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"Clarke, Michael"
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Clinical and Therapeutic Implications of Cancer Stem Cells
Cancers arise in tissues that can replicate and self-renew. Like normal tissues, cancers can replenish themselves, grow, and metastasize because of stem cells that are similar to normal stem cells but seem to respond less well to environmental stop signals in their niche. Therapy that targets cancer stem cells may be the next avenue of cancer treatment.
Journal Article
Achilles beside Gilgamesh : mortality and wisdom in early epic poetry
\"It is widely recognised that the epics of Homer are closely related to the earlier mythology and literature of the ancient Near East, above all the Babylonian Epic of Gilgamesh. But how should this influence our response to the meaning and message of either poem? This book addresses this question through an experiment in intertextual reading\"-- Provided by publisher.
Book
The 2019/2020 mega-fires exposed Australian ecosystems to an unprecedented extent of high-severity fire
Extreme fire seasons characterised by very large ‘mega-fires’ have demonstrably increased area burnt across forested regions globally. However, the effect of extreme fire seasons on fire severity, a measure of fire impacts on ecosystems, remains unclear. Very large wildfires burnt an unprecedented area of temperate forest, woodland and shrubland across south-eastern Australia in 2019/2020, providing an opportunity to examine the impact of extreme fires on fire severity patterns. We developed an atlas of wildfire severity across south-eastern Australia between 1988 and 2020 to test (a) whether the 2019/2020 fire season was more severe than previous fire seasons, and (b) if the proportion of high-severity fire within the burn extent (HSp) increases with wildfire size and annual area burnt. We demonstrate that the 2019/2020 wildfires in south-eastern Australia were generally greater in extent but not proportionally more severe than previous fires, owing to constant scaling between HSp and annual fire extent across the dominant dry-forest communities. However, HSp did increase with increasing annual fire extent across wet-forests and the less-common rainforest and woodland communities. The absolute area of high-severity fire in 2019/2020 (∼1.8 M ha) was larger than previously seen, accounting for ∼44% of the area burnt by high-severity fire over the past 33 years. Our results demonstrate that extreme fire seasons are a rare but defining feature of fire regimes across forested regions, owing to the disproportionate influence of mega-fires on area burnt.
Journal Article
Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV
Middle East respiratory syndrome coronavirus (MERS-CoV) is the causative agent of a severe respiratory disease associated with more than 2468 human infections and over 851 deaths in 27 countries since 2012. There are no approved treatments for MERS-CoV infection although a combination of lopinavir, ritonavir and interferon beta (LPV/RTV-IFNb) is currently being evaluated in humans in the Kingdom of Saudi Arabia. Here, we show that remdesivir (RDV) and IFNb have superior antiviral activity to LPV and RTV in vitro. In mice, both prophylactic and therapeutic RDV improve pulmonary function and reduce lung viral loads and severe lung pathology. In contrast, prophylactic LPV/RTV-IFNb slightly reduces viral loads without impacting other disease parameters. Therapeutic LPV/RTV-IFNb improves pulmonary function but does not reduce virus replication or severe lung pathology. Thus, we provide in vivo evidence of the potential for RDV to treat MERS-CoV infections.
Remdesivir (RDV) is a broad-spectrum antiviral drug with activity against MERS coronavirus, but in vivo efficacy has not been evaluated. Here, the authors show that RDV has superior anti-MERS activity in vitro and in vivo compared to combination therapy with lopinavir, ritonavir and interferon beta and reduces severe lung pathology.
Journal Article
Single-cell transcriptional diversity is a hallmark of developmental potential
Single-cell RNA sequencing (scRNA-seq) is a powerful approach for reconstructing cellular differentiation trajectories. However, inferring both the state and direction of differentiation is challenging. Here, we demonstrate a simple, yet robust, determinant of developmental potential—the number of expressed genes per cell—and leverage this measure of transcriptional diversity to develop a computational framework (CytoTRACE) for predicting differentiation states from scRNA-seq data. When applied to diverse tissue types and organisms, CytoTRACE outperformed previous methods and nearly 19,000 annotated gene sets for resolving 52 experimentally determined developmental trajectories. Additionally, it facilitated the identification of quiescent stem cells and revealed genes that contribute to breast tumorigenesis. This study thus establishes a key RNA-based feature of developmental potential and a platform for delineation of cellular hierarchies.
Journal Article
GS-5734 and its parent nucleoside analog inhibit Filo-, Pneumo-, and Paramyxoviruses
GS-5734 is a monophosphate prodrug of an adenosine nucleoside analog that showed therapeutic efficacy in a non-human primate model of Ebola virus infection. It has been administered under compassionate use to two Ebola patients, both of whom survived, and is currently in Phase 2 clinical development for treatment of Ebola virus disease. Here we report the antiviral activities of GS-5734 and the parent nucleoside analog across multiple virus families, providing evidence to support new indications for this compound against human viruses of significant public health concern.
Journal Article