<p> The <i>BRCA1</i> and <i>BRCA2</i> (<i>BRCA</i>) genes are two tumor suppressors that when mutated, predispose patients to breast and ovarian cancer. The <i>BRCA</i> genes encode proteins that mediate the repair of DNA double strand breaks. Functional loss of the <i> BRCA</i> genes is detrimental to the integrity of the genome because without access to functional <i>BRCA</i> protein, inefficient and error-prone repair pathways are used instead. These pathways, such as Non-homologous end joining, do not accurately repair the DNA, which can introduce mutations and genomic rearrangements. Ultimately the genome is not repaired faithfully and the predisposition to cancer greatly increases. In addition to their contribution to DNA repair, the <i>BRCA</i> genes have been shown to have transcriptional activity, and this functional role can also be a driving factor behind the tumor suppressor activity.</p><p> Robustness is the ability of a complex system to sustain viability despite perturbations to it. In the context of a complex disease such as cancer, robustness gives cancers the ability to sustain uncontrollable growth and invasiveness despite treatments such as chemotherapy that attempt to eliminate the tumor. A complex system is robust however can be fragile to perturbations that the system not optimized against. In cancers, these fragilities have the potential to be cancer specific targets that can eradicate the disease specifically. </p><p> Patients with mutations in <i>BRCA</i> tend to have breast and ovarian cancers that are difficult to treat; chemotherapy is the only option and no targeted therapies are available. Targeting the synthetic lethal interaction (SLI), a mechanism of robustness, between <i>BRCA</i> and <i>PARP1</i> genes was clinically effective in treating BRCA-mutated breast and ovarian cancers. This suggests that understanding robustness in cancers can reveal potential cancer specific therapies.</p><p> In this thesis, a computational approach was developed to identify candidate mechanisms of robustness in <i>BRCA</i>-mutated breast and ovarian cancers using the publicly accessible patient gene expression and mutation data from the Cancer Genome Atlas (TCGA). Results showed that in ovarian cancer patients with a <i>BRCA2</i> mutation, the expression of genes that function in the DNA damage response were kept at stable expression state compared to those patients without a mutation. The stable expression of genes in the DNA damage response may highlight a SLI gene network that is precisely controlled. This result is significant as disrupting this precision can potentially lead to cancer specific death. In breast cancers, genes that were differentially expressed in patients with <i>BRCA</i> mutations were identified. A Bayesian network was performed to infer candidate interactions between <i> BRCA1</i> and <i>BRCA2</i> and the differentially expressed <i> FLT3, HOXA11, HPGD, MLF1, NGFR, PLAT,</i> and <i>ZBTB16</i> genes. These genes function in processes important to cancer progression such as apoptosis and cell migration. The connection between these genes with BRCA may highlight how the BRCA genes influence cancer progression.</p><p> Taken together, the findings of this thesis enhance our understanding of the <i>BRCA</i> genes and their role in DNA damage response and transcriptional regulation in human breast and ovarian cancers. These results have been attained from systems-level models to identify candidate mechanisms underlying robustness of cancers. The work presented predicts interesting candidate genes that may have potential as drug targets or biomarkers in <i> BRCA</i>-mutated breast and ovarian cancers.</p><p>

<p> Cancer is a leading cause of morbidity and mortality, and one in three individuals in the U.S. will be diagnosed with cancer in their lifetime. At the molecular level, cancer is driven by the activity of oncogenes and the loss of activity of tumor suppressors. The availability of genomic data from large sets of tumor tissue have facilitated the identification of subgroups of patients whose tumors share molecular patterns of expression. These molecular signatures, in turn, can help identify clinically-useful patient subgroups and inform potential therapeutic strategies against cancer.</p><p> In chapter 1, I review the current theories behind carcinogenesis, the molecular factors that regulate gene expression, and statistical methods for analyzing genomic data. In chapter 2, I describe an approach, termed oncomix, developed to identify oncogene candidates from expression data obtained from tumor and adjacent normal tissue. I apply oncomix to breast cancer expression data and identify an oncogene candidate, <i>CBX2</i>, whose expression is gained in a subset of breast tumors. <i>CBX2</i> is expressed at low levels in most normal adult tissue, and the CBX2 protein contains a drug-targetable chromodomain, both of which are desirable properties in a potential therapeutic target. We then provide the first experimental evidence that <i>CBX2</i> regulates the growth of breast cancer cells. In chapter 3, I develop a method for identifying nuclear hormone receptors whose expression is lost in endometrial cancers relative to normal tissue. I report, for the first time, that the loss of expression of Thyroid Hormone Receptor Beta (<i>THRB</i>) is associated with better 5-year survival in endometrial cancer. The loss of <i>THRB</i> expression is independent of the loss of estrogen and progesterone receptor expression, two genes whose loss of expression is known to be associated with poor survival. <i> THRB</i> expression could be considered as a biomarker to risk-stratify endometrial cancer patients. In Chapter 4, I develop a user-friendly application for visualizing chromosomal copy number state obtained from three types of copy number input in single cells &ndash; fluorescence in situ hybridization (FISH), spectral karyotyping (SKY), and whole genome sequencing (WGS). This web application, termed aneuvis, automatically creates novel visualizations and summary statistics from a set of user-uploaded files that contain chromosomal copy number information.</p><p> In this thesis, I develop new computational approaches for identifying candidate molecular regulators of cancer. I also develop a new user-friendly tool to enable biological researchers to identify aneuploidy and chromosomal instability within populations of single cells. Applying these tools to breast and endometrial cancer genomic datasets has highlighted novel aspects of breast and endometrial cancer biology and may inform novel therapeutic strategies based on molecular patterns of genomic heterogeneity. The freely available software developed as part of these projects has the potential to enable other researchers to advance our understanding of cancer genomics and to inform novel therapeutic strategies against cancer.</p><p>

A taxonomic revision of Tatera (Rodentia: Gerbillinae) from tha study area of north-east Africa and Asia is undertaken. The results are discussed in terms of the zoogeography and evolutionary history of the genus Tatera. Five species of Tatera are recognized in north-east Africa; Tatera robusta. T. nlgricauda. T. valida, T.boehmi and T. phillipsi. T. philllpsi isreinstated from the synonymy of T. robusta. T. minuscula from Ethiopia is considered a taxon incertae sedis. A single species, T. indica. is present in Asia. The taxonomic study Is based on the statistical analysis of morphometrlc data, the evaluation of morphological characters and karyological data where available. Intraspecific variation, both non-geographlc and geographic is analysed. Species and their geographical races are defined and their distributions mapped. A matrix of diagnostic characters is included. The palaeontological literature of Tatera is reviewed. The faunal similarities, both present and past, of Africa and Asia are discussed, as are the major climatic and geophysical changes which are known to have occurred in the study area during the late Tertiary and Quaternary. The present day ecological requirements of the relevant Tatera taxa are also assessed. It is concluded that the genus Tatera probably evolved in Africa in the Pliocene and subsequently dispersed into Asia in the Pleistocene, possibly by way of a southern Red Sea landbridge. Evidence cited, includes the presence of fossil Tatera in the Middle Pliocene deposits of East Africa; the occurrence of Asiatic faunal elements in the fossil record of eastern Ethiopia; the presence of subsaharan African mammals in isolated localities in the south-west of peninsular Arabia; sea-bed cores supporting the view that the south of the Red Sea was periodically dry and the absence, to date, of fossil Tatera from palaeontological sites in North Africa and the Near East.

<p> Electrophysiological behaviors in cardiomyocytes, such as the action potential and calcium transient, are emergent properties arising from the interaction of an ensemble of ion channels, transporters, and pumps. In this Thesis, I integrate mathematical modeling with experiments to gain new insight into cardiac electrophysiology. Cardiomyocyte models are probed using population-based parameter sensitivity analysis to comprehensively generate quantitative predictions of how key behaviors are determined by the levels of ion channels, transporters, and pumps. Experimental tests ground these predictions in reality and provide opportunities for model improvement when predictions differ from experiments. In Chapter 2, this approach was applied to the determinants of calcium transient amplitude in rat cardiomyocytes. Experiments validated the unexpectedly large predicted effect of the transient outward potassium current on calcium transient amplitude in epicardial cardiomyocytes, but others demonstrated that the sarco/endoplasmic reticulum calcium ATPase had a much larger impact than predicted. Further exploration revealed that model calcium fluxes were inaccurately balanced, which we corrected to yield an improved model accurately reflecting our experiments and previous reports. In Chapter 3, the determinants of action potential duration in guinea pig cardiomyocytes predicted by parameter sensitivity analysis were tested using dynamic clamp, which found generally larger experimental effect sizes than predicted. We adjusted the model using a genetic algorithm to match our results, which led us to show that the overly stable model action potential resulted from higher levels of the slow delayed rectifier current than in our experiments. Subsequent analysis revealed how this current more effectively stabilizes the action potential than a related current, the rapid delayed rectifier. Finally, in Chapter 4 I take a global approach to model analysis, exploring competing models of the rabbit cardiomyocyte by comparing patterns of variability and correlations between behaviors across a population of models with randomly varied parameters. This found key experimentally testable differences between the models, representing a novel potential method for assessing how well these mathematical models represent the electrophysiological system of these cells. Overall, this work adds to our understanding of cardiac electrophysiology and represents a potential new paradigm for combining modeling and experiments to understand complex behaviors.</p><p>

<p> The Lesser Sunda Archipelago, also known as Nusa Tenggara, lies in the southeastern portion of Indonesia and extends between Bali in the west, and New Guinea in the east. While the Lesser Sundas themselves are oceanic islands that have never been land bridged to a continent the islands on either side do. Bali and the other Greater Sunda Islands of Java, Sumatra, and Borneo become periodically land bridged with Asia during glacial maxima forming the Sunda Shelf. New Guinea and Aru become periodically land bridged to Australia during glacial maxima and form the Sahul Shelf. Given their current orientation, the Lesser Sundas may act as &lsquo;stepping stones&rsquo; for animals and plants dispersing between the Sunda and Sahul Shelves and may act as a two-way filter for organisms dispersing between two of the world&rsquo;s great biogeographical realms. Alfred Russel Wallace&rsquo;s discovery of a pattern of clinal mixture of species from different biogeographical realms was a key insight leading to his identification of the Wallace Line and to his creation of the field of biogeography. Even though the Lesser Sundas played a critical role in the development of the field, this region has received little subsequent attention from historical biogeographers and our current understanding of Lesser Sunda biogeography has only modestly improved relative to what was known at the time of Wallace. The reptiles and amphibians of the Lesser Sundas represent a particularly interesting group of vertebrates from a biogeographical standpoint because they appear to show distributional patterns that are most consistent with a stepping-stone model of island colonization caused by the two-way filter zone. In Chapter 1, I review the geological and biogeographical literature for the Lesser Sundas and use these sources to formulate hypotheses concerning the colonization of the archipelago by rafting terrestrial vertebrates. In Chapters 2 through 4, I investigate the possibility that flying lizards, forest skinks, and fanged frogs have colonized the archipelago in a stepping-stone manner using a phylogenomic approach (using sequence data from mtDNA and hundreds of nuclear loci) whereby the relationships among island-specific lineages can be used to infer the sequence of island colonization. Flying lizards of the genus <i>Draco</i> form a monophyletic group that colonized the western Inner Arc islands of Lombok or Sumbawa from the Sunda Shelf around 10 million years ago when Lombok and Sumbawa first became land-positive. <i> Draco</i> continued expanding eastward through the Inner Arc until they reached Lembata, while a series of dispersal events from Flores south to Sumba, east to Timor, north to Wetar, west to Alor, and finally west to Pantar (the island immediately west of Lembata). The islands of Sumbawa and Flores contain multiple non-sister lineages that are parapatrically distributed and are exchanging migrants within an island. Forest Skinks of the genus <i> Sphenomorphus</i> show relatively little morphological divergence across their range yet exhibit large levels of genetic divergence. The oldest lineages of <i>Sphenomorphus</i> within the Lesser Sundas occur on the islands of Lombok and Flores and they expanded eastward through the Inner Arc until they reached Pantar. But rather than reaching Alor from neighboring Pantar, <i> Sphenomorphus</i> dispersed from Flores south to Sumba, then east to Timor, Alor, and Wetar. There are multiple non-sister lineages of <i> Sphenomorphus</i> on Lombok, Flores, and Sumba, and estimates of migration between lineages within each island suggest that these lineages are not interbreeding. Fanged frogs of the genus <i>Limnonectes</i> have colonized the Inner Arc of the Lesser Sundas from the Sunda Shelf. It is possible that <i> Limnonectes kadarsani</i> and <i>L. dammermani</i> diverged <i> in situ</i> on Lombok after which <i>L. kadarsani</i> dispersed east all the way to Lembata. But rather although a tree topology consistent with a stepping-stone pattern of island colonization is suggested by the mtDNA data, the phylogenomic results suggest a leap-frog pattern where Lembata is derived from West Flores, and these two lineages are closer related to Sumbawa than they are to Eastern Flores. The parapatrically distributed lineages on Flores are experiencing asymmetrical gene flow with successful migrants moving from west to east. In summary, the oldest islands of the western Inner Arc tend to harbor the most divergent lineages for all three focal taxa, a pattern expected from lineages originating from the Sunda Shelf. In <i>Draco </i> and <i>Sphenomorphus,</i> the islands of the eastern Inner Banda Arc are colonized by way of the &lsquo;Sumba Route&rsquo; where they disperse into the Outer Banda Arc island of Sumba and then move east to Timor, and finally north into the eastern Inner Arc. All three focal taxa show multiple non-sister lineages on some of the larger islands, suggesting either that multiple colonization events of a single island occurred, or possibly that formerly separated paleo-islands have since merged allowing for secondary contact of lineages that diverged in allopatry. These studies have shown that the biogeography of reptiles and amphibians within the Lesser Sundas is extremely complex. By examining biogeographical patterns across many co-distributed taxa these studies have the potential to provide insights into the geological history of the archipelago. From an evolutionary perspective, these studies highlight the presence of multiple independently evolving lineages within a currently described species occurring on the same island, which suggests that species diversity within reptiles and amphibians of the Lesser Sundas is underestimated.</p>

In this study, we reviewed the literature concerning the problem(s) of evil and found that, while there is a consensus that the logical problem of evil as raised by J. L. Mackie has been successfully addressed by Alvin Plantinga’s “Free Will Defense,” the evidential problem of evil as argued by William Rowe has yet to be resolved. The various solutions suggested by recognized scholars (e.g., John Hick and Richard Swinburne) have not met with broad acceptance. Most of the efforts to resolve the problem have been focused on Rowes’ factual premise (i.e., there are gratuitous evils). This approach has been fraught with difficulties and uncertainties as the determination of “gratuitousness” may be “beyond our ken.” Instead, this research aims to challenge Rowe’s theological premise (i.e., God prevents all gratuitous evils) by supplying a morally justifying reason (i.e., “tough-love) for God to exist in the presence of evil (gratuitous or otherwise). We also endeavor to stay within the bounds of Christian orthodoxy in affirming that God is omnipotent, omniscient, omnipresent, and the omnibenevolent creator of the universe. As Rowe insisted on keeping the discussion within the narrow confines of Restricted Standard Theism (i.e., an Omnigod creator without other religious claims), in the section for non-theists, we introduce a “Tough-love Proposal” that does not rely on biblical or religious literature. As humans deny God’s existence, God lets them go their own way (resulting in good and evil) and in “tough love,” waits patiently for them to respond to his message of salvation as proclaimed by the Church and the Holy Spirit. The evils in this world (gratuitous, excessive, horrendous . . .) are strictly the results of people living independently from God. Rowe’s argument that the presence of “gratuitous” evils makes God’s existence improbable is answered by the commonsense notion of “tough love” as often used in the restoration of broken relationships. The numerous requirements advocated by scholars for a “successful” theodicy are shown to be met by the “Tough-love Proposal,” using findings from other fields of knowledge (e.g., economics, psychology . . .). As God does not act in the same way toward believers and non-believers, in the section for theists, following the historical-grammatical method of hermeneutics (i.e., interpretation using lexical data, grammatical data, historical and cultural backgrounds, near and broader contexts), we apply Christian Scriptures and show that God promises that “all things work together for good to those who love God” (Romans 8:28), thus negating the possibility of gratuitous evils in (faithful) believers’ lives. The question raised by theists and non-theists concerning the creation of humans with “free will and no possibility of sinning” is answered by the “simplicity” of God, logically preventing him from creating a creature sharing the divine impeccability. Additionally, we propose some theories concerning the “world of death” (i.e., our world with the “survival of the fittest”) and the world of life (i.e., a new heaven and a new earth). In God’s sovereignty, we are free to choose the world/path that we desire. / Thesis (PhD)--University of Pretoria, 2020. / Church History and Church Policy / PhD / Unrestricted

My dissertation addresses two aspects of eukaryotic evolution, (1) the organization of eukaryotic diversity and (2) genomic variation in Foraminifera. The bulk of eukaryotic diversity is microbial with plants and animals representing just two of the estimated 75 lineages of eukaryotes. Among these microbial lineages, there are many examples of dynamic genome processes. Elucidating the origin and evolution of genome features requires a robust phylogenetic framework for eukaryotes. Taxon-rich molecular analyses provide a mechanism to test hypothesized evolutionary relationships and enable placement of diverse taxa on the tree of life. These analyses result in a well-resolved eukaryotic tree of life. Relaxed molecular clock analyses of this taxon-rich dataset place the origin on eukaryotes in the Paleoproterozoic, and suggest that all of the major lineages of eukaryotes diverged before the Neoproterozoic. This robust scaffold of the tree of eukaryotes is also used to elucidate common themes in genome evolution across eukaryotes. Mapping dynamic genome features onto this tree demonstrates that they are widespread in eukaryotes, and suggests that a common mechanism underlies genome plasticity. Foraminifera, a diverse lineage of marine amoebae, provide a good model system for investigating genome dynamics because they amplify portions of their genome and go through ploidy cycles during their life cycle. Assessment of nuclear dynamics in one species of Foraminifera, Allogromia laticollaris strain CSH, reveals that genome content varies according the life cycle stage and food source, which may differentially impact organismal fitness. The inclusion of diverse microbial eukaryotes enables better resolution of eukaryotic relationships and improves our understanding the dynamic nature of eukaryotic genomes.

The pine-needle scale insects; Chionaspis pinifoliae and C. heterophyllae are armored scale insects (Hemiptera: Diaspididae) with extensive native ranges throughout North America. In particular, C. pinifoliae is found on almost every species in the genus Pinus. Both species are economically important pests on pines, and over a century of scientific literature has considered these as only two morphological species. The life history of scale insects suggests they may form strongly structured metapopulations, resulting in high rates of host race formation and possibly speciation. Such newly originated species are likely to be morphologically similar. The geographic distribution and host use of these two species suggests they may represent a group of species that have gone unsampled due to their broad distribution or unrecognized due to their similar morphology. To explore the potential for species diversity in pine-needle scale insects I collected 366 individual insects from 320 localities across North America, representing 51 host species within the Pinaceae. I estimated species diversity by inferring species boundaries using genealogical concordance across allele genealogies of two nuclear loci and one mitochondrial locus. Using Maximum Likelihood allele genealogies in a majority-rule consensus to assess congruence, I conservatively detect 10 species in this group. However some of these 10 species contain morphological subgroups that conventional taxonomy would recognize as their own species. I explored alternate species delimitations using a range of species delimitation schemes based on genealogical concordance and mitochondrial divergence. I analyzed these delimitation schemes as species in a Bayesian species tree analysis, and infer that a delimitation of 26 species is the optimum scheme. This 26-species scheme also recognizes most of the aforementioned unique morphological subgroups, as species. Additionally, the genetic analyses for the above work occasionally recovered parasitoid sequences, from the 28S D2 and D3 subunits of ribosomal RNA. I included these sequences in a phylogeny of over 500 specimens from 18 of 19 families within the Chalcidoidea. I compared the phylogenetic results against a comprehensive list of parasitoids recorded from C. pinifoliae and C. heterophyllae, and find the 28s sequences indicate the parasitoid diversity utilizing these pine-feeding scale insects is much higher than previously thought.

Thesis (MTh)--Stellenbosch University, 2010. / ENGLISH ABSTRACT: In essence this thesis attempts to answer two questions: Broadly, what is “fundamentalism,” and particularly, “evangelical fundamentalism”? Ever since the terrorist attacks on the twin towers in New York on September 11, 2001, “fundamentalism” has become a synonymous term for these and any other militant Islamist attacks. Yet fundamentalism is historically an American and Protestant phenomenon. However, because fundamentalism is not merely a Protestant phenomenon but more distinctively a “sub-species” of nineteenth century evangelicalism in America, and because one cannot historically separate fundamentalism from evangelicalism, I prefer to adopt the term “evangelical fundamentalism.” Yet there is more to the term than simply defining it appropriately within a certain historical context. For example, many conservative evangelicals can neither be labeled, historically or theologically, as “fundamentalists” nor as “evangelical fundamentalists.” Definitions change over time. An understanding of the movement’s history—its resistance to modernity and engagement with postmodernity— will need to be examined as it opens up more questions concerning its identity and theology. After summarizing its historical development and evolution, I emphasize the fact that a simple definition does not exist—the movement is too heterogeneous. I therefore identify and adopt a plurality of senses or perspectives to the term and to what it means to be an “evangelical fundamentalist” today. / AFRIKAANSE OPSOMMING: In essensie poog hierdie tesis om twee vrae te beantwoord: Breedweg, wat is “fundamentalisme,” en in die besonder, “evangeliese fundamentalisme”? Sedert die terroriste-aanval op die tweelingtorings in New York op 11 September 2001, het “fundamentalisme” ‘n sinonieme term geword vir hierdie en soortgelyke militante Islamitiese aanvalle. Tog is fundamentalisme histories ‘n Amerikaanse en Protestantse fenomeen/verskynsel. Omdat fundamentalisme egter nie slegs ‘n protestantse fenomeen is nie, maar meer spesifiek ‘n “sub-spesie” van neëntiende eeuse evangeliekalisme of evangeliesgesindheid in Amerika, en omdat fundamentalisme en evangeliekalisme histories nie van mekaar geskei kan word nie, verkies ek om die term “evangeliese fundamentalisme” aan te neem. Daar is egter meer aan die term as om dit eenvoudig toepaslik binne ‘n sekere historiese konteks te definieer. Vele evangeliesgesindes kan byvoorbeeld nie histories of teologies as “fundamentaliste” of “evangeliese fundamentaliste” geëtiketeer word nie. Definisies verander met verloop van tyd. ‘n Begrip van die beweging se gekiedenis – sy weerstand teen modernisme en sy verbintenis met postmodernisme – sal ondersoek moet word aangesien dit meer vrae omtrent sy identiteit en teologie aan die lig bring. Na ‘n opsomming van sy historiese ontwikkeling en evolusie, belkemtoon ek die feit dat ‘n eenvoudige definisie nie bestaan nie – die beweging is te heterogeen. Ek identifiseer en verbind daarom ‘n pluraliteit/verskeidenheid van perspektiewe met die term of begrip van wat dit beteken om vandag ‘n “evangeliese fundamentalis” te wees.

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