Novel antibiotics are urgently needed to address the looming global crisis of antibiotic resistance. Historically, the primary source of clinically used antibiotics has been microbial secondary ...metabolism. Microbial genome sequencing has revealed a plethora of uncharacterized natural antibiotics that remain to be discovered. However, the isolation of these molecules is hindered by the challenge of linking sequence information to the chemical structures of the encoded molecules. Here, we present PRISM 4, a comprehensive platform for prediction of the chemical structures of genomically encoded antibiotics, including all classes of bacterial antibiotics currently in clinical use. The accuracy of chemical structure prediction enables the development of machine-learning methods to predict the likely biological activity of encoded molecules. We apply PRISM 4 to chart secondary metabolite biosynthesis in a collection of over 10,000 bacterial genomes from both cultured isolates and metagenomic datasets, revealing thousands of encoded antibiotics. PRISM 4 is freely available as an interactive web application at http://prism.adapsyn.com .
Increasing evidence suggests that the lung microbiome plays an important role in chronic obstructive pulmonary disease (COPD) severity. However, the dynamics of the lung microbiome during COPD ...exacerbations and its potential role in disease aetiology remain poorly understood.We completed a longitudinal 16S ribosomal RNA survey of the lung microbiome on 476 sputum samples collected from 87 subjects with COPD at four visits defined as stable state, exacerbation, 2 weeks post-therapy and 6 weeks recovery.Our analysis revealed a dynamic lung microbiota where changes appeared to be associated with exacerbation events and indicative of specific exacerbation phenotypes. Antibiotic and steroid treatments appear to have differential effects on the lung microbiome. We depict a microbial interaction network for the lung microbiome and suggest that perturbation of a few bacterial operational taxonomic units, in particular Haemophilus spp., could greatly impact the overall microbial community structure. Furthermore, several serum and sputum biomarkers, in particular sputum interleukin-8, appear to be highly correlated with the structure and diversity of the microbiome.Our study furthers the understanding of lung microbiome dynamics in COPD patients and highlights its potential as a biomarker, and possibly a target, for future respiratory therapeutics.
Respiratory viral infections represent the most common cause of allergic asthma exacerbations. Amplification of the type-2 immune response is strongly implicated in asthma exacerbation, but how virus ...infection boosts type-2 responses is poorly understood. We report a significant correlation between the release of host double-stranded DNA (dsDNA) following rhinovirus infection and the exacerbation of type-2 allergic inflammation in humans. In a mouse model of allergic airway hypersensitivity, we show that rhinovirus infection triggers dsDNA release associated with the formation of neutrophil extracellular traps (NETs), known as NETosis. We further demonstrate that inhibiting NETosis by blocking neutrophil elastase or by degrading NETs with DNase protects mice from type-2 immunopathology. Furthermore, the injection of mouse genomic DNA alone is sufficient to recapitulate many features of rhinovirus-induced type-2 immune responses and asthma pathology. Thus, NETosis and its associated extracellular dsDNA contribute to the pathogenesis and may represent potential therapeutic targets of rhinovirus-induced asthma exacerbations.
Viral respiratory tract infections are associated with asthma inception in early life and asthma exacerbations in older children and adults. Although how viruses influence asthma inception is poorly ...understood, much research has focused on the host response to respiratory viruses and how viruses can promote; or how the host response is affected by subsequent allergen sensitization and exposure. This review focuses on the innate interferon-mediated host response to respiratory viruses and discusses and summarizes the available evidence that this response is impaired or suboptimal. In addition, the ability of respiratory viruses to act in a synergistic or additive manner with TH2 pathways will be discussed. In this review we argue that these 2 outcomes are likely linked and discuss the available evidence that shows reciprocal negative regulation between innate interferons and TH2 mediators. With the renewed interest in anti-TH2 biologics, we propose a rationale for why they are particularly successful in controlling asthma exacerbations and suggest ways in which future clinical studies could be used to find direct evidence for this hypothesis.
Major issues in the implementation of screening for lung cancer by means of low-dose computed tomography (CT) are the definition of a positive result and the management of lung nodules detected on ...the scans. We conducted a population-based prospective study to determine factors predicting the probability that lung nodules detected on the first screening low-dose CT scans are malignant or will be found to be malignant on follow-up.
We analyzed data from two cohorts of participants undergoing low-dose CT screening. The development data set included participants in the Pan-Canadian Early Detection of Lung Cancer Study (PanCan). The validation data set included participants involved in chemoprevention trials at the British Columbia Cancer Agency (BCCA), sponsored by the U.S. National Cancer Institute. The final outcomes of all nodules of any size that were detected on baseline low-dose CT scans were tracked. Parsimonious and fuller multivariable logistic-regression models were prepared to estimate the probability of lung cancer.
In the PanCan data set, 1871 persons had 7008 nodules, of which 102 were malignant, and in the BCCA data set, 1090 persons had 5021 nodules, of which 42 were malignant. Among persons with nodules, the rates of cancer in the two data sets were 5.5% and 3.7%, respectively. Predictors of cancer in the model included older age, female sex, family history of lung cancer, emphysema, larger nodule size, location of the nodule in the upper lobe, part-solid nodule type, lower nodule count, and spiculation. Our final parsimonious and full models showed excellent discrimination and calibration, with areas under the receiver-operating-characteristic curve of more than 0.90, even for nodules that were 10 mm or smaller in the validation set.
Predictive tools based on patient and nodule characteristics can be used to accurately estimate the probability that lung nodules detected on baseline screening low-dose CT scans are malignant. (Funded by the Terry Fox Research Institute and others; ClinicalTrials.gov number, NCT00751660.).
Lung cancer may be prevented by a diet rich in fruits and vegetables as they are enriched with dietary antioxidant polyphenols, such as flavonoids, proanthocyanidins, lignans, stilbenes, and phenolic ...acids. Dietary polyphenols exert a wide range of beneficial biological functions beyond their antioxidative properties and are involved in regulation of cell survival pathways leading to anticarcinogenic and antimutagenic functions. There are sufficient evidence from in vitro, in vivo, and epidemiological studies to suggest that the dietary intervention of polyphenols in cancer prevention, including the chemopreventive ability of dietary polyphenols, act against lung carcinogens. Cohort and epidemiological studies in selected risk populations have evaluated clinical effects of polyphenols. Polyphenols have demonstrated three major actions: antioxidative activity, regulation of phase I and II enzymes, and regulation of cell survival pathways against lung carcinogenesis. They have also shown an inverse association of lung cancer occurrences among high risk populations who consumed considerable amounts of fruits and vegetables in their daily diet. In in vitro cell culture experimental models, polyphenols bind with electrophilic metabolites from carcinogens, inactivate cellular oxygen radicals, prevent membrane lipid peroxidation and DNA oxidative damage, and adduct formation. Further, polyphenols enhance the detoxifying enzymes such as the phase II enzymes, glutathione transferases and glucuronosyl transferases.
The relative roles of the endosomal TLR3/7/8 versus the intracellular RNA helicases RIG-I and MDA5 in viral infection is much debated. We investigated the roles of each pattern recognition receptor ...in rhinovirus infection using primary bronchial epithelial cells. TLR3 was constitutively expressed; however, RIG-I and MDA5 were inducible by 8-12 h following rhinovirus infection. Bronchial epithelial tissue from normal volunteers challenged with rhinovirus in vivo exhibited low levels of RIG-I and MDA5 that were increased at day 4 post infection. Inhibition of TLR3, RIG-I and MDA5 by siRNA reduced innate cytokine mRNA, and increased rhinovirus replication. Inhibition of TLR3 and TRIF using siRNA reduced rhinovirus induced RNA helicases. Furthermore, IFNAR1 deficient mice exhibited RIG-I and MDA5 induction early during RV1B infection in an interferon independent manner. Hence anti-viral defense within bronchial epithelium requires co-ordinated recognition of rhinovirus infection, initially via TLR3/TRIF and later via inducible RNA helicases.
Rhinoviruses (RVs), which are the most common cause of virally induced asthma exacerbations, account for much of the burden of asthma in terms of morbidity, mortality, and associated cost. ...Interleukin-25 (IL-25) activates type 2-driven inflammation and is therefore potentially important in virally induced asthma exacerbations. To investigate this, we examined whether RV-induced IL-25 could contribute to asthma exacerbations. RV-infected cultured asthmatic bronchial epithelial cells exhibited a heightened intrinsic capacity for IL-25 expression, which correlated with donor atopic status. In vivo human IL-25 expression was greater in asthmatics at baseline and during experimental RV infection. In addition, in mice, RV infection induced IL-25 expression and augmented allergen-induced IL-25. Blockade of the IL-25 receptor reduced many RV-induced exacerbation-specific responses including type 2 cytokine expression, mucus production, and recruitment of eosinophils, neutrophils, basophils, and T and non-T type 2 cells. Therefore, asthmatic epithelial cells have an increased intrinsic capacity for expression of a pro-type 2 cytokine in response to a viral infection, and IL-25 is a key mediator of RV-induced exacerbations of pulmonary inflammation.
The standard for measuring solar irradiance utilizes the units of watts per meter squared (W/m 2 ). Irradiance meters are both costly and limited in the ability to measure low irradiance values. With ...a lower cost and higher sensitivity in low light conditions, light meters measure luminous flux per unit area (illuminance) utilizing the units of lumens per meter squared or lux (lx). An effective conversion factor between W/m 2 and lx would enable the use of light meters to evaluate photovoltaic performance under low solar irradiance conditions. A survey of the literature found no definitive and readily available “rule of thumb” conversion standard between solar irradiance and illuminance. Easy-to-find Internet sources contain conflicting and widely varying values ranging from 688449 to 21000 lx for 1000 W/m 2 (1 Sun) of solar irradiance. Peer-reviewed literature contains Luminous Efficacy equivalent values ranging from 21 to 131 lx per W/m 2 . This manuscript explores the relationship and establishes a theoretical and laboratory measurement guide for the conversion between solar irradiance and illuminance. The conversion factor includes standards data, equipment calibration accuracy, and uncertainty estimates. Solar Irradiance of 1 Sun (1000 W/m 2 ) for an LED-based solar simulator is (116 ± 3) klx and (122 ± 1) klx for outdoor sunlight.
Background Helminth parasites have been reported to have beneficial immunomodulatory effects in patients with allergic and autoimmune conditions and detrimental consequences in patients with ...tuberculosis and some viral infections. Their role in coinfection with respiratory viruses is not clear. Objective Here we investigated the effects of strictly enteric helminth infection with Heligmosomoides polygyrus on respiratory syncytial virus (RSV) infection in a mouse model. Methods A murine helminth/RSV coinfection model was developed. Mice were infected by means of oral gavage with 200 stage 3 H polygyrus larvae. Ten days later, mice were infected intranasally with either RSV or UV-inactivated RSV. Results H polygyrus –infected mice showed significantly less disease and pulmonary inflammation after RSV infection associated with reduced viral load. Adaptive immune responses, including TH 2 responses, were not essential because protection against RSV was maintained in Rag1 −/− and Il4rα −/− mice. Importantly, H polygyrus infection upregulated expression of type I interferons and interferon-stimulated genes in both the duodenum and lung, and its protective effects were lost in both Ifnar1 −/− and germ-free mice, revealing essential roles for type I interferon signaling and microbiota in H polygyrus –induced protection against RSV. Conclusion These data demonstrate that a strictly enteric helminth infection can have remote protective antiviral effects in the lung through induction of a microbiota-dependent type I interferon response.
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