Network analysis of human glaucomatous optic nerve head astrocytes

<p>Abstract</p> <p>Background</p> <p>Astrocyte activation is a characteristic response to injury in the central nervous system, and can be either neurotoxic or neuroprotective, while the regulation of both roles remains elusive.</p> <p>Methods</p> <p>To decipher the regulatory elements controlling astrocyte-mediated neurotoxicity in glaucoma, we conducted a systems-level functional analysis of gene expression, proteomic and genetic data associated with reactive optic nerve head astrocytes (ONHAs).</p> <p>Results</p> <p>Our reconstruction of the molecular interactions affected by glaucoma revealed multi-domain biological networks controlling activation of ONHAs at the level of intercellular stimuli, intracellular signaling and core effectors. The analysis revealed that synergistic action of the transcription factors AP-1, vitamin D receptor and Nuclear Factor-kappaB in cross-activation of multiple pathways, including inflammatory cytokines, complement, clusterin, ephrins, and multiple metabolic pathways. We found that the products of over two thirds of genes linked to glaucoma by genetic analysis can be functionally interconnected into one epistatic network via experimentally-validated interactions. Finally, we built and analyzed an integrative disease pathology network from a combined set of genes revealed in genetic studies, genes differentially expressed in glaucoma and closely connected genes/proteins in the interactome.</p> <p>Conclusion</p> <p>Our results suggest several key biological network modules that are involved in regulating neurotoxicity of reactive astrocytes in glaucoma, and comprise potential targets for cell-based therapy.</p

ECONOMETRIC MODELING OF MANAGERIAL DECISIONS AT THE MACRO AND MICRO LEVELS

The theoretical and practical aspects of the application of the econometric approach to making managerial decisions in a crisis at the micro and macro levels are highlighted. Theoretical aspects determine the basic categories of the research problem: managerial decision, stages of managerial decision-making to determine the feasibility of using econometric methods, crisis and crisis phenomena, econometric approach. The specifics of making managerial decisions in a crisis at the micro and macro levels have been determined; the characteristic features, areas of problem solving and methods for solving managerial problems are considered, depending on the level of their formalization. Practical aspects highlight the rationale for the use of econometric methods at the stage of problem identification: identification of crisis phenomena in the relevant areas; a quantitative analysis of the crisis made it possible to identify and determine the imbalances. The advantages and disadvantages of the econometric approach to managerial decision-making are determined; general econometric methods of substantiating managerial decisions and their consequences are described. The features and advantages of Data-driven decision-making over Highest Paid Person's Opinion are determined; the types of information and analytical support of managerial decisions and the methods used for its formation are determined. The author's understanding of the concepts "econometric approach to managerial decision making", "information and analytical support of managerial decisions" is proposed. Practical aspects highlight the feasibility of using econometric methods and at the stage of justifying managerial decisions – the use of econometric methods in accordance with the scope of application, taking into account its specificity and state: a matrix "economic security – standard of living – innovative development" has been developed to justify the decision on the application of strategies to ensure economic security through changes in the level of innovative development and the standard of living of the population of the region (transformation strategy, innovative development strategy, human development strategy and growth strategy) on the basis of correlation-regression analysis, calculation of partial elasticity coefficients, a potentially most effective variant of reconfiguring the functional components of the innovation infrastructure was established; a model of authentic management of the development of the Ukrainian tourist services market has been developed, which assumes the use of specific mechanisms of authentic management and accounting for the authenticity of the cultural and historical resources of local tourism markets, the asymmetry of infrastructural and socio-economic development of markets, the spatial polarization of the location of climatic and recreational factors of local tourist markets; based on the results of the taxonomic analysis of the state of the hotel and restaurant industry, managerial solutions were proposed for the implementation of the strategy for the development of the hotel and restaurant industry for the coming period, including activities at the national level and at the level of individual business entities; an algorithm for making optimal decisions based on the development of the innovative potential of personnel has been developed: defining the problems of enterprise development; search for the reasons for the retardation of the development of the enterprise; determination of the reasons for the retardation of the development of the enterprise; determination of optimal solutions depending on the formulated problem; development of recommendations for achieving strategic goals, based on the construction of a "tree of opportunities"; a cognitive map (graph) of the process of making strategic decisions in the sphere of making strategic changes at mining and processing enterprises was built taking into account the influence of the following concepts: goals of strategic changes; the goals of the enterprise strategy implementation; the duration of the change lag; the level of encouragement of the team of changes; threshold opportunities for strategic change; unique opportunities for strategic change; average opportunities for strategic change; sufficiency of the potential for strategic changes; resistance to change; fiduciary corporate culture

Genetic Heritage of the Balto-Slavic Speaking Populations: A Synthesis of Autosomal, Mitochondrial and Y-Chromosomal Data

The Slavic branch of the Balto-Slavic sub-family of Indo-European languages underwent rapid divergence as a result of the spatial expansion of its speakers from Central-East Europe, in early medieval times. This expansion–mainly to East Europe and the northern Balkans–resulted in the incorporation of genetic components from numerous autochthonous populations into the Slavic gene pools. Here, we characterize genetic variation in all extant ethnic groups speaking Balto-Slavic languages by analyzing mitochondrial DNA (n = 6,876), Y-chromosomes (n = 6,079) and genome-wide SNP profiles (n = 296), within the context of other European populations. We also reassess the phylogeny of Slavic languages within the Balto-Slavic branch of Indo-European. We find that genetic distances among Balto-Slavic populations, based on autosomal and Y-chromosomal loci, show a high correlation (0.9) both with each other and with geography, but a slightly lower correlation (0.7) with mitochondrial DNA and linguistic affiliation. The data suggest that genetic diversity of the present-day Slavs was predominantly shaped in situ, and we detect two different substrata: ‘central-east European’ for West and East Slavs, and ‘south-east European’ for South Slavs. A pattern of distribution of segments identical by descent between groups of East-West and South Slavs suggests shared ancestry or a modest gene flow between those two groups, which might derive from the historic spread of Slavic people