Doctor of Philosophy

dissertationN-methyl-D-aspartate (NMDA) receptors are members of the ionotropic glutamate receptor family that have critical functions in neural plasticity as well as a number of nervous system pathologies. NMDA receptors have a great deal of diversity in the subtypes expressed in different regions of the nervous system throughout the course of development. A greater understanding of NMDA receptor functioning in the nervous system is therefore highly desirable to researchers and clinicians, but this understanding is limited by the current set of selective pharmacological tools. The goal of the work in this dissertation is to gain a greater understanding of how highly selective NMDA receptor antagonists can be developed from a distinct group of peptides derived from the venom of marine cone snails known as the Conantokins, natural products that block NMDA receptors in a subtype-selective manner. The work in this dissertation aims to further this objective through three separate approaches. In Chapter 2, a novel conantokin, Conantokin-Br, is functionally characterized, and structure-activity relationship studies are performed to identify sequence determinants of subtype selectivity. In Chapter 3, NMDA receptor NR2 subunit chimeras are generated and used to identify determinants of selectivity towards Conantokin-R and ConantokinRl-B on the glutamate binding subdomains of the NR2 subunits. In Chapter 4 the selective conantokin ConantokinRl-B is used to identify NR2B-containing NMDA receptor subtypes present in dissociated Ventral Respiratory Column cells. In Chapter 5, these results are summarized, and the overall significance of the work is described. It is hoped that the experiments performed in this work will one day lead to highly selective compounds that will further the frontiers of investigating the underlying functions and therapeutic potential of targeting NMDA receptors

Habits of Mind: Designing Courses for Student Success

Although content knowledge remains at the heart of college teaching and learning, forward-thinking instructors recognize that we must also provide 21st-century college students with transferable skills (sometimes called portable intellectual abilities) to prepare them for their futures (Vazquez, 2020; Ritchhart, 2015; Venezia & Jaeger, 2013; Hazard, 2012). To “grow their capacity as efficacious thinkers to navigate and thrive in the face of unprecedented change” (Costa et al., 2023), students must learn and improve important study skills and academic dispositions throughout their educational careers. If we do not focus on skills-building in college courses, students will not be prepared for the challenges that await them after they leave institutions of higher education. If students are not prepared for these postsecondary education challenges, then it is fair to say that college faculty have failed them

The Terebridae and teretoxins: Combining phylogeny and anatomy for concerted discovery of bioactive compounds

The Conoidea superfamily, comprised of cone snails, terebrids, and turrids, is an exceptionally promising group for the discovery of natural peptide toxins. The potential of conoidean toxins has been realized with the distribution of the first Conus (cone snail) drug, Prialt (ziconotide), an analgesic used to alleviate chronic pain in HIV and cancer patients. Cone snail toxins (conotoxins) are highly variable, a consequence of a high mutation rate associated to duplication events and positive selection. As Conus and terebrids diverged in the early Paleocene, the toxins from terebrids (teretoxins) may demonstrate highly divergent and unique functionalities. Recent analyses of the Terebridae, a largely distributed family with more than 300 described species, indicate they have evolutionary and pharmacological potential. Based on a three gene (COI, 12S and 16S) molecular phylogeny, including ~50 species from the West-Pacific, five main terebrid lineages were discriminated: two of these lineages independently lost their venom apparatus, and one venomous lineage was previously unknown. Knowing the phylogenetic relationships within the Terebridae aids in effectively targeting divergent lineages with novel peptide toxins. Preliminary results indicate that teretoxins are similar in structure and composition to conotoxins, suggesting teretoxins are an attractive line of research to discover and develop new therapeutics that target ion channels and receptors. Using conotoxins as a guideline, and innovative natural products discovery strategies, such as the Concerted Discovery Strategy, the potential of the Terebridae and their toxins are explored as a pioneering pharmacological resource

Characterization of the Conus bullatus genome and its venom-duct transcriptome

<p>Abstract</p> <p>Background</p> <p>The venomous marine gastropods, cone snails (genus <it>Conus</it>), inject prey with a lethal cocktail of conopeptides, small cysteine-rich peptides, each with a high affinity for its molecular target, generally an ion channel, receptor or transporter. Over the last decade, conopeptides have proven indispensable reagents for the study of vertebrate neurotransmission. <it>Conus bullatus </it>belongs to a clade of <it>Conus </it>species called <it>Textilia</it>, whose pharmacology is still poorly characterized. Thus the genomics analyses presented here provide the first step toward a better understanding the enigmatic <it>Textilia </it>clade.</p> <p>Results</p> <p>We have carried out a sequencing survey of the <it>Conus bullatus </it>genome and venom-duct transcriptome. We find that conopeptides are highly expressed within the venom-duct, and describe an <it>in silico </it>pipeline for their discovery and characterization using RNA-seq data. We have also carried out low-coverage shotgun sequencing of the genome, and have used these data to determine its size, genome-wide base composition, simple repeat, and mobile element densities.</p> <p>Conclusions</p> <p>Our results provide the first global view of venom-duct transcription in any cone snail. A notable feature of <it>Conus bullatus </it>venoms is the breadth of A-superfamily peptides expressed in the venom duct, which are unprecedented in their structural diversity. We also find SNP rates within conopeptides are higher compared to the remainder of <it>C. bullatus </it>transcriptome, consistent with the hypothesis that conopeptides are under diversifying selection.</p

The history of molded fiber packaging: a 20th century pulp story

Molded fiber packaging, which is also referred to as molded pulp packaging, has been around for a little over a hundred years now. From the first patent, dating from 1903, until approximately 25 years ago molded fiber packaging was a niche product used mainly for packing eggs. However, in the last two decades scientific understanding of the material properties and technology development improved the possibilities of application. Combined with an increased demand, due to a call for environmentally sound packaging materials, molded fiber has finally found a wider field of application.Industrial Design Engineerin

Packaging materials

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