Deferiprone and gallium-protoporphyrin have the capacity to potentiate the activity of antibiotics in Staphylococcus aureus small colony variants

Small colony variants (SCVs) of bacteria like Staphylococcus aureus are characterized by a reduced colony size and are linked to increased antibiotic tolerance and resistance. Their altered expression of virulence factors, slow growing properties and their ability to form biofilms make the eradication of SCVs challenging. In the context of biofilm-related infectious diseases involving S. aureus SCVs, a therapy targeting bacterial iron metabolism was evaluated. The combination of the iron-chelator deferiprone (Def) and the heme-analog gallium-protoporphyrin (GaPP), in solution and incorporated in a surgical wound gel, was tested for activity against planktonic and sessile SCVs. To this end, the activity of Def-GaPP was assessed against planktonic S. aureus SCVs, as well as against in vitro and in vivo biofilms in the colony biofilm model, an artificial wound model and a Caenorhabditis elegans infection model. While Def alone failed to show substantial antibacterial activity, GaPP and the combination of Def-GaPP demonstrated concentration- and strain-dependent antibacterial properties. Specifically, the Def-GaPP combination significantly reduced the bacterial load in an artificial wound model and increased the survival of S. aureus SCV infected C. elegans. When Def-GaPP were combined with gentamicin or ciprofloxacin, the triple combinations exceeded the antibiofilm activity of the individual compounds in the colony biofilm model. In targeting bacterial iron metabolism, Def-GaPP showed significant activity against planktonic and sessile SCVs. Moreover, Def-GaPP could potentiate the activity of gentamicin and ciprofloxacin. Delivered in a wound healing gel, Def-GaPP showed promise as a new topical strategy against infections with S. aureus SCVs.Katharina Richter, Nicky Thomas, Guimin Zhang, Clive A. Prestidge, Tom Coenye, Peter-John Wormald and Sarah Vreugd

Expanding the therapeutic potential of Statins by means of nanotechnology enabled drug delivery systems

Statins are effective lipid lowering agents traditionally used for the primary and secondary prevention of cardiovascular disease. Statins also exert a range of pleiotropic effects that make them attractive candidates for use in a wide range of disorders, in particular inflammatory and immune mediated conditions. However, the exploitation of such pleiotropic effects has been greatly hindered by poor bioavailability and adverse effects on muscles and the liver at higher doses. Nanotechnology is often suggested as the solution to this problem, as it enables an increased bioavailability of statins. Moreover, colloidal carriers can offer targeted drug delivery approaches that enable localised biological effects of statins, further reducing their potential for unwanted toxicity and adverse effects. This article reviews the available evidences for the increased potential of statin therapy when administered in nano-formulations such as nanocrystals, nanoparticles, liposomes, micelles and various nano-enabled devices. © 2014 Bentham Science Publishers

Thermodynamics of a collapsing shell in an expanding Universe

We describe the quasi-static collapse of a radiating, spherical shell of matter in de Sitter space-time using a thermodynamical formalism. It is found that the specific heat at constant area and other thermodynamical quantities exhibit singularities related to phase transitions during the collapse.Comment: 9 pages, 2 figures, accepted for publication in Phys. Lett.

Development of a novel cell-based assay system EPISSAY for screening epigenetic drugs and liposome formulated decitabine

Extent: 11 p.BACKGROUND: Despite the potential of improving the delivery of epigenetic drugs, the subsequent assessment of changes in their epigenetic activity is largely dependent on the availability of a suitable and rapid screening bioassay. Here, we describe a cell-based assay system for screening gene reactivation. METHODS: A cell-based assay system (EPISSAY) was designed based on a silenced triple-mutated bacterial nitroreductase TMnfsB fused with Red-Fluorescent Protein (RFP) expressed in the non-malignant human breast cell line MCF10A. EPISSAY was validated using the target gene TXNIP, which has previously been shown to respond to epigenetic drugs. The potency of a epigenetic drug model, decitabine, formulated with PEGylated liposomes was also validated using this assay system. RESULTS: Following treatment with DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors such as decitabine and vorinostat, increases in RFP expression were observed, indicating expression of RFP-TMnfsB. The EPISSAY system was then used to test the potency of decitabine, before and after PEGylated liposomal encapsulation. We observed a 50% higher potency of decitabine when encapsulated in PEGylated liposomes, which is likely to be due to its protection from rapid degradation. CONCLUSIONS: The EPISSAY bioassay system provides a novel and rapid system to compare the efficiencies of existing and newly formulated drugs that reactivate gene expression.Sue Ping Lim, Raman Kumar, Yamini Akkamsetty, Wen Wang, Kristen Ho, Paul M. Neilsen, Diego J. Walther, Rachel J. Suetani, Clive Prestidge and David F. Calle

On Black-Brane Instability In an Arbitrary Dimension

The black-hole black-string system is known to exhibit critical dimensions and therefore it is interesting to vary the spacetime dimension $D$, treating it as a parameter of the system. We derive the large $D$ asymptotics of the critical, i.e. marginally stable, string following an earlier numerical analysis. For a background with an arbitrary compactification manifold we give an expression for the critical mass of a corresponding black brane. This expression is completely explicit for ${\bf T}^n$, the $n$ dimensional torus of an arbitrary shape. An indication is given that by employing a higher dimensional torus, rather than a single compact dimension, the total critical dimension above which the nature of the black-brane black-hole phase transition changes from sudden to smooth could be as low as $D\leq 11$.Comment: 1+14 pages, 2 eps figures. Replaced with the published versio

Higher Spin Field Equation in a Virtual Black Hole Metric

In a quantum theory of gravity, fluctuations about the vacuum may be considered as Planck scale virtual black holes appearing and annihilating in pairs. Incident fields scattering from such fluctuations would lose quantum coherence. In a recent paper (hep-th/9705147), Hawking and Ross obtained an estimate for the magnitude of this loss in the case of a scalar field. Their calculation exploited the separability of the conformally invariant scalar wave equation in the electrovac C metric background, which is justified as a sufficiently good description of a virtual black hole pair in the limit considered. In anticipation of extending this result, the Teukolsky equations for incident fields of higher spin are separated on the vacuum C metric background and solved in the same limit. With the exception of spin 2 fields, these equations are shown in addition to be valid on the electrovac C metric background. The angular solutions are found to reduce to the spin- weighted spherical harmonics, and the radial solutions are found to approach hypergeometrics close to the horizons. By defining appropriate scattering boundary conditions, these solutions are then used to estimate the transmission and reflection coefficients for an incident field of spin s. The transmission coefficient is required in order to estimate the loss of quantum coherence of an incident field through scattering off virtual black holes.Comment: 23 pages, 3 figures, LaTeX, minor typo correcte

The influence of mineral fertilization of grassland leafhopper associations

Imperial Users onl

Concrete poetry and Conceptual art: connections, communication and interrelationships in text-image movements from 1953-1980

Concrete poetry and Conceptual art are often presented as separate or opposing movements. Although the pairing of Concrete poetry and Conceptual art has been disputed, this thesis argues that Concrete poetry and Conceptual art are connected and demonstrates how these international movements, which overlapped in the 1960s, are analogous by examining previously overlooked points of convergence. The historical framework of the research is 1953 to 1980 – from the earliest use of the term ‘Concrete poetry’ through to a widespread return to painting and figurative art in 1980. The research study focuses on predominantly British concrete poets, conceptual artists, figures associated with either or both movements, and those that denied the title of concrete poet or conceptual artist but produced work with similar qualities to the work associated with these movements. A selection of American practitioners has also been included due to American art and literary influences on British practitioners at the time. These practitioners were part of a countercultural shift in the 1960s and the social, political, cultural (and economic) contexts within which these practitioners were working is taken into consideration when analysing their work and activities. This thesis presents the dematerialisation of the art object using language (in Conceptual art) and the materialisation of language (in Concrete poetry) as complementary. In the last twenty years, there has been an increase in the number of scholars from literary and/or artistic disciplines comparing Concrete poetry and Conceptual art and arguing for or against a connection between them. This research contributes to existing knowledge via an examination of the infrastructure of the art and literary worlds in the 1950s, 1960s and 1970s (in particular, the cross-disciplinary spaces available to practitioners experimenting with Concrete poetry and Conceptual art), analyses of interactions between poets and artists which demonstrate that they were aware of each other and each other’s work, ideologies and theories, and an investigation into the role of poet-artists, intermedia or cross-disciplinary practitioners/figures, engaged with either or both movements, who blurred the boundaries between the visual arts and poetry. Overall, connections between Concrete poetry and (language-based) Conceptual art manifest as visual similarities, use of and an enthusiasm for the possibilities of language, interpersonal relationships and shared theoretical approaches, intermedia and interdisciplinary practices, poet/artist-run and institutional spaces, shared sources of funding, curation, collection and dissemination, and a reliance on the viewer/reader to interpret or ‘create’ the work

Dynamic and Thermodynamic Stability and Negative Modes in Schwarzschild-Anti-de Sitter

The thermodynamic properties of Schwarzschild-anti-de Sitter black holes confined within finite isothermal cavities are examined. In contrast to the Schwarzschild case, the infinite cavity limit may be taken which, if suitably stated, remains double valued. This allows the correspondence between non-existence of negative modes for classical solutions and local thermodynamic stability of the equilibrium configuration of such solutions to be shown in a well defined manner. This is not possible in the asymptotically flat case. Furthermore, the non-existence of negative modes for the larger black hole solution in Schwarzschild-anti-de Sitter provides strong evidence in favour of the recent positive energy conjecture by Horowitz and Myers.Comment: 21 pages, 5 figures, LaTe