Some fixed point theorems for generalized contractive mappings in complete metric spaces

We introduce new concepts of generalized contractive and generalized alpha-Suzuki type contractive mappings. Then, we obtain sufficient conditions for the existence of a fixed point of these classes of mappings on complete metric spaces and b-complete b-metric spaces. Our results extend the theorems of Ciric, Chatterjea, Kannan and Reich

Sensitisation to recombinant Aspergillus fumigatus allergens and clinical outcomes in COPD.

This is the author accepted manuscript. The final version is available from the European Respiratory Society via the DOI in this recordBACKGROUND: Variable clinical outcomes are reported with fungal sensitisation in COPD, and it remains unclear which fungi and what allergens associate with poorest outcomes. The use of recombinant as opposed to crude allergens for such assessment is unknown. METHODS: A prospective multicenter assessment of stable COPD (n=614) was undertaken in five hospitals across three countries: Singapore, Malaysia, and Hong Kong. Clinical and serological assessment was performed against a panel of 35 fungal allergens including crude and recombinant Aspergillus and non-Aspergillus allergens. Unsupervised clustering and Topological Data Analysis (TDA) approaches were employed using the measured sensitisation responses to elucidate if sensitisation sub-groups exist and their related clinical outcomes. RESULTS: Aspergillus fumigatus sensitisation associates with increased exacerbations in COPD. Unsupervised cluster analyses reveal two "fungal sensitisation" groups, one characterized by Aspergillus sensitisation and increased exacerbations, poorer lung function and worse prognosis. Polysensitisation in this group confers even poorer outcome. The second group, characterized by Cladosporium sensitisation is more symptomatic. Significant numbers of individuals demonstrate sensitisation responses to only recombinant (as opposed to crude) Aspergillus fumigatus allergens 1, 3, 5, and 6, and exhibit higher exacerbations, poorer lung function and an overall worse prognosis. TDA validated these findings and additionally identified a sub-group within "Aspergillus sensitised COPD" enriched for frequent exacerbators. CONCLUSION: Aspergillus sensitisation is a treatable trait in COPD. Measuring sensitisation responses to recombinant Aspergillus allergens identifies an important patient subgroup with poor COPD outcomes that remain overlooked by assessment of only crude Aspergillus allergens.Engineering and Physical Sciences Research Council (EPSRC)Singapore General Hospital Research GrantSingapore Ministry of Health's National Medical Research CouncilSingapore Ministry of Health's National Medical Research CouncilNational University of SingaporeSingapore Ministry of Education Academic Research FundSingapore Ministry of Education Academic Research FundSingapore Ministry of Education Academic Research FundSingapore Ministry of Education Academic Research FundSingapore Ministry of Education Academic Research FundSingapore Ministry of Education Academic Research FundSingapore Ministry of Education Academic Research FundSingapore Ministry of Education Academic Research FundSingapore Ministry of Education Academic Research FundSingapore Ministry of Education Academic Research FundBiomedical Research Council (BMRC) (Singapore)Biomedical Research Council (BMRC) (Singapore)Biomedical Research Council (BMRC) (Singapore)Singapore Immunology NetworkSingapore Immunology NetworkNational Medical Research Council (NMRC) (Singapore)Agency for Science Technology and Research (A*STAR) (Singapore)Agency for Science Technology and Research (A*STAR) (Singapore

The value relevance of corporate restructuring charges

Restructuring charges, Value relevance, Workforce reduction, Facilities closings, G1, G34, M4,

Protein kinase D interacts with neuronal nitric oxide synthase and phosphorylates the activatory residue serine1412

Neuronal Nitric Oxide Synthase (nNOS) is the biosynthetic enzyme responsible for nitric oxide (·NO) production in muscles and in the nervous system. This constitutive enzyme, unlike its endothelial and inducible counterparts, presents an N-terminal PDZ domain known to display a preference for PDZ-binding motifs bearing acidic residues at -2 position. In a previous work, we discovered that the C-terminal end of two members of protein kinase D family (PKD1 and PKD2) constitutes a PDZ-ligand. PKD1 has been shown to regulate multiple cellular processes and, when activated, becomes autophosphorylated at Ser 916, a residue located at -2 position of its PDZ-binding motif. Since nNOS and PKD are spatially enriched in postsynaptic densities and dendrites, the main objective of our study was to determine whether PKD1 activation could result in a direct interaction with nNOS through their respective PDZ-ligand and PDZ domain, and to analyze the functional consequences of this interaction. Herein we demonstrate that PKD1 associates with nNOS in neurons and in transfected cells, and that kinase activation enhances PKD1-nNOS co-immunoprecipitation and subcellular colocalization. However, transfection of mammalian cells with PKD1 mutants and yeast two hybrid assays showed that the association of these two enzymes does not depend on PKD1 PDZ-ligand but its pleckstrin homology domain. Furthermore, this domain was able to pull-down nNOS from brain extracts and bind to purified nNOS, indicating that it mediates a direct PKD1-nNOS interaction. In addition, using mass spectrometry we demonstrate that PKD1 specifically phosphorylates nNOS in the activatory residue Ser 1412, and that this phosphorylation increases nNOS activity and ·NO production in living cells. In conclusion, these novel findings reveal a crucial role of PKD1 in the regulation of nNOS activation and synthesis of ·NO, a mediator involved in physiological neuronal signaling or neurotoxicity under pathological conditions such as ischemic stroke or neurodegeneration.This work was supported by the Ministerio de Economía y Competitividad [SAF2011-26233 to T.I., BFU2009-10442 and BFU2012-37934 to I.R-C.]; Comunidad de Madrid [S2010/BMD-2331-Neurodegmodels-CM to T.I.]; and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas – CIBERNED, Instituto de Salud Carlos III, to T.I. Postdoctoral fellows L.S-R. and L.G-G. have been funded by research contracts from CIBERNED; Clara Aicart-Ramos is a recipient of a FPU predoctoral fellowship from Ministerio de Economía y Competitividad.Peer Reviewe