Stabilisation of MAD2 expression through inhibition of miR-433; A novel mechanism for restoring chemo-responsiveness in ovarian tumours

Epithelial ovarian carcinoma (EOC) is characterised by late diagnosis and recurrences, both of which contribute to the high morbidity and mortality of this cancer. Unfortunately, EOC has an innate susceptibility to become chemo-resistant. Specifically, up to 30% of patients may not respond to current standard chemotherapy (paclitaxel and platinum in combination) and of those who have an initial response, some patients relapse within a few months. Therefore, in order to improve patient outcome it is crucial to establish what factors influence a patients' individualised response to chemotherapy. We analysed MAD2 protein expression in a patient cohort of 35 ovarian tumours and a panel of 5 ovarian cancer cell lines. We have demonstrated that low nuclear MAD2 expression intensity was significantly associated with chemo-resistant ovarian tumours (p=0.0136). Moreover, in vitro studies of the 5 ovarian cancer cell lines revealed that reduced MAD2 expression was associated with paclitaxel resistance. In silico analysis identified a putative miR-433 binding domain in the MAD2 3′UTR and expression profiling of miR-433 in the ovarian cancer cell lines showed that low MAD2 protein expression was associated with high miR-433 levels. In vitro over-expression of miR-433 attenuated MAD2 protein expression with a concomitant increase in cellular resistance to paclitaxel. Over-expression of a morpholino oligonucleotide that blocks miR-433 binding to MAD2 3′UTR stabilised MAD2 protein expression and protects from miR-433 induced degradation. Furthermore, miR-433 expression analysis in 35 ovarian tumour samples revealed that high miR-433 expression was associated with advanced stage presentations (p=0.0236). In conclusion, ovarian tumours that display low nuclear MAD2 intensity are chemo-resistant and stabilising MAD2 expression by antagonising miR-433 activity is a potential mechanism for restoring chemo-responsiveness in these tumours.

On the solvation of L-aspartic acid

We use molecular statics and dynamics to study the stability of L-aspartic acid both in vacuo and solvated by polar and non-polar molecules using density functional theory in the generalized gradient approximation. We find that structures stable in vacuo are unstable in aqueous solution and vice versa. From our simulations we are able to come to some conclusions about the mechanism of stabilisation of zwitterions by polar protic solvents, water and methanol.

The smooth muscle pharmacology of maximakinin, a receptor-selective, bradykinin-related nonadecapeptide from the venom of the Chinese toad, Bombina maxima.

Structural homologues of vertebrate regulatory peptides found in defensive skin secretions of anuran amphibians often display enhanced bioactivity and receptor binding when compared with endogenous mammalian peptide ligands. Maximakinin, a novel N-terminally extended bradykinin (DLPKINRKGPRPPGFSPFR) from the skin venom of a Chinese toad (Bombina maxima), displays such activity enhancement when compared with bradykinin but is additionally highly selective for mammalian arterial smooth muscle bradykinin receptors displaying a 50-fold increase in molar potency in this smooth muscle type. In contrast, a 100-fold decrease in molar potency was observed at bradykinin receptors in intestinal and uterine smooth muscle preparations. Maximakinin has thus evolved as a “smart” defensive weapon in the toad with receptor/tissue selective targeting. Natural selection of amphibian skin venom peptides for antipredator defence, through inter-species delivery by an exogenous secretory mode, produces subtle structural stabilisation modifications that can potentially provide new insights for the design of selectively targeted peptide therapeutics.

Learning To Live Together

The rise of ethnic tensions has rendered the idea of pluralist societies more problematic than ever before. This article looks at the role played by adult education in helping to build peace in Northern Ireland, a society which is moving towards the stabilisation of its intercommunal conflict. A typology of peace education is put forward, outlining the various strategies adopted by those involved in adult learning or community relations work. Some general observations are added about the role of gender. Questions are then raised about how the impact of peace education progammes can be measured or assessed, and about the methodological problems facing all those attempting to draw conclusions about the role of education in conflict societies.

A click chemistry approach to C3 symmetric, G-quadruplex stabilising ligands.

Described is the structure-based design and synthesis of a series of tris-triazole G-quadruplex binding ligands utilising the copper catalysed azide–alkyne ‘click’ reaction. The results of G-quadruplex stabilisation by the ligands are reported and discussed.

Non-linear finite-element analysis of punching capacities of steel-concrete bridge deck slabs

Punching failure is the common failure mode in concrete bridge deck slabs when these structural components are subjected to local patch loads, such as tyre loads. Past research has shown that reinforced concrete slabs in girder–slab type bridges have a load-carrying capacity far greater than the ultimate static loads predicted by traditional design methods, because of the presence of compressive membrane action. However, due to the instability problems from punching failure, it is difficult to predict ultimate capacities accurately in numerical analyses. In order to overcome the instability problems, this paper establishes an efficient non-linear finite-element analysis using the commercial finite-element package Abaqus. In the non-linear finite-element analysis, stabilisation methods were adopted and failure criteria were established to predict the ultimate punching behaviour of deck slabs in composite steel–concrete bridges. The proposed non-linear finite-element analysis predictions showed a good correlation on punching capacities with experimental tests.

Foveal relocation by redistribution of the neurosensory retina

Aim - To describe a new surgical technique for foveal relocation, and to report the outcome in nine patients treated with this procedure. Methods - Nine consecutive patients with subfoveal choroidal neovascular membranes (CNVMs) secondary to age related macular degeneration underwent foveal relocation surgery by redistribution of the neurosensory retina (RNR). The technique involved induction of a retinal detachment via a single retinotomy, relocation of the fovea by 'sweeping' the retinal tissue with a retinal brush, and stabilisation of the retina in its new location using perfluorocarbon liquid peroperatively and silicone oil postoperatively. Results - In eight of nine eyes successful relocation of the fovea was achieved; in one eye the CNVM remained in a subfoveal location postoperatively. Visual acuity improved in two eyes, remained unchanged in three, and decreased in four eyes after a median follow up of 4 months (range 2.5-6 months). Complications included rupture of a foveal cyst with the development of a macular hole in one eye and epimacular membrane formation in another eye. In two eyes, macular retinal vessel closure occurred at the time of laser photocoagulation; one of these eyes later developed cystoid macular oedema and the other an epiretinal membrane. Recurrence of the CNVM was observed in one eye, but was controlled with further laser treatment. Conclusions - Foveal relocation by RNR appears to be feasible, obviating the need for extensive retinotomies or scleral shortening.

Changed reactivity of the 1-bromo-4-nitrobenzene radical anion in a room temperature ionic liquid

Radical anions of 1-bromo-4-nitrobenzene (p-BrC6H4NO2) are shown to be reactive in the room temperature ionic liquid N-butyl-N-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide, ([C(4)mPyrr][NTf2]), by means of voltammetric measurements. In particular, they are shown to react via a DISP type mechanism such that the electrolysis of p-BrC6H4NO2 occurs consuming between one and two electrons per reactant molecule, leading to the formation of the nitrobenzene radical anion and bromide ions. This behaviour is a stark contrast to that in conventional non-aqueous solvents such as acetonitrile, dimethyl sulfoxide or N,N-dimethylformamide, which suggests that the ionic solvent promotes the reactivity of the radical anion, probably via stabilisation of the charged products.

GHMP Kinases - Structures, Mechanisms and Potential for Therapeutically Relevant Inhibition

The GHMP kinases are a structurally related family of small molecule kinases named after four of its members - galactokinase, homoserine kinase, mevalonate kinase and phosphomevalonate kinase. The group also includes the enzymes N-acetylgalactosamine kinase, arabinose kinase, mevalonate 5-diphosphate decarboxylase, archeal shikimate kinase and 4-(cytidine 5'-diphospho)-2-c-methyl-D-erythritol kinase. In addition the group includes two members not known to be catalytically active, the Caenorhabditis elegans sex-fate determining protein XOL-1 and the Saccharomyces cerevisiae transcriptional activator Gal3p. Two catalytic mechanisms have been proposed for GHMP kinases. The structure of mevalonate kinase suggests that an aspartate residue acts as an active site base, removing a proton from the substrate to facilitate attack on the ? phosphate of MgATP. In contrast, in homoserine kinase there is no potential catalytic base and it is proposed that catalysis is driven by transition state stabilisation. Potential chemotherapeutic interventions against GHMP kinases fall into three main categories: inhibition of galactokinase to assist suffers of galactosemia, inhibition of mevalonate kinase or mevalonate 5-diphosphate decarboxylase to reduce flux through the cholesterol biosynthesis pathway and inhibition of bacterial GHMP kinases for novel anti-microbial therapies. These are in the early stages of development, but the accumulation of structural and mechanistic data will assist future progress.

Phillips-Heffron Power System Model for SmartPark and Suppression of Interarea Oscillations

This paper investigates the use of plug-in parking lots (SmartPark) as integral energy storage to improve small-signal stability using plug-in electric vehicles (PEV). The paper establishes the Phillips-Heffron model of a power system for a SmartPark solution. Based on this model, SmartPark-based stabilisers have been designed based using phase compensation to improve power system oscillation stability. The effectiveness of stabilisation superimposed on the active and reactive power regulators is verified by simulations obtained from a multi-machine power system model with SmartPark and a large-scale wind farm inclusion.

Coal combustion residues valorisation:Research and development on compressed brick production

This paper presents the results of an experimental investigation on compressive strength of unfired compressed brick obtained with coal combustion residues (CCRs) produced by the Niger Coal Society. Preliminary physical and optical (XRD and SEM) characterisation of coal slag, including lixiviation tests, have been carried out. Cement powder, lateritic clayey soil and sand have been chosen as stabilizing agents for bricks. 12 dosages have been tested and about 300 bricks have been produced with a hand-operated press. Results show uniaxial compressive strengths (UCSs) ranging from 4 MPa to 27 MPa for the highest cement stabilisation ratio. UCS higher than 7.5 MPa have been observed for stabilisation with 20% of laterite +10% cement after 45 days of curing. Obtained bricks showed good mechanical resistance and low weight. No health threat has been detected for the obtained samples. Study developments are oriented towards the analysis of Pozzolanic properties of CCRs, properties of hydrated lime stabilisation, thermal properties and durability assessment.© 2012 Elsevier Ltd. All rights reserved.

Preparation and characterisation of palladium, platinum and manganese di(organo)carbene complexes from quinolinone and quinolinium precursors

A series of palladium, platinum and manganese di(organo) carbene complexes have been prepared from 4-chloro-N-methylquinolinone by processes that involve alkylation before or after attachment to the metal unit; the nucleophilic heteroatoms necessary for eventual carbene formation and stabilisation are separated from the C-donor atom by three bonds.