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Journal articleSinganayagam A, Johnston SL, 2016,
Smoke and viruses-a hindrance to relaxing the airways?
, Clinical Science, Vol: 130, Pages: 839-841, ISSN: 1470-8736Inhaled β2-adrenoceptor agonists are a mainstay of therapy for airways diseases and are almost universally prescribed for patients with asthma or chronic obstructive pulmonary disease (COPD). Very few studies have evaluated the efficacy of these commonly used therapies during acute disease exacerbations which are frequently triggered by viral infection. In this edition of Clinical Science, Donovan et al. assess the ex vivo effects of the most commonly used short-acting β2-agonist salbutamol on small airway reactivity using precision cut lung slices (PCLS) from a mouse model of virus-induced exacerbation of COPD. They demonstrate that combined challenge with cigarette smoke and influenza infection in mice markedly impairs salbutamol-mediated airway relaxation. The findings of the present study suggest that cigarette smoke and respiratory virus infection may intefere with the ability of commonly prescribed therapies to effectively bronchodilate the airways.
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Journal articleWebb AJ, Kelwick R, Doenhoff MJ, et al., 2016,
A protease-based biosensor for the detection of schistosome cercariae
, Scientific Reports, Vol: 6, ISSN: 2045-2322Parasitic diseases affect millions of people worldwide, causing debilitating illnesses anddeath. Rapid and cost-effective approaches to detect parasites are needed, especially inresource-limited settings. A common signature of parasitic diseases is the release of specificproteases by the parasites at multiple stages during their life cycles. To this end, weengineered several modular Escherichia coli and Bacillus subtilis whole-cell-basedbiosensors which incorporate an interchangeable protease recognition motif into theirdesigns. Herein, we describe how several of our engineered biosensors have been applied todetect the presence and activity of elastase, an enzyme released by the cercarial larvae stageof Schistosoma mansoni. Collectively, S. mansoni and several other schistosomes areresponsible for the infection of an estimated 200 million people worldwide. Since ourbiosensors are maintained in lyophilised cells, they could be applied for the detection of S.mansoni and other parasites in settings without reliable cold chain access.
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Journal articleByrne B, Alguel Y, Scull NJ, et al., 2016,
Structure of eukaryotic purine/Hþ symporter UapA suggests a role for homodimerization in transport activity
, Nature Communications, Vol: 7, Pages: 1-9, ISSN: 2041-1723The uric acid/xanthine H+ symporter, UapA, is a high-affinity purine transporter from the filamentous fungus Aspergillus nidulans. Here we present the crystal structure of a genetically stabilized version of UapA (UapA-G411VΔ1–11) in complex with xanthine. UapA is formed from two domains, a core domain and a gate domain, similar to the previously solved uracil transporter UraA, which belongs to the same family. The structure shows UapA in an inward-facing conformation with xanthine bound to residues in the core domain. Unlike UraA, which was observed to be a monomer, UapA forms a dimer in the crystals with dimer interactions formed exclusively through the gate domain. Analysis of dominant negative mutants is consistent with dimerization playing a key role in transport. We postulate that UapA uses an elevator transport mechanism likely to be shared with other structurally homologous transporters including anion exchangers and prestin.
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Journal articleRussell AM, Adamali H, Molyneaux PL, et al., 2016,
Daily home spirometry: an effective tool for detecting progression in idiopathic pulmonary fibrosis
, American Journal of Respiratory and Critical Care Medicine, Vol: 194, Pages: 989-997, ISSN: 1535-4970Rationale: Recent clinical trial successes have created an urgent need for earlier and more sensitive endpoints of disease progression in idiopathic pulmonary fibrosis (IPF). Domiciliary spirometry permits more frequent measurement of FVC than does hospital-based assessment, which therefore affords the opportunity for a more granular insight into changes in IPF progression.Objectives: To determine the feasibility and reliability of measuring daily FVC in individuals with IPF.Methods: Subjects with IPF were given handheld spirometers and instruction on how to self-administer spirometry. Subjects recorded daily FEV1 and FVC for up to 490 days. Clinical assessment and hospital-based spirometry was undertaken at 6 and 12 months, and outcome data were collected for 3 years.Measurements and Main Results: Daily spirometry was recorded by 50 subjects for a median period of 279 days (range, 13–490 d). There were 18 deaths during the active study period. Home spirometry showed excellent correlation with hospital-obtained readings. The rate of decline in FVC was highly predictive of outcome and subsequent mortality when measured at 3 months (hazard ratio [HR], 1.040; 95% confidence interval [CI], 1.021–1.062; P ≤ 0.001), 6 months (HR, 1.024; 95% CI, 1.014–1.033; P < 0.001), and 12 months (HR, 1.012; 95% CI, 1.007–1.016; P = 0.001).Conclusions: Measurement of daily home spirometry in patients with IPF is highly clinically informative and is feasible to perform for most of these patients. The relationship between mortality and rate of change of FVC at 3 months suggests that daily FVC may be of value as a primary endpoint in short proof-of-concept IPF studies.
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Journal articleAwan AR, Shaw WM, Ellis T, 2016,
Biosynthesis of therapeutic natural products using synthetic biology
, Advanced Drug Delivery Reviews, Vol: 105, Pages: 96-106, ISSN: 1872-8294Natural products are a group of bioactive structurally diverse chemicals produced by microorganisms and plants. These molecules and their derivatives have contributed to over a third of the therapeutic drugs produced in the last century. However, over the last few decades traditional drug discovery pipelines from natural products have become far less productive and far more expensive. One recent development with promise to combat this trend is the application of synthetic biology to therapeutic natural product biosynthesis. Synthetic biology is a young discipline with roots in systems biology, genetic engineering, and metabolic engineering. In this review, we discuss the use of synthetic biology to engineer improved yields of existing therapeutic natural products. We further describe the use of synthetic biology to combine and express natural product biosynthetic genes in unprecedented ways, and how this holds promise for opening up completely new avenues for drug discovery and production.
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Journal articleFaisal M, Harun H, Hassan TM, et al., 2016,
Treatment of multiple-level tracheobronchial stenosis secondary to endobronchial tuberculosis using bronchoscopic balloon dilatation with topical mitomycin-C
, BMC PULMONARY MEDICINE, Vol: 16, ISSN: 1471-2466 -
Journal articleZhang Q, Cox M, Liang Z, et al., 2016,
Airway microbiota in severe asthma and relationship to asthma severity and phenotypes
, PLOS One, Vol: 11, ISSN: 1932-6203Background: The lower airways harbor a community of bacterial species which is altered in asthma. Objectives: We examined whether the lower airway microbiota were related to measures of asthma severityMethods: We prospectively recruited 26 severe asthma, 18 non-severe asthma and 12 healthy subjects. DNA was extracted from induced sputum and PCR amplification of the V3-V5 region of bacterial 16S rRNA gene was performed. Results: We obtained 138,218 high quality sequences which were rarefied at 133 sequences/sample. Twenty OTUs had sequences ≥1% of total. There were marked differences in the distribution of Phyla between groups (P=2.8x10-118). Bacteroidetes and Fusobacteria were reduced in non-severe and severe asthmatic groups. Proteobacteria were more common in non-severe asthmatics compared to controls (OR=2.26; 95% CI=1.94-2.64) and Firmicutes were increased in severe asthmatics compared to controls (OR=2.15; 95%CI=1.89-2.45). Streptococcal OTUs amongst the Firmicutes were associated with recent onset asthma, rhinosinusitis and sputum eosinophilia.Conclusions: Sputum microbiota in severe asthma differs from healthy controls and non-severe asthmatics, and is characterized by the presence of Streptococcus spp with eosinophilia. Whether these organisms are causative for the pathophysiology of asthma remains to be determined.
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Journal articleHussain H, Du Y, Scull NJ, et al., 2016,
Accessible mannitol-based amphiphiles (MNAs) for membrane protein solubilisation and stabilisation
, Chemistry, Vol: 22, ISSN: 0861-9255Integral membrane proteins are amphipathic molecules crucial for all cellular life. The structural study of these macromolecules starts with protein extraction from the native membranes, followed by purification and crystallisation. Detergents are essential tools for these processes, but detergent-solubilised membrane proteins often denature and aggregate, resulting in loss of both structure and function. In this study, a novel class of agents, designated mannitol-based amphiphiles (MNAs), were prepared and characterised for their ability to solubilise and stabilise membrane proteins. Some of MNAs conferred enhanced stability to four membrane proteins including a G protein-coupled receptor (GPCR), the β2 adrenergic receptor (β2AR), compared to both n-dodecyl-d-maltoside (DDM) and the other MNAs. These agents were also better than DDM for electron microscopy analysis of the β2AR. The ease of preparation together with the enhanced membrane protein stabilisation efficacy demonstrates the value of these agents for future membrane protein research.
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Journal articleClare F, Daniel O, Garner T, et al., 2016,
Assessing the ability of swab data to determine the true burden of infection for the amphibian pathogen Batrachochytrium dendrobatidis
, Ecohealth, Vol: 13, Pages: 360-367, ISSN: 1612-9210Batrachochytrium dendrobatidis (Bd) is a pathogenic fungus which causes the disease chytridiomycosisin amphibians by infecting the animals’ epidermis. The most commonly applied method for the detectionof Bd is the use of a sterile swab, rubbed over the keratinized areas of an amphibian and then processed to yieldDNA for detection by qPCR. This method has been used to infer a threshold of lethal infection in some species;however, how reliable and reproducible the swabbing method is at detecting the true burden of infectionsuffered by individuals is not known. European midwife toads, Alytes obstetricans, are susceptible to chytridiomycosisand are highly parasitised by Bd across Europe. By quantifying Bd-load throughout the entire skinand comparing this to swab results taken from the same individual, we determined whether epidermal swabsprovide a quantifiable and accurate indication of the true fungal burden suffered. Further, we examinedwhether we could infer a threshold for lethal infection based on comparison of swab data taken from infectedA. obstetricans exhibiting different clinical states. From swab data, we detected significantly higher fungalburdens from moribund metamorphs compared to visually healthy individuals; however, the ability of theseswab data to provide an accurate indication of the true fungal burden was not reliable. These data suggest thatfungal load dynamics play an important role in disease-induced mortality in A. obstetricans at these sites, butthat using swab data to infer an exact threshold for Bd-associated mortality might be inappropriate andmisleading.
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Journal articleZagura M, Tran S, Desai S, 2016,
Anomalous origin of the right coronary artery from the pulmonary trunk.
, BMJ Case Rep, Vol: 2016
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