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1
Link, Emma. „Genome-wide association of statin-induced myopathy“. Thesis, University of Oxford, 2009. http://ora.ox.ac.uk/objects/uuid:ca675486-d678-4200-8bb4-988a923e9c4c.
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Lowering LDL-cholesterol with statin therapy produces substantial reductions in cardiovascular events, and larger cholesterol reductions may produce larger benefits. Rarely, myopathy occurs with statins, especially at higher doses and in combination with certain medications. Similarly strong associations might exist between myopathy with high-dose statin regimens and genetic variants, especially those affecting blood statin levels. This study aimed to find genetic variants associated with statin-induced myopathy. A feasibility study was completed to assess whether plausible effect sizes of 5 to10-fold higher risks per genetic variants could be detected among 50-100 cases with statin-induced myopathy and to consider the best study design. A genome-wide association study was then carried out using approximately 300,000 genetic markers (and additional fine-mapping) in 85 people with definite or incipient myopathy and 90 controls, who were all taking 80mg simvastatin daily in a 12,000 participant trial of 80mg vs 20mg simvastatin daily. The cases were also compared to 2,300 additional controls who had not been exposed to intensive-dose statin therapy. Replication of the myopathy result and lipid-lowering associations were tested in a 20,000 participant trial of 40mg simvastatin daily versus placebo. The genome-wide scan yielded a single strong association (p = 4x10-9) of myopathy with the rs4363657 single nucleotide polymorphism (SNP) located within the SLCO1B1 gene on chromosome 12. This non-coding SNP was in nearly complete linkage disequilibrium (r2=0.97) with the non-synonymous rs4149056 SNP. The population prevalence of the rs4149056 C allele was 15%, and the odds ratio for myopathy was 4.5 (95% confidence interval 2.6 to 7.7) for each copy of the C allele and 16.9 (4.7 to 61.1) for CC vs TT homozygotes. Over 60% of these myopathy cases could be attributed to the C variant. The SLCO1B1 gene encodes the organic anion transport polypeptide OATP1B1, which has been shown to regulate hepatic uptake of statins. In literature reports, rs4149056 reduced statin transport and was associated with 37% (31% to 44%) higher systemic statin acid levels per C allele. The association of rs4149056 with myopathy was replicated in the trial of 40mg simvastatin daily, which also showed that it was associated with the cholesterol-lowering effects of simvastatin. No SNPs in any other region were clearly associated with myopathy (although comparison of the myopathy cases with the 2,300 controls identified a region of chromosome 1p12 that warrants further study). This study identified common variants in SLCO1B1 that influence the risks of statin-induced myopathy substantially. Genotyping these variants may be useful for tailoring both the statin dose and safety monitoring. More generally, such studies of the genetic determinants of serious adverse reactions with other drug classes may help to improve the balance between treatment efficacy and safety.
2
Johansson, Caroline. „Genome-wide association study of drug-induced angioedema“. Thesis, Uppsala universitet, Institutionen för biologisk grundutbildning, 2019. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-373135.
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3
Alrumaihi, Faris Abdulrahman I. „Assessment of UVR-induced DNA damage and repair in nuclear genome versus mitochondrial genome“. Thesis, University of Leicester, 2016. http://hdl.handle.net/2381/37614.
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DNA is a key molecular-target for the deleterious effects of ultraviolet radiation (UVR). Cells contain two types of DNA: nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) and UVR induces various types of damage in the both DNAs, notably CPDs and 8-oxodG. The aim of this thesis is to examine UVR induced DNA damage formation and repair in nDNA and mtDNA and to determine which is the most important genomic target with respect to cell killing in vitro using HaCaT calls as models of human skin. The cell viability data showed that UVB induces significant cell death, which increased over 48 h. SSR-exposure also showed significant levels of cell death after 24 h but with evidence of significant survival after 48 h. Alkaline modified comet assay data showed that CPDs and 8-oxodG were significantly produced in HaCaT cells exposed to UVB and SSR, with CPDs being formed in a greater yields and there being no significant repair of CPDs over 48 h post-exposure to UVB. However, HaCaT cells irradiated with SSR showed significant repair of both CPD and 8-oxodG over 48 h. QPCR data showed that UVB and SSR induced similar profiles of damage in both nDNA and mtDNA; despite the induced damage levels being higher with UVB. The data also showed that nDNA is the main target for UVR in HaCaT cells exposed to UVB and SSR. The UVB-induced QPCR-detectable DNA damage in nDNA and mtDNA was not fully repaired, with a significant level of DNA damage remaining at 48 h, however, there was significant repair of the induced-damage in nDNA post-exposure to SSR (correlating with survival/re-growth), whereas the damage to mtDNA was not fully repaired. The greater lethality of UVB is probably due to more the damage induced and poorer repair (notably of CPD) in nuclear DNA following UVB exposure. Whereas the proficient repair of SSR-induced CPD in nDNA probably dictates survival following SSR exposure – as there was still a notable level of residual damage in mtDNA post-SSR exposure. However, nDNA is the main target for UVR causing DNA damage and may lead to mutations, which increase the risk of skin cancer development.
4
Kim, Hyun-Min. „Genome instability induced by triplex forming mirror repeats in S.cerevisiae“. Diss., Georgia Institute of Technology, 2009. http://hdl.handle.net/1853/33874.
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The main goal of this research is to understand molecular mechanisms of GAA/TTC-associated genetic instability in a model eukaryotic organism, S. cerevisiae. We demonstrate that expanded GAA/TTC repeats represent a threat to eukaryotic genome integrity by triggering double-strand breaks and gross chromosomal rearrangements. The fragility potential strongly depends on the length of the tracts and orientation of the repeats relative to the replication origin and to block replication fork progression. MutSbeta complex and endonuclease activity of MutLalpha play an important role in facilitation of fragility. In addition to GAA/TTC triplex forming repeats, non-GAA polypurine polypyrimidine mirror repeats that are prone to the formation of similar structures were found to be hotspots for rearrangements in humans and other model organisms. These include H-DNA forming sequences located in the major breakpoint cluster region at BCL2, intron 21 of PKD1, and promoter region of C-MYC. Lastly, we have investigated the effect of the triplex-binding small molecules, azacyanines, on GAA-mediated fragility using the chromosomal arm loss assay. We have found that in vivo, azacyanines stimulate (GAA/TTC)-mediated arm loss in a dose dependent manner in actively dividing cells. Azacyanines treatment enhances the GAA-induced replication arrest. We discovered that also, azacyanines at concentrations that induce fragility also inhibit cell growth. Over 60% of yeast cells are arrested at G2/M stage of the cell cycle. This implies an activation of DNA-damage checkpoint response.
5
Yu, Chuanhe. „Genome rearrangement induced by Ac/Ds transposable element in plants“. [Ames, Iowa : Iowa State University], 2009. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3389166.
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6
Schalbetter, Stephanie. „Genome instability induced by structured DNA and replication fork restart“. Thesis, University of Sussex, 2012. http://sro.sussex.ac.uk/id/eprint/38853/.
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DNA replication is a central mechanism to all forms of life. Errors occurring during DNA replication can result in mutagenesis and genome rearrangements, which can cause various diseases. In this work I have investigated the stability of direct tandem repeats (TRs) in the context of replication and replication-associated repair mechanisms. During DNA replication the replication fork encounters many obstacles, such as DNA-protein barriers, secondary DNA structures and DNA lesions. How and if replication resumes or restarts in these circumstances in order to complete genome replication is not well understood and the fidelity of replication in response to such obstacles remains unclear. I have developed TR assays to assess replication errors in the context of replication fork restart and secondary structures. The results suggest that structured DNA (G4) can cause instability of TRs in the context of normal replication and that restarted replication can be intrinsically error-prone. Surprisingly, the mutagenic effect of G4-DNA on TR stability was not elevated in the context of replication fork restart. Therefore, deletions of TRs containing G4-DNA are not more susceptible to the compromised fidelity of a restarted replication fork. Structures such as stalled replication forks can induce checkpoint responses to maintain genome stability. The stabilisation of replication forks is central in the response to replication stress. These protective mechanisms include the regulation of enzymatic activities. Mus81-Eme1 is a structure-specific endonuclease which is regulated by the DNA replication checkpoint, but has also been shown to be required for replication fork restart in certain circumstances. In collaboration with Professor Neil McDonald I analysed a novel domain identified in Mus81-Eme1. Mutagenesis of key residues deduced from the protein structure and comparison of their genetic analysis to known phenotypes of Mus81-Eme1 suggests distinct requirements for this domain.
7
Li, Xiang. „STRESS-INDUCED GENETIC CHANGE IN FLAX REVEALS GENOME VARIATION MECHANISM“. Case Western Reserve University School of Graduate Studies / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=case1565964370435691.
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8
Johnson, James. „Large scale simulations of genome organisation in living cells“. Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/31206.
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Within every human cell, approximately two meters of DNA must be compacted into a nucleus with a diameter of around ten micrometers. Alongside this daunting storage problem, the 3D organisation of the genome also helps determine which genes are up- or down-regulated, which in turn effects the functionality of the cell itself. While the organisational structure of the genome can be revealed using experimental techniques such as chromosome conformation capture and its high-throughput variant Hi-C, the mechanisms driving this organisation are still unclear. The first two results chapters of this thesis use molecular dynamics simulations to investigate the effect of a potential organisational mechanisms for DNA known as the "bridging-induced attraction". This mechanism involves multivalent DNA-binding proteins bridging genomically distant regions of DNA, which in turn promotes further binding of proteins and compaction of the DNA. In chapter 2 (the first results chapter) we look at a model where proteins can bind non-specifically to DNA, leading to cluster formation for suitable protein-DNA interaction strengths. We also show the effects of protein concentration on the DNA, with a collapse from a swollen to a globular phase observed for suitably high protein concentrations. Chapter 3 develops this model further, using genomic data from the ENCODE project to simulate the "specific binding" of proteins to either active (euchromatin) or inactive (heterochromatin) regions. We were then able to compare contact maps for specific simulated chromosomes with the experimental Hi-C data, with our model reproducing well the topologically associated domains (TADs) seen in Hi-C contact maps. In chapter 4 of the thesis we use numerical methods to study a model for the coupling between DNA topology (in particular, supercoiling in DNA and chromatin) and transcription in a genome. We present details of this model, where supercoiling flux is induced by gene transcription, and can diffuse along the DNA. The probability of transcription is also related to supercoiling, as regions of DNA which are negatively supercoiled have a greater likelihood of being transcribed. By changing the magnitude of supercoiling flux, we see a transition between a regime where transcription is random and a regime where transcription is highly correlated. We also find that divergent gene pairs show increased transcriptional activity, along with transcriptional waves and bursts in the highly correlated regime { all these features are associated with genomes of living organisms.
9
Novoa, Carolina. „RecQ-like helicase SGS1 counteracts DNA : RNA hybrid induced genome instability“. Thesis, University of British Columbia, 2017. http://hdl.handle.net/2429/60964.
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Dividing cells are constantly under threat from both endogenous and exogenous DNA damaging stresses that can lead to mutations and structural variations in DNA. One contributor to genome instability is three-stranded DNA:RNA hybrid structures called R-loops. Though R-loops are known to induce DNA damage and DNA replication stress, it is unclear whether they are recognized and processed by an established DNA repair pathway prior to inducing DNA breaks. Canonically, DNA repair proteins work downstream of R-loop-induced DNA damage to stimulate repair and suppress genome instability. Recently, the possibility that some DNA repair pathways actively destabilize R-loops, thus preventing unscheduled DNA damage has emerged. Here we identify the helicase SGS1 as a suppressor of R-loop stability. Our data reveals that SGS1 depleted cells accumulate R-loops. In addition, we define a role for transcription in genome instability of cells lacking SGS1, which is consistent with an R-loop based mechanism. Hyper-recombination in SGS1 mutants is dependent on transcript length, transcription rate, and active DNA replication. Also, rDNA instability in sgs1Δ can be suppressed by ectopic expression of RNaseH1, a protein that degrades DNA:RNA hybrids. Interestingly, R-loops are known to form at rDNA loci. We favour a model in which SGS1 contributes to the stabilization of stalled replication forks associated with transcription complexes, and unresolved DNA:RNA hybrids. Finally, we showed that knockdown of the human Sgs1 orthologue BLM in HCT116 cells also led to the accumulation of more R-loops than control HCT116 cells. In summary, our data supports the idea that some DNA repair proteins involved in replication fork stabilization might also prevent and process R-loops.Science, Faculty of
Graduate
10
Lee, Jong Wook. „A genome-wide association study of cisplatin-induced hearing loss in children“. Thesis, University of British Columbia, 2014. http://hdl.handle.net/2429/48487.
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Cisplatin is an effective chemotherapeutic agent used for a variety of solid organ malignancies in children and adults. However, its clinical use is limited by the high incidence of cisplatin-induced ototoxicity (CIO), which can affect up to 40-60% of children treated. To date, the genetic basis for CIO has been studied with only focused candidate-gene approaches.
Here we report the findings of the first genome-wide association study (GWAS) of cisplatin-induced ototoxicity in children. We examined 738,432 genetics markers in a discovery cohort of 282 Canadian paediatric patients treated with cisplatin, followed by a replication study in an independent Canadian cohort of 82 children. In addition, clinical, therapeutic, and demographic characteristics of cases and controls were analysed to identify clinical factors that may also contribute to the susceptibility to CIO.
The genome-wide analyses identified a significant association within the toll-like receptor 4 (TLR4) gene on chromosome 9. The most highly associated single nucleotide polymorphism (SNP) rs960312 conferred a highly protective effect against cisplatin-induced hearing loss (P = 1.19x10-⁸ , odds ratio = 0.22). This variant was subsequently replicated in an independent paediatric cohort (P = 0.018, odds ratio = 0.25). This variant is a tag SNP for a TLR4 promoter haplotype reported to have significantly altered transcriptional efficiency of TLR4. In both cohorts, CIO is significantly associated with younger age (P = 3.41x10-⁶), concomitant vincristine use (P = 2.03x10-¹²), and germ-cell tumour type (P = 4.50x10-⁶). After correcting for these clinical factors, TLR4 rs960312 remains highly associated (Uncorrected P = 1.16x10-⁹ ; Corrected P = 1.01x10-⁹).
Several lines of evidence from in vitro and in vivo studies have implicated TLR4 in cisplatin-induced cochlear toxicity and hearing loss. Here we provide the first evidence linking TLR4 and CIO in human patients treated for cancer, leading to new insights into the mechanism underlying this pervasive and clinically limiting adverse drug reaction. The identification of additional markers that contribute to the susceptibility of CIO can be used to develop individualized patient treatments, which can potentially improve safety and treatment outcome of cisplatin.Medicine, Faculty of
Medical Genetics, Department of
Graduate
11
Antoniani, Chiara. „A genome editing approach to induce fetal hemoglobin expression for the treatment of β-hemoglobinopathies“. Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCB077.
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Les β-hémoglobinopathies (β-thalassémies et drépanocytose) sont des anémies génétiques qui touchent des milliers de nouveaux nés chaque année dans le monde. Ces maladies sont causées par des mutations affectant l'expression de l'hémoglobine chez l'adulte. Le seul traitement disponible est la transfusion sanguine à vie, associée à une chélation du fer. Pour les patients les plus touchés, la greffe de cellule souche hématopoïétique (CSH) demeure le seul traitement curatif. Néanmoins, la transplantation autologue de cellules souches génétiquement corrigées représente une alternative thérapeutique pour les patients dépourvus de donneur compatible. Certaines délétions naturelles comprenant les gènes de la β- et δ- globine dans le locus de l'hémoglobine sont corrélées à une persistance de l'expression de l'hémoglobine fœtale (HPFH) à l'âge adulte. Ainsi il a été démontré que un taux élevé d'hémoglobine fœtale (HbF) améliore l'évolution clinique de ces deux pathologies. Afin d'identifier les régions régulatrices potentielles de la γ-globine, nous avons combiné les données issues d'analyses de mutations rencontrées chez des patients HPFH avec les sites d'hybridation de facteur de transcription. Sur la base de cette analyse, en ayant recours à la technologie CRISPR/CAS9, nous avons développé un protocole permettant de générer: (i) la délétion d'un potentiel suppresseur de l'HbF situé entre les gènes des globines δ et γ, ciblé par le répresseur de l’HbF BCL11A chez les érythroblastes adultes; (ii) la plus courte délétion associée à des taux élevés d’HbF (délétion Corfu) chez les patients β-thalassemiques; (iii) une délétion de 13.6-kb rencontrée fréquemment chez les patients HPFH et incluant les gènes des globines β et δ ainsi que le potentiel suppresseur de l'HbF. Notre travail a montré que la délétion de la région génomique de 13.6-kb entraîne une forte production de HbF et une réduction concomitante de l'expression de la β-globine soit dans des lignées cellulaires érythroïdes humaines soit dans des érythroblastes primaires dérivées des cellules souches et progéniteurs hématopoïétiques (CSPH). Par ailleurs, nous avons montré que la génération de cette délétion sur des CSPHs issus de patients drépanocytaires entraîne une augmentation de la transcription de la γ-globine dans une proportion significative d'érythroblastes, conduisant à une amélioration du phénotype drépanocytaire. Enfin, nous avons exploré le mécanisme menant à la réactivation de l'expression de la γ-globine. Nous avons évalué des changements dans la conformation de la chromatine et des modifications épigénétiques dans le locus de la β-globine lors de la délétion ou de l'inversion de la région de 13.6 kb. Dans l'ensemble, cette étude contribue à la connaissance des mécanismes favorisant l'échange de l'hémoglobine fœtale à l'adulte et fournit des indices pour une approche d'édition du génome dans le traitement de la β-thalassémies et de la drépanocytoseΒ-hemoglobinopathies (β-thalassemias and sickle cell disease) are genetic anemias affecting thousands of newborns annually worldwide. β-thalassemias and sickle cell disease (SCD) are caused by mutations affecting the adult hemoglobin expression and are currently treated by red blood cell transfusion and iron chelation regiments. For patients affected by severe β-hemoglobinopathies, allogenic hematopoietic stem cell (HSCs) transplantation is the only definitive therapy. However, transplantation of autologous, genetically corrected HSCs represents an alternative therapy for patients lacking a suitable HSC donor. Naturally occurring large deletions encompassing β- and δ-globin genes in the β-globin gene cluster, defined as Hereditary Persistence of Fetal Hemoglobin (HPFH) traits, lead to increased fetal hemoglobin (HbF) expression ameliorating both thalassemic and SCD clinical phenotypes. In this study, we integrated transcription factor binding site analysis and HPFH genetic data to identify potential HbF silencers in the β-globin locus. Based on this analysis, we designed a CRISPR/Cas9 strategy disrupting: (i) a putative δγ-intergenic HbF silencer targeted by the HbF repressor BCL11A in adult erythroblasts; (ii) the shortest deletion associated with elevated HbF levels (“Corfu” deletion) in β-thalassemic patients, encompassing the putative δγ-intergenic HbF silencer; (iii) a 13.6-kb genomic region including the δ- and β-globin genes and the putative intergenic HbF silencer. Targeting the 13.6-kb region, but not the Corfu and the putative δγ-intergenic regions, caused a robust HbF re-activation and a concomitant reduction in β-globin expression in an adult erythroid cell line and in healthy donor hematopoietic stem/progenitor cells (HSPC)-derived erythroblasts. We provided a proof of principle of this potential therapeutic strategy: disruption of the 13.6-kb region in HSPCs from SCD donors favored the β-to-γ globin switching in a significant proportion of HSPC-derived erythroblasts, leading to the amelioration of the SCD cell phenotype. Finally, we dissected the mechanisms leading to HbF de-repression demonstrating changes in the chromatin conformation and epigenetic modifications within the β-globin locus upon deletion or inversion of the 13.6-kb region. Overall, this study contributes to the knowledge of the mechanisms underlying fetal to adult hemoglobin switching, and provides clues for a genome editing approach to the treatment of SCD and β-thalassemia
12
Prüßing, Katja [Verfasser]. „Genome-wide screen for modifiers of Abeta42-induced neurodegeneration in Drosophila / Katja Prüßing“. Aachen : Hochschulbibliothek der Rheinisch-Westfälischen Technischen Hochschule Aachen, 2012. http://d-nb.info/1026309840/34.
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13
McKnight, N. C. „A genome-wide screen for starvation-induced autophagy : identifies new modulators of autophagy“. Thesis, University College London (University of London), 2011. http://discovery.ucl.ac.uk/1302281/.
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Autophagy is a catabolic mechanism by which cytoplasmic components are sequestered and transported by a double-membrane vesicle called an autophagosome to the lysosome for degradation. This recycling of organelles and macromolecules provides the cell with amino acids in times of nutrient deprivation though we do not fully know how the process is triggered or controlled. It is a highly regulated process in mammalian cells and its deregulation has been shown to contribute to multiple diseases. In order to find new regulators of mammalian autophagy, I performed a genome-wide screen using the Dharmacon human siRNA library in a stable human cell line expressing GFP-LC3, a specific marker for autophagosomal membranes. First I incubated the cells with the siRNA pools then I starved the cells of amino acids. This initiated the formation of GFP-LC3-labelled autophagosomes that I quantified using the Cellomics VTiScan microscope and accompanying software. I measured the effect of specific siRNA-mediated knock-down on multiple parameters including spot count. Accounting for cell death and normalising the data, I generated a Z-score for each siRNA pool and retested the best 500 autophagy-increasing and 500 autophagydecreasing siRNAs as above. The 190 strongest siRNA pools were deconvoluted leaving 20 hits that reproduced the phenotype with three or four out of four duplexes. These 20 hits were then assayed for endogenous LC3 lipidation in a different cell line and the ability of their siRNA to reduce mRNA levels was determined. Four increasers of GFP-LC3 spots increased endogenous LC3 lipidation, suggesting that these proteins are either negative regulators of autophagy or inhibit the maturation or degradation of autophagosomes. Five decreasers of GFP-LC3 spots also inhibited endogenous LC3 lipidation and I have characterised two of these proteins required for autophagy. SCOC colocalises with early autophagy markers and may be providing a scaffold for autophagy machinery. WAC, through its reported binding partners, may be playing a role in both the autophagic and ubiquitin/proteasome pathways.
14
Chen, Meng. „Disruption of DNA methylation induces genome-specific changes in gene expression in Arabidopsis allotetraploids“. Texas A&M University, 2005. http://hdl.handle.net/1969.1/4776.
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Allopolyploids are formed by the combination of evolutionarily-diverged genomes, the
union of which leads to dynamic changes in gene expression and genome organization.
Expression patterns of orthologous genes are rapidly and stochastically established in
newly created allotetraploids, where gene silencing is maintained by microRNAs, DNA
methylation, and other chromatin modifications. Among them, DNA methylation has
been known as an important mechanism of epigenetic regulation of gene expression and
chromatin structure. However, it is unclear how DNA methylation affects genome-wide
expression of homoeologous genes in the natural polyploid Arabidopsis suecica that
contains genome of both A. thaliana and A. arenosa.
To understand the role that DNA methylation plays in the polyploidization process,
a comparative analysis was performed comparing up- or down-regulated genes in
met1-RNAi A. suecica lines with the non-additively expressed genes in the synthetic allotetraploids,
i.e., different from the mid-parent value. The previous studies indicated
that decreased DNA methylation in A. suecica induces A. arenosa-specific demethylation in centromere regions and differentially alters expression of >200 genes encoding
many transposons, unknown proteins and some other functional proteins that are located
along chromosomes, whereas >1,300 non-additively expressed genes in the synthetic
allotetraploids are distributed randomly along the chromosomes and encode various proteins
in metabolism, energy, cellular biogenesis, cell defense and aging, and hormonal
regulation.
The origins of the progenitors of the genes whose expressions are altered in both
met1-RNAi A. suecica and resynthesized allotetraploid were analyzed with single strand
conformation polymorphism (SSCP) analysis. Reactivated genes in met1-RNAi A.
suecica lines were predominately derived from the A. thaliana genome in euchromatic
regions, whereas the suppressed genes were mainly derived from the A. Arenosa genome,
indicating that changes in DNA methylation are genome-sensitive. The data suggest that
allotetraploids incidentally display chromosome-specific changes and genomedependent
regulation of homoeologous genes in response to DNA methylation perturbations.
15
Gerzenstein, Sabrina Melisa. „Pharmacogenomics of the Intraocular Pressure Response to Glucocorticoids“. Scholarly Repository, 2009. http://scholarlyrepository.miami.edu/oa_theses/285.
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Glucocorticoids (GCs) have been widely used as a therapeutic agent for diverse inflammatory ocular diseases. However, a high percentage of patients undergoing this treatment develop high intraocular pressure (IOP), which if left unsupervised may lead to glaucoma. It is believed that the IOP elevation in response to GC treatment has a genetic determinant. In order to test this hypothesis, we analyzed in 52 patients the presence of single nucleotide polymorphisms (SNPs) in the glucocorticoid receptor gene (GR), the principal mediator of GCs uptake by the cells. We studied six GR SNPs previously reported to be associated with sensitivity and resistance to GCs: GluArg22/23GluLys (codon 22-23), Asn363Ser (codon 363), IVS2+646C>G (intron 2/BclI), IVS3-46G>C (intron 3), IVS4-16G>T (intron 4), Asn766Asn (Codon 766). Nevertheless, the results of this preliminary study did not show any specific correlation between SNPs in the GR gene and IOP elevation. Therefore, we proceeded to perform a whole genome SNP screen with the DNA samples of these patients to search for possible target genes responsible for the elevated IOP after GC treatment. As a result, we identified forty-eight SNPs in thirty-three genes that correlate with the high IOP response. The gene showing the strongest association is a poorly known G-protein coupled receptor. In addition, four SNPs hit a single transporter gene. Other candidate genes identified are a translation elongation factor, an F-box protein, an oxysterol binding protein, and a solute carrier family gene. These results support our hypothesis that IOP elevation following GC treatment is a genetically determined response. GCs are a common treatment for innumerable medical conditions; we believe that a genetic association between GC treatment and its physiological response may be important for improving treatment management and drug development for retinal diseases as well as for other medical ailments. However, further studies need to be performed to analyze in depth the association between the candidate genes identified in this study and the steroid response.
16
Iwamoto, Yoshihiro. „Generation of macrophages with altered viral sensitivity from genome-edited rhesus macaque iPSCs to model human disease“. Doctoral thesis, Kyoto University, 2021. http://hdl.handle.net/2433/265185.
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17
Finneran, Bryan P. „Developing and Testing an ELISA Biosensor for Measuring UV-Induced Viral Genome and Protein Damage“. The Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1593640837647181.
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Nord, Angelique, und Sofia Olsson. „Kvinnors upplevelse av en förlossning som startat genom induktion“. Thesis, Högskolan i Borås, Akademin för vård, arbetsliv och välfärd, 2018. http://urn.kb.se/resolve?urn=urn:nbn:se:hb:diva-13733.
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Förlossningsvården är i ständig förändring. Att andel induktioner de senaste 20 åren har ökat är en av dem. Flera studier pekar i riktning mot att den ökningen kommer att fortsätta. Barnmorskan ska ha kunskap och förmåga att samtala, informera och stödja kvinnor under graviditet och förlossning även när det föreligger en ökad risk för graviditets- och förlossningskomplikationer, vilket det kan göra vid induktion. För att kunna ge ett gott stöd innan, under och efter en förlossning som startat genom induktion behöver barnmorskan kunskap om kvinnors upplevelser. Studiens syfte är att beskriva kvinnors upplevelse av en förlossning som startat genom induktion. En kvalitativ metod med induktiv ansats där datamaterialet utgörs av kvinnors skrivna berättelser. Analysen genomfördes med kvalitativ innehållsanalys enligt Elo och Kyngäs (2007). Elva kvinnor med erfarenhet av en förlossning som startat genom induktion har delgett sina upplevelser. I resultatet framkommer tre huvudkategorier; Att spegla sin förlossning i bilden av en normalförlossning, Att föda genererar många känslor och Bemötandet är centralt för upplevelsen av förlossningen. Resultatet visar att kvinnorna hade positiva förväntningar inför förlossningen som skulle startas genom induktion men att de beskrev även att det kändes som att inte föda på riktigt och att det gick emot deras tidigare tankar om att föda naturligt. De kände en oro för hur induktionen skulle komma att påverka barnet och uttryckte tankar om att de hade svårt att lita till sin kropp när förlossningen forcerats fram. Kvinnornas behov av information var stort och de upplevde ofta att de inte fått tillgång till det i den utsträckning som de önskat. Kvinnorna lade stort fokus på personalen och deras bemötande och det framkom att barnmorskans stöd var viktigt för kvinnans upplevelse av sin förlossning. En relation som byggde på ömsesidighet och respekt kunde uppväga upplevelsen av jobbiga undersökningar och interventioner.Obstetric care is in constant change. Currently one of them is the rise in frequency of induced labor. Several studies point towards a continuation of that trend. The midwife must have the knowledge and ability to speak to, inform and support women during pregnancy and childbirth also when there is an increased risk for complication, as with induced labour. To be able to give proper support before, during and after induced labor and delivery, the midwife needs knowledge about women’s experiences. The purpose of this study is to describe those experiences using qualitative method with an inductive approach where the data material is women’s written stories. The analysis was produced using qualitative content analysis, as per Elo and Kyngnäs (2007). Eleven women who have given birth using induced labor have shared their experiences. In the material three main categories stand out; Reflecting upon one's delivery in light of the idea of a normal labour and birth, Many emotions are generated by giving birth and The encounter is central for the experience of giving birth. The results show that the women had positive expectations ahead of the induction but also that they felt it was not the real way to give birth and it did not seem as natural as they would have wished. They expressed concerns about the effects the induction might have on their child and a feeling they could not fully trust their own bodies as the labor had been forced upon them. The women did not feel they had received as much information as they would have wished. They emphasized the reception they received from the personnel and that the support from the midwife was important. A relationship built on mutuality and respect could compensate for the discomforts of examinations and interventions.
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Ibrahim, Ghosn [Verfasser]. „Genome-wide transcriptome induced in osteoclast-like cells differentiated on three different hard tissues / Ghosn Ibrahim“. Bonn : Universitäts- und Landesbibliothek Bonn, 2020. http://d-nb.info/1218301813/34.
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Zimmermann, Philipp Konstantin [Verfasser], und Christof von [Akademischer Betreuer] Kalle. „Genome‐wide detection of induced DNA double strand breaks / Philipp Konstantin Zimmermann ; Betreuer: Christof von Kalle“. Heidelberg : Universitätsbibliothek Heidelberg, 2016. http://d-nb.info/118073517X/34.
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Sudbery, Ian Martin. „Methods for genome-scale gene perturbation studies of the TRAIL-induced apoptosis pathway in mammalian cell culture“. Thesis, University of Cambridge, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.612450.
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Akatsuka, Shinya. „Contrasting genome-wide distribution of 8-hydroxyguanine and acrolein-modified adenine during oxidative stress-induced renal carcinogenesis“. Kyoto University, 2007. http://hdl.handle.net/2433/135700.
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Janin, Grajcarek. „Genome-wide microhomologies enable precise template-free editing of biologically relevant deletion mutations“. Kyoto University, 2020. http://hdl.handle.net/2433/253215.
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Östblom, John. „Utredning av Valboåsens grundvattenmagasins förbindelse med Gavleån : En analys av halten löst syre genom mätningar“. Thesis, Högskolan i Gävle, Avdelningen för bygg- energi- och miljöteknik, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:hig:diva-19859.
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Gävle kommuns VA-huvudman Gästrike Vatten AB ansvarar för dricksvattenproduktionen i Gävle. För Gävles tätort tas vatten från Valboåsen som sträcker sig från öster om staden, genom staden och vidare norrut. Denna rapports syfte är att genom mätning av halten löst syre undersöka Valboåsens förbindelse till Gavleån. Detta kommer ge en ökad förståelse för åsens komplexitet. Resultatet kommer också att användas för att verifiera och utveckla den konceptuella modellen över flödena i åsens grundvattenmagasin som tagits fram av Midvatten AB. För att kunna mäta halten löst syre har en provtagning skett på grundvattenrör. I provtagningen ingick även så kallade slugtest där rörens kapacitet och anslutning till grundvattenmagasinet säkerställdes. Efter mätningen sammanställdes resultatet för att kunna jämföra halten löst syre i grundvattenrören mot den konceptuella modellen. Resultatet visade att halten löst syre i vattnet i de olika grundvattenrören stöder den konceptuella modellen till stora delar och gav även mer information om områden längs åsen där kunskap om flödesförhållandena tidigare var osäkra. Metoden i den utförda studien har visat stor användbarhet för att påvisa flödesförhållanden och ytvattenpåverkan i Valboåsen vilket visar att mätning av syrehalt kan vara mycket användbart i grundvattenutredningar angående ytvattenpåverkan. För att utöka studien av Valboåsen i framtiden behövs mer provtagning i grundvattenmagasinet på områden som inte ingick i denna studie.Gävle municipality's water company is Gästrike Vatten AB. They manages the drinking water production for the City of Gävle. The production starts in the ridge of Valbo which extends between Överhärde (located in the south part of Valbo) and Strömsbro (located in the north part of Gavle). Purpose of this report is to measure the dissolved oxygen content in the aquifer throughout the whole area to investigate where the infiltration from the nearby Gavle River occurs. The aim of the study is to get a better understanding of the complexity of the Valbo ridge. The measurements will help to verify or modify the conceptual model of the directions of water flow in the Valbo ridge, developed by Midvatten AB. Dissolved oxygen content was measured through ground water pipes. To assess the pipes’ capacity and connection to the aquifer, slug tests were performed. The dissolved oxygen data were analyzed and compared with the conceptual model. The results showed that the dissolved oxygen content in the water supported the conceptual model to a large extent and also gave previously unknown information on some stretches of the ridge. The method shows great potential for additional future studies in Valbo ridge and elsewhere. To expand the study further, a need for more sampling of the aquifer throughout the areas that were not included in this study.
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Boulocher, Caroline. „La mesure de l'arthrose : imagerie des lésions d'arthrose du genou induite par section du ligament croisé crânial chez le lapin“. Lyon 1, 2008. http://www.theses.fr/2008LYO10037.
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L'arthrose, conséquence de la dégradation du cartilage articulaire, entraîne un handicap algofonctionnel majeur. Il n'existe pas actuellement de moyens de détection précoce ni de stratégies thérapeutiques efficaces pour prévenir, ralentir ou réparer les dégradations articulaires. Les lésions d'arthrose induite par section du ligament croisé crânial (LCC) chez le lapin sont similaires à celles observées chez l'homme. Radiographie, échographie et IRM sont les méthodes de mesure de l'arthrose les plus utilisées chez l'homme. L'imagerie permet des examens non invasifs et in vivo, mais sont techniquement difficiles à réaliser chez le lapin et plus encore chez le lapin arthrosique. Après une étude de l'arthrose chez l'homme et chez l'animal, ce manuscrit présente les développements des techniques d'imagerie in vivo, chez le lapin normal et arthrosique réalisés au cours de cette thèse. Nous avons validé un protocole de mesure de l'épaisseur du cartilage chez le lapin par micro-IRM 3D à 7 teslas qui permettait une mesure in vivo, quantitative et longitudinale des lésions du cartilage. Nous avons montré l'intérêt de l’échographie lors des études précliniques in vivo chez le lapin, pour vérifier la section du LCC et mesurer les lésions méniscales. Une technique de radiographie standardisée et une échelle de mesure des lésions illustrées d'un atlas ont été créées; nous avons montré qu'elles étaient efficaces et fiables. Enfin, une nouvelle méthode de mesure automatisée des lésions radiographiques est présentéeOsteoarthritis (OA) results from articular cartilage degenerative changes and is a painful and invalidating disease. Experimental OA in the rabbit model shows close similarity with human disease. Such studies are essential for facilitating development of therapies and early diagnostic methods. Diagnostic imaging allows for non-invasive in-vivo evaluation of OA but is technically challenging in the rabbit. After reviewing human and animal OA, this thesis illustrates the development of in vivo diagnostic imaging methods in the rabbit model of osteoarthritis after cranial cruciate ligament transection. A micro-MRI protocol was created for quantitative in vivo cartilage thickness measurements in a 7T magnet and sensitivity to change was correlated with final macroscopic and histological evaluations. A protocol for knee joint ultrasonography in the rabbit model was developed and was both specific and sensitive in detecting meniscal lesions and cranial cruciate ligament transection. We created a standardized radiographic procedure with a semi-quantitative grading scale and an atlas which could be used as a template. A new automatized method for radiographic OA grading is presented
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Feldker, Nora [Verfasser]. „Genome-wide cooperation of the EMT inducer ZEB1 with AP-1 and YAP in aggressive breast cancer / Nora Feldker“. München : Verlag Dr. Hut, 2021. http://d-nb.info/1233525506/34.
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Ê¿AliÌ„, AhÌ£mad. „A study of spontaneous and 5-fluorodeoxyuridine induced chromosomal instability and its significance in the sheep (Ovis aries) genome“. Thesis, University of Bristol, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.392932.
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Tran, Anh Thuy. „Genome-wide RNA-interference screen for human host factors vital to influenza A virus-induced cell death and viral replication“. Journal of Virology, 2013. http://hdl.handle.net/1993/18323.
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Influenza virus is a globally significant infectious agent with the potential to cause catastrophic pandemic outbreaks. Present treatment of influenza infections is restricted to only four anti-viral drugs, but there are increasing global reports of anti-viral resistance in several seasonal strains and also the 2009 pandemic swine-origin influenza virus H1N1. Possible future pandemic outbreaks, emerging new strains and drug resistance underscore the need to understand this complex virus and its pathogenicity with the goal that novel targets can be uncovered for future therapeutic development.
Extensive lung tissue damage during influenza virus infection is proposed to contribute to the development of aberrant host immune responses. Strong evidence now demonstrates the significance of the cellular death pathway in promoting efficient influenza virus replication and disease progression. Viruses rely heavily on the machinery of their host for productive replication, which is also an Achilles’ heel that could be targeted for treatment. In pursuit of unraveling the complex nature of influenza virus replication, I carried out a global shRNA screen to identify specific host factors and signaling pathways that are involved in influenza-induced cell death and replication. In this study I identified 138 genes required for influenza viruses to induce infected host cell death. These genes were found to be involved in Protein Kinase A, NF-kB and PI3K signaling cascades. These signaling pathways are well known regulators of cell death and survival, which suggests influenza viruses may carefully regulate these pathways to reach a balance that suit their requirements for efficient proliferation, eventually at the cost of the host cell. I chose five candidate genes—BAD, MxB, TNFSF12-13,TNFSF13, and USP47—that were associated with apoptosis and the major signaling pathways determined in my network analysis to further verify the genome-wide screen as well as elucidate the role of these potentially novel host factors in influenza virus replication.
I show in my study that influenza virus-induced cytopathology and cell death are considerably inhibited in BAD knockdown cells and both virus replication and viral protein production also are dramatically reduced. I also report here that MxB depletion protected cells from virus-mediated cytopathology and resulted in significant inhibition of influenza virus replication for H1N1 and H3N2 subtypes. Additionally, I report that TNFSF12-13, TFNSF13, and USP47, similarly, are required for efficient influenza virus replication and induction of cell death. Depletion of these proteins resulted in significant inhibition of viral propagation and conferred protection of host cells to virus killing.
Overall, my study has provided a list of novel host factors that play significant roles during influenza virus infection. Further studies on these potential genes and their encoded protein products may uncover possible new targets for drug development for future therapeutic treatment. In addition to providing greater understanding of influenza virus infection, these studies will also highlight important fundamentals of cellular processes that may be broadly applicable to other fields of research.
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Yoshinaga, Daisuke. „Phenotype-Based High-Throughput Classification of Long QT Syndrome Subtypes Using Human Induced Pluripotent Stem Cells“. Kyoto University, 2020. http://hdl.handle.net/2433/253171.
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Weisheit, Isabel [Verfasser], und Dominik [Akademischer Betreuer] Paquet. „Detection of deleterious on-target effects after CRISPR-mediated genome editing in human induced pluripotent stem cells / Isabel Weisheit ; Betreuer: Dominik Paquet“. München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2021. http://d-nb.info/1239557302/34.
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Cerrato, Giulia. „Oleate : An Atypical Cellular Stress Inducer That Stalls Protein Secretion Oleate-Induced Aggregation of LC3 at the Trans-Golgi Network Is Linked to a Protein Trafficking Blockade A Genome-Wide RNA Interference Screen Disentangles the Golgi Tropism of LC3 Live Cell Imaging of LC3 Dynamics“. Thesis, université Paris-Saclay, 2021. http://www.theses.fr/2021UPASL023.
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Les diverses classes d’acides gras (chaines carbonées saturées ou cis-/trans- insaturées) influencent la physiologie au niveau de la cellule et de l’organisme de façon différente. Curieusement, ces catégories distinctes ont un effet important (mais différent) sur l’autophagie, le mécanisme intracellulaire de dégradation qui maintient l’homéostasie énergétique et protège les cellules contre le stress. L’oléate, l’acide gras cis-insaturé endogène et alimentaire le plus abondant, possède la propriété atypique d’induire une redistribution de la protéine LC3 (signe particulier d’autophagie) de manière non-canonique et préférentiellement dans l’appareil de Golgi. Puisqu’il a été montré que, d’une part, les acides gras cis-insaturés présentent des effets bénéfiques pour la santé et que, d’autre part, les acides gras trans-insaturés et saturés induisent des effets toxiques, nous avons décidé d’explorer les mécanismes à la base de la redistribution de LC3 au niveau de l’appareil de Golgi induite par l’oléate. Cette analyse pourrait nous éclairer sur l’origine des différents effets des acides gras sur la santé. Pour cela, un criblage robotisé du génome entier par ARNs interférents a permis d’identifier plusieurs gènes impliqués dans le transport des protéines lié à l’appareil de Golgi, et également dans la réponse intégrée au stress.Des expériences supplémentaires ont montré que l’oléate impacte la morphologie subcellulaire de l’appareil de Golgi, en corrélation avec le blocage de la sécrétion protéique conventionnelle (dépendante du Golgi) lorsque que la cargaison est bloquée au niveau du réseau trans-golgien. L’inhibition de la sécrétion protéique a été observée dans plusieurs systèmes expérimentaux, tant in vitro qu’in vivo. De plus, un criblage visant à rechercher des agents chimiques capables d’induire les mêmes effets cellulaires que l’oléate, a permis d’identifier plusieurs composés appartenant à diverses classes pharmacologiques. De la même manière que l’oléate ces composés induisent un blocage de la sécrétion protéique conventionnelle, renforçant l’idée que cette voie de perturbation du Golgi joue un rôle pharmacologique important. En conclusion, ces résultats montrent que l’oléate représente une classe de molécules agissant sur l’appareil de Golgi pour y induire l’agrégation de LC3, tout en bloquant en même temps la sécrétion protéiqueDistinct classes of fatty acids (FAs) (saturated or cis-/trans-unsaturated carbon chains) impact on cellular and organismal physiology in a different manner. Interestingly, these diverse categories have a profound (but different) effect on autophagy, the conserved intracellular degradation mechanism that maintains energy homeostasis and protects cells against stress. Oleate, the most abundant endogenous and dietary cis-unsaturated FA, has the atypical property to induce the redistribution of the LC3 protein (peculiar sign of autophagy) in a non-canonical fashion and preferentially to the Golgi apparatus. Intrigued by these observations, which might be related to the health-improving effects of cis-unsaturated FAs (and the notorious toxicity of trans-unsaturated and saturated FAs), we decided to explore the mechanisms causing the oleate-induced relocation of LC3 to the Golgi apparatus. To achieve this goal, a robotized RNA interference genome-wide screen led to the identification of multiple genes involved in the Golgi-related protein transport, as well as in the integrated stress response. Follow-up experiments revealed that oleate affected the subcellular morphology of the Golgi apparatus, correlating with a blockade of conventional (Golgi-dependent) protein secretion that caused secretory cargo to be stalled at the level of the trans-Golgi network. The inhibition of protein secretion was observed using several experimental systems, both in vitro and in vivo. Moreover, a systematic screen searching for other chemical entities that mimic the oleate-induced cellular effects led to the identification of several compounds belonging to rather different pharmacological classes. These “oleate mimetics” also shared with oleate the capacity to block conventional protein secretion, supporting the notion that this pathway of Golgi perturbation is indeed of pharmacological relevance. In conclusion, this research work shows that oleate represents a class of molecules that act on the Golgi apparatus to cause the recruitment of LC3 and to stall protein secretion
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Voßfeldt, Hannes [Verfasser], Aaron [Akademischer Betreuer] Voigt, Jörg B. [Akademischer Betreuer] Schulz, Ernst A. [Akademischer Betreuer] Wimmer und Till [Akademischer Betreuer] Marquardt. „A Genome-Wide RNAi Screen for Modifiers of Polyglutamine-Induced Neurotoxicity in Drosophila / Hannes Voßfeldt. Gutachter: Jörg B. Schulz ; Ernst A. Wimmer ; Till Marquardt. Betreuer: Aaron Voigt“. Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2013. http://d-nb.info/1044173467/34.
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Ricci, Maria Aurelia 1985. „Chromatin fibers are formed by heterogeneous groups of nucleosomes in vivo“. Doctoral thesis, Universitat Pompeu Fabra, 2015. http://hdl.handle.net/10803/298724.
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La arquitectura del genoma y la estructura de la cromatina, junto con los factores de transcripción son actores clave para la autorenovación, la pluripotencia y la diferenciación de las células madre embrionarias (ESCs).
Combinando una microscopía cuantitativa de super-resolución (STORM) con simulaciones numéricas hemos sido capaz de definir cómo los nucleosomas están empaquetados en vivo, y hemos identificado un nuevo modelo de organización de la fibra de cromatina.
Encontramos que la fibra de cromatina está formada por grupos de nucleosomas de diferentes tamaños, que llamamos "nucleosome clutches" y que estos están intercalados con regiones sin nucleosomas. Además, el número medio de nucleosomas y su nivel de compactación dentro de los clutches, está relacionado con el estado celular. Células madre pluripotentes, tienen en promedio clutches con menos nucleosomas incluidos y de menos densidad con respecto a las células diferenciadas.Nuclear architecture and chromatin structure, together with the transcriptional network are key players for self-renew, pluripotency and differentiation of embryonic stem cells (ESCs). Combining quantitative super-resolution microscopy (STORM) with computer simulations we resolved how nucleosomes are arranged in vivo, identifying a novel model of organization of the chromatin fiber. We found that chromatin fiber is formed by groups of nucleosomes of varying sizes, which we term “clutches” and these were interspersed with nucleosome-depleted regions. Moreover the median number of nucleosomes and their compaction inside clutches highly correlated with cellular state. Ground-state pluripotent stem cells had, on average, less dense clutches containing fewer nucleosomes with respect to differentiated cells.
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Guillot, Xavier. „Effets thérapeutiques et anti-inflammatoires de la cryothérapie dans les rhumatismes inflammatoires“. Thesis, Besançon, 2016. http://www.theses.fr/2016BESA3009/document.
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La cryothérapie est utilisée de manière large et empirique à visée adjuvante dans les rhumatismes inflammatoires, avec un niveau de preuve faible. Dans une revue systématique de la littérature, en poolant les données de 6 études non contrôlées, nous avons pu démontrer que la cryothérapie (locale ou corps entier) appliquée deux fois par jour pendant 7 à 15 jours réduisait significativement l'EVA douleur et le score d'activité DAS25 dans la polyarthrite rhumatoïde. La cryothérapie locale (glace ou gaz froide) montrait par ailleurs des effets taille intra-classes supérieurs à ceux obtenus en utilisant la cryothérapie corps entier. L'objectif de ce travail était de mesurer les effets de la cryothérapie locale sur al douleur, l'inflammation synoviale et systémique chez les patients arthritiques et dans le modèle murin d'arthrite à l'adjuvant. Dans les études randomisées CDRI et ALGGAR, nous avons évalué les effets de deux applications locales de froid (glace versus gaz froid) sur la douleur, l'activité Doppler et les taux protéiques de cytokines intra-articulaires controlatéraux non souffrant d'arthrites de genou non septiques. Les genoux arthritiques controlatéraux non traités étaient utilisés comme contrôles. Nous avons par ailleurs étudié in vitro les effets de l'hypothermie modérée (30°C pendant 2heures) sur l'expression protéique des cytokines dans un modèle de culture de rotules de rats arthritiques. Nous avons enfin étudié in vitro dans l'arthrite à l'adjuvant les effets de l'application sub-chronique de glace ou de gaz froid (2 fois par jour pendant 14 jours versus contrôles arthritiques non traités) sur le score d'arthrite, le diamètre de cheville, la transcription des gènes codant pour les cytokines pro-inflammatoires dans les pattes arrières (Q-RT-PCR) et l'expression protéique des cytokines dans le plasma (Multiplex et ELISA) après 14 jours de traitement. Dans l'étude CDRI, la cryothérapie locale (glace et gaz froid) réduisait significativement l'EVA douleur ainsi que le score Doppler dans les genoux traités, ces effets persistant le lendemain des deux applications. Dans une analyse intermédiaire des résultats de l'étude ALGGAR, en combinant les deux groupes de traitement (glace et gaz de froid), nous avons observé une baisse des taux d'IL-6, d'IL-1β et de VEGF dans le liquide articulaire arès deux applications. dans les cultures d'explants de rotules de rats arthritiques, l'hypothermie ponctuelle réduisait significativement les taux d'IL-6, IL-17A et IL-1β dans les pattes arrières après 14 jours de traitement. Les deux modalités réduisaient significativement les niveaux plasmatiques d'IL-17A et la glace réduisait en outre les taux d'IL-6 et de VEGF. Nous n'avons observé aucun effet de la cryothérapie locale sur le voie du TNF-α chez l'homme ni chez l'animal. Nos résultats démontrent pour la première fois un effet thérapeutique et anti-inflammatoire de la cryothérapie locale dans l'arthrite. Les effets biologiques était IL-6/IL-147 dépendants et TNF-α indépendants. Des études complémentaires permettront de mieux caractériser les mécanismes moléculaires sous-jacents et de déterminer su la cryothérapie locale pourrait être une alternative aux AINS et corticoïdes dans les rhumatismes inflammatoiresCryotheapy i widely and empirically used in an adjuvant setting in inflammatory rheumatic diseases, with a low level of evidence. We performed a systematic review of the literature and, by pooling data from 6 non-controlled studies, we could show that local cryotherapy (local or whole-body cryotherapy) applaied twice a day for 7-15 days significantly reduced the pain VAS and the DAS28 activity score in rheumatoid arthritis. Furthermore, local cryotherapy (ice packs or cold gas) showed significantly greater intra)class effect-sizes compared to whole-body cryotherapy. The aim of this work was to measure the effects of local cryotherapy on pain, synovial and systemic inflammation in arthrici patients and in the murine model of adjuvant-induced arthritis. First, in the CDRI and ALGGAR randomized studies, we evaluated the effects of 2 local cold applications (ice versus cold gas) on pain, power Doppler activity and intra-joint cytokine protein levels in 46 patients suffering from non-septic knee arthritides. Contralateral arthritic knee were used as control. Secondly, we studied the in vitro effects of mild hypothermia (30°C for 2 hours) on cytokine protein expression in a model of cultured arthritic rat patellae. Thidly, we studied the in vitro effects of sub-chronically applied ice or cold gas (twice a day for 14 days versus non-treated arthritic controls) on the arthritis score, the ankle diameter, pro-inflammatory cytokine gene transcription levelsin hind paws (Q-RT-PCR) and cytokine plasma protein levelx (Multiplex and ELISA) after 14 days of treatment. In the CDRI study, local cryotherapy (ice and cold gas) significantly reduced the pain VAS and the power Doppler score in treated kness, and these effects remained significant the day afetr 2 cold applicaitions. In an intermediate analysis of the ALGGAR study results, by pooling the 2 treatment groups, we could show significant decreases in IL-6 protein, IL-1β and VEGF synovial fluid protein levels after 2 cold applicatios. In arthritic rat patella explangt culture experiments, punctual hypothermia significantly reduced IL-6 protein levels. In vivon ice was more efficient on the clinical parameters and better tolerated compared to cold gas. Both techniques significantly reduced IL-6, IL-17A ans IL-1β gene transcription levels in hind paws after 14 days of treatment. Both techniques redcued IL-17A plasma protein levles, while ice also reduced IL-6 and VEGF plasma protein levels. Conversely, we observed no effect of local cryotherapy on the TNF-α pathway, neither in patients nor in our animal model. Here we demonstrate for the first time therapeutic and anti-inflammatory effet-cts of local cryothepary in arthritis. The biological effects were IL-6/IL-17-driven and TNF-α independent. Further studies will help elucidate the underlying molecular mlechanisms involved and detemrine whether local cryotherapy might be a safer alternative to NSAIDs ans corticosteroids in inflammatory rheumatic diseases
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Butzlaff, Malte Verfasser], Aaron [Akademischer Betreuer] Voigt, Jörg B. [Akademischer Betreuer] Schulz, Gerhard [Akademischer Betreuer] [Hunsmann und Reinhard [Akademischer Betreuer] Schuh. „A Genome-Wide Screen on Modifiers of Tau-Induced Neurodegeneration Using RNAi-Mediated Gene Silencing in Drosophila / Malte Butzlaff. Gutachter: Jörg B. Schulz ; Gerhard Hunsmann ; Reinhard Schuh. Betreuer: Aaron Voigt“. Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2011. http://d-nb.info/1042529086/34.
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Bürfent, Benedikt [Verfasser]. „The immunomodulatory capacity of helminths on inflammation: Impact of eosinophils on E. coli-induced sepsis and genome-wide transcriptome profiling of human monocytes stimulated with helminth extract and LPS implicate immune functions and diseases / Benedikt Bürfent“. Bonn : Universitäts- und Landesbibliothek Bonn, 2017. http://d-nb.info/1149154284/34.
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Khedher, Ahmed. „Utilisation de technologies d'édition du génome afin de générer des cardiomyocytes matures à partir de cellules souches pluripotentes humaines induites CtIP Fusion to Cas9 Enhances Transgene Integration by Homology-Dependent Repair“. Thesis, université Paris-Saclay, 2021. http://www.theses.fr/2021UPASL002.
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Les cardiomyocytes dérivés des cellules souches pluripotentes humaines induites (hiPSC-CMs) représentent des modèles in vitro prometteurs pour plusieurs applications scientifiques et thérapeutiques allant de la modélisation de pathologies à la découverte de médicaments et de la toxicologie prédictive à la médecine régénérative. Malgré les nombreux progrès dans ce domaine, les protocoles de différenciation actuels ne permettent pas d’atteindre le stade de maturité que l’on retrouve chez le myocarde adulte de l’Homme. En effet, certaines caractéristiques majeures des hiPSC-CMs demeurent similaires à celles de cardiomyocytes fœtaux telles que l’expression de plusieurs gènes cardiaques, l’électrophysiologie ou leur fonction contractile. En effet, des analyses transcriptomiques réalisés au sein de notre laboratoire à Sanofi ont révélé que les gènes KCNJ2 et CASQ2, impliqués respectivement dans l’électrophysiologie et la gestion du calcium, étaient sous-exprimés dans les hiPSC-CMs en comparaison aux cardiomyocytes adultes. Cette thèse avait pour objectif d’améliorer la maturation des hiPSC-CMs en utilisant des technologies d’édition du génome. Ainsi, nous avons généré des lignées stables de hiPSC-CMs qui expriment de manière inductible KCNJ2 ou CASQ2 ou les deux gènes simultanément puis nous avons examiné leurs phénotypes fonctionnels et électrophysiologiques par le biais de méthodes d’analyses complémentaires. A la suite à l’induction de l’expression de KCNJ2 et CASQ2 par la doxycycline, les hiPSC-CMs montraient des bénéfices phénotypiques tels que la diminution drastique de la fréquence des battements spontanés, une hyperpolarisation du potentiel de repos membranaire, la diminution de la durée du potentiel d’action et l’amélioration du flux de calcium transitoire. En plus de ces bénéfices attendus, l’expression concomitante de ces deux gènes a amélioré la pente de la pointe du potentiel de champ extracellulaire associée au courant sodique ainsi que la gestion du calcium. Nous avons ensuite évalué le bénéfice de l’expression de ces transgènes sur la toxicologie prédictive en testant des molécules agonistes ou antagonistes de canaux ioniques utilisées classiquement dans le cadre des essais précliniques de toxicité cardiaque. Nous avons notamment observé plus d’arythmies induites par l’E4031 avec les hiPSC-CMs exprimant conjointement KCNJ2 et CASQ2 par rapport aux cardiomyocytes contrôles. Ainsi, les hiPSC-CMs exprimant simultanément KCNJ2 et CASQ2 présentent un phénotype plus mature que les hiPSC-CMs natifs et de tels cardiomyocytes édités génétiquement peuvent être utiles pour l’évaluation de la toxicité cardiaque de nouveaux médicaments candidatsHuman induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a very promising model for several scientific and therapeutic applications ranging from disease modeling to drug discovery, and from predictive toxicology to regenerative medicine. Despite numerous efforts, current protocols do not yet lead to a maturation phenotype equivalent to adult human myocardium. Indeed, key features of hiPSC-CMs remaining closer to fetal stages of development, such as gene expression, electrophysiology and function. Transcriptome analysis performed at Sanofi have confirmed these findings at the genome-wide level. Indeed, KCNJ2 and CASQ2 which are implicated in the two major physiological characteristics of cardiac cells, their electrophysiological behavior and calcium handling, respectively, were expressed at very low levels in hiPSC-CMs in comparison with adult cardiomyocytes. This thesis aimed to improve the maturation of hiPSC-CMs by using genome editing technologies. We generated stable hiPSC-CMs with inducible expression of KCNJ2, or CASQ2 or both genes (KCNJ2-CASQ2 hiPSC-CMs) and studied their functional and electrophysiological phenotype by several complementary methods. Upon doxycycline induction of KCNJ2 and CASQ2, KCNJ2-CASQ2 hiPSC-CMs displayed phenotypic benefits expected from previous studies of each maturation gene, including a drastic reduction of spontaneous beating, hyperpolarized resting membrane potential, shortened action potential duration and enhanced calcium transients. In addition, co-expression of the two genes enhanced Na+ spike slope of extracellular field potential and Ca2+ handling. We tested four reference drugs and observed signatures of known cardiac effects in KCNJ2-CASQ2 hiPSC-CMs, including arrhythmias induced by QT prolonging drug (E-4031), which were more easily detected than in control hiPSC-CMs. Therefore, KCNJ2-CASQ2 hiPSC-CMs exhibited a more mature phenotype than hiPSC-CMs and such genetically engineered hiPSC-CMs could be useful for testing cardiac toxicity of novel candidate drugs
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Maroc, Laetitia. „Etude sur le changement de type sexuel et les cassures chromosomiques chez Candida glabrata A single Ho-induced doublestrand break at the MAT locus is lethal in Candida glabrata A new inducible CRISPR-Cas9 system useful for genome editing and study of double-strand break repair in Candida glabrata“. Thesis, université Paris-Saclay, 2021. http://www.theses.fr/2021UPASL008.
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Le changement de type sexuel est une des stratégies développées par les champignons afin de favoriser la reproduction sexuée. Ce mécanisme permet à une cellule haploïde de donner naissance à une cellule de type sexuel opposé de façon qu’elles puissent se féconder. Cela a particulièrement été bien étudié chez la levure sexuée Saccharomyces cerevisiae mais la raison pour laquelle les éléments du changement de type sexuel ont été conservés dans des espèces comme Candida glabrata chez qui ni reproduction sexuée, ni changement de type sexuel n’a lieu, n’est toujours pas connue. Nous avons montré précédemment que le changement de type sexuel peut être induit chez C. glabrata en exprimant l’endonucléase responsable de ce mécanisme chez S. cerevisiae et que cela était lié à une très forte létalité cellulaire. Dans ce travail, nous avons étudié le lien qui existe entre changement de type sexuel et forte létalité chez C. glabrataMating-type switching is one of the strategies developed by fungi to promote sexual reproduction and propagation. This mechanism enables one haploid cell to give rise to a cell of the opposite mating-type so that they can mate. It has been extensively studied in the sexual yeast Saccharomyces cerevisiae but little is known about why the mating-type switching components have been conserved in species like Candida glabrata, in which neither sexual reproduction nor mating-type switching is observed. We have previously shown that mating-type switching can be triggered, in C. glabrata, by expression of the endonuclease responsible of this mechanism in S. cerevisiae, but this leads to massive cell death. In this work, we studied the link existing between mating-type switching and cell death in C. glabrata
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Dobečka, Kryštof. „Experimentální přístupy pro studium jaterní enzymatické indukce zprostředkované pregnanovým X receptorem“. Master's thesis, 2021. http://www.nusl.cz/ntk/nusl-446103.
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Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Kryštof Dobečka Supervisor: PharmDr. Tomáš Smutný, Ph.D. Advisor: prof. PharmDr. Petr Pávek, Ph.D. Title of diploma thesis: Experimental approaches for studying hepatic enzyme induction mediated by pregnane X receptor The thesis focuses on hepatic pregnane X receptor (PXR)-mediated induction of biotransformation enzymes. Emphasis is placed on experimental models and methods which are used for the assessment of enzyme induction. In addition to summarizing its well- established role as a xenobiotic-sensing receptor, PXR is also presented as a transcription factor with an important role in endogenous pathways. Furthermore, cell and animal models are evaluated in terms of expression and function of PXR and its target xenobiotic-metabolising enzymes. Primary human hepatocytes in 2D cultures are considered to be the gold standard of in vitro hepatic models. However, 3D technologies are expected to be increasingly used in the future. The use of animal models is limited due to pronounced interspecies differences in PXR activation. Thus, humanized models have been established to overcome these limitations. Next, this thesis comments screening methods for an assessment of interaction between PXR and...
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Van, der Vyver Christell. „Stress-induced genome alterations in plants“. Thesis, 2002. http://hdl.handle.net/2263/29860.
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Královcová, Dita. „Kvantifikace genové exprese u Hep-2 a HL-60 buněk po indukci apoptózy“. Doctoral thesis, 2008. http://www.nusl.cz/ntk/nusl-274110.
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Selina, Shih-Ting Chu, und 朱詩婷. „Genome-wide Survey of Chronic Mild Stress Induced Neural Malfunction“. Thesis, 2012. http://ndltd.ncl.edu.tw/handle/73957834701534998285.
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碩士國立臺灣大學
醫學檢驗暨生物技術學研究所
100
Background: Stressful life events which consist of social or environmental distresses (negative stressors) commonly cause emotional change and thus lead to disorders on psychiatry or other neuro-endocrine-immune axis. The mechanisms of stress-caused functional changes in neuronal system remain unclear. Methods: We utilized 4-week CMS (Chronic Mild Stress) animal model mimicking the daily hassles from social or environments to provoke the unset of depression- or anxiety- like behaviors. Behavior evaluation (wheel-running, tail suspension, and forced swimming tests) were performed every week. MRI and microPET were also performed to observe the change of brain. At the endpoint, mice were sacrificed, the blood were collected for ROS analysis and cytokine array, while the urine were gathered for metabolomic assay, and the four parts including amygdala, hippocampus, prefrontal cortex and cerebral cortex of the brain were collected for whole genome gene and microRNA profiling. The microarray data were analyzed by GeneSpring, Metacore software to explore the potential pathways involved in neuro-pathologenesis under stress. Besides, we injected two lung cancer cell lines both intravenously and subcutaneously to see if emotion has any relations to cancer progression and metastasis. Results: Mice under CMS exhibits reduced motor activity and increased weight loss. The results of gene profiling show there were 505 genes with two-fold change in amygdala, 272 in hippocampus, 51 in prefrontal cortex and 331 in cerebral cortex while microRNA profiling showed 115, 61, 62and 60 microRNAs with two-fold change in these four parts respectively. These total 1005 genes with two-fold change are chosen for hierarchical clustering and can distinguish either the brain parts or treatment. The results reveal its tight connection to emotion regulation to the not only the genes but also the microRNAs. Most of CMS-affected genes are predicted to be involved in great networks related to neurological disease, nervous system development, cell growth, axon guidance, and transduction signaling, as well as many known or unknown genes that reportedly affect psychiatry. But there’s no enough evidence to conclude if emotion’s positively or negatively related to cancer progression and metastasis. Conclusion: These findings might provide insights into the molecular pathological mechanisms contributing to stress-induced neural malfunctions. Searching for compounds or drugs that can target the chronic stress-induced genes may be a potential therapy for related diseases.
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Tung, Chao-ling, und 董昭伶. „Whole genome analysis of methylation level in Zta-induced reactivation cells“. Thesis, 2007. http://ndltd.ncl.edu.tw/handle/69485742936771119109.
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碩士國立成功大學
分子醫學研究所
95
Epstein-Barr virus, a γ herpesvirus, that infects more than 90% of the human population and closely associated with several lymphoid and epithelial malignancies. EBV reactivation from latent infection is initiated by activation of two immediate-early viral promoters, Zp and Rp, which encode BZLF1 (Zta) and BRLF1 (Rta) proteins, respectively. The EBV genome is highly methylated in latently infected cells. The Zta is a key lytic transactivator that preferentially binds to the methylated viral genome and activates lytic viral gene expression. While many targets of Zta have been identified in the EBV genome, expressions of a number of cellular genes were also shown to be regulated during EBV reactivation. But the underlying mechanism of Zta-induced transactivation on target genes expression are still unknown. One of these cellular genes, early growth response-1 (Egr-1), has been showed to be upregulated in EBV-infected nasopharyngeal carcinoma cell line that was treated by chemicals to induce reactivation. Further investigation identified Zta responsive element (ZRE) on Egr-1 promoter that are responsible for the induction of Egr-1 expression. We have found that ZRE on Egr-1 promoter was also located within a CpG island. We hypothesize that the methylation play a role in regulation of target gene expression in Zta overexpressed cells. The current study applied Zta-overexpressed cellular model to investigate the significance of altered genomic methylation upon EBV reactivation. We have employed several advanced technologies to assay the global methylation status in the host genome. These include the human androgen receptor (HUMARA) assay for X-chromosome inactivation, Southern blot analysis against genome repetitive sequences, and methylation-sensitive quantification real-time PCR to examine methylation status of imprinting control region (ICR) of the IGF2/H19 imprinting genes. In addition, we performed high performance capillary electrophoresis (HPCE) to measure the methyl-cytosine level in the cells. The expressions of methylation-related proteins were assayed by Western blot analysis using antibodies against human DNA methyltransferase 1 (DNMT1), DNMT3a, DNMT3b and LINE-1 ORFs. Finally, the Egr-1 promoter, as one example of Zta-targeted cellular gene, was also investigated by methylation-sensititive real-time PCR. Our data indicated in both Zta+ and Zta- cells, the patterns of inactivated X-chromosome were skewed X-chromosome inactivation. The methylation status of inactivated X-chromosome was not different in Zta+ and Zta- cells. The methylation level of the repetitive elements (LINE, SINE-Alu and α-satellite), methyl-cytosine level and imprinted gene, IGF2/H19, were similar between these two cells. Expressions of methylation-related proteins were also not changed by Zta expression. In addition, our data indicated that the CpG island of Egr-1 promoter is not protected by methylation in Zta+ and Zta- cells. Thus it suggests that Zta might bind to the ZRE on the Egr-1 promoter to regulate the gene expression in Zta-overexpressed cells. Theses results suggest the global methylation pattern in the host genome is not changed upon reactivation.
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Ambrož, Antonín. „Regulace genové exprese HSP70 genů a její závislost na genotypu HSP70 genů“. Master's thesis, 2011. http://www.nusl.cz/ntk/nusl-312511.
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The topic of the presented thesis is the regulation of gene expression level of the three HSP70 genes in mononuclear cells. We investigated the dependence of expression regulation (induction) abiliy on selected point mutations, so-called SNPs (single nucleotide polymorphism) in the observed genes. The mononuclear cells were obtained from peripheral blood samples of healthy individuals. In order to analyze their gene expression, we selected individuals who were homozygous for at least one of the monitored point mutations. Taking into account the chosen criteria for healthy individuals we based on interviews with these individuals and their personal history. We determined the polymorphisms observed in two cell stress-inducible HSP70-1 (HSPA1A) and HSP70-2 (HSPA1B) genes and in one constitutively expressed gene HSP70-Hom (HSPA1L). Further, we have analyzed HSP70s gene expression regulation and the relation between the expression regulation and studied polymorphisms. We determined the degree of regulation of a gene expression in the studied genes in relation to two SNPs -110A/C (rs1008438), +190G /C (rs1043618) gene HSP70-1, and two SNPs +1267A/G (rs1061581), +2074G /C (rs539689 ) of the HSP70-2 gene, and the mutation of one five-nucleotide (rs9281590) HSP70-2 gene, and one SNP +2437T/C (rs2227956) of...
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Deem, Angela Kay. „Genome-destabilizing and Mutagenic Effects of Break-induced Replication in Saccharomyces cerevisiae“. 2011. http://hdl.handle.net/1805/2625.
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Indiana University-Purdue University Indianapolis (IUPUI)DNA suffers constant damage, leading to a variety of lesions that require repair. One of the most devastating lesions is a double-strand break (DSB), which results in physical dissociation of two pieces of a chromosome. Necessarily, cells have evolved a number of DSB repair mechanisms. One mechanism of DSB repair is break-induced replication (BIR), which involves invasion of one side of the broken chromosome into a homologous template, followed by copying of the donor molecule through telomeric sequences. BIR is an important cellular process implicated in the restart of collapsed replication forks, as well as in various chromosomal instabilities. Furthermore, BIR uniquely combines processive replication involving a replication fork with DSB repair. This work employs a system in Saccharomyces cerevisiae to investigate genetic control, physical outcomes, and frameshift mutagenesis associated with BIR initiated by a controlled HO-endonuclease break in a chromosome. Mutations in POL32, which encodes a third, non-essential subunit of polymerase delta (Pol delta), as well as RAD9 and RAD24, which participate in the DNA damage checkpoint response, resulted in a BIR defect characterized by decreased BIR repair and increased loss of the broken chromosome. Also, increased incidence of chromosomal fusions determined to be half-crossover (HCO) molecules was confirmed in pol32 and rad24, as well as a rad9rad50S double mutant. HCO formation was also stimulated by addition of a replication-inhibiting drug, methyl-methane sulfonate (MMS), to cells undergoing BIR repair. Based on these data, it is proposed that interruption of BIR after it has initiated is one mechanism of HCO formation. Addition of a frameshift mutation reporter to this system allowed mutagenesis associated with BIR DNA synthesis to be measured. It is demonstrated that BIR DNA synthesis is intrinsically inaccurate over the entire path of the replication fork, as the rate of frameshift mutagenesis during BIR is up to 2800-fold higher than normal replication. Importantly, this high rate of mutagenesis was observed not only close to the DSB where BIR is less stable, but also far from the DSB where the BIR replication fork is fast and stabilized. Pol proofreading and mismatch repair (MMR) are confirmed to correct BIR errors. Based on these data, it is proposed that a high level of DNA polymerase errors that is not fully compensated by error-correction mechanisms is largely responsible for mutagenesis during BIR. Pif1p, a helicase that is non-essential for DNA replication, and elevated dNTP levels during BIR also contributed to BIR mutagenesis. Taken together, this work characterizes BIR as an essential repair process that also poses risks to a cell, including genome destabilization and hypermutagenesis.
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Chen, Chih-Wei, und 陳志威. „The involvement of human deoxyuridine triphosphatase in ribonucleotide reductase-induced genome instability“. Thesis, 2016. http://ndltd.ncl.edu.tw/handle/45331076367404455361.
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博士國立陽明大學
生化暨分子生物研究所
104
The appropriate supply of dNTPs is critical for cell growth and genome integrity. However, it is unclear whether enzymes responsible for dNTP biosynthesis play roles in promoting genome instability in cancer cells. The purpose of this study is to investigate the interrelationship between dUTP pyrophosphatase (dUTPase) and ribonucleotide reductase (RNR) in determining genome stability. The results shown that decreasing expression of dUTPase elevates 53BP1 foci formation in colorectal and breast cancer cell lines. The analysis of tumor samples demonstrated the correlation between the combination of low dUTPase and high R2, a subunit of RNR, with poor prognosis in patients harboring colorectal or breast cancer. Further evidences revealed that overexpression of R2 in non-tumorigenic cells progressively promotes 53BP1 foci formation to trigger transformation phenotype. These cells display acceleration in replication fork velocity, elevation in genomic uracil and breaks at AT-rich common fragile sites. Consistently, overexpression of dUTPase is able to abolish R2-induced genome instability. Thus, the expression level of dUTPase determines whether high R2 is beneficial for developing genome instability in cancer cells. These results indicate the regulatory effects of dUTPase and R2 in driving genome instability in cancer cells.
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Voßfeldt, Hannes. „A Genome-Wide RNAi Screen for Modifiers of Polyglutamine-Induced Neurotoxicity in Drosophila“. Doctoral thesis, 2012. http://hdl.handle.net/11858/00-1735-0000-000F-4C98-1.
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Die Spinozerebelläre Ataxie Typ 3 (SCA3) oder Machado-Joseph-Krankheit (MJD) gehört zur Gruppe der neurodegenerativen Polyglutaminerkrankungen (PolyQ-Erkrankungen) und ist die häufigste autosomal-dominante zerebelläre Ataxie weltweit. Ein in der Länge hochvariabler Polyglutaminabschnitt ist vermutlich die Ursache für die Toxizität der ansonsten nicht verwandten Proteine, welche die PolyQ-Erkrankungen verursachen. Abgesehen von dem verlängerten Polyglutaminbereich scheinen die physiologische Funktion und der zelluläre Kontext dieser Proteine und ihrer Interaktionspartner entscheidend für die spezifische Pathogenese und den Krankheitsverlauf zu sein. Diese Arbeit soll dazu beitragen, genetische Interaktoren zu identifizieren, welche die PolyQ-Toxizität verstärken oder vermindern, um somit die molekularen Krankheitsmechanismen zu entschlüsseln, die durch die Trinukleotid-Wiederholungen ausgelöst werden.
Dafür wurde ein humanes, von Ataxin-3 abgeleitetes Transgen in den Facettenaugen von Drosophila exprimiert. Die daraus resultierende Degeneration der Photorezeptoren induziert einen Raue-Augen-Phänotyp (Rough Eye Phenotype, REP) in adulten Fliegen. Um genetische Modifikatoren des REP zu identifizieren, wurde die Expression bestimmter Gene (Fliegengene mit einem humanen Ortholog, insgesamt ca. 7.500) augenspezifisch per RNAi vermindert. Mögliche Veränderungen im beobachteten REP sind dann höchstwahrscheinlich auf den RNAi-vermittelten Knockdown der Genexpression zurückzuführen. Damit wären die stummgeschalteten Kandidatengene zur Modifizierung der PolyQ-induzierten Neurotoxizität fähig.
Die auf diese Weise identifizierten Genprodukte sind in verschiedene biologische Prozesse involviert und stehen stellvertretend für unterschiedlichste molekulare Funktionen. Für eine Auswahl von Kandidatengenen wurden zusätzliche Untersuchungen angestellt, um die Art und das Ausmaß der Interaktionen zu bestimmen. Dabei wurden neue Modifikatorengene analysiert, welche z. B. in die Methylierung von tRNA oder den Sphingolipid-Metabolismus involviert sind. Diese Ergebnisse können neue Erkenntnisse bei der Aufklärung der Pathogenese der MJD und anderer PolyQ-Erkrankungen hervorbringen und gleichzeitig zum Verständnis der Rolle von Ataxin-3 und seinen Modulatorproteinen beitragen.
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Guan-RuTseng und 曾冠儒. „Ecotypic variation in genome-wide transcription profiles induced by arsenic in Arabidopsis roots“. Thesis, 2010. http://ndltd.ncl.edu.tw/handle/10810075962456464785.
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碩士國立成功大學
生命科學系碩博士班
98
Arsenic (As) is considered as the most common toxic metalloid which is widely found in the environment. It primarily exists in the form of inorganic arsenate or arsenite. Under the circumstances of contaminated groundwater, As would penetrate into the food chain through irrigation of vegetables and crop plants and then threatens human health to cancer. However, what impact that As causes to the molecular response and gene expression of plants has not been extensively characterized currently, therefore this study aims to explore how plants respond the nature of toxicity and the mechanism of signal transductions when facing the abiotic stress. First, when Col-0 and Ws-2 seedlings were subjected to arsenate treatment for 2 days, the root elongation rate of Col-0 was found significantly higher than that of Ws-2. In addition, after the exogenous treatment of 100 μM arsenate for 3 hours, the result showed that arsenic accumulation in Ws-2 was 1.86 times higher in comparing with Col-0’s. Accordingly, Col-0 exhibited more tolerance to arsenate stress than Ws-2. Next, the ATH1 gene chip was used to compare the transcriptome of Col-0 and Ws-2. With the treatment of 100 μM arsenate for a short period of time (1.5hrs and 3 hrs), Aquaporin transporter family and LeOPT1-like transporter family genes showed more down-regulated gene numbers and were repressed with consistency. Besides, genes encoding glutathione transferase (GST) and ABC transporter were found to be significantly induced in Ws-2. Based on the definition of the tolerance-associated gene, 14 transcription factor genes could be sorted to 9 families : AP2/EREBP, bHLH, C2H2, C3H, MBF1, MYB-related, Trihelix, WRKY and ZIM. And Ethylene-related genes were found only regulated in Col-0. This might suggest that when Col-0 face the arsenate stress, Ethylene involved in the process. To sum up, this study presents a comprehensive survey of global transcriptional regulation under arsenate stress. The results described here will help to further our understanding of the underlying mechanisms of arsenate toxicity and tolerance in plants.
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Laubenthal, Julian, O. Zlobinskaya, Krzysztof Poterlowicz, Adolf Baumgartner, Michal R. Gdula, E. Fthenou, M. Keramarou et al. „Cigarette smoke-induced transgenerational alterations in genome stability in cord blood of human F1 offspring“. 2012. http://hdl.handle.net/10454/6063.
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The relevance of preconceptional and prenatal toxicant exposures for genomic stability in offspring is difficult to analyze in human populations, because gestational exposures usually cannot be separated from preconceptional exposures. To analyze the roles of exposures during gestation and conception on genomic stability in the offspring, stability was assessed via the Comet assay and highly sensitive, semiautomated confocal laser scans of gammaH2AX foci in cord, maternal, and paternal blood as well as spermatozoa from 39 families in Crete, Greece, and the United Kingdom. With use of multivariate linear regression analysis with backward selection, preconceptional paternal smoking (% tail DNA: P>0.032; gammaH2AX foci: P>0.018) and gestational maternal (% tail DNA: P>0.033) smoking were found to statistically significantly predict DNA damage in the cord blood of F1 offspring. Maternal passive smoke exposure was not identified as a predictor of DNA damage in cord blood, indicating that the effect of paternal smoking may be transmitted via the spermatozoal genome. Taken together, these studies reveal a role for cigarette smoke in the induction of DNA alterations in human F1 offspring via exposures of the fetus in utero or the paternal germline. Moreover, the identification of transgenerational DNA alterations in the unexposed F1 offspring of smoking-exposed fathers supports the claim that cigarette smoke is a human germ cell mutagen.
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Wang, Jixin. „Genome-wide Transcriptome Analysis of Laminar Tissue During the Early Stages of Experimentally Induced Equine Laminitis“. Thesis, 2010. http://hdl.handle.net/1969.1/ETD-TAMU-2010-12-8718.
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Equine laminitis is a debilitating disease that causes extreme sufferring in afflicted horses and often results in a lifetime of chronic pain. The exact sequence of pathophysiological events culminating in laminitis has not yet been characterized, and this is reflected in the lack of any consistently effective therapeutic strategy. For these reasons, we used a newly developed 21,000 element equine-specific whole-genome oligoarray to perform transcriptomic analysis on laminar tissue from horses with experimentally induced models of laminitis: carbohydrate overload (CHO), hyperinsulinaemia (HI), and oligofructose (OF). Samples were collected during the developmental (DEV) and Obel grade 1 (OG1) stages of laminitis for the CHO model. For the HI model, samples were collected at the Obel grade 2 (OG2) stage. For the OF model, samples were collected at the 12 h and 24 h time points. Appropriate control samples were obtained for all models.
This is the first genome-wide transcriptome analysis of laminar tissue using an equine 21,000 70-mer long oligoarray approach in CHO, HI and OF induced laminitis. Overall, we identified the differential expression of genes encoding S100 calcium binding proteins, extracellular matrix proteins, glycoproteins, transporters, olfactory receptors, genes involved in signal transduction, body‟s homeostasis, apoptosis, and immune response. Between CHO and OF models of laminitis, there were more shared genes. We discovered several common differentially expressed genes (i.e., ADAMTS1, CYCS and CXCL14) among all three models that are likely important to the pathogenesis of equine laminitis. We also discovered what appear to be central roles of apoptosis, inflammatory response, and intracellular ion homeostasis molecular processes in CHO and OF models of laminitis. Pathway analysis detected the NOD-like receptor signaling pathway, which is involved in recognition of intracellular bacteria in both the CHO and OF models of laminitis. Genetic network analysis indicated convergent pathway core molecules present in equine acute laminitis: p38 MAPK and NF-κB. Most importantly, our results of overexpression of anti-microbial genes (i.e., DEFB4, PI3, and CXCL14) suggest the central involvement of these genes in the progression of early equine laminitis and will allow refinement of current hypotheses of disease pathogenesis.