Inferring stabilizing mutations from protein phylogenies : application to influenza hemagglutinin

One selection pressure shaping sequence evolution is the requirement that a protein fold with sufficient stability to perform its biological functions. We present a conceptual framework that explains how this requirement causes the probability that a particular amino acid mutation is fixed during evolution to depend on its effect on protein stability. We mathematically formalize this framework to develop a Bayesian approach for inferring the stability effects of individual mutations from homologous protein sequences of known phylogeny. This approach is able to predict published experimentally measured mutational stability effects (ΔΔG values) with an accuracy that exceeds both a state-of-the-art physicochemical modeling program and the sequence-based consensus approach. As a further test, we use our phylogenetic inference approach to predict stabilizing mutations to influenza hemagglutinin. We introduce these mutations into a temperature-sensitive influenza virus with a defect in its hemagglutinin gene and experimentally demonstrate that some of the mutations allow the virus to grow at higher temperatures. Our work therefore describes a powerful new approach for predicting stabilizing mutations that can be successfully applied even to large, complex proteins such as hemagglutinin. This approach also makes a mathematical link between phylogenetics and experimentally measurable protein properties, potentially paving the way for more accurate analyses of molecular evolution

Urban community gardeners' knowledge and perceptions of soil contaminant risks

Although urban community gardening can offer health, social, environmental, and economic benefits, these benefits must be weighed against the potential health risks stemming from exposure to contaminants such as heavy metals and organic chemicals that may be present in urban soils. Individuals who garden at or eat food grown in contaminated urban garden sites may be at risk of exposure to such contaminants. Gardeners may be unaware of these risks and how to manage them. We used a mixed quantitative/qualitative research approach to characterize urban community gardeners' knowledge and perceptions of risks related to soil contaminant exposure. We conducted surveys with 70 gardeners from 15 community gardens in Baltimore, Maryland, and semi-structured interviews with 18 key informants knowledgeable about community gardening and soil contamination in Baltimore. We identified a range of factors, challenges, and needs related to Baltimore community gardeners' perceptions of risk related to soil contamination, including low levels of concern and inconsistent levels of knowledge about heavy metal and organic chemical contaminants, barriers to investigating a garden site's history and conducting soil tests, limited knowledge of best practices for reducing exposure, and a need for clear and concise information on how best to prevent and manage soil contamination. Key informants discussed various strategies for developing and disseminating educational materials to gardeners. For some challenges, such as barriers to conducting site history and soil tests, some informants recommended city-wide interventions that bypass the need for gardener knowledge altogether

Decreased thermal tolerance under recurrent heat stress conditions explains summer mass mortality of the blue mussel Mytilus edulis

Extreme events such as heat waves have increased in frequency and duration over the last decades. Under future climate scenarios, these discrete climatic events are expected to become even more recurrent and severe. Heat waves are particularly important on rocky intertidal shores, one of the most thermally variable and stressful habitats on the planet. Intertidal mussels, such as the blue mussel Mytilus edulis, are ecosystem engineers of global ecological and economic importance, that occasionally suffer mass mortalities. This study investigates the potential causes and consequences of a mass mortality event of M. edulis that occurred along the French coast of the eastern English Channel in summer 2018. We used an integrative, climatological and ecophysiological methodology based on three complementary approaches. We first showed that the observed mass mortality (representing 49 to 59% of the annual commercial value of local recreational and professional fisheries combined) occurred under relatively moderate heat wave conditions. This result indicates that M. edulis body temperature is controlled by non-climatic heat sources instead of climatic heat sources, as previously reported for intertidal gastropods. Using biomimetic loggers (i.e. 'robomussels'), we identified four periods of 5 to 6 consecutive days when M. edulis body temperatures consistently reached more than 30 °C, and occasionally more than 35 °C and even more than 40 °C. We subsequently reproduced these body temperature patterns in the laboratory to infer M. edulis thermal tolerance under conditions of repeated heat stress. We found that thermal tolerance consistently decreased with the number of successive daily exposures. These results are discussed in the context of an era of global change where heat events are expected to increase in intensity and frequency, especially in the eastern English Channel where the low frequency of commercially exploitable mussels already questions both their ecological and commercial sustainability.Funding Agency French Ministere de l'Enseignement Superieur et de la Recherche Region Hauts-de-France European Funds for Regional Economical Development Pierre Hubert Curien PESSOA Felloswhip Fundacao para a Ciencia e Tecnologia (FCT-MEC, Portugal) IF/01413/2014/CP1217/CT0004 National Research Foundation - South Africa 64801 South African Research Chairs Initiative (SARChI) of the Department of Science and Technology National Research Foundation - South Africainfo:eu-repo/semantics/publishedVersio

Serial CT analysis in idiopathic pulmonary fibrosis: comparison of visual features that determine patient outcome

Aims: Patients with idiopathic pulmonary fibrosis (IPF) receiving antifibrotic medication and patients with non-IPF fibrosing lung disease often demonstrate rates of annualised forced vital capacity (FVC) decline within the range of measurement variation (5.0%–9.9%). We examined whether change in visual CT variables could help confirm whether marginal FVC declines represented genuine clinical deterioration rather than measurement noise. Methods: In two IPF cohorts (cohort 1: n=103, cohort 2: n=108), separate pairs of radiologists scored paired volumetric CTs (acquired between 6 and 24 months from baseline). Change in interstitial lung disease, honeycombing, reticulation, ground-glass opacity extents and traction bronchiectasis severity was evaluated using a 5-point scale, with mortality prediction analysed using univariable and multivariable Cox regression analyses. Both IPF populations were then combined to determine whether change in CT variables could predict mortality in patients with marginal FVC declines. Results: On univariate analysis, change in all CT variables except ground-glass opacity predicted mortality in both cohorts. On multivariate analysis adjusted for patient age, gender, antifibrotic use and baseline disease severity (diffusing capacity for carbon monoxide), change in traction bronchiectasis severity predicted mortality independent of FVC decline. Change in traction bronchiectasis severity demonstrated good interobserver agreement among both scorer pairs. Across all study patients with marginal FVC declines, change in traction bronchiectasis severity independently predicted mortality and identified more patients with deterioration than change in honeycombing extent. Conclusions: Change in traction bronchiectasis severity is a measure of disease progression that could be used to help resolve the clinical importance of marginal FVC declines

Impact of Center Experience on Patient Radiation Exposure During Transradial Coronary Angiography and Percutaneous Intervention: A Patient-Level, International, Collaborative, Multi-Center Analysis.

BACKGROUND: The adoption of the transradial (TR) approach over the traditional transfemoral (TF) approach has been hampered by concerns of increased radiation exposure-a subject of considerable debate within the field. We performed a patient-level, multi-center analysis to definitively address the impact of TR access on radiation exposure. METHODS AND RESULTS: Overall, 10 centers were included from 6 countries-Canada (2 centers), United Kingdom (2), Germany (2), Sweden (2), Hungary (1), and The Netherlands (1). We compared the radiation exposure of TR versus TF access using measured dose-area product (DAP). To account for local variations in equipment and exposure, standardized TR:TF DAP ratios were constructed per center with procedures separated by coronary angiography (CA) and percutaneous coronary intervention (PCI). Among 57 326 procedures, we demonstrated increased radiation exposure with the TR versus TF approach, particularly in the CA cohort across all centers (weighted-average ratios: CA, 1.15; PCI, 1.05). However, this was mitigated by increasing TR experience in the PCI cohort across all centers (r=-0.8; P=0.005). Over time, as a center transitioned to increasing TR experience (r=0.9; P=0.001), a concomitant decrease in radiation exposure occurred (r=-0.8; P=0.006). Ultimately, when a center's balance of TR to TF procedures approaches 50%, the resultant radiation exposure was equivalent. CONCLUSIONS: The TR approach is associated with a modest increase in patient radiation exposure. However, this increase is eliminated when the TR and TF approaches are used with equal frequency-a guiding principle for centers adopting the TR approach

Structural Basis for Certain Naturally Occurring Bioflavonoids to Function as Reducing Co-Substrates of Cyclooxygenase I and II

Recent studies showed that some of the dietary bioflavonoids can strongly stimulate the catalytic activity of cyclooxygenase (COX) I and II in vitro and in vivo, presumably by facilitating enzyme re-activation. In this study, we sought to understand the structural basis of COX activation by these dietary compounds.A combination of molecular modeling studies, biochemical analysis and site-directed mutagenesis assay was used as research tools. Three-dimensional quantitative structure-activity relationship analysis (QSAR/CoMFA) predicted that the ability of bioflavonoids to activate COX I and II depends heavily on their B-ring structure, a moiety known to be associated with strong antioxidant ability. Using the homology modeling and docking approaches, we identified the peroxidase active site of COX I and II as the binding site for bioflavonoids. Upon binding to this site, bioflavonoid can directly interact with hematin of the COX enzyme and facilitate the electron transfer from bioflavonoid to hematin. The docking results were verified by biochemical analysis, which reveals that when the cyclooxygenase activity of COXs is inhibited by covalent modification, myricetin can still stimulate the conversion of PGG(2) to PGE(2), a reaction selectively catalyzed by the peroxidase activity. Using the site-directed mutagenesis analysis, we confirmed that Q189 at the peroxidase site of COX II is essential for bioflavonoids to bind and re-activate its catalytic activity.These findings provide the structural basis for bioflavonoids to function as high-affinity reducing co-substrates of COXs through binding to the peroxidase active site, facilitating electron transfer and enzyme re-activation

Predator Mimicry: Metalmark Moths Mimic Their Jumping Spider Predators

Cases of mimicry provide many of the nature's most convincing examples of natural selection. Here we report evidence for a case of predator mimicry in which metalmark moths in the genus Brenthia mimic jumping spiders, one of their predators. In controlled trials, Brenthia had higher survival rates than other similarly sized moths in the presence of jumping spiders and jumping spiders responded to Brenthia with territorial displays, indicating that Brenthia were sometimes mistaken for jumping spiders, and not recognized as prey. Our experimental results and a review of wing patterns of other insects indicate that jumping spider mimicry is more widespread than heretofore appreciated, and that jumping spiders are probably an important selective pressure shaping the evolution of diurnal insects that perch on vegetation

Bioavailable iron in the Southern Ocean: the significance of the iceberg conveyor belt

Productivity in the Southern Oceans is iron-limited, and the supply of iron dissolved from aeolian dust is believed to be the main source from outside the marine reservoir. Glacial sediment sources of iron have rarely been considered, as the iron has been assumed to be inert and non-bioavailable. This study demonstrates the presence of potentially bioavailable Fe as ferrihydrite and goethite in nanoparticulate clusters, in sediments collected from icebergs in the Southern Ocean and glaciers on the Antarctic landmass. Nanoparticles in ice can be transported by icebergs away from coastal regions in the Southern Ocean, enabling melting to release bioavailable Fe to the open ocean. The abundance of nanoparticulate iron has been measured by an ascorbate extraction. This data indicates that the fluxes of bioavailable iron supplied to the Southern Ocean from aeolian dust (0.01–0.13 Tg yr-1) and icebergs (0.06–0.12 Tg yr-1) are comparable. Increases in iceberg production thus have the capacity to increase productivity and this newly identified negative feedback may help to mitigate fossil fuel emissions

Does dog-ownership influence seasonal patterns of neighbourhood-based walking among adults? A longitudinal study

<p>Abstract</p> <p>Background</p> <p>In general dog-owners are more physically active than non-owners, however; it is not known whether dog-ownership can influence seasonal fluctuations in physical activity. This study examines whether dog-ownership influences summer and winter patterns of neighbourhood-based walking among adults living in Calgary, Canada.</p> <p>Methods</p> <p>A cohort of adults, randomly sampled from the Calgary metropolitan area, completed postal surveys in winter and summer 2008. Both winter and summer versions of the survey included questions on dog-ownership, walking for recreation, and walking for transportation in residential neighbourhoods. <b>Participation </b>in neighbourhood-based walking was compared, among dog-owners and non-owners, and in summer and winter, using general linear modeling. <b>Stability </b>of participation in neighbourhood-based walking across summer and winter among dog-owners and non-owners was also assessed, using logistic regression.</p> <p>Results</p> <p>A total of 428 participants participated in the study, of whom 115 indicated owning dogs at the time of both surveys. Dog-owners reported more walking for recreation in their neighbourhoods than did non-owners, both in summer and in winter. Dog-owners were also more likely than non-owners to report participation in walking for recreation in their neighbourhoods, in summer as well as in winter. Dog-owners and non-owners did not differ in the amount of walking that they reported for transportation, either in summer or in winter.</p> <p>Conclusions</p> <p>By acting as cues for physical activity, dogs may help their owners remain active across seasons. Policies and programs related to dog-ownership and dog-walking, such as dog-supportive housing and dog-supportive parks, may assist in enhancing population health by promoting physical activity.</p

A mechanistic model of infection: why duration and intensity of contacts should be included in models of disease spread

<p>Abstract</p> <p>Background</p> <p>Mathematical models and simulations of disease spread often assume a constant per-contact transmission probability. This assumption ignores the heterogeneity in transmission probabilities, e.g. due to the varying intensity and duration of potentially contagious contacts. Ignoring such heterogeneities might lead to erroneous conclusions from simulation results. In this paper, we show how a mechanistic model of disease transmission differs from this commonly used assumption of a constant per-contact transmission probability.</p> <p>Methods</p> <p>We present an exposure-based, mechanistic model of disease transmission that reflects heterogeneities in contact duration and intensity. Based on empirical contact data, we calculate the expected number of secondary cases induced by an infector (i) for the mechanistic model and (ii) under the classical assumption of a constant per-contact transmission probability. The results of both approaches are compared for different basic reproduction numbers <it>R</it>₀.</p> <p>Results</p> <p>The outcomes of the mechanistic model differ significantly from those of the assumption of a constant per-contact transmission probability. In particular, cases with many different contacts have much lower expected numbers of secondary cases when using the mechanistic model instead of the common assumption. This is due to the fact that the proportion of long, intensive contacts decreases in the contact dataset with an increasing total number of contacts.</p> <p>Conclusion</p> <p>The importance of highly connected individuals, so-called super-spreaders, for disease spread seems to be overestimated when a constant per-contact transmission probability is assumed. This holds particularly for diseases with low basic reproduction numbers. Simulations of disease spread should weight contacts by duration and intensity.</p