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Tackling microbial resistance requires continuous efforts for the development of new molecules with novel mechanisms of action and potent antimicrobial activity. Our group has previously identified metal-based compounds, [Ag(1,10-phenanthroline-5,6-dione)2]ClO4 (Ag-phendione) and [Cu(1,10-phenanthroline-5,6-dione)3](ClO4)2.4H2O (Cu-phendione), with efficient antimicrobial action against multidrug-resistant species. Herein, we investigated the ability of Ag-phendione and Cu-phendione to bind with double-stranded DNA using a combination of in silico and in vitro approaches. Molecular docking revealed that both phendione derivatives can interact with the DNA by hydrogen bonding, hydrophobic and electrostatic interactions. Cu-phendione exhibited the highest binding affinity to either major (− 7.9 kcal/mol) or minor (− 7.2 kcal/mol) DNA grooves. In vitro competitive quenching assays involving duplex DNA with Hoechst 33258 or ethidium bromide demonstrated that Ag-phendione and Cu-phendione preferentially bind DNA in the minor grooves. The competitive ethidium bromide displacement technique revealed Cu-phendione has a higher binding affinity to DNA (Kapp = 2.55 × 106 M−1) than Ag-phendione (Kapp = 2.79 × 105 M−1) and phendione (Kapp = 1.33 × 105 M−1). Cu-phendione induced topoisomerase I-mediated DNA relaxation of supercoiled plasmid DNA. Moreover, Cu-phendione was able to induce oxidative DNA injuries with the addition of free radical scavengers inhibiting DNA damage. Ag-phendione and Cu-phendione avidly displaced propidium iodide bound to DNA in permeabilized Pseudomonas aeruginosa cells in a dose-dependent manner as judged by flow cytometry. The treatment of P. aeruginosa with bactericidal concentrations of Cu-phendione (15 µM) induced DNA fragmentation as visualized by either agarose gel or TUNEL assays. Altogether, these results highlight a possible novel DNA-targeted mechanism by which phendione-containing complexes, in part, elicit toxicity toward the multidrug-resistant pathogen P. aeruginosa. Graphical abstract

Distributed point charge models (DCM) and their minimal variants (MDCM) have been integrated with tools widely used for condensed-phase simulations, including a virial-based barostat and a slow-growth algorithm for thermodynamic integration. Minimal DCM is further developed in a systematic fashion to reduce fitting errors in the electrostatic interaction energy, and a new fragment-based approach offers considerable speedup of the MDCM fitting process for larger molecules with increased numbers of off-centered charged sites. Finally, polarizable (M)DCM is also introduced in the present work. The developments are used in condensed-phase simulations of popular force fields with commonly applied simulation conditions. (M)DCM equivalents for a range of widely used water force fields and for fluorobenzene (PhF) are developed and applied along with the original models to evaluate the impact of reformulating the electrostatic term. Comparisons of the molecular electrostatic potential (MEP), electrostatic interaction energies, and bulk properties from molecular dynamics simulations for a range of models from simple TIPnP (n = 3-5) to the polarizable, multipolar iAMOEBA models for water and an existing quadrupolar model for PhF confirm that DCMs retain the accuracy of the original models, providing a homogeneous, efficient, and generic point charge alternative to a multipolar electrostatic model for force field development and multilevel simulations.

Remote visual inspection is a common approach to understanding the health of key components and substructures within nuclear power plants, particularly in difficult to access and high dosage areas. Interpretation of inspection footage is a manually intensive procedure and challenges arise in localizing and dimensioning defects directly from a video feed, which may be subject to uncertainty from a range of sources such as lens distortion, nonuniform lighting, and lack of depth from a monocular camera system. A common approach to addressing these issues is to develop a scaling factor based on identifying a reference object of known dimensions in the image and using this to size regions of interest. Manual, accurate identification of these reference objects is onerous, time consuming, and prone to variation across different human experts, therefore, robust identification of suitable reference objects in an automated, reliable, and repeatable manner is of significant value. In this paper we evaluate two approaches for the automated detection of reference objects in the inspection of graphite cores in the United Kingdom’s fleet of advanced gas-cooled reactors (AGRs). The first method is a multistep approach using tools from mathematical morphology. The approach uses a genetic algorithm to “grow” suitable structuring elements, refine the order of operations, and remove operations proposed by the human designer that have a negative impact on performance. The second approach uses semantic segmentation, a technique which is normally applied to scene labeling in computer vision applications, applied to produce a binary mask, separating the reference object from the background. We show that this second method performs significantly better than the mathematical morphology approach when applied to the identification of brick interface keyways in AGR inspection images. Though improved in terms of accuracy, it is recognized that a greater initial effort is required to train the approach, and as it utilizes black-box neural network approaches, the greater transparency offered by the mathematical morphology approach is lost. While explicability of techniques is often a highly desirable characteristic of automated analysis techniques applied to health assessment within nuclear power plants, the results of the reference object detection can be made explicit to the end user, ensuring that the human analyst is retained within the decision-making process thus mitigating the need for transparency.

This chapter provides an account of the journey taken by the College of Sciences and Health in Technological University Dublin over an eleven-year period, from 2010 to 2021, as it sought to address the challenges of gender inequality in STEM (Science, Technology, Engineering, Mathematics) disciplines. The start and end points for the journey are marked by the formation of the College and its eventual replacement following a reorganisation of the Higher Education landscape in Ireland and a structural reorganisation at University level. This chapter draws upon the authors’ collective experience of leadership within the managerial structures of the College and the University, and leadership on specific initiatives, to illustrate how consideration of gender equality and inequality featured within the journey taken by the College over this period of time. The chapter applies a broad lens to analyse the gender profile of the College’s people and practices, including its planning, its operational management, its leadership, its staff profile and its student cohorts over the eleven-year period. The chapter also focusses more narrowly on a set of specific initiatives undertaken within the College or across the University which impacted upon the College. Collectively, the two perspectives demonstrate how a STEM College evolved over an extended period of time, shaped by cultural changes and challenges and bolstered by initiatives that targeted the areas of greatest challenge. This eleven-year snapshot provides insight into a journey that has built momentum and has potential to continue into the future. The story communicated in this chapter will be of value to Higher Education leaders and practitioners that wish to learn from this experience and interpret the approach set out in this chapter for their own local context.

Drug-resistant

Visual inspection is an important activity common in the assessment of various assets in the nuclear industry. Visual inspection has applications ranging from determining the health of the nuclear reactor core itself [1, 2], determining the health of vital components of the nuclear power plant such as superheaters [3], assessing the conditions of welds in thick-walled pressure vessels common to Boiling Water Reactor (BWR) and Pressurized Water Reactors (PWR) [4] and many other applications. Each of these activities typically involves gathering a large amount of raw data either in the form of video or still images. At any given instance of this data it is only possible to resolve localised information therefore suitable processing is required to generate a global view of the asset.

The overproduction of reactive oxygen species (ROS) induces oxidative stress, a well-known process associated with aging and several human pathologies, such as cancer and neurodegenerative diseases. A large number of synthetic compounds have been described as antioxidant enzyme mimics, capable of eliminating ROS and/or reducing oxidative damage. In this study, we investigated the antioxidant activity of a water-soluble 1,10-phenantroline-octanediaoate Mn2+-complex on cells under oxidative stress, and assessed its capacity to attenuate alpha-synuclein (aSyn) toxicity and aggregation, a process associated with increased oxidative stress. This Mn2+-complex exhibited a significant antioxidant potential, reducing intracelular oxidation and increasing oxidative stress resistance in S. cerevisiae cells and in vivo, in G. mellonella, increasing the activity of the intracellular antioxidant enzymes superoxide dismutase and catalase. Strikingly, the Mn2+-complex reduced both aSyn oligomerization and aggregation in human cell cultures and, using NMR and DFT/molecular docking we confirmed its interaction with the C-terminal region of aSyn. In conclusion, the Mn2+-complex appears as an excellent lead for the design of new phenanthroline derivatives as alternative compounds for preventing oxidative damages and oxidative stress - related diseases.

This book undertakes a fundamental review of the existing international regime for taxing business profit. It steps back from the current political debates on how to combat profit shifting and how taxing rights over the profits of the digitalized economy should be allocated. Instead, it starts from first principles to ask how we should evaluate a tax on business profit—and whether there is any good rationale for such a tax in the first place. It then goes on to evaluate the existing regime and a number of alternatives that have been proposed. It argues that the existing regime is fundamentally flawed, and that there is a need for radical reform. The key conclusion from the analysis is that there would be significant gains from a reform that moved the regime towards taxing profit in the country in which a business made its sales to third parties. That conclusion informs two proposals that are put forward in detail and evaluated: the Residual Profit Allocation by Income (RPAI) and the Destination-based Cash Flow Tax (DBCFT). The book is authored by group of economists and lawyers—the Oxford International Tax Group, chaired by Michael Devereux. It draws insights from both economics and law—including economic theory, empirical evidence on the impact of taxes, and a detailed examination of practical issues of implementation—to assess the existing system and to consider fundamental reforms. This book will be useful to tax policy makers, tax professionals, academics, and anyone interested in tax policy.

This paper reviews developments since the 1970s in economic thinking about the design of taxes on business profit. It charts developments from proposals for a cash flow tax from the Meade Committee, to refinements of this in the form of an Allowance for Corporate Equity (ACEA) and levying the cash flow tax in the country of destination. It describes how the development of international trade and investment has led to ever-increasing problems in the international tax system with respect to economic efficiency, profit shifting, complexity and tax competition, and identifies why responding to these problems requires a major reform in the location of taxation.

Phenanthroline ligands are important metal-binding molecules which have been extensively researched for applications in both material science and medicinal chemistry. Azobenzene and its derivatives have received significant attention because of their ability to be reversibly switched between the E and Z forms and so could have applications in optical memory and logic devices or as molecular machines. Herein we report the formation and crystal structure of a highly unusual novel diazo-diphenanthroline compound, C24H14N6O2·2CHCl3.

The coordination of biologically active moieties to the axial positions of Pt(IV) derivatives of Pt(II) anticancer drugs allows the co-delivery and simultaneous activation of two pro-drugs for combination therapy. Pt(IV) complexes with a redox modulator as an axial ligand can kill cancer cells by a mechanism combining DNA platination and generation of oxidative stress. In this study we evaluated the cytotoxicity of Pt(IV) complexes based on the oxaliplatin scaffold and the pro-oxidant indole-3-propionate in cisplatin-sensitive and cisplatin-resistant ovarian cancer cells. A series of five complexes was synthesized and characterized by H-1 and Pt-195 NMR spectroscopy, IR spectroscopy, mass spectrometry and elemental analysis; trans-[Pt(DACH)(ox)(IPA)(OH)] (1), trans-[Pt(DACH)(ox)(IPA)(2)] (2), trans-[Pt(DACH)(ox)(IPA)(bz)] (3), trans-[Pt(DACH)(ox)(IPA)(suc)] (4), and trans-[Pt(DACH)(ox)(IPA)(ac)] (5) (DACH = 1,2-diaminocyclohexane (1R, 2R)-(-), ox = oxalate, IPA = indole 3-propionate, bz = benzoate, suc = succinate and ac = acetate). The complexes were shown to produce cellular reactive oxygen species (ROS) in a time-dependent manner. The most potent ROS producer, complex 1, also elicited the highest cytotoxicity. Complex 1 was shown to form the mono-and bis-adducts [Pt(DACH)(guanosine)( OH)](+) and [Pt(DACH)(guanosine)(2)](2+) in the presence of ascorbic acid, suggesting that on activation the released oxaliplatin will interact with DNA. A.A. acknowledges a PhD scholarship from Taibah University. D.T. acknowledges the Egyptian Ministry of Higher Education (MoHE) for funding her re search stay at the National University of Ireland Galway. peer-reviewed 2021-04-19

The synthesis of inherently chiral all-carbon C2-symmetric [12](1,6)pyrenophane 1 is reported. The cyclophane 1 was obtained via a ring-closing alkyne metathesis reaction using Mortreux's catalyst molybdenum hexacarbonyl and 2-fluorophenol as a phenol additive. The M and P enantiomers of the all-carbon pyrenophane 1 were demonstrated to be very stable in their enantiopure form even upon prolonged heating at 200 °C. [12](1,6)Pyrenophane-6-yne 1 was fully characterized by high-resolution mass spectrometry, nuclear magnetic resonance, UV-vis, and measured and calculated electronic circular dichroism spectroscopy.

Neurodegeneration mediates neurological disability in inflammatory demyelinating diseases of the CNS. The role of innate immune cells in mediating this damage has remained controversial with evidence for destructive and protective effects. This has complicated efforts to develop treatment. The time sequence and dynamic evolution of the opposing functions are especially unclear. Given limits of in vivo monitoring in human diseases such as multiple sclerosis (MS), animal models are warranted to investigate the association and timing of innate immune activation with neurodegeneration. Using noninvasive in vivo retinal imaging of experimental autoimmune encephalitis (EAE) in CX3CR1(GFP/+)-knock-in mice followed by transcriptional profiling, we are able to show 2 distinct waves separated by a marked reduction in the number of innate immune cells and change in cell morphology. The first wave is characterized by an inflammatory phagocytic phenotype preceding the onset of EAE, whereas the second wave is characterized by a regulatory, antiinflammatory phenotype during the chronic stage. Additionally, the magnitude of the first wave is associated with neuronal loss. Two transcripts identified - growth arrest-specific protein 6 (GAS6) and suppressor of cytokine signaling 3 (SOCS3) - might be promising targets for enhancing protective effects of microglia in the chronic phase after initial injury.

Pyrazolopyrimidinones are fused nitrogen-containing heterocyclic systems, which act as a core scaffold in many pharmaceutically relevant compounds. Pyrazolopyrimidinones have been demonstrated to be efficient in treating several diseases, including cystic fibrosis, obesity, viral infection and cancer. In this study using glioblastoma U-251MG cell line, we tested the cytotoxic effects of 15 pyrazolopyrimidinones, synthesised via a two-step process, in combination with cold atmospheric plasma (CAP). CAP is an adjustable source of reactive oxygen and nitrogen species as well as other unique chemical and physical effects which has been successfully tested as an innovative cancer therapy in clinical trials. Significantly variable cytotoxicity was observed with IC50 values ranging from around 11 μM to negligible toxicity among tested compounds. Interestingly, two pyrazolopyrimidinones were identified that act in a prodrug fashion and display around 5–15 times enhanced reactive-species dependent cytotoxicity when combined with cold atmospheric plasma. Activation was evident for direct CAP treatment on U-251MG cells loaded with the pyrazolopyrimidinone and indirect CAP treatment of the pyrazolopyrimidinone in media before adding to cells. Our results demonstrated the potential of CAP combined with pyrazolopyrimidinones as a programmable cytotoxic therapy and provide screened scaffolds that can be used for further development of pyrazolopyrimidinone prodrug derivatives.

The objective of this study was to investigate the antimicrobial and anticancer properties of a fucoidan extract and subsequent fractions isolated from the macroalgae Fucus vesiculosus. The fractions obtained (>300 kDa, 300 kDa fraction presented the lowest IC50 values (0.052% - 24 h; 0.032% - 6 days). The potential bioactivity of fucoidan as an antimicrobial and anticancer agent was demonstrated in this study. Hence, the related mechanisms of action should be explored in a near future. European Commission Horizon 2020 Science Foundation Ireland Spanish Ministry of Science, Innovation and Universities

Pyrazolopyrimidinone is a fused nitrogen-containing heterocyclic system, which acts as a core scaffold in many pharmaceutically relevant compounds. Pyrazolopyrimidinones have been demonstrated to be efficient in treating several diseases, including cystic fibrosis, obesity, viral infection and cancer. We have tested the synergistic anti-cancer effects of 15 pyrazolopyrimidinones, synthesised in a two-step process, combined with cold atmospheric plasma (CAP), a novel innovation generating reactive species with other unique chemical and physical effects. We identify two pyrazolopyrimidinones that act as prodrugs and display enhanced reactive-species dependent cytotoxicity when used in combination with cold atmospheric plasma. Synergistic activation was evident for both direct CAP treatment on prodrug loaded tumour cells and indirect CAP treatment of prodrug in media prior to adding to tumour cells. Our results demonstrate the potential of CAP combined with pyrazolopyrimidinones as a programmable cytotoxic therapy against cancer. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/429831v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@56c8aeorg.highwire.dtl.DTLVardef@1913ea9org.highwire.dtl.DTLVardef@a8f522org.highwire.dtl.DTLVardef@75a529_HPS_FORMAT_FIGEXP M_FIG C_FIG

This chapter sets out the key conceptual issues that arise in designing a business-level tax on profit in an international setting. It is in four parts—each addressing a basic question. First, what is meant by a tax on profit? We identify different approaches to taxing profit and show that there are a number of equivalences between taxes. Second, what criteria should be used for evaluating a business-level tax on profit in an international setting? We set out five criteria in some detail: economic efficiency, fairness, robustness to avoidance, ease of administration, and incentive compatibility. Third, given these criteria, is a business-level tax on profit a useful addition to the set of taxes that can be employed by national governments? We consider different possible underlying rationales for taxing business profit, especially in an international context. Fourth, is taxation at both the business and the owner-level problematic? We consider whether there is need for relief from this form of double taxation.

This chapter sets out and evaluates a number of possible reform options; we group options by four broad locations in which profit could be taxed. First, profit could in principle be taxed in the country of residence of the owners of the business. A second option is the country of residence of the parent company or business headquarters. A third option is the country where the business undertakes its functions and activities, or where its assets—defined broadly to include financial assets—are held. We refer to this location as ‘origin’. And finally, a business could be taxed in the location of its customers. We refer to this location as ‘destination’. Each of the activities taking place in these four locations might be thought to be necessary, but not sufficient, for the generation of profit, and therefore generate a nexus which would justify taxation. We evaluate specific options according to the five criteria set out in Chapter 2.

In this chapter we explain the broad approach taken in the two detailed proposals set out in Chapters 6 and 7, namely the RPAI and DBCFT respectively. We discuss the extent to which international coordination would be required, or desired. We then consider the costs of transition to a new system. In broad terms, we can compare incremental reforms which are based on the existing structure, with more fundamental reforms that more radically change that fundamental structure. We also discuss what should be required in terms of revenue requirements, and the likely redistribution of revenues among countries. We then discuss two issues which are common to the two options: the scope of the tax and the concept and definition of destination.

The enantioselective functionalization of nonactivated enantiotopic secondary C-H bonds is one of the greatest challenges in transition-metal-catalyzed C-H activation proceeding by an inner-sphere mechanism. Such reactions have remained elusive within the realm of Pd0 catalysis. Reported here is the unique reactivity profile of the IBiox ligand family in the Pd0 -catalyzed intramolecular arylation of such nonactivated secondary C-H bonds. Chiral C2 -symmetric IBiox ligands led to high enantioselectivities for a broad range of valuable indane products containing a tertiary stereocenter, as well as the arylation of secondary C-H bonds adjacent to amides. Depending on the amide substituents and upon control of reaction time, indanes containing labile tertiary stereocenters were also obtained with high enantioselectivities. Analysis of the steric maps of the IBiox ligands indicated that the level of enantioselectivity correlates with the difference between the two most occupied and the two less occupied space quadrants, and provided a blueprint for the design of even more efficient ligands.

Chronic infections of Pseudomonas aeruginosa in the lungs of cystic fibrosis (CF) patients are problematic in Ireland where inherited CF is prevalent. The bacteria&rsquo, s capacity to form a biofilm in its pathogenesis is highly virulent and leads to decreased susceptibility to most antibiotic treatments. Herein, we present the activity profiles of the Cu(II), Mn(II) and Ag(I) tdda-phen chelate complexes {[Cu(3,6,9-tdda)(phen)2].3H2O.EtOH}n (Cu-tdda-phen), {[Mn(3,6,9-tdda)(phen)2].3H2O.EtOH}n (Mn-tdda-phen) and [Ag2(3,6,9-tdda)(phen)4].EtOH (Ag-tdda-phen) (tddaH2 = 3,6,9-trioxaundecanedioic acid, phen = 1,10-phenanthroline) towards clinical isolates of P. aeruginosa derived from Irish CF patients in comparison to two reference laboratory strains (ATCC 27853 and PAO1). The effects of the metal-tdda-phen complexes and gentamicin on planktonic growth, biofilm formation (pre-treatment) and mature biofilm (post-treatment) alone and in combination were investigated. The effects of the metal-tdda-phen complexes on the individual biofilm components, exopolysaccharide, extracellular DNA (eDNA), pyocyanin and pyoverdine are also presented. All three metal-tdda-phen complexes showed comparable and often superior activity to gentamicin in the CF strains, compared to their activities in the laboratory strains, with respect to both biofilm formation and established biofilms. Combination studies presented synergistic activity between all three complexes and gentamicin, particularly for the post-treatment of established mature biofilms, and was supported by the reduction of the individual biofilm components examined.

Epigenetic agents such as histone deacetylase (HDAC) inhibitors are widely investigated for use in combined anticancer therapy and the co-administration of Pt drugs with HDAC inhibitors has shown promise for the treatment of resistant cancers. Coordination of an HDAC inhibitor to an axial position of a Pt(IV) derivative of cisplatin allows the combination of the epigenetic drug and the Pt chemotherapeutic into a single molecule. In this work we carry out mechanistic studies on the known Pt(IV) complex cis,cis,trans-[Pt(NH3)2Cl2(PBA)2] (B) with the HDAC inhibitor 4-phenylbutyrate (PBA) and its derivatives cis,cis,trans-[Pt(NH3)2Cl2(PBA)(OH)] (A), cis,cis,trans-[Pt(NH3)2Cl2(PBA)(Bz)] (C), and cis,cis,trans-[Pt(NH3)2Cl2(PBA)(Suc)] (D) (Bz = benzoate, Suc = succinate). The comparison of the cytotoxicity, effect on HDAC activity, reactive oxygen species (ROS) generation, γ-H2AX (histone 2A-family member X) foci generation and induction of apoptosis in cisplatin-sensitive and cisplatin-resistant ovarian cancer cells shows that A – C exhibit multimodal mechanisms involving DNA damage and apoptosis independent of cisplatin resistance.

Therapeutic options are limited for patients infected with Acinetobacter baumannii due to its multidrug-resistance profile. So, the search for new antimicrobials against this gram-negative bacterial pathogen has become a worldwide priority. The present study aimed to evaluate the effects of 1,10-phenanthroline (phen), 1,10-phenanthroline-5,6-dione (phendione), [Ag(phendione)(2)]ClO(4) (Ag-phendione) and [Cu(phendione)(3)](ClO(4))(2)·4H(2)O (Cu-phendione) on 26 carbapenemase-producing A. baumannii strains. The susceptibility to carbapenems was performed by detecting the metallo-beta-lactamase (MBL) genes by PCR and by determining the MIC. Also, disk diffusion method was applied to evaluate the susceptibility to other antimicrobial classes. The test compounds were evaluated on both planktonic- and biofilm-growing bacterial cells. The results revealed that all A. baumannii strains had the intrinsic bla(oxa-51) gene, and at least one of the bla(oxa-23) or bla(oxa-24) genes. The geometric mean MIC and minimum bactericidal concentration (MBC) values, respectively, were as follows: Cu-phendione (1.56 and 2.30 μM), Ag-phendione (2.48 and 3.63 μM), phendione (9.44 and 9.70 μM), and phen (70.46 and 184.28 μM). The test compounds (at 0.5 × MIC) affected the biofilm formation and disrupted the mature biofilm, in a typically dose-dependent manner, reducing biomass and viability parameters. Collectively, silver and copper-phendione derivatives presented potent antimicrobial action against planktonic- and biofilm-forming cells of carbapenemase-producing A. baumannii.

Herein we report the in-vivo characterisation and metabolic changes in Galleria mellonella larvae to a series of bischelate copper(II) phenanthroline-phenazine cationic complexes of [Cu(phen)2] 2+ (Cu-Phen), [Cu(DPQ) (Phen)]2+ (Cu-DPQ-Phen) and [Cu(DPPZ)(Phen)]2+ (Cu-DPPZ-Phen) (where phen = 1,10-phenanthroline, DPQ = dipyrido[3,2-ƒ:2′,3′-h]quinoxaline and DPPZ = dipyrido[3,2-a:2′,3′-c]phenazine). Our aim was to investigate the influence of the systematic extension of the ligated phenazine ligand in the G. mellonella model as a first step towards assessing the in-vivo tolerance and mode of action of the complex series with respect to the well-studied oxidative chemical nuclease, Cu-Phen. The Lethal Dose50 (LD50) values were established over dose ranges of 2 – 30 μg at 4-, 24-, 48- and 72 h by mortality assessment, with Cu-Phen eliciting the highest mortality at 4 h (Cu-Phen, 12.62 μg < Cu-DPQ-Phen, 21.53 μg < Cu-DPPZ-Phen, 26.07 μg). At other timepoints, a similar profile was observed as the phenazine π-backbone within the complex scaffold was extended. Assessment of both cellular response and related gene expression demonstrated that the complexes did not initiate an immune response. However, Label-Free Quantification proteomic data indicated the larval response was associated with upregulation of key proteins such as Glutathione S-transferase, purine synthesis and glycolysis/gluconeogenesis (e.g. fructose-bisphosphate aldolase and glyceraldehyde-3-phosphate). Both Cu-Phen and Cu-DPQ-Phen elicited a similar in-vivo response in contrast to Cu-DPPZ-Phen, which displayed a substantial increase in nitrogen detoxification proteins and proteins with calcium binding sites. Overall, the response of G. mellonella larvae exposure to the complex series is dominated by detoxification and metabolic proteome response mechanisms.

We model the effects of cash flow taxes on company profit which differ according to the base and location of the tax. Our model incorporates a multinational producing and selling in two countries with three sources of rent, each in a different location: a fixed basic production factor (located with initial production), mobile managerial skill, and a fixed final production factor (located with consumption). In the general case, we show that for national governments, there are trade-offs in choosing between alternative taxes. In particular, a cash-flow tax on a source basis creates welfare-impairing distortions to production and consumption, but is partially incident on the owners of domestic production who may be non-resident. By contrast, a destination-based cash-flow tax does not distort behaviour, but is incident only on domestic residents.

The discovery of the high-affinity, high-specificity folate receptor in mamalian kidney cells, coupled with the ability of folate to enter cells by folate receptor-mediated endocytosis and the subsequent elucidation of the folate receptor’s overexpression in specific cancer cell types; heralded the arrival of the area of chemotherapeutic folate targeting. The application of purely organic folate-based small-molecule drug conjugates that selectively target the folate receptor, which is over expressed in several diseases such as cancer, is well established. The application of inorganic folate-targeted drugs offers significant potential to expand and enhance this therapeutic approach. From the data made available to date, it is apparent that this aspect of inorganic medicinal chemistry is in its youth but has the capability to contribute greatly to cancer research, both in therapy and diagnosis. The union of folate-receptor targeting and inorganic medicine may also lead to the development of treatments for disorders such as chronic-inflammation, tuberculosis, neurodegenerative disease and leishmaniasis. In this review, we summarize what is known about the coordination chemistry of folic acid and the therapeutic potential of such complexes. We also describe approaches adopted to conjugate platinum drugs to folate- or folate-carrier- systems and their prospective ability to overcome problems associated with unwanted side-effects and resistance by improving their delivery and/or selectivity. The literature pertaining to non-platinum metal complex conjugates with folic acid is also reviewed revealing that this is an area that offers significant potential to develop targeted therapeutic approaches in areas such as chemotherapy and molecular imaging for diagnostics.

This paper considers the implications of the destination-based cash flow tax (DBCFT) for three common ways of shifting taxable profits between countries: through manipulation of transfer prices, the use of debt, and locating intangible assets in low taxed jurisdictions. It shows that none of these planning devices would be available under a DBCFT, if adopted universally. This is because intra-group payments between two countries do not affect tax liabilities in either country . If adopted unilaterally, however, there would be an incentive to shift profit to the adopting country, at the expense of non-adopting countries.

The “antibiotic era”, characterized by the overuse and misuse of antibiotics, over the last half-century has culminated in the present critical “era of resistance”. The treatment of bacterial infections is challenging because of a decline in the current arsenal of useful antibiotics and the slow rate of new drug development. The discovery of a new gene (mcr-1) in 2015, which enables bacteria to be highly resistant to polymyxins (such as colistin), the last line of antibiotic defence left, heralds a new level of concern as this gene is susceptible to horizontal gene transfer, with alarming potential to be spread between different bacterial populations, suggesting that the progression from “extensive drug resistance” to “pan-drug resistance” may be inevitable. Clearly there is a need for the development of novel classes of anti-bacterial agents capable of killing bacteria through mechanisms that are different to those of the known classes of antibiotics. 1,10-phenanthroline (phen) is a heterocyclic organic compound which exerts in vitro antimicrobial activity against a broad-spectrum of bacteria. The antimicrobial activity of phen can be significantly modulated by modifying its structure. The development of metal-phen complexes offers the medicinal chemist an opportunity to expand such structural diversity by controlling the geometry and varying the oxidation states of the metal centre, with the inclusion of appropriate auxiliary ligands in the structure, offering the opportunity to target different biochemical pathways in bacteria. In this review, we summarize what is currently known about the antibacterial capability of metal-phen complexes and their mechanisms of action.

Herein we report an in-depth study on the cytotoxic mechanism of action of four developmental cytotoxic copper(ii) complexes: [Cu(phen)2]2+ (Cu-Phen); [Cu(DPQ)(Phen)]2+ (Cu-DPQ-Phen); [Cu(DPPZ)(Phen)]2+; and [Cu(DPPN)(Phen)]2+ (where Phen = 1,10-phenanthroline, DPQ = dipyrido[3,2-f:2′,3′-h]quinoxaline, DPPZ = dipyrido[3,2-a:2′,3′-c]phenazine, and DPPN = benzo[i]dipyrido[3,2-a:2′,3′-c]phenazine). This complex class is known for its DNA intercalative properties and recent evidence—derived from an in vivo proteomic study—supports the potential targeting of mitochondrial function. Therefore, we focused on mitochondrial-mediated apoptosis related to cytotoxic activity and the potential impact these agents have on mitochondrial function. The Cu(ii) complexes demonstrated superior activity regardless of aromatic extension within the phenazine ligand to the previously demonstrated activity of cisplatin. Unique toxicity mechanisms were also identified in prior demonstrated cisplatin sensitive and resistant cell lines. Double strand breaks in genomic DNA, quantified by γH2AX foci formation, were then coupled with apoptotic gene expression to elucidate the mechanisms of cell death. These results indicate that while DNA damage-induced apoptosis by BAX, XIAP and caspase-9 and -3 expression is moderate for the Cu(ii) complexes when compared to cisplatin, protein targets independent of DNA exert a multimodal mechanistic effect. Significantly, mitochondrial gene expression of oxidative stress, protease expression, and fission/fusion processes—upregulated HMOX, DRP1 and LON, respectively—indicated an increased oxidative damage associated with compromised mitochondrial health upon exposure to these agents. These data support a unique mode of action by these complexes and provide valuable evidence of the developmental potential of these therapeutic inorganic complexes.