A nonantisense sequence-selective effect of a phosphorothioate oligodeoxynucleotide directed against the epidermal growth factor receptor in A431 cells

The overexpression of epidermal growth factor receptor (EGFr) has been implicated as a causative factor and a poor prognostic marker in a number of carcinomas. Therefore, strategies that down-regulate EGFr expression may be therapeutically useful. We designed antisense ODNs complementary to the initiation codon region of the EGFr mRNA and evaluated their efficacy in several tumor-derived cells, including the A431 cell line that express amplified levels of EGFr. A 15-mer phosphorothioate (PS) antisense ODN (erbB1AS15) induced a concentration-dependent reduction in proliferation that was accompanied by a change in the morphology of A431 cells into more tightly clustered and discrete colonies. A 15-mer sense (PS) control oligodeoxynucleotide (ODN) and a phosphodiester (PO) version of erbB1AS15 had little or no effect on cell number of morphology, and erbB1AS15 (PS) did not induce these effects in control cell lines expressing lower levels of EGFr. The effects of erbB1AS15 (PS) on A431 cells were not mediated by a true antisense mechanism in that there was no reduction in the level of EGFr mRNA or protein over a 24-hr period, as determined by Northern and Western blotting, respectively. However, autophosphorylation of the receptor was significantly reduced by erbB1AS15 (PS) and not by control ODNs. The results of further studies suggested that this effect was mediated by a direct, dose-dependent inhibition of the EGFr tyrosine kinase enzyme and was not due to impairment of either ligand-binding or receptor dimerization. These data suggest that erbB1AS15 (PS) can inhibit proliferation and alter the morphology of A431 cells by a sequence-selective, but nonantisense mechanism affecting receptor tyrosine kinase activity.

Business strategy and the environment in a traditional manufacturing sector

This research is concerned with the relationship between business strategy and the environment within traditional sectors. It has sought to learn more about the strategic environmental attitudes of SMEs compared with large companies operating under the same market conditions. The sector studied is the ceramics industry (including tableware & ornamental-ware, sanitary ware & tiles, bricks, industrial & advanced ceramics and refractories) in the UK and France. Unlike the automotive, oil, chemical, steel or metal processing sectors, this industry is one of the few industrial sectors which has rarely been considered. The information on this sector was gathered by interviewing people responsible for environmental issues. The actual programme of valid interviews represents approximately a quarter of the UK and French ceramics industry which is large enough to enable a quantitative analysis and significant and non-biased conclusions. As a whole, all companies surveyed agreed that the ceramics activity impacts on the environment, and that they are increasingly affected both by environmental legislation, and by various non-legislative pressures. Approaches to the environmental agenda differ significantly among large and small companies. Smaller companies feel particularly pressed both by the financial costs and management time required to meet complex and changing legislation. The results of this survey also suggest that the ceramics industry sees environmental issues in terms of increased costs rather than new business opportunities. This is due principally to fears of import substitution from countries with lower environmental standards. Finally, replies indicate that generally there is a low level of awareness of the current legislative framework, suggesting a need to shift from a regulatory approach to a more self-regulated approach which encourages companies to be more proactive

Monopoly in the UK:what determines whether the MMC finds against the investigated firms?

This paper draws on data from 73 UK Monopolies and Mergers Commission reports on monopoly between 1973 and 1995. It shows that there is a roughly two in three chance that the Commission will come to an adverse conclusion against the investigated firms in a given case. 75–80% of decisions can be explained purely in terms of the market share of the leading firm and knowledge of the broad nature of the alleged anti-competitive practice. An adverse finding is most likely in cases involving exclusive dealing, and least likely where other vertical restraints are involved.

Length, lexicality, and articulatory suppression in immediate recall:evidence against the articulatory loop

Influential models of short-term memory have attributed the fact that short words are recalled better than longer words in serial recall (the length effect) to articulatory rehearsal. Crucial for this link is the finding that the length effect disappears under articulatory suppression. We show, instead, that, under suppression, the length effect is abolished or reversed for real words but remains robust for nonwords. The latter finding is demonstrated in a variety of conditions: with lists of three and four nonwords, with nonwords drawn from closed and open sets, with spoken and written presentation, and with written and spoken output. Our interpretation is that the standard length effect derives from the number of phonological units to be retained. The length effect is abolished or reversed under suppression because this condition encourages reliance on lexical-semantic representations. Using these representations, longer words can more easily be reconstructed from degraded phonology than shorter words. © 2005 Elsevier Inc. All rights reserved.

Language against the odds, or rather not:the weak central coherence hypothesis and language

EV is a child with a talent for learning language combined with Asperger syndrome. EV’s talent is evident in the unusual circumstances of her acquisition of both her first (Bulgarian) and second (German) languages and the unique patterns of both receptive and expressive language (in both the L1 and L2), in which she shows subtle dissociations in competence and performance consistent with an uneven cognitive profile of skills and abilities. We argue that this case provides support for theories of language learning and usage that require more general underlying cognitive mechanisms and skills. One such account, the Weak Central Coherence (WCC) hypothesis of autism, provides a plausible framework for the interpretation of the simultaneous co-occurrence of EV’s particular pattern of cognitive strengths and weaknesses. Furthermore, we show that specific features of the uneven cognitive profile of Asperger syndrome can help explain the observed language talent displayed by EV. Thus, rather than demonstrating a case where language learning takes place despite the presence of deficits, EV’s case illustrates how a pattern of strengths within this profile can specifically promote language learning.

Have the GIPSI settled down? Breaks and multivariate stochastic volatility models for, and not against, the European financial integration

We investigate the integration of the European peripheral financial markets with Germany, France, and the UK using a combination of tests for structural breaks and return correlations derived from several multivariate stochastic volatility models. Our findings suggest that financial integration intensified in anticipation of the Euro, further strengthened by the EMU inception, and amplified in response to the 2007/2008 financial crisis. Hence, no evidence is found of decoupling of the equity markets in more troubled European countries from the core. Interestingly, the UK, despite staying outside the EMU, is not worse integrated with the GIPSI than Germany or France. © 2013 Elsevier B.V.

A comparative and longitudinal analysis of the evolving relationship between the environment and the strategy, structure and performance of selected organisations in the British carpet industry 1959-1986:a firms in sector perspective of organisational adaptation

Orthodox contingency theory links effective organisational performance to compatible relationships between the environment and organisation strategy and structure and assumes that organisations have the capacity to adapt as the environment changes. Recent contributions to the literature on organisation theory claim that the key to effective performance is effective adaptation which in turn requires the simultaneous reconciliation of efficiency and innovation which is afforded by an unique environment-organisation configuration. The literature on organisation theory recognises the continuing confusion caused by the fragmented and often conflicting results from cross-sectional studies. Although the case is made for longitudinal studies which comprehensively describe the evolving relationship between the environment and the organisation there is little to suggest how such studies should be executed in practice. Typically the choice is between the approaches of the historicised case study and statistical analysis of large populations which examine the relationship between environment and organisation strategy and/or structure and ignore the product-process relationship. This study combines the historicised case study and the multi-variable and ordinal scale approach of statistical analysis to construct an analytical framework which tracks and exposes the environment-organisation-performance relationship over time. The framework examines changes in the environment, strategy and structure and uniquely includes an assessment of the organisation's product-process relationship and its contribution to organisational efficiency and innovation. The analytical framework is applied to examine the evolving environment-organisation relationship of two organisations in the same industry over the same twenty-five year period to provide a sector perspective of organisational adaptation. The findings demonstrate the significance of the environment-organisation configuration to the scope and frequency of adaptation and suggest that the level of sector homogeneity may be linked to the level of product-process standardisation.

Evaluation of DNA enzymes targeted against the RNA component of human telomerase

Glioblastoma Multiforme (GBM) is a highly malignant form of brain cancer for which there is currently no effective cure. Consequently, developing new therapies and elucidating effective targets is crucial for this fatal disease. In recent years, DNA enzymes, deoxyribonucleic acid molecules with enzymatic activity, have emerged. In the same manner as ribozymes, DNA enzymes are able to effect cleavage of RNA in a sequence-specific manner, and operate with catalytic efficiency. In this study, two DNA enzymes were designed to target the template region of human telomerase RNA (hTR), utilising the 10-23 and 8-17 catalytic motifs elucidated by Santoro and Joyce (1997). Telomerase is an RNA-dependent DNA polymerase, which stabilises telomere lengths by adding hexameric repeats (TTAGGG in humans) to chromosome termini, thus preventing the telomere shortening that usually occurs during mitotic cell division. Telomerase activity, whilst absent in normal somatic tissues, is present in almost 90% of all tumours. Thus, there is speculation that telomerase may be the much sought universal target for therapeutic intervention in cancer. In vitro cleavage assays showed both DNA enzymes to be catalytically competent. Unmodified phosphodiester (PO) backbone DNA enzymes were rapidly degraded in the presence of serum, with a half-life of 10 minutes. The common approach of introducing phosphorothioate (PS) linkages was used in an effort to overcome this instability. As a result of concurrent activity and stability studies on the DNA enzymes with various numbers of PS linkages, the DNA enzymes with a PO core and PS arms were chosen for use in further cell work. The cleavage activity of both was shown to be specific and affected by temperature, pH, MgCI2 concentration and enzyme concentration. Both DNA enzyme motifs reduced telomerase activity in cell lysates, as assessed by the telomerase repeat amplification protocol (TRAP) with an IC50 of 100nM. DNA enzymes being polyanionic molecules do not readily cross biological barriers. Cellular association of naked DNA enzyme was inefficient at less than 2%. Cellular delivery of the DNA enzymes was effectively improved using commercial cationic lipid formulations. However, the lipid-mediated delivery of DNA enzymes to U87-MG cells over a 4-hour period did not significantly inhibit cell proliferation compared to controls. This is possibly due to an expected lag period between the inhibition of telomere maintenance and cell death. Therefore, biodegradable polymer microspheres were investigated as a potential delivery option for prolonged and sustained delivery. In vitro release profiles showed that after an initial burst, sustained release of DNA enzymes was observed over 35 days. Finally, the efficacy and specificity of the DNA enzymes were demonstrated in a luciferase based reporter assay. Specific inhibition of luciferase expression was displayed at 10nM. Thus DNA enzymes have potential against endogenous cellular targets.

The effects of the environment on the stability and expression of genetically engineered plasmids

The lac promoter is widely used in plasmid expression systems, even though it is prone to catabolite repression. As a consequence glycerol is often used as an alternative carbon source. Three plasmids containing various sizes of the staphylococcal protein A (SPA) gene, which are under the control of the lac promoter were investigated in continuous culture, to evaluate the effects of nutrient limitations on their stability and expression. The fears of catabolite repression were dispelled as a low expression plasmid (pPA16) produced a greater amount of truncated SPA under glucose limiting conditions (11 ug mg-1 cell protein) when compared to that using glycerol (8 ug mg-1 cell protein). Segregational instability was also observed under glycerol limiting conditions at all the dilution rates investigated. Whereas pPA16 was relatively stable under glucose limiting conditions, with SPA production being continuous. Experiments using excess glycerol with limited ammonium increased the stability of pPA16, (when compared to limited glycerol) with expression of SPA being continuous but reduced (6 ug mg-1 cell protein). With excess glucose and limited ammonium the copy numbers remained high but expression of SPA paralled that produced under glucose limiting conditions. This might indicate that the higher levels of glucose are reducing expression (catabolite repression) or that the low level of ammonium is affecting protein production. A high expression plasmid (pPA31) produced nearly 100 ug full length SPA mg-1 cell protein, while another high expression plasmid (pPA34) producing truncated SPA proved to be very unstable. An ELISA was developed to detect the SPA produced by these experiments, which could be adapted for western blotting or immunogold probing using electron microscopy. SPA was localised in electron lucent areas present in the periplasmic space of the E. coli host harbouring pPA16. While in the same host containing pPA31, SPA was localised not only in electron lucent areas but also around the whole of the outer-membrane.

Cadmium in the environment and high risk population groups

Cadmium has been widely used in various industries for the past fifty years, with current world production standing at around 16,755 tonnes per year. Very little cadmium is ever recycled and the ultimate fate of all cadmium is the environment. In view of reports that cadmium in the environment is increasing, this thesis aims to identify population groups 'at risk' of receiving dietary intakes of cadmium up to or above the current Food and Agricultural Organisation/World Health Organisation maximum tolerable intake of 70 ug/day. The study involves the investigation of one hundred households (260 individuals) who grow a large proportion of their vegetable diet in garden soils in the Borough of Walsall, part of an urban/industrial area in the United Kingdom. Measurements were made of the cadmium levels in atmospheric deposition, soil, house dust, diet and urine from the participants. Atmospheric deposition of cadmium was found to be comparable with other urban/industrial areas in the European Community, with deposition rates as high as 209 g ha-1 yr-1. The garden soils of the study households were found to contain up to 33 mg kg-1 total cadmium, eleven times the highest level usually found in agricultural soils. Dietary intakes of cadmium by the residents from food were calculated to be as high as 68 ug/day. It is suggested that with intakes from other sources, such as air, adventitious ingestion, smoking and occupational exposure, total intakes of cadmium may reach or exceed the FAO/WHO limit. Urinary excretion of cadmium amongst a non-smoking, non-occupationally exposed sub-group of the study population was found to be significantly higher than that of a similar urban population who did not rely on home-produced vegetables. The results from this research indicate that present levels of cadmium in urban/industrial areas can increase dietary intakes and body burdens of cadmium. As cadmium serves no useful biological function and has been found to be highly toxic, it is recommended that policy measures to reduce human exposure on the European scale be considered.

The effect of the environment on the mechanical properties of medical grade silicones

Silicone spacers have been in use as replacement joints in the human hand for over 30 years. Since they were first used there has been a number of designs all of which have had problems with fracture. This may be due to a defect in the material caused during implantation, or by bony intrusions within the arthritic hand after implantation. The aim of this research was to investigate the effect of the environment on the mechanical properties of medical grade silicones used for human implantation. The materials were subjected to static tensile testing after various forms of ageing. The environmental conditions included temperatures of 37 and 80°C and the environments of Ringer's solution, distilled water, and air. The environmental conditions employed resulted in reduced mechanical strength with ageing time of the silicones. This research supports the view that failure of silicone implants in the hand could be partly attributed to the effects of environmental ageing of the material.

Business and the environment:performance and reporting?

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