Foreign trade and marketing processes in the context of sustainable development

Purpose: The article aims to study foreign economic and trade relations between the countries of Central and Eastern Europe, the CIS and the Western European countries. In addition, the study improves forms of foreign economic cooperation between the countries and suggests the stages of its implementation in the integration group. Design/Methodology/Approach: Central and Eastern European countries are experiencing the increase and acceleration of the labour migration to Western European countries, which has a negative impact on their medium-and long-term development. As a theoretical and methodological basis, the article uses historical-logical, dialectical principles and contradictions, the method of the scientific abstraction. The process-system approach, which was used in the study of foreign economic relations between the partner countries, gained special importance in the argument of the need to implement stages. Findings: Authors presented the form of the foreign economic cooperation between the countries as the geostrategic economic block and the stages of its implementation. As the study shows, these stages will help to smooth out the economic inequality between the Central and Eastern regions of Europe and Western European countries. Practical implications: In practice, authors investigate the phased implementation of the geostrategic economic bloc form, which will reduce inequality between the partner countries of the European Union. Originality/Value: The economic inequality between developed and developing countries of the European Union is increasing every year, which can lead to the transformation of the integration group, so it is necessary to develop new forms and mechanisms of foreign economic relations between the partner countries.peer-reviewe

Search for Specific Biomarkers of IFNβ Bioactivity in Patients with Multiple Sclerosis

Myxovirus A (MxA), a protein encoded by the MX1 gene with antiviral activity, has proven to be a sensitive measure of IFNβ bioactivity in multiple sclerosis (MS). However, the use of MxA as a biomarker of IFNβ bioactivity has been criticized for the lack of evidence of its role on disease pathogenesis and the clinical response to IFNβ. Here, we aimed to identify specific biomarkers of IFNβ bioactivity in order to compare their gene expression induction by type I IFNs with the MxA, and to investigate their potential role in MS pathogenesis. Gene expression microarrays were performed in PBMC from MS patients who developed neutralizing antibodies (NAB) to IFNβ at 12 and/or 24 months of treatment and patients who remained NAB negative. Nine genes followed patterns in gene expression over time similar to the MX1, which was considered the gold standard gene, and were selected for further experiments: IFI6, IFI27, IFI44L, IFIT1, HERC5, LY6E, RSAD2, SIGLEC1, and USP18. In vitro experiments in PBMC from healthy controls revealed specific induction of selected biomarkers by IFNβ but not IFNγ, and several markers, in particular USP18 and HERC5, were shown to be significantly induced at lower IFNβ concentrations and more selective than the MX1 as biomarkers of IFNβ bioactivity. In addition, USP18 expression was deficient in MS patients compared with healthy controls (p = 0.0004). We propose specific biomarkers that may be considered in addition to the MxA to evaluate IFNβ bioactivity, and to further explore their implication in MS pathogenesis

Data on gut metagenomes of the patients with Helicobacter pylori infection before and after the antibiotic therapy

© 2017Antibiotic therapy can lead to the disruption of gut microbiota community with possible negative outcomes for human health. One of the diseases for which the treatment scheme commonly included antibiotic intake is Helicobacter pylori infection. The changes in taxonomic and functional composition of microbiota in patients can be assessed using “shotgun” metagenomic sequencing. Ten stool samples were collected from 4 patients with Helicobacter pylori infection before and directly after the H. pylori eradication course. Additionally, for two of the subjects, the samples were collected 1 month after the end of the treatment. The samples were subject to “shotgun” (whole-genome) metagenomic sequencing using Illumina HiSeq platform. The reads are deposited in the ENA (project ID: PRJEB18265)

Lethal Influenza Virus Infection in Macaques Is Associated with Early Dysregulation of Inflammatory Related Genes

The enormous toll on human life during the 1918–1919 Spanish influenza pandemic is a constant reminder of the potential lethality of influenza viruses. With the declaration by the World Health Organization of a new H1N1 influenza virus pandemic, and with continued human cases of highly pathogenic H5N1 avian influenza virus infection, a better understanding of the host response to highly pathogenic influenza viruses is essential. To this end, we compared pathology and global gene expression profiles in bronchial tissue from macaques infected with either the reconstructed 1918 pandemic virus or the highly pathogenic avian H5N1 virus A/Vietnam/1203/04. Severe pathology was observed in respiratory tissues from 1918 virus-infected animals as early as 12 hours after infection, and pathology steadily increased at later time points. Although tissues from animals infected with A/Vietnam/1203/04 also showed clear signs of pathology early on, less pathology was observed at later time points, and there was evidence of tissue repair. Global transcriptional profiles revealed that specific groups of genes associated with inflammation and cell death were up-regulated in bronchial tissues from animals infected with the 1918 virus but down-regulated in animals infected with A/Vietnam/1203/04. Importantly, the 1918 virus up-regulated key components of the inflammasome, NLRP3 and IL-1β, whereas these genes were down-regulated by A/Vietnam/1203/04 early after infection. TUNEL assays revealed that both viruses elicited an apoptotic response in lungs and bronchi, although the response occurred earlier during 1918 virus infection. Our findings suggest that the severity of disease in 1918 virus-infected macaques is a consequence of the early up-regulation of cell death and inflammatory related genes, in which additive or synergistic effects likely dictate the severity of tissue damage

Variability of Sequence Surrounding the Xist Gene in Rodents Suggests Taxon-Specific Regulation of X Chromosome Inactivation

One of the two X chromosomes in female mammalian cells is subject to inactivation (XCI) initiated by the Xist gene. In this study, we examined in rodents (voles and rat) the conservation of the microsatellite region DXPas34, the Tsix gene (antisense counterpart of Xist), and enhancer Xite that have been shown to flank Xist and regulate XCI in mouse. We have found that mouse regions of the Tsix gene major promoter and minisatellite repeat DXPas34 are conserved among rodents. We have also shown that in voles and rat the region homologous to the mouse Tsix major promoter, initiates antisense to Xist transcription and terminates around the Xist gene start site as is observed with mouse Tsix. A conservation of Tsix expression pattern in voles, rat and mice suggests a crucial role of the antisense transcription in regulation of Xist and XIC in rodents. Most surprisingly, we have found that voles lack the regions homologous to the regulatory element Xite, which is instead replaced with the Slc7a3 gene that is unassociated with the X-inactivation centre in any other eutherians studied. Furthermore, we have not identified any transcription that could have the same functions as murine Xite in voles. Overall, our data show that not all the functional elements surrounding Xist in mice are well conserved even within rodents, thereby suggesting that the regulation of XCI may be at least partially taxon-specific

Covalent Protein Modification with ISG15 via a Conserved Cysteine in the Hinge Region

The ubiquitin-like protein ISG15 (interferon-stimulated gene of 15 kDa) is strongly induced by type I interferons and displays antiviral activity. As other ubiquitin-like proteins (Ubls), ISG15 is post-translationally conjugated to substrate proteins by an isopeptide bond between the C-terminal glycine of ISG15 and the side chains of lysine residues in the substrates (ISGylation). ISG15 consists of two ubiquitin-like domains that are separated by a hinge region. In many orthologs, this region contains a single highly reactive cysteine residue. Several hundred potential substrates for ISGylation have been identified but only a few of them have been rigorously verified. In order to investigate the modification of several ISG15 substrates, we have purified ISG15 conjugates from cell extracts by metal-chelate affinity purification and immunoprecipitations. We found that the levels of proteins modified by human ISG15 can be decreased by the addition of reducing agents. With the help of thiol blocking reagents, a mutational analysis and miRNA mediated knock-down of ISG15 expression, we revealed that this modification occurs in living cells via a disulphide bridge between the substrates and Cys78 in the hinge region of ISG15. While the ISG15 activating enzyme UBE1L is conjugated by ISG15 in the classical way, we show that the ubiquitin conjugating enzyme Ubc13 can either be classically conjugated by ISG15 or can form a disulphide bridge with ISG15 at the active site cysteine 87. The latter modification would interfere with its function as ubiquitin conjugating enzyme. However, we found no evidence for an ISG15 modification of the dynamin-like GTPases MxA and hGBP1. These findings indicate that the analysis of potential substrates for ISG15 conjugation must be performed with great care to distinguish between the two types of modification since many assays such as immunoprecipitation or metal-chelate affinity purification are performed with little or no reducing agent present

Microfluidic droplet platform for ultrahigh-throughput single-cell screening of biodiversity

© 2017, National Academy of Sciences. All rights reserved.Ultrahigh-throughput screening (uHTS) techniques can identify unique functionality from millions of variants. To mimic the natural selection mechanisms that occur by compartmentalization in vivo, we developed a technique based on single-cell encapsulation in droplets of a monodisperse microfluidic double water-in-oil-in-water emulsion (MDE). Biocompatible MDE enables in-droplet cultivation of different living species. The combination of droplet-generating machinery with FACS followed by next-generation sequencing and liquid chromatography-mass spectrometry analysis of the secretomes of encapsulated organisms yielded detailed genotype/phenotype descriptions. This platform was probed with uHTS for biocatalysts anchored to yeast with enrichment close to the theoretically calculated limit and cell-to-cell interactions. MDE-FACS allowed the identification of human butyrylcholinesterase mutants that undergo self-reactivation after inhibition by the organophosphorus agent paraoxon. The versatility of the platform allowed the identification of bacteria, including slow-growing oral microbiota species that suppress the growth of a common pathogen, Staphylococcus aureus, and predicted which genera were associated with inhibitory activity

Activation of Human Monocytes by Live Borrelia burgdorferi Generates TLR2-Dependent and -Independent Responses Which Include Induction of IFN-β

It is widely believed that innate immune responses to Borrelia burgdorferi (Bb) are primarily triggered by the spirochete's outer membrane lipoproteins signaling through cell surface TLR1/2. We recently challenged this notion by demonstrating that phagocytosis of live Bb by peripheral blood mononuclear cells (PBMCs) elicited greater production of proinflammatory cytokines than did equivalent bacterial lysates. Using whole genome microarrays, we show herein that, compared to lysates, live spirochetes elicited a more intense and much broader transcriptional response involving genes associated with diverse cellular processes; among these were IFN-β and a number of interferon-stimulated genes (ISGs), which are not known to result from TLR2 signaling. Using isolated monocytes, we demonstrated that cell activation signals elicited by live Bb result from cell surface interactions and uptake and degradation of organisms within phagosomes. As with PBCMs, live Bb induced markedly greater transcription and secretion of TNF-α, IL-6, IL-10 and IL-1β in monocytes than did lysates. Secreted IL-18, which, like IL-1β, also requires cleavage by activated caspase-1, was generated only in response to live Bb. Pro-inflammatory cytokine production by TLR2-deficient murine macrophages was only moderately diminished in response to live Bb but was drastically impaired against lysates; TLR2 deficiency had no significant effect on uptake and degradation of spirochetes. As with PBMCs, live Bb was a much more potent inducer of IFN-β and ISGs in isolated monocytes than were lysates or a synthetic TLR2 agonist. Collectively, our results indicate that the enhanced innate immune responses of monocytes following phagocytosis of live Bb have both TLR2-dependent and -independent components and that the latter induce transcription of type I IFNs and ISGs

ISG15 Modulates Development of the Erythroid Lineage

Activation of erythropoietin receptor allows erythroblasts to generate erythrocytes. In a search for genes that are up-regulated during this differentiation process, we have identified ISG15 as being induced during late erythroid differentiation. ISG15 belongs to the ubiquitin-like protein family and is covalently linked to target proteins by the enzymes of the ISGylation machinery. Using both in vivo and in vitro differentiating erythroblasts, we show that expression of ISG15 as well as the ISGylation process related enzymes Ube1L, UbcM8 and Herc6 are induced during erythroid differentiation. Loss of ISG15 in mice results in decreased number of BFU-E/CFU-E in bone marrow, concomitant with an increased number of these cells in the spleen of these animals. ISG15-/- bone marrow and spleen-derived erythroblasts show a less differentiated phenotype both in vivo and in vitro, and over-expression of ISG15 in erythroblasts is found to facilitate erythroid differentiation. Furthermore, we have shown that important players of erythroid development, such as STAT5, Globin, PLC γ and ERK2 are ISGylated in erythroid cells. This establishes a new role for ISG15, besides its well-characterized anti-viral functions, during erythroid differentiation

Социально-экономическая эффективность проведения неонатального скрининга на спинальную мышечную атрофию в Российской Федерации

Background. Spinal muscular atrophy (SMA) is a severe rare disease that has been widely discussed in recent years. Achievements in etiopathogenetic therapy and the social significance of the disease (child population, high mortality), the cost of treatment attracted the attention of the public and the goverment, which, among other things, led to the formation of a separate area with the creation of a fund to finance the treatment of patients with orphan diseases.Aim. To conduct an analysis of the socio-economic efficiency of mass neonatal screening for SMA in the Russian Federation.Materials and methods. A survey of patients (their parents) and doctors was conducted. The current clinical guidelines and the standard of medical care for children with SMA were studied. The cost of medicines is taken from the State Register of Maximum Selling Prices. If the drug is not included in the List of Vital Essential and Necessary Drugs, cost information from the procurement data is used.Results. The socioeconomic burden of SMA on identified patients was about 3,994,289,548 rubles per year prior to screening. The very introduction of mass neonatal screening will amount to about 679,224,000 rubles in year. At the same time, a disease detected in a timely manner due to neonatal screening and timely prescribed effective treatment can lead to a reduction in the cost of specialized and palliative care by 54,073,271 rubles, direct non-medical costs by 88,137,423 rubles, and indirect costs by 154,197,900 rubles per year, which together is more than 7 % of the calculated burden of SMA.Conclusion. The introduction of mass screening will lead to the fact that the number of annually detected patients will increase from current values to the actual value of the prevalence when registering patients with milder forms of SMA. The need for drug supply with drugs and medical care in general will increase. At the same time, children diagnosed with SMA will not die in the early years of life, their survival rate, life expectancy will increase, the quality of life will improve, infant mortality will decrease, which is the main task of neonatal screening and one of the goals of the National Healthcare Project.Введение. Спинальная мышечная атрофия (СМА) – тяжелое редкое заболевание, которое в последние годы широко обсуждается. Достижения этиопатогенетической терапии и социальная значимость болезни (детская популяция, высокая смертность), стоимость лечения привлекли внимание общественности и правительства, что среди прочего привело к формированию отдельного направления с созданием фонда по финансированию лечения пациентов с орфанными болезнями.Цель исследования – провести анализ социально-экономической эффективности массового неонатального скрининга на СМА в Российской Федерации.Материалы и методы. Проведено анкетирование пациентов (их родителей) и врачей. Изучены действующие клинические рекомендации и стандарт медицинской помощи детям при СМА. Стоимость лекарственных препаратов взята из Государственного реестра предельных отпускных цен. Для препаратов, не входящих в Перечень жизненно необходимых и важнейших лекарственных препаратов, использовалась информация о стоимости из данных о закупках.Результаты. Социально-экономическое бремя СМА на выявленных пациентов составило порядка 3 994 289 548 руб. в год до введения скрининга. Затраты на внедрение массового неонатального скрининга составят около 679 224 000 руб. в год. При этом своевременное выявление болезни благодаря неонатальному скринингу и назначенное эффективное лечение позволяют снижать затраты на специализированную и паллиативную помощь на 54 073 271 руб., прямые немедицинские затраты на 88 137 423 руб., а также непрямые затраты на 154 197 900 руб. в год, что в совокупности составляет >7 % от рассчитанного бремени СМА. Выводы. Введение массового скрининга приведет к ежегодному выявлению пациентов и увеличению их числа с текущих значений до реальной величины распространенности при регистрации больных с более легкими формами СМА. Потребность в лекарственном обеспечении препаратами и медицинской помощи в целом возрастает. При этом дети со СМА не будут умирать в ранние годы жизни, их выживаемость, продолжительность жизни увеличатся, улучшится качество жизни, снизится младенческая смертность, что является основной задачей неонатального скрининга и одной из целей национального проекта «Здравоохранение»