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Characterization of Structural and Functional Flexibility in Herpesvirus Outer Tegument Proteins
No full textAbstract: Herpesviruses are large, enveloped, DNA viruses that infect nearly all vertebrates from fish to humans and cause diseases ranging from mild to fatal. They are morphologically complex and sandwiched between their genome-filled capsid and glycoprotein-studded envelope, herpesviruses feature a dynamic layer of viral proteins called the tegument. Tegument proteins play important structural roles in virion morphogenesis, but a detailed understanding of how these proteins operate is lacking. It is also becoming clear that many tegument proteins play regulatory roles in addition to their canonical functions in viral structure and assembly. Herpes simplex virus type 1 (HSV-1) UL11 is the smallest tegument protein. It is conserved among all herpesviruses and is found associated with cytoplasmic membranes through acyl modifications at its N-terminus. UL11 binds UL16, a tegument protein in HSV-1 that is also completely conserved. As UL16 binds capsids in the cytoplasm, the interaction between these two proteins is thought to form a physical link between the capsid and the envelope and play a structural role in secondary envelopment, the step of viral maturation and egress in which nucleocapsids gain their final envelope. In HSV-1, this interaction requires tegument protein UL21. UL21 is conserved among alphaherpesviruses and is found in the cytoplasm and nucleus in transfected and infected cells. With capsid-associated UL21, UL16 and UL11 bind glycoprotein E, forming an even more stable link between the capsid and the envelope. HSV-1 UL51 is another conserved tegument protein that is associated with membranes by lipid modification. It too is thought to play structural roles in virion morphogenesis through interactions with conserved tegument proteins UL7 and UL14 and glycoprotein E to affect secondary envelopment. In addition to these structural roles that are not completely understood, there is evidence that UL11, UL16, UL21, and UL51 also function independently of their complexes. To provide context for exploration of the multiple roles of these proteins, we have characterized them structurally and biochemically. In addition to determining the crystal structures of HSV-1 UL21 domains, which revealed novel protein folds, we have characterized each of these proteins as being conformationally flexible, which likely contributes to their multifunctionality. Current work focuses on carefully characterizing binding interactions, including two novel interactions with nucleic acids, and assessing their structural implications to better unravel the mechanisms of the many functions these proteins play during viral replication.Thesis (Ph.D.)--Tufts University, 2018.Submitted to the Dept. of Biochemistry.Advisor: Ekaterina Heldwein.Committee: Andrew Bohm, Michael Forgac, Claire Moore, and Thomas Schwartz.Keywords: Biochemistry, Biophysics, and Microbiology
Fishing for answers: Investigating Fibrodysplasia Ossificans Progressiva using a novel adult zebrafish model
No full textAbstract: Fibrodysplasia Ossificans Progressiva (FOP) is a rare, autosomal dominant genetic disorder in humans characterized by the gradual ossification of fibrous tissues, including skeletal muscle, tendons, and ligaments. In humans, activating mutations in the Type I BMP/TGFβ family member receptor, ACVR1, are associated with FOP. Zebrafish acvr1l, previously known as alk8, is the functional ortholog of human ACVR1. The objective of this work is to create and characterize the first adult zebrafish model for FOP, providing a useful tool to study the development and progression of FOP-like symptoms. Constitutively active mutations in zebrafish acvr1l cause early lethal defects. Therefore, to study roles for activating acvr1l mutations in adult zebrafish, gateway cloning was used to create a vector containing the hsp70l heat shock promoter driving the expression of mCherry-tagged constitutively active Acvr1l (Q204D). Constructs were injected into single cell stage BMP response element reporter (Bre:GFP) zebrafish to create stable Tg(Bre:GFP); Tg(hsp70l:acvr1l_Q204D-mCherry) lines. Beginning at 2 weeks post fertilization, developmentally staged transgenic animals were subjected to daily one-hour heat shock treatments (3 weeks to 12 months) to induce Acvr1lQ204D expression. Micro-CT was used on whole animals to confirm FOP-like skeletal defects. Acvr1lQ204D-expressing animals displayed HO formation, abnormal spinal curvature, vertebral fusions, and malformation of pelvic fins, as compared to heat shocked Tg(Bre:GFP) animals and non-heat shocked controls. Histological stains (Safranin O and Hall and Brunt's Quadruple Stain) were used to confirm the presence of cartilaginous proteoglycans and mineralized tissue formation in the HO lesions. As injury is a known trigger for HO development in human FOP patients, several injury models were tested on Acvr1lQ204D-expressing animals to induce the formation of reliable, replicable HO. Activin A injection, cardiotoxin injection, and caudal fin clip injuries were all developed. None of these methods resulted in HO formation at the site of injury. However, cardiotoxin injected and caudal fin clipped animals did develop HO at distant sties, including the body cavity and along the spine. In summary, these results suggest that heat-shocked Acvr1lQ204D-expressing adult zebrafish provide an informative model for human FOP, but further work is needed to identify an effective method for inducing reliable site-directed HO.Thesis (Ph.D.)--Tufts University, 2018.Submitted to the Dept. of Cell, Molecular & Developmental Biology.Advisor: Pamela Yelick.Committee: Leif Oxburgh, Clifford Rosen, Laura Liscum, and Aris Economides.Keywords: Biology, Molecular biology, and Genetics
The World Game, SMFA Senior Thesis Project, May 2018.
No full textI grew up in a colorful, lively, Jewish household. My parents came from a background of Eastern European Jewry and my childhood was filled with lyrical prayer and objects of both beauty and spiritual significance. My mother's parents always lived near us and I would spend hours with my grandmother, an artist, playing in her studio with broken bits of Italian ceramics, Chinese perfume bottles, and Czech puppets that she kept around for inspiration. As I grew into an artist myself, that attachment to illustrated objects grew as well. I was pulled to clay, metal, stone, and paint, all tangible mediums that contained elemental power and intrinsic history outside of what I did with them. My muses were artists who worked centuries before me; I was drawn to the raw power of creating by hand and the idea of being able to imbue every work with a part of myself. In my practice today, that obsession with craft meets with my attachment to history and to the memories gathered in my family space. I think about how living creatures set an example by collecting, hoarding, and utilizing the materials around them, and how these actions allow for the creation of a home. I see repeated patterns and organic colors everywhere, and I strive to include a color story in every piece I create. My work is a way to tell my own stories through objects of meaning and painted narratives that point simultaneously to my past and my future.Keywords: Majolica, low-fire glazing, terra cotta ceramics, naive folk art, illustrated history, handmade toys
Ohne Titel SMFA Senior Thesis Project May 2018.
No full textKeywords: painting, plaster, paper, color, form, sculpture, mixed media, paper pulp, pulp, installation
Notes on Raising You.
No full textRachel Shiloach explored expressive movement in performative, time-based, and two-dimensional media. Her main concerns, regarding her art, are how to reach the core of a subject, tell a story in an honest way, and save a touch of improvisation, imagination, and humor.Keywords: video, performance, choreography, director, disembodied voice, site specific, relationship, mother and child, growing up, movement, audience, narrative, sound, control, freedom
Then the Woman on the Brokeback Mountain.
No full textMa Chih Ching is an interdisciplinary artist who works with various media, including painting, drawing, sculpture, printmaking, papermaking and animation.Keywords: cuteness, found object, welding, painting, fine arts, installation, gaze, surveillance, privacy, asian, collage, pornography, friendship, people
Fear, Unsettled; Poe, Wilde, and Gothic Anxiety.
No full textThis work concerns itself with the establishment of the unsettling as a new affective critical category