Showing papers by "Research Triangle Park published in 2016"
University of Bristol1, Harvard University2, University Hospitals Bristol NHS Foundation Trust3, Research Triangle Park4, University of Toronto5, University of Oxford6, University of Ottawa7, Paris Descartes University8, University of London9, University of York10, University of Birmingham11, University of Southern Denmark12, University of Liverpool13, University of East Anglia14, Loyola University Chicago15, University of Aberdeen16, Kaiser Permanente17, Baruch College18, McMaster University19, Cochrane Collaboration20, McGill University21, Ottawa Hospital Research Institute22, University of Louisville23, University of Melbourne24
TL;DR: Risk of Bias In Non-randomised Studies - of Interventions is developed, a new tool for evaluating risk of bias in estimates of the comparative effectiveness of interventions from studies that did not use randomisation to allocate units or clusters of individuals to comparison groups.
Abstract: Non-randomised studies of the effects of interventions are critical to many areas of healthcare evaluation, but their results may be biased. It is therefore important to understand and appraise their strengths and weaknesses. We developed ROBINS-I (“Risk Of Bias In Non-randomised Studies - of Interventions”), a new tool for evaluating risk of bias in estimates of the comparative effectiveness (harm or benefit) of interventions from studies that did not use randomisation to allocate units (individuals or clusters of individuals) to comparison groups. The tool will be particularly useful to those undertaking systematic reviews that include non-randomised studies.
8,028 citations
TL;DR: Misinterpretation and abuse of statistical tests, confidence intervals, and statistical power have been decried for decades, yet remain rampant as discussed by the authors, and there are no interpretations of these concepts that are at once simple, intuitive, correct, and foolproof Instead, correct use and interpretation of these statistics requires an attention to detail which seems to tax the patience of working scientists.
Abstract: Misinterpretation and abuse of statistical tests, confidence intervals, and statistical power have been decried for decades, yet remain rampant A key problem is that there are no interpretations of these concepts that are at once simple, intuitive, correct, and foolproof Instead, correct use and interpretation of these statistics requires an attention to detail which seems to tax the patience of working scientists This high cognitive demand has led to an epidemic of shortcut definitions and interpretations that are simply wrong, sometimes disastrously so-and yet these misinterpretations dominate much of the scientific literature In light of this problem, we provide definitions and a discussion of basic statistics that are more general and critical than typically found in traditional introductory expositions Our goal is to provide a resource for instructors, researchers, and consumers of statistics whose knowledge of statistical theory and technique may be limited but who wish to avoid and spot misinterpretations We emphasize how violation of often unstated analysis protocols (such as selecting analyses for presentation based on the P values they produce) can lead to small P values even if the declared test hypothesis is correct, and can lead to large P values even if that hypothesis is incorrect We then provide an explanatory list of 25 misinterpretations of P values, confidence intervals, and power We conclude with guidelines for improving statistical interpretation and reporting
1,584 citations
Journal Article•
TL;DR: This paper provided definitions and a discussion of basic statistics that are more general and critical than typically found in traditional introductory expositions, and provided an explanatory list of 25 misinterpretations of P values, confidence intervals, and power.
Abstract: Misinterpretation and abuse of statistical tests, confidence intervals, and statistical power have been decried for decades, yet remain rampant. A key problem is that there are no interpretations of these concepts that are at once simple, intuitive, correct, and foolproof. Instead, correct use and interpretation of these statistics requires an attention to detail which seems to tax the patience of working scientists. This high cognitive demand has led to an epidemic of shortcut definitions and interpretations that are simply wrong, sometimes disastrously so-and yet these misinterpretations dominate much of the scientific literature. In light of this problem, we provide definitions and a discussion of basic statistics that are more general and critical than typically found in traditional introductory expositions. Our goal is to provide a resource for instructors, researchers, and consumers of statistics whose knowledge of statistical theory and technique may be limited but who wish to avoid and spot misinterpretations. We emphasize how violation of often unstated analysis protocols (such as selecting analyses for presentation based on the P values they produce) can lead to small P values even if the declared test hypothesis is correct, and can lead to large P values even if that hypothesis is incorrect. We then provide an explanatory list of 25 misinterpretations of P values, confidence intervals, and power. We conclude with guidelines for improving statistical interpretation and reporting.
1,354 citations
TL;DR: In this paper, the authors present a spatial analysis of 2013-2015 national drinking water PFAS concentrations from the U.S. Environmental Protection Agency's (US EPA) third Unregulated Contaminant Monitoring Rule (UCMR3) program.
Abstract: Drinking water contamination with poly- and perfluoroalkyl substances (PFASs) poses risks to the developmental, immune, metabolic, and endocrine health of consumers. We present a spatial analysis of 2013–2015 national drinking water PFAS concentrations from the U.S. Environmental Protection Agency’s (US EPA) third Unregulated Contaminant Monitoring Rule (UCMR3) program. The number of industrial sites that manufacture or use these compounds, the number of military fire training areas, and the number of wastewater treatment plants are all significant predictors of PFAS detection frequencies and concentrations in public water supplies. Among samples with detectable PFAS levels, each additional military site within a watershed’s eight-digit hydrologic unit is associated with a 20% increase in PFHxS, a 10% increase in both PFHpA and PFOA, and a 35% increase in PFOS. The number of civilian airports with personnel trained in the use of aqueous film-forming foams is significantly associated with the detection of ...
744 citations
TL;DR: This randomised, double-blind, triple-dummy, placebo-controlled and active-controlled trial of varenicline and bupropion with nicotine patch and placebo in smokers with and without psychiatric disorders compared the relative neuropsychiatric safety risk and efficacy.
724 citations
TL;DR: In this paper, the authors present the ESTIMATE checklist, which includes a list of questions to consider when justifying the choice of analysis method, describing the analysis, and interpreting the results.
678 citations
TL;DR: Evidence supports efficacy of exposure therapy including the manualized version Prolonged Exposure (PE); cognitive therapy (CT), cognitive processing therapy (CPT), cognitive behavioral therapy (CBT)-mixed therapies ( moderate SOE); eye movement desensitization and reprocessing (EMDR) and narrative exposure therapy (low-moderate SOE).
540 citations
TL;DR: A transformation approach involving overexpression of the maize (Zea mays) Baby boom (Bbm) and maize Wuschel2 (Wus2) genes, which produced high transformation frequencies in numerous previously nontransformable maize inbred lines is reported.
Abstract: While transformation of the major monocot crops is currently possible, the process typically remains confined to one or two genotypes per species, often with poor agronomics, and efficiencies that place these methods beyond the reach of most academic laboratories. Here, we report a transformation approach involving overexpression of the maize (Zea mays) Baby boom (Bbm) and maize Wuschel2 (Wus2) genes, which produced high transformation frequencies in numerous previously nontransformable maize inbred lines. For example, the Pioneer inbred PHH5G is recalcitrant to biolistic and Agrobacterium tumefaciens transformation. However, when Bbm and Wus2 were expressed, transgenic calli were recovered from over 40% of the starting explants, with most producing healthy, fertile plants. Another limitation for many monocots is the intensive labor and greenhouse space required to supply immature embryos for transformation. This problem could be alleviated using alternative target tissues that could be supplied consistently with automated preparation. As a major step toward this objective, we transformed Bbm and Wus2 directly into either embryo slices from mature seed or leaf segments from seedlings in a variety of Pioneer inbred lines, routinely recovering healthy, fertile T0 plants. Finally, we demonstrated that the maize Bbm and Wus2 genes stimulate transformation in sorghum (Sorghum bicolor) immature embryos, sugarcane (Saccharum officinarum) callus, and indica rice (Oryza sativa ssp indica) callus.
516 citations
TL;DR: The new GSK Solvent Sustainability Guide enables GSK scientists to objectively assess solvents and facilitates both comparison of individual sustainability criteria, and a composite score and colour for rank ordering, incorporating multiple facets of sustainability.
475 citations
TL;DR: The Metabolicomics Workbench provides data from the Common Fund's Metabolomics Resource Cores, metabolite standards, and analysis tools to the wider metabolomics community and seeks data depositions from metabolomics researchers across the world.
Abstract: The Metabolomics Workbench, available at www.metabolomicsworkbench.org, is a public repository for metabolomics metadata and experimental data spanning various species and experimental platforms, metabolite standards, metabolite structures, protocols, tutorials, and training material and other educational resources. It provides a computational platform to integrate, analyze, track, deposit and disseminate large volumes of heterogeneous data from a wide variety of metabolomics studies including mass spectrometry (MS) and nuclear magnetic resonance spectrometry (NMR) data spanning over 20 different species covering all the major taxonomic categories including humans and other mammals, plants, insects, invertebrates and microorganisms. Additionally, a number of protocols are provided for a range of metabolite classes, sample types, and both MS and NMR-based studies, along with a metabolite structure database. The metabolites characterized in the studies available on the Metabolomics Workbench are linked to chemical structures in the metabolite structure database to facilitate comparative analysis across studies. The Metabolomics Workbench, part of the data coordinating effort of the National Institute of Health (NIH) Common Fund's Metabolomics Program, provides data from the Common Fund's Metabolomics Resource Cores, metabolite standards, and analysis tools to the wider metabolomics community and seeks data depositions from metabolomics researchers across the world.
452 citations
TL;DR: An analysis of data from two randomised, double-blind, placebo-controlled studies of at least 32 weeks duration has shown a close relationship between baseline blood eosinophil count and clinical efficacy of mepolizumab in patients with severe eOSinophilic asthma and a history of exacerbations.
Food and Drug Administration1, University of Birmingham2, Colorado State University3, Cornell University4, University of Barcelona5, University of Alberta6, University of Turku7, Leiden University8, Edith Cowan University9, Markey Cancer Center10, Research Triangle Park11, University of Luxembourg12, University of California, Davis13, King Abdulaziz University14, Duke University15
TL;DR: The narrow range of chemical analyses in current use by the medical community today will be replaced in the future by analyses that reveal a far more comprehensive metabolic signature, expected to describe global biochemical aberrations that reflect patterns of variance in states of wellness, more accurately describe specific diseases and their progression, and greatly aid in differential diagnosis.
Abstract: Metabolomics is the comprehensive study of the metabolome, the repertoire of biochemicals (or small molecules) present in cells, tissues, and body fluids. The study of metabolism at the global or “-omics” level is a rapidly growing field that has the potential to have a profound impact upon medical practice. At the center of metabolomics, is the concept that a person’s metabolic state provides a close representation of that individual’s overall health status. This metabolic state reflects what has been encoded by the genome, and modified by diet, environmental factors, and the gut microbiome. The metabolic profile provides a quantifiable readout of biochemical state from normal physiology to diverse pathophysiologies in a manner that is often not obvious from gene expression analyses. Today, clinicians capture only a very small part of the information contained in the metabolome, as they routinely measure only a narrow set of blood chemistry analytes to assess health and disease states. Examples include measuring glucose to monitor diabetes, measuring cholesterol and high density lipoprotein/low density lipoprotein ratio to assess cardiovascular health, BUN and creatinine for renal disorders, and measuring a panel of metabolites to diagnose potential inborn errors of metabolism in neonates. We anticipate that the narrow range of chemical analyses in current use by the medical community today will be replaced in the future by analyses that reveal a far more comprehensive metabolic signature. This signature is expected to describe global biochemical aberrations that reflect patterns of variance in states of wellness, more accurately describe specific diseases and their progression, and greatly aid in differential diagnosis. Such future metabolic signatures will: (1) provide predictive, prognostic, diagnostic, and surrogate markers of diverse disease states; (2) inform on underlying molecular mechanisms of diseases; (3) allow for sub-classification of diseases, and stratification of patients based on metabolic pathways impacted; (4) reveal biomarkers for drug response phenotypes, providing an effective means to predict variation in a subject’s response to treatment (pharmacometabolomics); (5) define a metabotype for each specific genotype, offering a functional read-out for genetic variants: (6) provide a means to monitor response and recurrence of diseases, such as cancers: (7) describe the molecular landscape in human performance applications and extreme environments. Importantly, sophisticated metabolomic analytical platforms and informatics tools have recently been developed that make it possible to measure thousands of metabolites in blood, other body fluids, and tissues. Such tools also enable more robust analysis of response to treatment. New insights have been gained about mechanisms of diseases, including neuropsychiatric disorders, cardiovascular disease, cancers, diabetes and a range of pathologies. A series of ground breaking studies supported by National Institute of Health (NIH) through the Pharmacometabolomics Research Network and its partnership with the Pharmacogenomics Research Network illustrate how a patient’s metabotype at baseline, prior to treatment, during treatment, and post-treatment, can inform about treatment outcomes and variations in responsiveness to drugs (e.g., statins, antidepressants, antihypertensives and antiplatelet therapies). These studies along with several others also exemplify how metabolomics data can complement and inform genetic data in defining ethnic, sex, and gender basis for variation in responses to treatment, which illustrates how pharmacometabolomics and pharmacogenomics are complementary and powerful tools for precision medicine. Our metabolomics community believes that inclusion of metabolomics data in precision medicine initiatives is timely and will provide an extremely valuable layer of data that compliments and informs other data obtained by these important initiatives. Our Metabolomics Society, through its “Precision Medicine and Pharmacometabolomics Task Group”, with input from our metabolomics community at large, has developed this White Paper where we discuss the value and approaches for including metabolomics data in large precision medicine initiatives. This White Paper offers recommendations for the selection of state of-the-art metabolomics platforms and approaches that offer the widest biochemical coverage, considers critical sample collection and preservation, as well as standardization of measurements, among other important topics. We anticipate that our metabolomics community will have representation in large precision medicine initiatives to provide input with regard to sample acquisition/preservation, selection of optimal omics technologies, and key issues regarding data collection, interpretation, and dissemination. We strongly recommend the collection and biobanking of samples for precision medicine initiatives that will take into consideration needs for large-scale metabolic phenotyping studies.
TL;DR: All-cause mortality was unaffected by combination therapy and secondary outcomes were on-treatment rate of decline in forced expiratory volume in 1 s (FEV1) and a composite of cardiovascular events, and therefore secondary outcomes should be interpreted with caution.
TL;DR: Unexpectedly, efficient spray-induced control of fungal infections in the distal tissue involved passage of CYP3-dsRNA via the plant vascular system and processing into small interfering (si)RNAs by fungal DICER-LIKE 1 (FgDCL-1) after uptake by the pathogen.
Abstract: Meeting the increasing food and energy demands of a growing population will require the development of ground-breaking strategies that promote sustainable plant production. Host-induced gene silencing has shown great potential for controlling pest and diseases in crop plants. However, while delivery of inhibitory noncoding double-stranded (ds)RNA by transgenic expression is a promising concept, it requires the generation of transgenic crop plants which may cause substantial delay for application strategies depending on the transformability and genetic stability of the crop plant species. Using the agronomically important barley—Fusarium graminearum pathosystem, we alternatively demonstrate that a spray application of a long noncoding dsRNA (791 nt CYP3-dsRNA), which targets the three fungal cytochrome P450 lanosterol C-14α-demethylases, required for biosynthesis of fungal ergosterol, inhibits fungal growth in the directly sprayed (local) as well as the non-sprayed (distal) parts of detached leaves. Unexpectedly, efficient spray-induced control of fungal infections in the distal tissue involved passage of CYP3-dsRNA via the plant vascular system and processing into small interfering (si)RNAs by fungal DICER-LIKE 1 (FgDCL-1) after uptake by the pathogen. We discuss important consequences of this new finding on future RNA-based disease control strategies. Given the ease of design, high specificity, and applicability to diverse pathogens, the use of target-specific dsRNA as an anti-fungal agent offers unprecedented potential as a new plant protection strategy.
TL;DR: The performance of emerging air quality sensor technologies in a real-world setting is demonstrated; the variable agreement between sensors and reference monitors indicates that in situ testing of sensors against benchmark monitors should be a critical aspect of all field studies.
Abstract: . Advances in air pollution sensor technology have enabled the development of small and low-cost systems to measure outdoor air pollution. The deployment of a large number of sensors across a small geographic area would have potential benefits to supplement traditional monitoring networks with additional geographic and temporal measurement resolution, if the data quality were sufficient. To understand the capability of emerging air sensor technology, the Community Air Sensor Network (CAIRSENSE) project deployed low-cost, continuous, and commercially available air pollution sensors at a regulatory air monitoring site and as a local sensor network over a surrounding ∼ 2 km area in the southeastern United States. Collocation of sensors measuring oxides of nitrogen, ozone, carbon monoxide, sulfur dioxide, and particles revealed highly variable performance, both in terms of comparison to a reference monitor as well as the degree to which multiple identical sensors produced the same signal. Multiple ozone, nitrogen dioxide, and carbon monoxide sensors revealed low to very high correlation with a reference monitor, with Pearson sample correlation coefficient (r) ranging from 0.39 to 0.97, −0.25 to 0.76, and −0.40 to 0.82, respectively. The only sulfur dioxide sensor tested revealed no correlation (r 0.5), step-wise multiple linear regression was performed to determine if ambient temperature, relative humidity (RH), or age of the sensor in number of sampling days could be used in a correction algorithm to improve the agreement. Maximum improvement in agreement with a reference, incorporating all factors, was observed for an NO2 sensor (multiple correlation coefficient R2adj-orig = 0.57, R2adj-final = 0.81); however, other sensors showed no apparent improvement in agreement. A four-node sensor network was successfully able to capture ozone (two nodes) and PM (four nodes) data for an 8-month period of time and show expected diurnal concentration patterns, as well as potential ozone titration due to nearby traffic emissions. Overall, this study demonstrates the performance of emerging air quality sensor technologies in a real-world setting; the variable agreement between sensors and reference monitors indicates that in situ testing of sensors against benchmark monitors should be a critical aspect of all field studies.
Georgia Institute of Technology1, Earth System Research Laboratory2, University of Colorado Boulder3, University of Cambridge4, University of Miami5, University of California, Berkeley6, Max Planck Society7, Cooperative Institute for Research in Environmental Sciences8, Carnegie Mellon University9, Reed College10, Forschungszentrum Jülich11, Rice University12, University of Kentucky13, Leibniz Association14, University of Washington15, Research Triangle Park16, Princeton University17, Geophysical Fluid Dynamics Laboratory18, University of Alaska Fairbanks19, York University20, University of Calgary21, Paris Diderot University22, Heidelberg University23, Weizmann Institute of Science24, University of California, Irvine25, Washington University in St. Louis26
TL;DR: Impacts of NO3-BVOC chemistry on air quality and climate are outlined, and critical research needs to better constrain this interaction to improve the predictive capabilities of atmospheric models.
Abstract: . Oxidation of biogenic volatile organic compounds (BVOC) by the nitrate radical (NO3) represents one of the important interactions between anthropogenic emissions related to combustion and natural emissions from the biosphere. This interaction has been recognized for more than 3 decades, during which time a large body of research has emerged from laboratory, field, and modeling studies. NO3-BVOC reactions influence air quality, climate and visibility through regional and global budgets for reactive nitrogen (particularly organic nitrates), ozone, and organic aerosol. Despite its long history of research and the significance of this topic in atmospheric chemistry, a number of important uncertainties remain. These include an incomplete understanding of the rates, mechanisms, and organic aerosol yields for NO3-BVOC reactions, lack of constraints on the role of heterogeneous oxidative processes associated with the NO3 radical, the difficulty of characterizing the spatial distributions of BVOC and NO3 within the poorly mixed nocturnal atmosphere, and the challenge of constructing appropriate boundary layer schemes and non-photochemical mechanisms for use in state-of-the-art chemical transport and chemistry–climate models. This review is the result of a workshop of the same title held at the Georgia Institute of Technology in June 2015. The first half of the review summarizes the current literature on NO3-BVOC chemistry, with a particular focus on recent advances in instrumentation and models, and in organic nitrate and secondary organic aerosol (SOA) formation chemistry. Building on this current understanding, the second half of the review outlines impacts of NO3-BVOC chemistry on air quality and climate, and suggests critical research needs to better constrain this interaction to improve the predictive capabilities of atmospheric models.
TL;DR: Findings show that early-life antibiotic treatments alter the gut microbiota and its metabolic capacities, intestinal gene expression and T-cell populations, accelerating T1D onset in non-obese diabetic mice.
Abstract: The early life microbiome plays important roles in host immunological and metabolic development. Because the incidence of type 1 diabetes (T1D) has been increasing substantially in recent decades, we hypothesized that early-life antibiotic use alters gut microbiota, which predisposes to disease. Using non-obese diabetic mice that are genetically susceptible to T1D, we examined the effects of exposure to either continuous low-dose antibiotics or pulsed therapeutic antibiotics (PAT) early in life, mimicking childhood exposures. We found that in mice receiving PAT, T1D incidence was significantly higher, and microbial community composition and structure differed compared with controls. In pre-diabetic male PAT mice, the intestinal lamina propria had lower Th17 and Treg proportions and intestinal SAA expression than in controls, suggesting key roles in transducing the altered microbiota signals. PAT affected microbial lipid metabolism and host cholesterol biosynthetic gene expression. These findings show that early-life antibiotic treatments alter the gut microbiota and its metabolic capacities, intestinal gene expression and T-cell populations, accelerating T1D onset in non-obese diabetic mice.
TL;DR: Baseline blood eosinophil levels may represent an informative marker for exacerbation reduction with ICS/LABA in patients with COPD and a history of moderate/severe exacerbations.
Abstract: Objective We performed a review of studies of fluticasone propionate (FP)/salmeterol (SAL) (combination inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA)) in patients with COPD, which measured baseline (pretreatment) blood eosinophil levels, to test whether blood eosinophil levels ≥2% were associated with a greater reduction in exacerbation rates with ICS therapy.
Methods Three studies of ≥1-year duration met the inclusion criteria. Moderate and severe exacerbation rates were analysed according to baseline blood eosinophil levels (<2% vs ≥2%). At baseline, 57–75% of patients had ≥2% blood eosinophils. Changes in FEV1 and St George's Respiratory Questionnaire (SGRQ) scores were compared by eosinophil level.
Results For patients with ≥2% eosinophils, FP/SAL was associated with significant reductions in exacerbation rates versus tiotropium (INSPIRE: n=719, rate ratio (RR)=0.75, 95% CI 0.60 to 0.92, p=0.006) and versus placebo (TRISTAN: n=1049, RR=0.63, 95% CI 0.50 to 0.79, p<0.001). No significant difference was seen in the <2% eosinophil subgroup in either study (INSPIRE: n=550, RR=1.18, 95% CI 0.92 to 1.51, p=0.186; TRISTAN: n=354, RR=0.99, 95% CI 0.67 to 1.47, p=0.957, respectively). In SCO30002 (n=373), no significant effects were observed (FP or FP/SAL vs placebo). No relationship was observed in any study between eosinophil subgroup and treatment effect on FEV1 and SGRQ.
Discussion Baseline blood eosinophil levels may represent an informative marker for exacerbation reduction with ICS/LABA in patients with COPD and a history of moderate/severe exacerbations.
TL;DR: A thorough characterization of the Published Kinase Inhibitor Set is provided and chemical starting points for designing new chemical probes of orphan kinases are identified and the utility of these leads are illustrated by developing a selective inhibitor for the previously untargeted kinases LOK and SLK.
Abstract: Despite the success of protein kinase inhibitors as approved therapeutics, drug discovery has focused on a small subset of kinase targets. Here we provide a thorough characterization of the Published Kinase Inhibitor Set (PKIS), a set of 367 small-molecule ATP-competitive kinase inhibitors that was recently made freely available with the aim of expanding research in this field and as an experiment in open-source target validation. We screen the set in activity assays with 224 recombinant kinases and 24 G protein-coupled receptors and in cellular assays of cancer cell proliferation and angiogenesis. We identify chemical starting points for designing new chemical probes of orphan kinases and illustrate the utility of these leads by developing a selective inhibitor for the previously untargeted kinases LOK and SLK. Our cellular screens reveal compounds that modulate cancer cell growth and angiogenesis in vitro. These reagents and associated data illustrate an efficient way forward to increasing understanding of the historically untargeted kinome.
University of California, San Diego1, BC Cancer Research Centre2, University of Arkansas for Medical Sciences3, Oregon Health & Science University4, Drexel University5, University of Maryland, Baltimore6, Thermo Fisher Scientific7, Simon Fraser University8, Vrije Universiteit Brussel9, Stanford University10, Research Triangle Park11, National Institutes of Health12, Royal Society of Chemistry13, University of Oxford14, University of Michigan15, University at Buffalo16, Newcastle University17, European Bioinformatics Institute18, University of Pennsylvania19, Southern Methodist University20, University of Manchester21, La Jolla Institute for Allergy and Immunology22, J. Craig Venter Institute23, Leibniz Association24, Brunel University London25, Georgia State University26
TL;DR: The state of OBI and several applications that are using it are described, such as adding semantic expressivity to existing databases, building data entry forms, and enabling interoperability between knowledge resources.
Abstract: The Ontology for Biomedical Investigations (OBI) is an ontology that provides terms with precisely defined meanings to describe all aspects of how investigations in the biological and medical domains are conducted. OBI re-uses ontologies that provide a representation of biomedical knowledge from the Open Biological and Biomedical Ontologies (OBO) project and adds the ability to describe how this knowledge was derived. We here describe the state of OBI and several applications that are using it, such as adding semantic expressivity to existing databases, building data entry forms, and enabling interoperability between knowledge resources. OBI covers all phases of the investigation process, such as planning, execution and reporting. It represents information and material entities that participate in these processes, as well as roles and functions. Prior to OBI, it was not possible to use a single internally consistent resource that could be applied to multiple types of experiments for these applications. OBI has made this possible by creating terms for entities involved in biological and medical investigations and by importing parts of other biomedical ontologies such as GO, Chemical Entities of Biological Interest (ChEBI) and Phenotype Attribute and Trait Ontology (PATO) without altering their meaning. OBI is being used in a wide range of projects covering genomics, multi-omics, immunology, and catalogs of services. OBI has also spawned other ontologies (Information Artifact Ontology) and methods for importing parts of ontologies (Minimum information to reference an external ontology term (MIREOT)). The OBI project is an open cross-disciplinary collaborative effort, encompassing multiple research communities from around the globe. To date, OBI has created 2366 classes and 40 relations along with textual and formal definitions. The OBI Consortium maintains a web resource (http://obi-ontology.org) providing details on the people, policies, and issues being addressed in association with OBI. The current release of OBI is available at http://purl.obolibrary.org/obo/obi.owl.
TL;DR: Adopting stronger policies to reduce establishments of new forest insects and diseases would shift the major costs of control to the source and alleviate the economic burden now borne by homeowners and municipalities.
Abstract: We review and synthesize information on invasions of nonnative forest insects and diseases in the United States, including their ecological and economic impacts, pathways of arrival, distribution within the United States, and policy options for reducing future invasions. Nonnative insects have accumulated in United States forests at a rate of ~2.5 per yr over the last 150 yr. Currently the two major pathways of introduction are importation of live plants and wood packing material such as pallets and crates. Introduced insects and diseases occur in forests and cities throughout the United States, and the problem is particularly severe in the Northeast and Upper Midwest. Nonnative forest pests are the only disturbance agent that has effectively eliminated entire tree species or genera from United States forests within decades. The resulting shift in forest structure and species composition alters ecosystem functions such as productivity, nutrient cycling, and wildlife habitat. In urban and suburban areas, loss of trees from streets, yards, and parks affects aesthetics, property values, shading, stormwater runoff, and human health. The economic damage from nonnative pests is not yet fully known, but is likely in the billions of dollars per year, with the majority of this economic burden borne by municipalities and residential property owners. Current policies for preventing introductions are having positive effects but are insufficient to reduce the influx of pests in the face of burgeoning global trade. Options are available to strengthen the defenses against pest arrival and establishment, including measures taken in the exporting country prior to shipment, measures to ensure clean shipments of plants and wood products, inspections at ports of entry, and post-entry measures such as quarantines, surveillance, and eradication programs. Improved data collection procedures for inspections, greater data accessibility, and better reporting would support better evaluation of policy effectiveness. Lack of additional action places the nation, local municipalities, and property owners at high risk of further damaging and costly invasions. Adopting stronger policies to reduce establishments of new forest insects and diseases would shift the major costs of control to the source and alleviate the economic burden now borne by homeowners and municipalities.
TL;DR: An aqueous-phase mechanism for isoprene SOA formation coupled to a detailed gas-phase isopane oxidation scheme is developed, based on aerosol reactive uptake coefficients for water-soluble isopene oxidation products, including sensitivity to aerosol acidity and nucleophile concentrations.
Abstract: . Isoprene emitted by vegetation is an important precursor of secondary organic aerosol (SOA), but the mechanism and yields are uncertain. Aerosol is prevailingly aqueous under the humid conditions typical of isoprene-emitting regions. Here we develop an aqueous-phase mechanism for isoprene SOA formation coupled to a detailed gas-phase isoprene oxidation scheme. The mechanism is based on aerosol reactive uptake coefficients (γ) for water-soluble isoprene oxidation products, including sensitivity to aerosol acidity and nucleophile concentrations. We apply this mechanism to simulation of aircraft (SEAC4RS) and ground-based (SOAS) observations over the southeast US in summer 2013 using the GEOS-Chem chemical transport model. Emissions of nitrogen oxides (NOx ≡ NO + NO2) over the southeast US are such that the peroxy radicals produced from isoprene oxidation (ISOPO2) react significantly with both NO (high-NOx pathway) and HO2 (low-NOx pathway), leading to different suites of isoprene SOA precursors. We find a mean SOA mass yield of 3.3 % from isoprene oxidation, consistent with the observed relationship of total fine organic aerosol (OA) and formaldehyde (a product of isoprene oxidation). Isoprene SOA production is mainly contributed by two immediate gas-phase precursors, isoprene epoxydiols (IEPOX, 58 % of isoprene SOA) from the low-NOx pathway and glyoxal (28 %) from both low- and high-NOx pathways. This speciation is consistent with observations of IEPOX SOA from SOAS and SEAC4RS. Observations show a strong relationship between IEPOX SOA and sulfate aerosol that we explain as due to the effect of sulfate on aerosol acidity and volume. Isoprene SOA concentrations increase as NOx emissions decrease (favoring the low-NOx pathway for isoprene oxidation), but decrease more strongly as SO2 emissions decrease (due to the effect of sulfate on aerosol acidity and volume). The US Environmental Protection Agency (EPA) projects 2013–2025 decreases in anthropogenic emissions of 34 % for NOx (leading to a 7 % increase in isoprene SOA) and 48 % for SO2 (35 % decrease in isoprene SOA). Reducing SO2 emissions decreases sulfate and isoprene SOA by a similar magnitude, representing a factor of 2 co-benefit for PM2.5 from SO2 emission controls.
Research Triangle Park1, Umeå University2, Mario Negri Institute for Pharmacological Research3, University of North Carolina at Chapel Hill4, University of Strasbourg5, National Institutes of Health6, United States Environmental Protection Agency7, University of Bari8, Technical University of Denmark9, University of Milano-Bicocca10, Food and Drug Administration11, Lockheed Martin Corporation12, Research Institute for Fragrance Materials13, University of Milan14, United States Department of Agriculture15
TL;DR: This project demonstrated the possibility to screen large libraries of chemicals using a consensus of different in silico approaches and the efficacy of using predictive computational models trained on high-throughput screening data to evaluate thousands of chemicals for ER-related activity and prioritize them for further testing.
Abstract: BACKGROUND: Humans are exposed to thousands of man-made chemicals in the environment. Some chemicals mimic natural endocrine hormones and, thus, have the potential to be endocrine disruptors. Most ...
TL;DR: In this article, the authors reveal the molecular mechanism of p62/Sqstm1-dependent malignant progression, and suggest that molecular targeting of P62/sqstmm1 represents a potential chemotherapeutic approach against hepatocellular carcinoma (HCC).
Abstract: p62/Sqstm1 is a multifunctional protein involved in cell survival, growth and death, that is degraded by autophagy. Amplification of the p62/Sqstm1 gene, and aberrant accumulation and phosphorylation of p62/Sqstm1, have been implicated in tumour development. Herein, we reveal the molecular mechanism of p62/Sqstm1-dependent malignant progression, and suggest that molecular targeting of p62/Sqstm1 represents a potential chemotherapeutic approach against hepatocellular carcinoma (HCC). Phosphorylation of p62/Sqstm1 at Ser349 directs glucose to the glucuronate pathway, and glutamine towards glutathione synthesis through activation of the transcription factor Nrf2. These changes provide HCC cells with tolerance to anti-cancer drugs and proliferation potency. Phosphorylated p62/Sqstm1 accumulates in tumour regions positive for hepatitis C virus (HCV). An inhibitor of phosphorylated p62-dependent Nrf2 activation suppresses the proliferation and anticancer agent tolerance of HCC. Our data indicate that this Nrf2 inhibitor could be used to make cancer cells less resistant to anticancer drugs, especially in HCV-positive HCC patients.
TL;DR: E-cigarette use has increased rapidly among U.S. adults and efforts are warranted to provide consumers with accurate information on the health effects of e-cigarettes and to ensure that flavoring and other unregulated features do not promote nicotine addiction, particularly among young adults.
TL;DR: Substantial, targeted control of tomato softening is reported, without affecting other aspects of ripening, by silencing a gene encoding a pectate lyase.
Abstract: Controlling the rate of softening to extend shelf life was a key target for researchers engineering genetically modified (GM) tomatoes in the 1990s, but only modest improvements were achieved. Hybrids grown nowadays contain 'non-ripening mutations' that slow ripening and improve shelf life, but adversely affect flavor and color. We report substantial, targeted control of tomato softening, without affecting other aspects of ripening, by silencing a gene encoding a pectate lyase.
TL;DR: Mepolizumab treatment was shown to exert a durable response, with patients who previously received mepolizumAB in MENSA or SIRIUS maintaining reductions in exacerbation rate and OCS dosing throughout COSMOS.
University of California, Berkeley1, University of Texas at El Paso2, University of California, Los Angeles3, Purdue University4, National Institute of Chemical Physics and Biophysics5, Fraunhofer Society6, Research Triangle Park7, University of Girona8, Spanish National Research Council9, Swiss Federal Institute of Aquatic Science and Technology10, ETH Zurich11, European Chemicals Agency12, Duke University13, Heriot-Watt University14, United States Environmental Protection Agency15, DuPont16, Ca' Foscari University of Venice17, Brown University18, University of Illinois at Urbana–Champaign19, National Institute of Standards and Technology20, GlobalFoundries21, Environment Canada22, Arizona State University23, Connecticut Agricultural Experiment Station24, University of Massachusetts Amherst25
TL;DR: Environmental realism in ENM hazard assessments should involve greater coordination among ENM quantitative analysts, exposure modelers, and ecotoxicologists, across government, industry, and academia.
Abstract: 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
TL;DR: Binge-eating disorder is associated with poorer psychological and physical well-being, including major depressive and other psychiatric disorders, and the use of cognitive behavioral therapy (CBT) and selective serotonin reuptake inhibitors, but they differ in content and timing.
Abstract: Background The best treatment options for binge-eating disorder are unclear. Purpose To summarize evidence about the benefits and harms of psychological and pharmacologic therapies for adults with binge-eating disorder. Data sources English-language publications in EMBASE, the Cochrane Library, Academic OneFile, CINAHL, and ClinicalTrials.gov through 18 November 2015, and in MEDLINE through 12 May 2016. Study selection 9 waitlist-controlled psychological trials and 25 placebo-controlled trials that evaluated pharmacologic (n = 19) or combination (n = 6) treatment. All were randomized trials with low or medium risk of bias. Data extraction 2 reviewers independently extracted trial data, assessed risk of bias, and graded strength of evidence. Data synthesis Therapist-led cognitive behavioral therapy, lisdexamfetamine, and second-generation antidepressants (SGAs) decreased binge-eating frequency and increased binge-eating abstinence (relative risk, 4.95 [95% CI, 3.06 to 8.00], 2.61 [CI, 2.04 to 3.33], and 1.67 [CI, 1.24 to 2.26], respectively). Lisdexamfetamine (mean difference [MD], -6.50 [CI, -8.82 to -4.18]) and SGAs (MD, -3.84 [CI, -6.55 to -1.13]) reduced binge-eating-related obsessions and compulsions, and SGAs reduced symptoms of depression (MD, -1.97 [CI, -3.67 to -0.28]). Headache, gastrointestinal upset, sleep disturbance, and sympathetic nervous system arousal occurred more frequently with lisdexamfetamine than placebo (relative risk range, 1.63 to 4.28). Other forms of cognitive behavioral therapy and topiramate also increased abstinence and reduced binge-eating frequency and related psychopathology. Topiramate reduced weight and increased sympathetic nervous system arousal, and lisdexamfetamine reduced weight and appetite. Limitations Most study participants were overweight or obese white women aged 20 to 40 years. Many treatments were examined only in single studies. Outcomes were measured inconsistently across trials and rarely assessed beyond end of treatment. Conclusion Cognitive behavioral therapy, lisdexamfetamine, SGAs, and topiramate reduced binge eating and related psychopathology, and lisdexamfetamine and topiramate reduced weight in adults with binge-eating disorder. Primary funding source Agency for Healthcare Research and Quality.
TL;DR: The results therefore provide the earliest report of MOF-nanofiber textile composites capable of ultra-fast degradation of CWAs and exhibit excellent reactivity for detoxifying CWAs.
Abstract: The threat associated with chemical warfare agents (CWAs) motivates the development of new materials to provide enhanced protection with a reduced burden. Metal–organic frame-works (MOFs) have recently been shown as highly effective catalysts for detoxifying CWAs, but challenges still remain for integrating MOFs into functional filter media and/or protective garments. Herein, we report a series of MOF–nanofiber kebab structures for fast degradation of CWAs. We found TiO2 coatings deposited via atomic layer deposition (ALD) onto polyamide-6 nanofibers enable the formation of conformal Zr-based MOF thin films including UiO-66, UiO-66-NH2, and UiO-67. Cross-sectional TEM images show that these MOF crystals nucleate and grow directly on and around the nanofibers, with strong attachment to the substrates. These MOF-functionalized nanofibers exhibit excellent reactivity for detoxifying CWAs. The half-lives of a CWA simulant compound and nerve agent soman (GD) are as short as 7.3 min and 2.3 min, respectively. These results therefore provide the earliest report of MOF–nanofiber textile composites capable of ultra-fast degradation of CWAs.