The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR.

Metabolism and ageing are intimately linked. Compared with ad libitum feeding, dietary restriction consistently extends lifespan and delays age-related diseases in evolutionarily diverse organisms. Similar conditions of nutrient limitation and genetic or pharmacological perturbations of nutrient or energy metabolism also have longevity benefits. Recently, several metabolites have been identified that modulate ageing; however, the molecular mechanisms underlying this are largely undefined. Here we show that α-ketoglutarate (α-KG), a tricarboxylic acid cycle intermediate, extends the lifespan of adult Caenorhabditis elegans. ATP synthase subunit ß is identified as a novel binding protein of α-KG using a small-molecule target identification strategy termed drug affinity responsive target stability (DARTS). The ATP synthase, also known as complex V of the mitochondrial electron transport chain, is the main cellular energy-generating machinery and is highly conserved throughout evolution. Although complete loss of mitochondrial function is detrimental, partial suppression of the electron transport chain has been shown to extend C. elegans lifespan. We show that α-KG inhibits ATP synthase and, similar to ATP synthase knockdown, inhibition by α-KG leads to reduced ATP content, decreased oxygen consumption, and increased autophagy in both C. elegans and mammalian cells. We provide evidence that the lifespan increase by α-KG requires ATP synthase subunit ß and is dependent on target of rapamycin (TOR) downstream. Endogenous α-KG levels are increased on starvation and α-KG does not extend the lifespan of dietary-restricted animals, indicating that α-KG is a key metabolite that mediates longevity by dietary restriction. Our analyses uncover new molecular links between a common metabolite, a universal cellular energy generator and dietary restriction in the regulation of organismal lifespan, thus suggesting new strategies for the prevention and treatment of ageing and age-related diseases.

Economic Assessment of Reverse Algorithm Syphilis Screening in a High Prevalence Population.

BACKGROUND: More laboratories are screening for syphilis with automated treponemal immunoassays. We compared direct costs and downstream consequences when a local public health laboratory switches from a traditional algorithm (nontreponemal screening) to a reverse algorithm (treponemal screening). METHODS: We created a decision analysis model based on laboratory and surveillance data to estimate the cost-effectiveness of a reverse syphilis-screening algorithm from the perspectives of the Los Angeles County Public Health Laboratory and the Los Angeles County Department of Public Health (laboratory + STD Program costs) in 2015 US dollars. RESULTS: The estimated total costs for the Department (Public Health Laboratories) were $2,153,225 ($367,119) for the traditional algorithm and $2,197,478 ($239,855) for the reverse algorithm. Reverse algorithm screening was estimated to detect an additional 626 cases of syphilis, 9.7% more than the traditional algorithm. The incremental cost-effectiveness ratio for the reverse algorithm from the Public Health Department's perspective was $39 per additional syphilis case detected. Cost of follow-up, screening test costs, positivity rates, and frequency of repeat infections most affected the cost-effectiveness of reverse algorithm. Costs were significantly higher for the reverse algorithm when the enzyme Immunoassay/chemiluminescence immunoassay screening test cost was the same as the published Centers for Medicaid Services treponemal test cost. CONCLUSIONS: Using the reverse algorithm would have been slightly more expensive for the Los Angeles County Department of Public Health, but would have identified more syphilis cases and would have resulted in lower laboratory costs.

Impacts of Urban Water Conservation Strategies on Energy, Greenhouse Gas Emissions, and Health: Southern California as a Case Study.

OBJECTIVES: To determine how urban water conservation strategies in California cities can affect water and energy conservation efforts, reduce greenhouse gas emissions, and benefit public health. METHODS: We expanded upon our 2014 health impact assessment of California's urban water conservation strategies by comparing the status quo to 2 options with the greatest potential impact on the interrelated issues of water and energy in California: (1) banning landscape irrigation and (2) expanding alternative water sources (e.g., desalination, recycled water). RESULTS: Among the water conservation strategies evaluated, expanded use of recycled water stood out as the water conservation strategy with potential to reduce water use, energy use, and greenhouse gas emissions, with relatively small negative impacts for the public's health. CONCLUSIONS: Although the suitability of recycled water for urban uses depends on local climate, geography, current infrastructure, and finances, analyses similar to that presented here can help guide water policy decisions in cities across the globe facing challenges of supplying clean, sustainable water to urban populations.

Considerations of Environmentally Relevant Test Conditions for Improved Evaluation of Ecological Hazards of Engineered Nanomaterials.

Engineered nanomaterials (ENMs) are increasingly entering the environment with uncertain consequences including potential ecological effects. Various research communities view differently whether ecotoxicological testing of ENMs should be conducted using environmentally relevant concentrations-where observing outcomes is difficult-versus higher ENM doses, where responses are observable. What exposure conditions are typically used in assessing ENM hazards to populations? What conditions are used to test ecosystem-scale hazards? What is known regarding actual ENMs in the environment, via measurements or modeling simulations? How should exposure conditions, ENM transformation, dose, and body burden be used in interpreting biological and computational findings for assessing risks? These questions were addressed in the context of this critical review. As a result, three main recommendations emerged. First, researchers should improve ecotoxicology of ENMs by choosing test end points, duration, and study conditions-including ENM test concentrations-that align with realistic exposure scenarios. Second, testing should proceed via tiers with iterative feedback that informs experiments at other levels of biological organization. Finally, environmental realism in ENM hazard assessments should involve greater coordination among ENM quantitative analysts, exposure modelers, and ecotoxicologists, across government, industry, and academia.

Stemming the tide of drug-resistant Neisseria gonorrhoeae: the need for an individualized approach to treatment.

Drug-resistant Neisseria gonorrhoeae poses a significant public health challenge. In recent years, gonococci resistant to first- and second-line antibiotics have spread worldwide and new strains have developed that are increasingly resistant to third-generation cephalosporins, which are currently our last line of available treatments. Given the timeline required to develop new drugs or an effective vaccine for N. gonorrhoeae, a top priority is to use the drugs that are available as effectively as possible. Currently, clinical management of gonorrhoea is based upon treatment guidelines informed by international gonococcal antimicrobial susceptibility surveillance programmes. This approach, although currently the most practical, is subject to a number of limitations since surveillance data inherently provide population-level information. As a result, basing treatment guidelines on these data can result in the prescription of more aggressive or broader treatment than is needed by individual patients and hence inadvertently contribute to the development and spread of resistance to important drugs. Clearly, methods are needed that provide patient-specific drug susceptibility information in a time frame that would allow clinicians to prescribe individualized treatment regimens for gonorrhoea. Fortunately, in recent years, there have been a number of advances in the development of rapid methods for characterizing both the genotype and the drug resistance phenotype of N. gonorrhoeae strains. Here, we review these advances and propose additional studies that would help facilitate a transition towards an individualized treatment approach for gonorrhoea.

A call to action: training public health students to be effective agents for social change.

In the 21st century, we face enormous public health challenges that differ fundamentally from those of the last century, because these challenges involve widespread societal change and complexity. To address these challenges, public health professionals need to be able to place their work in a larger social context, understand local and global perspectives on a deeper level, and effectively engage a wide variety of stakeholders. To confer these skills, we need to change the way we train our students. We present two examples of low-cost innovative approaches to teaching public health that promote active engagement with individuals across a wide range of backgrounds and fields and that train students to be effective agents for change.

Toxicity of metal oxide nanoparticles in Escherichia coli correlates with conduction band and hydration energies.

Metal oxide nanoparticles (MOx NPs) are used for a host of applications, such as electronics, cosmetics, construction, and medicine, and as a result, the safety of these materials to humans and the environment is of considerable interest. A prior study of 24 MOx NPs in mammalian cells revealed that some of these materials show hazard potential. Here, we report the growth inhibitory effects of the same series of MOx NPs in the bacterium Escherichia coli and show that toxicity trends observed in E. coli parallel those seen previously in mammalian cells. Of the 24 materials studied, only ZnO, CuO, CoO, Mn2O3, Co3O4, Ni2O3, and Cr2O3 were found to exert significant growth inhibitory effects; these effects were found to relate to membrane damage and oxidative stress responses in minimal trophic media. A correlation of the toxicological data with physicochemical parameters of MOx NPs revealed that the probability of a MOx NP being toxic increases as the hydration enthalpy becomes less negative and as the conduction band energy approaches those of biological molecules. These observations are consistent with prior results observed in mammalian cells, revealing that mechanisms of toxicity of MOx NPs are consistent across two very different taxa. These results suggest that studying nanotoxicity in E. coli may help to predict toxicity patterns in higher organisms.

Zebrafish high-throughput screening to study the impact of dissolvable metal oxide nanoparticles on the hatching enzyme, ZHE1.

The zebrafish is emerging as a model organism for the safety assessment and hazard ranking of engineered nanomaterials. In this Communication, the implementation of a roboticized high-throughput screening (HTS) platform with automated image analysis is demonstrated to assess the impact of dissolvable oxide nanoparticles on embryo hatching. It is further demonstrated that this hatching interference is mechanistically linked to an effect on the metalloprotease, ZHE 1, which is responsible for degradation of the chorionic membrane. The data indicate that 4 of 24 metal oxide nanoparticles (CuO, ZnO, Cr2 O3 , and NiO) could interfere with embryo hatching by a chelator-sensitive mechanism that involves ligation of critical histidines in the ZHE1 center by the shed metal ions. A recombinant ZHE1 enzymatic assay is established to demonstrate that the dialysates from the same materials responsible for hatching interference also inhibit ZHE1 activity in a dose-dependent fashion. A peptide-based BLAST search identifies several additional aquatic species that express enzymes with homologous histidine-based catalytic centers, suggesting that the ZHE1 mechanistic paradigm could be used to predict the toxicity of a large number of oxide nanoparticles that pose a hazard to aquatic species.

Implementation of a multidisciplinary approach to solve complex nano EHS problems by the UC Center for the Environmental Implications of Nanotechnology.

UC CEIN was established with funding from the US National Science Foundation and the US Environmental Protection Agency in 2008 with the mission to study the impact of nanotechnology on the environment, including the identification of hazard and exposure scenarios that take into consideration the unique physicochemical properties of engineered nanomaterials (ENMs). Since its inception, the Center has made great progress in assembling a multidisciplinary team to develop the scientific underpinnings, research, knowledge acquisition, education and outreach that is required for assessing the safe implementation of nanotechnology in the environment. In this essay, the development of the infrastructure, protocols, and decision-making tools that are required to effectively integrate complementary scientific disciplines allowing knowledge gathering in a complex study area that goes beyond the traditional safety and risk assessment protocols of the 20th century is outlined. UC CEIN's streamlined approach, premised on predictive hazard and exposure assessment methods, high-throughput discovery platforms and environmental decision-making tools that consider a wide range of nano/bio interfaces in terrestrial and aquatic ecosystems, demonstrates the implementation of a 21st-century approach to the safe implementation of nanotechnology in the environment.

Genome-wide bacterial toxicity screening uncovers the mechanisms of toxicity of a cationic polystyrene nanomaterial.

By exploiting a genome-wide collection of bacterial single-gene deletion mutants, we have studied the toxicological pathways of a 60-nm cationic (amino-functionalized) polystyrene nanomaterial (PS-NH(2)) in bacterial cells. The IC(50) of commercially available 60 nm PS-NH(2) was determined to be 158 µg/mL, the IC(5) is 108 µg/mL, and the IC(90) is 190 µg/mL for the parent E. coli strain of the gene deletion library. Over 4000 single nonessential gene deletion mutants of Escherichia coli were screened for the growth phenotype of each strain in the presence and absence of PS-NH(2). This revealed that genes clusters in the lipopolysaccharide biosynthetic pathway, outer membrane transport channels, ubiquinone biosynthetic pathways, flagellar movement, and DNA repair systems are all important to how this organism responds to cationic nanomaterials. These results, coupled with those from confirmatory assays described herein, suggest that the primary mechanisms of toxicity of the 60-nm PS-NH(2) nanomaterial in E. coli are destabilization of the outer membrane and production of reactive oxygen species. The methodology reported herein should prove generally useful for identifying pathways that are involved in how cells respond to a broad range of nanomaterials and for determining the mechanisms of cellular toxicity of different types of nanomaterials.

Dispersion and stability optimization of TiO2 nanoparticles in cell culture media.

Accurate evaluation of engineered nanomaterial toxicity requires not only comprehensive physical-chemical characterization of nanomaterials as produced, but also thorough understanding of nanomaterial properties and behavior under conditions similar to those used for in vitro and in vivo toxicity studies. In this investigation, TiO(2) nanoparticles were selected as a model nanoparticle and bovine serum albumin (BSA) was selected as a model protein for studying the effect of protein-nanoparticle interaction on TiO(2) nanoparticle dispersion in six different mammalian, bacteria, and yeast cell culture media. Great improvement in TiO(2) dispersion was observed upon the addition of BSA, even though the degree of dispersion varied from medium to medium and phosphate concentration in the cell culture media was one of the key factors governing nanoparticle dispersion. Fetal bovine serum (FBS) was an effective dispersing agent for TiO(2) nanoparticles in all six media due to synergistic effects of its multiple protein components, successfully reproduced using a simple "FBS mimic" protein cocktail containing similar concentrations of BSA, γ-globulin, and apo-transferrin.

Children's and parents' views on hospital contact isolation: A qualitative study to highlight children's perspectives.

BACKGROUND: To date, there has been a paucity of studies conducted on the experiences of children under hospital contact isolation precautions. Furthermore, the studies that have examined children's experiences at the hospital typically reflect the perspectives of their parents, and few have directly involved interviews with children themselves, and even fewer with children in isolation. METHODS: To address this gap, we conducted semi-structured, open-ended interviews with hospitalized children to assess their experiences of being placed in isolation. Where possible, the children's parents also completed written surveys to assess parental perspectives on their child's experiences. RESULTS: Two important findings of the study were the children's resilience during a difficult time and children's varying awareness of the pathophysiology of infections as it relates to isolation precautions. Examination of the parent-child dyads elucidated some discordance between parents' and children's perspectives on how children experienced their isolation, on what the children's preferred activities were while in isolation, and how much children understood about the reasons they were in isolation. CONCLUSION: This study supports earlier studies that suggest that the benefits of isolation procedures may be outweighed by how negatively isolation is experienced by patients, particularly when the patients are children. It also highlights the need for child-friendly isolation signs. Because parental and child perceptions differed in cases where data from both were available, this study suggests larger studies on children's perspectives and/or on parent-child dyads are needed.

Health Challenges and Assets of Forest-Dependent Populations in Cameroon.

Indigenous populations often have poorer health outcomes than the general population. Marginalization, colonization, and migration from traditional lands have all affected traditional medicine usage, health access, and indigenous health equity. An in-depth understanding of health for specific populations is essential to develop actionable insights into contributing factors to poor indigenous health. To develop a more complete, nuanced understanding of indigenous health status, we conducted first-person interviews with both the indigenous Baka and neighboring Bantu villagers (the reference population in the region), as well as local clinicians in Southern Cameroon. These interviews elucidated perspectives on the most pressing challenges to health and assets to health for both groups, including access to health services, causes of illness, the uses and values of traditional versus modern medicine, and community resilience during severe health events. Baka interviewees, in particular, reported facing health challenges due to affordability and discrimination in public health centers, health effects due to migration from their traditional lands, and a lack of culturally appropriate public health services.

A recombinant courtship pheromone affects sexual receptivity in a plethodontid salamander.

Pheromones are important chemical signals for many vertebrates, particularly during reproductive interactions. In the terrestrial salamander Plethodon shermani, a male delivers proteinaceous pheromones to the female as part of their ritualistic courtship behavior. These pheromones increase the female's receptivity to mating, as shown by a reduction in courtship duration. One pheromone component in particular is plethodontid receptivity factor (PRF), a 22-kDa protein with multiple isoforms. This protein alone can act as a courtship pheromone that causes the female to be more receptive. We used a bacterial expression system to synthesize a single recombinant isoform of PRF. The recombinant protein was identical to the native PRF, based on mass spectrometry, circular dichroism spectra, and a behavioral bioassay that tested the effects of recombinant PRF (rPRF) on female receptivity (21% reduction in courtship duration). The rPRF appears to mimic the activity of a mixture of PRF isoforms, as well as a mixture of multiple different proteins that comprise the male courtship gland extract. Pheromones that are peptides have been characterized for some vertebrates; to date, however, rPRF is one of only 2 synthesized vertebrate proteins to retain full biological activity.

Critical evaluation of FDA-approved respiratory multiplex assays for public health surveillance.

INTRODUCTION: Clinical management and identification of respiratory diseases has become more rapid and increasingly specific due to widespread use of PCR(polymerase chain reaction) multiplex technologies. Although significantly improving clinical diagnosis, multiplexed PCR assays could have a greater impact on local and global disease surveillance. The authors wish to propose methods of evaluating respiratory multiplex assays to maximize diagnostic yields specifically for surveillance efforts. Areas covered: The authors review multiplexed assays and critically assess what barriers have limited these assays for disease surveillance and how these barriers might be addressed. The manuscript focuses specifically on the case study of using multiplexed assays for surveillance of respiratory pathogens. The authors also provide a method of validation of specific surveillance measures. Expert commentary: Current commercially available respiratory multiplex PCR assays are widely used for clinical diagnosis; however, specific barriers have limited their use for surveillance. Key barriers include differences in testing phase requirements and diagnostic performance evaluation. In this work the authors clarify phase testing requirements and introduce unique diagnostic performance measures that simplify the use of these assays on a per target basis for disease surveillance.

How to better monitor and clean irregular surfaces in operating rooms: Insights gained by using both ATP luminescence and RODAC assays.

BACKGROUND: A major limitation to developing evidence-based approaches to infection prevention is the paucity of real-time, quantitative methods for monitoring the cleanliness of environmental surfaces in clinical settings. One solution that has been proposed is adenosine triphosphate (ATP) bioluminescence assays, but this method does not provide information about the source of the ATP. MATERIALS/METHODS: To address this gap, we conducted a study in which ATP bioluminescence was coupled with traditional RODAC sampling and matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry to assess which organisms were viable and present. Using this mixed assessment approach, we evaluated cleaning of 5 different types of high-touch surfaces (overhead lights, door handles, anesthesia keyboards, mattresses, and side tables) in operating rooms. RESULTS: Whether surfaces tested cleaner after turnaround than they did before turnaround depended on the surface type. Before and after cleaning, flat, covered surfaces (mattresses and side tables) were more likely to pass as "clean" by ATP assay than uncovered, irregularly shaped surfaces (overhead lights, door handles, and anesthesia keyboards). Irregularly shaped surfaces were more likely to pass by RODAC assay than by ATP assay after cleaning. CONCLUSION: Our results suggest that irregularly shaped surfaces in operating rooms may require enhanced covering, cleaning, and monitoring protocols compared to more regularly shaped surfaces.

An Assessment of Climate Change Impacts on Los Angeles (California USA) Hospitals, Wildfires Highest Priority.

Introduction Although many studies have delineated the variety and magnitude of impacts that climate change is likely to have on health, very little is known about how well hospitals are poised to respond to these impacts. Hypothesis/Problem The hypothesis is that most modern hospitals in urban areas in the United States need to augment their current disaster planning to include climate-related impacts. METHODS: Using Los Angeles County (California USA) as a case study, historical data for emergency department (ED) visits and projections for extreme-heat events were used to determine how much climate change is likely to increase ED visits by mid-century for each hospital. In addition, historical data about the location of wildfires in Los Angeles County and projections for increased frequency of both wildfires and flooding related to sea-level rise were used to identify which area hospitals will have an increased risk of climate-related wildfires or flooding at mid-century. RESULTS: Only a small fraction of the total number of predicted ED visits at mid-century would likely to be due to climate change. By contrast, a significant portion of hospitals in Los Angeles County are in close proximity to very high fire hazard severity zones (VHFHSZs) and would be at greater risk to wildfire impacts as a result of climate change by mid-century. One hospital in Los Angeles County was anticipated to be at greater risk due to flooding by mid-century as a result of climate-related sea-level rise. CONCLUSION: This analysis suggests that several Los Angeles County hospitals should focus their climate-change-related planning on building resiliency to wildfires. Adelaine SA , Sato M , Jin Y , Godwin H . An assessment of climate change impacts on Los Angeles (California USA) hospitals, wildfires highest priority. Prehosp Disaster Med. 2017;32(5):556-562.

Comparing three treponemal tests for syphilis screening.

We compared the performance and ease of use for three high-throughput treponemal immunoassays: Phoenix Biotech Trep-Sure Total Antibody EIA, Siemens ADVIA® Centaur Syphilis Assay, and DiaSorin LIAISON® Treponema Assay. One thousand serum samples submitted for routine screening were used in this study. Each assay demonstrated comparable sensitivity, specificity, and percent agreement (98-100%) compared with Treponema pallidum particle agglutination (TP-PA). Thus, treponemal immunoassays are an acceptable alternative for syphilis screening or confirmatory testing. Batch sizes and technologist active time varied between each treponemal immunoassay; the chemiluminescence platforms offered significantly greater ability to batch (random access vs. fixed batch sizes) in less time. When we compared the results obtained using a reverse algorithm approach to those obtained using a traditional algorithm, we found that the reverse algorithm identified 38 additional seropositive individuals that were not detected using the traditional algorithm. Clinical evaluation was useful for resolving cases with discordant serology.

Needs and challenges for assessing the environmental impacts of engineered nanomaterials (ENMs).

The potential environmental impact of nanomaterials is a critical concern and the ability to assess these potential impacts is top priority for the progress of sustainable nanotechnology. Risk assessment tools are needed to enable decision makers to rapidly assess the potential risks that may be imposed by engineered nanomaterials (ENMs), particularly when confronted by the reality of limited hazard or exposure data. In this review, we examine a range of available risk assessment frameworks considering the contexts in which different stakeholders may need to assess the potential environmental impacts of ENMs. Assessment frameworks and tools that are suitable for the different decision analysis scenarios are then identified. In addition, we identify the gaps that currently exist between the needs of decision makers, for a range of decision scenarios, and the abilities of present frameworks and tools to meet those needs.