Tolkien and the Classics (2019) edited by Roberto Arduini, Giampaolo Canzonieri and Claudio A. Testi

Book review, by Luke Shelton, of Tolkien and the Classics (2019), edited by Roberto Arduini, Giampaolo Canzonieri and Claudio A. Test

‘Small Hands Do Them Because They Must’: examining the reception of The Lord of the Rings among young readers

This project explores how the reception of J.R.R. Tolkien’s The Lord of the Rings by younger readers differs from the understanding of the novel preponed by scholarship. A questionnaire and two activities were used to assess the reception of thirty young readers. The data set created from these responses was then compared to the current understanding of Tolkien’s work among scholars, as determined by a lengthy literature review. While several of the traditional aspects of a thesis for an English PhD are maintained, the study also employs methods and analysis from other fields. In this way, the study is unique and, perhaps, groundbreaking in its approach to reception studies. The specific areas of investigation are young readers’ understanding of the genre, characters, and setting of The Lord of the Rings. By examining the ideas that young readers have about genre, this project provides commentary on the impulse critics have to confine texts to easily-defined categories. By analyzing young readers’ response to characterization, this project confronts the assumption that children have a simplistic reading of characters. Finally, by discussing young readers’ interpretation of setting, this project validates the environmental and ecological concerns of this young readership. The narrow aim of the project is to fill a gap in Tolkien reception studies by examining the response of readers younger than eighteen, and thereby improve understanding of J.R.R. Tolkien’s readership. The larger goal of the study is to confront and reexamine the assumptions of literary scholars and critics. This study demonstrates the disconnect between much of the scholarly conversations about fantasy literature and the lived experiences of young readers. It gives voice to a population that is underrepresented in scholarly conversations, and it supports the idea of more inclusive and diverse critical discussions

Tolkien and the Classics (2019) edited by Roberto Arduini, Giampaolo Canzonieri and Claudio A. Testi

Book review, by Luke Shelton, of Tolkien and the Classics (2019), edited by Roberto Arduini, Giampaolo Canzonieri and Claudio A. Test

The physiological, pharmacological and toxicological roles of Nrf2 in the kidney

Nrf2 is a transcription factor that, under conditions of chemical stress, is able to evade its cytosolic repression and translocate to the nucleus to initiate the transcription of a battery of cytoprotective genes, such as those involved in the detoxication of xenobiotics. Nrf2 has previously been shown to afford protection against chronic and acute renal injury, yet, relatively little is known about the mechanism by which Nrf2 affords this protection, and the extent of its transcriptional roles in the kidney. This thesis seeks to further our understanding of the physiological, pharmacological and toxicological roles of Nrf2 in the kidney. Using an iTRAQ-based proteomic approach to quantify protein expression levels in the kidneys of Nrf2+/+ and Nrf2-/- mice, acutely treated with vehicle or the potent Nrf2 inducer CDDO-Me (3 mg/kg), we demonstrated that 189 proteins were differentially expressed in the Nrf2-/- mouse kidney, compared to Nrf2+/+, and 42 proteins were differentially expressed in the CDDO-Me treated Nrf2+/+ mouse kidney, compared to vehicle. The key finding was that the kidneys of Nrf2-/- mice are deficient in proteins that mediate cellular redox balance, the metabolism of a range of xenobiotics, and the regulation of core metabolic processes, including energy metabolism and the synthesis and recycling of amino acids. Functional demonstration of a reduction in energy metabolism was demonstrated by assessing total NADPH and GSH, of which Nrf2-/- mouse kidneys had 35% and 30% less than their Nrf2+/+ counterparts, respectively. A single acute dose of CDDO-Me failed to augment the expression of proteins, other than Nqo1, that were shown to be regulated by Nrf2 at the basal level in the mouse kidney, however qPCR analysis of these kidneys revealed that CDDO-Me has an effect at the transcriptional level which has not fully translated within the timeframe of this study. In summary, we have provided evidence that Nrf2 regulates the expression of an array of proteins that contribute to cell defence and the maintenance of homeostasis in the kidney, supporting current interest in Nrf2 as a novel therapeutic target in a number of renal diseases. MicroRNAs are a recently discovered RNA-regulatory element that show promise in their use as biomarkers of physiological and pathological events. In order to provide insight into the microRNAs under Nrf2 control in the kidney, we performed an unbiased microRNA array analysis on kidney homogenates from Nrf2+/+ and Nrf2-/- mice, treated with vehicle or CDDO-Me, and then validated several promising microRNA candidates using targeted qPCR analysis. Of particular note are miR-466h-3p, the expression of which was significantly increased in the CDDO-Me treated Nrf2+/+ mouse kidney and decreased in the Nrf2-/- mouse kidney, compared to their respective controls, and miR-28c and 144, which were both significantly decreased in the CDDO-Me treated Nrf2+/+ mouse kidney, and increased in the Nrf2-/- mouse kidney. This novel analysis represents the first step in characterising the renal Nrf2 microRNA-ome, which could reveal novel mechanisms of Nrf2 function and markers of its activity that could translate to the clinic. Recent interest in the use of CDDO-Me as a therapeutic intervention for late-stage chronic kidney disease has culminated in a phase III clinical trial (BEACON), which was subsequently terminated due to unforeseen adverse cardiac events, of which the cause has yet to be identified. In order to determine whether the drive to produce more potent Nrf2 inducers has inadvertently led to the generation of inherently more toxic compounds, the relationship between potency towards Nrf2 and toxicity was evaluated for CDDO-Me and related triterpenoids, and other classes of Nrf2 inducer. Using a rat H4IIE-ARE8L luciferase reporter cell line to determine in vitro therapeutic indices, it was discovered that within the compounds tested an increase in potency toward Nrf2 of four magnitudes results was associated with an increase in toxicity of only two magnitudes, resulting in a relative increase in in vitro safety. This data indicates that it is possible to generate potent Nrf2-inducers that are not inherently toxic, and suggests that therapeutic targeting of Nrf2 continues to hold promise as a novel treatment for a range of diseases. In summary, by using a proteomic approach we have identified an array of renal Nrf2-regulated proteins that contribute to various cytoprotective and metabolic processes in the kidney, supporting current interest in the therapeutic targeting of Nrf2 as treatment for renal disease. Additionally, the microRNAs under Nrf2 regulation in the kidney have also been identified, and represent the first step in fully characterising the Nrf2 microRNA-ome. Finally, it was shown that the drive to produce more potent Nrf2 inducers has not led to the generation of inherently more toxic compounds; indeed an increase in potency is associated with a relative increase in in vitro safety, suggesting that the targeting of Nrf2 is still a promising therapeutic route. Overall, the work presented in this thesis has furthered our understanding of the physiological, pharmacological and toxicological roles of Nrf2 in the kidney

Chemical Tuning Enhances Both Potency Toward Nrf2 and In Vitro Therapeutic Index of Triterpenoids

The transcription factor Nrf2 protects against a number of experimental pathologies, and is a promising therapeutic target. The clinical investigation of a potent Nrf2-inducing agent, the triterpenoid (TP) bardoxolone methyl (BARD), was recently halted due to adverse cardiovascular events in chronic kidney disease patients, although the underlying mechanisms are yet to be resolved. The majority of small molecule Nrf2 inducers are electrophilic and trigger Nrf2 accumulation via the chemical modification of its redox-sensitive repressor Keap1. Therefore, it is pertinent to question whether the therapeutic targeting of Nrf2 could be hindered in many cases by the inherent reactivity of a small molecule inducer toward unintended cellular targets, a key mechanism of drug toxicity. Using H4IIE-ARE8L hepatoma cells, we have examined the relationship between (a) Nrf2 induction potency, (b) toxicity and (c) in vitro therapeutic index (ratio of b:a) for BARD and a number of other small molecule activators of Nrf2. We show that BARD exhibits the highest potency toward Nrf2 and the largest in vitro therapeutic index among compounds that have been investigated clinically (namely BARD, sulforaphane and dimethylfumarate). Through further examination of structurally related TPs, we demonstrate that an increase in potency toward Nrf2 is associated with a relatively smaller increase in toxicity, indicating that medicinal chemistry can be used to enhance the specificity of a compound as an inducer of Nrf2 signaling whilst simultaneously increasing its therapeutic index. These findings will inform the continuing design and development of drugs targeting Nrf

Augmented Reality in Astrophysics

Augmented Reality consists of merging live images with virtual layers of information. The rapid growth in the popularity of smartphones and tablets over recent years has provided a large base of potential users of Augmented Reality technology, and virtual layers of information can now be attached to a wide variety of physical objects. In this article, we explore the potential of Augmented Reality for astrophysical research with two distinct experiments: (1) Augmented Posters and (2) Augmented Articles. We demonstrate that the emerging technology of Augmented Reality can already be used and implemented without expert knowledge using currently available apps. Our experiments highlight the potential of Augmented Reality to improve the communication of scientific results in the field of astrophysics. We also present feedback gathered from the Australian astrophysics community that reveals evidence of some interest in this technology by astronomers who experimented with Augmented Posters. In addition, we discuss possible future trends for Augmented Reality applications in astrophysics, and explore the current limitations associated with the technology. This Augmented Article, the first of its kind, is designed to allow the reader to directly experiment with this technology.Comment: 15 pages, 11 figures. Accepted for publication in Ap&SS. The final publication will be available at link.springer.co

Chemical tuning enhances both potency toward Nrf2 and<em> in vitro</em> therapeutic index of triterpenoids

The transcription factor Nrf2 protects against a number of experimental pathologies, and is a promising therapeutic target. The clinical investigation of a potent Nrf2-inducing agent, the triterpenoid (TP) bardoxolone methyl (BARD), was recently halted due to adverse cardiovascular events in chronic kidney disease patients, although the underlying mechanisms are yet to be resolved. The majority of small molecule Nrf2 inducers are electrophilic and trigger Nrf2 accumulation via the chemical modification of its redox-sensitive repressor Keap1. Therefore, it is pertinent to question whether the therapeutic targeting of Nrf2 could be hindered in many cases by the inherent reactivity of a small molecule inducer toward unintended cellular targets, a key mechanism of drug toxicity. Using H4IIE-ARE8L hepatoma cells, we have examined the relationship between (a) Nrf2 induction potency, (b) toxicity and (c) in vitro therapeutic index (ratio of b:a) for BARD and a number of other small molecule activators of Nrf2. We show that BARD exhibits the highest potency toward Nrf2 and the largest in vitro therapeutic index among compounds that have been investigated clinically (namely BARD, sulforaphane and dimethylfumarate). Through further examination of structurally related TPs, we demonstrate that an increase in potency toward Nrf2 is associated with a relatively smaller increase in toxicity, indicating that medicinal chemistry can be used to enhance the specificity of a compound as an inducer of Nrf2 signaling whilst simultaneously increasing its therapeutic index. These findings will inform the continuing design and development of drugs targeting Nrf2.</p

Evaluation Findings: School and Workplace Strategies 2005-2007

This report is an evaluation developed to provide updates on the progress of the Missouri Foundation for Health’s Tobacco Prevention and Cessation Initiative (TPCI). The report provides an overview of the activities and outcomes regarding school and workplace strategies that occurred between 2005 and 2007.https://openscholarship.wustl.edu/cphss/1099/thumbnail.jp

One-way trip: Influenza virus' adaptation to gallinaceous poultry may limit its pandemic potential

We hypothesise that some influenza virus adaptations to poultry may explain why the barrier for human-to-human transmission is not easily overcome once the virus has crossed from wild birds to chickens. Since the cluster of human infections with H5N1 influenza in Hong Kong in 1997, chickens have been recognized as the major source of avian influenza virus infection in humans. Although often severe, these infections have been limited in their subsequent human-to-human transmission, and the feared H5N1 pandemic has not yet occurred. Here we examine virus adaptations selected for during replication in chickens and other gallinaceous poultry. These include altered receptor binding and increased pH of fusion of the haemagglutinin as well as stalk deletions of the neuraminidase protein. This knowledge could aid the delivery of vaccines and increase our ability to prioritize research efforts on those viruses from the diverse array of avian influenza viruses that have greatest human pandemic potential

Implementing microbicides in low-income countries.

The magnitude of the global human immunodeficiency virus (HIV) epidemic is determined by women from lower income countries, specifically sub-Saharan Africa. Microbicides offer women who are unable to negotiate safe sex practices a self-initiated HIV prevention method. Of note, is its potential to yield significant public health benefits even with relatively conservative efficacy, coverage and user adherence estimates, making microbicides an effective intervention to invest scarce healthcare resources. Existing healthcare delivery systems provide an excellent opportunity to identify women at highest risk for infection and to also provide an access point to initiate microbicide use. Innovative quality improvement approaches, which strengthen existing sexual reproductive health services and include HIV testing, and linkages to care and treatment services, provide an opportunity to lay the foundations for wide-scale provision of microbicides. The potential to enhance health outcomes in women and infants and potentially affect rates of new HIV infection may soon be realised