The isolation, purification, and clinical deployment of antibiotics is one of the major drivers of decrease in morbidity and mortality from infectious bacteria in the 20th century. The rapid, ubiquitous deployment of antibiotics encouraged swift development and distribution of antibiotic resistance. New, novel techniques, technologies, and ultimately therapeutic antimicrobial compounds will be required to counter the rise of antibiotic resistant microbes. Historically, mimicking naturally occurring compounds has been the most fruitful method for discovering new antibiotics; unsurprisingly, many recent efforts have focused on expanding the cultivation and detection of previously unknown microbes and compounds, respectively. Other techniques explore developing compounds de novo, reverse-engineering potential therapies from a detailed understanding of the biochemistry of pathogens. We describe a novel peptide screening tool in E. coli designed to be used for such an application. This platform, termed PepSeq, is capable of screening millions of peptides simultaneously by using Illumina sequencing technology. Additionally, we have explored several peptide scaffolds that have a conserved secondary structure with a large randomizable domain of several amino acids, which allows the screening for new and novel biochemical interactions with more stable structure than a simple linear peptide. Finally, we have developed a bioinformatics workflow that complements PepSeq that allows analysis of PepSeq data for peptide motifs of interest, vastly streamlining motif identification and verification.

The last one hundred years of American literature have witnessed the development of three elemental movements: naturalism, in the late nineteenth and early twentieth centuries, represented by such authors as Stephen Crane and Theodore Dreiser; nihilism, predominant in the 1920's and 1930's, represented best by Ernest Hemmingway; and the post-World War II literature which will be called literature of the quest, represented by such authors as Saul Bellow, William Styron, Philip Roth, John Updike, and others. The first chapter will show briefly the historical development of these three movements in American literature, their distinctive features, and their relationship to American moral and social values. Chapters Two through Four will analyze in detail the three distinctive aspects of this emerging literary form--the literature of the quest. The last chapter will focus on one novel, Letting Go, by Philip Roth, as an example of this literature.

The isolation, purification, and clinical deployment of antibiotics is one of the major drivers of decrease in morbidity and mortality from infectious bacteria in the 20th century. The rapid, ubiquitous deployment of antibiotics encouraged swift development and distribution of antibiotic resistance. New, novel techniques, technologies, and ultimately therapeutic antimicrobial compounds will be required to counter the rise of antibiotic resistant microbes. Historically, mimicking naturally occurring compounds has been the most fruitful method for discovering new antibiotics; unsurprisingly, many recent efforts have focused on expanding the cultivation and detection of previously unknown microbes and compounds, respectively. Other techniques explore developing compounds de novo, reverse-engineering potential therapies from a detailed understanding of the biochemistry of pathogens. We describe a novel peptide screening tool in E. coli designed to be used for such an application. This platform, termed PepSeq, is capable of screening millions of peptides simultaneously by using Illumina sequencing technology. Additionally, we have explored several peptide scaffolds that have a conserved secondary structure with a large randomizable domain of several amino acids, which allows the screening for new and novel biochemical interactions with more stable structure than a simple linear peptide. Finally, we have developed a bioinformatics workflow that complements PepSeq that allows analysis of PepSeq data for peptide motifs of interest, vastly streamlining motif identification and verification.

This study belongs to one of the categories of hermeneutical issues - the New Testament use of the Old Testament. The writer assumes that Luke uses Malachi’s motifs, especially “Malachi’s eschatological figures’ arrival” motif in Malachi 3 and 4. Malachi’s eschatological figures are the messenger of the Lord (Mal. 3:1)/Elijah (Mal. 4:5-6). Ha Adon is the messenger of the covenant (Mal. 3:1). The writer identifies Ha Adon with the messenger of the covenant. Ha Adon is the “One who comes in the name of the Lord” in Luke. The writer attempts to prove that Luke was greatly influenced by “Malachi’s eschatological arrival” motif. According to the writer’s view, the literary and thematic structure of the Gospel of Luke reflects Malachi’s motif: temple emphasis, the infancy narratives including John’s and Jesus’ births, and the beginnings of John’s and Jesus’ ministries. John’s preaching is reminiscent of Malachi’s oracle. The Lord’s messenger and Ha Adon/the messenger of the Lord are identified as John the Baptist and Jesus respectively, and their missions are fulfilled in Luke. John the Baptist is seen as Malachi’s eschatological Elijah in Luke. The prophecy of Ha Adon’s sudden coming to His temple is fulfilled in Jesus’ three visits to the temple in Luke. The Travel Narrative in Luke echoes “the Way of the Lord” idea in Malachi; “the Way of the Lord” motif has thematically a long history in the Old Testament. “The Way of the Lord” concept in Exodus and Isaiah is reused in Malachi, and is theologically expanded in its meaning in Luke. This study shows that Luke alludes to or reflects Malachi’s themes in addition to “Malachi’s eschatological figures’ arrival” motif. The Gospel of Luke can be seen in the perspective of “the Way of the Lord” motif: the preparation of the Lord’s Way (1:1- 4:13); the presentation of the Lord’s Way (4:14-19:46), and the perfection of the Lord’s Way (19:47-24:53). There are simple allusions to Malachi, and thematic and literary parallels between Malachi and Luke: for example--“the Day of the Lord” theme and “the sending of messengers” motif. “Malachi’s eschatological figures’ arrival” motif is clearly shown in Luke. / Thesis (PhD)--University of Pretoria, 2010. / New Testament Studies / unrestricted

The treatment and/or prevention of cancer by selective down regulation of cancer causing gene (oncogene) transcription would represent a significant advance in the area of anticancer drug design. Non-canonical higher order DNA structures formed in oncogene promoter regions are novel targets for the modulation of oncogene expression. An obvious advantage of selectively targeting oncogene expression would be that general cytotoxicity would be minimized and the negative side effects of current chemotherapy approaches could be minimized or eliminated. To provide a foundation for the design of drugs that target oncogene promoter G-quadruplexes and i-Motifs, the basic understanding is required of the folding of guanine and cytosine rich sequences and how small molecules bind to these structures. The research reported here focuses on higher order DNA structures of two oncogenes, K-ras that is overexpressed in pancreatic cancer, and Bcl-2 that is overexpressed in a number of cancers, and one non-oncogene, HAR1. We have probed the overall structure, stability, and binding of a model drug compounds to G-quadruplex and i-Motif DNA structures in these genes. The overall objectives of this work were: 1) to understand the relationship between oligonucleotide sequence and intramolecular folding topology and stability, and 2) to understand the mechanisms for the selective binding of small molecules to these structures. Biophysical techniques including: microcalorimetry, spectroscopy, analytical ultracentrifugation, gel electrophoresis, and computational methods were used to characterize both the folding and the binding interactions. We have shown that the native K-ras purine and pyrimidine rich sequences form stable G-quadruplexes and i-Motifs. We have also characterized four G-rich sequences found within the reading frame of the human HAR1 gene. This is the first report on the formation of stable G-quadruplex motifs within the RF of any gene. The model drug, TMPyP4, binds to the Bcl-2, K-ras, and HAR1 G-quadruplexes by two different binding modes, end binding and intercalation. The significance of this research is that the results of the K-ras and Bcl-2 studies could lead to the design of drugs that selectively target oncogenes while the HAR1 results could provide new approaches to the treatment of Schizophrenia and Alzheimer’s disease.

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Transcription factors (TFs) control gene expression by binding to highly specific DNA sequences in gene regulatory regions. This TF binding is central to control myriad biological processes. Indeed, transcriptional dysregulation has been associated with many diseases such as autoimmune diseases and cancer. In this thesis, I studied the transcriptional regulation of cytokines and gene transcriptional dysregulation in cancer. Cytokines are small proteins produced by immune cells that play a key role in the development of the immune system and response to pathogens and inflammation. I mined three decades of research and developed a user-friendly database, CytReg, containing 843 human and 647 mouse interactions between TFs and cytokines. I analyzed CytReg and integrated it with phenotypic and functional datasets to provide novel insights into the general principles that govern cytokine regulation. I also predicted novel cytokine promoter-TF interactions based on cytokine co-expression patterns and motif analysis, and studied the association of cytokine transcriptional dysregulation with disease. Transcriptional dysregulation can be caused by single nucleotide variants (SNVs) affecting TF binding sites (TFBS). Therefore, I created a database of altered TFBS (aTFBS-DB) by calculating the effect (gain/loss) of all possible SNVs across the human genome for 741 TFs. I showed how the probabilities to gain or disrupt TFBSs in regulatory regions differ between the major TF families, and that cis-eQTL SNVs are more likely to perturb TFBSs than common SNVs in the human population. To further study the effect of somatic SNVs in TFBS, I used the aTFBS-DB to develop TF-aware burden test (TFABT), a novel algorithm to predict cancer driver SNVs in gene promoters. I applied the TFABT to the Pan-Cancer Analysis of Whole Genomes (PCAWG) cohort and identified 2,555 candidate driver SNVs across 20 cancer types. Further, I characterized these cancer drivers using functional and biophysical assay data from three cancer cell lines, demonstrating that most SNVs alter transcriptional activity and differentially recruit cofactors. Taken together, these studies can be used as a blueprint to study transcriptional mechanisms in specific cellular processes (i.e. cytokine expression) and the effect of transcriptional dysregulation in disease (i.e. cancer).

My dissertation offers the first complete compilation of all known examples of the door motif in Roman Italy, from its initial appearance in the second century BCE, to its disappearance in the early fourth century CE. My research expands the corpus from 91 examples to 242 examples. The door motif can be defined as the fundamental rather than incidental rendering of a door found in various media in Roman art. In this project, I examine seven types of works with this motif: domestic decorations, urns, altars, cippi, loculus slabs, stelae, and sarcophagi. Particular attention is paid to the distribution of this extant material, their chronology, context, formal characteristics, and any unusual features related to the door motif’s appearance. In addition, this dissertation includes catalogue entries with the most up-to-date information on the location, date, findspot, descriptions, and images of every example of the door motif found on the Italian peninsula. Despite considerable earlier literature on the door motif, the subject has not been systematically investigated. In current and previous scholarship, the door motif is often mentioned but almost always in passing, and primarily in relation to its appearance in funerary contexts or occasionally in domestic wall paintings. The two most extensive publications on the door motif, now forty-five years old, are incomplete and focus largely on the door’s symbolic meaning. My dissertation compiles and updates this existing scholarship to present the only comprehensive catalogue of door motif examples in Roman Italy. In addition, by gathering this previously disparate material, I use the catalogued group of objects to open new discussions that focus specifically on the depiction of the door. These discussions include the door’s formal characteristics, context, and frequency of its appearance. In re-examining the door motif and its representation more closely, this dissertation also provides a foundation for future scholars to ask new questions about the image’s meaning. Altogether, the materials presented in this dissertation provide a new foundation for the examination of the popular door motif and a springboard for future scholarship.

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