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1. The Novel bis-1,2,4-Triazine MIPS-0004373 Demonstrates Rapid and Potent Activity against All Blood Stages of the Malaria Parasite.

Author

Ellis, Katherine, Lucantoni, Leonardo, Chavchich, Marina, Abraham, Matthew, De Paoli, Amanda, Luth, Madeline, Zeeman, Anne-Marie, Delves, Michael, Terán, Fernando, Straschil, Ursula, Baum, Jake, Kocken, Clemens, Ralph, Stuart, Winzeler, Elizabeth, Avery, Vicky, Edstein, Michael, Baell, Jonathan, and Creek, Darren

Subjects
Plasmodium, antimalarial, malaria, triazine, Animals, Malaria, Male, Parasites, Plasmodium berghei, Triazines
Abstract

Novel bis-1,2,4-triazine compounds with potent in vitro activity against Plasmodium falciparum parasites were recently identified. The bis-1,2,4-triazines represent a unique antimalarial pharmacophore and are proposed to act by a novel but as-yet-unknown mechanism of action. This study investigated the activity of the bis-1,2,4-triazine MIPS-0004373 across the mammalian life cycle stages of the parasite and profiled the kinetics of activity against blood and transmission stage parasites in vitro and in vivo. MIPS-0004373 demonstrated rapid and potent activity against P. falciparum, with excellent in vitro activity against all asexual blood stages. Prolonged in vitro drug exposure failed to generate stable resistance de novo, suggesting a low propensity for the emergence of resistance. Excellent activity was observed against sexually committed ring stage parasites, but activity against mature gametocytes was limited to inhibiting male gametogenesis. Assessment of liver stage activity demonstrated good activity in an in vitro P. berghei model but no activity against Plasmodium cynomolgi hypnozoites or liver schizonts. The bis-1,2,4-triazine MIPS-0004373 efficiently cleared an established P. berghei infection in vivo, with efficacy similar to that of artesunate and chloroquine and a recrudescence profile comparable to that of chloroquine. This study demonstrates the suitability of bis-1,2,4-triazines for further development toward a novel treatment for acute malaria.

Published
2021

5. Apicoplast-derived isoprenoids are essential for biosynthesis of GPI protein anchors, and consequently for egress and invasion in Plasmodium falciparum.

Author

Bulloch, Michaela S., Huynh, Long K., Kennedy, Kit, Ralton, Julie E., McConville, Malcolm J., and Ralph, Stuart A.

Subjects
GLYCOSYLPHOSPHATIDYLINOSITOL, ERYTHROCYTES, BIOLOGICAL membranes, PLASMODIUM falciparum, PLASMODIUM
Abstract

Glycophosphatidylinositol (GPI) anchors are the predominant glycoconjugate in Plasmodium parasites, enabling modified proteins to associate with biological membranes. GPI biosynthesis commences with donation of a mannose residue held by dolichol-phosphate at the endoplasmic reticulum membrane. In Plasmodium dolichols are derived from isoprenoid precursors synthesised in the Plasmodium apicoplast, a relict plastid organelle of prokaryotic origin. We found that treatment of Plasmodium parasites with apicoplast inhibitors decreases the synthesis of isoprenoid and GPI intermediates resulting in GPI-anchored proteins becoming untethered from their normal membrane association. Even when other isoprenoids were chemically rescued, GPI depletion led to an arrest in schizont stage parasites, which had defects in segmentation and egress. In those daughter parasites (merozoites) that did form, proteins that would normally be GPI-anchored were mislocalised, and when these merozoites were artificially released they were able to attach to but not invade new red blood cells. Our data provides further evidence for the importance of GPI biosynthesis during the asexual cycle of P. falciparum, and indicates that GPI biosynthesis, and by extension egress and invasion, is dependent on isoprenoids synthesised in the apicoplast. Author summary: The plastid apicoplast organelle of the malaria parasite Plasmodium falciparum has long been recognised as a drug target. However, the downstream metabolic pathways have not been fully elucidated. In this study we inhibited apicoplast function in blood-stage P. falciparum and, following the depletion of essential apicoplast-derived isoprenoids, we observed that levels of the polyisoprenoid alcohol, dolichol-phosphate, were also depleted. This led to a block in the synthesis of glycophosphatidylinositols (GPIs), which are abundant plasma membrane glycolipids and serve as membrane anchors for major surface proteins. Severe parasite impairments followed with incomplete membrane segmentation of their daughter merozoites, which could subsequently neither egress nor reinvade host red blood cells. Our data implicates dolichol as an essential parasite metabolite, dependent on normal apicoplast function, and reveals novel roles for GPI anchored proteins. The widespread phenotype following disrupted dolichol synthesis supports aspects of GPI biosynthesis as potential future drug targets. [ABSTRACT FROM AUTHOR]

Published
2024
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18. Evangelicalism, cultural influences and theological change : considered with special reference to the thought of Thomas Rawson Birks (1810-1883)

Author

Brown, Ralph Stuart and John Wolffe

Subjects
900, History
Abstract

This thesis presents a detailed analysis of the thought of the leading nineteenth century Anglican Evangelical theologian Thomas Rawson Birks (1810-1883). It is organised on a broadly chronological basis and discusses Birks's dogmatic and philosophical theology, sermons, and journalism. It also takes full account of his contributions to contemporary debates on social, political and scientific issues, considering them in relation to their cultural and ideological context. The study presents an assessment of the nature and importance of B irks's theological output. It also considers Birks's thought in relation to the changing character of nineteenth-century Evangelicalism itself and to the wider question of the relationship between cultural influences and theological change. The thesis will argue that B irks's distinctive interpretations of central Evangelical doctrines represented an original and important contribution to the Evangelical tradition. B irks's career also reflects some prominent ideological tendencies and concerns through which the religious character of the Evangelical movement as a whole can be better understood. Finally, this thesis aims to demonstrate that Birks's intellectual and scientific interests, philosophical outlook and religious sensibility reveal him to have been a representative product of mainstream Victorian culture.

Published
1996
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22. Safe Lab Design: A Call for Papers

Author

Mary Beth Mulcahy, Ralph Stuart, Melinda C. Box, Ellen Sweet, and Michael Labosky

Subjects
Chemical Health and Safety, General Chemistry
Published
2021

24. Teaching and Learning about Sustainability

Author

Irvin J. Levy, Catherine H. Middlecamp, Matthew A. Fisher, Catherine T. Hunt, Catherine H. Middlecamp, John 'Jack' R. Fowle, Ralph Stuart, Christopher J. Welch, John C. Warner, Satinder (Sut) Ahuja, Anastasia G. Ilgen, Louise J. Criscenti, Young-Shin Jun, Martial Taillefert, Sebastien Kerisit, R. Le and Irvin J. Levy, Catherine H. Middlecamp, Matthew A. Fisher, Catherine T. Hunt, Catherine H. Middlecamp, John 'Jack' R. Fowle, Ralph Stuart, Christopher J. Welch, John C. Warner, Satinder (Sut) Ahuja, Anastasia G. Ilgen, Louise J. Criscenti, Young-Shin Jun, Martial Taillefert, Sebastien Kerisit, R. Le

Published
2015

32. Chromosome-level genome of Schistosoma haematobium underpins genome-wide explorations of molecular variation

Author

Stroehlein, Andreas J., primary, Korhonen, Pasi K., additional, Lee, V. Vern, additional, Ralph, Stuart A., additional, Mentink-Kane, Margaret, additional, You, Hong, additional, McManus, Donald P., additional, Tchuenté, Louis-Albert Tchuem, additional, Stothard, J. Russell, additional, Kaur, Parwinder, additional, Dudchenko, Olga, additional, Aiden, Erez Lieberman, additional, Yang, Bicheng, additional, Yang, Huanming, additional, Emery, Aidan M., additional, Webster, Bonnie L., additional, Brindley, Paul J., additional, Rollinson, David, additional, Chang, Bill C. H., additional, Gasser, Robin B., additional, and Young, Neil D., additional

Published
2022
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33. Report on 2020 ACS Safety Summit: Opportunities in Chemical Safety Communication

Author

Seva Rostovtsev, Rachel Brian, Marta Gmurczyk, Kali A. Miller, Christopher McCarthy, Timothy Gallagher, Susan R. Morrissey, and Ralph Stuart

Subjects
geography, Engineering, Chemical Health and Safety, Summit, geography.geographical_feature_category, Chemical safety, business.industry, Social benefits, Engineering ethics, General Chemistry, Laboratory safety, business
Abstract

To optimize the technical, economic, and social benefits of the chemical enterprise, the practice of chemistry must consider and address best safety practices from concept through research, develop...

Published
2020

40. The United States and World Energy: A Discussion Paper, Department of State.

Author

Department of State, Washington, DC. and Smith, Ralph Stuart

Abstract

This publication is a summary of the world energy situation and its impact on the United States. A brief review of some interrelated diplomatic, commercial, and technical aspects of the energy crisis and their implications for the U.S. and its foreign policy is presented first. Next, discussions of world supplies, uses and problems with different fuels including fossil fuels, solar, wind, nuclear, and geothermal are given. The distinction is made between resources and reserves. Finally, a concluding discussion is given that indicates what direction U.S. foreign policy on energy should go. It is suggested that the U.S. should play a major role in bringing the world through the transitional period ahead. (MR)

Published
1977

46. A Community Approach to Academic Research Safety

Author

Ralph Stuart, Leah McEwen, and Samuella B. Sigmann

Subjects
business.industry, Paradigm shift, General Chemistry, Sociology, Safety culture, Community approach, Public relations, business
Abstract

Since 2012, stakeholders have advocated for the need to create a more positive academic research safety culture. Here, we make the case for supporting a paradigm shift from a rule-based culture to a risk-based one. The community structure should include common language, support teams, and education in safety science.

Published
2019

47. Bringing Safety to Chemistry for Life

Author

Ralph Stuart and Joseph M. Pickel

Subjects
Strategic planning, 0303 health sciences, geography, Chemical Health and Safety, Summit, geography.geographical_feature_category, 05 social sciences, 050301 education, 030311 toxicology, General Chemistry, Chemical society, Ethos, 03 medical and health sciences, Chemical safety, Political science, Engineering ethics, Chemistry (relationship), 0503 education
Abstract

In recent years, the chemistry enterprise as a whole has experienced a monumental shift in the way that it understands and approaches safety, both within society and as part of the science of chemistry. The American Chemical Society (ACS) has embraced this change and has committed to modelling it by incorporating “safety” into its core values. In early 2018, a Safety Summit involving stakeholders from across the chemistry enterprise was convened to consider strategies for “accelerating the adoption of an ethos of safety across the chemical enterprise”. The summit resulted in a better understanding of the factors influencing the implementation of safe chemical practices, programs in progress to effect change in this area, and gaps where additional effort is needed. Opportunities were identified where the ACS could make a meaningful impact on chemical safety and which aligned with the goals of the Society. In this paper, we will describe how the ACS strategic plan addresses the chemical safety challenges in relation to both historical influences and the current environment.

Published
2019

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