Regulatory Architecture of Non-Apoptotic Cell Death Program in C. Elegans

Cell death is prevalent in animal development, homeostasis, and disease. While apoptotic cell death has been extensively studied, many dying cells in development do not exhibit apoptotic morphology, and mice lacking core apoptotic regulators have mostly normal rates of developmental programmed cell death. However, little is known about how alternative death programs are set in motion. In the nematode Caenorhabditis elegans, most cells fated to die by apoptosis are eliminated as young, undifferentiated cells, for no obvious functional reasons. The male nematode’s linker cell, in contrast, dies as an older, differentiated cell, whose life and death subserve precise and important functions. The linker cell first undertakes a long migration along a characteristic path, elongating the male gonad into its proper, mature shape. Once the gonad has attained its final shape and the linker cell has completed its migration, the linker cell then dies to connect the gonad to the environment and allow male fertility. Linker cell death is genetically and morphologically non-apoptotic. Instead, this death program requires the temporal regulator LIN-29, the SARM-like protein TIR-1, the mitogen-activated protein kinase kinase (MAPKK) SEK-1, and the glutamine-rich protein PQN-41. SARM and MAPKKs have been implicated in non-apoptotic degeneration of axon distal segments following axotomy, and some developmental and pathological cell death events in vertebrates resemble the morphology of the dying linker cell. Thus, the molecular mechanism governing linker cell death may be conserved; however, neither the initiating death signals nor the target/s of linker cell death regulators are known. Using classical genetics, I have investigated the initiating mechanisms of linker cell death. I have characterized the cell-autonomous involvement of a histone 3, lysine 4 methyltransferase complex centered on the Trithorax/MLL-like catalytic subunit SET-16. I then demonstrated that two opposing spatial cues, the Wnt ligands EGL-20 and LIN-44, cooperate with LIN-29 to control linker cell death initiation. I showed that the Abdominal- B-like Hox transcription factor NOB-1 likely acts upstream of these two Wnt pathways, and that the Tailless/Tlx nuclear hormone receptor NHR-67 acts in parallel to these regulators to promote linker cell death in addition to linker cell migration. Finally, I show that the Wnt pathways and all known linker cell death mediators require the heat shock factor HSF-1 for cell death. Importantly, HSF-1 function in linker cell death is distinct from, and competes with, its role in stress responses. My studies demonstrate that HSF-1, previously thought to be primarily protective, is a key downstream regulator of a nonapoptotic cell death program. I have also developed a method to isolate large numbers of linker cells from staged worms populations, to enable a comprehensive characterization of the transcriptional program driving linker cell death

28th Fungal Genetics Conference

Full abstracts from the 28th Fungal Genetics Conference Asilomar, March 17-22, 2015

On the developmental origins of human material culture

Material culture – tools, technology, and instrumental skills – has allowed humans to live in almost every habitat on earth. This thesis investigates the developmental roots of human material culture by examining basic tool-use skills and cultural learning abilities in young children. The introduction presents the concepts of the Zone of Latent Solutions (Tennie, Call, & Tomasello, 2009), cumulative culture, and Vygotsky’s (1978) theories as the theoretical background for the following five experiments. Chapter 2 identifies a list of tool-use behaviours that children can invent individually and thus represent an ontogenetic and phylogenetic basis of human tool culture. Chapter 3 extends this list by several behaviours involving the use of two tools in combination (Associative tool use). Chapter 4 focuses on a cultural behaviour that children can only acquire socially. It uses an adapted version of the spaghetti tower task (Caldwell & Millen, 2008a) to study whether children can copy a material cultural product that they could not have invented on their own and whether they can do so without action information. Chapter 5 uses the same task to investigate whether groups of children can produce a ratchet effect. The discussion summarizes the findings and presents limitations and directions for future research

The reaction against realism in contemporary American fiction: a study of the work of John Hawkes, John Barth and Thomas Pynchon

This thesis explores the reaction against realism in the work of three contemporary American novelists, John Barth, John Hawkes and Thomas Pynchon, with a view both to elucidating their individual literary styles and concerns, and to suggesting why these writers no longer consider realism a valid fictional mode. Chapter One defines realism as a product of a nineteenth century philosophical and scientific world-view; it traces the changes which have developed in twentieth century thinking from the work of Einstein and Freud, and suggests the different effects these have had on novelists. The chapter continues with a brief analysis of one work by each of four writers in fields other than literature, Herbert Marcuse, Norman 0. Brown, Theodore Roszak, and Alan Watts; the work of these writers can be seen to parallel the attempts of the three novelists to express in their fiction the possibility of alternative realities. Chapter Two examines the fiction of John Hawkes; it traces a development in his fiction from the overtly experimental early novels, to the apparently more straightforward later ones, exposing this apparent return to convention as an illusion, and suggesting that "reality" to John Hawkes has never been less important than in his most recent work, Travesty. The chapter locates Hawkes' central concerns as a novelist in his exploration of the unconscious and of the power of the human imagination. Chapter Three explores both the multi-referential and the playfully satiric nature of John Barth's fiction; it examines the development from The Sot-Weed Factor, which exposes the inadequacy of the realistic world-view when it is placed in a twentieth century context, to chimera, which celebrates the vitality and significance of fictions within life. Chapter Four is a discussion of the work of Thomas Pynchon, and provides the central focus of the thesis. It suggests that Pynchon's real achievement lies in his uncompromising rejection of the concept of a single, definable reality, of linear approaches to experience, of the inevitability of cause and effect, in other words, the underlying structures of realism, because he has created in their place a more complete alternative that recognizes the validity of multiple versions of reality. The conclusion puts forward the view that these writers share a loathing for the prescriptiveness of reality, and that their fiction becomes an act of rebellion against all the limitations imposed upon the human imagination and its freedom