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Generation and analysis of mutant mouse model to study roles of KLKs in cutaneous inflammation
Eliáš, Jan ; Kašpárek, Petr (advisor) ; Drbal, Karel (referee)
Kallikrein-related peptidases (KLKs) are a subgroup of serine proteases of undisputable importance for a variety of functions, whose dysregulation has been linked to several pathological phenotypes. Among those pathologies, the Netherton syndrome stands out, since it is one of the very few that has its mechanism directly linked to KLK proteases as the main culprit of the disease, namely KLK5, KLK7 and to a lesser degree, KLK14. In this case, a mutation in the SPINK5 gene leads to uncontrolled hyperactivity of those proteases, which results in epidermal barrier breach due to excessive epidermal desquamation and severe inflammation of the skin. Inflammation mechanisms of NS are still relatively poorly understood, with important roles being attributed to the activities of KLKs in the processing of immune system molecules and also to the dysregulation of the cutaneous microbiome. TNFα signalling plays a key role in the homeostasis and immune response in the skin. Chronic skin infections may lead to deleterious effects with strong participation of TNFα signalling. To address the degree of its effects on the pathogenesis of NS, we have created a mouse model where the TNFR1 is disrupted by knockout of the Tnfr1 gene on the background of a previously established mouse model of the Netherton syndrome. We...
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Structure and physiological role of the mitochondrial permeability transition pore
Eliáš, Jan ; Mráček, Tomáš (advisor) ; Kalous, Martin (referee)
Mitochondrial permeability transition pore (mPTP) is Ca2+ dependent channel localised in the inner mitochondrial membrane. One of its defining characteristics is inhibition by nanomolar concentrations of immunosuppressant cyclosporine A (CsA). Together with additional interacting proteins, which regulate its opening, mPTP forms a permeability transition protein complex. Persistent opening of mPTP is accompanied by mitochondrial swelling and a subsequent collapse of organelle, which precedes release of proapoptotic proteins and programmed cell death. Channel forming unit of mPTP remains unknown, despite intense and long-lasting study. Numerous proteins were proposed to play a role of channel forming subunit of mPTP, including complex of ANT and VDAC, ANT alone, PiC or even ATP synthase. Despite the fact, that molecular structure remains elusive, mPTP seems to play a role in a range of pathophysiological processes or diseases associated with them. Among others this includes ischemia/reperfusion injury, neurological and muscle dystrophies, or tumorigenesis. Keywords: mitochondria, mitochondrial permeability transition pore, cyclosporine A, programmed cell death, ATP synthase, oxidative phosphorylation apparatus.
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Static and dynamic analysis of plain and fiber-reinforced concrete using discrete meso-scale model
Květoň, Josef ; Vorel,, Jan (referee) ; Šejnoha,, Michal (referee) ; Eliáš, Jan (advisor)
Předkládaná práce se zabývá matematickým modelováním chování betonu. K numerické analýze je použit diskrétní částicový model. Tento model zjednodušuje meso-strukturu materiálu na systém propojených diskrétních částic -- konvexních mnohostěnů. Tyto částice jsou uvažovány ideálně tuhé a jejich vzájemná interakce je předepsána na kontaktech sousedních částic. Při hledání nespojitého pole posunů a rotací jsou zjednodušeně předpokládány malé deformace. Práce popisuje dvě rozšíření implementovaná do stávající verze modelu, konkrétně (i) přidání reprezentace krátké rozptýlené výztuže a (ii) implicitní dynamický řešič. První z hlavních částí práce se zabývá modelováním kompozitů s krátkou rozptýlenou výztuží. Krátká vlákna rozptýlená v materiálu přispívají k zlepšení jinak nepříznivé tahové pevnosti betonu. Vlákna jsou v částicovém modelu reprezentována nepřímo, zohledněním tření mezi vláknem a cementovou matricí silami, které působí proti otevírání trhlin. S pomocí tohoto rozšíření model dokáže předpovídat chování vláknobetonu zahrnující tahové zpevnění i navýšení počtu trhlin. Druhá z hlavních částí se zabývá odezvou materiálu na dynamické zatížení. Beton vykazuje rozdílné chování pro různé rychlosti zatěžování. V případě pomalého, kvazi-statického, zatěžování se počáteční mikro-trhliny lokalizují v makro-trhlinu. Dochází-li k rychlému zatěžování, energie nahromaděná v tělese není spotřebována pouze jednou trhlinou, ale dochází k jejímu větvení. V případě rychlých procesů je hlavním faktorem setrvačnost hmoty, která je zatížením urychlována. Struktura materiálu a setrvačnost částic je v mezo-úrovňovém diskrétním modelu zahrnuta. Přesto ale další jevy probíhající pod rozlišovací úrovní modelu ovlivňují výsledné chování materiálu. Proto je do modelu přidána fenomenologická závislost konstitutivního zákona na rychlosti přetváření. Numerické simulace těles rozličných tvarů zatěžovaných různou rychlostí deformace jsou porovnány s experimenty z literatury.
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Probabilistic discrete model of concrete fracturing
Kaděrová, Jana ; Lehký, David (referee) ; Konečný,, Petr (referee) ; Eliáš, Jan (advisor)
The thesis presents results of a numerical study on the performance of 3D discrete meso–scale lattice–particle model of concrete. The existing model was extended by introducing the spatial variability of chosen material parameter in form of random field. An experimental data from bending tests on notched and unnotched beams was exploited for the identification of model parameters as well as for the subsequent validation of its performance. With the basic and the extended randomized version of the model, numerical simulations were calculated so that the influence of the rate of fluctuation of the random field (governed by the correlation length) could be observed. The final part of the thesis describes the region in the beam active during the test in which the most of the fracture energy is released in terms of its size and shape. This region defines the strength of the whole member and as shown in the thesis, it does not have a constant size but it is influenced by the geometrical setup and the correlation length of the random field.
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Optimization of prestress tendon path
Středulová, Monika ; Lehký, David (referee) ; Eliáš, Jan (advisor)
The thesis explores possibilities of applying genetic algorithms on the problem of finding the optimal prestressed concrete tendon path. The objective of the thesis is to develop a genetic algorithm based on the Automatic Dynamic Penalization method and to test its robustness on selected analytical functions. Subsequently, the algorithm is connected to a Time Dependent Analysis module for the computation of prestressed concrete structure to solve selected examples of prestressed beams in the form of a constrained optimization problem. The algorithm is developed in the Python programming language with the help of the Distributed Evolutionary Algorithm library.
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Optimalization of Financing of the Selected Company - Cost Management
Eliáš, Jan ; Duranti, David (referee) ; Ptáček, Roman (advisor)
The subject of this bachelor thesis is analysis of the cost management of a particular enterprise. The thesis is divided into two parts, theoretical and practical. The purpose of the theoretical part is describing the subject matter and familiarizing with key terms and with the methodology of analysis of the cost management. The practical part is then focused on analysis of the current state of cost management in the enterprise ALDO Metal s.r.o which is a manufacturing company focused on custom manufacture of metal parts and units. In conclusion the overall results of the analysis are evaluated and the author outlines improvement proposals and recommendations to improve the cost management in this enterprise.
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CRISPR/Cas9-based genome editing in mice: state of the art and future perspectives
Eliáš, Jan ; Kašpárek, Petr (advisor) ; Čáp, Michal (referee)
Mutant mice are crucial tools for understanding gene functions in vivo. Recently, generation of mouse mutants was revolutionized by rapid developement of programmable nucleases, predominantly by the CRISPR/Cas9 system. Genome editing based on introduction of CRISPR/Cas9 components into early stage mouse embyros allows fast and inexpensive generation of gene-deficient animal models, especially when compared to the traditional techniques based on modification of embryonic stem cells (ESCs). The ability of CRISPR/Cas9 to induce double-strand break (DSB) at a given location of genomic DNA enables effective gene-ablation by random modification of the coding sequences or by complete ablation of the gene. However, precise modification of the gene sequences, such as incorporation of a DNA fragment into specific loci, are still difficult to make. In this work, I present a review of CRISPR/Cas9 system, its use in production of mutant mice and possible modifications of the system to increase the efficiency of precise gene-targeting. Keywords: CRISPR/Cas9, mouse, transgenesis, homologous recombination
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Crack path calculation using linear elastic fracture mechanics
Bónová, Kateřina ; Malíková, Lucie (referee) ; Eliáš, Jan (advisor)
This diploma thesis deals with the different possible calculations of crack path. Specifically, it focuses on criteria based on maximum tangential stress, minimal strain energy density, crack tip displacement, and local symmetry. These criteria are used for calculations in ANSYS software to estimate possible crack paths on four simple structures. The thesis also contains the codes created in ANSYS. Using these, the crack trajectory of a given structure can be calculated by any of the four criteria described.
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Approximate Polynomial Greatest Common Divisor
Eliaš, Ján ; Zítko, Jan (advisor) ; Hnětynková, Iveta (referee)
Title: Approximate Polynomial Greatest Common Divisor Author: Ján Eliaš Department: Department of Numerical Mathematics, MFF UK Supervisor: Doc. RNDr. Jan Zítko, CSc., Department of Numerical Mathematics, MFF UK Abstract: The computation of polynomial greatest common divisor (GCD) ranks among basic algebraic problems with many applications. The Euclidean algorithm is the oldest and usual technique for computing GCD. However, the GCD computation problem is ill-posed, particularly when some unknown noise is applied to the polyno- mial coefficients. Since the Euclidean algorithm is unstable, new methods have been extensively studied in recent years. Methods based on the numerical rank estimation represent one group of current meth- ods. Their disadvantage is that the numerical rank cannot be computed reliably due to the sensitivity of singular values on noise. The aim of the work is to overcome the ill-posed sensitivity of GCD computation in the presence of noise. Keywords: AGCD, Sylvester matrix, numerical rank, TLS
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