Computational Design and Experimental Discovery of an Anti-estrogenic Peptide Derived from Alpha-Fetoprotein

Breast cancer is the most common cancer among women, and tamoxifen is the preferred drug for estrogen receptor-positive breast cancer treatment. Many of these cancers are intrinsically resistant to tamoxifen or acquire resistance during treatment. Consequently, there is an ongoing need for breast cancer drugs that have different molecular targets. Previous work has shown that 8-mer and cyclic 9-mer peptides inhibit breast cancer in mouse and rat models, interacting with an unsolved receptor, while peptides smaller than eight amino acids did not. We show that the use of replica exchange molecular dynamics predicts the structure and dynamics of active peptides, leading to the discovery of smaller peptides with full biological activity. Simulations identified smaller peptide analogues with the same conserved reverse turn demonstrated in the larger peptides. These analogues were synthesized and shown to inhibit estrogen-dependent cell growth in a mouse uterine growth assay, a test showing reliable correlation with human breast cancer inhibition.

Extensive clonal spread and extreme longevity in saw palmetto, a foundation clonal plant

The lack of effective tools have hampered our ability to assess the size, growth and ages of clonal plants. With Serenoa repens (saw palmetto) as a model, we introduce a novel analytical framework that integrates DNA fingerprinting and mathematical modelling to simulate growth and estimate ages of clonal plants. We also demonstrate the application of such life-history information of clonal plants to provide insight into management plans. Serenoa is an ecologically important foundation species in many Southeastern United States ecosystems; yet, many land managers consider Serenoa a troublesome invasive plant. Accordingly, management plans have been developed to reduce or eliminate Serenoa with little understanding of its life history. Using Amplified Fragment Length Polymorphisms, we genotyped 263 Serenoa and 134 Sabal etonia (a sympatric non-clonal palmetto) samples collected from a 20 X 20 m study plot in Florida scrub. Sabal samples were used to assign small field-unidentifiable palmettos to Serenoa or Sabal and also as a negative control for clone detection. We then mathematically modelled clonal networks to estimate genet ages. Our results suggest that Serenoa predominantly propagate via vegetative sprouts and 10000-year-old genets may be common, while showing no evidence of clone formation by Sabal. The results of this and our previous studies suggest that: (i) Serenoa has been part of scrub associations for thousands of years, (ii) Serenoa invasion are unlikely and (ii) once Serenoa is eliminated from local communities, its restoration will be difficult. Reevaluation of the current management tools and plans is an urgent task.

Extensive clonal spread and extreme longevity in saw palmetto, a foundation clonal plant

The lack of effective tools has hampered our ability to assess the size, growth and ages of clonal plants. With Serenoa repens (saw palmetto) as a model, we introduce a novel analytical frame work that integrates DNA fingerprinting and mathematical modelling to simulate growth and estimate ages of clonal plants. We also demonstrate the application of such life-history information of clonal plants to provide insight into management plans. Serenoa is an ecologically important foundation species in many Southeastern United States ecosystems; yet, many land managers consider Serenoa a troublesome invasive plant. Accordingly, management plans have been developed to reduce or eliminate Serenoa with little understanding of its life history. Using Amplified Fragment Length Polymorphisms, we genotyped 263 Serenoa and 134 Sabal etonia (a sympatric non-clonal palmetto) samples collected from a 20 x 20 m study plot in Florida scrub. Sabal samples were used to assign small field-unidentifiable palmettos to Serenoa or Sabal and also as a negative control for clone detection. We then mathematically modelled clonal networks to estimate genet ages. Our results suggest that Serenoa predominantly propagate via vegetative sprouts and 10000-year-old genets maybe common, while showing no evidence of clone formation by Sabal. The results of this and our previous studies suggest that: (i) Serenoa has been part of scrub associations for thousands of years, (ii) Serenoa invasions are unlikely and (ii) once Serenoa is eliminated from local communities, its restoration will be difficult. Reevaluation of the current management tools and plans is an urgent task.

Harry Potter and the Theory of Things

This thesis investigates the boundaries between body and object in J.K. Rowling’s Harry Potter series, seven children’s literature novels published between 1997 and 2007. Lord Voldemort, Rowling’s villain, creates Horcruxes—objects that contain fragments of his soul—in order to ensure his immortality. As vessels for human soul, these objects rupture the boundaries between body and object and become “things.” Using contemporary thing theorists including John Plotz and materialists Jean Baudrillard and Walter Benjamin, I look at Voldemort’s Horcruxes as transgressive, liminal, unclassifiable entities in the first chapter. If objects can occupy the juncture between body and object, then bodies can as well. Dementors and Inferi, dark creatures that Rowling introduces throughout the series, live devoid of soul. Voldemort, too, becomes a thing as he splits his soul and creates Horcruxes. These soulless bodies are uncanny entities, provoking fear, revulsion, nausea, and the loss of language. In the second chapter, I use Sigmund Freud’s theorization of the uncanny as well as literary critic Kelly Hurley to investigate how Dementors, Inferi, and Voldemort exist as body-turned-object things at the juncture between life and death. As Voldemort increasingly invests his immaterial soul into material objects, he physically and spiritually degenerates, transforming from the young, handsome Tom Marvolo Riddle into the snake-like villain that murdered Harry’s parents and countless others. During his quest to find and destroy Voldemort’s Horcruxes, Harry encounters a different type of object, the Deathly Hallows. Although similarly accessing boundaries between body/object, life/death, and materiality/immateriality, the three Deathly Hallows do not transgress these boundaries. Through the Deathly Hallows, Rowling provides an alternative to thingification: objects that enable boundaries to fluctuate, but not breakdown. In the third chapter, I return to thing theorists, Baudrillard, and Benjamin to study how the Deathly Hallows resist thingification by not transgressing the boundaries between body and object.