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Investigation of the role of the KEAP1-NRF2 antioxidant pathway in the therapy of secondary acute myeloid leukaemia
Myšáková, Michaela ; Pimková, Kristýna (advisor) ; Suttnar, Jiří (referee)
The development of therapy resistance is a long-standing problem in treating cancer, particularly in the treatment of myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML), where the hypomethylating agent 5-azacytidine (AZA) is the first choice of treatment. To enhance therapeutic efficacy, AZA is often combined with other agents such as pevonedistat (Pevo), a NEDDylation inhibitor targeting the ubiquitin-proteasome system. While initial results showed a synergistic effect of the AZA and Pevo combination in treating MDS and AML, dual resistance has been described, underlining the importance of understanding the mechanisms behind the resistance development. Our previous data demonstrated an essential role of redox homeostasis and antioxidant system represented by Nuclear factor erythroid 2-related factor 2 (NRF2) in AZA resistance. The Kelch-like ECH-associated protein 1 (KEAP1)-NRF2 pathway is the master regulator of antioxidative defence in cells crucial for maintaining redox balance. However, hyperactivation of NRF2 has been implicated in therapy resistance and cancer progression. We hypothesised that NRF2 is crucial in MDS/AML therapy resistance, particularly in resistance to combined AZA and Pevo therapy. We worked with cells sensitive and resistant to AZA and Pevo and monitored...
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Benchmark of the Computational Tools for the Prediction of the Effect of Mutations on Protein Stability
Berezný, Matej ; Martínek, Tomáš (referee) ; Musil, Miloš (advisor)
Návrh proteínov vyžaduje informáciu o tom ako mutácie ovplyvňujú celkovú stabilitu proteinu. Pre tento prípad existuje mnoho verejne dostupných nástrojov avšak ich kolektívne používanie či porovnávanie je veľmi pracné. Presne pre tento prípad som vyvinul BenchStab; konzolovú aplikáciu/Python knižnicu navrhnutú pre rýchlu a priamočiaru manipuláciu s 18 prediktormi, umožňujúc hromadné získavanie mutačných výsledkov. Zároveň som vytvoril novú unikátnu dátovú sadu, získanú z FireProtDB. Tento dataset som použil na porovnanie 24 rôznych predikčných metód pomocou rôznych metrík.
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Comparative and phylogenetic analysis of viruses in the University Hospital Brno
Švestková, Tereza ; Sedlář, Karel (referee) ; Nykrýnová, Markéta (advisor)
This thesis is focused on the SARs-CoV-2 coronavirus associated with severe acute respiratory syndrome, which was first identified in 2019. This coronavirus caused a pandemic that affected almost the entire world. Knowledge of the genetic information is needed for vaccine development, to determine infectivity and to predict the evolution of SARs-CoV-2 variants. To obtain genetic information, RNA must be sequenced and these genomic sequences must be assembled. By comparing the assembled genomes, it is possible to find out which part of the organism has mutated. Phylogenetic analysis is performed on the basis of the concordance or divergence in the assembled genomes, which indicates the evolution of the organism and shows the evolutionary relationship with other organisms. The practical part is focused on the assembly of genomes from samples from patients in the University Hospital Brno and evaluation of the quality of the assembly. After the genomes are assembled, the next goal is to evaluate the variability and subsequent phylogenetic analysis.
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Predictor of the Effect of Amino Acid Substitutions on Protein Function
Musil, Miloš ; Martínek, Tomáš (referee) ; Bendl, Jaroslav (advisor)
This thesis discusses the issue of predicting of the effect of amino acid substitutions on protein funkcion, based on phylogenetic analysis method, inspired by tool MAPP. Significant number of genetic diseases is caused by nonsynonymous SNPs manifested as single point mutations on the protein level. The ability to identify deleterious substitutions could be useful for protein engineering to test whether the proposed mutations do not damage protein function same as for targeting disease causing harmful mutations. However the experimental validation is costly and the need of predictive computation methods has risen. This thesis describes desing and implementation of a new in silico predictor based on the principles of evolutionary analysis and dissimilarity between original and substituting amino acid physico-chemical properties. Developed algorithm was tested on four datasets with 74,192 mutations from 16,256 sequences in total. The predictor yields up to 72 % accuracy and in the comparison with the most existing tools, it is substantially less time consuming. In order to achieve the highest possible efficiency, the optimization process was focused on selection of the most suitable (a) third-party software for calculation of a multiple sequence alignment, (b) overall decision threshold and (c) a set of physico-chemical properties.
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Comparison of genomes by synteny block analysis
Pavel, Tomáš ; Škutková, Helena (referee) ; Maděránková, Denisa (advisor)
The theoretical part of this bachelor thesis is aimed at basics of genetics. Term of gene and mutation are introduced in this section. There are gene and chromosome mutations mentioned and described. Following section is devoted to comparative genomics and especially to synteny. There is described what the synteny actually is and how the synteny arises. The end of the theoretical part of this thesis is about the evolution and there are described ways of sorting permutation vectors. The practical part of this bachelor thesis includes description of developed software. Output of this software is a dot-plot which shows detected synteny blocks. Indexes of these blocks are listed in GUI. The second important output is number of permutation steps. This number determines evolutionary distance between two analysed DNA sequences. The very last section is aimed at analyse of synthetic and real DNA sequences.
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Multi-Agent System for the Prediction of the Effect of Mutations on Protein Stability
Doseděl, Ondřej ; Martínek, Tomáš (referee) ; Musil, Miloš (advisor)
Proteiny jsou základním stavebním blokem všech žijících organismů, kde jsou zodpovědné za mnoho důležitých procesů. Jsou složeny z řetězců aminokyselin. Tyto řetězce mohou být jakkoliv změněné. Tomuto procesu se říká mutace a může být samovolná nebo indukovaná v laboratoři. Cílem této práce bylo vytvoření nových modelů pro určení stability proteinů. Skládá se ze dvou modelů. První model je multi-agentní systém pro klasifikaci stability proteinů. Nejlepší multi-agentní systém získal přesnost 0.7 a 0.41 MCC. Druhá část se~zabývala predikcí konkrétních hodnot G, kde byl vytvořený Extreme Gradient Boosting model, který získal 1.67 RMSE a 0.53 PCC. Součástí této práce byly představené 2 datasety, které jsou na sobě plně nezávislé, použitelné pro trénování a validaci modelů.
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Evolutionary models for evaluation of organisms relationship
Gregorová, Kateřina ; Maděránková, Denisa (referee) ; Škutková, Helena (advisor)
The work is focused on the study and description of evolutionary models for the evaluation of the evolutionary distances of DNA sequences and protein sequences in the amino acids and the codon representation. In the framework of this work was created a program that evaluates the genetic distance between DNA sequences and protein sequences for the use of some evolutionary models. The program calculates the genetic distance of the compared sequences and on the basis thereof renders the phylogenetic tree. This can be relatively easily and quickly evaluate the affinity of the organisms. For easy operation is part of the evaluation program also graphical user interface (GUI).
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Machine Learning as a Tool for the Prediction of the Effect of Mutations on Protein Stability
Dúbrava, Juraj Ondrej ; Martínek, Tomáš (referee) ; Musil, Miloš (advisor)
The main focus of this thesis is the prediction of the effect of amino acid substitutions on protein stability. My goal was to develop a predictive tool for the classification of the effect of mutations by combining several machine learning techniques. The implemented predictor, which utilizes SVM and Random forest methods, has achieved higher accuracy than any of the integrated methods. The novel predictive tool was compared with the existing ones using independent testing dataset. The predictor has yield 67 % accuracy and MCC 0,3.
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Attributes Calculating for Prediction of Effects of Mutation on Protein Function
Matějíček, Jiří ; Burgetová, Ivana (referee) ; Jaša, Petr (advisor)
This bachelor thesis deals with the bioinformatics techniques for the acquisition of attributes useful for prediction of mutation effects on the protein function. The work primarily aims to develop a user-friendly application for calculation of attributes of mutations from the protein sequence and structure. The developed application serves for integration of specialized tools such as FoldX. The standardized interface enables to implement additional computational tools and collect a diverse set of attributes from different sources. These attribute sets can then serve as an input for different prediction methods and help to improve predictions of mutation effects.
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Interactive Database for the Storage and Maintenance of the Biological Data
Dúbrava, Juraj Ondrej ; Martínek, Tomáš (referee) ; Musil, Miloš (advisor)
Cieľom tejto práce je vytvorenie novej databázy dát pre proteínovú stabilitu, ktorá bude udržiavať a poskytovať experimentálne dáta. Výsledkom práce je databáza FireProtDB, ktorá poskytuje manuálne overené experimentálne dáta z dostupných zdrojov a implementuje grafické užívateľské rozhranie, ktoré poskytuje dôležité informácie o dátach spoločne s možnosťou vyhľadávania umožňujúcim vytvárať dotazy na mieru a cieliacim na užívateľov, ktorí hľadajú dáta pre vytváranie dátových sád pre nástroje využívajúce strojové učenie.
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