Reshaping our understanding of species’ roles in landscape-scale networks

Data associate with Ecology Letters manuscript number: ELE-01021-2018.R2; Hackett et al. Reshaping our understanding of species’ roles in landscape-scale networks<div><br></div><div>See READ ME text file for specific detail</div

Combined bezafibrate and medroxyprogesterone acetate: potential novel therapy for acute myeloid leukaemia

Background: The majority of acute myeloid leukaemia (AML) patients are over sixty years of age. With current treatment regimens, survival rates amongst these, and also those younger patients who relapse, remain dismal and novel therapies are urgently required. In particular, therapies that have anti-leukaemic activity but that, unlike conventional chemotherapy, do not impair normal haemopoiesis. Principal Findings: Here we demonstrate the potent anti-leukaemic activity of the combination of the lipid-regulating drug bezafibrate (BEZ) and the sex hormone medroxyprogesterone acetate (MPA) against AML cell lines and primary AML cells. The combined activity of BEZ and MPA (B/M) converged upon the increased synthesis and reduced metabolism of prostaglandin D2 (PGD2) resulting in elevated levels of the downstream highly bioactive, anti-neoplastic prostaglandin 15-deoxy Δ12,14 PGJ2 (15d-PGJ2). BEZ increased PGD2 synthesis via the generation of reactive oxygen species (ROS) and activation of the lipid peroxidation pathway. MPA directed prostaglandin synthesis towards 15d-PGJ2 by inhibiting the PGD2 11β -ketoreductase activity of the aldo-keto reductase AKR1C3, which metabolises PGD2 to 9α11β-PGF2α. B/M treatment resulted in growth arrest, apoptosis and cell differentiation in both AML cell lines and primary AML cells and these actions were recapitulated by treatment with 15d-PGJ2. Importantly, the actions of B/M had little effect on the survival of normal adult myeloid progenitors. Significance: Collectively our data demonstrate that B/M treatment of AML cells elevated ROS and delivered the anti-neoplastic actions of 15d-PGJ2. These observations provide the mechanistic rationale for the redeployment of B/M in elderly and relapsed AML

Impact of T2R38 receptor polymorphisms on Pseudomonas aeruginosa infection in cystic fibrosis

The T2R38 (taste receptor 2 member 38) bitter taste receptor on respiratory epithelia detects Pseudomonas aeruginosa N-acyl-l-homoserine lactones (AHLs). In vitro, T2R38 activation by AHLs initiates calcium-mediated increases in nitric oxide production and ciliary beat frequency, dependent on polymorphisms in the TAS2R38 gene (1). In patients with chronic rhinosinusitis, the TAS2R38 genotype is proposed to modify mucosal responses to P. aeruginosa (1). Polymorphisms in the TAS2R38 gene result in two high-frequency haplotypes associated with taste perception of the bitter compound phenylthiocarbamide (2). The “taster” haplotype codes proline-alanine-valine (PAV), and the “nontaster” haplotype codes alanine-valine-isoleucine (AVI) at positions 49, 262, and 296 in the receptor protein. Responses to AHLs in vitro are greatest in PAV/PAV epithelial cells, and this genotype is reported to be protective against P. aeruginosa in the sinonasal airway (1). P. aeruginosa is the most frequently isolated respiratory pathogen in cystic fibrosis (CF), and chronic infection is associated with accelerated rates of disease progression. Determining the impact of TAS2R38 polymorphisms on P. aeruginosa infection in CF could have implications for patient risk stratification and, as naturally occurring and synthetic agonists to T2R38 are already in clinical use (3), could identify promising therapeutic targets. We characterized T2R38 localization in the CF airway and investigated the hypothesis that TAS2R38 polymorphisms would modify the prevalence and impact of P. aeruginosa infection in CF. Some of the results of these studies have previously been reported in the form of abstracts

Governance disclosure quality and market valuation of firms

This study develops a ‘comply or explain’ index which captures compliance and quality of explanations given for non-compliance with the corporate governance codes in UK and Germany. In particular, we explain, how compliance and quality of explanations provided in non-compliance disclosures, and various other internal corporate governance mechanisms, affect the market valuation of firms in the two countries. A dynamic generalised method of moments (GMM) estimator is employed as the research technique for our analysis, which enabled us to control for the potential effects of endogeneity in our models. The findings of our content analysis suggest that firms exhibit significant differences in compliance, board independence and ownership structure in both countries. The ‘comply or explain’ index is positively associated with the market valuation of UK firms suggesting that compliance and quality governance disclosure is value relevant in the UK. Institutional blockholders’ ownership is however, negatively associated with the market value of firms, which raises questions about the monitoring role of institutional shareholders in both countries. We argue that both compliance and explanations given for non-compliance are equally important, as long as valid reasons and justifications for non-compliance are provided by the reporting companies. These findings thus imply that the ‘comply or explain’ principle is working well and that UK and German companies could benefit from the flexibility offered by this principle. With respect to the role of board size, board independence, ownership structure, and institutional ownership of firms, this study offers policy implications