Structure-activity studies on polymyxin derivatives carrying three positive charges only reveal a new class of compounds with strong antibacterial activity

Recent years have brought in an increased interest to develop improved polymyxins. The currently used polymyxins, i.e. polymyxin B and colistin (polymyxin E) are pentacationic lipopeptides that possess a cyclic heptapeptide part with three positive charges, a linear "panhandle" part with two positive charges, and a fatty acyl tail. Unfortunately, their clinical use is shadowed by their notable nephrotoxicity. We have previously developed a polymyxin derivative NAB739 which lacks the positive charges in the linear part. This derivative is better tolerated than polymyxin B in cynomolgus monkeys and is, in contrast to polymyxin B, excreted into urine in monkeys and rats. Here we have conducted further structure-activity relationship (SAR) studies on 17 derivatives with three positive charges only. We discovered a remarkably antibacterial class, as exemplified by NAB815, that carries two positive charges only in the cyclic part. (C) 2017 Elsevier Inc. All rights reserved.Peer reviewe

“Intensities”:the sensory dimensions of the poetry of the Great War

Abstract. This paper provides an analysis on the topic of the senses as represented in a selection of the poetry of the First World War. Drawing from sensory studies, cultural studies and close reading, this paper aims to expand the existing corpus of research into the poetry of the Great War by introducing an approach that leans on second-hand sensory data, or ‘sensory impressions’, in the poetry, through which the sensory and experiential dimension of the War can be better understood. Aiming for a balanced approach, the corpus of poetry chosen as subject for analysis encompasses not only prominent soldier-poets, but also certain home front poets. In particular, this paper focuses on the aspect of excessive sensory stimuli as told by these poets, and the effect of these stimuli on the human sensorium, psyche and body

The polymyxin derivative NAB739 is synergistic with several antibiotics against polymyxin-resistant strains of Escherichia coli, Klebsiella pneumoniae and Acinetobacter baumannii

The antibiotic crisis has reinstated polymyxins, once abandoned because of their toxicity. Now, preclinical studies have revealed better tolerated and more effective derivatives of polymyxins such as NAB739. Simultaneously, polymyxin-resistant (PMR) strains such as the mcr-1 strains have received lots of justified publicity, even though they are still very rare. Here we show that NAB739 sensitizes the PMR strains to rifampin, a classic "anti-Gram-positive" antibiotic excluded by the intact outer membrane (OM) permeability barrier, as well as to retapamulin, the surrogate of lefamulin, an antibiotic under development against Gram-positive bacteria. Polymyxin B was used as a comparator. The combination of NAB739 and rifampin was synergistic against ten out of eleven PMR strains of Escherichia coll. (Fractional Synergy Indices, FICs, 0.14-0.19) and that of NAB739 and retapamulin against all the tested eleven strains (FICs 0.19-0.25). Against PMR Klebsiella pneumoniae (n = 7), the FICs were 0.13-0.27 for NAB739 + rifampin and 0.14-0.28 for NAB739 + retapamulin. Against Acinetobacter baumannii (n = 2), the combination of NAB739 and rifampin had the FIC of 0.09-0.19. Furthermore, NAB739 and meropenem were synergistic (FICs 0.25-0.50) against four out of five PMR strains that were simultaneously resistant to meropenem.Peer reviewe

Dipolar and scalar 3^3He and 129^{129}Xe frequency shifts in mm-sized cells

We describe a $^{3}$He-$^{129}$Xe comagnetometer operating in stemless anodically bonded cells with a 6 mm$^3$ volume and a $^{129}$Xe spin coherence time of 300 sec. We use a $^{87}$Rb pulse-train magnetometer with co-linear pump and probe beams to study the nuclear spin frequency shifts caused by spin polarization of $^{3}$He. By systematically varying the cell geometry in a batch cell fabrication process we can separately measure the cell shape dependent and independent frequency shifts. We find that a certain aspect ratio of the cylindrical cell can cancel the effects of $^3$He magnetization that limit the stability of vapor-cell comagnetometers. Using this control we also observe for the first time a scalar $^{3}$He-$^{129}$Xe collisional frequency shift characterized by an enhancement factor $\kappa_{\text{HeXe}} = -0.011\pm0.001$.Comment: 4 pages, 4 figure

Evaluation of Multidrug Efflux Pump Inhibitors by a New Method Using Microfluidic Channels

Fluorescein-di-β-d-galactopyranoside (FDG), a fluorogenic compound, is hydrolyzed by β-galactosidase in the cytoplasm of Escherichia coli to produce a fluorescent dye, fluorescein. We found that both FDG and fluorescein were substrates of efflux pumps, and have developed a new method to evaluate efflux-inhibitory activities in E. coli using FDG and a microfluidic channel device. We used E. coli MG1655 wild-type, ΔacrB (ΔB), ΔtolC (ΔC) and ΔacrBΔtolC (ΔBC) harboring plasmids carrying the mexAB-oprM (pABM) or mexXY-oprM (pXYM) genes of Pseudomonas aeruginosa. Two inhibitors, MexB-specific pyridopyrimidine (D13-9001) and non-specific Phe-Arg-β-naphthylamide (PAβN) were evaluated. The effects of inhibitors on pumps were observed using the microfluidic channel device under a fluorescence microscope. AcrAB-TolC and analogous pumps effectively prevented FDG influx in wild-type cells, resulting in no fluorescence. In contrast, ΔB or ΔC easily imported and hydrolyzed FDG to fluorescein, which was exported by residual pumps in ΔB. Consequently, fluorescent medium in ΔB and fluorescent cells of ΔC and ΔBC were observed in the microfluidic channels. D13-9001 substantially increased fluorescent cell number in ΔBC/pABM but not in ΔBC/pXYM. PAβN increased medium fluorescence in all strains, especially in the pump deletion mutants, and caused fluorescein accumulation to disappear in ΔC. The checkerboard method revealed that D13-9001 acts synergistically with aztreonam, ciprofloxacin, and erythromycin only against the MexAB-OprM producer (ΔBC/pABM), and PAβN acts synergistically, especially with erythromycin, in all strains including the pump deletion mutants. The results obtained from PAβN were similar to the results from membrane permeabilizer, polymyxin B or polymyxin B nonapeptide by concentration. The new method clarified that D13-9001 specifically inhibited MexAB-OprM in contrast to PAβN, which appeared to be a substrate of the pumps and permeabilized the membranes in E. coli

Common Inflammation-Related Candidate Gene Variants and Acute Kidney Injury in 2647 Critically Ill Finnish Patients

Acute kidney injury (AKI) is a syndrome with high incidence among the critically ill. Because the clinical variables and currently used biomarkers have failed to predict the individual susceptibility to AKI, candidate gene variants for the trait have been studied. Studies about genetic predisposition to AKI have been mainly underpowered and of moderate quality. We report the association study of 27 genetic variants in a cohort of Finnish critically ill patients, focusing on the replication of associations detected with variants in genes related to inflammation, cell survival, or circulation. In this prospective, observational Finnish Acute Kidney Injury (FINNAKI) study, 2647 patients without chronic kidney disease were genotyped. We defined AKI according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria. We compared severe AKI (Stages 2 and 3, n = 625) to controls (Stage 0, n = 1582). For genotyping we used iPLEXTM Assay (Agena Bioscience). We performed the association analyses with PLINK software, using an additive genetic model in logistic regression. Despite the numerous, although contradictory, studies about association between polymorphisms rs1800629 in TNFA and rs1800896 in IL10 and AKI, we found no association (odds ratios 1.06 (95% CI 0.89–1.28, p = 0.51) and 0.92 (95% CI 0.80–1.05, p = 0.20), respectively). Adjusting for confounders did not change the results. To conclude, we could not confirm the associations reported in previous studies in a cohort of critically ill patients

Beyond merger syndrome and cultural differences:New avenues for research on the “human side” of global mergers and acquisitions (M&As)

This paper focuses on research on the “human side” of global mergers and acquisitions (M&As). We argue that there is a need for a more fine-grained understanding of the “human side,” which requires conceptualizing M&As as practice-oriented processes. Drawing on the practice approach, we outline avenues for further research on the “human side” of global M&As. The research directions include (1) multilayered identity dynamics, (2) emotional processes, (3) participation and change agency, (4) resistance, (5) human resource management (HRM) practices and tools, and (6) new forms of communication

Heme oxygenase-1 repeat polymorphism in septic acute kidney injury

Acute kidney injury (AKI) is a syndrome that frequently affects the critically ill. Recently, an increased number of dinucleotide repeats in the HMOX1 gene were reported to associate with development of AKI in cardiac surgery. We aimed to test the replicability of this finding in a Finnish cohort of critically ill septic patients. This multicenter study was part of the national FINNAKI study. We genotyped 300 patients with severe AKI (KDIGO 2 or 3) and 353 controls without AKI (KDIGO 0) for the guanine-thymine (GTn) repeat in the promoter region of the HMOX1 gene. The allele calling was based on the number of repeats, the cut off being 27 repeats in the S-L (short to long) classification, and 27 and 34 repeats for the S-M-L2 (short to medium to very long) classification. The plasma concentrations of heme oxygenase-1 (HO-1) enzyme were measured on admission. The allele distribution in our patients was similar to that published previously, with peaks at 23 and 30 repeats. The S-allele increases AKI risk. An adjusted OR was 1.30 for each S-allele in an additive genetic model (95% CI 1.01-1.66; p = 0.041). Alleles with a repeat number greater than 34 were significantly associated with lower HO-1 concentration (pPeer reviewe

Identifying Cultural and Cognitive Proximity between Managers and Customers in Tornio and Haparanda Cross Border Region

Daily intercultural interactions in cross-border regions such as those between customers and managers can be a source of knowledge and ideas. However, such interactions can pose distinctive constraints and opportunities for learning and exchange of ideas. This study adopts a relatively fine–grained quantitative approach to study elements of cognitive and cultural proximity which have a major impact on these interactions. It is based on a survey of 91 managers of small service firms and 312 customers in the twin city of Tornio and Haparanda on the border between Finland and Sweden. Seven elements of proximity were identified and measured. Six elements of perceived cognitive and cultural proximity including values, conservative values towards new ideas, knowledge and use of technology, use of a foreign language, sufficiently focusing or providing specific details and ways of solving problems were found significant in terms of shaping perceptions of Swedish and Finnish managers and customers, which shape these interactions. The results enhance our understanding of how daily cross-border intercultural can be examined in the context of cross-border regional knowledge transfer