции была 180 доз у 2 (66,6%) детей и 240 доз ‒ у 1 (33,4%) ребенка. Фаза продолжения составила 180 доз у 2 (66,6%) детей и 320 ‒ у 1 (33,4%) ребенка соответственно.Исходы основного курса химиотерапии в большинстве случаев хорошие – рассасывание воспалительных изменений, уплотнение очагов и фиброзирование легочной ткани.Заключение. У больных туберкулезом детей при отсутствии бактериовыделения лечение назначается по результатам тестов на лекарственную чувствительность у источника инфекции. Ограниченность выявленного туберкулезного процесса позволяет сокращать срок лечения детей и при МЛУ возбудителя. Исходы укороченных курсов лечения у детей с туберкулезом благоприятные, чаще рассасывание и уплотнение изменений в легких. У детей с ВИЧ-инфекцией низкая приверженность к лечению ВИЧ-инфекции в социально неблагополучных семьях требует длительно

    The Structural Complexity of the Human BORIS Gene in Gametogenesis and Cancer

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    BORIS/CTCFL is a paralogue of CTCF, the major epigenetic regulator of vertebrate genomes. BORIS is normally expressed only in germ cells but is aberrantly activated in numerous cancers. While recent studies demonstrated that BORIS is a transcriptional activator of testis-specific genes, little is generally known about its biological and molecular functions.Here we show that BORIS is expressed as 23 isoforms in germline and cancer cells. The isoforms are comprised of alternative N- and C-termini combined with varying numbers of zinc fingers (ZF) in the DNA binding domain. The patterns of BORIS isoform expression are distinct in germ and cancer cells. Isoform expression is activated by downregulation of CTCF, upregulated by reduction in CpG methylation caused by inactivation of DNMT1 or DNMT3b, and repressed by activation of p53. Studies of ectopically expressed isoforms showed that all are translated and localized to the nucleus. Using the testis-specific cerebroside sulfotransferase (CST) promoter and the IGF2/H19 imprinting control region (ICR), it was shown that binding of BORIS isoforms to DNA targets in vitro is methylation-sensitive and depends on the number and specific composition of ZF. The ability to bind target DNA and the presence of a specific long amino terminus (N258) in different isoforms are necessary and sufficient to activate CST transcription. Comparative sequence analyses revealed an evolutionary burst in mammals with strong conservation of BORIS isoproteins among primates.The extensive repertoire of spliced BORIS variants in humans that confer distinct DNA binding and transcriptional activation properties, and their differential patterns of expression among germ cells and neoplastic cells suggest that the gene is involved in a range of functionally important aspects of both normal gametogenesis and cancer development. In addition, a burst in isoform diversification may be evolutionarily tied to unique aspects of primate speciation

    The Task of Combinatorial Optimization: the Se arch for an Optimal Production and Transport Plan When Organizing Production in New Te rritories

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    The purpose of this article is to solve one of the tasks of production activities. A company aims to expand individual production facilities and to subsequently determine output and transportation volumes from each of the outlets (local production sites, warehouses, etc.). The hypothesis is that a solution to the production problems can be found in a set of five linear programming problems: the production problem, the center placement problem, the flow problem, the time minimization problem, and the transportation problem. The paper presents the main algorithms for finding optimal solutions, formulates a complex task, builds a model and implements an algorithm for finding optimal solutions. It was shown that such a problem can be formulated in the framework of a complex linear programming problem. The model test is produced on 38 vertices with 16 entry points, 3 exit points. It is shown that such a task can be solved and visualized by means of the Matlab package. Modifications of the model and possible solution algorithms depending on the data sample size are considered. The developed model can be applied at an enterprise or at any production facility where the main task is to search for the optimal combinatorial version of goods, provided that ,first, production costs and the costs of transportation of finished products are minimized and, second, profit is at a maximum. Third, the cost of launching opening new production facilities are kept at a minimum. Such a task corresponds exactly to the economic situation, when the enterprise has yet to expand (open new production sites), and it tries to decide where to produce items from its list of products and determine its output considering the available raw materials and decide on dispatch methods. Such a problem is non-trivial combinatorial in nature.Целью данной статьи является решение одной из нетривиальных задач производственной деятельности, возникшее на предприятии лесной направленности. Предприятие ставит целью расширение отдельных пунктов производства с последующим определением: объемов производства и транспортировки с каждой из точек (мест производства, складов и т. д.). Гипотеза заключается в том, что решение такой производственной проблемы лежит в комплексном решении пяти задач линейного программирования: производственная задача (классическая постановка), задача размещения центров, задача максимального потока, задачи минимизации времени, транспортная задача. В работе представлены основные алгоритмы поиска оптимального решения, сформулирована комплексная задача, построена модель и реализован алгоритм поиска оптимального решения. Было показано, что такую задачу возможно сформулировать в рамках комплексной задачи линейного программирования. Тест модели произведен на 38 вершинах с 16 пунктами входа, 3 пунктами выхода. Показано, что такую задачу возможно решать и визуализировать средствами пакета Matlab. Рассмотрены модификации модели и возможные алгоритмы решения в зависимости от объема выборки данных. Разработанная модель может быть применена на предприятии любой производственной направленности, где стоит главной задачей поиск оптимального комбинаторного варианта вектора товаров при условии, во-первых, минимизации производственных издержек и затрат на транспортировку готовой продукции, во-вторых, получения максимальной прибыли, в-третьих, минимальных издержек при открытии новых пунктов производства. Такая задача в точности подходит к экономической ситуации, когда предприятию еще предстоит расшириться (открыть новые пункты производства), и оно осуществляет попытки по определению мест производства из рассматриваемого списка, объема производства из имеющегося в наличии сырья, способа отправки (как можно больше товара). Такая проблема носит характер нетривиально комбинаторный

    Widespread Expression of BORIS/CTCFL in Normal and Cancer Cells

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    BORIS (CTCFL) is the paralog of CTCF (CCCTC-binding factor; NM_006565), a ubiquitously expressed DNA-binding protein with diverse roles in gene expression and chromatin organisation. BORIS and CTCF have virtually identical zinc finger domains, yet display major differences in their respective C- and N-terminal regions. Unlike CTCF, BORIS expression has been reported only in the testis and certain malignancies, leading to its classification as a “cancer-testis” antigen. However, the expression pattern of BORIS is both a significant and unresolved question in the field of DNA binding proteins. Here, we identify BORIS in the cytoplasm and nucleus of a wide range of normal and cancer cells. We compare the localization of CTCF and BORIS in the nucleus and demonstrate enrichment of BORIS within the nucleolus, inside the nucleolin core structure and adjacent to fibrillarin in the dense fibrillar component. In contrast, CTCF is not enriched in the nucleolus. Live imaging of cells transiently transfected with GFP tagged BORIS confirmed the nucleolar accumulation of BORIS. While BORIS transcript levels are low compared to CTCF, its protein levels are readily detectable. These findings show that BORIS expression is more widespread than previously believed, and suggest a role for BORIS in nucleolar function

    Novel CTCF binding at a site in exon1A of BCL6 is associated with active histone marks and a transcriptionally active locus

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    BCL6 is a zinc-finger transcriptional repressor, which is highly expressed in germinal centre B-cells and is essential for germinal centre formation and T-dependent antibody responses. Constitutive BCL6 expression is sufficient to produce lymphomas in mice. Deregulated expression of BCL6 due to chromosomal rearrangements, mutations of a negative autoregulatory site in the BCL6 promoter region and aberrant post-translational modifications have been detected in a number of human lymphomas. Tight lineage and temporal regulation of BCL6 is, therefore, required for normal immunity, and abnormal regulation occurs in lymphomas. CCCTC-binding factor (CTCF) is a multi-functional chromatin regulator, which has recently been shown to bind in a methylation-sensitive manner to sites within the BCL6 first intron. We demonstrate a novel CTCF-binding site in BCL6 exon1A within a potential CpG island, which is unmethylated both in cell lines and in primary lymphoma samples. CTCF binding, which was found in BCL6-expressing cell lines, correlated with the presence of histone variant H2A.Z and active histone marks, suggesting that CTCF induces chromatin modification at a transcriptionally active BCL6 locus. CTCF binding to exon1A was required to maintain BCL6 expression in germinal centre cells by avoiding BCL6-negative autoregulation. Silencing of CTCF in BCL6-expressing cells reduced BCL6 mRNA and protein expression, which is sufficient to induce B-cell terminal differentiation toward plasma cells. Moreover, lack of CTCF binding to exon1A shifts the BCL6 local chromatin from an active to a repressive state. This work demonstrates that, in contexts in which BCL6 is expressed, CTCF binding to BCL6 exon1A associates with epigenetic modifications indicative of transcriptionally open chromatin

    Signs of positive selection of somatic mutations in human cancers detected by EST sequence analysis

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    BACKGROUND: Carcinogenesis typically involves multiple somatic mutations in caretaker (DNA repair) and gatekeeper (tumor suppressors and oncogenes) genes. Analysis of mutation spectra of the tumor suppressor that is most commonly mutated in human cancers, p53, unexpectedly suggested that somatic evolution of the p53 gene during tumorigenesis is dominated by positive selection for gain of function. This conclusion is supported by accumulating experimental evidence of evolution of new functions of p53 in tumors. These findings prompted a genome-wide analysis of possible positive selection during tumor evolution. METHODS: A comprehensive analysis of probable somatic mutations in the sequences of Expressed Sequence Tags (ESTs) from malignant tumors and normal tissues was performed in order to access the prevalence of positive selection in cancer evolution. For each EST, the numbers of synonymous and non-synonymous substitutions were calculated. In order to identify genes with a signature of positive selection in cancers, these numbers were compared to: i) expected numbers and ii) the numbers for the respective genes in the ESTs from normal tissues. RESULTS: We identified 112 genes with a signature of positive selection in cancers, i.e., a significantly elevated ratio of non-synonymous to synonymous substitutions, in tumors as compared to 37 such genes in an approximately equal-sized EST collection from normal tissues. A substantial fraction of the tumor-specific positive-selection candidates have experimentally demonstrated or strongly predicted links to cancer. CONCLUSION: The results of EST analysis should be interpreted with extreme caution given the noise introduced by sequencing errors and undetected polymorphisms. Furthermore, an inherent limitation of EST analysis is that multiple mutations amenable to statistical analysis can be detected only in relatively highly expressed genes. Nevertheless, the present results suggest that positive selection might affect a substantial number of genes during tumorigenic somatic evolution
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