TBK1 regulates regeneration of pancreatic β-cells

Small-molecule inhibitors of non-canonical IκB kinases TANK-binding kinase 1 (TBK1) and IκB kinase ε (IKKε) have shown to stimulate β-cell regeneration in multiple species. Here we demonstrate that TBK1 is predominantly expressed in β-cells in mammalian islets. Proteomic and transcriptome analyses revealed that genetic silencing of TBK1 increased expression of proteins and genes essential for cell proliferation in INS-1 832/13 rat β-cells. Conversely, TBK1 overexpression decreased sensitivity of β-cells to the elevation of cyclic AMP (cAMP) levels and reduced proliferation of β-cells in a manner dependent on the activity of cAMP-hydrolyzing phosphodiesterase 3 (PDE3). While the mitogenic effect of (E)3-(3-phenylbenzo[c]isoxazol-5-yl)acrylic acid (PIAA) is derived from inhibition of TBK1, PIAA augmented glucose-stimulated insulin secretion (GSIS) and expression of β-cell differentiation and proliferation markers in human embryonic stem cell (hESC)-derived β-cells and human islets. TBK1 expression was increased in β-cells upon diabetogenic insults, including in human type 2 diabetic islets. PIAA enhanced expression of cell cycle control molecules and β-cell differentiation markers upon diabetogenic challenges, and accelerated restoration of functional β-cells in streptozotocin (STZ)-induced diabetic mice. Altogether, these data suggest the critical function of TBK1 as a β-cell autonomous replication barrier and present PIAA as a valid therapeutic strategy augmenting functional β-cells

Deferiprone: Pan-selective Histone Lysine Demethylase Inhibition Activity and Structure Activity Relationship Study

Deferiprone (DFP) is a hydroxypyridinone-derived iron chelator currently in clinical use for iron chelation therapy. DFP has also been known to elicit antiproliferative activities, yet the mechanism of this effect has remained elusive. We herein report that DFP chelates the Fe 2+ ion at the active sites of selected iron-dependent histone lysine demethylases (KDMs), resulting in pan inhibition of a subfamily of KDMs. Specifically, DFP inhibits the demethylase activities of six KDMs - 2A, 2B, 5C, 6A, 7A and 7B - with low micromolar IC 50 s while considerably less active or inactive against eleven KDMs - 1A, 3A, 3B, 4A-E, 5A, 5B and 6B. The KDM that is most sensitive to DFP, KDM6A, has an IC 50 that is between 7- and 70-fold lower than the iron binding equivalence concentrations at which DFP inhibits ribonucleotide reductase (RNR) activities and/or reduces the labile intracellular zinc ion pool. In breast cancer cell lines, DFP potently inhibits the demethylation of H3K4me3 and H3K27me3, two chromatin posttranslational marks that are subject to removal by several KDM subfamilies which are inhibited by DFP in cell-free assay. These data strongly suggest that DFP derives its anti-proliferative activity largely from the inhibition of a sub-set of KDMs. The docked poses adopted by DFP at the KDM active sites enabled identification of new DFP-based KDM inhibitors which are more cytotoxic to cancer cell lines. We also found that a cohort of these agents inhibited HP1-mediated gene silencing and one lead compound potently inhibited breast tumor growth in murine xenograft models. Overall, this study identified a new chemical scaffold capable of inhibiting KDM enzymes, globally changing histone modification profiles, and with specific anti-tumor activities

Cell Nucleus-Targeting Zwitterionic Carbon Dots

An innovative nucleus-targeting zwitterionic carbon dot (CD) vehicle has been developed for anticancer drug delivery and optical monitoring. The zwitterionic functional groups of the CDs introduced by a simple one-step synthesis using beta-alanine as a passivating and zwitterionic ligand allow cytoplasmic uptake and subsequent nuclear translocation of the CDs. Moreover, multicolor fluorescence improves the accuracy of the CDs as an optical code. The CD-based drug delivery system constructed by non-covalent grafting of doxorubicin, exhibits superior antitumor efficacy owing to enhanced nuclear delivery in vitro and tumor accumulation in vivo, resulting in highly effective tumor growth inhibition. Since the zwitterionic CDs are highly biocompatible and effectively translocated into the nucleus, it provides a compelling solution to a multifunctional nanoparticle for substantially enhanced nuclear uptake of drugs and optical monitoring of translocation.open

Nanotechnology in Head and Neck Cancer: The Race Is On

Rapid advances in the ability to produce nanoparticles of uniform size, shape, and composition have started a revolution in the sciences. Nano-sized structures herald innovative technology with a wide range of potential therapeutic and diagnostic applications. More than 1000 nanostructures have been reported, many with potential medical applications, such as metallic-, dielectric-, magnetic-, liposomal-, and carbon-based structures. Of these, noble metallic nanoparticles are generating significant interest because of their multifunctional capacity for novel methods of laboratory-based diagnostics, in vivo clinical diagnostic imaging, and therapeutic treatments. This review focuses on recent advances in the applications of nanotechnology in head and neck cancer, with special emphasis on the particularly promising plasmonic gold nanotechnology

Intracellular SERS nanoprobes for distinction of different neuronal cell types.

Distinction between closely related and morphologically similar cells is difficult by conventional methods especially without labeling. Using nuclear-targeted gold nanoparticles (AuNPs) as intracellular probes we demonstrate the ability to distinguish between progenitor and differentiated cell types in a human neuroblastoma cell line using surface-enhanced Raman spectroscopy (SERS). SERS spectra from the whole cell area as well as only the nucleus were analyzed using principal component analysis that allowed unambiguous distinction of the different cell types. SERS spectra from the nuclear region showed the developments during cellular differentiation by identifying an increase in DNA/RNA ratio and proteins transcribed. Our approach using nuclear-targeted AuNPs and SERS imaging provides label-free and noninvasive characterization that can play a vital role in identifying cell types in biomedical stem cell research

Legitimisation strategies and managerial capture: a critical discourse analysis of employment relations in Nigeria

YesIrrespective of the fundamental role of legitimacy in industrial relations as well as social and organisational life, little is known of the subtle meaning-making strategies through which organisational concepts, such as employment relations and engagement, are legitimised in modern world of work, particularly in developing countries such as Nigeria, which results in managerial capture. As a result, this paper explores the discursive legitimisation strategies used when making sense of employment relations in Nigeria’s conflictual, non-participatory employment relations terrain. Relying on Leeuwen’s (1995) legitimisation strategies, critical discourse analysis (CDA) and call by Bailey, Luck & Townsend (2009) and Legge (1995) to widen employment relations discourse, we explore interview, focus group and shadow report data, and distinguish and analyse five legitimisation strategies. The strategies include authorisation, moralisation, mythopoesis, rationalisation, and management. Therefore, we contend that while these specific legitimisation strategies appear in separate data source, their recurrent manifestation and application underscores legitimising discourse of managerial capture in Nigeria’s employment relations

Are anti-sticky costs endemic in the Arabian Gulf Region?

This dataset was employed to investigate the endemism of anti-sticky costs in emerging economies of the Gulf Co-operation Council (GCC) countries by measuring the degree of adjustment between operating revenues and costs for companies in those countries. It includes panel data on operating expenses, sales revenue, current total assets, staff wages and salaries, and GDP in a sticky cost model derived from a Cobb-Douglas cost function to measure the percentage change in operating expenses due to a 1% increase or decrease in sales revenue. Our results from analysis the data in this dataset did not find evidence of sticky costs in four of the five countries.THIS DATASET IS ARCHIVED AT DANS/EASY, BUT NOT ACCESSIBLE HERE. TO VIEW A LIST OF FILES AND ACCESS THE FILES IN THIS DATASET CLICK ON THE DOI-LINK ABOV

International transfer pricing and income shifting: evidence from the UK

The potential use of international transfer pricing (ITP) as an income-shifting mechanism by multinational enterprises (MNEs) has long been recognized. However, there is relatively little evidence to substantiate or discount this claim in relation to UK-based foreign-controlled enterprises (FCEs). This paper examines the possible use of ITP as an income-shifting mechanism by FCEs operating in the UK. The methodological approach involves the comparison of the profitability (performance) and dividend (post-performance) distributions of a sample of FCEs with those of UK-controlled enterprises (UKCEs) over a two-year period. The two samples are matched on the basis of their total assets (capability). Results reveal significant differences in the profitability and dividend distributions of the two groups. FCEs underperform UKCEs, but their level of dividend distribution outstrips those of UKCEs. Based on this sample of seventy-two companies, a firm is more likely to be an FCE, rather than a UKCE, if it reports a combination of lower performance and higher post-performance distribution. Evidence of significant income shifting by FCEs is confirmed and the claim that ITP is the key mechanism for such shifts cannot be dismissed.