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Post-traumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 new). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (for example, GRIA1, GRM8 and CACNA1E), developmental, axon guidance and transcription factors (for example, FOXP2, EFNA5 and DCC), synaptic structure and function genes (for example, PCLO, NCAM1 and PDE4B) and endocrine or immune regulators (for example, ESR1, TRAF3 and TANK). Additional top genes influence stress, immune, fear and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation.

Hypertension affects more than one billion people worldwide. Here we identify 113 novel loci, reporting a total of 2,103 independent genetic signals (P

This paper describes the technology and organization of the production of works on waterproofing the joints of highly prefabricated coating panels on a soft roof. The process of manufacturing waterproofing works can be divided into three stages - preparatory, main and final ones. Each stage has its own technological features and rules for performing work. The quality of execution of each stage affects the quality of work as a whole, ultimately providing the necessary reliability and strength of the coating.

As of the end of 2017, in Moscow, there are 286 mapped five-story fully-assembled residential buildings of K-7, II-32, II-35, 1605-AM, 1MG-300 series with total area of 1046,7 thousand square meters. They were built at the beginning of the era of mass construction, in 1959 - 1962 years, and were distinguished by thin outer walls of lightweight ribbed expanded clay panels with unstable thermal protection properties. The technologies used in the construction of such buildings do not allow reconstructing them. Nowadays, the task of demolition of the neighborhood of five-storey houses in Moscow with the maximum possible reduction in terms of production of works and the maximum quality of work is very important. It is also necessary to ensure safe work and compliance with all sanitary standards. The order of execution of the works has a mathematical solution method. It identifies issues that arise in the alternating sections performing the process of demolition.

The use of virtual structures in the area of CAD may have an impact on the design labour coefficient and on the works cost reduction. When developing and further functioning of virtual structures in organization, there are a number of issues related to the employees search and employment, work with CAD, with staff, payment for activities, acquisition and storage of information, reporting, interaction between the virtual team members, etc. The full activity of project organizations, both within the large and independent companies, requires for new procedural developments based on the information systems. The procedure of virtual structures development and implementation in organization is proposed to resolve this issue.

The article looks into virtual units of construction design companies. Challenges in virtual organization of construction design are discussed. Modern society is characterized by transition to informational model of organization. Also, we can talk about environmental engineering, that is, to improve the quality of information environment. New forms of organization can be classified according to such characteristics as scope and nature of the activity, type of ownership, legal status, and size. These forms, along with the virtual organization, include financial and industrial groups, business unions, and clusters. It is accepted to highlight main advantages of virtual organizations in the free choice of high-class resources while reducing time costs.

At the present time we consider the construction operations development triggered by the modern technologies development. The electronics, robotics, artificial intelligence, wireless technologies and more became the present-day production attribute. The creation of virtual organizations has become the expected solution of business communities. Following in the footsteps of information boom, in this article we consider the problem of construction field virtualisation, in particular: characteristics of virtuality and virtual structures operation, in-virtual organization work peculiarities, difficulties faced by the company manager with such form of work and criteria for the assessment of organization efficiency. The virtual organization is deemed to be the voluntary cooperation form of partners, aimed at project work type. This is the unique team, the basic resources of which are time and technologies. In general such organization does not have any geographical origin and it works using the Internet. In the context given herein, the virtual structure is considered in CAD conditions that is based on the high degree of construction field IT. Specific relations between the employees make the impact on the work process, therefore a number of both subjective (social, individual, etc.) and objective (financial) indices are given.

A review of the current state of the theory and practice of bioenergy production from waste allowed us to identify the scientific and applied problem of substantiating the rational configuration of a modular anaerobic bioenergy system, taking into account the volume of organic waste generated in settlements. To solve this problem, this paper develops an approach and an algorithm for matching the configuration of a modular anaerobic bioenergy production system with the amount of organic waste generated in residential areas. Unlike the existing tools, this takes into account the peculiarities of residential areas, which is the basis for accurate forecasting of organic waste generation and, accordingly, determining the configuration of the bioenergy production system. In addition, for each of the scenarios, the anaerobic digestion process is modeled, which allows us to determine the functional indicators that underlie the determination of a rational configuration in terms of cost and environmental performance. Based on the use of the developed tools for the production conditions of the Golosko residential area, Lviv (Ukraine), possible scenarios for the installation of modular anaerobic bioenergy production systems are substantiated. It was found that the greatest annual benefits are obtained from the processing of mixed food and yard waste. The payback period of investments in modular anaerobic bioenergy production systems for given conditions of a residential area largely depends on their configuration and ranges from 3.3 to 8.4 years, which differ from each other by 2.5 times. This indicates that the developed toolkit is of practical value, as it allows the coordination of the rational configuration of modular anaerobic bioenergy production systems with real production conditions. In the future, it is recommended to use the proposed decision support system to model the use of biomass as an energy resource in residential areas, which ensures the determination of the rational configuration of a modular anaerobic bioenergy production system for given conditions.

The modern system of national education, developing in the competence paradigm, puts on the agenda the need to form students' communicative skills that belong to the category of critical competencies of a meta-subject nature. The article discusses the methodological features and pedagogical conditions for forming meta-subject skills of schoolchildren in foreign language lessons. An attempt is proposed to determine the characteristics of the meta-subject approach, including a complex of personality traits that allow the student to act in a given communication situation at the level determined by the age-related psychological characteristics and the possibilities of the social experience of a younger student. The authors used the following research methods: utilizing the study and generalization of pedagogical experience and the survey method, the communicative, regulatory - behavioral and motivational characteristics of a younger student, which must be taken into account when introducing pedagogical technologies focused on meta-subject results in foreign language lessons, are concretized. The analysis of the real practice of an educational activity is aimed at establishing a set of features of the pedagogical support of the meta subject approach within the framework of the "foreign language" discipline in primary school. Based on the analysis of scientific literature on research and practical experience, several strategies have been identified that ensure the effective implementation of meta-subject results in younger students in foreign language lessons.

Both peripheral neuropathy and depression can be viewed as neurodegeneration's consequences of diabetes, at least in part coexisting with or resulting from sodium-calcium dysbalance. This study aims to assess the therapeutic potential of the orally applied reverse-mode inhibitor of the sodium-calcium exchanger (NCX) KB-R7943 in the streptozotocin (STZ) diabetes model in rats. A pilot pharmacokinetic (PK) study with high-performance liquid chromatography with high-resolution tandem mass spectrometric detection revealed higher drug exposure (AUC), lower volume of distribution (Vd) and clearance (Cl), and faster decline of the plasma concentration (ƛ) in rats with diabetes vs. controls. Brain and heart accumulation and urinary excretion of the unmetabolized KB-R7943 at least 24 h were also demonstrated in all rats. However, heart and hippocampus KB-R7943 penetration (AUCtissue/AUCplasma) was higher in controls vs. diabetic rats. The development of thermal, mechanical, and chemical-induced allodynia was assessed with the Cold plate test (CPT), Randall-Stiletto (R–S) test, and 0.5% formalin test (FT). Amitriptyline 10 mg/kg, KB-R7943 5 mg/kg, or 10 mg/kg p.o once daily was applied from the 28th to the 49th day. The body weight, coat status, CPT, R–S, and FT were evaluated on days (−5), 0, and 42. On day 41, a forced swim test and 24-h spontaneous physical activities were assessed. The chronic treatment effects were calculated as % of the maximum. A dose-depended amelioration of neuropathic and depression-like effects was demonstrated. The oral application of KB-R7943 for potentially treating neurodegenerative consequences of diabetes merits further studies. The brain, heart, and kidneys are essential contributors to the PKs of this drug, and their safety involvement needs to be further characterized.

BackgroundThe origin of sex differences in prevalence and presentation of neuropsychiatric and behavioral traits is largely unknown. Given established genetic contributions and correlations, we tested for a sex-differentiated genetic architecture within and between traits.MethodsUsing European ancestry genome-wide association summary statistics for 20 neuropsychiatric and behavioral traits, we tested for sex differences in single nucleotide polymorphism (SNP)-based heritability and genetic correlation (rg < 1). For each trait, we computed per-SNP z scores from sex-stratified regression coefficients and identified genes with sex-differentiated effects using a gene-based approach. We calculated correlation coefficients between z scores to test for shared sex-differentiated effects. Finally, we tested for sex differences in across-trait genetic correlations.ResultsWe observed no consistent sex differences in SNP-based heritability. Between-sex, within-trait genetic correlations were high, although

Manufacturing companies are always looking for ways to outperform their competitors. They are constantly trying to improve their efficiency and reduce costs. One method that improves efficiency and maximises the availability of production equipment is total productive maintenance (TPM), which is a lean optimisation philosophy tool that focuses on the optimisation of maintenance. Although TPM is known for improving maintenance, there are many obstacles to its successful implementation. Failure to properly implement TPM can result in additional costs and lost time, and it can have a negative impact on employees. For these reasons, a survey was prepared and conducted among several companies, each involved in a different field of work and having a different number of employees. The main findings of this research are the key factors that can negatively impact the implementation of TPM and lean tools in general, as well as suggestions for improvements that can ensure their successful implementation and sustainability. An analysis was conducted based on the size of each company as well as the job roles within them. The study covers issues that may arise during the implementation of TPM and other lean tools at all levels of the hierarchy in an enterprise and provides guidance on how to manage situations that may prevent the successful application of TPM.

Rare genetic variants can cause epilepsy, and genetic testing has been widely adopted for severe, paediatric-onset epilepsies. The phenotypic consequences of common genetic risk burden for epilepsies and their potential future clinical applications have not yet been determined. Using polygenic risk scores (PRS) from a European-ancestry genome-wide association study in generalized and focal epilepsy, we quantified common genetic burden in patients with generalized epilepsy (GE-PRS) or focal epilepsy (FE-PRS) from two independent non-Finnish European cohorts (Epi25 Consortium, n = 5705; Cleveland Clinic Epilepsy Center, n = 620; both compared to 20 435 controls). One Finnish-ancestry population isolate (Finnish-ancestry Epi25, n = 449; compared to 1559 controls), two European-ancestry biobanks (UK Biobank, n = 383 656; Vanderbilt biorepository, n = 49 494), and one Japanese-ancestry biobank (BioBank Japan, n = 168 680) were used for additional replications. Across 8386 patients with epilepsy and 622 212 population controls, we found and replicated significantly higher GE-PRS in patients with generalized epilepsy of European-ancestry compared to patients with focal epilepsy (Epi25: P = 1.64×10-15; Cleveland: P = 2.85×10-4; Finnish-ancestry Epi25: P = 1.80×10-4) or population controls (Epi25: P = 2.35×10-70; Cleveland: P = 1.43×10-7; Finnish-ancestry Epi25: P = 3.11×10-4; UK Biobank and Vanderbilt biorepository meta-analysis: P = 7.99×10-4). FE-PRS were significantly higher in patients with focal epilepsy compared to controls in the non-Finnish, non-biobank cohorts (Epi25: P = 5.74×10-19; Cleveland: P = 1.69×10-6). European ancestry-derived PRS did not predict generalized epilepsy or focal epilepsy in Japanese-ancestry individuals. Finally, we observed a significant 4.6-fold and a 4.5-fold enrichment of patients with generalized epilepsy compared to controls in the top 0.5% highest GE-PRS of the two non-Finnish European cohorts (Epi25: P = 2.60×10-15; Cleveland: P = 1.39×10-2). We conclude that common variant risk associated with epilepsy is significantly enriched in multiple cohorts of patients with epilepsy compared to controls-in particular for generalized epilepsy. As sample sizes and PRS accuracy continue to increase with further common variant discovery, PRS could complement established clinical biomarkers and augment genetic testing for patient classification, comorbidity research, and potentially targeted treatment.

A review of the current state of the theory and practice of bioenergy production from waste allowed us to identify the scientific and applied problem of substantiating the rational configuration of a modular anaerobic bioenergy system, taking into account the volume of organic waste generated in settlements. To solve this problem, this paper develops an approach and an algorithm for matching the configuration of a modular anaerobic bioenergy production system with the amount of organic waste generated in residential areas. Unlike the existing tools, this takes into account the peculiarities of residential areas, which is the basis for accurate forecasting of organic waste generation and, accordingly, determining the configuration of the bioenergy production system. In addition, for each of the scenarios, the anaerobic digestion process is modeled, which allows us to determine the functional indicators that underlie the determination of a rational configuration in terms of cost and environmental performance. Based on the use of the developed tools for the production conditions of the Golosko residential area, Lviv (Ukraine), possible scenarios for the installation of modular anaerobic bioenergy production systems are substantiated. It was found that the greatest annual benefits are obtained from the processing of mixed food and yard waste. The payback period of investments in modular anaerobic bioenergy production systems for given conditions of a residential area largely depends on their configuration and ranges from 3.3 to 8.4 years, which differ from each other by 2.5 times. This indicates that the developed toolkit is of practical value, as it allows the coordination of the rational configuration of modular anaerobic bioenergy production systems with real production conditions. In the future, it is recommended to use the proposed decision support system to model the use of biomass as an energy resource in residential areas, which ensures the determination of the rational configuration of a modular anaerobic bioenergy production system for given conditions. [ABSTRACT FROM AUTHOR]

The aim of the research is: to investigate the level of the development of creative potential of students – future foreign language teachers, to apply the program of group activity developed by us in order to develop the creativity of respondents, to analyze its effectiveness. The following theoretical methods of the research were used to solve the tasks formulated in the article: a categorical method, structural and functional methods, the methods of the analysis, systematization, modeling, generalization. Also we used experimental methods, such as statement research. For the last one we used such methodology, as: the test «Circles» by E.P. Thorens; the author’s methodology «The development of Creativity of teenagers» (Михальчук, Eр. Івашкевич & Яцюрик, 2021). The results of the research. In our research low results were obtained at both heuristic and reconstructive research levels. This indicates considerable difficulties that are arisen in a case when students are characterized with: a) the emergence of the ideas of solving the problem; b) making the design of the personal development; c) the embodiment of the idea in the activity, in communication with other students within the micro-group; d) the analysis and the evaluation of the results of pupils’ own creativity or innovation. The results having been obtained by us also indicate the need to organize special training for adolescents in order to make targeted influences on the development of their creativity. In such a way we’ve to make some conclusions. The concept of «creativity» is more general, because it includes creative qualities. Creativity reflects, in addition to subjective moments, also the process of reconciling novelty, innovation of the activity generated by the subject with the existing (so-called stereotypical) socio-cultural context. We consider creativity as the process of interaction that necessarily leads to the personal development. We also define creativity as an activity that creates something new, original, which is included not only into the history of the creator, but also into the history of science, art, etc. A similar point of view is expressed by us when we define creativity as going beyond the existing human knowledge, overcoming certain boundaries and obstacles. In such a way creativity means the creation of something new, which can mean both the transformation of the consciousness and behavior of the subject, generated by the person, but also which is alienated from his/her products. Conclusions. According to received data of our empirical research we offer some more definitions of the creativity, focusing the reader’s attention on the procedural aspect of this activity. In particular, we define creativity as the creation of something new in a situation where the problem-stimulus causes the invention of the so-called dominant, around which there are concentrated the necessary subjective statistics to solve this problem, requiring mandatory reference to their past, the person’s experience. The problem of creativity is considered by us through the concept of intellectual activity. The last is the phenomenon of self-movement of the activity, which is manifested in the process of cognitive activity of the individual, which goes beyond the requirements of this particular problem situation. In this process in the content of the ability to continue cognition independently outside there are actual the requirements of the initial situation, which situationally are not stimulated by productive activity and the secret of external forms of creativity is hidden. We mean the ability to see in the subject something new what other people do not see. Thus, the creative process is a kind of «derivative» of the intellect, refracted through the motivational sphere of the individual, which inhibits or stimulates its manifestations. After all, intelligence is determined by the dialectical relationships between two constructs. Defining, thus, the nature of creativity dwells on its immanent phenomenon, which considers creative abilities of the individual. We believe that understanding of human creative abilities should be considered as a kind of projection of unresolved problem of the nature of creativity. Although, in our opinion, having been given the existence of a variety of approaches of solving this problem, there are two main (or fundamental) ones: the approach to study creative abilities given the individual psychological differences of the subjects (B.М. Тeplov) and the approach of L.S. Vygotskyi (studying of creative abilities taking into account the personal qualities of a man). Defining the nature of creativity, we proceed from the delineation of the essence of the creative process, and from the characteristics of the creative product itself. This review coincides with our vision of this problem, because with this approach it is possible to consider the phenomenon of creativity not so much given the constant with genetic neurophysiological characteristics of homo, the creator, but taking into account the psychological manifestations of the individual’s ability to self-actualization (such as to the process of the man’s cognitive activity). We focus our attention on the position of the development of gifted and talented children. We believe that the learning and the development of such children creates an ideal model of creative human development, and the problem of the development of creativity should be considered in the paradigm of activity mediated by the creative abilities of the subject.

Introduction: Colorectal cancer is the third most common cancer type worldwide. Fluoropyrimidines and their prodrug-based regimens are widely applied as primary medications. The main enzyme responsible for the rate-limiting step in pyrimidine and for the 5-fluorouracil catabolism is dihydropyrimidine dehydrogenase (DPD).Aim: We aimed to screen DPD level and the changes of plasma antioxidant capacity of colorectal cancer patients on 5-fluorouracil regimen. Materials and methods: Human DPD Elisa Kit based on sandwich enzyme-linked immune-sorbent assay and spectrophotometric methods (FRAP and ABTS) were used in the study.Results: No statistically significant changes in plasma scavenging activity according to the results obtained in the ABTS system have been observed after evaluating all patients and considering DPD concentration. A decrease of the ferric reducing ability of patients’ plasma taken after the administered treatment was found. The increase of DPD level is accompanied by a decrease in the p values and therefore the statistical significance of the differences increases.Conclusions: Based on the aforementioned observations, it could be concluded that some aspects of plasma antioxidant capacity and individuals’ antioxidant status might be involved in the pathogenesis of the disease and could be altered by the activity of some enzymes. The cancer therapy in question, by the specificity of its mechanism of action, can modify patient’s oxidative status.

Objectives SPECTRUM is a unique multi-disciplinary, cross-sector collaborative research partnership between academics, government, and community organizations in Manitoba working together to address complex social problems. In our first research project, partners identified the need for quantitative evidence around outcomes of children involved with Child Protection Services (CPS), using linked administrative data. Approach From the SPECTRUM partnership, a research team with CPS expertise was established, including government policy-makers, community organizations representing First Nations families, and academics from multiple disciplines. The research is guided by an Advisory Circle of First Nations Knowledge Keepers. Linking health, education, CPS, and justice data we developed a matched cohort identifying children involved with CPS (2007-2018) for whom there was discretion in the decision to 1) place them in out-of-home care (n=19,718), or 2) keep them in their family home while providing services (n=28,154). Instrumental Variable analysis, with CPS agency as the instrument, will be used to compare outcomes. Results Following the trajectories of these two groups of CPS-involved children over time, we will compare their mental and physical health, educational achievement, and justice system involvement while accounting for individual-level (e.g., age, sex, chronic health conditions) and family-level (e.g., family income, maternal mental health, number of siblings) factors that may contribute to these outcomes. Preliminary findings will be workshopped with the SPECTRUM partnership to facilitate discussions on framing the evidence for policy makers. The SPECTRUM policy team will then prepare policy recommendations for government to consider. The Advisory Circle and a youth advisory squad will facilitate contextualizing and mobilizing findings. Actions taken by government in response to material provided will be monitored and will inform the development of subsequent research projects conducted by SPECTRUM. Conclusion Government and community stakeholder involvement throughout bolsters the likelihood of evidence translating into program and policy changes. This is not a situation where academics are telling government how to do their jobs – this is government, community organizations, and academics working together with the shared goal of better outcomes for children.

Vintage postporn es un podcast colectivo (de Rachele Borghi, Slavina y Emilie Viney) que hace transitar las palabras, las aproximaciones, las temáticas y las voces de la postpornografía tal como se desarrolló en España e Italia entre 2000 y 2015. Si “mi sexualidad es una creación artística” según afirma Lucía Egaña Rojas en su documental epónimo, “Vintage postporn” se enfoca en el cuerpo como laboratorio de experimentación y placer y también como herramienta de resistencia. Con citas de Emma Goldman y Diana Pornoterrorista Rachele Borghi es pornactivista transfeminista, profesora titular de geografía en la Universidad de la Sorbona. Estudia las transgresiones performáticas en el espacio público como reacción en contra de las normas impuestas así como el cuerpo entendido como laboratorio y herramienta de resistencia. Sus líneas de investigación son la visibilización de las normas en los espacios públicos e institucionales (especialmente la academia), las prácticas que permiten romperlas y los espacios de contagio entre ámbitos académicos, artísticos y militantes. Sus contactos con colectivos postporno y queer le han permitido cuestionar su propia práctica, su posicionamiento en la academia y han resaltado la urgencia de encontrar y experimentar nuevos acercamientos para no reproducir el binomio teoría-producción teórica / practica-producción militante. Décolonialité et privilège. Devenir complices (2021, ed. Daronnes) es su último ensayo. slavina es performer, escritora y educadora transfeminista: define porno-activismo su ámbito de investigación y creación. vive y trabaja entre Italia y el estado español. su producción está enfocada en las políticas del cuerpo y de los cuidados y se desarrolla a través de la realización de experiencias de empoderamiento erotico comunitario. en sus proyectos (video, cabaret, talleres) trabaja el potencial político de las intimidades compartidas. en 2012 ha publicado un libro de relatos eróticos en italiano, pero su orgullo es sobretodo lo de haber facilitado feministement las conexiones entre su tierra de origen y el contexto transfeminista español, traduciendo y promoviendo autorxs y obras. es co-fundadora del colectivo psicoerótica femminista, una experimentación terapéutica creativa y colectiva que integra pornografía y psicoanálisis. en sus ratos libres es madre y practica yoga. Emilie Viney es catedrática de geografía de la enseñanza segundaria y docente en la Universidad de la Sorbona. Enseña entre otras cosas geografía de la dominación, geografía de los sexos y sexualidad, epistemología de la geografía. Se interesa por la manera de transmitir los saberes en geografía sin reproducir las relaciones de poder mediante pedagogías críticas. Se involucra con gusto en los proyectos en los que Rachele Borghi le invita a participar.

Russian-Japanese relations are historically ambiguous. Recently, the situation began to change and the Cross Year of Japan in Russia and Russia in Japan project (2018-2019) influenced these changes. The article is an overview of the materials of the Russian and Japanese media on the activities of this international project.

Background. We previously found that a decrease in the number of NKT cells and activated CD 25+ peripheral blood lymphocytes (PBLs) before neoadjuvant chemotherapy was associated with an increased likelihood of disease progression in patients with locally advanced triple-negative breast cancer (TN BC).The purpose of this study was to determine the relationship between the initial number of NKT-and CD 25+ PBLs and relapsefree survival (RFS)/overall survival (OS ) in patients with TN BC who received neoadjuvant chemotherapy with cisplatin and paclitaxel followed by surgery.Material and Methods. The study included patients with stage II and III TN BC. The follow-up time was 36 and 66.9 months. Immediately before chemotherapy, the percentage of CD 3+CD 16+CD 56+ (NKT) -, CD 25+- and CD 8+ PBLs was determined by flow cytometry. Statistical analysis of the data was carried out using the Statistics 7 software package. The Kaplan-Meier method was used to determine the relationship between immunological parameters and RFS/ OS .Results. The decreased level of NKT cells before treatment was associated with a decrease in the 3-year RFS [Me: 20.1 (0.533 and 39.7) months] compared to that observed in patients with higher percentage of these cells than in the control (Me was not achieved). There were no statistically significant differences in the 3-year OS between the groups. The initially reduced number of CD 25+ lymphocytes in comparison with the control was associated with decreased rates of both RFS and OS . The difference in DFS and OS was more significant between the groups of patients who simultaneously had an increased initial number of both NKT and CD 25+ cells and patients in whom both cell populations were below normal levels.Conclusion. The initial (prior to chemotherapy) number of NKT and activated CD 25+ PBLs can apparently be a predictive factor in TN BC patients, who received neoadjuvant chemotherapy with cisplatin and paclitaxel.

Knockout of the memory suppressor gene histone deacetylase 2 (Hdac2) in mice elicits cognitive enhancement, and drugs that block HDAC2 have potential as therapeutics for disorders affecting memory. Currently available HDAC2 catalytic activity inhibitors are not fully isoform specific and have short half-lives. Antisense oligonucleotides (ASOs) are drugs that elicit extremely long-lasting, specific inhibition through base pairing with RNA targets. We utilized an ASO to reduce Hdac2 messenger RNA (mRNA) in mice and determined its longevity, specificity, and mechanism of repression. A single injection of the Hdac2-targeted ASO in the central nervous system produced persistent reduction in HDAC2 protein and Hdac2 mRNA levels for 16 weeks. It enhanced object location memory for 8 weeks. RNA sequencing (RNA-seq) analysis of brain tissues revealed that the repression was specific to Hdac2 relative to related Hdac isoforms, and Hdac2 reduction caused alterations in the expression of genes involved in extracellular signal-regulated kinase (ERK) and memory-associated immune signaling pathways. Hdac2-targeted ASOs also suppress a nonpolyadenylated Hdac2 regulatory RNA and elicit direct transcriptional suppression of the Hdac2 gene through stalling RNA polymerase II. These findings identify transcriptional suppression of the target gene as a novel mechanism of action of ASOs. Keywords: antisense oligonucleotide, Hdac2, memory, autism, Alzheimer's disease, extra-coding RNA, transcription

The article discusses the stereotyping and mythologization of the image of Russia, identified as a result of an analysis of the modern Spanish press. The empirical base of the study consists of articles of electronic versions of socio-political newspapers “ABC”, “El Pais”, “El Mundo” from 2014 to 2018. The considered time interval is associated with significant changes in international relations and the emergence of differences between the West and Russia on key issues of its foreign and domestic policy. Immediate response of the international community to the actions of Russia has contributed to fundamental changes in its perceptions about the global media space. An important component of the image of the world in the media sphere is the image of the state, which is created primarily through the media. It is formed on the basis of actual events of the surrounding reality, reflects their dynamics, expresses the public consciousness and influences it. Creating a media image of Russia, Spanish newspapers rely on stereotypical ideas and myths about it existing in the West, and also take part in the creation of new ones. Stereotyping and mythologization form a specific negative perception matrix, which negatively affects the image of Russia and demonizes it.

We have recently identified several aroylhydrazone-based molecular hybrids with antiseizure activity. We aimed to investigate the analgesic activity of these molecules further. Male ICR mice were injected intraperitoneally with the tested substances or with the vehicle only (controls). We performed hot plate tests, formalin test and maximal electroshock (MES) test and further studied the cytokine proteome in the brain. In silico analysis was performed for prediction of the physicochemical parameters and activity. The furan-substituted aroylhydrazone-based 2H-chromene hybrid showed a significant increase of the latent time as compared with the baseline values (p < .05). Both the chlorine-substituted and the methyl-substituted aroylhydrazone-based coumarin derivatives significantly decreased the first phase of the formalin test (p < .05). We also found suppression of all the cytokines which were overexpressed in the model of acute seizures (MES test) and in the formalin paw test. The in silico model predicted hydroxymethylglutaryl coenzyme A synthetase 2 (HMGCS2) enhancer activity. Further testing is needed to confirm the mechanism of the potentially beneficial effects of the tested substances and to evaluate the toxicity and efficacy of the proposed molecules.

The purpose of the article is to analyze the political media memes’ structure and to compare them with simulacra according to the theory of Jean Baudrillard. We consider, that media memes have a clear structure via they could spread in social media. This structure also allows media memes to spread in media. Through analysis of political media memes’ spreading, generating and evolution as viral units, we could understand post-truth policy. Comparison of political media memes with simulacra could became one more step to better understanding of viral information and post-truth.

Chemotherapy is among the primary methods of treating advanced breast cancer. It was shown that clinical efficacy of various chemotherapeutic agents in many cases depends not only on their direct cytostatic and/or cytotoxic effect upon tumor cells, but also on their ability to modulate phenotype of the tumor cells and to influence anti-tumor immune response. Initial state of the immune system and its response to treatment is crucial. Antitumor response involves cells of innate and adaptive immunity (NK, NKT, T cells). These populations are heterogeneous and contain, e.g., cells with antitumor activity and regulatory (suppressor) cells that suppress immune response and promote tumor progression. The aim of this work was to determine the relationship between the initial state of cellular immunity of patients suffering from locally advanced breast cancer with triple negative phenotype, and clinical effect of chemotherapy (cisplatin + doxorubicin/paclitaxel), and studying effects of the therapy upon subpopulation profiles of peripheral blood lymphocytes in the patients. We registered the terms of the disease progression as well as overall survival and progression-free survival. The disease progressed in 25 of 53 cases (47.2%) whereas 28 of 53 patients (52.8%) remained progression-free. The observation period was 35.5 months. Laboratory examination of the patients included immunophenotyping of peripheral blood lymphocytes and determination of NK cell cytotoxic activity before and after chemotherapy. Percentages of effectors and regulatory lymphocyte populations were determined. The results obtained showed that, for some lymphocyte subsets, the pre-treatment differences of cell percentage deviations from control were found between the progression-free groups and patients with progression of the disease. The differences in percentages of NKT cells and lymphocytes expressing CD25 activation marker proved to be most significant. Decreased number of NKT cells and activated CD25+ lymphocytes prior to chemotherapy was associated with increased probability of disease progression. Reduced percentage of NKT cells against control was observed in 56% of patients from the progression group (PD), and only 21.4% in the group free of disease progression (DF). [OR = 4.6 (95% CI 1.4 to 15.4)]. Percentage of CD25+ lymphocytes was decreased from 68.2% in the PD group, and 28.6% for DF patients [OR = 5.4 (95% CI 1.6-18.1)]. We studied relationships between the overall survival (OS) and percentage of perforin-containing NK, NKT, and T cells, and mean perforin fluorescence density (PFD) in these lymphocyte subsets in 26 of the 53 patients before treatment. A statistically significant positive correlation was revealed between OS and perforin PFD in all the three cell populations under study. Normalization of the parameters altered before treatment, and an increase of T cell numbers was observed in the disease-free patients.

The article presents the scientific and theoretical analysis of the state of development of the problem on adaptation of children of early age in the conditions of a preschool institution. It is determined that the problem of adaptation to the conditions of a preschool institution concerns a child aged 2–6 years. It turns out that the process of gradual entry into the world of widespread social connections and its development was called socialization. It is noted that socialization provides individualization, because only in social connections, communication, interaction, self-determination takes place in the socio-cultural space and self-awareness is developed. It is proved that the formation of a personality in preschool years is a progressive development of «Me» at every new stage of childhood. It is stated that the first impressions and first lessons of communication are taken by a child in the family: here he / she feels the attitude towards him / herself, observes the relationship between adults, takes over their forms of behavior, here the moral features of his / her characteris formed. It is noted that the most important formation during the crisis of the third year is the emergence of a new feeling «Me». The development of a new attitude to him / herself arises as a result of the formation of a child’s self-esteem under the influence of an adult’s assessment of his / her achievements. It is established that personality-based development of a child is not possible without the help of an adult.

Шляхом проведення епістемологічної оцінки в статті здійснено спробу подолання утопічних й дистопічних міркувань, які превалюють в судженнях щодо впливу Інтернету на організацію публічної сфери, а також проведено постмодерністський перегляд теорії Ю. Габермаса з точки зору сучасної медіа-революції. Обґрунтовано формування не-егалітарної мережевої публічної сфери, яка постає як паралельні дискурсивні арени, на яких члени соціальних груп виробляють і розповсюджують контрдискурси, що в свою чергу дозволяє їм формулювати опозиційні інтерпретації власних ідентичностей, інтересів та потреб. Зроблено висновок про те, що демократія виявляє себе не стільки в кібер-просторі, скільки через реальну структуру суспільних відносин, що дозволяє виконувати ряд завдань, серед яких розвиток інституту громадського діалогу та формування соціальної солідарності. Разом з тим вказано, що відбувається значне послаблення символічної влади традиційних відправників повідомлень (інститутів влади), що здійснюють управління за допомогою історично закодованих соціальних практик (як-то: політична ідеологія, релігія, традиційні цінності). Вказано на ряд факторів, які компрометують репрезентативність віртуальної сфери, а саме: нерівність доступу до інформації, фрагментація політичного дискурсу, мімікрія до існуючої політичної культури, а не створення нової. Підкреслено вагому перспективу в розробці життєздатних варіантів цифрового майбутнього й конфігурації моделей позитивних зрушень.

Epilepsy is one of most reported neurological disorders after migraine, stroke and Alzheimer's disease. Empiric clinical data reveal that seizures and epilepsy more likely affect men than women. The aim of present study was to investigate the effect of steroid adrenal and gonadal hormones on the intensity, dynamics and latency of kainic acid-evoked seizure and lethality in a rat model of epileptogenesis. After surgical adrenalectomy/gonadectomy, male rats were at random assorted in groups and treated from postoperative day 1 to day 5 with corticosterone (30 mg/kg), estradiol (0.03 mg/kg), progesterone (75 mg/kg), dihydroprogesterone (75 mg/kg) and dihydrotestosterone (0.75 mg/kg). Spontaneous recurrent seizures generated by kainic acid were assessed. The treatment with corticosterone eliminated the aggravation of kainic acid-evoked seizures produced by adrenalectomy/gonadectomy. The application of corticosterone decreased the seizure intensity by 31% and prevented seizure-associated animal death. The effect of estradiol treatment was quite opposite. Estradiol treatment exacerbated the somatic and behavioural aspects of kainic acid-evoked epilepsy-like syndrome. The hormone increased the intensity of kainic acid-evoked seizures by 31%, decreased the latency of clonic weak seizures by 49% and enhanced the associated lethality by 133%. The treatment with progesterone or dihydroprogesterone produced minor alterations in intensity and latency of kainic acid-evoked seizures in the operated male rats. The application of dihydrotestosterone significantly aggravated the kainic acid-evoked seizures. In summary, hormonal unbalance could play an important role for seizure susceptibility in epileptogenesis. Corticosterone has better anti-seizure activity than progesterone and testosterone has significant pro-convulsive activity.

The article covers the results of clinical application of a domestic drug based on recombinant tumor necrosis factor-alphathymosin-alpha1 (Refnot) in 20 patients with metastatic skin melanoma. Refnot was administered at a dose of 100 000 IU subcutaneously 1–5 days every week, the cycle 3 or 4 weeks. During the therapy the levels of vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2) were determined in patients serum before therapy, every 3 or 4 weeks of treatment until disease progression. In patients with stabilization of the disease showed a decreasing level of VEGF and FGF. In the case of the detection of the progression level of VEGF and FGF have.

Pregabalin and gabapentin are amino-acid derivatives of gamma-aminobutyric acid. They have a high affinity to the α2δ protein in the central nervous system and both have been shown to be effective for neuropathic pain disorder. The aim of this study was to investigate the efficacy of gabapentin and pregabalin in animal models of neuropathic pain, and to correlate with clinical outcomes in patients with diabetic neuropathy. Gabapentin (60 mg/kg) and pregabalin (30 mg/kg) attenuate mechanical, tactile and heat hypersensitivity in rats with chronic constriction injury of the sciatic nerve and streptozotocin (STZ)-induced diabetes. There is no evidence that one of the drugs is superior to another at the different rat models and tests. In the incisional pain model, there was partial efficacy of gabapentin. Our clinical data suggest that relative to the baseline pain score, the treatment with pregabalin at doses of 300 mg/day or gabapentin at doses of 900 mg/day would be effective and well tolerated in patients diagnosed with moderate diabetic polyneuropathy. The study suggested that pregabalin may provide better analgesic outcomes than gabapentin on the sixth month of treatment. In conclusion, the comparative effects of gabapentinoids in animal models of neuropathic pain and neuropathic patients are suggestive of similar pathophysiological mechanisms being involved, but successful outcome is determined by a patient's individuality and the drug nature as well as the drug tolerability.

The research is devoted to the study of the subject-subject interaction at the higher educational institutions.The concept essence of subject-subject interaction has been clarified and its structure has been stipulated in the article. The authors have defined the components of the subject-subject interaction. They are the following: motivational, communicative and activity ones. The psycho-pedagogical conditions of the subject-subject interaction at the higher educational institutions have been justified. Thecriteria and indicators to estimate the subject-subject interaction level have been defined. The features of subject-subject interaction at the higher educational institutions have been empirically determined, namely: 1) favourable communicative atmosphere being provided by equal positions of teachers and students; the communicative positions formation, searching common ground for effective joint activities in the process of subject-subject interaction; 2) the content of educational material and selection of forms and means of educational-cognitive activity; 3) mutual activity of interaction subjects. The results obtained while having implemented the substantiated programme gave the possibility to stipulate the practical recommendations to the teachers of higher educational institutions in order to raise the interaction level in classes and develop military professionals’ competence.The evidence testified the hypotheses. The analysis of scientific sources shows that the study of interaction in psychology is carried out in such basic directions: the clarification of the categories of the status of the concept of «interaction», the isolation of the components of its structure and content, the definition of its place in the development of mental processes of the individual, as well as in system processes of higher order.

The aim of this study was to estimate the genetic diversity of Greek and Bulgarian grapevine varieties with the use of microsatellite markers. The studied samples were collected from various productive vineyards, consisting of eight Greek and nine Bulgarian native varieties. In order to create a genetic profile for each sample, a multiplex PCR reaction method was used amplifying simultaneously seven microsatellite loci. Statistical analysis of data showed that there was a high degree of genetic heterogeneity among most of the varieties studied, highlighting the discriminative power of the chosen set of markers. Moreover, the synonymy of (I) Greek Pamid and Bulgarian Pamid and (II) Greek Zoumiatiko and Bulgarian Dimyat was suggested, as each variety pair had identical allele profiles in all loci examined. Regarding the Greek Mavrud and Bulgarian Mavrud varieties, there was a close genetic relationship between them, however, they did not share common alleles in all microsatellite loci and, therefore, should not be characterized as synonyms. On the other hand, Greek and Bulgarian Keratsouda, which were supposed to be common varieties, were found to be genetically different, supporting that these two varieties should be considered as homonyms. Despite the genotypic assay performed herein, we believe that additional molecular work is needed for the efficient management of Greek and Bulgarian grapevine genepools, as well as to safely suggest any synonym or homonym annotation.