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1
Sailer, Zachary. "Predicting Phenotypes in Sparsely Sampled Genotype-Phenotype Maps". Thesis, University of Oregon, 2019. http://hdl.handle.net/1794/24231.
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Naturally evolving proteins must navigate a vast set of possible sequences to evolve new functions. This process depends on the genotype-phenotype map. Much effort has been directed at measuring protein genotype phenotype maps to uncover evolutionary trajectories that lead to new functions. Often, these maps are too large to comprehensively measure. Sparsely measured maps, however, are prone to missing key evolutionary trajectories. Many groups turn to computational models to infer missing phenotypes. These models treat mutations as independent perturbations to the genotype-phenotype map. A key question is how to handle non-independent effects known as epistasis. In this dissertation, we address two sources of epistasis: 1) global and 2) local epistasis. We find that incorporating global epistasis improves our predictive power, while local epistasis does not. We use our model to infer unknown phenotypes in the Plasmodium falciparum chloroquine transporter (PfCRT) genotype-phenotype map, a protein responsible for conferring drug resistance in malaria. From these predictions, we uncover key evolutionary trajectories that led high resistance. This dissertation includes previously published and unpublished co-authored material.2020-01-11
2
Arbon, Jed. "Phenotype-genotype correlation between the Hippo pathway and 3D craniofacial phenotypes". Thesis, University of Iowa, 2016. https://ir.uiowa.edu/etd/3042.
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Introduction: The purpose of this study was to examine phenotypic expression of craniofacial form, shape, and size as it relates to the genotype of an individual. Shape analyses were completed on 3-D images of each subject's craniofacial structure by landmarking 45 points of interest on the cranial base, facial bones, and upper and lower jaws. A candidate gene analysis was undertaken focusing on specific genes in the Hippo Signaling Pathway to examine genotype-phenotype correlations that play a role in craniofacial development. This study is a continuation of a larger project aimed at the identification of candidate genes associated with human dento-skeletal bite problems led by Dr. Lina Moreno-Uribe.
Methods: The sample size for our study included 166 individuals who had never been treated orthodontically at the time of records. Each individual was genotyped and a CBCT of the craniofacial complex was captured. Each CBCT image was landmarked by a single observer using 45 points to mark points on the cranial base and facial bones including the maxilla and mandible. General Procrustes superimposition was used to find correlations with phenotype and genotype. Size analysis was completed with average Euclidean Distances and ANOVA analysis.
Results: 2 SNP's from the FOX03 gene had significant associations with size. The AA genotyped individuals appeared larger in overall size than AB genotyped individuals. 3 SNP's had statistically significant associations with facial form. The FOX06 SNPs had significant associations with increased anterior-posterior growth of the maxilla. The AJUBA SNP had significant associations with increased overall craniofacial breadth.
Conclusion: Genes in the Hippo signaling pathway have specific roles in the development of facial form and size.
3
Bloomfield, Kelly Louise, i n/a. "Investigation of the Role of Thioredoxin in the Invasive Phenotype and its Interaction with the Transcription Factor Sp1". Griffith University. School of Biomolecular and Biomedical Science, 2003. http://www4.gu.edu.au:8080/adt-root/public/adt-QGU20031021.120018.
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Thioredoxin is a small ubiquitous oxido-reductase found in all species. The highly conserved active site, which facilitates thioredoxins redox activity, contains two redox active cysteine residues. Thioredoxin has numerous protein substrates to which it donates H+ ions and it can also function as a free radical scavenger. Through these activities thioredoxin is able to influence the redox state of not only its protein targets, but also the entire cellular environment. Thioredoxin has been implicated in many biological functions, and one mechanism by which it influences these functions is through interactions with a number of transcription factors including NF-kappa-B and p53. Thioredoxin also has numerous extracellular biological roles. It has been shown that thioredoxin is actively secreted from a number of normal and transformed cell lines including fibroblasts and activated B and T cells. This study investigates the role of thioredoxin in embryonic implantation and cancer cell metastasis, two physiological functions which rely on the same basic processes. Thioredoxin expression has previously been shown to be increased in many cancers. However it has not yet been established whether this increase is a causative or a side effect of the cancerous phenotype. Similarly thioredoxin expression has previously been shown to be increased during different phases of the oestrus cycle and pregnancy. This thesis describes the role of thioredoxin in embryonic implantation using a marmoset model. A thioredoxin cDNA was isolated and subsequently sequenced. Preliminary antibody experiments indicated that the anti human thioredoxin monoclonal antibodies available in our laboratory would recognise marmoset thioredoxin. Subsequently immunocytochemistry using anti human thioredoxin antibodies was carried out on sectioned marmoset uterus and embryonic tissue. The results indicated that thioredoxin is expressed by cells at the embryonic-maternal interface of early implantation sites. Further studies demonstrated that thioredoxin is also expressed and secreted by cultured blastocysts in vitro. This thesis also describes the role of thioredoxin in cancer cell metastasis. Results of this study indicate that thioredoxin is actively involved in facilitating the invasive phenotype of breast cancer cells. The two cell lines utilised were MCF-7, a well differentiated, relatively non-invasive breast cancer cell line; and MDA-MB-231, a poorly differentiated, highly invasive breast cancer cell line. The cell lines were transfected with thioredoxin sense, antisense and 1SS (encodes thioredoxin with both active cysteine residues mutated to serine residues and is thus redox inactive) constructs. The results demonstrate that when endogenous thioredoxin levels are increased, i.e. transfected with a sense thioredoxin construct, the invasive breast cancer cell line MDA-MB-231 becomes more invasive, conversely when endogenous levels are decreased, i.e. transfected with antisense or 1SS constructs, the invasive capacity of these cells decreases. However, when the endogenous level of thioredoxin was manipulated in the relatively non-invasive cell line MCF-7 very little effect was observed. Results also indicate that thioredoxin has the ability to act as a chemoattractant for actively invading breast cancer cells. Both of these functions appear to be dependent on thioredoxin's redox activity. Additional studies described in this thesis have shown that thioredoxin is involved in the regulation of Sp1 in vitro. Sp1 is a transcription factor known to regulate the transcription of a number of genes whose products are intimately involved in the invasive phenotype. The results in this study suggest that Sp1 DNA binding is regulated by thioredoxin such that when reduced by the enzyme its binding to DNA is facilitated. Results also indicate that Sp1 may regulate the transcription of thioredoxin by binding to Sp1 sites within the thioredoxin promoter.
4
Bloomfield, Kelly Louise. "Investigation of the Role of Thioredoxin in the Invasive Phenotype and its Interaction with the Transcription Factor Sp1". Thesis, Griffith University, 2003. http://hdl.handle.net/10072/366170.
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Thioredoxin is a small ubiquitous oxido-reductase found in all species. The highly conserved active site, which facilitates thioredoxins redox activity, contains two redox active cysteine residues. Thioredoxin has numerous protein substrates to which it donates H+ ions and it can also function as a free radical scavenger. Through these activities thioredoxin is able to influence the redox state of not only its protein targets, but also the entire cellular environment. Thioredoxin has been implicated in many biological functions, and one mechanism by which it influences these functions is through interactions with a number of transcription factors including NF-_B and p53. Thioredoxin also has numerous extracellular biological roles. It has been shown that thioredoxin is actively secreted from a number of normal and transformed cell lines including fibroblasts and activated B and T cells. This study investigates the role of thioredoxin in embryonic implantation and cancer cell metastasis, two physiological functions which rely on the same basic processes. Thioredoxin expression has previously been shown to be increased in many cancers. However it has not yet been established whether this increase is a causative or a side effect of the cancerous phenotype. Similarly thioredoxin expression has previously been shown to be increased during different phases of the oestrus cycle and pregnancy. This thesis describes the role of thioredoxin in embryonic implantation using a marmoset model. A thioredoxin cDNA was isolated and subsequently sequenced. Preliminary antibody experiments indicated that the anti human thioredoxin monoclonal antibodies available in our laboratory would recognise marmoset thioredoxin. Subsequently immunocytochemistry using anti human thioredoxin antibodies was carried out on sectioned marmoset uterus and embryonic tissue. The results indicated that thioredoxin is expressed by cells at the embryonic-maternal interface of early implantation sites. Further studies demonstrated that thioredoxin is also expressed and secreted by cultured blastocysts in vitro. This thesis also describes the role of thioredoxin in cancer cell metastasis. Results of this study indicate that thioredoxin is actively involved in facilitating the invasive phenotype of breast cancer cells. The two cell lines utilised were MCF-7, a well differentiated, relatively non-invasive breast cancer cell line; and MDA-MB-231, a poorly differentiated, highly invasive breast cancer cell line. The cell lines were transfected with thioredoxin sense, antisense and 1SS (encodes thioredoxin with both active cysteine residues mutated to serine residues and is thus redox inactive) constructs. The results demonstrate that when endogenous thioredoxin levels are increased, i.e. transfected with a sense thioredoxin construct, the invasive breast cancer cell line MDA-MB-231 becomes more invasive, conversely when endogenous levels are decreased, i.e. transfected with antisense or 1SS constructs, the invasive capacity of these cells decreases. However, when the endogenous level of thioredoxin was manipulated in the relatively non-invasive cell line MCF-7 very little effect was observed. Results also indicate that thioredoxin has the ability to act as a chemoattractant for actively invading breast cancer cells. Both of these functions appear to be dependent on thioredoxin's redox activity. Additional studies described in this thesis have shown that thioredoxin is involved in the regulation of Sp1 in vitro. Sp1 is a transcription factor known to regulate the transcription of a number of genes whose products are intimately involved in the invasive phenotype. The results in this study suggest that Sp1 DNA binding is regulated by thioredoxin such that when reduced by the enzyme its binding to DNA is facilitated. Results also indicate that Sp1 may regulate the transcription of thioredoxin by binding to Sp1 sites within the thioredoxin promoter.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Biomolecular and Biomedical Sciences
Full Text
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Berry, Mike A. "An exploration of asthma phenotypes". Thesis, University of Leicester, 2006. http://hdl.handle.net/2381/29513.
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In this thesis the long term stability of eosinophilic bronchitis has been investigated in a longitudinal study. Induced sputum has been used to investigate a possible difference in expression of IL-13 in asthma and eosinophilic bronchitis. Bronchoscopy has been used to compare the airway immunopathology of eosinophilic and non eosinophilic asthma and the long term stability and response to inhaled corticosteroids in non eosinophilic asthma was studied in a prospective randomised controlled trial. Alveolar nitric oxide concentration has been validated as a measure of distal lung inflammation. Finally the role of TNF-alpha and response to etanercept has been investigated in patients with refractory asthma. Evolution from eosinophilic bronchitis into asthma was rare, decline in lung function was not increased, although female gender, smoking and prolonged eosinophilic airway inflammation were independent risk factors for an accelerated decline. IL-13 concentrations were elevated in asthma compared to eosinophilic bronchitis, suggesting a role for this cytokine in the development of airway hyperresponsiveness. Non eosinophilic asthma remained stable over the period of investigation and was associated with reduced response to inhaled corticosteroids. Mast cells were present in airway smooth muscle in eosinophilic and non eosinophilic asthma but not normal controls. Subepithelial layer thickening was a feature of eosinophilic but not non eosinophilic asthma. Alveolar nitric oxide was increased in refractory asthma and reduced by oral but not inhaled corticosteroids.
6
Yuan, Qiu-Ping. "Trinucleotide repeats and neuropsychiatric phenotypes /". Stockholm : [Karolinska institutets bibl.], 2001. http://diss.kib.ki.se/2001/91-7349-058-X/.
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Jadon, Deepak. "Biomarkers of psoriatic arthritis phenotypes". Thesis, University of Bath, 2016. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.683546.
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Background: Psoriatic arthritis (PsA) is a chronic heterogenous inflammatory arthritis with five phenotypes. The two least studied phenotypes are investigated in this thesis, including: psoriatic spondyloarthropathy (PsSpA) and psoriatic arthritis mutilans (PAM). The aims of this thesis were to determine the prevalence, clinical characteristics and radiographic characteristics of PsSpA and PAM in a cohort of PsA patients, and serum-soluble bone- turnover biomarkers of these phenotypes. Aims: Comparisons were made with PsA patients without axial disease (pPsA), and ankylosing spondylitis (AS) patients. Methods: A prospective single-centre cross-sectional study was conducted of PsA and AS patients. Serum on psoriasis-only patients (PsC) and healthy controls (HC) were also obtained. Multivariate clinical, radiographic, genetic and serum biomarker comparisons were made between these five groups of subjects. Results: The study enrolled 201 PsA and 201 AS patients, who were then reclassified as 118 PsSpA, 127 pPsA and 157 AS cases, alongside 200 PsC and 50 HC subjects. Several clinical biomarkers, imaging biomarkers, serum-soluble biomarkers and genetic biomarkers were identified that differentiate PsSpA from pPsA and AS. PsSpA affected a significant proportion of PsA patients, and was not a milder version of AS. PsSpA involvement was as disabling and clinically impactful as AS. PAM was found to be associated with PsSpA, and clinical biomarkers of PAM occurrence and radiographic progression were identified. Conclusions: In conclusion, this thesis indicates that PsSpA is on a spectrum of musculoskeletal disease, in between pPsA and AS; with PsSpA comprising a continuum itself, and with a phenotype expression related to disease duration. These findings may prompt the inception of an international-consensus classification system for PsSpA, for which there is a great clinical need. Given that PsSpA has its own discrete clinical and biomarker signature, its clinical management and research should be tailored from that of pPsA and AS. Ultimately this may further the effort for stratified and personalised medicine.
8
Ding, Zhihao. "The genetics of cellular phenotypes". Thesis, University of Cambridge, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708712.
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Heinzmann, Silke. "Nutritional modulation of metabolic phenotypes". Thesis, Imperial College London, 2010. http://hdl.handle.net/10044/1/6320.
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Diet and other lifestyle factors play a critical role in the risk of developing many diseases. Metabolic profiles contain a wealth of biochemical and physiological information and are influenced by various factors such as gender, age, BMI or genetic background. Diet is an important factor, and long-term dietary habits as well as short-term food challenges influence the metabolic phenotype. Metabolic profiling technology can be used to discover novel single or combination biomarkers of food intake. To aid personalised healthy lifestyle recommendations, it is necessary to characterise the metabolic phenotype of individuals and to establish the extent to which we can beneficially influence this phenotype by nutritional intervention. This thesis aims to evaluate metabonomics as a tool for systematically detecting metabolites related to inter-individual and food-related differences. In order to address these aims a nutrition study was undertaken, where individuals followed a strict diet regime consuming a standard diet including specific food challenges, spot urine collections were made throughout the study period. 1H NMR spectroscopy was performed to generate urinary metabolic profiles, which were subsequently analysed and interpreted using multivariate mathematical modelling methods. Clear metabolic signatures pertaining to the consumption of specific dietary components and ‘biomarker’ metabolites associated with particular foods were extracted. Further validation of a potential biomarker was undertaken interrogating a large-scale epidemiologic dataset, the INTERMAP Study. Inter-individual variation in the metabolic profile was observed, both in relation to differences in response to food ingestion and metabolic differences independent from immediate food ingestion. Among these alterations were metabolites originating from gut microbial-mammalian co-metabolism. The influence of the gut microbiota on the metabolic phenotype and obesity was further investigated using microbially modulated murine models. This thesis characterises the effects of the interaction of diet and microbial metabolism on the metabolic phenotype and provides a template for assessing complex dietary interventions with respect to beneficially modulating metabolism.
10
Holberg, Catharine Jean 1944. "Genetic epidemiology of asthma phenotypes". Diss., The University of Arizona, 1998. http://hdl.handle.net/10150/565581.
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Müller, Andrea Martina. "Genetic association analysis with survival phenotypes". Diss., lmu, 2009. http://nbn-resolving.de/urn:nbn:de:bvb:19-99742.
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Cross, Elaine. "Behavioural phenotypes in the mucopolysaccharide disorders". Thesis, University of Manchester, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.566569.
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This thesis investigated behaviour and behavioural phenotypes in the Mucopolysaccharide (MPS) disorders. The MPS disorders are a group of rare lysosomal storage disorders which are characterised by a period of normal development followed by gradual cognitive and/or physical decline.Paper 1 describes a systematic review of the extant literature on cognitive, motor, social, linguistic and behavioural presentation in all of the MPS disorders. 25 papers were reviewed and the methodology they employed was assessed. Sleep disturbance was found to be part of the behavioural phenotype of MPS III. In MPS I and II fearfulness and sleep problems occurred in most cases. In MPS II participants with the mild form were found to have relatively normal development and few or no behavioural problems, while those with the severe form had behavioural problems, delayed speech, delayed development and limited motor function. High rates of challenging behaviour, most commonly associated with aggression, hyperactivity, orality, unusual affect and temper tantrums were consistently observed in children with MPS III.Paper 2 describes an empirical study investigating the behavioural phenotype of MPS III, Sanfilippo syndrome. Parents of 20 children with MPS III, 5 adults with MPS III and 25 children with Intellectual Disability (ID) completed questionnaires relating to their son/daughter’s behaviour and adaptive skills. The frequency of challenging behaviours displayed by children aged 2-9 years with MPS III and ID were high but not significantly different. Behaviours associated with hyperactivity, orality, body movements and inattention were seen significantly more frequently in 2-9 year olds with MPS III than ID. The frequency of challenging behaviours displayed by children with MPS III and their adaptive skills was found to decrease with age. Children age 10-15 years with MPS III displayed significantly fewer problem behaviours than children of the same age with ID. It is recommended that parents with a child with MPS III aged 2-9 years are offered clinical services to support them with managing challenging behaviour while those with a child of 10 years or over are offered support with managing health concerns and end of life care.The third Paper, provides an evaluation of the strengths and limitations of the literature review and the empirical study. The findings and clinical implications from both studies are discussed. The process of conducting research into rare, life limiting, genetic syndromes is reflected upon and recommendations for replication and further research are made.
13
Graham, Amy Eve. "Macrophage phenotypes in giant cell arteritis". Thesis, University of Leeds, 2018. http://etheses.whiterose.ac.uk/22602/.
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Giant cell arteritis (GCA) is the commonest form of vasculitis that affects individuals over 50 years of age, predominantly occurring within medium and large-sized arteries. Without immediate glucocorticoid treatment, GCA can culminate in blindness and stroke. T-cells and macrophages are found to infiltrate through the arterial wall and are intricately involved in disease pathogenesis, from arterial destruction to neointimal hyperplasia resulting in tissue ischemia. Macrophages perform an array of different functions in GCA arteries however disease heterogeneity, along with poor characterisation of macrophage phenotypes has hindered studies into the role of macrophages. I hypothesise that the heterogeneity of histological and clinical manifestations seen between individuals with GCA is in part due to the phenotypic heterogeneity of macrophages found within the artery wall of different patients. A THP-1 cell line model was developed to enable identification of phenotype-specific macrophage markers which were confirmed at the RNA and protein level. M(LPS, IFN-gamma) markers ANKRD22 and GBP5 were used to characterise M1 macrophages and M(IL-4) marker MRC1, and M(IL-10) marker CD163 were used to characterise M2 macrophages in temporal artery biopsies using immunohistochemistry. M1 and M2 macrophages were found within each layer of the artery wall layer (adventitia, media and intima) and inter-individual variation in macrophage infiltration patterns was observed. M1 macrophages correlated with media destruction and greater expression of ANKRD22 was significantly associated with increased arterial inflammatory infiltration. Greater MRC1 staining was significantly associated with patients who reached 5mg of glucocorticoids sooner. Identification of all markers within each artery layer suggested different macrophage phenotypes co-exist. Arterial expression of ANKRD22 and MRC1 may identify different groups of patients who require different treatment strategies. Macrophage phenotype heterogeneity and downstream immunological processes may therefore in part explain the variation seen between patients in terms of their clinical presentation, long-term sequelae and response to treatment.
14
Oliveira, Ana Filipa Martins. "Microglial clearance function: dependence on phenotypes". Master's thesis, Faculdade de Ciências e Tecnologia, 2011. http://hdl.handle.net/10362/6715.
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Dissertação para obtenção do Grau de Mestre em
Genética Molecular e BiomedicinaMicroglia are active sensors of the brain and respond promptly to even minor disturbance in their microenvironment. A feature of this response is the accumulation of these cells at the site of lesion. Neonatal jaundice is a common condition of the newborn and may determine injury to neurons and glial cells, such as microglia, when levels of unconjugated bilirubin (UCB) are excessive. With the objective to evaluate whether microglia have a protective or deleterious role, we decided to assess, using the Boyden chamber, the chemotactic effect of free unbound UCB (fUCB), as well as the migration ability of UCB-treated microglia in the absence or in the presence of chemotatic compounds, such as ATP and S100B. Also, we intended to evaluate the effect of glycoursodeoxycholic acid (GUDCA) as a modulator. To characterize our usual model of microglia isolation, phenotypic evaluation of cultures with different days in vitro (DIV) was performed by estimating cell morphology, nuclear factor-kappaB (NF-κB) activation and phagocytic ability. We observed that fUCB did not act as a chemotactic compound for microglia and that cells treated with UCB showed decreased migration ability. Co-incubation with GUDCA prevented this effect and enhanced microglia migration. However, reduced effects were observed in the presence of ATP and abolished when using S100B. Isolated microglia with 2 DIV showed features of activation, but presentedramified morphology of the “resting” state, less NF-κB activation and increased phagocytosis at 13 DIV. Data indicate that microoglia exposure to UCB leads to a reduced migration ability and that co-incubation with GUDCA prevents this deleterious effect, resulting in an increased migration. Characterization of microglia phenotypes, along the time in culture, point to 13 DIV cells as the most suitable for studies intended to evaluate microglia reactivity to UCB, and probably to other stimuli.
15
Dahl, Andrew. "Methods to jointly analyze multiple phenotypes". Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:ed466a17-e96f-482b-b164-aa7ceefd94d4.
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Linear mixed models (LMMs) have re-emerged as a central tool in statistical genetics. Fixed effects capture genetic variants tested for association. Random effects leverage aggregate relatedness while remaining agnostic to specific genetic mechanisms, naturally modeling heritability and controlling for polygenic background and confounding from population or family structure in genome-wide association studies (GWAS). Multiple random effects can partition heritability amongst many biologically meaningful variance components (VCs). Concurrently, genetic studies have begun to analyze multiple traits. This can improve power by adding data and can inform the path from genotype to phenotype, e.g. with graphical models, pleiotropy detection or endophenotyping. Multi-trait analyses are natural for biobanks and high-throughput phenotypic measurements like gene expression, medical images or metabolites. Following these advances, this thesis develops three multi-trait mixed models. phenix imputes missing phenotype data by modifying probabilistic matrix factorization to incorporate genetic relatedness. General linear mixed models (GLMMs) generalize and unify multi-VC, multi-trait and likelihood-penalized mixed models. Finally, compressive mixed models (CMMs) combine the two, obtaining the imputation and computational benefits of phenix and the heritability estimation and multi-VC capabilities of GLMMs. phenix essentially always outperforms all competitors in imputation and can improve GWAS power. GLMMs accurately estimate heritability despite (measured) confounders, can improve phenotype prediction, and increase gene-based, multi-trait association signal. CMMs regularly improve prediction, scale to thousands of phenotypes, and can uncover plausible GWAS hits entirely missed by LMMs. Altogether, multi-trait mixed models are invaluable for intrinsically multitrait tasks, like phenotype imputation and low-rank decomposition, and, surprisingly, can be much faster than LMMs; however, I find only small, and inconsistent, benefits for single-trait-oriented objectives like heritability estimation and out-of-sample prediction. The challenges in this thesis are primarily computational. Naively, multi-trait approaches model an N × P matrix of P phenotypes measured on N samples as a long Gaussian vector, inducing prohibitive O(N3P3) computations. Fortunately, the parsimonious matrix normals underlying mixed models enable simpler O(N3+P3) expressions. This is summarized by a new decomposition for positive semidefinite tensor products that, under a crucial assumption, facilitates cheap evaluation of ubiquitous low-level operations like multiplication.
16
Warner, Daniel Augustus. "Phenotypes and Survival of Hatchling Lizards". Thesis, Virginia Tech, 2001. http://hdl.handle.net/10919/31023.
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The phenotypes of hatchling reptiles are influenced by the environmental conditions that embryos experience during incubation, by yolk invested into the egg, and by the genetic contributions of the parents. Phenotypic traits are influenced by these factors in ways that potentially affect the fitness of hatchlings. The physical conditions that embryos experience within the nest affects development, hatching success, and hatchling phenotypes. Thus, the nest site that a female selects can influence the survival of her offspring as well as her overall fitness. In Chapter 1, I addressed this issue through a nest site selection experiment designed to determine the substrate temperature and moisture conditions that female eastern fence lizards (Sceloporus undulatus) select when provided a range of conditions from which to choose. In general, I found that females selected nest sites with conditions that yield high hatching success.
In Chapter two, I investigated the relative contributions of incubation moisture conditions, maternal yolk investment, and clutch (genotype) to variation in hatchling phenotypes and survival under field conditions. Eggs from 28 clutches were distributed among two moisture treatments; wet (-150 kPa) and dry (-530 kPa). In another treatment, yolk was removed from eggs to determine the affect of yolk quantity on hatchling phenotypes. After hatching, several phenotypic traits (mass, snout-vent length, tail length, body shape, thermal preference, running speed, desiccation rate, and growth rate) were measured. Hatchlings were subsequently marked and released at a field site in southwest Virginia. Hatchlings were recaptured twice weekly prior to winter and the following spring to monitor growth and survival. I found that incubation moisture and yolk removal affected only hatchling body size; individuals from the dry and yolk removed treatments were smaller in body size than those from the wet treatment. However, clutch was the most important source of phenotypic variation; all phenotypes were affected by clutch. Significant clutch effects suggested the possibility that phenotypic variation had at least some genetic basis. In the field, survival was not affected by incubation moisture and yolk removal, and overall survival was not associated with hatchling body size. Survivors and nonsurvivors differed only in growth rate in the field and running speed measured in the laboratory. Survivors ran faster and grew more slowly than nonsurvivors. To examine the association of clutch with survival, I used clutch mean values to look at the relationship between phenotype and survival. Clutches that produced relatively slow growing individuals and fast runners had higher survival rates than clutches that produced relatively rapid growing individuals and slow runners. In order to grow rapidly, an individual must eat more than slowly growing individuals. Thus, rapid growth rate may increase risk of predation through its association with foraging activity. Individuals that run fast should be capable of capturing prey and evading predators more effectively than individuals that run slowly. Overall, these results emphasize the importance of clutch to variation in phenotypes and survival in hatchling Sceloporus undulatus.Master of Science
17
Ried, Janina S. [Verfasser], i H. Erich [Akademischer Betreuer] Wichmann. "Phenotype set enrichment analysis : genome wide analysis of multiple phenotypes / Janina S. Ried. Betreuer: H.-Erich Wichmann". München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2013. http://d-nb.info/1036836894/34.
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Swarbrick, Michael. "Candidate genes for obesity and related phenotypes". University of Western Australia. Dept. of Pathology, 2002. http://theses.library.uwa.edu.au/adt-WU2004.0033.
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The current epidemic of obesity poses a substantial threat to public health worldwide. Obesity is associated with many deleterious health conditions, including type 2 diabetes, hypertension, dyslipidaemia, respiratory conditions, arthritis, and some forms of cancer. Moreover, the rising prevalence of obesity has been accompanied by a substantial increase in the cost of treating these conditions. Obesity results from a complex interaction between behavioural, environmental, and genetic factors. While the recent increase in the prevalence of obesity is largely due to behavioural factors (for example, physical inactivity); it has also been observed that genetic factors make a large contribution to individual susceptibility. In fact, studies indicate that as much as 50 - 80% of the variation in measures of obesity can be attributed to the effects of genes. Furthermore, closer examination of this genetic component using segregation analysis has indicated the presence of common genes for obesity, with large effects on the phenotype. However, these putative major genes for obesity have not yet been identified. The aim of this thesis was to investigate the role of three distinct genetic loci in obesity and related cardiovascular factors, including type 2 diabetes and dyslipidaemia. The aim of the first investigation was to test whether a common polymorphism (Pro12Ala) in the gene encoding peroxisome proliferator-activated receptor gamma 2 (PPAR-γ2) was associated with obesity and other cardiovascular risk factors in a large group of Caucasian subjects. PPAR-γ2 is an adipogenic transcription factor, which also regulates insulin sensitivity in adipose tissue. No association was observed between the Pro12Ala polymorphism and obesity in Caucasians, but obese subjects carrying the Ala allele displayed an altered blood lipid profile compared with obese Pro/Pro subjects. As the Pro12Ala polymorphism may exacerbate the risk of cardiovascular disease by modifying blood lipid profile in obesity, this relationship was examined further in a separate population. The aim of the second investigation was to determine whether the Pro12Ala polymorphism was associated with obesity, dyslipidaemia, diabetes and carotid intima-medial wall thickening in a population at high risk of developing cardiovascular disease. Australian Aboriginal people display high rates of mortality from cardiovascular disease, and it is possible that their increased susceptibility is due to genetic factors. However, the results from the Aboriginal population confirmed the results of the first study: there was no intrinsic association between the Pro12Ala variant and obesity. In addition, the Ala allele was not associated with deleterious changes in blood lipid profile, as it was in Caucasians. The aim of the third investigation was to confirm the presence of a quantitative trait locus (QTL) for obesity on chromosome 20q13. Highly polymorphic genetic markers in this region were tested for linkage and association with several measures of obesity in a Caucasian population. None of the measures of obesity were linked to or associated with markers spanning 20q13, suggesting that this chromosomal region does not contain a major locus for obesity in this Caucasian population. In the fourth investigation, the 5' sequence of Agouti Signalling Protein (ASIP) was identified. ASIP is a candidate gene for obesity, as it is expressed at high levels in adipocytes, and may participate in several obesity-related processes. Three new exons and two alternative promoters were identified for the ASIP gene. These results may lead to greater understanding of the role of ASIP in obesity and adipocyte metabolism; and may also be used to direct further research into genetic variation within this candidate gene. In conclusion, extensive study of two established candidate genetic loci revealed no association with measures of obesity. Therefore, it is likely that loci other than these make significant contributions to obesity in humans. Further investigation of novel candidate genes, such as ASIP, may allow the identification of novel genetic polymorphisms and new pathways important for the genetic basis of obesity.
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Garduno, Paz Monica Vanessa. "The origin of alternative phenotypes in fishes". Thesis, University of Glasgow, 2009. http://theses.gla.ac.uk/934/.
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A basic aim of evolutionary biology is to explain the enormous diversity among animal and plant species. But also within species there is often large genetic and phenotypic variation, and such variation is necessary for evolution to create new reproductively isolated species. The present thesis is directed to explain differentiation within populations highlighting and discussing the significance of phenotypic plasticity as an evolutionary process that leads to the expression of alternative phenotypes within a species. Such phenotypic expressions are particularly interesting, because the process by which new species are formed typically involves a temporary stage within the splitting species, that is, different heritable and distinct types that coexist within the same population. Such phenotypes may be raw material for full species formation, and the study of alternative-phenotype species should therefore be particularly worthwhile in speciation research. When alternative phenotypes are not entirely genetic they may arise as a result of developmental plasticity, when organisms develop in accordance with local abiotic and biotic conditions. Subject to developmental plasticity, alternative phenotypes, take different developmental routes depending on the local selection pressures, or depending on the environmental conditions experienced during development. Here, laboratory experiments showed that three-spined sticklebacks exhibit alternative phenotypes as a plastic response to physical environment and diet, demonstrating and supporting the idea that environmental inputs modulate the expression of traits through phenotypic plasticity during ontogeny. When, morphological differences arise, discrete morphological characteristics are originated and may be reinforced by the continuous presence of same environmental conditions. Here is demonstrated that these discrete morphological characteristics lead the individuals to specialise on specific prey or habitat types. Moreover, it is showed that plasticity may also play a role in the final stages of species formation, when reproductive isolation completes the speciation process. It is shown that diet-induced morphology has an important influence in mate preferences representing a strong potential to generate reproductive isolation via assortative mating, and this mate preferences may be highly efficient to maintaining isolation, thus the hypothesis of ecological speciation is supported. Finally, in this study, two alternative-phenotype lakes are described. It is suggested that the origin of the segregated alternative phenotypes in both lakes is a consequence of ecological traits divergences; however in one of the lakes the alternative phenotypes arose from a founder population, meanwhile in the second lake the alternative phenotypes may arose by the ecological adaptation of the forms in allopatry.
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Spagnolo, Paolo. "Genetic determinants of clinical phenotypes of sarcoidosis". Thesis, Imperial College London, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.498439.
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Agniel, Denis Madison. "Statistical Methods for Multivariate and Complex Phenotypes". Thesis, Harvard University, 2014. http://nrs.harvard.edu/urn-3:HUL.InstRepos:13070048.
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Many important scientific questions can not be studied properly using a single measurement as a response. For example, many phenotypes of interest in recent clinical research may be difficult to characterize due to their inherent complexity. It may be difficult to determine the presence or absence of disease based on a single measurement, or even a few measurements, or the phenotype may only be defined based on a series of symptoms. Similarly, a set of related phenotypes or measurements may be studied together in order to detect a shared etiology. In this work, we propose methods for studying complex phenotypes of these types, where the phenotype may be characterized either longitudinally or by a diverse set of continuous, discrete, or not fully observed components.
In chapter 1, we seek to identify predictors that are related to multiple components of diverse outcomes. We take up specifically the question of identifying a multiple regulator, where we seek a genetic marker that is associated with multiple biomarkers for autoimmune disease. To do this, we propose sparse multiple regulation testing (SMRT) both to estimate the relationship between a set of predictors and diverse outcomes and to provide a testing framework in which to identify which predictors are associated with multiple elements of the outcomes, while controlling error rates. In chapter 2, we seek to identify risk profiles or risk scores for diverse outcomes, where a risk profile is a linear combination of predictors. The risk profiles will be chosen to be highly correlated to latent traits underlying the outcomes. To do this, we propose semiparametric canonical correlation analysis (sCCA), an updated version of the classical canonical correlation analysis. In chapter 3, the scientific question of interest pertains directly to the progression of disease over time. We provide a testing framework in which to detect the association between a set of genetic markers and the progression of disease in the context of a GWAS. To test for this association while allowing for highly nonlinear longitudinal progression of disease, we propose functional principal variance component (FPVC) testing.
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Yu, Zhonghao. "Metabolomics analyses to better understand complex phenotypes". Diss., Ludwig-Maximilians-Universität München, 2013. http://nbn-resolving.de/urn:nbn:de:bvb:19-172737.
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In dieser Doktorarbeit werden drei Metabolomics-Studien der KORA Kohorte behandelt. Das Ziel dieser Doktorarbeit war, ein besseres Verständnis der Rolle des Metabolismus von komplexen Phänotypen anhand von Unterschieden im Blutbild, des Geschlechts und anhand von Veränderungen des Metabolitenprofils bei multifaktoriellen Krankheiten wie Typ 2 Diabetes mellitus zu erhalten.
Um Artefakte auszuschließen wurden strikte Qualitätskontrollen aller gemessenen Metaboliten durchgeführt. Durch die Analyse von Blutplasma und -serum von 377 Personen konnten wir zeigen, dass die Konzentrationen der Metaboliten in Blutplasma und -serum stark korrelieren und darüber hinaus eine hohe Reproduktionsrate zeigen, bei der Blutplasma besser abschneidet. Im Gegensatz dazu zeigt das Blutserum höhere Metabolitenkonzentrationen und könnte deswegen besser für den Nachweis von Konzentrationsunterschieden geeignet sein.
Ein weiteres Ergebnis dieser Doktorarbeit war der Nachweis von signifikanten geschlechtsspezifischen Unterschieden der Konzentrationen von 102 der ausgewerteten 131 Metaboliten. Dabei wurden die Daten von mehr als 3300 Personen der KORA Kohorte verwendet und die Analysen einer konservativen Bonferroni-Korrektur unterzogen.
Darüber hinaus identifizierten wir potentielle Biomarker für Prä-Diabetes durch die Analyse von 140 Metaboliten in nüchtern abgegebenen Blutseren von 4297 Personen der KORA Kohorte. Wir konnten zeigen, dass Personen mit gestörter Glukosetoleranz (IGT) signifikant unterschiedliche Konzentrationen von drei Metaboliten (Glycin, lysoPhosphatidylcholine (LPC) 18:2 und acetylcarnitine) im Vergleich zu gesunden Personen aufweisen. Darüber hinaus konnten wir nachweisen, dass geringere Konzentrationen der Metaboliten Glycin und LPC bei Probanden mit Typ 2 Diabetes oder IGT vorhanden sind. Die in dieser Studie identifizierten Metaboliten sind biologisch unabhängig von zuvor entdeckten Diabetes Risikofaktoren. Durch weitere Analysen und die Einbeziehung systembiologischer Ansätze entdeckten wir sieben Diabetesrisiko Susseptibilitätsgene, welche durch Expressionsdaten bestätigt wurden.
Metabolomics welches auf der Analyse von Stoffwechselzwischen- und Endprodukten basiert, ist eine wertvolle Methode besonders in der biomedizinischen Forschung, um Krankheitsmechanismen aufzuklären. Nachdem angemessene Qualitätskontrollen etabliert und der Einfluss von komplexen Störfaktoren (z.B. das Geschlecht) aufgeklärt wurden, konnte der Zusammenhang zwischen Krankheit und Metabolismus weiter an Klarheit gewinnen. Die Entdeckungen in unserer T2D Studie zeigen, dass die Analyse von Konzentrationsprofilen helfen kann neue Krankheitsrisikomarker genauso wie neue Wirkungspfade zu identifizieren, die möglicherweise das Ziel zur Heilung einer Krankheit sein könnten.
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Kelly, Anne Margaret. "Platelets : relating functional phenotypes to transfusion outcomes". Thesis, University of Cambridge, 2015. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708623.
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Yelensky, Roman. "Proxy genotypes and phenotypes for human genetics". Thesis, Massachusetts Institute of Technology, 2008. http://hdl.handle.net/1721.1/45913.
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Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2008.Includes bibliographical references.
Genetic mapping by association is an unbiased approach to discover genes and pathways influencing disease traits and response to drugs and environmental exposures. There are two key obstacles to mapping in humans: (1) The full sequence of study subjects cannot yet be obtained; and (2) There are substantial limits to the phenotypes that can be safely elicited or measured. Geneticists thus rely on practically measurable sets of genotypes to proxy for the sequence and human in-vitro models that proxy for in-vivo genetics and physiology while allowing for perturbation and characterization in high throughput. This thesis presents the development of one important class of proxy genotypes, those that capture most common genetic variation, as well as an evaluation and refinement of proxy phenotypes offered by one commonly used in-vitro model, the lymphoblastoid cell-line.Capturing common human genetic variation for genome-wide association studies requires genotyping a feasible subset of proxy (or "tag") SNPs. We investigated selection and analysis of tag SNPs, examined the relationship between investment in genotyping and statistical power, and evaluated whether power is compromised when tags are selected from an incomplete resource such as HapMap. We demonstrate an efficient haplotypebased tagging approach and other methods that dramatically increase tagging efficiency. Examining all observed haplotypes for association increases power to detect rare causal alleles, while reducing power for common alleles. Power is robust to completeness of the reference panel and holds across demographically related groups.Lymphoblastoid cell lines (LCLs) are being developed into an in-vitro model where genetics of human gene expression, drug response, and other traits can be studied under controlled conditions. However, the impact of the immortalization process, the relative influence of non-genetic factors, and reproducibility of measured traits are not yet understood.
(cont.) We addressed these questions while mapping loci for response to chemotherapy and found that traits in LCLs are subject to substantial confounders and are only modestly reproducible in independent experiments. Despite this, RNA expression of many genes is affected by genetic variation and predicts response to drugs; integrating SNPs, RNA, and drug response can identify novel pharmacogenetic variation mediated by RNA.
by Roman Yelensky.
Ph.D.
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Yang, Hsiu-Mien. "Genes and phenotypes in Type 1 diabetes". Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609241.
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Mullon, C. D. L. "Investigating the evolution of sex-specific phenotypes". Thesis, University College London (University of London), 2012. http://discovery.ucl.ac.uk/1362849/.
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This thesis uses theoretical models to investigate a diverse set of questions that revolve around the evolution sex-specific phenotypes. Chapter 1 studies the evolution of sex-determining mechanisms. It investigates the evolutionary change in the coding sequences of sex determining genes associated with the recruitment of a top regulatory gene in Drosophila. We find that this recruitment coincided with changes in the evolution of all the genes of the sex determining pathway. We discuss how these changes are tied with the genes' molecular functions, and highlight the limits of inference from DNA sequence change only. Chapter 2 investigates the genomic distribution of sexually antagonistic alleles. Our study predicts that the interplay of sexually antagonistic selection and genetic drift leads to the accumulation of sexually antagonistic alleles on the X in XY species and, on the autosomes in ZW species, especially when sexual competition is strong among males. Chapter 3 studies the evolution and consequences of sex-specific reproductive variance by constructing a population genetic model that is based on an explicit representation of sexual reproduction. In particular, we derive the probability of fixation for mutations affecting male and female reproductive traits in different ways and find that sex-specific reproductive variance may have profound consequences for the evolution of sex-specific phenotypes. Finally, chapter 4 adapts this latter model to investigate the evolution of developmental instability in the presence of female choice. Developmental instability can be selected for by female choice. But it can have very dire consequences for other aspects of the phenotype, notably in female fecundity and offspring survival. We discuss the effects of reproductive variance on whether these detrimental effects are capable of preventing developmental instability. Overall, this thesis highlights how not only sex-specific selection, but also sex-specific variance in gene transmission contribute to variation in sex-specific phenotypes.
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Winter, Peter B. "Quantifying Complex Behavioral Phenotypes in C. elegans". Thesis, Northwestern University, 2016. http://pqdtopen.proquest.com/#viewpdf?dispub=10043987.
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The study of C. elegans has led to ground-breaking discoveries in gene-function, neuronal circuits, and physiological responses. However, subtle behavioral phenotypes, are often difficult to measure and reproduce across experiments. As part of my dissertation work, I used experimental and computational techniques to quantify and model the dynamics of movement and reproductive behaviors. For movement behaviors, I developed a mathematical approach to correcting the uncertainty of tracking individual animals in a free-moving population, created behavioral profiles for each individual, and used a network to reveal the progression of behavioral changes in the aging process. For reproductive behaviors, I used perturbations in temperature to dissect the key processes that modify the dynamics of the C. elegans reproductive system. The primary goal of creating this set of tools and approaches was to acquire high-quality data for mathematically modeling how individuals respond to environmental stress and modify their behaviors during ageing.
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Miranda, Eduardo de Paula 1984. "Linked biology = from phenotypes towards phylogenetic trees". [s.n.], 2013. http://repositorio.unicamp.br/jspui/handle/REPOSIP/275498.
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Orientador: André SantanchèDissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Computação
Made available in DSpace on 2018-08-24T12:38:30Z (GMT). No. of bitstreams: 1 Miranda_EduardodePaula_M.pdf: 3021722 bytes, checksum: 93a67943f673753c003a021060a55b6c (MD5) Previous issue date: 2013
Resumo: Um grande número de estudos em biologia, incluindo os que envolvem a reconstrução de árvores filogenéticas, resultam na produção de uma enorme quantidade de dados -- por exemplo, descrições fenotípicas , matrizes de dados morfológicos , árvores filogenéticas, etc. Biólogos enfrentam cada vez mais o desafio e a oportunidade de efetivamente descobrir conhecimento a partir do cruzamento e comparação de vários conjuntos de dados, nem sempre conectados e integrados. Neste trabalho, estamos interessados em um contexto específico da biologia em que biólogos aplicam ferramentas computacionais para construir e compartilhar descrições digitais dos seres vivos. Nós propomos um processo que parte de fontes de dados fragmentadas, que nós mapeamos para grafos, em direção a uma plena integração das descrições através de ontologias. Os bancos de dados de grafos intermediam o processo de evolução. Eles são menos dependentes de esquema e, uma vez que ontologias também são grafos, o processo de mapeamento do grafo inicial para uma ontologia torna-se uma sequência de transformações no grafo. Nossa motivação parte da ideia de que a conversão de descrições fenotípicas em uma rede de relações e a busca de conexões entre elementos relacionados irá aumentar a capacidade de resolver problemas mais complexos suportados por computadores. Este trabalho detalha os princípios de concepção por trás do nosso processo e duas implementações práticas como prova de conceito
Abstract: A large number of studies in biology, including those involving phylogenetic trees reconstruction, result in the production of a huge amount of data -- e.g., phenotype descriptions, morphological data matrices, phylogenetic trees, etc. Biologists increasingly face a challenge and opportunity of effectively discovering useful knowledge crossing and comparing several pieces of information, not always linked and integrated. In this work, we are interested in a specific biology context, in which biologists apply computational tools to build and share digital descriptions of living beings. We propose a process that departs from fragmentary data sources, which we map to graphs, towards a full integration of descriptions through ontologies. Graph databases mediate this evolvement process. They are less schema dependent and, since an ontology is also a graph, the mapping process from the initial graph towards an ontology becomes a sequence of graph transformations. Our motivation stems from the idea that transforming phenotypical descriptions in a network of relationships and looking for links among related elements will enhance the ability of solving more complex problems supported by machines. This work details the design principles behind our process and two practical implementations as proof of concept
Mestrado
Ciência da Computação
Mestre em Ciência da Computação
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Johns, Neil. "Phenotypes and genetic markers of cancer cachexia". Thesis, University of Edinburgh, 2016. http://hdl.handle.net/1842/23392.
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Cancer cachexia is a chronic wasting syndrome characterised by loss of weight, composed principally of muscle and fat. Patients with advanced cachexia demonstrate loss of appetite, early satiety, severe weight loss, weakness, anaemia and fluid retention. Affected individuals are also likely to report/experience decreased quality of life, decreased levels of physical performance, increased levels of fatigue, increased risks of treatment failure (be it chemotherapy, radiotherapy or surgery), increased risks of treatment side effects, and an increased mortality rate. Cachexia is therefore an extremely important, yet often underappreciated cause of cancer patient morbidity and mortality which requires urgent attention. Weight loss is significantly associated with cancer morbidity and mortality. It has been observed that half of all cancer patients experience weight loss and one-third lose more than 5% of their original body weight. Skeletal muscle loss appears to be the most significant event in cachexia and is associated with a poor outcome. However it is not known why some patients with the same tumour lose weight and muscle mass whilst others do not. The main aim of this thesis was to determine if the genetic makeup of individual patients might contribute to their propensity to lose weight or skeletal muscle. Previous studies had suggested an association between weight loss and SNPs on genes concerned with innate immunity and particularly the cell adhesion molecule Pselectin, however the strength of any gene association study depends on the precision with which it is possible to characterise the phenotype in question. A second aim of this thesis was to explore refining the clinical phenotyping of patients to discriminate those with evidence of muscle fibre atrophy versus those without. Phenotype The conventional phenotype for cachexia is weight loss (WL) but it is unknown the extent to which loss of body mass reflects loss of muscle or fat mass. Recent progress in cross sectional imaging analysis means that it is now possible to gain a direct measure of muscle mass from routine diagnostic CT scanning. However, in the absence of a longitudinal series of scans it is not possible to estimate whether low muscularity (LM) is longstanding or not. By combining a measure of active weight loss with low muscularity it was hoped that such a composite measure would reflect actual muscle loss/fibre atrophy. Compared with non-cachectic cancer patients, patients with LM or LM+ > 2%WL, mean muscle fibre diameter was reduced by about 25% (p = 0.02 and p = 0.001 respectively). No significant difference in muscle fibre diameter was observed if patients had WL alone. Regardless of classification, there was no difference in fibre number or proportion of fibre type across all myosin heavy chain isoforms. Mean muscle protein content was reduced and the ratio of RNA/DNA decreased in patients with either > 5%WL or LM+ > 2%WL. These findings support the use of composite measures (WL and LM) to try and identify those patients with evidence of active muscle fibre atrophy. This novel clinical phenotyping provides an accurate method to enable the conduct of candidate gene studies in the investigation of the genetics of cancer cachexia where the primary focus is on muscle wasting rather than overall weight loss. Genotype In an ideal world it would be possible to explore the entire genome and look for associations with the different phenotypes of cachexia. However, to do so would require considerable resource in terms of the cost of genome wide analysis and the cost of phenotyping large enough cohorts of patients (3000-10000). To address these issues I therefore adopted a candidate gene approach. A total of 154 genes associated with cancer cachexia were identified and explored for associated polymorphisms. Of these 154 genes, 119 had a combined total of 281 polymorphisms with functional and/or clinical significance in terms of cachexia associated with them. Of these, 80 polymorphisms (in 51 genes) were replicated in more than one study with 24 polymorphisms found to influence two or more hallmarks of cachexia (i.e. inflammation, loss of fat mass and/or lean mass and reduced survival). Such election of candidate genes and polymorphisms is a key element of multigene study design. The systematic review provides a contemporary basis to select genes and/or polymorphisms for further association studies in cancer cachexia, and to develop their potential as susceptibility biomarkers of cachexia. Phenotype – genotype associations A total of 1276 patients were recruited, phenotyped and genotyped. There were 545 new patients and 731 patients from a previous study. In our new cohort and in keeping with the previous literature, patients who carried the C allele of the rs6136 SNP in the SELP gene, were at a reduced risk of developing cachexia defined by WL. This association applied to all degrees of weight loss ( > 5%, > 10% or > 15%), and not just at the > 10% level as described previously in the literature. When examining newly identified SNPs in a stage 1 analysis for the weight loss phenotype that included 1276 cancer patients, twelve new candidate SNPs were significant. Six of these SNPs are associated with muscle metabolism in five genes (IGF1, CPN1, FOXO1, FOXO3, and ACVR2B), three are associated with adipose tissue metabolism in two genes (LEPR and TOMM40 (APOE on the reverse strand)), two with corticosteroid signalling in one gene (IFT172 (GCKR on the reverse strand)) and one with the immune response in one gene (TLR4). Two polymorphisms (rs1935949 and rs4946935) in the gene encoding for FOXO3 were consistently associated with WL of increasing severity ( > 5% and > 10%). On the basis that WL is a continuum in the cachectic process, the observation that both SELP and FOXO3 associate with the higher degrees of WL suggests that these genetic signatures may be of particular significance. The role of P-selectin in the genesis of cachexia remains to be determined. When examining all SNPs in a stage 1 analysis for the LM phenotype, 5 SNPs were associated significantly with the cachexia phenotype: (i) rs4291 in the angiotensin converting enzyme (ACE) gene in chromosome 17; this gene has been associated with muscle function and metabolism; (ii) rs10636 in chromosome 16 in the metallothionein 2a gene; this gene has been shown to be involved in zinc dyshomeostasis which may contribute to cancer cachexia; (iii) rs1190584 in chromosome 14 in the WDR20 gene; this gene encodes a WD repeat-containing protein that functions to preserve and regulate the activity of the USP12-UAF1 deubiquitinating enzyme complex; (iv) rs3856806 in the peroxisome proliferator-activated receptor gamma (PPARG) gene in chromosome 3 which has been demonstrated to be involved in fatty acid and glucose metabolism; and (v) rs3745012 in chromosome 18 in the lipin 2 (LPIN2) gene; this gene represents a candidate gene for human lipodystrophy, characterised by loss of body fat, fatty liver, hypertriglyceridemia, and insulin resistance. When examining all SNPs in a stage 1 analysis for the LM + > 2%WL phenotype 4 SNPs were associated significantly with the cachexia phenotype. rs12409877 in the leptin receptor (LEPR) located on chromosome 3, LEPR binds leptin and is involved in adipose tissue regulation. rs2268757 located in the activin receptor type-2B (ACVR2B) gene on chromosome 3, ACVR2B is a high affinity activin type 2 receptor which mediates signalling by a subset of TGF-β family ligands including myostatin, activin, GDF11 and others. SNPs in the tumour necrosis factor (TNF) (rs1799964) and ACE (rs4291) genes were also significantly associated with the phenotype. Whether genes demonstrating significant associations with the cachexia phenotypes had altered transcript expression in muscle from cancer patients with or without those phenotypes was also investigated.
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Ashbrook, David. "A systems-genetics analyses of complex phenotypes". Thesis, University of Manchester, 2015. https://www.research.manchester.ac.uk/portal/en/theses/a-systemsgenetics-analyses-of-complex-phenotypes(a3e7ad8e-b23b-40fd-821e-26a6c1a63d38).html.
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Complex phenotypes are traits which are influenced by many factors, and not just a single gene, as for classical Mendelian traits. The brain, and its resultant behaviour, gives us a large subset of complex phenotypes to examine. Variation in these traits is affected by a range of different influences, both genetic and environmental, including social interactions and the effects of parents. Systems-genetics provides us with a framework in which to examine these complex traits, seeking to connect genetic variants to the phenotypes they cause, through intermediate phenotypes, such as gene expression and protein levels. This approach has been developed to exploit and analyse massive data sets generated for example in genomics and transcriptomics. In the first half of this thesis, I combine genetic linkage data from the BXD recombinant inbred mouse panel with genome-wide association data from humans to identify novel candidate genes, and use online gene annotations and functional descriptions to support these candidates. Firstly, I discovered MGST3 as a novel regulator of hippocampus size, which may be linked to neurodegenerative disorders. Secondly, I identified that CMYA5, MCTP1, TNR and RXRG are associated with mouse anxiety-like phenotypes and human bipolar disorder, and provide evidence that MCTP1, TNR and RXRG may be acting via inter-cellular signalling in the striatum. The second half of this thesis uses different cross-fostering designs between genetically variable BXD lines and the genetically uniform C57BL/6J strain to identify indirect genetic effects and the loci underlying them. With this, I have found novel loci expressed in mothers that alter offspring behaviour, novel loci expressed in offspring affecting the level of maternal care, and novel loci expressed in offspring, which alter the behaviour of their nestmates, as well as the level of maternal care they receive. Further I provide evidence of co-adaptation between maternal and offspring genotypes, and a positive indirect genetic effect of offspring on their nestmates, supportive of a role for kin selection. Finally, I demonstrate that the BXD lines can be used to investigate genes with parent-of-origin dependent expression, which have an indirect genetic effect on maternal care. In conclusion, this thesis identifies a number of novel loci, and in some cases genes, associated with complex traits. Not only are these techniques applicable to other phenotypes and other questions, but the candidates I identify can now be examined further in vitro or in vivo.
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Kelaini, Sophia. "Metabolic profiling studies of tumour cell phenotypes". Thesis, Imperial College London, 2010. http://hdl.handle.net/10044/1/6207.
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Ovarian cancer is a devastating disease affecting millions of women worldwide. Initially successful chemotherapy using platinum-based drugs is often followed by a relapse after which platinum therapy is usually ineffective and prognosis poor. The mechanism by which platinum resistance develops and its reversal to a more sensitive phenotype are of major interest in modern medical oncology, especially for ovarian cancer which has overall low survival rates. In this study, different types of in vivo-derived and in vitro cell models of platinum resistance were examined within a metabolic context using ¹H NMR spectroscopy and bioinformatics-based approaches to test the hypothesis that a metabolic signature of a platinum resistance phenotype could be defined. The in vitro-derived cell models of platinum resistance focused on the study of the Mlh1 gene, whose loss of expression has been shown to play a role in the development of resistance to platinum drugs and mitochondrial dysfunction. A comparative metabolic analysis of a transient Mlh1 expression cell model (HEK-293T) involving kidney cell lines of common genetic background and the ovarian cancer cell lines A2780 and its platinum resistant sub-line CP70 of well-established Mlh1 status was conducted. This resulted in the definition of a metabolic signature associated with Mlh1 expression, which included metabolites such as glutathione, alanine, myo-inositol and phosphocholine. It also achieved to associate the loss of MLh1 to mitochondria. The in vivo-imitating cell model focused on the normoxic & hypoxic baseline metabolic profiling of isogenic ovarian cancer cells that were clinically sensitive (PEA1 and PEO1) or resistant (PEA2 and PEO4) to platinum. The ¹H NMR-generated results showed oxygen level-related changes in glucose, lactate, pyruvate, acetate, and choline-related metabolites. Overall, this study managed to contribute towards the understanding of platinum resistance in ovarian cancer through a metabolic spectrum using a variety of analytical and methodological tools.
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Hanish, Alyson Elizabeth. "Sleep-related phenotypes: adolescence and PAX6 haploinsufficiency". Diss., University of Iowa, 2014. https://ir.uiowa.edu/etd/2220.
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Sleep health and sufficient sleep are particularly important during adolescence when important physical, cognitive, emotional, and social changes occur. Given the potential role of PAX6 in pineal development and circadian regulation, adolescents with PAX6 haploinsufficiency may be more likely to experience sleep-related problems compared to adolescents without these deletions or mutations. Haploinsufficiency of PAX6 can result from WAGR syndrome, a contiguous gene deletion syndrome in which multiple genes are involved, or point mutations and microdeletions affecting only PAX6, which result in isolated aniridia. The purpose of this dissertation is to examine pineal volume, melatonin concentrations, and sleep disturbance in individuals with PAX6 haploinsufficiency, as well describe validity of self-report measures of sleep problems in adolescents. Results are presented in three papers.
Although PAX6 haploinsufficiency is rare and minimal research has focused on the role of PAX6 in circadian regulation, irregular patterns of sleep-wake rhythm have been studied in children and adolescents with neurodevelopmental disorders (e.g. autism spectrum disorders), another population with possible abnormalities in melatonin physiology. The first paper presents an integrative review to synthesize the literature regarding the sleep-related measures currently being used to assess sleep disturbance in adolescents with a neurodevelopmental disorder. The second paper reports significantly reduced pineal volume, reduced melatonin secretion, and greater parent-report of sleep disturbance in individuals with PAX6 haploinsufficiency versus controls. Paper 3 further characterizes the sleep-related-phenotype associated with an abnormality in the PAX6 gene using self-report questionnaires and actigraphy in adolescents with PAX6 haploinsufficiency, as well as performs preliminary validation studies on age-appropriate self-report tools to measure sleep in adolescents. Results demonstrate similar self-reported daytime sleepiness, sleep disturbance, and sleep-related impairment in adolescents with PAX6 haploinsufficiency compared to the healthy comparison group; however, actigraphy data documented increased time from lights off to sleep in the PAX6 haploinsufficiency group. Self-reported sleep questionnaire scores and objective actigraphy variables (e.g. total sleep time) were significantly correlated in the healthy comparison group only; however, a lack of correlation among sleep-related measures in adolescents with PAX6 haploinsufficiency suggests potential limitations in using self-reported sleep measures in this population. This study used a combination of physiological and patient-reported health measures, and although WAGR syndrome and isolated aniridia due to PAX6 insufficiency are rare disorders, describing the sleep-related phenotypes in this population contributes to knowledge of assessment and treatment of sleep disorders in general, facilitating research in additional adolescent populations.
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Ades, Lesley Carole. "The Marfan syndrome and related phenotypes : delineation of various phenotypes and analysis of the fibrillin gene (FBN1) for putative mutations /". Title page, abstract and contents only, 1995. http://web4.library.adelaide.edu.au/theses/09MD/09mda232.pdf.
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Kuhr, Jan-Timm. "Statistical properties of microbial phenotypes and colony growth". Diss., lmu, 2012. http://nbn-resolving.de/urn:nbn:de:bvb:19-139733.
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Huang, Wei-Chun. "The expression of matrix metalloproteinases in macrophage phenotypes". Thesis, University of Bristol, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.551288.
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Macrophages, matrix metalloproteinases (MMPs) and tissue inhibitor of MMPs (TIMPs) are key factors in atherosclerotic plaque formation and plaque rupture, both of which are driven by macrophage accumulation and activation. The thesis investigated whether distinct phenotypes of macrophages may play different roles in MMP or TIMP expression during inflammation or plaque formation. The results showed that classically activated Ml macrophages significantly up-regulated MMP-l, MMP-3, MMP-7, MMP-IO, MMP-12, MMP-14 and MMP-25 and down-regulated TIMP-3, which suggests a strong increase in matrix-degrading potential. Patterns of response to classical activation in vitro are dominated by LPS and pro-inflammatory cytokines, only MMP-12, MMP-14 and MMP-25 expressions being partly affected by interferon-y. On the other hand, alternatively activated M2 macrophages strongly up-regulated MMP-II, MMP-12 and MMP-25, and this was accompanied by lower expression of many other MMPs and greater expression of TIMP-3. Hence alternative activation may rather selectively increase the potential for elastolysis by MMP-12, without promoting degradation of other matrix components. The MMP expression stimulated by classical activation depended on activation of mitogen activated protein kinases, phosphinositide-3 kinase, and inhibitor of K.8 kinase-2. In addition, MMP-l, and MMP-I0 co-localised with nuclear localised NF-KB in human atherosclerotic plaques. Furthermore, unstable plaques have higher COX-2, MMP-I, MMP-3, MMP-IO and MMP-14 expression in foam cell macro phages when compared to stable human coronary atherosclerotic plaques. By contrast, stable plaques had higher expression of the M2 marker, CD206, and TIMP-3 than human unstable plaques. In conclusion, Ml macrophages selectively increase the balance of several MMPs over TIMPs in macrophages in vitro and in unstable plaques, an example of inflammation in vivo. However, only limited groups of MMPs and TIMP-3 were significantly over-expressed in M2 macrophages.
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Martin, Neil. "Investigating phenotypes of asthma in elite performance athletes". Thesis, University of Leicester, 2012. http://hdl.handle.net/2381/28464.
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There is a high prevalence of exercise induced bronchoconstriction (EIB) in elite athletes. It has been suggested that damage to the airway epithelium is the key effector process and that EIB in athletes is due to different mechanisms than exercise induced asthma. Whether testing strategies are as valid in athletes is controversial, but regulatory bodies continue to advocate the use of objective tests for diagnosis. How responses to these relate to sport, airways inflammation and to symptoms is unclear. We investigated responses to direct and indirect challenge tests and patterns of airways inflammation in symptomatic, international, endurance athletes. We focused on differences between pool-based and non-pool based endurance athletes to see if environmental factors played a significant role. We also investigated the interaction between airways epithelial and human lung mast cells in vitro and compared these between healthy and asthmatic donors. Of the challenges assessed, EVH related most closely to eosinophilic airways inflammation. The other tests examined did not relate particularly closely to each other, to eosinophilic airways inflammation or to markers of mast cell activation. There were no differences between pool and non-pool based athletes in terms of patterns of airways inflammation or airway mediator release in response to challenge testing. Pool-based athletes had significantly more airways hypereactivity when compared to non-pool based athletes. Those who test positive to EVH have more eosinophilic airways inflammation and more epithelial cells in their sputum than those who have a negative test. All indirect challenge tests increased the level of PGE2 in the airways compared to direct testing, even when corrected for degree of bronchoconstriction, suggesting epithelial stress. In vitro, an intact, healthy epithelium significantly suppresses constituitive and IgE mediated human lung mast cell histamine secretion. This suppression is attenuated in asthmatic or injured epithelium and is mediated by a small, labile, lipid soluble mediator. There is a significant heterogeneity in airways inflammation and airways hyperreactivity in elite performance athletes. The role of the epithelial cell in the development of EIB requires further exploration. The interaction between the epithelium and human lung mast cells needs to be fully elucidated and its potential for therapeutic manipulation further explored.
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Siller, Steven Thornton. "Strategically developed phenotypes and the evolution of signals". Thesis, University of Oxford, 1997. http://ora.ox.ac.uk/objects/uuid:01e30a68-b444-40a3-adb2-2245ea045161.
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In the first part of this thesis, a general one dimensional theory of strategically determined phenotypes is developed and applied to biological signalling games. Abstract modular modelling techniques are utilised to solve hitherto analytically intractable problems including error-prone signalling, and how to incorporate genetic features into optimization models. Links are drawn between previous biological models, such as the War of Attrition and Strategic Handicap mod- els. Mistakes in previous biological models are recognised and, where possible, rectified. A number of novel insights into biological phenomena arising from the models are presented, including analyses of: when free signals are possible; honest signalling of future paternal investment; dimorphic signals; the effects of the mechanisms of female discrimination in sexual selection on male signalling strategies; and the effects of relatedness on the magnitude and stability of equi- librium signalling strategies. It is argued that Zahavi's proposed demarcation between signal selection and natural selection is unjustifiable from a theoretical perspective. The second part of the thesis concerns the epistatic handicap process of sex- ual selection. Unlike the conditional and revealing handicap mechanisms, the epistatic or 'Zahavian' handicap mechanism of sexual selection has hitherto found scant support in the theoretical literature, as it appeared to function only under the most extreme conditions. A continuous game theory model, a quantitative genetics model, and a three locus major gene model are presented which show that the epistatic handicap mechanism can function, independent of the Fisher process of sexual selection, under reasonable assumptions. More- over, the game theory model illuminates the connection between the strategic and epistatic handicap mechanisms. The quantitative genetics and major gene models, together with a fourth model, are also used to show that a general argu- ment concerning indirect genetic correlations, which has appeared in a number of papers on sexual selection, is specious. Finally, a general theorem on games that satisfy the single-crossing condition (also known as the sorting, Spence-Mirrless, or constant sign condition) which underlies many of the results presented in the first part of the thesis is proven in appendix C. Applying a limit result to this general theorem provides a new proof of, and extensions to, Nash's existence result for equilibria to strategic- form games without having to resort to Kakutani's fixed point theorem.
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Fusco, Eleonora. "Development of compartment phenotypes in the mammalian striatum". Thesis, Massachusetts Institute of Technology, 1997. http://hdl.handle.net/1721.1/10310.
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Hallit, Souheil. "Wheezing phenotypes and risk factors in early life". Thesis, Bordeaux, 2018. http://www.theses.fr/2018BORD0073/document.
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Les phénotypes de l’asthme sont affectés par l’exposition à de multiples facteurs durant la grossesse. Pour évaluer cette hypothèse, deux études ont été menées : l’une en France, l’autre au Liban. Dans l'étude française, l'objectif était de décrire les phénotypes respiratoires de sifflement chez l’enfant entre l’âge de deux mois et d’un an, et d'évaluer les facteurs de risque associés à ces phénotypes de sifflement dans une grande cohorte de naissance. Dans l'étude libanaise, les objectifs étaient d'évaluer les associations entre l'utilisation de médicaments, d'alcool, de cigarettes et/ou de narguileh, et l'exposition aux pesticides/détergents pendant la grossesse avec l'asthme infantile au Liban et de valider la version arabe du test de contrôle de l'asthme (ACT) chez ces enfants et d’identifier les facteurs de risque qui pourraient affecter le contrôle de l'asthme.Méthodes: Nous avons étudié 18 041 nourrissons de la cohorte de naissance ELFE (Étude Longitudinale Française depuis l'Enfance). Les parents ont signalé une respiration sifflante et des symptômes respiratoires à deux et 12 mois, et ont répondu à un questionnaire complet (exposition pendant la grossesse, allergie parentale). Le plan d'étude du projet libanais consistait en une étude cas-témoins, menée entre Décembre 2015 et Avril 2016, recrutant 1503 enfants, âgés de 3 à 17 ans. Le questionnaire administré évaluait les caractéristiques sociodémographiques (âge, sexe, niveau d'éducation des deux parents), les antécédents familiaux d'asthme et d'autres facteurs de risque connus de l'asthme (système de chauffage à domicile, antécédents d'otites récidivantes, humidité dans la maison, enfant allant à une garderie, fumer et boire de l'alcool pendant la grossesse, exposition aux pesticides et aux détergents).Résultats: Les enfants sans symptômes (témoins) représentaient 77,2%, 2,1% avaient une respiration sifflante à deux mois mais pas de respiration sifflante à un an (sifflement intermittent), 2,4% avaient une respiration sifflante persistante et 18,3% avaient une respiration sifflante à un an. En comparant les sifflements persistants aux contrôles, on a observé qu’avoir un frère ou une sœur (ORa = 2,19) ou deux frères et sœurs (ORa = 2,23) contre aucun, une toux nocturne (OR = 5,2), une détresse respiratoire (OR = 4,1) et un excès de sécrétions bronchiques (OR = 3,47 ) à deux mois, un reflux chez l'enfant à 2 mois (OR = 1,55), des antécédents d'asthme maternel (OR = 1,46) et le tabagisme maternel pendant la grossesse (OR = 1,57) étaient significativement associés à une respiration sifflante persistante. Ces mêmes facteurs, avec en sus une éruption cutanée chez l'enfant à 2 mois (OR = 1,13) et des antécédents paternels d'asthme (OR = 1,32) étaient significativement associés à une augmentation de la probabilité d'une respiration sifflante. Avoir un frère (ORa = 1,9) en comparaison à ne pas en avoir, une toux nocturne à 2 mois (OR = 1,76) et un excès de sécrétions bronchiques à 2 mois (OR = 1,65) étaient significativement associés à une respiration sifflante persistante par rapport à une respiration sifflante intermittenteAsthma in childhood seems affected by exposure to various factors in early life. To assess this hypothesis, we conducted 2 studies: one in France, and the other in Lebanon. In the French study, we aimed at describing wheezing phenotypes between the ages of two months and one year, and assess risk factors associated with these wheezing phenotypes in a large birth cohort. In the Lebanese study, the aims were to evaluate the associations between caregiver-reported use of medications, alcohol, cigarette and/or waterpipe (WP), and exposure to pesticides/detergents during pregnancy with childhood-onset asthma in Lebanon and to validate the Arabic version of the Asthma Control Test (ACT) among these children and identify risk factors that might affect asthma control.Methods: We studied 18,041 infants from the ELFE (French Longitudinal Study of Children) birth cohort. Parents reported wheezing and respiratory symptoms at two and 12 months, and answered a complete questionnaire (exposure during pregnancy, parental allergy).The study design of the Lebanese project consisted of a case-control study, conducted between December 2015 and April 2016, recruited 1503 children, aged between 3-16 years old. A questionnaire assessed the sociodemographic characteristics (age, gender, education level of both parents), the family history of asthma, and other known risk factors of asthma (heating system at home, child history of recurrent otitis, humidity in the house, child went to a daycare, smoking and drinking alcohol during pregnancy, exposure to pesticides and detergents).Results: Children with no symptoms (controls) accounted for 77.2%, 2.1% had had wheezing at two months but no wheezing at one year (intermittent wheezing), 2.4% had persistent wheezing, while 18.3% had incident wheezing at one year. Comparing persistent wheezing to controls showed that having one sibling (ORa=2.19) or 2 siblings (ORa=2.23) compared to none, nocturnal cough (OR=5.2), respiratory distress (OR=4.1) and excess bronchial secretions (OR=3.47) at two months, reflux in the child at 2 months (OR=1.55), maternal history of asthma (OR=1.46) and maternal smoking during pregnancy (OR=1.57) were significantly associated with persistent wheezing. These same factors, along with cutaneous rash in the child at 2 months (OR=1.13) and paternal history of asthma (OR=1.32) were significantly associated with increased odds of incident wheezing. Having one sibling (ORa=1.9) compared to none, nocturnal cough at 2 months (OR=1.76) and excess bronchial secretions at 2 months (OR=1.65) were significantly associated with persistent compared to intermittent wheezing.In the Lebanese study, the multivariate analysis showed that children living in North and South Lebanon and the children living in areas where pesticides are frequently used had an increased risk of asthma (ORa=1.625; ORa=13.65; ORa=3.307) respectively. Smoking WP during pregnancy and cigarette during lactation would increase the risk of asthma in children (ORa=6.11; ORa=3.44 respectively). A high Cronbach’s alpha was found for the full scale (0.959). As for the asthma control scale (ACT), the correlation factors between each item of the ACT scale and the whole scale ranged between 0.710 and 0.775 (p<0.001 for all items). Mother’s low educational level as well as the history of asthma in the mother and the father would significantly increase the risk of uncontrolled asthma (Beta= 1.862; Beta= 3.534; and Beta= 1.885 respectively). Cigarette smoking during breastfeeding and waterpipe smoking by the mother during pregnancy were both significantly associated with uncontrolled asthma (Beta= 2.105; Beta=2.325 respectively). Mother’s high educational level was significantly associated with more asthma control (Beta= -0.715)
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Du, Plessis Kari. "Analysis of antifungal resistance phenotypes in transgenic grapevines". Thesis, Stellenbosch : Stellenbosch University, 2012. http://hdl.handle.net/10019.1/71621.
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Thesis (MSc)--Stellenbosch University, 2012.ENGLISH ABSTRACT: The latest strategies in the protection of crops against microbial pathogens are rooted in harnessing the natural, highly complex defense mechanisms of plants through genetic engineering to ultimately reduce the application of chemical pesticides. This approach relies on an in-depth understanding of plant-pathogen interactions to develop reasonable strategies for plant improvement. Among the highly specialized defense mechanisms in the plant’s arsenal against pathogen attack, is the de novo production of proteinaceous antimicrobial peptides (AMPs) as part of the plant’s innate immunity. These AMPs are small, cysteine-rich peptides such as plant defensins that are known for their broad-spectrum of antifungal activity. These plant defensin peptides have been found to be present in most, if not all plant species and the defensin encoding genes are over-represented in plant genomes. Most of these defensins are generally the products of single genes, allowing the plant to deliver these molecules relatively rapidly and with minimal energetic expense to the plant. These factors contribute to establishing AMPs as excellent candidates for genetic engineering strategies in the pursuit of alternative crop protection mechanisms. The first antimicrobial peptide identified and isolated from grapevine, Vv-AMP1, was found to be developmentally regulated and exclusively expressed in berries from the onset of ripening. Recombinantly produced Vv-AMP1 showed strong antifungal activity against a wide range of plant pathogenic fungi at remarkably low peptide concentrations in vitro, however, no in planta defense phenotype could thus far be linked to this peptide. In this study, the antifungal activity of Vv-AMP1 constitutively overexpressed in its native host (Vitis vinifera) was evaluated against grapevine-specific necrotrophic and biotrophic fungi. Firstly, a hardened-off genetically characterised transgenic V. vinifera (cv. Sultana) population overexpressing Vv-AMP1 was generated and morphologically characterized. In order to evaluate the in planta functionality of Vv-AMP1 overexpressed in grapevine, this confirmed transgenic population was subjected to antifungal assays with the necrotrophic fungus, B. cinerea and the biotrophic powdery mildew fungus, Erysiphe necator. For the purpose of infection assays with a biotrophic fungus, a method for the cultivation and infection with E. necator was optimized to generate a reproducible pathosystem for this fungus on grapevine. Detached leaf assays according to the optimized method with E. necator revealed programmed cell death (PCD) associated resistance linked to overexpression of Vv-AMP1 that can be compared to that of the highly resistant grapevine species, Muscadinia rotundifolia. Contrastingly, whole-plant infection assays with B. cinerea revealed that Vv-AMP1 overexpression does not confer V. vinifera with elevated resistance against this necrotrophic fungus. An in silico analysis of the transcription of defensin-like (DEFL) genes previously identified in grapevine was included in this study. This analysis revealed putative co-expression of these DEFL genes and other genes in the grapevine genome driven by either tissue- or cultivar specific regulation or the plant’s response to biotic and abiotic stress stimuli. In conclusion, this study contributed to our knowledge regarding Vv-AMP1 and revealed an in planta defense phenotype for this defensin in grapevine. In silico analysis of the DEFL genes in grapevine further revealed conditions driving expression of these genes allowing for inferences to be made regarding the possible biological functions of DEFL peptides in grapevine.
AFRIKAANSE OPSOMMING: Die nuutste strategieë wat deel vorm van die beskerming van plant gewasse teen mikrobiese patogene het hul oorsprong in die inspanning van die natuurlike, hoogs gekompliseerde verdedigingsmeganismes van die plant deur middel van genetiese enginieurswese ten einde die gebruik van chemiese plaagdoders te verlaag. Hierdie benadering maak staat op ‘n in-diepte begrip van plant-patogeen interaksies om verstandige strategieë vir plantverbetering te kan ontwikkel. Van hierdie hoogs-gespesialiseerde verdedigingsmeganismses in die plant se arsenaal teen patogeen aanvalle sluit die de novo produksie van proteinagtige antimikrobiese peptiede (AMPs) in as deel van die plant se ingebore immuunstelsel. Hierdie AMPs is klein, sisteïen-ryke peptiede soos die plant “defensins” en is bekend vir hul breë-spektrum antifungiese aktiwiteit. Hierdie plant defensinpeptiede word aangetref in meeste, indien nie alle plant spesies nie en die defensin koderende gene word oor-verteenwoordig in plant genome. Meeste van hierdie defensins is gewoonlik die produkte van enkele gene wat die plant in staat stel om hierdie molekules relatief spoedig en met minimale energie verbruik in die plant te vorm. Hierdie faktore dra by tot die vestiging van AMPs as uitstekende kandidate vir genetiese ingenieursstrategieë as deel van die strewe na alternatiewe gewasbeskermingsmeganismes. Die eerste antimikrobiese peptied wat geïdentifiseer en geïsoleer is uit wingerd, Vv-AMP1, word beheer deur die ontwikkelingsstadium en word eksklusief uitgedruk in korrels vanaf die aanvang van rypwording. Rekombinant-geproduseerde Vv-AMP1 het sterk antifungiese aktiwiteit getoon teen ‘n wye reeks plantpatogeniese swamme teen merkwaardige lae peptied konsentrasies in vitro, alhoewel geen in planta verdedigingsfenotipe tot dusver gekoppel kon word aan hierdie peptied nie. In hierdie studie was die antifungiese aktiwiteit van Vv-AMP1 wat ooruitgedruk is in sy natuurlike gasheerplant (Vitis vinifera) ge-evalueer teen wingerd-spesifieke nekrotrofiese- en biotrofiese swamme. Eerstens is ‘n afgeharde geneties-gekarakteriseerde transgeniese V. vinifera (cv. Sultana) populasie wat Vv-AMP1 ooruitdruk gegenereer en morfologies gekarakteriseer. Om die in planta funksionaliteit van Vv-AMP1 ooruitgedruk in wingerd te evalueer is hierdie bevestigde transgeniese populasie blootgestel aan antifungiese toetse met die nekrotrofiese swam, B. cinerea en die biotrofiese swam, Erysiphe necator. Vir die doel om infeksiestudies uit te voer met ‘n biotrofiese swam is ‘n metode geoptimiseer vir die kweek en infeksies met E. necator wat gelei het tot ‘n herhaalbare patosisteem vir hierdie swam op wingerd. Blaarstudies, volgens die pas-verbeterde metode vir E. necator infeksies het ‘n geprogrammeerde seldood-geassosieërde weerstand, gekoppel aan die ooruitdrukking van Vv-AMP1 onthul, wat vergelyk kan word met dié van die hoogs-weerstandige wingerdspesie, Muscadinia rotundifolia. Hierteenoor het heel-plant infeksie studies met B. cinerea onthul dat Vv-AMP1 ooruitdrukking geen verhoogde weerstand teen dié nekrotrofiese swam aan V. vinifera bied nie. ‘n In silico analise van die transkripsie van defensin-agtige (DEFL) gene wat vroeër in wingerd geïdentifiseer is, is by hierdie studie ingesluit. Hierdie analise het vermeende gesamentlike uitdrukking van hierdie DEFL gene en ander gene in die wingerd genoom onthul wat aangedryf word deur weefsel- of kultivar-spesifieke regulering of die plant se reaksie tot biotiese en abiotiese stress stimuli. Ten slotte, hierdie resultate het bygedra tot ons kennis in verband met Vv-AMP1 en het ‘n in planta verdedigingsfenotipe vir hierdie defensin in wingerd onthul. In silico analiese van die DEFL gene in wingerd het verder toestande onthul wat die uitdrukking van hierdie gene aandryf wat ons toelaat om aannames te maak ten opsigte van die moontlike biologiese funksies van DEFL peptiede in wingerd en ondersteun die opstel en toets van hipoteses vir die rol en megansimes van aksie van die wingerd defensin familie.
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Raffetseder, Johanna. "Interplay of human macrophages and Mycobacterium tuberculosis phenotypes". Doctoral thesis, Linköpings universitet, Avdelningen för mikrobiologi och molekylär medicin, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-132321.
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Mycobacterium tuberculosis (Mtb) is the pathogen causing tuberculosis (TB), a disease most often affecting the lung. 1.5 million people die annually due to TB, mainly in low-income countries. Usually considered a disease of the poor, also developed nations recently put TB back on their agenda, fueled by the HIV epidemic and the global emergence of drug-resistant Mtb strains. HIV-coinfection is a predisposing factor for TB, and infection with multi-drug resistant and extremely drug resistant strains significantly impedes and lengthens antibiotic treatment, and increases fatality. Mtb is transmitted from a sick individual via coughing, and resident macrophages are the first cells to encounter the bacterium upon inhalation. These cells phagocytose intruders and subject them to a range of destructive mechanisms, aiming at killing pathogens and protecting the host. Mtb, however, has evolved to cope with host pressures, and has developed mechanisms to submerge macrophage defenses. Among these, inhibition of phagosomal maturation and adaptation to the intracellular environment are important features. Mtb profoundly alters its phenotype inside host cells, characterized by altered metabolism and slower growth. These adaptations contribute to the ability of Mtb to remain dormant inside a host during latent TB infection, a state that can last for decades. According to recent estimates, one third of the world’s population is latently infected with Mtb, which represents a huge reservoir for active TB disease. Mtb is also intrinsically tolerant to many antibiotics, and adaptation to host pressures enhances tolerance to first-line TB drugs. Therefore, TB antibiotic therapy takes 6 to 9 months, and current treatment regimens involve a combination of several antibiotics. Patient noncompliance due to therapeutic side effects as well as insufficient penetration of drugs into TB lesions are reasons for treatment failure and can lead to the rise of drug-resistant populations. In view of the global spread of drug-resistant strains, new antibiotics and treatment strategies are urgently needed. In this thesis, we studied the interplay of the primary host cell of Mtb, human macrophages, and different Mtb phenotypes. A low-burden infection resulted in restriction of Mtb replication via phagolysosomal effectors and the maintenance of an inactive Mtb phenotype reminiscent of dormant bacteria. Macrophages remained viable for up to 14 days, and profiling of secreted cytokines mirrored a silent infection. On the contrary, higher bacterial numbers inside macrophages could not be controlled by phagolysosomal functions, and intracellular Mtb shifted their phenotype towards active replication. Although slowed mycobacterial replication is believed to render Mtb tolerant to antibiotics, we did not observe such an effect. Mtb-induced macrophage cell death is dependent on ESAT6, a small mycobacterial virulence factor involved in host cell necrosis and the spread of the pathogen. Although well-studied, the fate of ESAT6 inside infected macrophages has been enigmatic. Cultivation of Mtb is commonly carried out in broth containing detergent to avoid aggregation of bacilli due to their waxy cell wall. Altering cultivation conditions revealed the presence of a mycobacterial capsule, and ESAT6 situated on the mycobacterial surface. Infection of macrophages with this encapsulated Mtb phenotype resulted in rapid ESAT6-dependent host cell death, and ESAT6 staining was lost as bacilli were ingested by macrophages. These observations could reflect the earlier reported integration of ESAT6 into membranes followed by membrane rupture and host cell death. In conclusion, the work presented in this thesis shows that the phenotype of Mtb has a significant impact on the struggle between the pathogen and human macrophages. Taking the bacterial phenotype into account can lead to the development of drugs active against altered bacterial populations that are not targeted by conventional antibiotics. Furthermore, deeper knowledge on Mtb virulence factors can inform the development of virulence blockers, a new class of antibiotics with great therapeutic potential.
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Ng, Yi Shiau. "Identifying and defining clinical phenotypes in mitochondrial disease". Thesis, University of Newcastle upon Tyne, 2017. http://hdl.handle.net/10443/3742.
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Mitochondrial disease is an umbrella term that encompasses many clinically, biochemically and genetically heterogeneous conditions, which develop as a consequence of impaired oxidative phosphorylation. The diagnosis of mitochondrial disease requires coordinated multidisciplinary input, starting with a high index of clinical suspicion and meticulous assessment, followed by systematic biochemical and genetic investigations. More recently, the advent of next generation sequencing has rapidly identified novel disease genes and mechanisms in many previously undiagnosed cases. However, the aspects of natural history, disease progression and prognostication associated with many of these genetic variants require further elucidation. Furthermore, genotype-specific treatment guidance and surveillance strategy for complications are lacking in a routine clinical setting. The MRC Mitochondrial Disease Patient Cohort (UK) is a national collaborative project initiated by three centres of NHS Highly Specialised Service for Rare Mitochondrial Disorders: Newcastle, London and Oxford. Newcastle is the largest centre and has enrolled over 55% of patients (~800), to date. My aim has been to utilise the longitudinal data collected for this national cohort database to facilitate deep phenotyping of common and rare genetic variants, investigate phenotype-genotype correlations and identify treatable complications of mitochondrial disease. In this thesis, I show that sudden adult death syndrome and severe intestinal pseudo-obstruction are two previously under-recognized clinical entities associated with the m.3243A > G mutation, the most common pathogenic heteroplasmic mitochondrial DNA mutation in adult patients. The significant implications of these findings for clinical practice are highlighted. Extrapyramidal movement disorders are identified in 5% of patients followed up in Newcastle. I sought to determine the spectrum of extrapyramidal movement disorders in children and adults, and interrogate the genotype-phenotype correlation that may provide screening guidance for generalists. Mutations in RMND1 (Required for Meiotic Nuclear Division protein 1) and YARS2 (mitochondrial tyrosyl-tRNA synthetase) genes both result in combined mitochondrial respiratory chain deficiencies, but their clinical phenotypes are distinctive. Survival in patients with RMDN1 deficiency is influenced by the presence of kidney disease, as shown in the multi-centre collaborative study that I have drawn together. Myopathy, lactic acidosis and sideroblastic anaemia (MLASA) is a classic syndrome associated with mutations in YARS2. vi However, such a syndromic presentation is not always evident in all patients, and I sought to demonstrate that cardio-respiratory insufficiency is a prominent, potentially treatable, complication in patients who harbour mutations in YARS2 without having the complete MLASA phenotype. Understanding the spectrum of clinical phenotypes and providing appropriate, accurate genetic counselling for heteroplasmic mitochondrial DNA point mutations is challenging under normal circumstances, but this is particularly difficult when the specific mutation is rare and phenotypic data are scant. I sought to perform a detailed analysis of patients harbouring the m.13094T>C mutation in MT-ND5.
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Chowdhury, Salim Akhter. "Identification of Coordinately Dysregulated Subnetworks in Complex Phenotypes". Case Western Reserve University School of Graduate Studies / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1277912839.
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Swearingen, Matt Charles. "Phenotypes of Salmonella SdiA in Mice and Pigs". The Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1374076511.
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Ritchey, Brian Michael. "Quantitative Trait Loci Mapping Of Macrophage Atherogenic Phenotypes". Cleveland State University / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=csu1510080975338565.
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Nagui, Refki Khalil Peter. "Hox genes and the evolution of adaptive phenotypes". Thesis, Lyon 1, 2014. http://www.theses.fr/2014LYO10288/document.
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Les populations sont soumises à des pressions sélectives qui agissent sur certains traits entraînant une divergence phénotypique. L'évolution des morphologies adaptatives est souvent liée avec des changements de structures préexistantes. Les insectes semi-Aquatiques ont subi une croissance de pattes exagérée qui est associée à leur adaptation et locomotion efficace à la surface de l'eau. Cette croissance excessive a facilitée l'exploitation de l'habitat aquatique restreint pour les espèces terrestres apparentées. En outre, le groupe dérivé des gerris a subi des modifications supplémentaires au niveau des pattes, de sorte que la deuxième patte (P2) est plus longue que la troisième patte (P3). Ce plan d'organisation inversé par rapport à celui des espèces terrestres, est associé à la spécialisation pour une vie sur l'eau. Les gerris ont acquis un mode de locomotion dérivée qui consiste à ramer par des mouvements simultanés de leurs P2 et des mouvements plus subtils de leurs P3 pour s'orienter. La structure et la croissance des pattes des insectes semi-Aquatiques sont réalisées durant l'embryogenèse. En effet, la nymphe qui éclot possède des pattes fonctionnelles. Il a été démontré que le facteur de transcription Hox, Ubx, est impliqué dans cette inversion du plan des pattes. Cependant, les mécanismes génétiques responsables de ces adaptations restent toujours obscurs. La thèse présentée examine ces questions à travers deux axes : premièrement, déterminer les gènes et les voies de signalisation responsables du développement et de la croissance remarquable des pattes ; deuxièmement, étudier le rôle du gène Hox impliqué dans l'inversion du plan des pattes caractéristique des gerrisPopulations are faced with selective pressures that act on certain traits resulting in phenotypic divergence. The evolution of adaptive morphological traits is often associated with changes in pre-Existing structures. In semiaquatic insects, a dramatic growth of thoracic appendages is associated with their adaptation and efficient locomotion on the water surface. This particular leg allometry facilitated the exploitation of aquatic habitats, a restricted niche for their terrestrial relatives; and hence opens a new array of ecological opportunities. Additionally, the derived group of water striders has undergone further appendage modification, such that T2-Legs are longer than T3-Legs, a ground plan associated with the specialization to open water. Water striders have evolved a derived mode of locomotion through rowing on water. They move their mid-Legs in simultaneous sweeping strokes for propulsion, and move their hind-Legs in fine movements for orientation. Leg specification and elongation in semiaquatic insects happens during early embryogenesis as the newly hatching nymphs emerge with functional legs. The Hox transcription factor Ubx was found to be implicated in the reversal in leg ground plan. Nonetheless, the genetic mechanisms underlying these leg adaptive changes are still poorly understood. The presented thesis investigates these questions through two main goals: first, to uncover the genes and pathways implicated in the development and dramatic elongation of the legs; second, to examine the dynamics of Hox control responsible for the reversal in leg ground plan characteristic of water striders
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Kathuria, Annie. "Cellular phenotypes associated with autism : an iPSC study". Thesis, King's College London (University of London), 2016. http://kclpure.kcl.ac.uk/portal/en/theses/cellular-phenotypes-associated-with-autism-an-ipsc-study(8c9e2181-d107-4e58-a897-672069cd7bab).html.
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Autism is a neurodevelopmental disorder that affects around 700,000 in the UK (Baird G. et al., 2006; Burgha et al., 2011) and these numbers are constantly increasing. Nonetheless, our understanding of the cellular and molecular processes underlying autism is limited. This has hindered the development of effective treatments and created a need for human specific models. The potential of modeling autism through the use of human induced pluripotent stem cells (iPSCs) is an exciting advancement towards uncovering the mechanisms underlying a disorder that affects the lives of so many people. Recent studies report that mutations in the SHANK3 gene are a major cause of autism (Nemirovsky et al., 2015; Bentancur et al., 2013; Buccoto et.al, 2013). This project aimed to track and compare the development of neurons generated from iPSCs lines derived from SHANK3 patients and healthy individuals. These lines were produced from hair root biopsies from three categories of individuals: three healthy control individuals, two autistic patients with a heterozygous deletion in the SHANK3 gene and one sporadic ASD individual. iPSCs were differentiated into hypothalamic neurons and their structural and functional development was tracked during the various stages of neuralisation. These studies revealed that during early neuronal development, SHANK3 iPSC derived neurons have a smaller cell soma, but more and longer primary neurites than control cells. These morphogenetic deficits were rescued by overexpressing SHANK3. Further, embryonic stem cell lines, with homozygous and heterozygous deletion of the SHANK3 gene, gave rise to neurons with similar morphogenetic deficits to those seen in the SHANK3 patient neurons. Both studies validate that the reduced expression of SHANK3 is the cause for these morphogenetic deficits. The discovery of these early morphological defects in human SHANK3 mutant neurons has provided new insight into the mechanisms underpinning autism. This research has also developed a robust cell-based platform that can, not only be used to test these potential mechanisms, but also as a screen for potential therapies.
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Jansson, Désirée S. "Genus Brachyspira in birds : phenotypes, phylogeny and pathogenicity /". Uppsala : Dept. of Clinical Sciences, Swedish University of Agricultural Sciences, 2009. http://epsilon.slu.se/200914.pdf.
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Shirinian, Lena Alma. "Bacterial phenotypes and molecular mechanisms of mechanosensitive channels". College Park, Md. : University of Maryland, 2005. http://hdl.handle.net/1903/3246.
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Thesis (M.S.) -- University of Maryland, College Park, 2005.Thesis research directed by: Dept. of Biology. Title from t.p. of PDF. Includes bibliographical references. Published by UMI Dissertation Services, Ann Arbor, Mich. Also available in paper.
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Andrews, Tallulah. "Clustering genes by function to understand disease phenotypes". Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:06bfce1f-4ae0-4715-9ee3-290c43ae9b18.
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Developmental disorders including: autism, intellectual disability, and congenital abnormalities are present in 3-8% of live births and display a huge amount of phenotypic and genetic heterogeneity. Traditionally, geneticists have identified individual monogenic diseases among these patients but a majority of patients fail to receive a clinical diagnosis. However, the genomes of these patients frequently harbour large copynumber variants (CNVs) but their interpretation remains challenging. Using pathway analysis I found significant functional associations for 329 individual phenotypes and show that 39% of these could explain the patientsâ multiple co-morbid phenotypes; and multiple associated genes clustered within individual CNVs. I showed there was significantly more such clustering than expected by chance. In addition, the presence of a multiple functionally-related genes is a significant predictor of CNV pathogenicity beyond the presence of known disease genes and size of the CNV. This clustering of functionally-related genes was part of a broader pattern of functional clusters across the human genome. These genome-wide functional clusters showed tissuespecific expression and some evidence of chromatin-domain level regulation. Furthermore, many genome-wide functional clusters were enriched in segmental duplications making them prone to CNV-causing mutations and were frequently seen disrupted in healthy individuals. However, the majority of the time a pathogenic CNV affected the entire functional cluster, where as benign CNVs tended to affect only one or two genes. I also showed that patients with CNVs affecting the same functional cluster are significantly more phenotypically similar to each other than expected even if their CNVs do not affect any of the same genes. Lastly, I considered one of the major limitations in pathway analysis, namely ascertainment biases in functional information due to the prioritization of genes linked to human disease, and show how the modular nature of gene-networks can be used to identify and prioritize understudied genes.