Prosaic works of Evgeny Nikolayevich Chirikov

Bakalářská práce pojednává o exilové tvorbě významného ruského spisovatele, dramatika a publicisty konce 19. a počátku 20. století a migranta v meziválečném Československu Jevgenije Nikolajeviče Čirikova. V první části se zaměříme na Čirikovu literární činnost v Rusku, publikace v časopisech a důvody, kvůli kterým byl nucen opustit Rusko. Druhá část se věnuje jeho životu v Československu, kde ve svých dílech reflektuje závažná témata jako je revoluce, občanská válka a bolševismus. Jeho tvorba byla přeložena do mnoha dalších jazyků včetně češtiny. Práce si klade za cíl vytvoření uceleného přehledu života a díla spisovatele v emigraci.The bachelor thesis deals with the exile work of Yevgeny Nikolayevich Chirikov, an important Russian writer, playwright and publicist of the late 19th and early 20th century and a migrant in interwar Czechoslovakia. In the first part we will focus on Chirikov's literary activity in Russia, his publications in magazines and the reasons that forced him to leave Russia. The second part focuses on his life in Czechoslovakia, where his works reflect on serious themes such as revolution, civil war and Bolshevism. His work has been translated into many other languages, including Czech. The thesis aims to create a comprehensive overview of the writer's life and work in exile.Ústav východoevropských studiíInstitute of East European StudiesFilozofická fakultaFaculty of Art

Development of a Scalable Synthesis of HP-β-CD Pluronic Polyrotaxanes

Polyrotaxanes are polymers that have macrocycles threaded onto them, analogous to beads threaded onto a string. These materials are used for a variety of different biomedical applications.1-3 The Thompson group has been developing 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) polyrotaxanes as therapeutics for the treatment of Niemann-Pick Type C (NPC) disease. NPC is a debilitating genetic disorder where cholesterol accumulates in the lysosomes of cells.4 Developing a scalable process is crucial for the advancement of these materials as NPC therapeutics. The goal of this project is to optimize the only protocol for the synthesis of HP-β-CD/Pluronic polyrotaxanes in order to develop a synthetic method that can be operated on the multi-gram scale to support preclinical studies.5 Each component of the protocol was screened to determine which combination lead to the formation of polyrotaxanes with the highest yields and threading efficiencies in the shortest amount of time. Threading efficiency is a measure of how many HP-β-CD molecules are threaded onto each polymer. In addition to optimizing the current protocol, we have also explored flowing the reaction mixture through a bath sonicator and using a hydraulic press as alternative syntheses. It was found that probe sonication and bath sonication are both necessary components of the protocol. This indicates that sufficient agitation of the reaction mixture is required to promote the non-covalent threading reaction. Furthermore, bath sonication for one hour, followed by stirring for two days gave the highest threading efficiency. The results of these studies have simplified the existing protocol, but additional studies are needed to reveal whether this protocol is robust enough for efficient preparation of other HP-β-CD/Pluronic polyrotaxane derivatives

Pedagogical Giftedness as a Key Prerequisite for Efficient Modern Educational System

Introduction. The paper represents the analysis of the ability to teach within the context of the study of the phenomenon of giftedness and psychological structure of a teacher’s professional activities. The objective of the paper is to analyze key areas of the development of the concept of teacher giftedness. This approach allows to describe the basic qualities of the efficient pedagogical activity at the stage of training teachers at higher school. Materials and Methods. Description of key areas of the concept of pedagogical giftedness is based on the ability theory, proposed by V. D. Shadrikov. At the same time, modeling processes of goal-oriented development of pedagogical giftedness is based on a set of modern research psychological methods of structuralfunctional analysis allowing for prediction of properties of the pedagogical system of a teacher, which has such characteristics as varying degrees of success. Organizational methods (first of all, comparative) open up possibilities for assessing the effectiveness of giftedness-in-training development at different stages of teacher training – pre-university, undergraduate and post-graduate. The choice of empirical methods is substantiated by the results of theoretically modeling the structure and ways of development of pedagogical giftedness at the stage of professional self-determination at school, under conditions of educational and independent professional activity. Out of interpretative methods, the most significant (in the context of planned results) are genetic, structural and functional methods . Results. Based on the analysis of the theory of abilities, taking into account the progress in the activitybased approach, a new understanding of the object of psychological sciences as the inner personal world, the methodological validity of the concept of goal-oriented development of pedagogical gift under conditions of teacher training is substantiated. The results obtained make it possible to get a fresh look at the problem of the teacher’s professionally valuable qualities and translate its solution from analytical to systemic research methodology. In the concept proposed by the authors first time ever, the phenomenon of giftedness is considered within the context of its formation in teacher college student, while the subject of the bulk of contemporary research is the object of pedagogical influence. Discussion and Conclusion. The practical application of the study results can significantly modernize the process of teacher training in pedagogical colleges and universities. They will be useful for the teaching staff of pedagogical universities, secondary vocational education institutions, and departments of continuing education

THE PROBLEM OF INTEGRATION OF PSYCHOLOGICAL KNOWLEDGE IN MODERN PSYCHOLOGY

The problem of integration of psychological knowledge, which is topical for modern psychology, is discussed. It is shown that the condition for its solution is the development of fundamental problems of the subject, method, explanation in psychology. The main provisions of communicative methodology, a new understanding of the subject of psychology as the inner world of a person, the use of which allows us to approach a productive solution to the problem of integration in modern psychology, are considered.Обсуждается актуальная для современной психологии проблема интеграции психологического знания. Показано, что условием ее решения является разработка фундаментальных проблем предмета, метода, объяснения в психологии. Рассматриваются основные положения коммуникативной методологии, нового понимания предмета психологии как внутреннего мира человека, использование которых позволяет подойти к продуктивному решению проблемы интеграции в современной психологии.Исследование выполнено за счет гранта Российского научного фонда № 22-28-00089, https://rscf.ru/project/22-28-00089/

Differentiation of mouse bone marrow derived stem cells toward microglia-like cells

<p>Abstract</p> <p>Background</p> <p>Microglia, the macrophages of the brain, have been implicated in the causes of neurodegenerative diseases and display a loss of function during aging. Throughout life, microglia are replenished by limited proliferation of resident microglial cells. Replenishment by bone marrow-derived progenitor cells is still under debate. In this context, we investigated the differentiation of mouse microglia from bone marrow (BM) stem cells. Furthermore, we looked at the effects of FMS-like tyrosine kinase 3 ligand (Flt3L), astrocyte-conditioned medium (ACM) and GM-CSF on the differentiation to microglia-like cells.</p> <p>Methods</p> <p>We assessed <it>in vitro-</it>derived microglia differentiation by marker expression (CD11b/CD45, F4/80), but also for the first time for functional performance (phagocytosis, oxidative burst) and <it>in situ </it>migration into living brain tissue. Integration, survival and migration were assessed in organotypic brain slices.</p> <p>Results</p> <p>The cells differentiated from mouse BM show function, markers and morphology of primary microglia and migrate into living brain tissue. Flt3L displays a negative effect on differentiation while GM-CSF enhances differentiation.</p> <p>Conclusion</p> <p>We conclude that <it>in vitro-</it>derived microglia are the phenotypic and functional equivalents to primary microglia and could be used in cell therapy.</p

Polyglutamine Induced Misfolding of Huntingtin Exon1 is Modulated by the Flanking Sequences

Polyglutamine (polyQ) expansion in exon1 (XN1) of the huntingtin protein is linked to Huntington's disease. When the number of glutamines exceeds a threshold of approximately 36–40 repeats, XN1 can readily form amyloid aggregates similar to those associated with disease. Many experiments suggest that misfolding of monomeric XN1 plays an important role in the length-dependent aggregation. Elucidating the misfolding of a XN1 monomer can help determine the molecular mechanism of XN1 aggregation and potentially help develop strategies to inhibit XN1 aggregation. The flanking sequences surrounding the polyQ region can play a critical role in determining the structural rearrangement and aggregation mechanism of XN1. Few experiments have studied XN1 in its entirety, with all flanking regions. To obtain structural insights into the misfolding of XN1 toward amyloid aggregation, we perform molecular dynamics simulations on monomeric XN1 with full flanking regions, a variant missing the polyproline regions, which are hypothesized to prevent aggregation, and an isolated polyQ peptide (Qn). For each of these three constructs, we study glutamine repeat lengths of 23, 36, 40 and 47. We find that polyQ peptides have a positive correlation between their probability to form a β-rich misfolded state and their expansion length. We also find that the flanking regions of XN1 affect its probability to^x_page_count=28 form a β-rich state compared to the isolated polyQ. Particularly, the polyproline regions form polyproline type II helices and decrease the probability of the polyQ region to form a β-rich state. Additionally, by lengthening polyQ, the first N-terminal 17 residues are more likely to adopt a β-sheet conformation rather than an α-helix conformation. Therefore, our molecular dynamics study provides a structural insight of XN1 misfolding and elucidates the possible role of the flanking sequences in XN1 aggregation

Conformational Targeting of Fibrillar Polyglutamine Proteins in Live Cells Escalates Aggregation and Cytotoxicity

Misfolding- and aggregation-prone proteins underlying Parkinson's, Huntington's and Machado-Joseph diseases, namely alpha-synuclein, huntingtin, and ataxin-3 respectively, adopt numerous intracellular conformations during pathogenesis, including globular intermediates and insoluble amyloid-like fibrils. Such conformational diversity has complicated research into amyloid-associated intracellular dysfunction and neurodegeneration. To this end, recombinant single-chain Fv antibodies (scFvs) are compelling molecular tools that can be selected against specific protein conformations, and expressed inside cells as intrabodies, for investigative and therapeutic purposes.Using atomic force microscopy (AFM) and live-cell fluorescence microscopy, we report that a human scFv selected against the fibrillar form of alpha-synuclein targets isomorphic conformations of misfolded polyglutamine proteins. When expressed in the cytoplasm of striatal cells, this conformation-specific intrabody co-localizes with intracellular aggregates of misfolded ataxin-3 and a pathological fragment of huntingtin, and enhances the aggregation propensity of both disease-linked polyglutamine proteins. Using this intrabody as a tool for modulating the kinetics of amyloidogenesis, we show that escalating aggregate formation of a pathologic huntingtin fragment is not cytoprotective in striatal cells, but rather heightens oxidative stress and cell death as detected by flow cytometry. Instead, cellular protection is achieved by suppressing aggregation using a previously described intrabody that binds to the amyloidogenic N-terminus of huntingtin. Analogous cytotoxic results are observed following conformational targeting of normal or polyglutamine-expanded human ataxin-3, which partially aggregate through non-polyglutamine domains.These findings validate that the rate of aggregation modulates polyglutamine-mediated intracellular dysfunction, and caution that molecules designed to specifically hasten aggregation may be detrimental as therapies for polyglutamine disorders. Moreover, our findings introduce a novel antibody-based tool that, as a consequence of its general specificity for fibrillar conformations and its ability to function intracellularly, offers broad research potential for a variety of human amyloid diseases