Structural insights into Clostridium perfringens delta toxin pore formation

Clostridium perfringens Delta toxin is one of the three hemolysin-like proteins produced by C. perfringens type C and possibly type B strains. One of the others, NetB, has been shown to be the major cause of Avian Nectrotic Enteritis, which following the reduction in use of antibiotics as growth promoters, has become an emerging disease of industrial poultry. Delta toxin itself is cytotoxic to the wide range of human and animal macrophages and platelets that present GM2 ganglioside on their membranes. It has sequence similarity with Staphylococcus aureus β-pore forming toxins and is expected to heptamerize and form pores in the lipid bilayer of host cell membranes. Nevertheless, its exact mode of action remains undetermined. Here we report the 2.4 Å crystal structure of monomeric Delta toxin. The superposition of this structure with the structure of the phospholipid-bound F component of S. aureus leucocidin (LukF) revealed that the glycerol molecules bound to Delta toxin and the phospholipids in LukF are accommodated in the same hydrophobic clefts, corresponding to where the toxin is expected to latch onto the membrane, though the binding sites show significant differences. From structure-based sequence alignment with the known structure of staphylococcal α-hemolysin, a model of the Delta toxin pore form has been built. Using electron microscopy, we have validated our model and characterized the Delta toxin pore on liposomes. These results highlight both similarities and differences in the mechanism of Delta toxin (and by extension NetB) cytotoxicity from that of the staphylococcal pore-forming toxins

Strengthening the role of community health workers in supporting the recovery of ill, undernourished children post hospital discharge: qualitative insights from key stakeholders in Bangladesh and Kenya

Background: Even when undernourished children in low- and middle-income countries are treated using World Health Organisation recommended guidelines, they remain at elevated risk of death following hospital discharge. The role of community health workers (CHWs) in supporting post-discharge recovery to improve outcomes has not been adequately explored. Methods: Qualitative research was conducted as part of the Childhood Acute Illnesses and Nutrition (CHAIN) Network in rural and urban Bangladesh and Kenya. Interviews were conducted with family members of a total of 64 acutely ill children admitted in four hospitals (two rural and two urban- across both contexts). Children included those with undernutrition, and interviews were repeated in family members’ homes over several months. Data collected from families were supplemented by observations in facilities and homes, key informant interviews with CHWs and policy makers in Bangladesh, and a review of relevant guidelines. Findings: Guidelines suggest that CHWs could play a role not only in initially referring undernourished children to hospital, but also in supporting recovery post-discharge. However, the specific mechanisms to link CHWs into hospital discharge and post-discharge support processes are not specified. Data suggest a range of access and communication challenges that community health workers (CHWs) could potentially contribute towards overcoming. However, few families we interviewed reported any therapeutic interactions with CHWs post-discharge, especially in Kenya. Although CHWs are generally available in communities, they face significant challenges in conducting their roles, including unmanageable workloads, few incentives, lack of equipment and supplies and inadequate support from supervisors and some community members. Conclusion/recommendations: There is need for context sensitive policy and guidance documents that include specific recommendations on post-discharge linkage or down-referral to support for vulnerable children. Consideration should be given to introducing and supporting a dedicated staff member (whether defined as a CHW or patient advocate) whose tasks and responsibilities include playing a linking role between family members and community-based post-discharge support services. These additional tasks should take into consideration the broader responsibilities of CHWs, and consider recognised challenges such as appropriate recognition, training and remuneration. Potential interventions need to be evaluated in carefully designed and conducted studies

Whose Sense of Place? A Political Ecology of Amenity Development

Using a political ecology framework, this chapter examines the ways in which sense of place and amenity migration contribute to alternative residential development, which relies on uneven use of conservation subdivision features in the American West. Using case studies from Central Oregon, this chapter demonstrates how senses of place and developer decision-making are tied to wider political economic changes. It highlights the roles that amenity migrants and developers, two groups that are sometimes identical, play in landscape transformations that simultaneously draw on a particular sense of place and commodify landscapes in new ways

Linking like with like: optimising connectivity between environmentally-similar habitats

Habitat fragmentation is one of the greatest threats to biodiversity. To minimise the effect of fragmentation on biodiversity, connectivity between otherwise isolated habitats should be promoted. However, the identification of linkages favouring connectivity is not trivial. Firstly, they compete with other land uses, so they need to be cost-efficient. Secondly, linkages for one species might be barriers for others, so they should effectively account for distinct mobility requirements. Thirdly, detailed information on the auto-ecology of most of the species is lacking, so linkages need being defined based on surrogates. In order to address these challenges we develop a framework that (a) identifies environmentally-similar habitats; (b) identifies environmental barriers (i.e., regions with a very distinct environment from the areas to be linked), and; (c) determines cost-efficient linkages between environmentally-similar habitats, free from environmental barriers. The assumption is that species with similar ecological requirements occupy the same environments, so environmental similarity provides a rationale for the identification of the areas that need to be linked. A variant of the classical minimum Steiner tree problem in graphs is used to address c). We present a heuristic for this problem that is capable of handling large datasets. To illustrate the framework we identify linkages between environmentally-similar protected areas in the Iberian Peninsula. The Natura 2000 network is used as a positive ‘attractor’ of links while the human footprint is used as ‘repellent’ of links.Wecompare the outcomes of our approach with cost-efficient networks linking protected areas that disregard the effect of environmental barriers. As expected, the latter achieved a smaller area covered with linkages, but with barriers that can significantly reduce the permeability of the landscape for the dispersal of some species

Citizen science: a new approach to advance ecology, education, and conservation

Citizen science has a long history in the ecological sciences and has made substantial contributions to science, education, and society. Developments in information technology during the last few decades have created new opportunities for citizen science to engage ever larger audiences of volunteers to help address some of ecology’s most pressing issues, such as global environmental change. Using online tools, volunteers can find projects that match their interests and learn the skills and protocols required to develop questions, collect data, submit data, and help process and analyze data online. Citizen science has become increasingly important for its ability to engage large numbers of volunteers to generate observations at scales or resolutions unattainable by individual researchers. As a coupled natural and human approach, citizen science can also help researchers access local knowledge and implement conservation projects that might be impossible otherwise. In Japan, however, the value of citizen science to science and society is still underappreciated. Here we present case studies of citizen science in Japan, the United States, and the United Kingdom, and describe how citizen science is used to tackle key questions in ecology and conservation, including spatial and macro-ecology, management of threatened and invasive species, and monitoring of biodiversity. We also discuss the importance of data quality, volunteer recruitment, program evaluation, and the integration of science and human systems in citizen science projects. Finally, we outline some of the primary challenges facing citizen science and its future.Dr. Janis L. Dickinson was the keynote speaker at the international symposium at the 61th annual meeting of the Ecological Society of Japan. We appreciate the Ministry of Education, Culture, Sports, Science and Technology in Japan for providing grant to Hiromi Kobori (25282044). Tatsuya Amano is financially supported by the European Commission’s Marie Curie International Incoming Fellowship Programme (PIIF-GA-2011- 303221). The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the funding agencies or the Department of the Interior or the US Government.This is the final version of the article. It was first available from Springer via http://dx.doi.org/10.1007/s11284-015-1314-

Understanding biomolecular motion, recognition, and allostery by use of conformational ensembles

We review the role conformational ensembles can play in the analysis of biomolecular dynamics, molecular recognition, and allostery. We introduce currently available methods for generating ensembles of biomolecules and illustrate their application with relevant examples from the literature. We show how, for binding, conformational ensembles provide a way of distinguishing the competing models of induced fit and conformational selection. For allostery we review the classic models and show how conformational ensembles can play a role in unravelling the intricate pathways of communication that enable allostery to occur. Finally, we discuss the limitations of conformational ensembles and highlight some potential applications for the future

Exploiting bacterial DNA gyrase as a drug target: current state and perspectives

DNA gyrase is a type II topoisomerase that can introduce negative supercoils into DNA at the expense of ATP hydrolysis. It is essential in all bacteria but absent from higher eukaryotes, making it an attractive target for antibacterials. The fluoroquinolones are examples of very successful gyrase-targeted drugs, but the rise in bacterial resistance to these agents means that we not only need to seek new compounds, but also new modes of inhibition of this enzyme. We review known gyrase-specific drugs and toxins and assess the prospects for developing new antibacterials targeted to this enzyme

Disruption of paired-associate learning in rat offspring perinatally exposed to dioxins

The prevalence of cognitive abnormalities in children has partly been ascribed to environmental chemical exposure. Appropriate animal models and tools for evaluating higher brain function are required to examine this problem. A recently developed behavioral test in which rats learn six unique flavor-location pairs in a test arena was used to evaluate paired-associate learning, a hallmark of the higher cognitive function that is essential to language learning in humans. Pregnant Long-Evans rats were dosed by gavage with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or 2,3,7,8-tetrabromodibenzo-p-dioxin (TBDD) at a dose of 0, 200, or 800 ng/kg (referred as Control, TCDD-200, TCDD-800, TBDD-200, or TBDD-800, hereafter) on gestational day 15, and the offspring was tested during adulthood. Paired-associate learning was found to be impaired in the TCDD-200 and TBDD-200 groups, but not in either group exposed to 800 ng/kg, the observations of which were ensured by non-cued trials. As for the emotional aspect, during habituation, the TCDD-200 and TBDD-200 groups showed significantly longer latencies to enter the test arena from a start box than the Control, TCDD-800, and TBDD-800 groups, suggesting that the TCDD-200 and TBDD-200 groups manifested anxiety-like behavior. Thus, both the chlorinated dioxin and its brominated congener affected higher brain function to a similar extent in a nearly identical manner. Use of the behavioral test that can evaluate paired-associate learning in rats demonstrated that in utero and lactational exposure to not only TCDD but also TBDD perturbed higher brain function in rat offspring in a nonmonotonic manner

Lawson criterion for ignition exceeded in an inertial fusion experiment

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion

Height and body-mass index trajectories of school-aged children and adolescents from 1985 to 2019 in 200 countries and territories: a pooled analysis of 2181 population-based studies with 65 million participants

Summary Background Comparable global data on health and nutrition of school-aged children and adolescents are scarce. We aimed to estimate age trajectories and time trends in mean height and mean body-mass index (BMI), which measures weight gain beyond what is expected from height gain, for school-aged children and adolescents. Methods For this pooled analysis, we used a database of cardiometabolic risk factors collated by the Non-Communicable Disease Risk Factor Collaboration. We applied a Bayesian hierarchical model to estimate trends from 1985 to 2019 in mean height and mean BMI in 1-year age groups for ages 5–19 years. The model allowed for non-linear changes over time in mean height and mean BMI and for non-linear changes with age of children and adolescents, including periods of rapid growth during adolescence. Findings We pooled data from 2181 population-based studies, with measurements of height and weight in 65 million participants in 200 countries and territories. In 2019, we estimated a difference of 20 cm or higher in mean height of 19-year-old adolescents between countries with the tallest populations (the Netherlands, Montenegro, Estonia, and Bosnia and Herzegovina for boys; and the Netherlands, Montenegro, Denmark, and Iceland for girls) and those with the shortest populations (Timor-Leste, Laos, Solomon Islands, and Papua New Guinea for boys; and Guatemala, Bangladesh, Nepal, and Timor-Leste for girls). In the same year, the difference between the highest mean BMI (in Pacific island countries, Kuwait, Bahrain, The Bahamas, Chile, the USA, and New Zealand for both boys and girls and in South Africa for girls) and lowest mean BMI (in India, Bangladesh, Timor-Leste, Ethiopia, and Chad for boys and girls; and in Japan and Romania for girls) was approximately 9–10 kg/m2. In some countries, children aged 5 years started with healthier height or BMI than the global median and, in some cases, as healthy as the best performing countries, but they became progressively less healthy compared with their comparators as they grew older by not growing as tall (eg, boys in Austria and Barbados, and girls in Belgium and Puerto Rico) or gaining too much weight for their height (eg, girls and boys in Kuwait, Bahrain, Fiji, Jamaica, and Mexico; and girls in South Africa and New Zealand). In other countries, growing children overtook the height of their comparators (eg, Latvia, Czech Republic, Morocco, and Iran) or curbed their weight gain (eg, Italy, France, and Croatia) in late childhood and adolescence. When changes in both height and BMI were considered, girls in South Korea, Vietnam, Saudi Arabia, Turkey, and some central Asian countries (eg, Armenia and Azerbaijan), and boys in central and western Europe (eg, Portugal, Denmark, Poland, and Montenegro) had the healthiest changes in anthropometric status over the past 3·5 decades because, compared with children and adolescents in other countries, they had a much larger gain in height than they did in BMI. The unhealthiest changes—gaining too little height, too much weight for their height compared with children in other countries, or both—occurred in many countries in sub-Saharan Africa, New Zealand, and the USA for boys and girls; in Malaysia and some Pacific island nations for boys; and in Mexico for girls. Interpretation The height and BMI trajectories over age and time of school-aged children and adolescents are highly variable across countries, which indicates heterogeneous nutritional quality and lifelong health advantages and risks