Locked Nucleic Acid Gapmers and Conjugates Potently Silence ADAM33, an Asthma-Associated Metalloprotease with Nuclear-Localized mRNA

Two mechanisms dominate the clinical pipeline for oligonucleotide-based gene silencing, namely, the antisense approach that recruits RNase H to cleave target RNA and the RNAi approach that recruits the RISC complex to cleave target RNA. Multiple chemical designs can be used to elicit each pathway. We compare the silencing of the asthma susceptibility gene ADAM33 in MRC-5 lung fibroblasts using four classes of gene silencing agents, two that use each mechanism: traditional duplex small interfering RNAs (siRNAs), single-stranded small interfering RNAs (ss-siRNAs), locked nucleic acid (LNA) gapmer antisense oligonucleotides (ASOs), and novel hexadecyloxypropyl conjugates of the ASOs. Of these designs, the gapmer ASOs emerged as lead compounds for silencing ADAM33 expression: several gapmer ASOs showed subnanomolar potency when transfected with cationic lipid and low micromolar potency with no toxicity when delivered gymnotically. The preferential susceptibility of ADAM33 mRNA to silencing by RNase H may be related to the high degree of nuclear retention observed for this mRNA. Dynamic light scattering data showed that the hexadecyloxypropyl ASO conjugates self-assemble into clusters. These conjugates showed reduced potency relative to unconjugated ASOs unless the lipophilic tail was conjugated to the ASO using a biocleavable linkage. Finally, based on the lead ASOs from (human) MRC-5 cells, we developed a series of homologous ASOs targeting mouse Adam33 with excellent activity. Our work confirms that ASO-based gene silencing of ADAM33 is a useful tool for asthma research and therapy

Paul V. Kroskrity (ed.): Telling Stories in the Face of Danger: Language Renewal in Native American Communities

Norman: University of oklahoma Press, 2012, 288 pp., 3 illustrations, 2 maps, $24.95 (paper)

Native sustainment: The North Fork Mono tribe's stories, history, and teaching of its land and water tenure in 1918 and 2009

This dissertation focuses on the North Fork Mono (or Nium) Tribe's historiography and oral narratives about its land and water tenure. I begin with a recounting of my recent experiences in elementary school curriculum development about Native Americans and the environment and a discussion of the clash in worldviews that this work brought to the surface. Then, by drawing on secondary sources, on archival research into federal land records and anthropologists' correspondence and field notes, on an analysis of the content and structure of traditional stories recorded by the anthropologist E. W. Gifford in 1918 (and of Gifford's publications), and on my participation in and observation of the 2009 California Tribal Water Summit, I describe the traditional Nium fire regime and the history of the Tribe's land and water tenure. My dissertation supports the Tribe's sovereignty and environmental jurisdiction; I focus on an investigation of how the Nium have expressed water tenure and rights in the watershed of the San Joaquin River and on how Nium stories operate as educational media. My literary and historical analysis shows how Nium narratives can drive ecological restoration and how these narratives sustain people, land, and water by articulating the connections among all these entities. In clarifying this sustainment—this persistent, reciprocal support and nourishment among Nium people, land, and water over time—for a broader audience, my objective is to contribute to other groups' capacities to sustain themselves and that which surrounds them—to accomplish the goal, in other words, of sustainability education

Paul V. Kroskrity (ed.): Telling Stories in the Face of Danger: Language Renewal in Native American Communities

Norman: University of oklahoma Press, 2012, 288 pp., 3 illustrations, 2 maps, $24.95 (paper)

Connecting the Stars: Chinese Star Stories and the Art of Storytelling through a Cultural and Personal Lens

This thesis explores the role of auto ethnography in researching and analyzing Chinese cosmology myths. Star stories are more than entertainment; they provide a visual means of recognizing and honoring cultural traditions from around the world. While Chinese myths told in America are disconnected from the original contexts from which they emerged, Chinese cosmologies are still connected through stars and constellations to the celestial part of their original setting. These star stories are largely unfamiliar to American audiences, including outdoor and experiential educators and cultural Chinese American groups, who will find it to be of interest. The material will also appeal to the various cultural entities and social mediated communities who engage in global interactions that influence one another in their intercultural exchanges. I use phenomenological data from this research to develop and enrich my personal storytelling style, reflecting on my heritage and examining my identity in the personal, cultural, and spiritual dimensions. I then perform the collected star lore tales at outdoor youth camps for under served youth and communities in California. In this way, I test oral storytelling as a means of engendering new learning about environmental sustainability. The results reveal meaningful ways that these stories and storytelling help participants cultivate awareness and caring for personal and cultural sustainable relationships with the environment and each other

Feedforward inhibition and inhibitory synaptic plasticity generate sparse, selective, and background-invariant representations of auditory stimuli in a spiking model of zebra finch caudomedial nidopallium

<p>Pattern decorrelation and the separation of signal from noise are defining aspects of several sensory circuits. In a recent study of the zebra finch auditory stream, Schneider and Woolley (2013) reported a population of higher-order auditory cortex cells—broad spiking units of the caudomedial nidopallium (NCM)—that responded to specific sets of zebra finch songs, exclusively when the songs were played at intensities that permitted behavioural recognition against background noise. Here we describe a spiking model of the broad-spiking NCM cells (and accompanying circuit) that accurately replicates the sparse firing rates, selectivity patterns, and signal-to-noise dependences observed in vivo. Using leaky integrate-and-fire neurons as outputs and the physiologically recorded primary auditory cortex trains from Schneider and Woolley (2013) as templates for input ensembles, we demonstrate that the implementation of inhibitory synaptic plasticity in a feedforward inhibitory module with a dynamic spiking threshold is sufficient to produce the selective, non-linear receptive fields necessary for cell-song specificity and behaviourally relevant firing patterns. Notably, the model recreates a linear increase in output firing rate as a function of the signal-to-noise ratio—but not of the input firing rate—in a manner that is consistent with both the biologically recorded NCM firing patterns and the behavioural variables relevant to signal extraction. We also describe preliminary evidence regarding multiple impinging signals (songs) and the embedding of these feedforward modules in larger networks with lateral connectivity.</p> <p> </p

The stories hold water: Learning and burning in North Fork Mono homelands

This essay describes aspects of an eco-cultural restoration program and closely associated educational initiatives and negotiations between the North Fork Mono Tribe and United States governmental agencies. We base our educational approach in Indigenous narrative and land-based experience. We seek not to explain land and water but to help guide students, policymakers, and other learners to come to understand land and water. We consider land, water, plants, and animals as narrators and as sources of knowledge – as primary historical sources, texts that narrate settler colonial and Indigenous history and the physical and cultural changes that colonialism has wrought. As we argue, approaches that combine narratives with visits to the land are key methods in land based education. In addition to describing the theoretical foundations of our curriculum, the essay provides accounts of obstacles presented to us by state education authorities and of successful negotiations to appropriately include tribal knowledge in updates to the California State Water Plan and in agreements with the U.S. Forest Service regarding tribal jurisdictio