64 research outputs found
Viral fibrotic scoring and drug screen based on MAPK activity uncovers EGFR as a key regulator of COVID-19 fibrosis
No full textUnderstanding the molecular basis of fibrosis, the lethal complication of COVID-19, is urgent. By the analysis of RNA-sequencing data of SARS-CoV-2-infected cells combined with data mining we identified genes involved in COVID-19 progression. To characterize their implication in the fibrosis development we established a correlation matrix based on the transcriptomic data of patients with idiopathic pulmonary fibrosis. With this method, we have identified a cluster of genes responsible for SARS-CoV-2-fibrosis including its entry receptor ACE2 and epidermal growth factor EGF. Then, we developed Vi-Fi scoring—a novel drug repurposing approach and simultaneously quantified antiviral and antifibrotic activities of the drugs based on their transcriptomic signatures. We revealed the strong dual antifibrotic and antiviral activity of EGFR/ErbB inhibitors. Before the in vitro validation, we have clustered 277 cell lines and revealed distinct COVID-19 transcriptomic signatures of the cells with similar phenotypes that defines their suitability for COVID-19 research. By ERK activity monitoring in living lung cells, we show that the drugs with predicted antifibrotic activity downregulate ERK in the host lung cells. Overall, our study provides novel insights on SARS-CoV-2 dependence on EGFR/ERK signaling and demonstrates the utility of EGFR/ErbB inhibitors for COVID-19 treatment
Immunoproteasome Activity and Content Determine Hematopoietic Cell Sensitivity to ONX-0914 and to the Infection of Cells with Lentiviruses
No full textProteasomes are intracellular structures responsible for protein degradation. The 20S proteasome is a core catalytic element of the proteasome assembly. Variations of catalytic subunits generate different forms of 20S proteasomes including immunoproteasomes (iPs), which are present mostly in the immune cells. Certain cells of the immune system are primary targets of retroviruses. It has been shown that several viral proteins directly affect proteasome functionality, while inhibition of proteasome activity with broad specificity proteasome inhibitors stimulates viral transduction. Here we specifically addressed the role of the immunoproteasomes during early stages of viral transduction and investigated the effects of specific immunoproteasome inhibition and activation prior to infection using a panel of cell lines. Inhibition of iPs in hematopoietic cells with immunoproteasome-specific inhibitor ONX-0914 resulted in increased infection by VSV-G pseudotyped lentiviruses. Moreover, a tendency for increased infection of cloned cells with endogenously decreased proteasome activity was revealed. Conversely, activation of iPs by IFN-γ markedly reduced the viral infectivity, which was rescued upon simultaneous immunoproteasome inhibition. Our results indicate that immunoproteasome activity might be determinative for the cellular antiretroviral resistance at least for the cells with high iP content. Finally, therapeutic application of immunoproteasome inhibitors might promote retroviral infection of cells in vivo
PB1760: PREDICTION OF DRUG SENSITIVITY AND GENETIC VULNERABILITY FOR ACUTE LEUKEMIA SUBTYPES USING GRAPH OF SIGNALING PATHWAY CORRELATIONS.
No full textБруно Латур и аналитическая эпистемология
No full textIn the article, the author examines the theory of knowledge of Bruno Latour from the perspective of analytic epistemology. Representatives of this approach-as well as Bruno Latour himself- are trying to answer the question: "What is knowledge?". The author explicates the difference between Latour's theory and the basic premises of the analytic epistemologists. In order to do this, the author highlights the theoretical foundations of Latour's theory of knowledge and demonstrates the conventions in the analysis of knowledge which this approach violates. Using the distinctions of analytic epistemology, the author classifies Latour's theory as a purist antisceptic invariantistic externalism. Such a theoretical position is one of the most common views on knowledge in this field. This classification of Latour's views makes it possible to identify the problems specific to this position. The author demonstrates that Latour's theory avoids some of these problems, that some of the problems have a solution specific to this theory, and that some of the problems are not specifically addressed within it. The advantage of Latour's theory is that it copes well with the two main challenges of analytic theories of knowledge: the Gettier problem and the prob- 117 lem of skepticism. In the conclusion, the author offers a critique specific to Latour's theory and presents possible objections to it
Formation of prerequisites for the renovationist schism among the liberal nobility and clergy of Orel guberniya in 1900–1917
No full textBased on the analysis of the periodicals of Orel guberniya of the early 20th century, as well as information on the public utterances of provincial public fi gures on the Church question in the pre-revolutionary period, the author reconstructs the process of formation of Renovationist schism among the liberal nobility and clergy of the province of Orel, trying to explain the presence of succession between the supporters of the reform of the Church in diff erent periods. The author also traces the emergence of ideas of Christian socialism in the province, which later became central to Soviet Renovationism. The study of the genesis of these ideas in the province during the period from the First Russian revolution to the February revolution makes it possible to understand the connection between religious and political factors in this dramatic period. When describing the events known to historians of the “Church revolution” of 1917 in Orel guberniya, the article draws on a unique material of personal origin, i.e. a detailed description of these events by one of the priests who was a participant and witness. The author of the article formulates his view on the processes of using the ideas of reforming the Church by various political parties from the Cadets to the Bolsheviks, finds a point of convergence of interests of those who fought for political power, and those who, being a certain stratum of the regional clergy, expressed their readiness to ensure the interests of the existing power, quickly changing their “patrons” if necessary. Moreover, attention is drawn to the facts of a rapid and radical change in the political position of certain representatives of Orel priesthood precisely during the implementation of serious revolutionary changes in the Russian state. The author was able to identify these names, specify them in the article and establish the diff erences between the schismatic element and those who really cared about the welfare of the Church
Dark matter production via a non-minimal coupling to gravity
No full textInternational audienceWe study postinflationary scalar dark matter production via its non-minimal coupling to gravity. During the inflaton oscillation epoch, dark matter is produced resonantly for a sufficiently large non-minimal coupling . We find that backreaction on the curvature and rescattering effects typically become important for the values of above , which invalidate simple estimates of the production efficiency. At large couplings, the dark matter yield becomes almost independent of , signifying approximate quasi-equilibrium in the inflaton-dark matter system. Although the analysis gets complicated by the presence of apparent negative energy in the Jordan frame, this behaviour can be regularized by introducing mild dark matter self-interaction. Using lattice simulations, we delineate parameter space leading to the correct dark matter relic abundance
BANKING SECTOR MODERNIZATION(SPANISH RECIPE)
No full textThe aim of the research is to analyze transformation of the Spanish banking sector after the financial crisis of the year 2008. The author examines a hypothesis that banking system played an important role in the development of Spain’s economy. Spain’s banking sector was substantially transformed during the economic crisis, and now serves as a prerequisite for development of Spain’s national economy during post crisis perio
The Annalistic Writing in Novgorod ca. 1200
No full textThe paper is concerned with the analysis of textual differences between the Elder and the Younger versions of the First Novgorodian Chronicle. The author shows that several groups of differences are concentrated in the same part of the text: in the annals for the 12th century. They increase toward the end of the century, are the most numerous in the annals for the 1190s, and never cross the edge of the annals for 1199/1200. This chronological boundary is very impressive and cannot be incidental. The differences in question are both supplementary readings of the Elder Version (notes on some events absent in the Younger Version, more detailed datings, etc.) and of the Younger Version (additional details on some events of the 1190s). The author shows that all these differences must be attributed to an editor active soon after 1199 (the Elder Version reflecting the state of the text before this editorial episode, and the Younger version reflecting the results of it). This conclusion enables the author to challenge Alexey Gippius’ (1997) and Alan Timberlake’s (2000) theories on the relationship of the texts in question, and to suggest a new, somewhat simpler theory
Emetine in Combination with Chloroquine Induces Oncolytic Potential of HIV-1-Based Lentiviral Particles
No full textChloroquine and Emetine are drugs used to treat human parasitic infections. In addition, it has been shown that these drugs have an antiviral effect. Both drugs were also found to cause a suppressive effect on the growth of cancer cells of different origins. Here, using the replication-deficient HIV-1-based lentiviral vector particles, we evaluated the ability of the combination of these drugs to reduce viral transduction efficiency. We showed that these drugs act synergistically to decrease cancer cell growth when added in combination with medium containing lentiviral particles. We found that the combination of these drugs with lentiviral particles decreases the viability of treated cells. Taken together, we state the oncolytic potential of the medium containing HIV-1-based particles provoked by the combination of Chloroquine and Emetine
PathMiner: A library for mining of path-based representations of code
No full textOne recent, significant advance in modeling source code for machine learning algorithms has been the introduction of path-based representation - an approach consisting in representing a snippet of code as a collection of paths from its syntax tree. Such representation efficiently captures the structure of code, which, in turn, carries its semantics and other information. Building the path-based representation involves parsing the code and extracting the paths from its syntax tree; these steps build up to a substantial technical job. With no common reusable toolkit existing for this task, the burden of mining diverts the focus of researchers from the essential work and hinders newcomers in the field of machine learning on code. In this paper, we present PathMiner - an open-source library for mining path-based representations of code. PathMiner is fast, flexible, well-tested, and easily extensible to support input code in any common programming language. Preprint [https://doi.org/10.5281/zenodo.2595271]; released tool [https://doi.org/10.5281/zenodo.2595257].Software Engineerin
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