Our world continues to undergo significant and extraordinary changes. Technology is firmly becoming embedded into society, population is steadily increasing, and a greater awareness of our fragile environment is emerging. Cities are responding. There is a reclaiming of the American downtown. Suburban USA still sprawls at alarming rates, but cities are beginnng to shed their image of havens for crime and the homeless. A more acute investigation at the neighborhood scale reveals situations more reluctant to adapt. Pieces of the urban fabric over time have been torn from their whole. Some, the result of neglect, while others are the victims of sweeping Modernist ideas that never came to fuition, leaving racial, social and economic barriers that halt the momentum of change. This thesis project, Philadelphia Public Housing: Reknitting the Urban Fabric, addreses these issues by forming a bridge between a place, with its inherent urban language and the people who inhabit that place. In an age of mass produced housing, how does one create an architecture at the urban scale that harmoniously coexists in an environment of crafted, historic housing, while embracing a standardized set of parts and assembly, maintaining integrity and promoting the building of community? / Master of Architecture

Quantitative Trait Loci (QTL) mapping has been widely used to identify genetic loci attributable to the variation observed in complex traits. In recent years, gene expression phenotypes have emerged as a new type of quantitative trait for which QTL can be mapped. Locating sequence variation that has an effect on gene expression (eQTL) is thought to be a promising way to elucidate the genetic architecture of quantitative traits. This thesis explores a number of methodological aspects of eQTL mapping (also known as “genetical genomics”) and considers some practical strategies for applying this approach to livestock populations. One of the exciting prospects of genetical genomics is that the combination of expression studies with fine mapping of functional trait loci can guide the reconstruction of gene networks. The thesis begins with an analysis in which correlations between gene expression and meat quality traits in pigs are investigated in relation to a pork meat quality QTL previously identified. The influence on power due to factors including sample size and records of matched subjects is discussed. An efficient experimental design for two-colour microarrays is then put forward, and it is shown to be an effective use of microarrays for mapping additive eQTL in outbred crosses under simulation. However, designs optimised for detecting both additive and dominance eQTL are found to be less effective. Data collected from livestock populations usually have a pedigreed structure. Many family-based association mapping methods are rather computationally intensive, hence are time-consuming when analysing very large numbers of traits. The application of a novel family-based association method is demonstrated; it is shown to be fast, accurate and flexible for genetical genomics. Furthermore, the results show that multiple testing correction alone is not sufficient to control type I errors in genetical genomics and that careful data filtering is essential. While it is important to limit false positives, it is desirable not to miss many true signals. A multi-trait analysis based on grouping of functionally related genes is devised to detect some of the signals overlooked by a univariate analysis. Using an inbred rat dataset, 13 loci are identified with significant linkage to gene sets of various functions defined by Gene Ontology. Applying this method to livestock species is possible, but the current level of annotations is a limiting factor. Finally, the thesis concludes with some current opinions on the development of genetical genomics and its impact on livestock genetics research.

Linkage between markers and genes that affect a phenotype of interest may be determined by examining differences in marker allele frequency in the extreme progeny of a cross between two inbred lines. This strategy is usually employed when pooling is used to reduce genotyping costs. When the cross progeny are asexual the extreme progeny may be selected by multiple generations of asexual reproduction and selection. In this thesis I will analyse this method of measuring phenotype in asexual cross progeny. The aim is to examine the behaviour of marker allele frequency due to selection over many generations, and also to identify statistically significant changes in frequency in the selected population. I will show that stochasticity in marker frequency in the selected population arises due the finite initial population size. For Mendelian traits, the initial population size should be at least in the low to mid hundreds to avoid spurious changes in marker frequency in the selected population. For quantitative traits the length of time selection is applied for, as well as the initial population size, will affect the stochasticity in marker frequency. The longer selection is applied for, the more chance of spurious changes in marker frequency. Also for quantitative traits, I will show that the presence of epistasis can hinder changes in marker frequency at selected loci, and consequently make identification of selected loci more difficult. I also show that it is possible to detect epistasis from the marker frequency by identifying reversals in the direction of marker frequency change. Finally, I develop a maximum likelihood based statistical model that aims to identify significant changes in marker frequency in the selected population. I will show that the power of this statistical model is high for detecting large changes in marker frequency, but very low for detecting small changes in frequency.

Large bowel cancer, or colorectal cancer (CRC) is the third most common cause of cancer worldwide and the fourth biggest cause of cancer mortality. Twin studies have shown that the heritable contribution is ~35%, with ~5% of cases due to rare, high-penetrance mutations. In the last decade, the use of genome-wide association studies on large, well-characterised case-control cohorts of CRC has facilitated the identification of over 25 common genetic variants that carry with them an increased predisposition to colorectal cancer, invoking the common-disease common variant paradigm. As almost all of these variants lie within non-coding regions, the underlying causal mechanism is to-date poorly understood for the majority of these loci, and it is thought that they mediate risk by influencing gene expression levels. To test this hypothesis, an agnostic approach that utilises expression quantitative trait loci (eQTL) analysis was first carried on 115 normal colorectal mucosa samples and 59 peripheral blood mononuclear cells (PBMC). As these heritable variation on gene expression are likely to be subtle, there is a strong emphasis on the technical methodology to minimise experimentally-induced non-biological variations, including the extraction of high-quality RNA from primary tissue, the selection and validation of reference genes for normalisation of gene expression quantification, as well as internal validation of the samples and data processing. Thereafter, the association between the 25 CRC risk variants and the expression of their cis-genes were examined systematically, demonstrating that ten of these variants are also tissue-specific eQTLs. This intermediate phenotype strongly suggests that they confer risk, at least in part, by modifying regulatory mechanisms. One of the best eQTL associations (Xp22.2) is investigated in further detail to reveal a novel indel polymorphism (Indel24) at the distal promoter region of target gene SHROOM2 that influenced both transcript abundance and CRC risk more than the original tagging SNP. Functional verification with gene reporter assays indicated that Indel24 displays differential allelic control over transcriptional activity. Further in silico analysis and mutations to the reporter gene constructs provided evidence that Indel24 modulates transcription by modifying the spacing between CCAAT motifs and the consequent binding affinity of NF-Y transcription factor. siRNA depletion of NF-Y was associated with a reduction in transcriptional activity of the Indel24 gene construct as well as endogenous SHROOM2, which is strongly supportive of the interaction between Indel24 and NF-Y in the transcriptional activation of SHROOM2. Preliminary evidence is suggestive of SHROOM2 being expressed at the top of the intestinal epithelial crypt and playing a role in cell cycle regulation. Hypothesis-driven approaches can also be of utility in demonstrating functionality of CRC risk variants, complementing the hypothesis-free approach of eQTL analysis. Guided by a recently discovered gene-environment interaction between the 16q22.1 risk variant and circulating vitamin D levels, the influence of the rs9929218 SNP on CDH1 gene expression was examined, in relation to the expression of putative regulatory genes derived from in silico analysis and studies of other target genes. Although there was no direct association between rs9929218 and CDH1 expression, there were multiple two-way interactions that were together suggestive of rs9929218 influencing the VDR/FOXO4 regulation of CDH1. This provides functional support for the mechanism underlying the epidemiological observation of the gene-environment interaction between 16q22.1 and vitamin D, and demonstrates a candidate-based approach in deciphering the link between genetic locus and CRC susceptibility. In summary, the research presented in this thesis has validated the experimental rationale of utilising expression studies of normal colorectal mucosa to hone in on the molecular mechanisms and susceptibility genes underlying the association between common genetic variation and CRC risk.

No description available.

[Abstract]: Crown rot (causal organism: Fusarium pseudograminearum) is a significantdisease affecting wheat in Australia. Although first reported over 60 years ago, the disease has become more prevalent in recent years due to the adoption ofminimum tillage and stubble retention practices. Breeding for resistance to crown rot is difficult - phenotypic selection, which is usually done at harvest, istime-consuming, expensive, and subject to between year variability due to sensitivity to environmental conditions. For these reasons, the coupling ofmolecular techniques with conventional plant breeding (marker-assisted selection) has the potential to more rapidly and reliably identify genomic regionsthat contribute to resistance. The objective of this study was to identify, validate,and pyramid quantitative trait loci (QTL) for resistance to crown rot present in aW21MMT70 x Mendos doubled haploid wheat population.Replicated seedling trials were conducted in 2001, 2003, and 2005. In eachseedling trial, W21MMT70 displayed partial resistance to crown rot whereasMendos seedlings were susceptible. A bulked segregant analysis (BSA), using390 simple sequence repeat (SSR) markers chosen for their coverage of thewheat genome, was initially conducted based upon the 2001 seedling trial data inan attempt to rapidly identify genomic regions associated to resistance. The BSAdid not reveal any markers associated with resistance to crown rot. As a result, afull mapping study was conducted. One hundred and twenty eight (128) SSRmarkers were mapped across the population to produce a framework map.Previously screened AFLP markers were added to the map. Composite intervalmapping revealed eight QTL associated with resistance. Of these, three (locatedon chromosomes 2B, 2D, and 5D) were consistently detected in each of the threeseedling trials. Two QTL (on chromosomes 1A and 3B) were detected in two ofthe three trials. The 2D, 3B, and 5D QTL were inherited from W21MMT70,whereas the 1A and 2B QTL were inherited from Mendos.Two software programs were used to identify epistatic interactions betweenQTL. While the results of the two programs differed markedly, both programsdetected a highly significant interaction between the W21MMT70 inherited 5DQTL and a locus on chromosome 2D inherited from Mendos. The overall effectof the epistatic interactions was not as great as the additive effects of nonepistaticQTL. Nonetheless, the presence of epistasis may indicate that,particularly in the case of 5D, the effect of this QTL may be dependent on thebackground into which it is introgressed.Validation of three W21MMT70-inherited QTL (on chromosomes 2D, 3B, and5D) was conducted on three F2 populations with W21MMT70 as one of theparents. While the 5D QTL was validated in two of the three crosses, neither the2D nor the 3B QTL were detected in any of the F2 validation populations. It islikely that the size of the F2 populations (the largest composed of 94 individuals),in conjunction with the variability that is inherent when screening for resistanceto crown rot, precluded validation of these regions. Validation of the 2BMendos-inherited QTL was conducted on a Sunco x Batavia doubled haploidpopulation because Sunco possesses the same Triticum timopheevi 2B introgression that is present in Mendos. This validated QTL (designatedQ.CR..usq-2B2) explained 11 % of the phenotypic variance in the Sunco xBatavia population.To assess the effectiveness of pyramiding QTL for resistance to crown rot, a 2-49x W21MMT70 population was examined. A number of lines of this populationperformed significantly better than each of the parents in the replicated seedlingtrial that was conducted. Four QTL, located on chromosomes 1A, 1D, 2D, and3B, were detected. The 1A and 1D QTL were inherited from 2-49 whereas the2D and 3B QTL were inherited from W21MMT70. The 1A QTL from 2-49 hasnot been previously validated, and this QTL has been designated QCr.usq-1A1.The 3B QTL (designated QCr.usq-3B1) had the highest effect (LRS 42.1;explaining 21.0 % of the phenotypic variance) in the 2-49 x W21MMT70population. The 2D QTL (QCr.usq-2D1) was shown to have a minor effect. The5D QTL that was inherited from W21MMT70 in the W21MMT70 x Mendospopulation was not detected in the 2-49 x W21MMT70 population. A number ofpossible explanations for the inability to detect this QTL in the 2-49 xW21MMT70 population are discussed.

This diploma thesis is based on a project emphasizing the land art principle that creates an illusion and intervenes thus into space on grounds of a historical event or an object missing in a certain area. The practical part consists of seven land art schemes with an introduction of the concept itself and the last key concept is in addition realized on Vitkov Hill. The overall design of Vitkov area suggests park changes and ground shaping of the park itself that is also supplemented by land art enhancing historical aspects of the place. The concept focuses mainly on an oversized asphalt lane that is nowadays, with its flat shape, considered as the top of such prominent hill, the real peak is therefore missing. Having said that, the project attempts to restore its natural and imperfect appearance of the complex. Furthermore, the scorched pathway becomes due to summer season an unfriendly place to stay. As a result, the project provides a solution in form of a return to a slightly narrowed sunken lane placed under the ground level and paved with stones. Alongside the main holloway there are sand pathways for walkers and a running track so far spontaneously created in the lawn by passing runners. Asphalt lane therefore stays only one, designated especially for inline skaters. Around the aforementioned routes there are suggested both elevated and deepened spots that offer even more magnificent view. All proposed terrain changes are supposed to evoke a false impression that Vitkov hill has never been flattened, as it in present day, and one is a mere visitor passing through paths that allow visitors to embrace sense of reaching the top. Despite the fact that Vitkov hill monument is a public area having its indisputable significance, it seems to be often forgotten. Apart from the recreational purposes of the park, this green hill is also a prominent feature in Prague´s city views and, last but not least, a memorial of one of the most important battles related to the Czech history. This land art project has been involved into International Landscape Festival 2018 held in Prague and foreshadows thus the event from early stages. The project then becomes a real work of art placed in public area with an intention to accentuate the suffering in the historical battle as a painful event that should be remembered by the nation. Simultaneously, it points out at a missing tree that symbolizes ephemerality of values. Land art thus emphasizes an abstract image of growing Lilacs and Acacia trees standing against each other in the battlefield as the soldiers in Vitkov or from the present day point of view, Karlín and Žižkov. Defeated Acacia trees epitomize Crusaders fleeting away from victorious Hussites (Lilacs) down the Karlín Hill and the only thing that remains is only one fallen soldier (Accia tree) and a lot of pikes sunken in the ground. Other land art projects have much in common. For instance, they are located in cities and their surroundings known well by the author. Apart from visible aspects, they lay emphasis especially on inner connectedness expressed through an illusion. A passerby should be able to notice that there is an imperfection, in particular area, he has not spotted before. He therefore intentionally finds himself in a position where he should open his fantasy because the place is speaking to him through shades and silhouettes of an absent reality. This thesis also demonstrates how popular initiative can change the city and bring interesting ideas as in case of High Line in New York. Lastly, land art literary research provides insight not just into land art as artistic movement but also as a feature in public area commonly discussed due to its inappropriate composition. The diploma thesis focuses mainly on Czech authors.

No description available.

Most human traits are influenced by a combination of genetic and environmental effects. Heritability expresses the proportion of trait variance that can be explained by genetic factors, and the 1980s heralded the beginning of studies that aimed to pinpoint genetic loci that contribute to trait variation, also known as quantitative trait loci (QTLs). Subsequently, the availability of cheap, high-resolution genotyping chips ushered in the era of genome-wide association studies (GWAS). These genetic studies have discovered many associations between single-nucleotide polymorphisms (SNPs) and complex traits, but these associations do not explain the genetic component of these traits entirely. This is known as the ‘missing heritability’ problem. Within this thesis, 40 medically-relevant human complex traits are studied in order to identify new QTLs. These traits include eye biometric traits, blood biochemical traits and anthropometric traits measured in approximately 28,000 individuals belonging to family-based samples from the general Scottish population (the Generation Scotland study) or from population isolates from Croatian (Korčula, Vis) or Scottish (Shetland, Orkney) islands. These individuals had been genotyped using commercially-available arrays, and unobserved genotypes were imputed using the Haplotype Reference Consortium (HRC) dataset. In parallel to standard GWAS, these traits are analysed using two other statistical genetics approaches: variance component linkage analysis and regional heritability (RH) mapping. Each study is analysed separately, in order to detect study-specific genetic effects that may not generalise across populations. At the same time, because most traits are available in several studies, this also enables meta-analysis, which boosts the power of discovery and can reveal cross-study genetic effects. These methods are a priori complementary to each other, exploiting different aspects of human genetic variation, such as the segregation of variants within families (identity by descent, IBD), or the presence of the same variant throughout the general population (identity by state, IBS). The strengths and weaknesses of these methods are systematically assessed by applying them to real and simulated datasets.

The purpose of this paper is to examine the properties of the envelope and the extraneous loci associated with the solution curves of ordinary differential equations of the first order and degree greater than one.