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Molecular causes and mechanisms of hereditary cholestasis and statin-induced myopathy
Neřoldová, Magdaléna ; Jirsa, Milan (advisor) ; Dvořáková, Lenka (referee) ; Bronský, Jiří (referee)
The discovery of the molecular basis of Rotor syndrome consisting in biallelic inactivating mutations in both SLCO1B1 and SLCO1B3 genes encoding hepatic transporters OATP1B1 and OATP1B3, together with the previously described association of the rs4149056 variant in OATP1B1 with statin-induced myopathy (SM), led us to hypothesis that private variants in OATP1B1 and OATP1B3 confer predisposition to SM. This hypothesis was not supported by our study of 88 patients in whom exome sequencing was performed. Interestingly, we detected candidate variants in several genes mutated in recessively inherited muscle disorders, namely CLCN1, whose carriage may predispose to SM. Pathogenic variants in several dozens of causative genes underlie hereditary cholestasis. We performed exome sequencing in 51 unexplained cases and revealed several unexpected diagnoses such as autosomal recessive polycystic polyposis, cutaneous porphyria or nephronophthisis. The most remarkable finding was that of yet unreported F11R deficiency due to a homozygous splice mutation found simultaneously in an index patient suffering from liver cirrhosis and her healthy sister. The F11R protein is involved in formation of tight intercellular junctions and mutations in F11r predispose to liver failure in mice. The finding of bialellic variants...
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Gut microbiome and its changes related to therapy of chronic diseases
Hurych, Jakub ; Cinek, Ondřej (advisor) ; Kolář, Milan (referee) ; Falt, Přemysl (referee)
This work examines the response of the gut microbiome to therapeutic interventions in three longitudinal studies of chronic gastrointestinal diseases: Crohn's disease, celiac autoimmunity and irritable bowel syndrome. Multiple methods of stool microbiome analysis (especially massively parallel 16S rDNA or 18S rDNA sequencing and metagenomic sequencing) followed by bioinformatic and statistical analysis were used. In Crohn's disease, we detected a previously undescribed secondary nature of changes in the gut bacteriome after anti-TNF treatment. In celiac disease autoimmunity, where previous works described an effect of probiotic intervention on serological markers of the disease, the gut bacteriome and metabolome, we described the absence of significant changes in beneficial gut protozoa. In irritable bowel syndrome, we observed a significant response of the bacteriome after administering four doses of mixed microbiota transplantation but no response in the reduction of clinical symptoms. The results of these studies could contribute to a better understanding of the gut microbiome's role in the pathogenesis of these serious diseases. Keywords: microbiome, Crohn's disease, celiac disease, irritable bowel syndrome
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Inhibition of TET-1 protein by iron chelators
Antonyová, Veronika ; Jakubek, Milan (advisor) ; Mikula, Ivan (referee) ; Gumulec, Jaromír (referee)
EN The objective of this work was to study novel synthetic iron chelators and to study their potential use in inhibition of TET1 (ten-eleven translocation methylcytosine dioxygenase 1) protein. Epigenetic mechanisms, such as hydroxymethylation of DNA, are promising target in many serious pathologies, including oncological disorders. In the presented study, we intended to discover novel inhibitors by screening small libraries of heterocyclic molecules, such as pyrrolo[3,2-b]pyrrole derivatives with hydrazide (compound 1) or hydrazone (compound 2-6) iron-binding group and hydrazone-based iron chelators (compound 7-10). Within the scope of this study, we used various analytical and biochemical techniques for the purpose of characterization of novel cancer therapies based on TET1 protein inhibition. The absorbance and the complexation of tested compounds with Fe(II) ions was studied by UV-Vis spectroscopy. Inhibition of TET1 protein was studied by fluorometric assay based on ELISA and further supported by microscale thermoporesis and in silico docking. The cytotoxicity of compounds on cancer cell lines was measured by MTT assay and intracellular distribution was determined by live-cell imaging. This study presents a biochemical analysis of potential TET1 protein inhibitors and brings significant...
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Innovative Schools and Their Networks in Post-Socialist Context: The Case Study of Gymnázium Přírodní Škola
Pražák, Daniel ; Dvořák, Dominik (advisor) ; Pol, Milan (referee) ; Michek, Stanislav (referee)
In recent years, there has been a great expansion of school networking in foreign education systems, but this approach appears less often in the Czech environment. This dissertation presents a case study that analyses the interaction of schools cooperating with the Gymnasium Přírodní škola through the concept of networking. The main sources of data are interviews with actors, school documents and field notes of the researcher. The study describes the mutual influence and sharing of elements of the innovative model between the schools involved in this network. Special attention is paid to the factors that facilitate or hinder effective networking and innovation sharing, as well as the role of principals, teachers and student involvement as active agents of change. The work thus connects previous research knowledge with the unique Czech context, which enriches the professional literature on networking of educational institutions. The results offer insight into the dynamics and challenges associated with creating effective educational networks and bring support for innovation in education through networking. KEYWORDS school networking, innovative educational models, inter-organizational collaboration, inter- organizational learning, school leadership, secondary education, students as actors, case...
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Hydrogels modified by amphiphilic structures
Heger, Richard ; Sedlařík, Vladimír (referee) ; Kráčalík, Milan (referee) ; Pekař, Miloslav (advisor)
The submitted dissertation deals with the influence of amphiphilic structures on hydrogel properties. Additions of various amphiphilic substances associated with the formation of highly ordered structures affect the mechanical, transport and structural properties of hydrogels. The main inspiration for this type of work was living tissue, more precisely the extracellular matrix, which is often mimicked by hydrocolloids, and its high orderliness is responsible for its unique properties. The knowledge obtained from this tissue was applied to the hydrogel systems studied in this work. Various cross-linked hydrogel matrices (physically cross-linked agarose and gelatin, ionically cross-linked alginate and chemically cross-linked mixture of polyvinyl alcohol and chitosan) were suitable representatives for this work. These hydrogel systems were modified by the addition of various amphiphilic substances. The human body’s own phospholipid, lecithin, or variously charged more classic surfactants (CTAB, SDS and Triton X-100). Experimentally, this work is divided into three areas, the study of mechanical properties using rheology, the description of transport properties via release and flow experiments using various model drugs (rhodamine 6G, eosin B, amido black 10B, methylene blue and riboflavin), and morphological characterization using SEM. The characterization of hydrogel systems was supported by other techniques used in this work, such as drying and swelling experiments or gas sorption.
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Capuchin Monasteries in the Diocese of Litoměřice between 1900 and 1950
Frýba, Luboš ; Buben, Milan (advisor) ; Šmíd, Marek (referee)
This thesis aims to present six Capuchin monasteries in the Litoměřice diocese in the first half of the 20th century. The focus is on the internal workings of each convent: education, building activities, equipment and related communication with other institutions or persons. The history of the monasteries itself is preceded by introductory chapters introducing the history of the Capuchins in the Czech lands and the development of the relations of the Catholic Church with the various state formations that replaced each other in our territory in the first half of the 20th century. An important chapter is also devoted to important personalities, with shorter medallions presenting religious, Quardians and other persons who have made a significant contribution to the modern history of these six convents. In connection with the monasteries of the Litoměřice diocese, themes such as the postoloprt massacre after second World War, the "K" action. It is also necessary to briefly mention the current state of the monasteries and their use.
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Bridging the Gap: Towards Unified Approach to Perfect and Imperfect Information Games
Moravčík, Matej ; Hladík, Milan (advisor) ; Pilarski, Patrick (referee) ; Kroupa, Tomáš (referee)
From the onset of AI research, games have played an important part, serving as a benchmark for progress in artificial intelligence. Recent approaches using search in combination with learning from self-play have shown strong performance and the ability to generalize across a wide range of perfect information games. In contrast, the leading algorithms for imperfect information traditionally used a small, abstract version of a game and solved this abstraction in one go. This thesis introduces a chain of improvements for imperfect information algorithms that culminates in two significant milestones that helped bridge the gap between perfect and imperfect information games. The first milestone is DeepStack - the first agent that successfully used a combination of sound search and a learned value function in imperfect information games. This led to the first AI to achieve victory over human professional players in no-limit poker. The second milestone is Player of Games - a universal algorithm that can master both perfect and imperfect information games starting from scratch. 1
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System for Precise Measurement of Electrical Length of Coaxial Cables
Podr, Michal ; Polívka,, Milan (referee) ; Šebesta, Jiří (advisor)
This thesis describes a study of the measuring methods determining the electrical length of coaxial cable without using a vector network analyzer. First, a general theory of management and its various parameters is briefly discussed. This section is focused more specifically on the coaxial cable and its parameters. The next part is graphically analyzed process considerations in the design of measurement methods and outlined the block structure of the system. The third section describes the working process, prototype testing of the bridge, its measurement and design of the measuring system. In the fourth part the software is described. In conclusion, the results of the work are discussed, accuracy of the measurement system, the obtained parameters chosen with regard to the principle of the measurement system and the overall evaluation of the applicability in practice.
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Research on Effective Methods of Exhausting
Pech, Ondřej ; Kratochvíl, Zdeněk (referee) ; Černecký,, Jozef (referee) ; Pavelek, Milan (advisor)
Many production technologies generate a variety of gas pollutants, which are unhealthy. The aim is therefore to minimize the content of such gas pollutants in the work environment. The highest capture efficiency of gas pollutants offers the local exhausting. Its disadvantage is the necessity to surround the source of pollutants, or to be as close as possible which is usually not technically or technologically possible. A possible alternative is to use a reinforced exhaust system that achieves greater capture distances. In the initial stage of the solution of the dissertation, a review of reinforced exhaust systems was carried out. Further, an existing measurement system was modified for measurements with the partition above the exhaust slot and the measurement system was partially automated. In order to investigate the case with pollutants having a lower density than the air, the workbench - the partition was moved above the exhaust slot. Based on of the literature review, a modification of the reinforced slot exhaust system was proposed. The modification consisted in the adjustment of the air inlet adjustment where a set of holes and a tube assembly were used instead of the slot. Such setup allowed for higher flow turbulence and thus for an increased exhaust efficiency. Subsequently, the inlet streams from the slot, holes and tubes were visualized by the smoke method. Further measurements were carried out by the tracer gas method for the determination of the exhaust efficiency. Measurements of velocity fields in front of the proposed configurations of the reinforced slot exhaust hood were also carried out. In conclusion, an energy performance assessment was carried out by means of the measurement of the electric power input to the fans with the determination of the electric loss power.
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