Arterial variants, defined as atypical presentations of anatomy including aberrant origin, course, and branching pattern, are important to be aware of because of their effects in the clinical setting as well as their possible link to pathology. Much research has already been done focusing on specific arterial variants in a specific region in the body. However, more research is needed to determine if there is a relationship between arterial variants in different regions of the body. The purpose of this study is to examine the whole-body arterial system of body donors in order to assess if there is a relationship between the presence of arterial variants in one region of the body to the other. The entire arterial system of twenty-five formalin fixed body donors was examined for the presence of arterial variants. The data was separated into two main categories, central variants (e.g. arch of the aorta, unpaired abdominal aortic branches) and peripheral variants (e.g. upper and lower extremities). The relationship between the central and peripheral variants was determined using quantitative observation, specifically, by examining the percent frequency of cases where arterial variants were co-occurring. Of the body donors examined, all were found to have at least one arterial variant, with an average of 8.7 variants per body. Arterial variants were most commonly found in the foregut with prevalence of 80%, the midgut (68%), left subclavian (60%), right upper extremity (52%), and the left upper extremity (48%). Of the central arterial variants, a percent frequency of 20% was found for the arch of the aorta, 20% for the coronary artery, 12% for the hindgut, 28% for the right renal, and 28% for the left renal. For the peripheral variants, the percent frequencies were as follows: brain variants were 4%, right carotid 8%, left carotid 0%, right subclavian 28%, left upper extremity 40%, right suprarenal 24%, left suprarenal 12%, right phrenic 24%, left phrenic 12%, gonadal 4%, right iliac 40%, left iliac 32%, and right lower extremity 40%. Examination of the relationship between central variants and peripheral variants reveals that the most common arterial variants to occur in tandem in the sample were those of the variant foregut with variants of the left subclavian artery (52% of cases), the upper and lower extremities (36-44% and 40-44% of cases, respectively), and the right iliac artery (36% of cases). The most common central arterial variants to co-occur were the variants of the foregut and midgut observed in 64% of cases. The frequency of cases involving normal central anatomy and variant peripheral anatomy indicates that vascular variants in the periphery are likely unrelated to variants in the central body cavities. However, it does seem like there are “hot spots” for arterial variants to occur, including the foregut, midgut left subclavian artery, right and left upper extremities, the right iliac artery, and the right and left lower extremities. Although there was no discernable pattern found between vascular variants in the present study, that does not preclude the possibility that there is a significant relationship between certain vascular variants. Either way, the high prevalence of cases with multiple arterial variations suggests that they may be more likely to occur than previously thought.

The RSA cryptosystem, named after its inventors, Rivest, Shamir and Adleman, is the most widely known and widely used public-key cryptosystem in the world today. Compared to other public-key cryptosystems, such as elliptic curve cryptography, RSA requires longer keylengths and is computationally more expensive. In order to address these shortcomings, many variants of RSA have been proposed over the years. While the security of RSA has been well studied since it was proposed in 1977, many of these variants have not. In this thesis, we investigate the security of five of these variants of RSA. In particular, we provide detailed analyses of the best known algebraic attacks (including some new attacks) on instances of RSA with certain special private exponents, multiple instances of RSA sharing a common small private exponent, Multi-prime RSA, Common Prime RSA and Dual RSA.

Recently, remotely sensed multispectral data have been proved to be very useful for many applications in the field of Earth surveys. For certain applications, however, limits in the spatial resolution of satellite sensors and variation in ground surface restrict the usefulness of the available data, since the observed spectral signature of the pixels is the result of a number of surface materials found in the area of the pixel. Two mixed pixel classification techniques which have shown high correlation with vegetation coverage of single pixels are described in this thesis: the vegetation indices and the linear mixing model. The two approaches are adjusted in order to deal with sets of pixels and not individual pixels. The sets of pixels are treated as statistical distributions and moments can be estimated. The vegetation indices and the linear mixing model can then be expressed in terms of these statistics. The illumination direction is an important factor that should be taken into account in mixed pixel classification, since it modifies the statistics of the distributions of pixels, and has received no attention until now. The effect of illumination on the relation between the vegetation indices and the proportion of sets of mixed pixels is examined. It is demonstrated that some vegetation indices, which are defined from the ratio of statistics in two spectral bands, can be considered relatively invariant to illumination changes. Finally, a new illumination invariant mixing model is proposed which is expressed in terms of some photometric invariant statistics. It is shown to perform very well and it can be used to un-mix accurately sets of pixels under many illumination angles. The newly introduced mixing model can be considered a suitable choice in the mixed pixel classification field. Key words: Mixed pixels, sets of pixels, vegetation index, illumination invariants.

Warfarin, the most commonly prescribed anticoagulant, is principally metabolized by cytochrome P450 2C9 which functions by inhibiting the Vitamin K epoxide reductase. Genes CYP2C9 and VKORC1 code for these two proteins, respectively. CYP2C9 and VKORC1 exhibit genetic polymorphisms that have been shown to affect warfarin response and favorably facilitate warfarin dosing and improve clinical outcomes. However, none of these studies have involved populations from sub-Saharan Africa where the potential benefit of optimal dosing and reduced complications is greatest. Therefore, the thesis describes a study designed to investigate the role of genetic variations in CYP2C9 and VKORC1 on the time taken to reach a stable therapeutic international normalized ratio (INR) and warfarin dose required to maintain a therapeutic INR. This was a cross-sectional study of patients on warfarin to determine the relationship between genetic polymorphism in CYP2C9 and VKORC1 amongst black and mixed ancestry South Africans and clinical surrogates of warfarin metabolism. Medical records were accessed to determine time to INR and warfarin doses. DNA was extracted from blood samples, and genotyping for polymorphism in CYP2C9 (*2,*3,*8,*11) and VKORC1 (1173C>T, 1639G>A, 3730G>A) was accomplished by PCR-RFLP, Sanger sequencing and iPlex Mass Sequencing. Our results show that the genetic profile of CYP2C9 and VKORC1 differs between Black Africans (BA) and their Mixed Ancestry (MA) counterparts. VKORC1-1639AA genotype was observed at frequencies of 0.11 and 0.01 in the MA and BA, respectively. Time to stable INR was not influenced by CYP2C9 and VKORC1. Furthermore, compared to known genetic polymorphisms in these genes from population out of Africa, both qualitative and quantitative differences were observed. Finally, we found that VKORC1 genetic variation significantly affected the doses of warfarin in MA but had no effect in BA. These results suggest that further research in this area is warranted, and that it will be important to include populations from sub-Saharan Africa in future if the potential to develop personalized algorithms which integrate pharmacogenomics to assist with effective warfarin dosing and prevention of warfarin related complications is to be realized.

The goal of the diploma thesis is to design and to assess a solution of a northern bypass of the road I/23, which will divert a transit traffic from Rosice. The town is situated approximately 25 kilometers west of Brno, in the South Moravian region. Three variants are worked out. The variant A and the variant B connects smoothly with a bypass of a neighboring village Zastávka. The variant A then copied a route designed in a local development plan and goes through a built-up part of the town Rosice in the area of the street Na Mýtě. The variant B is designed to avoid passage through this area and bypasses Rosice in north, behind a housing estate Kamínky. The variant C is designed in case an absence of a bypass of the village Zastávka. It connects with existing road I/23 in the village Zastávka in the area of an intersection of streets Lipová – Stará osada. The goal of the bypass is to divert the current transit traffic from Rosice

One of the primary challenges in clinical genetics is the interpretation of the numerous genetic variants identified through sequencing applications. Assessing the impact of missense variants where only one amino acid is substituted is particularly difficult. In this study, we examined the structural characteristics of amino acids affected by missense substitutions in 26,690 pathogenic variants and compared them to 11,302 common variants found in the general population. This analysis was conducted across 6,747 protein structures. The residues were annotated using 7 protein features with a total of 35 feature subtypes. Subsequently, we assessed the burden of both common and pathogenic missense variants across these features. Additionally, we carried out separate analyses relative to protein function (with variants grouped in 24 protein functional classes) and relative to diseases (with variants grouped in 86 diseases). Through a comprehensive analysis of the entire dataset, we identified 25 pathogenic features that play a crucial role in the overall fitness and stability of proteins. Additionally, when we conducted individual analyses for 24 protein functional classes, we discovered specific features that are relevant to each function. For the disease analysis we identified 3 main clusters. Type I diseases primarily result from ordered mutations and are mainly affected by charge loss. This cluster is dominated by transporter protein class and includes diseases linked to X-chromosome. Type II diseases involve hydrolases and are characterized by enriched variants at the protein core, resulting in protein destabilization. Type III diseases involve extracellular matrix proteins (mainly collagen), are predominantly found in disordered regions, and are affected by charge gain and introduction of polar residues. Gly variants are particularly relevant in this cluster, as collagen proteins require Gly in every third residue in the collagen triple-helix. Considering the structural aspects when interpreting mutations associated with diseases offers valuable insights into their underlying mechanisms. Our work can serve as resource to delineate and understand variant pathogenicity by mapping a genetic variant into its structural context.

No abstract provided. / Thesis / Master of Arts (MA) / Scope and contents: The first part of the thesis is an orientation to the novel itself, since the entire work must be taken as the only meaningful context for a consideration of the substantive variants. The second part consists of an examination of the selected revisions in the light of the full context and of James's theory of revision. The third part is a record of substantive variants. The appendices contain a report on computer collation of a section of the text and two extended notes on specific substantive variants.

Doctor of Philosophy / Before the early 2000s, many producers were heavily selecting for production traits without accounting for the negative relationship between many production traits and fertility. The large decrease in fertility that occurred as a result of these selection practices put a heavy burden on producers. Replacement heifer development is the third largest cost incurred by producers, behind feed and labor. Consequently, the failure of a heifer to conceive in her first breeding season translates directly into financial loss for the producer and lasting consequences on the animal's longevity and performance in subsequent breeding seasons. To make improvements in a trait, or traits, of interest, producers often selectively breed two animals with desirable characteristics. However, the complex nature of fertility traits limits the effectiveness of this method. As a result, researchers have been attempting to identify biological molecules whose abundance differs between cattle of differing fertility potential, termed molecular markers, that could be used to identify superior cattle earlier and more accurately. While a good amount of research has been conducted in mature cows and in a laboratory setting, very few studies have attempted to identify molecular markers of fertility in heifers. Therefore, the objective of this work was to identify different biological molecules (genomic variants, genes, proteins, and metabolites) whose abundance differed between heifers with varying fertility potential. Investigation into DNA variations led to the identification of three variants that were associated with fertility, 16 variants that were associated with health, and 29 variants that were associated with both health and fertility. Given that some variants can impact a trait by changing gene expression, we attempted to identify variations in RNA that were having this effect on heifer fertility. Although some variants were found to influence gene expression, we were unable to correlate these changes with fertility differences. However, in a different study, we were able to identify two genes (APMAP and DNAI7), as well as one protein (alpha-ketoglutarate-dependent-dioxygenase FTO), that differed significantly between fertile and sub-fertile heifers. Importantly, the results of this study allowed us to create a biological profile that was capable of accurately distinguishing 21/22 heifers based on their fertility potential. Finally, investigation of the metabolite profile revealed one metabolite (2-dehydro-D-gluconate) that was differentially abundant between fertile and sub-fertile heifers. Overall, this work sheds light on the complex nature of heifer fertility and provides several potential molecular that could be used to distinguish between heifers of varying reproductive potential.

Rare disease variants are receiving increasing importance in the past few years as the potential cause for many complex diseases, after the common disease variants failed to explain a large part of the missing heritability. With the advancement in sequencing techniques as well as computational capabilities, statistical methodology for analyzing rare variants is now a hot topic, especially in case-control association studies. In this thesis, we initially present two related statistical methodologies designed for case-control studies to predict the number of common and rare variants in a particular genomic region underlying the complex disease. Genome-wide association studies are nowadays routinely performed to identify a few putative marker loci or a candidate region for further analysis. These methods are designed to work with SNP data on such a genomic region highlighted by GWAS studies for potential disease variants. The fundamental idea is to use Bayesian methodology to obtain bivariate posterior distributions on counts of common and rare variants. While the first method uses randomly generated (minimal) ancestral recombination graphs, the second method uses ensemble clustering method to explore the space of genealogical trees that represent the inherent structure in the test subjects. In contrast to the aforesaid methods which work with SNP data, the third chapter deals with next-generation sequencing data to detect the presence of rare variants in a genomic region. We present a non-parametric statistical methodology for rare variant association testing, using the well-known Kolmogorov-Smirnov framework adapted for genetic data. it is a fast, model-free robust statistic, designed for situations where both deleterious and protective variants are present. It is also unique in utilizing the variant locations in the test statistic.

CENP-A est le variant d’histone qui remplace spécifiquement l’histone H3 au niveau des centromères et confère ses propriétés uniques à la chromatine centromérique. La cristallographie aux rayon X, ainsi que la digestion à la MNase des nucléosomes contenant CENP-A suggèrent une flexibilité de l’ADN entrant et sortant de ce nucléosome. Néanmoins ces déductions restent aujourd’hui au stade hypothétique, en particulier, rien n’est connu sur le rôle éventuelle de cette particularité dans la fonction du nucléosome CENP-A. L’utilisation de la cryo-électromicroscopie nous a permis de déterminer les caractéristiques de la dynamique de l’ADN sortant du nucléosome CENP-A. Nos analyses biochimiques, de protéomiques et de pseudo-génétiques révèlent que la flexibilité élevée de l’ADN du nucléosome CENP-A ne permet pas l’interaction avec l’histone de liaison H1. In vitro, remplacer les 2 tours de l’hélice aN de CENP-A avec les 3 tours de l’hélice aN de H3 permet de restaurer l’interaction de l’histone H1. In vivo, le replacement des nucléosomes CENP-A par des nucléosomes contenant ce même nucléosome hybride aN-CENP-A permet également le recrutement de H1, mais cela conduit également à la délocalisation d’un certain nombre de protéines du kinétochore. Ce kinétochore ne permet pas une ségrégation correcte des chromosomes et il conduit à des phases de mitose et de cytokinèse défectueuses. L’ensemble de ces données montre que la conservation au cours de l’évolution de la flexibilité de l’ADN dans le nucléosome CENP-A est essentielle pour l’accomplissement de la division cellulaire. / CENP-A is a histone variant, which replaces histone H3 at centromeres and confers unique properties to centromeric chromatin. The crystal structure and MNase digestion of CENP-A nucleosome suggests flexible nucleosomal DNA ends but their dynamics in solution remains elusive and their implication in centromere function is unknown. Using electron cryo-microscopy we determined the dynamic solution properties of the CENP-A nucleosome. Our biochemical, proteomic and genetic data reveal that the high flexibility of the DNA ends impairs histone H1 binding to the CENP-A nucleosome. Substituting the 2-turn aN-helix of CENP-A with the 3-turn N-helix of H3 results in particles able to bind histone H1. In vivo replacement of CENP-A nucleosomes with the same NH3-CENP-A hybrid nucleosomes leads to H1 recruitment, delocalization of kinetochore proteins and significant mitotic and cytokinesis defects. Put together, ourdata reveal that the evolutionarily conserved flexible ends of the CENP-A nucleosomes are essential to ensure the fidelity of the mitotic pathway.