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ObjectiveThe purpose of the study was to determine trends in the prevalence of individual health risk factors across time and to examine if their associations with mortality have changed over time.MethodsData from the National Health and Nutrition Examination Surveys (NHANES III- 1988-1994 and NHANES 1999-2014; age ≥20 years) was used to examine differences in the odds ratio (OR) of 5-year mortality risk associated with various common health risk factors over the two survey periods using weighted logistic regression analysis adjusting for age, sex, obesity category and white ethnicity (n = 28,279).ResultsOver 97% of individuals had at least one of the 19 risk factors examined with no difference in the prevalence over time (P>0.34). The prevalence of lifestyle, social/mental and physical risk factors (2.2 to 19.1%) increased over time (P0.1), but were significantly associated with a higher 5-year OR for mortality in 1999-2014 (PConclusionHealth risk factors have both increased and decreased in prevalence over time, along with changes in the association between many of the risk factors and mortality risk. Taken together, these changes complicate interpretation of temporal trends and warrant cautious interpretation of population health patterns based on surveillance data.

Since World War I, helmets have been used to protect the head in warfare, designed primarily for protection against artillery shrapnel. More recently, helmet requirements have included ballistic and blunt trauma protection, but neurotrauma from primary blast has never been a key concern in helmet design. Only in recent years has the threat of direct blast wave impingement on the head-separate from penetrating trauma-been appreciated. This study compares the blast protective effect of historical (World War I) and current combat helmets, against each other and 'no helmet' or bare head, for realistic shock wave impingement on the helmet crown. Helmets included World War I variants from the United Kingdom/United States (Brodie), France (Adrian), Germany (Stahlhelm), and a current United States combat variant (Advanced Combat Helmet). Helmets were mounted on a dummy head and neck and aligned along the crown of the head with a cylindrical shock tube to simulate an overhead blast. Primary blast waves of different magnitudes were generated based on estimated blast conditions from historical shells. Peak reflected overpressure at the open end of the blast tube was compared to peak overpressure measured at several head locations. All helmets provided significant pressure attenuation compared to the no helmet case. The modern variant did not provide more pressure attenuation than the historical helmets, and some historical helmets performed better at certain measurement locations. The study demonstrates that both historical and current helmets have some primary blast protective capabilities, and that simple design features may improve these capabilities for future helmet systems.

BackgroundThe association between metabolic syndrome (MetS) and all-cause mortality is well established but it is unclear if there are differences in mortality risk among the 32 possible MetS combinations. Hence, the purpose of this study is to evaluate the associations between different MetS combinations and its individual components with all-cause mortality, and to examine differences in the association by age and sex.MethodsA merged sample of 82,717 adults from 7 U.S. cohorts was used.ResultsIn our sample, MetS was present in 32% of men, 34% of women, 28% of younger adults (18-65 years) and 62% of older adults (>65 years) with 14,989 deaths over 14.6 ± 7.4 years of follow-up. Risk of all-cause mortality was higher in younger individuals with a greater number of MetS factors present, but in older adults having all 5 MetS factors was the only combination significantly associated with mortality. Regardless of age or sex, elevated blood pressure was the MetS factor most consistently present in MetS combinations that were significantly and most strongly associated with mortality. In fact, elevated blood pressure in the absence of other risk factors was significantly associated with mortality in men (HR, 95% CI = 1.56, 1.33-1.84), women (HR = 1.62, 1.44-1.81) and younger adults (HR = 1.61, 1.45-1.79). Conversely, waist circumference, glucose and triglycerides in isolation were not associated with mortality (p>0.05).ConclusionIn a large U.S. population, different combinations of MetS components vary substantially in their associations with all-cause mortality. Men, women and younger individuals with MetS combinations including elevated blood pressure had stronger associations with greater mortality risk, with minimal associations between MetS and mortality risk in older adults. Thus, we suggest that future algorithms may wish to consider differential weighting of these common metabolic risk factors, particularly in younger populations.

ObjectiveTo investigate scaling approaches for evaluating the development of peak VO2 and improving the identification of low cardiopulmonary fitness in Southern Chinese children and adolescents.MethodsNine hundred and twenty Chinese children and adolescents (8 to 16 years) underwent graded cardiopulmonary exercise test on a treadmill until volitional exhaustion. Peak VO2 was corrected for the effects of body mass by ratio or allometric scaling. Z score equations for predicting peak VO2 were developed. Correlations between scaled peak VO2, z scores, body size and age were tested to examine the effectiveness of the approach.ResultsEight hundred and fifty-two participants (48% male) were included in the analyses. Absolute peak VO2 significantly increased with age in both sexes (both PConclusionsAbsolute and allometric scaled peak VO2 values are provided for Hong Kong Chinese children and adolescents by age and sex. Peak VO2 z scores improve the evaluation of cardiopulmonary fitness, allowing comparisons across ages and sex and will likely provide a better metric for tracking change over time in children and adolescents, regardless of body size and age.

Mouse syngeneic tumor models are widely used tools to demonstrate activity of novel anti-cancer immunotherapies. Despite their widespread use, a comprehensive view of their tumor-immune compositions and their relevance to human tumors has only begun to emerge. We propose each model possesses a unique tumor-immune infiltrate profile that can be probed with immunotherapies to inform on anti-tumor mechanisms and treatment strategies in human tumors with similar profiles. In support of this endeavor, we characterized the tumor microenvironment of four commonly used models and demonstrate they encompass a range of immunogenicities, from highly immune infiltrated RENCA tumors to poorly infiltrated B16F10 tumors. Tumor cell lines for each model exhibit different intrinsic factors in vitro that likely influence immune infiltration upon subcutaneous implantation. Similarly, solid tumors in vivo for each model are unique, each enriched in distinct features ranging from pathogen response elements to antigen presentation machinery. As RENCA tumors progress in size, all major T cell populations diminish while myeloid-derived suppressor cells become more enriched, possibly driving immune suppression and tumor progression. In CT26 tumors, CD8 T cells paradoxically increase in density yet are restrained as tumor volume increases. Finally, immunotherapy treatment across these different tumor-immune landscapes segregate into responders and non-responders based on features partially dependent on pre-existing immune infiltrates. Overall, these studies provide an important resource to enhance our translation of syngeneic models to human tumors. Future mechanistic studies paired with this resource will help identify responsive patient populations and improve strategies where immunotherapies are predicted to be ineffective.

The Honghe-Hani landscape in China is a UNESCO World Natural Heritage site due to the beauty of its thousands of rice terraces, but these structures are in danger from the invasive crayfish Procambarus clarkii. Crayfish dig nest holes, which collapse terrace walls and destroy rice production. Under the current control strategy, farmers self-report crayfish and are issued pesticide, but this strategy is not expected to eradicate the crayfish nor to prevent their spread since farmers are not able to detect small numbers of crayfish. Thus, we tested whether environmental DNA (eDNA) from paddy-water samples could provide a sensitive detection method. In an aquarium experiment, Real-time Quantitative polymerase chain reaction (qPCR) successfully detected crayfish, even at a simulated density of one crayfish per average-sized paddy (with one false negative). In a field test, we tested eDNA and bottle traps against direct counts of crayfish. eDNA successfully detected crayfish in all 25 paddies where crayfish were observed and in none of the 7 paddies where crayfish were absent. Bottle-trapping was successful in only 68% of the crayfish-present paddies. eDNA concentrations also correlated positively with crayfish counts. In sum, these results suggest that single samples of eDNA are able to detect small crayfish populations, but not perfectly. Thus, we conclude that a program of repeated eDNA sampling is now feasible and likely reliable for measuring crayfish geographic range and for detecting new invasion fronts in the Honghe Hani landscape, which would inform regional control efforts and help to prevent the further spread of this invasive crayfish.

Reports from state health departments and the Centers for Disease Control and Prevention indicate that the annual number of reported human vibriosis cases in New England has increased in the past decade. Concurrently, there has been a shift in both the spatial distribution and seasonal detection of Vibrio spp. throughout the region based on limited monitoring data. To determine environmental factors that may underlie these emerging conditions, this study focuses on a long-term database of Vibrio parahaemolyticus concentrations in oyster samples generated from data collected from the Great Bay Estuary, New Hampshire over a period of seven consecutive years. Oyster samples from two distinct sites were analyzed for V. parahaemolyticus abundance, noting significant relationships with various biotic and abiotic factors measured during the same period of study. We developed a predictive modeling tool capable of estimating the likelihood of V. parahaemolyticus presence in coastal New Hampshire oysters. Results show that the inclusion of chlorophyll a concentration to an empirical model otherwise employing only temperature and salinity variables, offers improved predictive capability for modeling the likelihood of V. parahaemolyticus in the Great Bay Estuary.

CARMA-BCL10-MALT1 signalosomes play important roles in antigen receptor signaling and other pathways. Previous studies have suggested that as part of this complex, MALT1 functions as both a scaffolding protein to activate NF-κB through recruitment of ubiquitin ligases, and as a protease to cleave and inactivate downstream inhibitory signaling proteins. However, our understanding of the relative importance of these two distinct MALT1 activities has been hampered by a lack of selective MALT1 protease inhibitors with suitable pharmacologic properties. To fully investigate the role of MALT1 protease activity, we generated mice homozygous for a protease-dead mutation in MALT1. We found that some, but not all, MALT1 functions in immune cells were dependent upon its protease activity. Protease-dead mice had defects in the generation of splenic marginal zone and peritoneal B1 B cells. CD4+ and CD8+ T cells displayed decreased T cell receptor-stimulated proliferation and IL-2 production while B cell receptor-stimulated proliferation was partially dependent on protease activity. In dendritic cells, stimulation of cytokine production through the Dectin-1, Dectin-2, and Mincle C-type lectin receptors was also found to be partially dependent upon protease activity. In vivo, protease-dead mice had reduced basal immunoglobulin levels, and showed defective responses to immunization with T-dependent and T-independent antigens. Surprisingly, despite these decreased responses, MALT1 protease-dead mice, but not MALT1 null mice, developed mixed inflammatory cell infiltrates in multiple organs, suggesting MALT1 protease activity plays a role in immune homeostasis. These findings highlight the importance of MALT1 protease activity in multiple immune cell types, and in integrating immune responses in vivo.

Neisseria gonorrhoeae is an obligate human pathogen and the causative agent of the sexually-transmitted disease gonorrhea. The control of this disease has been compromised by the increasing proportion of infections due to antibiotic-resistant strains, which are growing at an alarming rate. The MtrCDE tripartite multidrug efflux pump, belonging to the hydrophobic and amphiphilic efflux resistance-nodulation-cell division (HAE-RND) family, spans both the inner and outer membranes of N. gonorrhoeae and confers resistance to a variety of antibiotics and toxic compounds. We here report the crystal structure of the inner membrane MtrD multidrug efflux pump, which reveals a novel structural feature that is not found in other RND efflux pumps.

Active efflux of antimicrobial agents is one of the most important strategies used by bacteria to defend against antimicrobial factors present in their environment. Mediating many cases of antibiotic resistance are transmembrane efflux pumps, composed of one or more proteins. The Neisseria gonorrhoeae MtrCDE tripartite multidrug efflux pump, belonging to the hydrophobic and amphiphilic efflux resistance-nodulation-cell division (HAE-RND) family, spans both the inner and outer membranes of N. gonorrhoeae and confers resistance to a variety of antibiotics and toxic compounds. We here describe the crystal structure of N. gonorrhoeae MtrE, the outer membrane component of the MtrCDE tripartite multidrug efflux system. This trimeric MtrE channel forms a vertical tunnel extending down contiguously from the outer membrane surface to the periplasmic end, indicating that our structure of MtrE depicts an open conformational state of this channel.

High-throughput parallel sequencing is a powerful tool for the quantification of microbial diversity through the amplification of nuclear ribosomal gene regions. Recent work has extended this approach to the quantification of diversity within otherwise difficult-to-study metazoan groups. However, nuclear ribosomal genes present both analytical challenges and practical limitations that are a consequence of the mutational properties of nuclear ribosomal genes. Here we exploit useful properties of protein-coding genes for cross-species amplification and denoising of 454 flowgrams. We first use experimental mixtures of species from the class Collembola to amplify and pyrosequence the 5' region of the COI barcode, and we implement a new algorithm called PyroClean for the denoising of Roche GS FLX pyrosequences. Using parameter values from the analysis of experimental mixtures, we then analyse two communities sampled from field sites on the island of Tenerife. Cross-species amplification success of target mitochondrial sequences in experimental species mixtures is high; however, there is little relationship between template DNA concentrations and pyrosequencing read abundance. Homopolymer error correction and filtering against a consensus reference sequence reduced the volume of unique sequences to approximately 5% of the original unique raw reads. Filtering of remaining non-target sequences attributed to PCR error, sequencing error, or numts further reduced unique sequence volume to 0.8% of the original raw reads. PyroClean reduces or eliminates the need for an additional, time-consuming step to cluster reads into Operational Taxonomic Units, which facilitates the detection of intraspecific DNA sequence variation. PyroCleaned sequence data from field sites in Tenerife demonstrate the utility of our approach for quantifying evolutionary diversity and its spatial structure. Comparison of our sequence data to public databases reveals that we are able to successfully recover both interspecific and intraspecific sequence diversity.

Attine ants are dependent on a cultivated fungus for food and use antibiotics produced by symbiotic Actinobacteria as weedkillers in their fungus gardens. Actinobacterial species belonging to the genera Pseudonocardia, Streptomyces and Amycolatopsis have been isolated from attine ant nests and shown to confer protection against a range of microfungal weeds. In previous work on the higher attine Acromyrmex octospinosus we isolated a Streptomyces strain that produces candicidin, consistent with another report that attine ants use Streptomyces-produced candicidin in their fungiculture. Here we report the genome analysis of this Streptomyces strain and identify multiple antibiotic biosynthetic pathways. We demonstrate, using gene disruptions and mass spectrometry, that this single strain has the capacity to make candicidin and multiple antimycin compounds. Although antimycins have been known for >60 years we report the sequence of the biosynthetic gene cluster for the first time. Crucially, disrupting the candicidin and antimycin gene clusters in the same strain had no effect on bioactivity against a co-evolved nest pathogen called Escovopsis that has been identified in ∼30% of attine ant nests. Since the Streptomyces strain has strong bioactivity against Escovopsis we conclude that it must make additional antifungal(s) to inhibit Escovopsis. However, candicidin and antimycins likely offer protection against other microfungal weeds that infect the attine fungal gardens. Thus, we propose that the selection of this biosynthetically prolific strain from the natural environment provides A. octospinosus with broad spectrum activity against Escovopsis and other microfungal weeds.

Annual revenue flow to developing countries for ecotourism (or nature-based tourism) could be as large as US$ 210×10(12), providing an enormous financial incentive against habitat loss and exploitation. However, is ecotourism the most privately and/or socially valuable use of rainforest land? The question is rarely answered because the relevant data, estimates of profits and fixed costs, are rarely available. We present a social cost-benefit analysis of land use in an ecotourism cluster in the Tambopata region of Amazonian Peru. The net present value of ecotourism-controlled land is given by the producer surplus (profits plus fixed costs of ecotourism lodges): US$ 1,158 ha(-1), which is higher than all currently practiced alternatives, including unsustainable logging, ranching, and agriculture. To our knowledge, this is the first sector-wide study of profitability and producer surplus in a developing-country ecotourism sector and the first to compare against equivalent measures for a spectrum of alternative uses. We also find that ecotourism-controlled land sequesters between 5.3 to 8.7 million tons of above-ground carbon, which is equivalent to between 3000-5000 years of carbon emissions from the domestic component of air and surface travel between the gateway city of Cusco and the lodges, at 2005 emission rates. Ecotourism in Tambopata has successfully monetized the hedonic value of wild nature in Amazonian Peru, and justifies the maintenance of intact rainforest over all alternative uses on narrow economic grounds alone.

Fig trees are pollinated by fig wasps, which also oviposit in female flowers. The wasp larvae gall and eat developing seeds. Although fig trees benefit from allowing wasps to oviposit, because the wasp offspring disperse pollen, figs must prevent wasps from ovipositing in all flowers, or seed production would cease, and the mutualism would go extinct. In Ficus racemosa, we find that syconia ('figs') that have few foundresses (ovipositing wasps) are underexploited in the summer (few seeds, few galls, many empty ovules) and are overexploited in the winter (few seeds, many galls, few empty ovules). Conversely, syconia with many foundresses produce intermediate numbers of galls and seeds, regardless of season. We use experiments to explain these patterns, and thus, to explain how this mutualism is maintained. In the hot summer, wasps suffer short lifespans and therefore fail to oviposit in many flowers. In contrast, cooler temperatures in the winter permit longer wasp lifespans, which in turn allows most flowers to be exploited by the wasps. However, even in winter, only in syconia that happen to have few foundresses are most flowers turned into galls. In syconia with higher numbers of foundresses, interference competition reduces foundress lifespans, which reduces the proportion of flowers that are galled. We further show that syconia encourage the entry of multiple foundresses by delaying ostiole closure. Taken together, these factors allow fig trees to reduce galling in the wasp-benign winter and boost galling (and pollination) in the wasp-stressing summer. Interference competition has been shown to reduce virulence in pathogenic bacteria. Our results show that interference also maintains cooperation in a classic, cooperative symbiosis, thus linking theories of virulence and mutualism. More generally, our results reveal how frequency-dependent population regulation can occur in the fig-wasp mutualism, and how a host species can 'set the rules of the game' to ensure mutualistic behavior in its symbionts.