Host-virus interactions in chronic Hepatitis B

Hepatitis B virus (HBV) is a blood-borne human pathogen of worldwide importance. It replicates in the hepatocytes in the liver and causes a disease known as Hepatitis B. Approximately 3% of the world population are chronically infected with HBV. Chronic Hepatitis B (CHB) is the number one cause of hepatocellular carcinoma in the world leading to close to 1 million deaths every year. Treatment options are limited and none of them are curative due to persistence of the viral covalently closed circular (ccc)DNA, a plasmid-like molecule which serves as the template for viral transcription and replication. New therapies are urgently needed that would decrease the global burden of HBV. A better understanding of the HBV immunobiology and host-virus interactions is critical in this regard. Due to the narrow species and tissue tropism, research in this area has been hindered by a lack of suitable experimental in vivo models of HBV infection leaving a lot of gaps in our understanding of the viral immunobiology. For example, HBV interaction with the host innate immune system has been a matter of debates for years. Although most viruses trigger various pathogen recognition receptors (PRRs) in the cells they infect leading to the induction of interferons and an antiviral state, HBV does not seem to do that. It remained controversial however, whether this is because HBV is invisible to PRRs (i.e. acting as a “stealth virus”) or because it efficiently suppresses innate immune responses very early after infection. Another example is HBV immune control. In the natural history of CHB most of the patients reach the so called HBeAg-negative chronic infections stage, when the virus is under control characterized by no or a very low viral load in the absence of noticeable immune activity that is otherwise known to control the HBV replication. In this thesis we used human liver biopsy material from a large biobank of the University Hospital Basel in order to shed light on host-virus interactions in chronic hepatitis B. We established a novel short-term ex vivo liver biopsy culture system, allowing to study innate immune activation in situ in the human liver. We successfully used this system to demonstrate that HBV does not induce innate immune responses in the human liver in CHB. Importantly, HBV did also not interfere with the experimental induction of innate responses, suggesting that it behaves like a “stealth virus” staying under the radar of the cell’s defense systems. As a follow-up to this study, we discuss the implication of these findings on the potential use of modulators of innate immunity as novel therapeutics for the treatment of chronic hepatitis B. In a separate study, we sought to get an insight on how the host controls the virus during the HBeAg-negative chronic infection (ENCI) stage. By carefully analyzing HBV replication intermediates in the liver biopsies of patients of different stages of CHB, we have discovered that HBV replication is specifically inhibited downstream of pregenomic (pg)RNA production during the ENCI stage of CHB. Our findings provide a starting point for further studies in this direction that eventually should identify the mechanism behind this inhibition and harness it for therapeutic use

Proteogenomic characterization of hepatocellular carcinoma

We performed a proteogenomic analysis of hepatocellular carcinomas (HCCs) across clinical stages and etiologies. We identified pathways differentially regulated on the genomic, transcriptomic, proteomic and phosphoproteomic levels. These pathways are involved in the organization of cellular components, cell cycle control, signaling pathways, transcriptional and translational control and metabolism. Analyses of CNA-mRNA and mRNA-protein correlations identified candidate driver genes involved in epithelial-to-mesenchymal transition, the Wnt-β- catenin pathway, transcriptional control, cholesterol biosynthesis and sphingolipid metabolism. The activity of targetable kinases aurora kinase A and CDKs was upregulated. We found that CTNNB1 mutations are associated with altered phosphorylation of proteins involved in actin filament organization, whereas TP53 mutations are associated with elevated CDK1/2/5 activity and altered phosphorylation of proteins involved in lipid and mRNA metabolism. Integrative clustering identified HCC subgroups with distinct regulation of biological processes, metabolic reprogramming and kinase activation. Our analysis provides insights into the molecular processes underlying HCCs

Integrative proteogenomic characterization of hepatocellular carcinoma across etiologies and stages.

Proteogenomic analyses of hepatocellular carcinomas (HCC) have focused on early-stage, HBV-associated HCCs. Here we present an integrated proteogenomic analysis of HCCs across clinical stages and etiologies. Pathways related to cell cycle, transcriptional and translational control, signaling transduction, and metabolism are dysregulated and differentially regulated on the genomic, transcriptomic, proteomic and phosphoproteomic levels. We describe candidate copy number-driven driver genes involved in epithelial-to-mesenchymal transition, the Wnt-β-catenin, AKT/mTOR and Notch pathways, cell cycle and DNA damage regulation. The targetable aurora kinase A and CDKs are upregulated. CTNNB1 and TP53 mutations are associated with altered protein phosphorylation related to actin filament organization and lipid metabolism, respectively. Integrative proteogenomic clusters show that HCC constitutes heterogeneous subgroups with distinct regulation of biological processes, metabolic reprogramming and kinase activation. Our study provides a comprehensive overview of the proteomic and phophoproteomic landscapes of HCCs, revealing the major pathways altered in the (phospho)proteome

Neopopulism and Neopopulist Parties in Twentieth Century Russia. A Bibliography

University of Technology, Kazan / Memorial, Mosco

Legal and civil patriotic education in Russia university as a factor of sustainable development societies

The article analyzes the problem of forming patriotism and citizenship during the period of students ’ education in higher educational institutions. Educational work is considered as an integral part of the educational activity of a higher educational institution. The goals and objectives of legal and civil patriotic education, its role in the formation of a fullfledged citizen and patriot of their country are formulated. The article reveals the successful experience of individual educational institutions in organizing mass events of a civil-patriotic orientation among students, as well as the difficulties and problems in conducting them. Special attention is paid to the experience of the Kazan National Research Technological University

Tourist and recreational potential of the regions of the Republic of Tatarstan as a factor of sustainable development of the region (on the example of Zainsk district)

. The article is devoted to the complex of natural, historical, cultural, religious, architectural and other sights identified during the work of local lore, concentrated in the Zainsk region of the Republic of Tatarstan, which are considered as a promising basis for the active development of the tourist and recreational sphere of the region. The conclusion is made about the need for reconstruction, restoration of heritage sites, improvement of settlements, construction of ethnographic complexes. To improve the quality of service, a network of infrastructure facilities is required. Ethnostization of these objects will emphasize the uniqueness of the area, to the greatest extent attract the attention of tourists

Humanistic meanings in the educational conventions of modernity: on the problem of understanding the philosophical content of subjectivity

A holistic understanding of the current approaches and strategies circulating in the educational environment, where in a situation of global transformation, there is an intensive search for ways and methods to overcome the crisis, is relevant. Within the framework of the pedagogical and philosophical analysis, the authors attempt to discover new aspects of the humanistic content of subjectivity. It is necessary to recognize the absolute value in students, which is seen through the manifestation of individual qualities and abilities. This means that it is necessary to ontologically recognize any subject of knowledge as self-sufficient, regardless of the ranks on the institutional ladder that are common in social structures, in other words, it is necessary to go beyond the boundaries of evaluative categories that, as is known, determine the intellectual status of the subject according to the degree of acquired and certified knowledge. First, the teacher overcomes his power complex, dominance over the student, which is deliberately placed by the traditional approach in the position of ignorant and incompetent person. Secondly, the emphasis on such concepts as discipline, norm, and standard has been changed. Third, the strengthening of group solidarity, to guarantee the basic social meanings in a world of increasing risks, where there is a growing desire to consolidate not with society as a whole, as in previous eras, but with a separate small group. Fourth, the most important conceptual link in these constructions is the ability to communicate. Fifth, there is a rejection of excessive rationalistic perception of reality. A new post-materialistic pedagogical paradigm is formulated, which puts in the first place the deep aspects of the subject, conditioned by his emotionality, soulfulness, humanity, which are least associated with such behavioral parameters as punctuality, perseverance, and academic performance