Structural Polymorphism in Tau Filaments: An Implication for Neurodegenerative Diseases

Tau filaments are the pathological hallmark of >20 neurodegenerative diseases including Alzheimer's disease, Pick's disease, and progressive supranuclear palsy. In the adult human brain, six isoforms of tau are expressed that differ by presence or absence of the second of the four semiconserved repeats. As a consequence, half of the tau isoforms have three repeats (3R tau), whereas the other half has four repeats (4R tau). Site-directed spin labeling of recombinant tau in conjunction with electron paramagnetic resonance spectroscopy was used to obtain structural insights into tau filaments. The studies showed that the filaments of 4R tau and 3R tau share a highly ordered core structure in the third repeat with parallel, in-register arrangement of beta-strands. This structure in 3R and 4R is conserved regardless of whether full-length isoforms (htau40 and htau23) or truncated constructs (K18 and K19) are used. When mixed, 3R tau and 4R tau coassembled into heterogeneous filaments. Hence, these findings indicate that there are at least three compositionally distinct types of filaments: homogeneous 3R tau, homogeneous 4R tau, and heterogeneous 3R/4R tau. In vitro experiments show that the seeded filament growth, a prerequisite for tau spreading in tissue culture and brain, is crucially dependent on the isoform composition of individual seeds. Seeds of 3R tau and 3R/4R tau recruit both types of isoforms whereas seeds of 4R tau can recruit 4R tau, but not 3R tau, establishing an asymmetric barrier. Conformational templating of 4R tau onto 3R tau seeds eliminates this barrier, giving rise to a new type of tau filament. Conformational studies at the molecular level of tau filaments were done using Double electron-electron resonance spectroscopy, which allows the determination of distances between pairs of spin labels. These studies revealed structural differences between filaments of 3R tau and 4R tau. Furthermore, they indicated that 4R tau assumed the conformation of 3R tau when templated on 3R tau seeds. Our measurements have also provided insights into the heterogeneity of tau filament structure. Conformational differences due to variation in filament composition and seeding properties of tau filaments have shown that they are structurally polymorphic in nature. This structural polymorphism of tau filaments has widespread implications in understanding and treatment of neurodegenerative diseases.

Covered in Dust: Coming of Age in a Gazebo Factory

This memoir chronicles the three summers I spent working in the factories at Chestnut Hill Gazebos. It focuses on three narrative strands: the day-to-day life of a factory worker, the struggles within and eventual breakdown of my relationship with my girlfriend, and how my job at Chestnut Hill helped me critique my fundamentalist Christian roots by forcing me into a deeper understanding of my faith and its relationship to the world outside the confines of my upbringing. The critical afterword uses essays by Leona Toker and other theorists as a framework for understanding how I approached several different problems when writing my memoir, such as how to present incomplete memories of events, whether or not to condense events for the sake of a more streamlined narrative, and whether or not a memoirist should use composite characters. I explain how various practitioners and critics influenced my decisions, and I also compare my approach to the practices of other memoirists.

Citation Methodologies in Eusebius’ Historia ecclesiastica and Other Ancient Historiography

This dissertation examines ancient historiographic citation methodologies in light of Mikhail Bakhtin’s dichotomy between polyphony and monologization. In particular, this dissertation argues that Eusebius of Caesarea’s Historia ecclesiastica (HE) abandons the monologic citation methodology typical of previous Greek and Hellenistic historiography and introduces a polyphonic citation methodology that influences subsequent late-ancient Christian historiography to varying degrees. Whereas Pre-Eusebian Greek and Hellenistic historiographers typically use citations to support the single authorial consciousness of the historiographer, Eusebius uses citations to counterbalance his own shortcomings as a witness to past events. Eusebius allows his citations to retain their own voice, even when they conflict with his. The result is a narrative that transcends the point of view of any single individual and makes multiple witnesses, including the narrator, available to the reader. Post-Eusebian late-ancient Christian historiographers exhibit the influence of Eusebius’ innovation, but they are not as intentional as Eusebius in their use of citation methodologies. Many subsequent Christian historiographers use both monologic and polyphonic citation methodologies. Their tendency to follow Eusebius’ practice of citing numerous lengthy citations sometimes emphasizes points of view that oppose the author’s point of view. When an opposing viewpoint surfaces in enough citations, a polyphonic citation methodology emerges. The reader holds the two different narrative strands in tension as the author continues to give voice to opposing viewpoints. After illustrating the citation methodologies with passages from numerous Greek, Hellenistic, and late ancient Christian historiographers, this dissertation concludes with a short computational analysis that uses natural language processing to reveal some broad trends that highlight the previous findings and suggest a possibility for future research.