Dissertations / Theses on the topic 'Genetic Function'
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Shi, Bu-Jun. "Expression and function of cucumoviral genomes." Title page, contents and summary only, 1997. http://web4.library.adelaide.edu.au/theses/09PH/09phs5546.pdf.
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Bibliography: leaves 104-130. The aim of this thesis is to characterise subgenomic RNAs of cucumoviruses and the functions of their encoding genes. Strains of cucumber mosaic virus (CMV) are classified into two major subgroups (I and II) on the basis of nucleotide sequence homology. The V strain of tomato aspermy virus (V-TAV) and a subgroup I CMV strain (WAII) are chosen to determine whether the 2b genes encoded by these viruses are expressed 'in vivo'. For further investigation of the 2b gene function, cDNA clones of three genomic RNAs of V-TAV are constructed. Using the infectious cDNA clones of V-TAV, a mutant virus containing only one of the two repeats is constructed.
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Obeidat, Ma’en. "Genetic determinants of lung function measures." Thesis, University of Nottingham, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.580163.
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The evidence of a genetic contribution to lung function measures, both baseline and in response to bronchodilator has been well established. Candidate gene studies have identified more than 100 genes suggested to contribute to variability in lung function. Apart from alpha 1 antitrypsin (AA T) gene; which is the most documented genetic risk factor for COPD, the findings were not consistent and replication of findings was limited. Similarly, most P2-adrenergic receptor agonist pharmacogenetic studies focused on the ADRB2 gene, yet with conflicting reports. Unravelling genetic determinants of lung function measures will help us better understand the normal functioning of the airways, the pathophysiology of respiratory diseases and help develop novel therapies. Work presented in this thesis describes a series of studies undertaken to examine the contribution of common single nucleotide polymorphisms (SNPs) to variability in lung function. Through contributing to large scale meta-analysis of genome-wide association studies (GWASs) in the SpiroMeta consortium (discovery n= 20,288 and replication n=54,276), we were able to identify five novel loci influencing forced expiratory volume in one second (FEV I) or its ratio to forced vital capacity (FEVIIFVC): GSTCD-INTS12(4q24), HTR4 (5q31-q33), AGER(6p21.3), TNS1 (2q35-q36), and THSD4 (15q23). I also showed their corresponding mRNAs to be expressed in airway related cell types. These loci point to novel pathways regulating lung function; potentially through lung development and tissue remodelling pathways, and were at large independent from smoking behaviour. Molecular characterisation of GSTCD-INTSl2identified novel transcripts in the lung, and putative promoter regions were mapped. Interestingly, a degree of correlation of expression was found for GSTCD- INTS 12 mRNAs in multiple airway cell types, suggesting shared regulatory mechanisms. Given the absence of any overlap between previously reported candidate genes for lung function and SpiroMeta GW AS loci, an evaluation of candidate genes was undertaken in theunique SpiroMeta sample (n=20,288) which did not support a role for the majority of the candidate genes tested. A potential role for AAT among smokers and PDE4D in the general population was however, suggested. The GW AS of response to salbutamol in severe asthma subjects has identified a number of novel loci; particularly the association of DLClon chromosome 8.This novel pathway association (GTPase activating protein! GTP-GDP/ Rho A) offers the potential to develop new therapies and to design personalised medicine approaches to help individuals with asthma. Future work will involve refining the association regions through population based re-sequencing approaches followed by detailed functional characterisation of associated genes to delineate the mechanisms underlying their associations with lung function.
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Yu, Chris 1981. "Characterizing function inlining with genetic programming." Thesis, Massachusetts Institute of Technology, 2004. http://hdl.handle.net/1721.1/33392.
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Thesis (M. Eng.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 2004.Includes bibliographical references (leaves 74-75).
Function inlining is a compiler optimization where the function call is replaced by the code from the function itself. Using a form of machine learning called genetic programming, this thesis examines which factors are important in determining which function calls to inline to maximize performance. A number of different heuristics are generated for inlining decisions in the Trimaran compiler, which improve on performance from the current default inlining heuristic. Also, trends in function inlining are examined over the thousands of compilation runs that are completed.
by Chris Yu.
M.Eng.
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Golby, Jessica A. "Genetic analysis of Drosophila NSF function /." Thesis, Connect to this title online; UW restricted, 2003. http://hdl.handle.net/1773/10247.
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Georgiou, Marios Andrew. "A molecular genetic analysis of commissureless function." Thesis, King's College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.271968.
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Birkett, Paul Brian Lawrie. "Genetic predisposition to schizophrenia and cognitive function." Thesis, King's College London (University of London), 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.431227.
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Reed, Patricia. "Function of bacteriophage Orf recombinases in genetic exchange." Thesis, Durham University, 2006. http://etheses.dur.ac.uk/4917/.
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Recombination events in bacteriophages frequently occur by illegitimate exchange at short tracts of sequence homology, enabling these viruses to acquire novel genes and serve as vehicles for horizontal gene transfer. The emergence of new pathogenic organisms due to the acquisition of virulence determinants from bacterial viruses has stimulated considerable interest in the mechanisms of phage recombination. Bacteriophage λ encodes its own recombination system, consisting of Exo, β and γ proteins. An additional λ recombinase, Orf, participates in the early stages of exchange, supplying a function equivalent to the Escherichia coli RecFOR complex. The host enzyme complex promotes the loading of the RecA strand exchange protein onto SSB-coated ssDNA. This thesis describes the purification and biochemical analysis of the λ Orf protein, in parallel with two distantly related homologs from E. coli cryptic prophage DLP12 and Staphylococcus aureus phage ɸETA.X Orf was found to belong to a family of proteins originating from diverse lambdoid phage and prophage sources. Members of this family reside within a conserved genetic module located between phage replication and cell lysis functions. Orf exists as a homodimer, arranged as a toroid with a shallow cleft running perpendicular to the central cavity. K binds preferentially to DNA containing single- stranded regions, and associates with E. coli SSB protein in the presence of ssDNA. The Orf homolog from E. coli DLP12 displayed similar properties. This work suggests that members of the Orf family function as recombination mediator proteins, stimulating the assembly of strand exchange proteins onto ssDNA, and highlights the importance of overcoming the barrier presented by SSB proteins during lambdoid phage recombination.
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Buender, Til. "Structural, biochemical and genetic dissection of RPS19 function." Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609522.
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Marcão, Ana Maria Lopes. "Arylsulfatase A : Genetic epidemiology and structure/ function studies." Doctoral thesis, Universidade do Porto. Reitoria, 2003. http://hdl.handle.net/10216/9650.
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Marcão, Ana Maria Lopes. "Arylsulfatase A : Genetic epidemiology and structure/ function studies." Tese, Universidade do Porto. Reitoria, 2003. http://hdl.handle.net/10216/9650.
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Sheehan, Susan. "Exploring the Genetics Regulating Kidney Function." Fogler Library, University of Maine, 2007. http://www.library.umaine.edu/theses/pdf/SheehanS2007.pdf.
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Taranova, Olena V. Pevny Larysa. "Genetic analysis of SOX2 function in mouse neural progenitors." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2006. http://dc.lib.unc.edu/u?/etd,286.
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Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2006.Title from electronic title page (viewed Oct. 10, 2007). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Curriculum in Neurobiology, School of Medicine." Discipline: Neurobiology; Department/School: Medicine.
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Gallagher, William. "Somatic genetic analysis of p53 function and cisplatin resistance." Thesis, University of Glasgow, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.321095.
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Gilmour, Darren T. "Reverse genetic analysis of SPARC function in vertebrate embryogenesis." Thesis, University of Cambridge, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.314018.
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de, Marvao Antonio. "Anthropometric and genetic determinants of cardiac morphology and function." Thesis, Imperial College London, 2015. http://hdl.handle.net/10044/1/56050.
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Background Cardiac structure and function result from complex interactions between genetic and environmental factors. Population-based studies have relied on 2-dimensional cardiovascular magnetic resonance as the gold-standard for phenotyping. However, this technique provides limited global metrics and is insensitive to regional or asymmetric changes in left ventricular (LV) morphology. High-resolution 3-dimensional cardiac magnetic resonance (3D-CMR) with computational quantitative phenotyping, might improve on traditional CMR by enabling the creation of detailed 3D statistical models of the variation in cardiac phenotypes for use in studies of genetic and/or environmental effects on cardiac form or function. Purpose To determine whether 3D-CMR is applicable at scale, and provides methodological and statistical advantages over conventional imaging for large-scale population studies and to apply 3D-CMR to anthropometric and genetic studies of the heart. Methods 1530 volunteers (54.8% females, 74.7% Caucasian, mean age 41.3±13.0 years) without self-reported cardiovascular disease were recruited prospectively to the Digital Heart Project. Using a cardiac atlas-based software, these images were computationally processed and quantitatively analysed. Parameters such as myocardial shape, curvature, wall thickness, relative wall thickness, end-systolic wall stress, fractional wall thickening and ventricular volumes were extracted at over 46,000 points in the model. The relationships between these parameters and systolic blood pressure (SBP), fat mass, lean mass and genetic variationswere analysed using 3D regression models adjusted for body surface area, gender, race, age and multiple testing. Targeted resequencing of titin (TTN), the largest human gene and the commonest genetic cause of dilated cardiomyopathy, was performed in 928 subjects while common variants (~700.000) were genotyped in 1346 subjects. Results Automatically segmented 3D images were more accurate than 2D images at defining cardiac surfaces, resulting in fewer subjects being required to detect a statistically significant 1 mm difference in wall thickness. 3D-CMR enabled the detection of a strong and distinct regionality of the effects of SBP, body composition and genetic variation on the heart. It shows that the precursors of the hypertensive heart phenotype can be traced to healthy normotensives and that different ratios of body composition are associated with particular gender-specific patterns of cardiac remodelling. In 17 asymptomatic subjects with genetic variations associated with dilated cardiomyopathy, early stages of ventricular impairment and wall thinning were identified, which were not apparent by 2D imaging. Conclusions 3D-CMR combined with computational modelling provides high-resolution insight into the earliest stages of heart disease. These methods show promise for population-based studies of the anthropometric, environmental and genetic determinants of LV form and function in health and disease.
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Paul, Dirk Stefan. "Maps of open chromatin : from genetic signals to function." Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.607719.
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Greetham, Matthew James. "Proteins that function at telomeres : genetic and biochemical investigation." Thesis, University of Newcastle upon Tyne, 2015. http://hdl.handle.net/10443/2882.
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The telomere is a nucleoprotein structure found at the ends of all eukaryotic chromosomes that plays a key role in ageing and cellular proliferation. It prevents chromosome ends being recognised and processed as double strand breaks and therefore preserves genomic integrity. This study aimed to further investigate the role of a telomere capping protein complex found in S. cerevisiae, which comprises three proteins, Cdc13, Stn1 and Ten1 forming the CST complex. The CST complex associates with the single stranded G‐rich overhangs found at telomere ends acting as a nucleating centre for various telomere associated factors, and preventing access to enzymes that might process the telomere as a double strand break, in particular exonucleases. This is evidenced from genetic studies involving temperature‐sensitive mutants of CDC13, STN1, TEN1 all of which accumulated single stranded DNA at the telomere end resulting in activation of the G2/M checkpoint. However, the ability of these proteins to protect telomere‐like structures in vitro has yet to be demonstrated. Furthermore, similarities have been drawn between the domain architecture of the components of the CST complex and Replication protein A (RPA) a ubiquitous single stranded DNA binding protein extensively involved in DNA metabolism. This has led to the suggestion that CST could be a telomere specific version of RPA. In this study, an in vitro telomere protection assay was developed and optimised to directly test the ability of CST and RPA to inhibit 5’ to 3’ resection of telomere mimics and non‐telomere controls. It was found that while RPA was able to protect telomere and non‐telomere control substrates from resection, Cdc13 only protected telomeres. Furthermore, it was found that the DNA binding domain of Cdc13 was able to inhibit resection by the 5’ to 3’ exonuclease, λ‐exonuclease, and was able to outcompete RPA for binding to the 3’ G‐rich overhang found at the end of the telomere mimic. The two small subunits of the CST complex, Stn1 and Ten1, were not able to inhibit nuclease resection by λ‐exonuclease at telomere mimics or nontelomere controls. Two synthetic genetic arrays and quantitative fitness analyses were carried out using temperature‐sensitive alleles of STN1 and RPA3 (the second largest subunit of the CST ii complex and the smallest subunit of the RPA heterotrimer respectively). The aim of these screens was to determine the extent to which the genetic interaction profiles of these screens overlapped with that demonstrated previously for cdc13‐1. It was found that, similarly to cdc13‐1, the stn1‐13 temperature‐sensitive phenotype was suppressed by deletion of EXO1 or nonsense‐mediated mRNA decay genes. However, deletion of a genome integrity checkpoint protein required for cell cycle arrest in G2/M, RAD9, in the stn1‐13 background, enhanced the temperature‐sensitive phenotype, suggesting that the G2/M checkpoint was important for the vitality of stn1‐ 13 strains in contrast to cdc13‐1. It was also found that deletion of the two subunits of the Ku heterodimer (YKU70 and YKU80) did not affect the growth of rpa3‐313 strains in contrast to cdc13‐1 and stn1‐13 strains where these deletions had a negative effect on growth. In addition deletion of EXO1 had no effect on the fitness of rpa3‐313 strains in contrast to its suppressive effect on temperature‐sensitivity in the cdc13‐1 and stn1‐ 13 background. These results demonstrate biochemically that Cdc13 and RPA inhibit 5’ to 3’ resection at telomere ends. Furthermore they demonstrate the importance of STN1 in preserving the telomere end, and the involvement of the nonsense‐mediated mRNA decay pathway in disrupting CST‐mediated telomere capping. Finally they underline the difficulty of disentangling the role of RPA in telomere capping using genetic techniques due to its extensive involvement in DNA metabolism throughout the cell.
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Hashimi, Sara Tajyar. "Dissecting genetic regulation of dendritic cell activation and function." Diss., Restricted to subscribing institutions, 2008. http://proquest.umi.com/pqdweb?did=1779835211&sid=4&Fmt=2&clientId=1564&RQT=309&VName=PQD.
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Meir, Eli. "Modeling genetic networks to aid in understanding their function /." Thesis, Connect to this title online; UW restricted, 2003. http://hdl.handle.net/1773/5263.
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Ekaterinaki, Nelly. "Expression and function of TN7 transposition proteins." Thesis, University of Glasgow, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.303343.
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Allard, Patrick 1974. "Expression, regulation and function of the stem-loop binding protein during mammalian oogenesis." Thesis, McGill University, 2005. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=85663.
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Although mRNAs encoding the histone proteins are among the most abundant mRNAs in mammalian oocytes, the mechanism regulating their translation in these cells has not been identified. Most histone mRNAs are not polyadenylated but instead carry in their 3'-utr a highly conserved stem-loop structure. In somatic cells, the stem-loop binding protein (SLBP) is expressed during S-phase of the cell cycle and associates with the stem-loop of histone mRNAs promoting their processing and translation and thereby coordinating their expression to DNA replication. As histone mRNAs are abundant in immature oocytes which are in G2 of the cell cycle and in ovulated or mature oocytes which are in M-phase, I examined the expression and the regulation of histone mRNAs in immature and maturing mouse oocytes. First, I described SLBP expression during oogenesis and pre-implantation embryonic development. I showed that SLBP is present at low levels in the nucleus of the immature oocyte and accumulates significantly during maturation of the oocyte. At both stages, SLBP is the only stem-loop binding activity present. I showed that SLBP meiotic accumulation correlates with the adenylation of SLBP mRNA and is mediated by the presence of a cytoplasmic polyadenylation element in SLBP 3'-utr. Also, I demonstrated that histones are synthesized in the immature and mature oocyte and that the translation of a reporter mRNA bearing the histone 3'-utr increases dramatically during oocyte maturation consistent with the accumulation of SLBP. I specifically blocked SLBP accumulation using RNA interference and observed that both translation of the reporter mRNA and endogenous histone synthesis are significantly reduced. Moreover, SLBP-depleted eggs display a significant decrease in pronuclear size and in the total amount of histones detectable on their chromatin. Finally, I also showed that elevating the amount of SLBP in immature (G2) oocytes is sufficient to increase translatio
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Diril, Muhammed Kasim. "Genetic analysis of stoned B-stonin 2 function in vivo." [S.l.] : [s.n.], 2005. http://webdoc.sub.gwdg.de/diss/2005/diril/diril.pdf.
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Tan, Elaine May. "Genetic strategies for elucidating neural circuit function in the brain." Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2006. http://wwwlib.umi.com/cr/ucsd/fullcit?p3211372.
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Thesis (Ph. D.)--University of California, San Diego, 2006.Title from first page of PDF file (viewed June 13, 2006). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references.
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Kay, Linda. "Influence of genetic polymorphisms on beta2-adrenoceptor expression and function." Thesis, University of Sheffield, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.489852.
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The Pradrenoceptor gene (ADRB2) is polymorphic at a number of loci both within the promoter and coding region. These polymorphisms have been shown to influence both the function and expression of the Beta2-adrenoceptor. However, these findings have been based on studies in transfected cell lines. The aim of the present study was to establish whether polymorphisms in ADRB2 are similarly influential in primary human cell systems. To this end the model system studied was the Beta2-adrenoceptor expressed in human lung mast cells. This study considered single nucleotide polymorphisms (SNPs) and their possible influence on (a) Beta-agonist-mediated responses of mast cells, (b) desensitisation of Beta2adrenoceptor- mediated responses and, (c) expression of the Betap2-adrenoceptor. In addition to individual SNPs, the effect of multiple SNPs (the extended haplotype) on these parameters was also considered. Eleven previously reported polymorphic positions within the ADRB2 were studied for influences of SNPs on Beta2-adrenoceptor function and expression. The only SNPs that influenced (a) p-agonist-mediated responses were 491 C>T (thrI64ile) and -367 T>C, (b) desensitisation of Beta2-adrenoceptor-mediated responses was 46 G>A (glyI6arg) and (c) expression of the P2-adrenoceptor was 491 C>T (thrI64ile). Analysis of multiple SNPs within the ADRB2 indicated that there were three principal extended haplotypes. However, none ofthese haplotypes influenced Beta2-adrenoceptor function or expression. These findings indicate that certain polymorphisms in the ADRB2 influence human pulmonary Pradrenoceptor function and expression.
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Mak, Philip. "An application of genetic algorithms to a function allocation problem." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape7/PQDD_0015/MQ48281.pdf.
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Prescher, Finnvid. "Seed orchards - genetic considerations on function, management and seed procurement /." Umeå : Dept. of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences, 2007. http://epsilon.slu.se/200775.pdf.
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Hedner, Margareta. "Olfactory Function : The Influence of Demographic, Cognitive, and Genetic Factors." Doctoral thesis, Stockholms universitet, Psykologiska institutionen, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-85907.
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Olfactory function is affected by demographic, cognitive, and genetic factors. In the present thesis, three empirical studies investigated individual differences in olfactory ability. Study I explored demographic and cognitive correlates in common olfactory tasks; odor detection, odor discrimination, and odor identification. The results indicated that old age influenced performance negatively in all tasks, and that semantic memory proficiency and executive functioning were related to odor discrimination and odor identification performance. No cognitive influence was observed for measurements of olfactory threshold. Using population-based data, Study II investigated a potential influence of the ApoE gene on olfactory identification after controlling for health status, semantic memory, and preclinical and clinical dementia. The main finding was that the ApoE- ɛ4 allele interacted with age, such that older ɛ4-carriers had an impaired odor identification performance relative to older non-carriers. Importantly, the negative ApoE- ɛ4 effect on olfactory proficiency was independent of clinical dementia conversion within five years. Study III investigated the effects of the BDNF val66met polymorphism on olfactory change over a five-year interval, in a community dwelling sample of young and old age cohorts. The results showed that age-related decline in olfactory identification was influenced by the BDNF val66met. In middle-aged subjects, no effect of BDNF val66met was observed although older val homozygote carriers showed a selectively larger olfactory decline than the older met carriers. Overall, results suggest that the relative influence of demographic and cognitive factors vary across different olfactory tasks and that two genes (ApoE and BDNF) impact age-related deficits in odor identification. Potential theoretical and practical implications of the findings are discussed as well as potential limitations of association studies in genomics research.
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Ranlund, S. M. "Biomarkers of brain function in psychosis and their genetic basis." Thesis, University College London (University of London), 2016. http://discovery.ucl.ac.uk/1493030/.
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Psychotic disorders, including schizophrenia and bipolar disorder, are amongst the most severe and enduring mental illnesses. Recent research has identified several genetic variants associated with an increased risk of developing psychosis; however, it remains largely unknown how these lead to the illness. This is where endophenotypes – heritable traits associated with the illness and observed in unaffected family members of patients – could be valuable. Endophenotypes are linked to the genetic underpinnings of disorders, and can help elucidate the functional effects of genetic risk variants. This thesis investigates endophenotypes for psychosis, with the overall aim of identify such biological markers, as well as to examine the relationships between different endophenotypes and their associations with genetic risk for psychosis. A family design has been used throughout, including patients with psychosis, their unaffected first-degree relatives, as well as healthy controls. In chapter 1, I review the endophenotype approach and those markers proposed for psychosis genetic research. Chapters 2 and 3 investigate whether different neurophysiological measures are potential endophenotypes for psychosis. In chapter 2, resting state EEG was studied and it was shown that risk groups, including unaffected relatives and people with an at-risk mental state, presented no abnormalities. This suggests that – rather than endophenotypes – the low frequency electrophysiological abnormalities seen in chronic patients in this study might be related to illness progression or long-term medication effects, and be more useful as biomarkers in non-genetic research. In chapter 3, I used dynamic causal modelling to investigate effective connectivity – the influence that one neuronal system exerts over another – underlying the mismatch negativity evoked potential, a marker of pre-attentive auditory perception. Results indicate that, compared to controls, both patients and their relatives show abnormalities of the excitability of superficial pyramidal cells in prefrontal cortex. Hence, this appears to be linked to the genetic aetiology of psychosis, and constitutes a potential endophenotype. Chapters 4 and 5 investigate several pre-identified endophenotypes for psychosis: Electrophysiological (the P300 event related potential), cognitive (working memory, spatial visualisation, and verbal memory), and neuroanatomical (lateral ventricular volume). In chapter 4, the associations between these endophenotypes were examined. Results showed that the P300 amplitude and latency are independent measures; the former indexing attention and working memory and the latter possibly a correlate of basic speed of processing. Importantly, individuals with psychosis, their unaffected relatives, and healthy controls all showed similar patterns of associations between all pairs of endophenotypes, supporting the notion of a continuum of psychosis across the population. Lastly, in chapter 5, polygenic risk scores – a measure of the combined effect of a large number of common genetic risk variants – were used to investigate the relationships between genetic risk for schizophrenia and bipolar disorder, and the endophenotypes studied in the previous chapter. Results showed that higher polygenic score for schizophrenia nominally predicts poorer performance on a spatial visualisation task; providing some evidence that the two traits share genetic risk variants as hypothesised. No other associations approached significance, possibly due to insufficient statistical power. However, as discovery samples grow, the use of polygenic scores is promising. This thesis has thus contributed to the field of mental health research by investigating key electrophysiological, cognitive and imaging endophenotypes for psychosis, as well as their genetic influences. Well defined and reliably measured endophenotypes are valuable in mental health research by clarifying the functional effects of identified genetic risk factors, and by providing ways of identifying groups of people with similar abnormalities, both within and between current diagnostic categories.
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Radhakrishnan, Aparna. "Genetic variation studies of megakaryopoiesis, platelet formation and platelet function." Thesis, University of Cambridge, 2014. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708102.
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Stevens, Robin J. "Genetic analysis of synaptogyrin function in the synaptic vesicle cycle." Thesis, Massachusetts Institute of Technology, 2012. http://hdl.handle.net/1721.1/70105.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2012.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.
Cataloged from student-submitted PDF version of thesis.
Includes bibliographical references.
Neuronal communication relies on the continual replenishment of synaptic vesicles that are primed for neurotransmitter release in response to action potentials. A vast array of proteins is required to mediate synaptic vesicle biogenesis, trafficking, docking, exocytosis, and endocytosis. Synaptogyrin and synaptophysin are abundant and evolutionarily conserved synaptic vesicles proteins that were identified over twenty years ago, yet their exact function in the synaptic vesicle cycle remains unknown. To further elucidate the role of these proteins, we have generated and characterized a synaptogyrin null mutant in Drosophila, whose genome encodes a single synaptogyrin isoform and lacks a synaptophysin homolog. Here we demonstrate that Drosophila synaptogyrin is abundantly expressed in neurons, where it localizes to the presynaptic terminal of the larval neuromuscular junction (NMJ). Drosophila lacking synaptogyrin are viable and fertile and have no overt deficits in motor function or courtship behavior. Ultrastructural analysis of mutant larvae revealed an increase in average synaptic vesicle diameter as well as enhanced variability in the size of synaptic vesicles. In addition, the resolution of endocytic cisternae into synaptic vesicles in response to robust exocytosis is defective in synaptogyrin mutants. While basal synaptic transmission at the larval NMJ is unaffected, synaptogyrin mutants do display increased facilitation during high-frequency stimulation, indicating that synaptic vesicle exocytosis is abnormally regulated during strong stimulation conditions. These results suggest that, while not required for neurotransmission, Drosophila synaptogyrin nevertheless modulates synaptic vesicle exo-endocytosis, especially during elevated rates of synaptic vesicle fusion.
by Robin J. Stevens.
Ph.D.
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Soler, Artigas María. "Genetic epidemiology of lung function and chronic obstructive pulmonary disease." Thesis, University of Leicester, 2015. http://hdl.handle.net/2381/31980.
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Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide. Lung function measures obtained through spirometry play a key role in the diagnosis of COPD. Both COPD and lung function are affected by genetic factors, and identifying genetic variants that have an effect on lung function or COPD risk has the potential to lead to improved treatment and prevention of COPD. This thesis is structured in five chapters, an introductory, a concluding chapter and three main chapters which present different approaches that aim to bring insights into the genetics of COPD and lung function. Chapter 2 tests the association with COPD risk of genetic variants previously associated with lung function, and tests their combined effect on lung function and COPD risk, in order to explore the role of risk prediction. Chapter 3 aims to identify new genetic variants associated with lung function and tests the association of genetic variants genome-wide. Chapter 4 focuses on the analysis of low frequency variants using different approaches and methodologies, and includes two studies. One study assesses associations of low frequency variants genome-wide, and the other focuses on genetic regions associated with lung function, in order to improve the localization of association signals that often comprise broad regions and several genes. These studies overall have identified 16 new genetic variants associated with lung function, have shown the association with COPD of 4 genetic variants previously associated with lung function, and present suggestive evidence of association with COPD for low frequency variants within regions associated with lung function.
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Guo, Ruijian. "Genetic and environmental components of sperm function in Drosophila melanogaster." Technische Universität Dresden, 2019. https://tud.qucosa.de/id/qucosa%3A37772.
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Sperm function has been studied in multiple research fields as it is essential to male fertility. In previous studies a variety of sperm traits have been examined as an assessment of sperm function. Among those traits, sperm viability, sperm motility and sperm metabolism are often commonly examined. However, sperm function can be influenced by both environmental and genetic factors. Specifically, nuclear genome has been demonstrated to play a role in sperm function, especially in sperm competitive capacity. There are increasing evidence for effects of mitochondrial genome on sperm function. Mitochondrial genetic variance has been suggested to
affect sperm length and sperm viability in seed beetle and sperm metabolism in rodent. Given the coordinated collaborations between nuclear and mitochondrial genomes in OXPHOS, replication and transcription of mitochondrial genome as well as intergenomic signalling, potential mitonuclear effects on sperm function are expected even though empirical evidence so far remains less. A recent review summarised all the previous work on environmental effects on sperm and found that various factors affects sperm function but largely neglected in ecology and evolution. In the study, we used D. melanogaster as a model to disentangle both genetic and environmental components of sperm function at sperm cell, ejaculate and offspring levels.
We found environmental effects on sperm function in D. melanogaster. Specifically, sperm incubation buffers affect sperm viability in chapter 2 and dietary PUFAs influence sperm volume and metabolism in chapter 4. Nuclear effects were found on sperm viability, sperm quality and male fertility in chapter 3. Mitochondrial genome was found to have an effect on sperm function, i.e. sperm viability and sperm quality differed among mitochondrial haplotypes examined. In addition, sperm function was further modified by the interaction of nuclear and mitochondrial genomes in ageing male. Sperm quality and fertilization success were suggested to be dependent on age-related mitonuclear interaction in chapter 3. Moreover, we examined the mitonuclear coadaptation hypothesis in the function of D. melanogaster sperm. No evidence for mitonuclear coadaptation hypothesis was found for sperm function in D. melanogaster as there were no difference between coadapted and non-coadapted lines in sperm traits examined. Lastly, we found that sperm viability, sperm quality and sperm metabolic rate cannot predict male fertility in D. melanogaster as correlation analysis revealed no relationship between them. Our experiment explored and disentangled the genetic and environmental components of sperm function at multiple levels in D.melanogaster systematically. Our results suggested that both mitochondrial and nuclear genome as well as the interaction between them play a role in sperm function in D. melanogaster. In addition to genetic components, our findings revealed environmental components of Drosophila sperm and suggested that it was phenotypic plastic.
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Klejnot, John Timothy. "Molecular genetic studies of cryptochrome 2 function in Arabidopsis thaliana." Diss., Restricted to subscribing institutions, 2008. http://proquest.umi.com/pqdweb?did=1666130271&sid=3&Fmt=2&clientId=1564&RQT=309&VName=PQD.
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Taylor, Michael Robert. "Genetic and biochemical analysis of zebrafish with visual function defects /." Thesis, Connect to this title online; UW restricted, 2002. http://hdl.handle.net/1773/9242.
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Ma, Yong. "Genetic and biochemical analysis of dispatched function in hedgehog signaling." Available to US Hopkins community, 2003. http://wwwlib.umi.com/dissertations/dlnow/3080721.
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Kim, Changhyeon. "Development of a Genetic Transformation System of Raspberry Cultivars for Gene Function Analysis." Thesis, North Dakota State University, 2018. https://hdl.handle.net/10365/29223.
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An Agrobacterium-mediated transformation system of purple raspberry ‘Amethyst’ was established after a series of experiments that determined the effect of genotype, inoculum density, and co-cultivation time on transformation. In this study, a plant regeneration protocol was established for ‘Joan J’ and ‘Polana’ (the regeneration protocol of ‘Amethyst’ was previously developed). Agrobacterium-mediated transformation was conducted for all three cultivars. The minimum killing level of hygromycin B and kanamycin was determined. Inoculum density and co-cultivation time were optimized. Polymerase chain reaction (PCR) verified a successful transformation of ‘Amethyst’ with the frequency of 3.3 ~ 4.4 % when leaves were infected with Agrobacterium EHA105 at the cell density of OD600 0.3 and co-cultivated for 3 days in the medium with 25.0 mg∙l-1 kanamycin. Transgenic lines with the PtFIT gene were hydroponically grown under iron sufficiency or deficiency. The real-time quantitative PCR verified the gene expression in response to iron sufficiency and deficiency conditions.
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Wan, Wen. "Semi-Parametric Techniques for Multi-Response Optimization." Diss., Virginia Tech, 2007. http://hdl.handle.net/10919/29425.
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The multi-response optimization (MRO) problem in response surface methodology (RSM) is quite common in industry and in many other areas of science. During the optimization stage in MRO, the desirability function method, one of the most flexible and popular MRO approaches and which has been utilized in this research, is a highly nonlinear function. Therefore, we have proposed use of a genetic algorithm (GA), a global optimization tool, to help solve the MRO problem. Although a GA is a very powerful optimization tool, it has a computational efficiency problem. To deal with this problem, we have developed an improved GA by incorporating a local directional search into a GA process.
In real life, practitioners usually prefer to identify all of the near-optimal solutions, or all feasible regions, for the desirability function, not just a single or several optimal solutions, because some feasible regions may be more desirable than others based on practical considerations. We have presented a procedure using our improved GA to approximately construct all feasible regions for the desirability function. This method is not limited by the number of factors in the design space.
Before the optimization stage in MRO, appropriate fitted models for each response are required. The parametric approach, a traditional RSM regression technique, which is inflexible and heavily relies on the assumption of well-estimated models for the response of interests, can lead to highly biased estimates and result in miscalculating optimal solutions when the userâ s model is incorrectly specified. Nonparametric methods have been suggested as an alternative, yet they often result in highly variable estimates, especially for sparse data with a small sample size which are the typical properties of traditional RSM experiments.
Therefore, in this research, we have proposed use of model robust regression 2 (MRR2), a semi-parametric method, which combines parametric and nonparametric methods. This combination does combine the advantages from each of the parametric and nonparametric methods and, at the same time, reduces some of the disadvantages inherent in each.Ph. D.
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Lee, Kin-shing, and 李鍵成. "In vivo study of asporin function in cartilage tissues." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/207898.
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Asporin (ASPN) is a risk factor for osteoarthritis and intervertebral disc degeneration. Its expression increases with aging and degeneration. D14 (14 aspartate-repeat polymorphism) is the risk allele and D13 is the most common allele. In vitro studies suggest that Asporin functions as a negative regulator of Tgf-β signaling, an important stimulator of matrix formation in bone and cartilage. However, the in vivo role of Asporin in development or its involvement in the pathogenesis of degenerative cartilage diseases is unclear. Here, we use mouse as a model to study the impact of Asporin in the intervertebral discs of the spine.
In wide type mice, we showed that Asporin is expressed and localized in the nucleus pulposus and annulus fibrosis of intervertebral discs, and the articular cartilage in knee joints. Furthermore, Asporin expressing cells in these tissues are active in Tgf-β signaling, suggesting a relationship between Asporin and Tgf-β signaling and a role in disc and articular joint maintenance. Using natural degeneration with aging, and models for induced degeneration in the mouse-tail discs, Asporin expression was shown to be up-regulated in nucleus pulposus and annulus fibrosis cells of degenerating intervertebral discs. These cells are also active in Tgf-β signaling supporting a potential relationship with the pathogenesis of disc degeneration.
Transgenic mice overexpressing Asporin in cartilage tissues were generated to study this relationship and the impact on the differentiation and function of disc cells. Interestingly, overexpression of Asporin in the nucleus pulposus leads to enhanced production and deposition of extracellular matrix such as glycosaminoglycans, with concomitant changes in cell morphology, suggesting Asporin altered the extracellular matrix niche of resident nucleus pulposus cells. However, such changes are only observed in discs in the tail region but not in lumbar discs. We propose a relationship to mechanical loading as an environmental factor. Molecular analysis of transgene expressing cells showed Tgf-β signaling is active and its downstream target genes up-regulated. Furthermore, overexpression of Asporin enhances differentiation of notochordal-like cells (NCCs) in mouse nucleus pulposus toward the more mature nucleus pulposus cells (NPCs) and chondrocyte-like cells (CLCs) that are more abundant in the human nucleus pulposus and other larger animals that prompt to intervertebral disc degeneration.
This study provided new insights into the function of Asporin in the pathogenesis of intervertebral disc degeneration. We proposed a model whereby Asporin, as a genetic risk factor, alters the extracellular environment of the nucleus pulposus, that in conjunction with environmental factors such as mechanical loading, enhances Tgf-β signaling, and consequentially, promotes the maturation of NCCs towards NPCs and CLCs, a hallmark of degenerative process proposed in human and other larger animal models. These transgenic mice provide the opportunity to better understand the relationship between genetic and environmental factors, and the molecular controls leading to the maturation process of NCCs in intervertebral disc degeneration.published_or_final_version
Biochemistry
Doctoral
Doctor of Philosophy
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Chen, Shen Liang. "Function of transcription cofactors in terminal muscle differentiation /." St. Lucia, Qld, 2001. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe16099.pdf.
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Blevins, Todd Lucas. "Molecular genetic analysis of siRNA biogenesis and function in Arabidopsis thaliana /." [S.l.] : [s.n.], 2009. http://edoc.unibas.ch/diss/DissB_8814.
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Eriksson, Jonas. "Genetic and Genomic Studies in Chicken : Assigning Function to Vertebrate Genes." Doctoral thesis, Uppsala universitet, Institutionen för medicinsk biokemi och mikrobiologi, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-162597.
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A major challenge in the post-genomic era is to understand how genome sequence variants (genotype) give rise to the enormous diversity observed in terms of morphology, physiology and behavior (phenotype) among living organisms. Domestic animals—with their tremendous phenotypic variation—are excellent model organisms for determining the relationships between genotype and phenotype. In this thesis, I describe the utilization of the chicken, in combination with modern genetic and genomic approaches, in developing our understanding of the genetic mechanisms underlying phenotypic variation. These studies provide novel information on the genetics behind variation in carotenoid- and melanin-based pigmentation—observed in many organisms—and also cast light on the genetic basis of chicken domestication. In paper I, we report that the yellow skin phenotype—observed in most commercial chickens—is caused by one or several tissue-specific mutations altering the expression of beta-carotene oxygenase 2 (BCO2 or BCDO2) in skin. In addition, we present the first conclusive evidence of a hybrid origin of the domestic chicken, since the allele causing yellow skin most likely originates from the grey jungle fowl (Gallus sonneratii) and not from the previously described sole ancestor, the red jungle fowl (Gallus gallus). In paper II, we detect a number of loci that were likely important during the domestication process of chicken and the later specialization into meat (broiler) and egg (layer) producing lines. One of the major findings was that worldwide, almost all domestic chickens carry a missense mutation in TSHR (thyroid stimulating hormone receptor) in a position that is completely conserved amongst vertebrates. We speculate that this “domestication-mutation” has played an important role in the transformation of the wild red jungle fowl ancestor into the modern domestic chicken. In paper III, we demonstrate that the dilution of red (pheomelanin) pigmentation—observed in the plumage of the Inhibitor of Gold chicken—is caused by a frame-shift mutation in the catechol-O-methyltransferase domain containing 1 (COMTD1) gene. The production and regulation of pheomelanin is poorly understood and this discovery advances our current knowledge of this pathway.
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Zhan, Yougen 1968. "Proteomics and genetic studies of dystroglycan function in the nervous system." Thesis, McGill University, 2006. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=102771.
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Muscular dystrophies are a group of diseases that are often caused by loss-of-function mutations affecting the dystrophin glycoprotein complex (DGC). The common feature of the diseases is muscle degeneration, which is often associated with mental retardation and various retinal defects, including ones of synaptic transmission. However, the mechanisms of the disease remain largely unknown, especially those in the central nervous system. I have focused on dystroglycan (DG), the transmembrane protein in the DGC that links the cytoskeleton to the extracellular matrix and is essential for muscle survival and brain development. I have used proteomics and Drosophila genetics to study DG function in the brain and retina.Using proteomics I found that beta-DG is directly associated with the GTPase dynamin 1 in the retina and in the brain together with alpha-DG and Grb2, and immunohistochemically beta-DG was colocalized with dynamin 1 in the outer plexiform layer where photoreceptor terminals are localized. Moreover, loss of DG in differentiated DG-null embryonic stem cells significantly increases dynamin-mediated transferrin-uptake and re-expression of DG in null cells by infection with an adenovirus containing DG reduced transferrin uptake to levels seen in wild-type cells. This result implies that one of mechanisms in muscular dystrophy might be the altered synaptic vesicle endocytosis, especially in the retina where synaptic transmission defect has been known for decades.
Muscular dystrophies show not only impaired retinal synaptic transmission and several DG-related congenital muscular dystrophies also display retinal structural defects. To further understand the roles of DG in the retina, I used Drosophila eye as a model and demonstrated for the first time that DG is required cell-autonomously for photoreceptor morphogenesis in the developing visual system. Deficiency of DG in the eye causes severe disruption of retinal structure, aberrant lens formation and abolition of electroretinogram in the adult fly eye. These adult defects appear derived from autonomous photoreceptor cell (PRC) defects in the early pupa including size arrest, loss of polarity and progressive degeneration. All defects in the eye, however, can be reversed by re-expression of wild type DG in DG-deficient PRCs, suggesting DG functions cell-autonomously in PRCs and non-autonomously for lens. In the 3rd instar larvae DG is present in the apical tips and the basal membranes of PRCs, two polarized locations opposing the extracellular matrix. At the pupal stage it continues to mainly distribute at the apical rhabdomere and basal membrane of PRCs. Over-expression of DG leads to larger ommatidia but the PRC number remains unchanged, suggesting that DG is both necessary for and sufficient to promote PRC expansion. By rescue experiments, I demonstrated that the extracellular DG alone could not rescue DG-deficient eye defects, whereas the intracellular DG can substantially ameliorate PRC degeneration and structural defects while some PRCs remain disorganized, a sign of disrupted PRC planar polarity in absence of the extracellular DG. Therefore, our data suggest that the degeneration and planar polarity disruption in DG-deficient PRCs are two independent processes that appear to require the respective function of intracellular and extracellular DG. In summary, our experiments demonstrated several novel findings and provided the basis for future investigations on DG function and the molecular mechanisms of nervous system defects in muscular dystrophies.
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Harpham, Colin. "Development of a novel radial basis function network using genetic algorithms." Thesis, University of Derby, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.411390.
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Kelly, David Christopher. "Genetic approaches to the study of epithelial function in Drosophila melanogaster." Thesis, University of Glasgow, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.321066.
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Whitlock, Rajenda. "The consequences of genetic impoverishment for plant community structure and function." Thesis, University of Sheffield, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.419639.
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Yeang, Han Xian Aw. "Modulation of dendritic cell function by molecular, pharmacological and genetic approaches." Thesis, University of Liverpool, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.548801.
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Warmke, Jeffrey Wayne. "Genetic analysis of myosin light chain-2 function in Drosophila melanogaster /." The Ohio State University, 1990. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487677267730356.
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Wang, Ying. "Genetic dissection of adaptor molecules in lymphocyte development, homeostasis and function." Aix-Marseille 2, 2006. http://www.theses.fr/2006AIX22035.
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LAT (Linker for activation of T cells) assembles an essential platform for recruiting multiple proteins after TCR engagement. Mice homozygous for a single mutation in tyrosine residue 136 of the LAT adaptor showed impeded T cell development. However, later in life they accumulated polyclonal Th2 CD4+ effector T cells, which triggered tissue eosinophilia and massive maturation of B cells into plasma cells secreting high level IgG1 and IgE. To investigate the molecular and cellular pathways that might be involved in the triggering of this pathological condition, we used short-term and long-term adoptive transfer into hosts that were specifically deprived of T cells. We found that CD4 T cells from LATY136F mutant mice displayed similar homeostasis to their wild-type counterpart at the beginning of the reconstitution. However, 8 weeks after reconstitution, transfer of the LATY136F derived CD4 T cells gives rise to a condition that fully reproduce the lymphoproliferative disease originally observed in LATY136F mice. Accordingly, the reconstituted mice showed a large accumulation of CD4 T cells and B cells in secondary lymphoid organs, as well as hypergammaglobulinemia IgG1 and IgE in serum, and eosinophilia in multiple tissues. This demonstrated that the LATY136F disorder was T cell autonomous. Further results derived from comparison between CD3 epsilon-deprived hosts that are either MHCII-sufficient or-deficient showed that in the absence of MHCII molecules, LATY136F CD4 T cells were capable, however with a two-fold reduced efficiency, of proliferating and of helping B cells to mature into IgG1 and IgE plasma cells. These results suggested that the lymphopoliferation of CD4 T cells in LATY136F mutant mice and the ensuing T/B cooperation that leads to massive amount of IgE and IgG1 are largely independent on MHC Class II molecules. This almost TCR-independent and thus “autistic” behavior vis-à-vis MHC Class II molecule appears to be a unique property of CD4 T cells harboring the LATY136F mutation. NTAL (non-T cell activation linker, also called LAB), a newly identified transmembrane adaptor protein, shared structural similarity with LAT. It is highly expressed in B cells, NK cells and mast cells. NTAL/LAB is rapidly phosphorylated by 4 Src-family kinases (Lck or Lyn) and Syk- family kinases (ZAP-70 or Syk) after ligation of BCR, FcγRI and FcεRI receptors. The major proteins that associated with NATL/LAB after phosphorylation were identified as Grb2, SOS1, C-Cbl and Gab1 etc. The disruption of NTAL/LAB expression in B cell line can lead to decreased calcium mobilization and Erk activation, which suggested that NTAL/LAB is acting in BCR-mediated calcium flux and Ras-MAPK activation. To delineate the respective roles of NTAL/LAB and LAT in B cell development and function, Ntal-deficient mice were generated and crossed with Lat-deficient mice. B cells developed with same efficiency in Lat-/- Ntal-/- double-deficient mice and in mice lacking either of the two adaptors and in wild-type mice, which demonstrated that NATL/LAB is dispensable in B cell development. Upon B cell antigen receptor cross-linking, Ntal-/- B cells exhibited slightly increased Ca2+ mobilization and proliferation. Analysis of T-dependent and T-independent humoral responses showed that Ntal-deficient mice had increased levels of natural antibodies and slightly increased humoral response to a T-dependent antigen. Specific serum immunoglobulins at normal titers were produced in response to T cell-independent antigens. Although NTAL is also expressed in plasma cells, its absence did not affect the hypergammaglobulinemia E and G1 that developed in mice with a mutation in tyrosine 136 of LAT. Therefore, NTAL does not play in B cells a role symmetric to the role played by LAT in T cellsL’adaptateur transmembranaire LAT (Linker for Activation of T cells) constitue une plateforme moléculaire assurant le recrutement de nombreuses protéines impliquées dans la transduction des signaux médiés par le TCR. Les souris homozygotes pour une mutation ponctuelle de la tyrosine 136 du domaine intracytoplasmique de LAT présentent un défaut dans le développement des lymphocytes T. En outre, elles développent progressivement une lymphoprolifération T CD4+ polyclonale qui est associée à une éosinophilie tissulaire et à une maturation massive des cellules B en plasmocytes sécrétant des niveaux élevés d’IgG1 et d’IgE. Pour disséquer les mécanismes cellulaires et moléculaires associés au développement de cette pathologie, nous avons mis en oeuvre un système de transfert adoptif à court terme et à long terme dans des hôtes présentant une immunodéficience sélective en lymphocytes T. Nous avons montré que les cellules T CD4+ des souris mutantes LATY136F présentent une homéostasie similaire à celle des cellules wt en début de reconstitution. En revanche, 8 semaines après reconstitution, les cellules T CD4+ desLATY136F induisent une pathologie lymphoproliférative qui reproduit en tout point celle observée initialement dans les souris LATY136F. Ainsi, les souris reconstituées présentent-elles une accumulation massive de cellules T CD4+ et de lymphocytes B dans les organes lymphoïdes secondaires, une ypergammaglobulinémie IgG1 et IgE et une éosinophilie marquée dans de nombreux tissus. Ceci démontre que les lymphocytes T sont nécessaires et suffisants pour induire la pathologie LATY136F. Par comparaison des reconstitutions réalisées dans des hôtes déficients en CD3 et exprimant ou non les molécules d’histocompatibilité de classe II, nous avons établi que les lymphocytes T CD4+ LATY136F conservent, en l’absence de molécules d’histocompatibilité de classe II, leur capacité à proliférer et à stimuler la maturation des lymphocytes B en plasmocytes sécrétant des IgG1 et des IgE -avec une efficacité néanmoins deux fois moindre-. Ces résultats suggèrent que la lymphoprolifération des cellules T CD4+ dans les souris mutantes LATY136F et que la coopération T/B associée qui conduit à des concentrations sériques considérables d’IgE et IgG1 sont, pour une large part, indépendants des moléculesd’histocompatibilité de classe II. Ce comportement largement indépendant du TCR et pouvant à ce titre être qualifié de comportement autistique vis-à-vis des molécules de classe II apparaît comme une propriété unique des cellules T CD4+ portant la mutation LATY136F. NTAL (Non T cell Activation Linker, également appelé LAB) est un adaptateur transmembranaire récemment identifié qui possède des similarités structurales avec LAT. NTAL est fortement exprimé dans les cellules B, les cellules NK et les mastocytes. NTAL est rapidement phosphorylé par les kinases de la famille Src (Lck ou Fyn) et de la famille Syk (Zap-70 ou Syk) après engagement du récepteur des cellules B (BCR) ou des récepteurs au fragment Fc des immunoglobulines de type FcγRI et FcεRI. Les principales protéines identifiées comme associées à la molécule NTAL phosphorylée sont Grb2, SOS1, C-Cbl, Gab1. La suppression de l’expression de NTAL dans une lignée B conduit à une diminution des flux calciques et de l’activation des molécules Erk, ce qui suggère que NTAL participe à l’induction des flux calciques et à l’activation de la voie Ras-MAPKassociées à la stimulation du BCR. Pour identifier les rôles respectifs de NTAL et de LAT dans le développement et la fonction des lymphocytes B, des souris déficientes pour Ntal ont été générées et croisées avec des souris déficientes pour LAT. L’ analyse de ces souris a montré que les cellules B se développent avec la même efficacité dans les souris doublement déficientes Lat-/-Ntal-/-, dans les souris déficientes dans l’un de ces deux gènes et dans les souris wild-type, ce qui démontre que NTAL n’est pas indispensable pour le développement des lymphocytes B. L’agrégation des récepteurs des cellules B induit, par ailleurs, des niveaux de prolifération et des niveaux de flux calciques légèrement augmentés dans les souris déficientes pour Ntal. L’analyse des réponses humorales T dépendantes et T indépendantes a montré que les souris déficientes pour Ntal possèdent, en outre, des niveaux augmentés d’anticorps naturels et des réponses humorales légèrement amplifiées en réponse à des antigènes T dépendants. Des titres normaux d’immunoglobulines sériques spécifiques sont observés en réponse à des antigènes T indépendants. Enfin, bien que NTAL soit également exprimé dans les plasmocytes, son absence n’affecte pas l’hypergammaglobulinémie E et G1 sedéveloppant dans les souris porteuses de la mutation LATY136F. NTAL ne constitue donc pas dans les lymphocytes B l’équivalent fonctionnel de LAT dans les lymphocytes T
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Trebble, Peter. "Glucocorticoid receptor function : new insights from genetic and chemical biology approaches." Thesis, University of Manchester, 2013. https://www.research.manchester.ac.uk/portal/en/theses/glucocorticoid-receptor-function-new-insights-from-genetic-and-chemical-biology-approaches(b55c612b-eda1-4908-a0df-ec916f03ade2).html.
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Glucocorticoids (Gc) are vital for development, maintenance of glucose homeostasis and the resolution of inflammation. As potent modulators of the immune response Gc are routinely prescribed in the management of a variety of inflammatory diseases including asthma and rheumatoid arthritis. However clinical use of Gc is limited by variation in patient sensitivity to Gc treatment and development of a wide range of side effects. In this thesis I present two studies that have advanced our understanding of Gc action in vivo. The first defines and characterises the cause of familial glucocorticoid resistance, and the second describes the action of two potent non-steroidal Gc in a cell line model. Familial Gc Resistance: Cases of primary generalised Gc resistance are very rare and typically present as mineralocorticoid and androgen excess leading to hypertension, hypokalemia and hirsutism. Gc resistance is attributed to loss of function mutations within the glucocorticoid receptor (GR). Here I identify a family with a novel mutation in GR exon 6 that gives rise to a very mild phenotype. Analysis of transformed patient peripheral blood lymphocytes revealed a 50% reduction in full length GR but no expression of a mutant form. As this did not rule out expression in vivo, the mutant receptor (Δ612GR) was characterised in a cell line. Investigation using reporter genes revealed that Δ612GR lacked any activity, but had dominant negative action when co expressed with full length GR. In response to Gc Δ612GR was not phosphorylated or targeted for degradation. Fluorophore tagged Δ612GR was unable to translocate to the nucleus in response to Gc, but delayed the translocation of full length GR when co-expressed. Together this indicates that Δ612GR is unable to bind ligand but has dominant negative action upon full length GR most likely due to heterodimerisation. Therefore I describe a novel GR mutation that results in Gc resistance but presents with a mild very phenotype. Novel Non-steroidal Gc: Non-steroidal Gc can be used as tools to determine how ligand structure directs GR function. Here I describe two highly potent non steroidal Gc ligands, GSK47867A and GSK47869A which alter the kinetics of receptor activity. Treatment with either ligand induces slow GR nuclear translocation, promotes GR nuclear retention and prolongs transcriptional activity following ligand withdrawal. Crystal structure analysis revealed that GSK47867A and GSK47869A specifically alter the surface charge of the GR at a site important for Hsp90 binding. GR bound to GSK47867A and GSK47869A shows prolonged activity in the presence of Hsp90 inhibitor geldanamycin. Therefore this work identifies a new chemical series that could prolong GR activity due to altered pharmacodynamics rather than altered pharmacokinetics.In summary this work uses a combination of genetic and chemical biology approaches to broaden our understanding of GR function. Characterisation of naturally occurring GR mutations gives insight into the complex function of the GR, and non-steroidal Gc act as useful tools that will aid in the design of improved therapeutics.
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Ma, Jiya. "A Genetic Algorithm for Solar Boat." Thesis, Högskolan Dalarna, Datateknik, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:du-3488.
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Genetic algorithm has been widely used in different areas of optimization problems. Ithas been combined with renewable energy domain, photovoltaic system, in this thesis.To participate and win the solar boat race, a control program is needed and C++ hasbeen chosen for programming. To implement the program, the mathematic model hasbeen built. Besides, the approaches to calculate the boundaries related to conditionhave been explained. Afterward, the processing of the prediction and real time controlfunction are offered. The program has been simulated and the results proved thatgenetic algorithm is helpful to get the good results but it does not improve the resultstoo much since the particularity of the solar driven boat project such as the limitationof energy production