Curr Top Microbiol
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Pseudomonas aeruginosa is the leading pathogen of chronic cystic fibrosis (CF) lung infection. Life-long persistance of P. aeruginosa in the CF lung requires a sophisticated habitat-specific adaptation of this pathogen to the heterogeneous and fluctuating lung environment. Due to the high selective pressure of inflamed CF lungs, P. aeruginosa increasingly experiences complex physiological and morphological changes. ⋯ Metabolic factors that are positively selected in response to the specific environment of CF lung include the outer membrane protein OprF, the microaerophilic oxidase Cbb3-2, the blue copper protein azurin, the cytochrome c peroxidase c551 and the enzymes of the arginine deiminase pathway ArcA-ArcD. These metabolic adaptations probably support the growth of P. aeruginosa within oxygen-depleted CF mucus. The deeper understanding of the physiological mechanisms of niche specialization of P. aeruginosa during CF lung infection will help to identify new targets for future anti-pseudomonal treatment strategies to prevent the selection of mutator isolates and the establishment of chronic CF lung infection.
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Since its discovery in 1955, respiratory syncytial virus (RSV) has consistently been noted to be the single most important cause of lower respiratory tract illness in infants <1 year of age. RSV also causes repeat infections and significant disease throughout life. In addition to the young child, persons with compromised immune, pulmonary or cardiac systems, and the elderly have significant risk from infection. ⋯ The available data on burden of disease suggests there are at least four potential target populations for a vaccine, the young infant, young children >4-6 months of age, pregnant women, and the elderly. A link between infection in the young infant and later reactive airway disease and mortality in developing countries is needed. Each target population has different vaccine safety and efficacy concerns and may warrant a different type of vaccine.
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The Food and Agriculture Organization (FAO) of the United Nation's view on One Health is broad as it extends from human, animal-domestic and wildlife-and environmental health. Though the nidus of work originated within FAO's animal health service of the Agriculture and Consumer Protection Department, it is clearly an area of work that would include other departments such as Natural Resources Management and the Environment, Forestry, Fisheries and Aquaculture, Economic and Social Development, Legal Services, and communication. ⋯ FAO's animal health service sees its work in One Health as contributing to all eight Millennium Development Goals, recognising the importance of animal health to human health, food safety, nutrition and food security, ameliorating poverty and hunger, natural resource management and partnerships. Some examples of FAO's operationalising One Health approaches or principles are introduced.
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Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the intestinal tract. Nearly all tumors have a mutation in the KIT or, less often, platelet-derived growth factor receptor (PDGFRA) or B-rapidly Accelerated Fibrosarcoma (BRAF) gene. The discovery of constitutive KIT activation as the central mechanism of GIST pathogenesis, suggested that inhibiting or blocking KIT signaling might be the milestone in the targeted therapy of GISTs. ⋯ The most common mechanism of resistance is through polyclonal acquisition of second site mutations in the kinase domain, which highlights the future therapeutic challenges in salvaging these patients after failing kinase inhibitor monotherapies. More recently, sunitinib (Sutent, Pfizer, New York, NY), which inhibits vascular endothelial growth factor receptor (VEGFR) in addition to KIT and PDGFRA, has proven efficacious in patients who are intolerant or refractory to imatinib. This review summarizes the recent knowledge on targeted therapy in GIST, based on the central role of KIT oncogenic activation, as well as discussing mechanisms of resistance.
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Activation of the PI3 kinase pathway can induce skeletal muscle hypertrophy, defined as an increase in skeletal muscle mass. In mammals, skeletal muscle hypertrophy occurs as a result of an increase in the size, as opposed to the number, of pre-existing skeletal muscle fibers. This pathway's effects on skeletal muscle have been implicated most prominently downstream of Insulin-like growth factor 1 signaling. ⋯ Blockade of RAPTOR also facilitates myostatin's inhibition of muscle differentiation. When added to post-differentiated myotubes, myostatin causes a decrease in their diameter - however, this does not happen through the normal "atrophy pathway." Rather than causing upregulation of the E3 ubiquitin ligases MuRF1 and MAFbx, previously shown to mediate skeletal muscle atrophy, myostatin decreases expression of these atrophy markers in differentiated myotubes, as well as other genes normally upregulated during differentiation, such as MyoD and myogenin. These findings show that myostatin signaling acts by blocking genes induced during differentiation, even in a myotube, as opposed to activating the distinct "atrophy program."