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Differences in histone acetylation in normoxia and hypoxia
Čepek, Pavel ; Poljaková, Jitka (advisor) ; Eckschlager, Tomáš (referee)
Histones and their N and C terminal tails undergo different covalent modifications that regulate gene transcription. Among these histone modifications are methylation, ubiquitinilation, SUMOylation, ADP- ribosylation, phosphorylation, proline izomerization, deimination and acetylation. Histone acetylation is regulated by histonacetyltransferases (HATs) and histondeacetylases (HDACs). The balance between acetylation/deacetylation influences chromatin condensation and thus regulates gene transcription. Acetylation balance is disrupted in many human cancers and this fact can contribute to the development of malignant diseases. Histondeacetylase inhibitors (HDACi) can restore this acetylation imbalance. One of these HDACi is valproic acid (VPA) which has been used in treatment of epilepsy for decades. VPA shows antitumour effect in many studies. Decreased expression of n-myc oncoprotein, inhibition of tumour growth and angiogenesis are one of these anticancer effects observed in neuroblastoma cell lines after treatment with VPA. Despite the fact that exact mechanism of antitumour effect of VPA remains unclear, one of the most important mechanisms is hyperacetylation of histone H3 and H4. It is shown in this work that VPA increases acetylation of histones H3 and H4 in human neuroblastoma cell lines...
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Molecular genetics of celiac disease
Němečková, Iva ; Daňková, Pavlína (advisor) ; Tučková, Ludmila (referee)
Celiac disease is an organ-specific autoimmune disease that arises as a consequence of hypersensitivity to the grain gluten in genetically susceptible individuals. Genetic predisposition are HLA-DQ2 and HLA-DQ8 genes, which are necessary but not sufficient for the emergence of celiac disease; it is involved in approximately 40% of the inheritance. In the course of the time, other genes that might contribute to the pathogenesis of celiac disease are being discovered. Among these so-called candidate genes, which are sought on the basis of known knowledge of molecular mechanisms of innate and adaptive immune responses, are for example: MIC, TNF, CTLA-4, CD28, ICOS, MYO9B, MMP, TLR and PTPN22. Immune response triggered by gluten peptide penetration into the lamina propria leads to mucosal damage. Different gluten peptides are involved in the pathology of celiac disease in different ways, some peptides trigger an adaptive immune response, while others, such as peptide p31- 43, triggers an innate immune response.
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Gene Therapy and the Evolution of Cancer Treatment
Douglas, James Joshua ; Černá, Marie (advisor)
The continued understanding of gene structure, function and how its product interacts in the human body has lead to new wave of ideas on cancer therapy. Gene therapy, which 20 years ago was just a dream is now a very real possibility and alternative to the conventional treatments. Three new methods of utilizing alternative gene structure and manipulating the body's response to induce a tumor effect are presented here. Immunotherapy is the induction of the human immune system against an unwanted antigen. Viral oncolysis is the utilization and manipulation of natural human pathogens against tumor cells. Gene transfer is the addition of deletion of vital genes responsible for cell growth and apoptosis.
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Quantitative analysis of D2 dopamine receptors in clinically non-functioning pituitary adenomas
Gabalec, Filip ; Čáp, Jan (advisor) ; Fryšák, Zdeněk (referee) ; Hána, Václav (referee)
Quantitative analysis of D2 dopamine receptors in clinically non-functioning pituitary adenomas Introduction Clinically non-functioning pituitary adenomas account for about one-third of pituitary tumors. The majority of them are pathologically classified as gonadotropinomas or null-cell adenomas without hormonal expression. The rest represent silent corticotroph adenomas and plurihormonal tumors. Conservative therapy with dopamine agonists is effective in some cases only depending on the expression of dopamine 2 receptors (D2R). Objective The aim of this study was to quantitatively estimate D2R expression in clinically nonfunctioning pituitary adenomas and correlate the results with adenoma type according to pathological classification. Methods and results Out of the 87 adenomas investigated, 63 expressed gonadotropins, 7 were silent corticotroph adenomas, 7 were plurihormonal tumors, and only 6 did not express any pituitary hormone on immunohistochemical investigation. With the use of the reverse transcriptase real-time PCR technique, D2R mRNA was expressed in all adenomas with very heterogeneous quantity. The expression was very low in corticotroph adenomas (relative median quantity after normalization to housekeeping gene 0.01) and lower in plurihormonal tumors (median 0.4) than in gonadotroph...
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Genetic health disorders of cattle
NOVÁKOVÁ, Petra
The main aim is to summarize and describe the possibilities of improving genetic resistance of cattle against mastitis with the assistance of genetic selection. Effort to reveal all genetic mastitis parameters is difficult and long term researches of genes associated with mastitis are just in the beginning. The first part is devoted to a description of mastitis, which is one of the major health problems in the breed of dairy cattle and has many of negative impacts. Next are listed selected genes that scientists have so far managed to connect with the disease.
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Expression of cholinergic gene locus in a mouse model of Alzheimer's disease
Zimčík, Pavel
(anglický jazyk) The most common senile dementia, Alzheimer disease (AD), is characterized by a decline of memory and high cognitive functions. Typical post-mortem brain lesions are extracellular amyloid deposits, intracellular neurofibrilary tangles and ruined cholinergic and other neurotransmitters systems. Connection between damaged central cholinergic system and beta-amyloid accumulation remains obscure. We examined parietal cortex of young adult (7- month-old) female APPswe/PS1dE9 double transgenic mice which develope beta-amyloid fragments at high rate. Cholinergic synapses of these mice demonstrate functional presynaptic (stimulated acetylcholine release) as well as postsynaptic (muscarinic receptor-induced Gprotein activation) deficits and reduction of cholinergic markers. The mRNA levels of choline acetyltransferase, vesicular acetylcholine transporter and M1 to M4 subtypes of muscarinic receptors were determined in transgenic and littermate controls using qPCR. Obtained experimental data does not show any changes in measured mRNA levels. These observations indicate that reduction of cholinergic synaptic markers and function is due to posttranscriptional events.
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Diseases of the eye and ear in dogs
Plocová, Markéta ; Fiala Šebková, Naděžda (advisor) ; Chmelíková, Eva (referee)
The work deals with the description of selected diseases of the eye and ear. In order to better understand the different diseases and disorders caused by them, there is first described the anatomy and physiology of the competent organs of vision and hearing, and the location of their centers in the brain. Some breeds, due to their anatomical and genetic foundation have predisposition to certain diseases or disorders. Selected diseases of vision and hearing are described in view of anatomical and physiological eventually. Part of the description of diseases is also an overview of the clinical signs and symptoms. Some of selected diseases are genetic and can be inherited from generation to generation. For these heritable diseases are mentioned the possible candidate genes and their localization. Next I explain the congenital diseases that may occur during prenatal or postnatal development. For each disease I present the table with breeds where the disease occurs.
Eye diseases mentioned in this work are largely genetic in origin, so there is described in detail the genetic basis of the disease with a potential name of the candidate gene, the mutation and its localization. I deal with the diseases of the Primary Lens Luxation (PLL), Canine Multifocal Retinopathy (CMR), Multifocal Retinal Dysplasia (MRD), Collie Eye Anomaly (CEA), Dry eye syndrome and curly hair (CKCSID), Glaucoma, Progressive Retinal Atrophy (PRA) . For these hereditary diseases, it is important for breeders to eliminate their occurrence with the consistent breeding work.
The most common diseases of the ear are called otities, ie. ear infections. These infections can lead to damage and finally to the complete loss of hearing. As a separate chapter I mention hearing disorder in Dalmatians, which is associated to the coat color. Next I deal with the neurological symptoms of ear disease, complication associated with total canal ablation and bulla osteotomy, pathological changes in congenital ear disorder MPS (Mucopolysaccharidosis), disorders of the inner ear and the vestibular system.
Finally, it should be noted that thanks to the latest findings of diseases, they are better described and it is achieved better recognition of diseases and their causes, but their prevention is dependent on the origin of the disease. For diseases obtained it is important for the dogs to ensure the welfare conditions, while for hereditary diseases it is necessary the negative selection in the respective breeding of the affected breed.
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Prevention of health complications in hyperphenylalaninemia - one of the most common metabolic disorders
Havrlíková, Eva ; Pazdírková, Renáta (advisor)
Phenylketonuria (PKU) is a metabolic disorder affecting the metabolism of essential aromatic amino acid phenylalanine. The mode of inheritance for PKU is autosomal recessive. Nearly all cases are caused by mutations in the gene encoding PAH and its deficiency, which has been mapped to chromosome 12. More than 500 have been identified, the most common mutation in The Czech Republic and in The Europe is R408W. The hepatic enzyme phenylalanine hydroxylase (PAH) catalyzes the conversion of phenylalanine to tyrosine. Complete enzyme deficiency results in classical PKU, in which serum phenylalanine concentration exceeds 20 mg/dL (1200 micromol/L) and levels are elevated in the urine. Residual enzyme activity causes mild PKU (phenylalanine concentration 10 to 20 mg/dL, 600 to 1200 micromol/L) and mild hyperphenylalanemia (mild HPA, phenylalanine concentration 2.5 to 10 mg/dL, 150 to 600 micromol/L). Tyrosine concentration is normal or nearly normal. Tetrahydrobiopterin (BH4) is a cofactor required for PAH activity. Defects in BH4 metabolism account for approximately 1-2 percent of patients with elevated phenylalanine levels. In untreated patients, the hallmark of the disease is mental retardation and other neurological and psychical symptoms including epilepsy, but because of widespread neonatal screening,...
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Immunopathological and immunogenetic aspects of haematopietic stem cell and solid organ transplantations
Jindra, Pavel ; Boudová, Ludmila (advisor) ; Fakan, František (referee) ; Slavčev, Antonij (referee)
The genetic diversity of KIR genes and genotypes resembles of the HLA. Although the genes encoding KIR and HLA are located in different chromosomes and segregate independently, there is some evidence of some kind of co-evolution. Therefore, one could expect reduced KIR diversity within the HLA restricted population. A total of 41 unrelated individuals homozygous for ancestral HLA haplotype AH8.1 (HLA-A*0101-Cw*0701-B*0801- DRB1*0301-DQB1*0201), were typed for KIR genes. Over all, fourteen different genotypes were identified. The observed frequencies of KIR genes and genotypes composition generally mirror the published frequencies in Caucasians. Non-framework genes with frequency of more than 90 % included KIR2DL1, KIR2DL3, KIR3DL1, KIR2DS4 and KIR2DP1. Except for the KIR2DS4, all activating genes presented frequencies bellow 50 %. KIR2DS5 was the least frequent among activating genes (17 %), whereas KIR2DL5 (37 %) among inhibitory ones. The most frequent (39 %) was AA genotype. 22 individuals (54 %) had a copy of KIR haplotype A and B (AB genotype), whereas 3 (7%) were homozygous for B (BB genotype). Nine of 14 reported genotypes occurred only in one individual. Comparing with published and recorded genotypes (www.allelefrequencies.net), 5 genotypes were reported in less than 20 individuals worldwide and...
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Disorders of iron metabolism in skin and chronic liver diseases
Krátká, Karolína ; Horák, Jiří (advisor) ; Ehrmann, Jiří (referee) ; Lata, Jan (referee) ; Martásek, Pavel (referee)
Iron is one of the important biogenic trace elements and its role in the mammalian body is indispensable. In nature there is another element with similar characteristics. Iron is part of a series of compounds that provide key functions such as cellular respiration and oxygen transport to tissues. It is also important for cell proliferation and differentiation, the regulation of gene expression and applies also in the immune system. Given that the effects of iron accumulation in genetic hemochromatosis have been investigated in detail, in recent years, increasing attention and concern about the consequences of iron accumulation also in other diseases. Because the results of previous studies are inconclusive and often mutually contradictory, the aim of this work to analyze and clarify the relationship between HFE gene mutations and iron metabolism in the pathogenesis and progression of some skin and chronic liver disease among genetic hemochromatosis.
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