Epithelial cell–derived secreted and transmembrane 1a signals to activated neutrophils during pneumococcal pneumonia

Airway epithelial cell responses are critical to the outcome of lung infection. In this study, we aimed to identify unique contributions of epithelial cells during lung infection. To differentiate genes induced selectively in epithelial cells during pneumonia, we compared genome-wide expression profiles from three sorted cell populations: epithelial cells from uninfected mouse lungs, epithelial cells from mouse lungs with pneumococcal pneumonia, and nonepithelial cells from those same infected lungs. Of 1,166 transcripts that were more abundant in epithelial cells from infected lungs compared with nonepithelial cells from the same lungs or from epithelial cells of uninfected lungs, 32 genes were identified as highly expressed secreted products. Especially strong signals included two related secreted and transmembrane (Sectm) 1 genes, Sectm1a and Sectm1b. Refinement of sorting strategies suggested that both Sectm1 products were induced predominantly in conducting airway epithelial cells. Sectm1 was induced during the early stages of pneumococcal pneumonia, and mutation of NF-kB RelA in epithelial cells did not diminish its expression. Instead, type I IFN signaling was necessary and sufficient for Sectm1 induction in lung epithelial cells, mediated by signal transducer and activator of transcription 1. For target cells, Sectm1a bound to myeloid cells preferentially, in particular Ly6GbrightCD11bbright neutrophils in the infected lung. In contrast, Sectm1a did not bind to neutrophils from uninfected lungs. Sectm1a increased expression of the neutrophil-attracting chemokine CXCL2 by neutrophils from the infected lung. We propose that Sectm1a is an epithelial product that sustains a positive feedback loop amplifying neutrophilic inflammation during pneumococcal pneumonia

Gossip in the workplace and the implications for HR management : a study of gossip and its relationship to employee cynicism

Gossip is a common phenomenon in the workplace and yet relatively little is understood about its influence to employees. This study adopts social information theory and social cognitive theory to interpret the diverse literature on gossip, and to develop and test hypotheses concerning some of the antecedents of gossip, with an aim of developing knowledge of the relationship between gossip and employee behaviour in the workplace. The study analysed survey data in a two stage process, from 362 employees across a range of industries in Taiwan. The findings revealed that job-related gossip predicted employee cynicism and mediated the relationship between psychological contract violation and cynicism, and that non-job-related gossip showed a similar but weaker effect to employee cynicism. The contribution made by this paper is of value to both the academic subject domain and managers in Human Resources. Firstly, we have identified two constructs of gossip, job related and non-job related gossip not previously reported and a validated scale has been created. Secondly, we have confirmed that these different constructs of gossip impact differently on employee behaviour and therefore HR managers should be cautious about gossip in the workplace, as it can cause cynical behaviour amongst employees

Divergent roles of IL-23 and IL-12 in host defense against Klebsiella pneumoniae

Interleukin (IL)-23 is a heterodimeric cytokine that shares the identical p40 subunit as IL-12 but exhibits a unique p19 subunit similar to IL-12 p35. IL-12/23 p40, interferon γ (IFN-γ), and IL-17 are critical for host defense against Klebsiella pneumoniae. In vitro, K. pneumoniae–pulsed dendritic cell culture supernatants elicit T cell IL-17 production in a IL-23–dependent manner. However, the importance of IL-23 during in vivo pulmonary challenge is unknown. We show that IL-12/23 p40–deficient mice are exquisitely sensitive to intrapulmonary K. pneumoniae inoculation and that IL-23 p19−/−, IL-17R−/−, and IL-12 p35−/− mice also show increased susceptibility to infection. p40−/− mice fail to generate pulmonary IFN-γ, IL-17, or IL-17F responses to infection, whereas p35−/− mice show normal IL-17 and IL-17F induction but reduced IFN-γ. Lung IL-17 and IL-17F production in p19−/− mice was dramatically reduced, and this strain showed substantial mortality from a sublethal dose of bacteria (103 CFU), despite normal IFN-γ induction. Administration of IL-17 restored bacterial control in p19−/− mice and to a lesser degree in p40−/− mice, suggesting an additional host defense requirement for IFN-γ in this strain. Together, these data demonstrate independent requirements for IL-12 and IL-23 in pulmonary host defense against K. pneumoniae, the former of which is required for IFN-γ expression and the latter of which is required for IL-17 production

Zcchc11 Uridylates Mature miRNAs to Enhance Neonatal IGF-1 Expression, Growth, and Survival

The Zcchc11 enzyme is implicated in microRNA (miRNA) regulation. It can uridylate let-7 precursors to decrease quantities of the mature miRNA in embryonic stem cell lines, suggested to mediate stem cell maintenance. It can uridylate mature miR-26 to relieve silencing activity without impacting miRNA content in cancer cell lines, suggested to mediate cytokine and growth factor expression. Broader roles of Zcchc11 in shaping or remodeling the miRNome or in directing biological or physiological processes remain entirely speculative. We generated Zcchc11-deficient mice to address these knowledge gaps. Zcchc11 deficiency had no impact on embryogenesis or fetal development, but it significantly decreased survival and growth immediately following birth, indicating a role for this enzyme in early postnatal fitness. Deep sequencing of small RNAs from neonatal livers revealed roles of this enzyme in miRNA sequence diversity. Zcchc11 deficiency diminished the lengths and terminal uridine frequencies for diverse mature miRNAs, but it had no influence on the quantities of any miRNAs. The expression of IGF-1, a liver-derived protein essential to early growth and survival, was enhanced by Zcchc11 expression in vitro, and miRNA silencing of IGF-1 was alleviated by uridylation events observed to be Zcchc11-dependent in the neonatal liver. In neonatal mice, Zcchc11 deficiency significantly decreased IGF-1 mRNA in the liver and IGF-1 protein in the blood. We conclude that the Zcchc11-mediated terminal uridylation of mature miRNAs is pervasive and physiologically significant, especially important in the neonatal period for fostering IGF-1 expression and enhancing postnatal growth and survival. We propose that the miRNA 3′ terminus is a regulatory node upon which multiple enzymes converge to direct silencing activity and tune gene expression

A Synthetic Chloride Channel Restores Chloride Conductance in Human Cystic Fibrosis Epithelial Cells

Mutations in the gene-encoding cystic fibrosis transmembrane conductance regulator (CFTR) cause defective transepithelial transport of chloride (Cl−) ions and fluid, thereby becoming responsible for the onset of cystic fibrosis (CF). One strategy to reduce the pathophysiology associated with CF is to increase Cl− transport through alternative pathways. In this paper, we demonstrate that a small synthetic molecule which forms Cl− channels to mediate Cl− transport across lipid bilayer membranes is capable of restoring Cl− permeability in human CF epithelial cells; as a result, it has the potential to become a lead compound for the treatment of human diseases associated with Cl− channel dysfunction

Elevated Incidence of Dental Caries in a Mouse Model of Cystic Fibrosis

Saliva bicarbonate constitutes the main buffering system which neutralizes the pH fall generated by the plaque bacteria during sugar metabolism. We found that the saliva pH is severely decreased in a mouse model of cystic fibrosis disease (CF). Given the close relationship between pH and caries development, we hypothesized that caries incidence might be elevated in the mouse CF model.). are enhanced at low pH values, we speculate that the decrease in the bicarbonate content and pH buffering of the saliva is at least partially responsible for the increased severity of lesions observed in the CF mouse

Tetrabenzoporphyrin and -mono-, - Cis -di- and tetrabenzotriazaporphyrin derivatives: Electrochemical and spectroscopic implications of meso CH Group replacement with nitrogen

Nonperipherally hexyl-substituted metal-free tetrabenzoporphyrin (2H-TBP, 1a) tetrabenzomonoazaporphyrin (2H-TBMAP, 2a), tetrabenzo-cis-diazaporphyrin (2H-TBDAP, 3a), tetrabenzotriazaporphyrin (2H-TBTAP, 4a), and phthalocyanine (2H-Pc, 5a), as well as their copper complexes (1b-5b), were synthesized. As the number of meso nitrogen atoms increases from zero to four, Îmax of the Q-band absorption peak becomes red-shifted by almost 100 nm, and extinction coefficients increased at least threefold. Simultaneously the blue-shifted Soret (UV) band substantially decreased in intensity. These changes were related to the relative electron-density of each macrocycle expressed as the group electronegativity sum of all meso N and CH atom groups, âχR. X-ray photoelectron spectroscopy differentiated between the three different types of macrocyclic nitrogen atoms (the Ninner, (NH)inner, and Nmeso) in the metal-free complexes. Binding energies of the Nmeso and Ninner,Cu atoms in copper chelates could not be resolved. Copper insertion lowered especially the cathodic redox potentials, while all four observed redox processes occurred at larger potentials as the number of meso nitrogens increased. Computational chemical methods using density functional theory confirmed 1b to exhibit a Cu(II) reduction prior to ring-based reductions, while for 2b, Cu(II) reduction is the first reductive step only if the nonperipheral substituents are hydrogen. When they are methyl groups, it is the second reduction process; when they are ethyl, propyl, or hexyl, it becomes the third reductive process. Spectro-electrochemical measurements showed redox processes were associated with a substantial change in intensity of at least two main absorbances (the Q and Soret bands) in the UV spectra of these compounds

Five areas to advance branding theory and practice

The paper suggests five areas to advance branding theory and practice based on the authors’ recent work in brand management. In this commentary, we aim to put forward suggestions and ideas for further research in brand management; ideas, which we believe will have an impact on the way branding is researched and practiced by both academics and practitioners alike. We will focus on the future of branding in the following areas, inspired by our own work in the field: (1) branding in higher education, (2) branding in Asia Pacific, (3) brand ambidexterity, (4) brand innovation on social media, and (5) brand likeability

Under-regulated and unaccountable?:Explaining variation in stop and search rates in Scotland, England and Wales

From a position of near parity in 2005/6, by 2012/13 recorded search rates in Scotland exceeded those in England/Wales seven times over. This divergence is intriguing given the demands placed on the police, and the legal capacity to deal with these are broadly similar across the two jurisdictions. The aim of this paper is to unpack this variation. Using a comparative casestudy approach, the paper examines the role of structural ‘top-down’ determinants of policing: substantive powers of search, rules and regulations, and scrutiny. Two arguments are presented. First, we argue that the remarkable rise of stop and search in Scotland has been facilitated by weak regulation and safeguards. Second, we argue that divergence between the two jurisdictions can also be attributed to varying levels of political and public scrutiny, caused, in part, by viewing stop and search almost exclusively through the prism of ‘race’. In Scotland, the significance of these factors is made evident by dint of organisational developments within the last decade; by the introduction of a target driven high-volume approach to stop and search in Strathclyde police force circa 1997 onwards; and the national roll-out of this approach following the single service merger in April 2013. The salient point is that the Strathclyde model was not hindered by legal rules and regulations, nor subject to policy and political challenge; rather a high discretion environment enabled a high-volume approach to stop and search to flourish