Translation inhibition by rocaglates activates a species-specific cell death program in the emerging fungal pathogen Candida auris

Fungal infections are a major contributor to infectious disease-related deaths worldwide. Recently, global emergence of the fungal pathogen Candida auris has caused considerable concern because most C. auris isolates are resistant to fluconazole, the most commonly administered antifungal, and some isolates are resistant to drugs from all three major antifungal classes. To identify novel agents with bioactivity against C. auris, we screened 2,454 compounds from a diversity-oriented synthesis collection. Of the five hits identified, most shared a common rocaglate core structure and displayed fungicidal activity against C. auris These rocaglate hits inhibited translation in C. auris but not in its pathogenic relative Candida albicans Species specificity was contingent on variation at a single amino acid residue in Tif1, a fungal member of the eukaryotic initiation factor 4A (eIF4A) family of translation initiation factors known to be targeted by rocaglates. Rocaglate-mediated inhibition of translation in C. auris activated a cell death program characterized by loss of mitochondrial membrane potential, increased caspase-like activity, and disrupted vacuolar homeostasis. In a rocaglate-sensitized C. albicans mutant engineered to express translation initiation factor 1 (Tif1) with the variant amino acid that we had identified in C. auris, translation was inhibited but no programmed cell death phenotypes were observed. This surprising finding suggests divergence between these related fungal pathogens in their pathways of cellular responses to translation inhibition. From a therapeutic perspective, the chemical biology that we have uncovered reveals species-specific vulnerability in C. auris and identifies a promising target for development of new, mechanistically distinct antifungals in the battle against this emerging pathogen. IMPORTANCE Emergence of the fungal pathogen Candida auris has ignited intrigue and alarm within the medical community and the public at large. This pathogen is unusually resistant to antifungals, threatening to overwhelm current management options. By screening a library of structurally diverse molecules, we found that C. auris is surprisingly sensitive to translation inhibition by a class of compounds known as rocaglates (also known as flavaglines). Despite the high level of conservation across fungi in their protein synthesis machinery, these compounds inhibited translation initiation and activated a cell death program in C. auris but not in its relative Candida albicans Our findings highlight a surprising divergence across the cell death programs operating in Candida species and underscore the need to understand the specific biology of a pathogen in attempting to develop more-effective treatments against it.Published versio

Bio-GO-SHIP: The Time is Right to Establish Global Repeat Sections of Ocean Biology

In this article, we present Bio-GO-SHIP, a new ocean observing program that will incorporate sustained and consistent global biological ocean observations into the Global Ocean Ship-based Hydrographic Investigations Program (GO-SHIP). The goal of Bio-GO-SHIP is to produce systematic and consistent biological observations during global ocean repeat hydrographic surveys, with a particular focus on the planktonic ecosystem. Ocean plankton are an essential component of the earth climate system, form the base of the oceanic food web and thereby play an important role in influencing food security and contributing to the Blue Economy. Despite its importance, ocean biology is largely under-sampled in time and space compared to physical and chemical properties. This lack of information hampers our ability to understand the role of plankton in regulating biogeochemical processes and fueling higher trophic levels, now and in future ocean conditions. Traditionally, many of the methods used to quantify biological and ecosystem essential ocean variables (EOVs), measures that provide valuable information on the ecosystem, have been expensive and labor- and time-intensive, limiting their large-scale deployment. In the last two decades, new technologies have been developed and matured, making it possible to greatly expand our biological ocean observing capacity. These technologies, including cell imaging, bio-optical sensors and \u27omic tools, can be combined to provide overlapping measurements of key biological and ecosystem EOVs. New developments in data management and open sharing can facilitate meaningful synthesis and integration with concurrent physical and chemical data. Here we outline how Bio-GO-SHIP leverages these technological advances to greatly expand our knowledge and understanding of the constituents and function of the global ocean plankton ecosystem

Bio-GO-SHIP: the time is right to establish global repeat sections of ocean biology

© The Author(s), 2022. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Clayton, S., Alexander, H., Graff, J. R., Poulton, N. J., Thompson, L. R., Benway, H., Boss, E., & Martiny, A. Bio-GO-SHIP: the time is right to establish global repeat sections of ocean biology. Frontiers in Marine Science, 8, (2022): 767443, https://doi.org/10.3389/fmars.2021.767443.In this article, we present Bio-GO-SHIP, a new ocean observing program that will incorporate sustained and consistent global biological ocean observations into the Global Ocean Ship-based Hydrographic Investigations Program (GO-SHIP). The goal of Bio-GO-SHIP is to produce systematic and consistent biological observations during global ocean repeat hydrographic surveys, with a particular focus on the planktonic ecosystem. Ocean plankton are an essential component of the earth climate system, form the base of the oceanic food web and thereby play an important role in influencing food security and contributing to the Blue Economy. Despite its importance, ocean biology is largely under-sampled in time and space compared to physical and chemical properties. This lack of information hampers our ability to understand the role of plankton in regulating biogeochemical processes and fueling higher trophic levels, now and in future ocean conditions. Traditionally, many of the methods used to quantify biological and ecosystem essential ocean variables (EOVs), measures that provide valuable information on the ecosystem, have been expensive and labor- and time-intensive, limiting their large-scale deployment. In the last two decades, new technologies have been developed and matured, making it possible to greatly expand our biological ocean observing capacity. These technologies, including cell imaging, bio-optical sensors and 'omic tools, can be combined to provide overlapping measurements of key biological and ecosystem EOVs. New developments in data management and open sharing can facilitate meaningful synthesis and integration with concurrent physical and chemical data. Here we outline how Bio-GO-SHIP leverages these technological advances to greatly expand our knowledge and understanding of the constituents and function of the global ocean plankton ecosystem.The Bio-GO-SHIP pilot program was funded under the National Oceanographic Partnership Program as an inter-agency partnership between NOAA and NASA, with the US Integrated Ocean Observing System and NOAA's Global Ocean Monitoring and Observing program (HA, SC, JG, AM, and NP). HA was supported by a WHOI Independent Research and Development award. AM was supported by funding from NSF OCE-1848576 and 1948842 and NASA 80NSSC21K1654. JG was funded by NASA from grants 80NSSC17K0568 and NNX15AAF30G. LT was supported by award NA06OAR4320264 06111039 to the Northern Gulf Institute by NOAA's Office of Oceanic and Atmospheric Research, U.S. Department of Commerce

\u27Physical Activity 4 Everyone\u27 school-based intervention to prevent decline in adolescent physical activity levels: 12 month (mid-intervention) report on a cluster randomised trial

Background: Adolescence is a recognised period of physical activity decline, particularly among low-income communities. We report the 12-month (midpoint) effects of a 2-year multicomponent physical activity intervention implemented in disadvantaged secondary schools. Methods: A cluster randomised trial was undertaken in 10 secondary schools located in disadvantaged areas in New South Wales, Australia. Students in Grade 7 were recruited, with follow-up in Grade 8. The intervention was guided by socioecological theory and included seven physical activity strategies, and six implementation adoption strategies. The primary outcome was mean minutes of moderate-to-vigorous physical activity (MVPA) per day assessed using Actigraph GT3X accelerometers. Outcome data were analysed using repeated measures linear mixed models. Results: At baseline, 1150 (93%) students participated in the data collection (mean age 12 years, 48% boys) and 1050 (79%) students participated at 12-month follow-up. By the 12-month follow-up, the six implementation adoption strategies had been used to support schools to deliver four of the seven physical activity elements. There was a significant group-by-time interaction for mean minutes of MVPA per day in favour of the intervention group (adjusted difference between groups at follow-up=3.85 min, 95% CI (0.79 to 6.91), p≤0.01), including significantly more vigorous physical activity (2.45 min, p≤0.01), equating to 27 min more MVPA per week. Summary: At 12-month follow-up, the intervention had reduced the decline in physical activity among adolescents from disadvantaged schools. The intervention may assist students to meet physical activity guidelines

Resistance to natural and synthetic gene drive systems

Scientists are rapidly developing synthetic gene drive elements intended for release into natural populations. These are intended to control or eradicate disease vectors and pests, or to spread useful traits through wild populations for disease control or conservation purposes. However, a crucial problem for gene drives is the evolution of resistance against them, preventing their spread. Understanding the mechanisms by which populations might evolve resistance is essential for engineering effective gene drive systems. This review summarizes our current knowledge of drive resistance in both natural and synthetic gene drives. We explore how insights from naturally occurring and synthetic drive systems can be integrated to improve the design of gene drives, better predict the outcome of releases and understand genomic conflict in general

Collaborative social-epidemiology: A co-analysis of the cultural and structural determinants of health for Aboriginal youth in Victorian schools

Social-epidemiology that excludes Aboriginal voices often fails to capture the full and complex social worlds of Aboriginal people. Using data from an existing co-designed Victorian government Adolescent Health and Wellbeing Survey (2008/9), we worked with Aboriginal organizations to identify data priorities, select measures, interpret data, and contextualize findings. Using this participatory co-analysis approach, we selected "cultural" and "structural" determinants identified by Aboriginal organizations as important and modelled these using principal component analysis. Resulting components were then modelled using logistic regression to investigate associations with "likely being well" (Kessler-10 score < 20) for 88 Aboriginal adolescents aged 11-17 years. Principal component analysis grouped 11 structural variables into four components and 11 cultural variables into three components. Of these, "grew up in Aboriginal family/community and connected" associated with significantly higher odds of "likely being well" (OR = 2.26 (1.01-5.06), p = 0.046). Conversely, "institutionally imposed family displacement" had significantly lower odds (OR = 0.49 (0.24-0.97), p = 0.040) and "negative police contact and poverty" non-significantly lower odds (OR = 0.53 (0.26-1.06), p = 0.073) for "likely being well". Using a co-analysis participatory approach, the voices of Aboriginal researchers and Aboriginal organizations were able to construct a social world that aligned with their ways of knowing, doing, and being. Findings highlighted institutionally imposed family displacement, policing, and poverty as social sites for health intervention and emphasized the importance of strong Aboriginal families for adolescents

Use of a handheld Doppler to measure brachial and femoral artery occlusion pressure

Objective: Measurement of arterial occlusion pressure (AOP) is essential to the safe and effective use of blood flow restriction during exercise. Use of a Doppler ultrasound (US) is the “gold standard” method to measure AOP. Validation of a handheld Doppler (HHDOP) device to measure AOP could make the measurement of AOP more accessible to practitioners in the field. The purpose of this study was to determine the accuracy of AOP measurements of the brachial and femoral arteries using an HHDOP.Methods: We simultaneously measured AOP using a “gold standard” US and a HHDOP in the dominant and non-dominant arms (15 males; 15 females) and legs (15 males; 15 females).Results: There were no differences in limb circumference or limb volume in the dominant and non-dominant arms and legs between males and females or between the dominant and non-dominant arms and legs of males and females. The differences between US and HHDOP measures of AOP in the dominant and non-dominant arms and legs were either not significant or small (&lt;10 mmHg) and of little practical importance. There were no sex differences in AOP measurements of the femoral artery (p &gt; 0.60). Bland–Altman analysis yielded an average bias (−0.65 mmHg; −2.93 mmHg) and reasonable limits of agreement (±5.56 mmHg; ±5.58 mmHg) between US and HHDOP measures of brachial and femoral artery AOP, respectively.Conclusion: HHDOP yielded acceptable measures of AOP of the brachial and femoral arteries and can be used to measure AOP by practitioners for the safe and effective use of blood flow restriction. Due to the potential differences in AOP between dominant and non-dominant limbs, AOP should be measured in each limb

The Physical Activity 4 Everyone Cluster Randomized Trial : 2-Year Outcomes of a School Physical Activity Intervention Among Adolescents

Acknowledgments The Physical Activity 4 Everyone intervention trial was funded by the New South Wales Ministry of Health through the New South Wales Health Promotion Demonstration Research Grants Scheme and conducted by Hunter New England Population Health (a unit of the Hunter New England Local Health District), in collaboration with the University of Newcastle and University of Wollongong. Infrastructure support was provided by Hunter Medical Research Institute. The research team acknowledges the importance of making research data publically available. Access to the accelerometer data from this study may be made available to external collaborators following the development of data transfer agreements. Further results arising from the study can be found at www.goodforkids.nsw.gov.au/high-schools/. No financial disclosures were reported by the authors of this paper.Peer reviewedPublisher PD