Allosteric regulation and substrate activation in cytosolic nucleotidase II from Legionella pneumophila

Cytosolic nucleotidase II (cN-II) from Legionellapneumophila (Lp) catalyzes the hydrolysis of GMP and dGMP displaying sigmoidal curves, whereas catalysis of IMP hydrolysis displayed a biphasic curve in the initial rate versus substrate concentration plots. Allosteric modulators of mammalian cN-II did not activate LpcN-II although GTP, GDP and the substrate GMP were specific activators. Crystal structures of the tetrameric LpcN-II revealed an activator-binding site at the dimer interface. A double mutation in this allosteric-binding site abolished activation, confirming the structural observations. The substrate GMP acting as an activator, partitioning between the allosteric and active site, is the basis for the sigmoidicity of the initial velocity versus GMP concentration plot. The LpcN-II tetramer showed differences in subunit organization upon activator binding that are absent in the activator-bound human cN-II structure. This is the first observation of a structural change induced by activator binding in cN-II that may be the molecular mechanism for enzyme activation. DatabaseThe coordinates and structure factors reported in this paper have been submitted to the Protein Data Bank under the accession numbers and . The accession number of GMP complexed LpcN-II is . Structured digital abstract bulleted'' id=''febs12727-list-0001''> andby() andby() Structured digital abstract was added on 5 March 2014 after original online publication]

Managing i-branding to create brand equity

Purpose: Given the emergent nature of i-branding as an academic field of study and a lack of applied research output, the aim of this paper is to explain how businesses manage i-branding to create brand equity.<br/><br/>Design/methodology/approach: Within a case-study approach, seven cases were developed from an initial sample of 20 food businesses. Additionally, utilising secondary data, the analysis of findings introduces relevant case examples from other industrial sectors.<br/><br/>Findings: Specific internet tools and their application are discussed within opportunities to create brand equity for products classified by experience, credence and search characteristics. An understanding of target customers will be critical in underpinning the selection and deployment of relevant i-branding tools. Tools facilitating interactivity – machine and personal – are particularly significant.<br/><br/>Research limitations/implications: Future research positioned within classification of goods constructs could provide further contributions that recognise potential moderating effects of product/service characteristics on the development of brand equity online. Future studies could also employ the i-branding conceptual framework to test its validity and develop it further as a means of explaining how i-branding can be managed to create brand equity.<br/><br/>Originality/value: While previous research has focused on specific aspects of i-branding, this paper utilises a conceptual framework to explain how diverse i-branding tools combine to create brand equity. The literature review integrates fragmented literature around a conceptual framework to produce a more coherent understanding of extant thinking. The location of this study within a classification of goods context proved critical to explaining how i-branding can be managed.

Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age

The genetic contribution to the variation in human lifespan is approximately 25%.  Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality.  We performed a genome-wide association meta-analysis of 7729 long-lived individuals of European descent (≥ 85 years) and 16121 younger controls (< 65 years) followed by replication in an additional set of 13060 long-lived individuals and 61156 controls. In addition, we performed a subset analysis in cases ≥ 90 years. We observed genome-wide significant association with longevity, as reflected by survival to ages beyond 90 years, at a novel locus, rs2149954, on chromosome 5q33.3 (OR = 1.10, P =1.74 x 10-8). We also confirmed association of rs4420638 on chromosome 19q13.32 (OR = 0.72, P = 3.40 x 10-36), representing the TOMM40/APOE/APOC1 locus. In a prospective meta-analysis (n = 34103) the minor allele of rs2149954 (T) on chromosome 5q33.3 associates with increased survival (HR = 0.95, P = 0.003). This allele has previously been reported to associate with low blood pressure in middle age. Interestingly, the minor allele (T) associates with decreased cardiovascular mortality risk, independent of blood pressure. We report on the first GWAS-identified longevity locus on chromosome 5q33.3 influencing survival in the general European population. The minor allele of this locus associates with low blood pressure in middle age, although the contribution of this allele to survival may be less dependent on blood pressure. Hence, the pleiotropic mechanisms by which this intragenic variation contributes to lifespan regulation have to be elucidated.<br/>