1998 Fine Art Graduation Exhibition Catalogue

Fine Art ProgramFanshawe College McIntosh GalleryUniversity of Western Ontario April 16th to May 3rd., 1998 Guest Speaker: Michael P. Gibson Director: Michael Gibson Galleryhttps://first.fanshawec.ca/famd_design_fineart_gradcatalogues/1009/thumbnail.jp

A Complete Electron Microscopy Volume of the Brain of Adult Drosophila melanogaster.

Drosophila melanogaster has a rich repertoire of innate and learned behaviors. Its 100,000-neuron brain is a large but tractable target for comprehensive neural circuit mapping. Only electron microscopy (EM) enables complete, unbiased mapping of synaptic connectivity; however, the fly brain is too large for conventional EM. We developed a custom high-throughput EM platform and imaged the entire brain of an adult female fly at synaptic resolution. To validate the dataset, we traced brain-spanning circuitry involving the mushroom body (MB), which has been extensively studied for its role in learning. All inputs to Kenyon cells (KCs), the intrinsic neurons of the MB, were mapped, revealing a previously unknown cell type, postsynaptic partners of KC dendrites, and unexpected clustering of olfactory projection neurons. These reconstructions show that this freely available EM volume supports mapping of brain-spanning circuits, which will significantly accelerate Drosophila neuroscience. VIDEO ABSTRACT

Honesty, Lemons, and Symbolic Signals

Under asymmetric information, dishonest sellers lead to market unraveling in the lemons model. An additional cost of dishonesty is that language becomes cheap talk. We develop instead a model where people derive utility from actions (what they say), as well as from outcomes, so talk is costly. We find that the existence of honest agents that mean what they say is not enough to make trade more likely, unless a traceability condition that prevents arbitrage is met. When we introduce a continuum of misrepresentation cost types and qualities, full market unraveling is not possible and babbling equilibria are eliminated. More generally, costly talk is a special kind of signal, a symbolic signal that presupposes linguistic conventions, otherwise truth and falsehood, as well as misrepresentation costs, are undefined

HGG-44. STRESSED TO DEATH: EGFRvIII EXPRESSION RENDERS GLIOBLASTOMA CELLS MORE SENSITIVE TO ER STRESS INDUCING CHEMOTHERAPEUTICS

Epidermal growth factor receptor (EGFR) is often overexpressed and/or mutated cancer. The most common mutation is EGFRvIII and has been found to correlate with tumor aggressiveness and poor outcome. In glioblastoma (GBM) expression of EGFRvIII is linked to cell-signaling pathways required for increased cell proliferation, cancer stem-cell self-renewal and tumor invasiveness. Although the mechanisms by which EGFRvIII confers increased tumorigenecity are not fully understood, recent evidence suggests that endoplasmic reticulum (ER) proteostasis plays a key role in tumor aggressiveness and resistance to therapy. Here we sought to determine the role of EGFRvIII expression on GBM ER stressed-induced cell death. U87 and U87 EGFRviii expressing cells were exposed to the following ER stress inducers: 2-deoxy-D-glucose (2-DG, 0.5mM), velcade (10nM), tunicamycin (0.05ug/ml) or withaferin A (WA, 1uM) and viability determined by MTS assay. EGFRvIII expressing cells were approximately 2-fold more sensitive to these ER stress inducers; viability of 2-DG, velcade, tunicamycin and WA treated U87 cells was 71.1 + 3.6%, 92.5 + 2.7%, 55.3 + 3.8% and 77.2 + 6%, respectfully, verses 24.5 + 1.1%, 46.8 + 3, 22.7 + 2.1% and 19.5%, respectfully in EGFRvIII expressing U87 cells. Western blot analysis demonstrated higher levels of ER stress markers, GRP78 and CHOP. Effective mediation of ER stress is necessary for cancer cells to maintain uncontrolled growth and enhanced protein production. However this dependence provides a target for treatment intervention. Our data suggests that patients whose tumors express EGFRvIII may benefit from ER stress inducing chemotherapies

Progress towards a representative network of Southern Ocean protected areas

Global threats to ocean biodiversity have generated a worldwide movement to take actions to improve conservation and management. Several international initiatives have recommended the adoption of marine protected areas (MPAs) in national and international waters. National governments and the Commission for the Conservation of Antarctic Marine Living Resources have successfully adopted multiple MPAs in the Southern Ocean despite the challenging nature of establishing MPAs in international waters. But are these MPAs representative of Southern Ocean biodiversity? Here we answer this question for both existing and proposed Antarctic MPAs, using benthic and pelagic regionalizations as a proxy for biodiversity. Currently about 11.98% of the Southern Ocean is protected in MPAs, with 4.61% being encompassed by no-take areas. While this is a relatively large proportion of protection when compared to other international waters, current Antarctic MPAs are not representative of the full range of benthic and pelagic ecoregions. Implementing additional protected areas, including those currently under negotiation, would encompass almost 22% of the Southern Ocean. It would also substantially improve representation with 17 benthic and pelagic ecoregions (out of 23 and 19, respectively) achieving at least 10% representation

Exploiting metabolic susceptibilities in glioblastoma via glycolytic inhibition and ketogenic therapy

e13558 Background: Glioblastoma (GBM) remains one of the most lethal primary brain tumors in children and adults. Despite enormous efforts to elucidate the genetic and epigenetic drivers of this disease, the prognosis for patients diagnosed with GBM remains dismal. Because tumor cell metabolism differs greatly from that of normal non-cancerous cells, it is possible to develop therapies which more effectively target the cancer cell while sparing normal cells. Growing in popularity is the ketogenic diet, which is a high fat, very low carbohydrate diet resulting in the production of ketone bodies, acetoacetate (AA) and β-hydroxybutyrate (βHB) to generate ATP. Methods: Analysis conducted by open-access GBM patient database, mts assay, Western blot, neurosphere assay, and TEM. Results: Enzymes required for ketone metabolism (BDH1 and OXCT1) were significantly downregulated in GBM while glycolytic enzymes were significantly upregulated (HK2, HK1, SLC2A3, NAMPT, G6PD). GBM stem cell (GSC) markers (CD44, STAT3) positively correlated with glycolytic enzymes. Ultrastructural analysis of GSCs indicated that about half of the mitochondria were missing cristae, highly suggestive of an increased glycolytic dependency. Treatment of patient-derived GSC lines as well as non-stem cell lines SJGBM2 (pediatric) and U87 (adult) resulted in a dose-dependent decrease in viability in response to the glycolytic inhibitor 2-deoxy-D-glucose (2-DG). When cells were exposed to ketone bodies, AA but not βHB induced a dose-dependent decrease in cell viability with 10 mM reducing viability ranging from 20-80% of non-treated controls. Western blot analysis demonstrated robust caspase activation and PARP cleavage in response to AA. Furthermore, AA significantly reduced GSC neurosphere formation at 2.5 mM suggesting inhibition of GSC self-renewal pathways. Combined treatment of low dose 2-DG (50 μM) with increasing concentrations of AA resulted in more cell death than either treatment. The effect was more than additive at the low concentrations of AA (1- 5 mM) suggesting synergy. Conclusions: Glycolytic inhibition in conjunction with the ketogenic diet may be a promising therapeutic route for this difficult-to-treat cancer

Novel Curcumin Inspired Bis-Chalcone Promotes Endoplasmic Reticulum Stress and Glioblastoma Neurosphere Cell Death

Glioblastoma (GBM) has a dismal prognosis and successful elimination of GBM stem cells (GSCs) is a high-priority as these cells are responsible for tumor regrowth following therapy and ultimately patient relapse. Natural products and their derivatives continue to be a source for the development of effective anticancer drugs and have been shown to effectively target pathways necessary for cancer stem cell self-renewal and proliferation. We generated a series of curcumin inspired bis-chalcones and examined their effect in multiple patient-derived GSC lines. Of the 19 compounds synthesized, four analogs robustly induced GSC death in six separate GSC lines, with a half maximal inhibitory concentration (IC50) ranging from 2.7–5.8 μM and significantly reduced GSC neurosphere formation at sub-cytotoxic levels. Structural analysis indicated that the presence of a methoxy group at position 3 of the lateral phenylic appendages was important for activity. Pathway and drug connectivity analysis of gene expression changes in response to treatment with the most active bis-chalcone 4j (the 3,4,5 trimethoxy substituted analog) suggested that the mechanism of action was the induction of endoplasmic reticulum (ER) stress and unfolded protein response (UPR) mediated cell death. This was confirmed by Western blot analysis in which 4j induced robust increases in CHOP, p-jun and caspase 12. The UPR is believed to play a significant role in GBM pathogenesis and resistance to therapy and as such represents a promising therapeutic target