Exposure to parabens at the concentration of maximal proliferative response increases migratory and invasive activity of human breast cancer cells in vitro

Alkyl esters of p–hydroxybenzoic acid (parabens) are widely used as preservatives in personal care products, foods and pharmaceuticals. Their oestrogenic activity, their measurement in human breast tissue and their ability to drive proliferation of oestrogen-responsive human breast cancer cells has opened a debate on their potential to influence breast cancer development. Since proliferation is not the only hallmark of cancer cells, we have investigated the effects of exposure to parabens at concentrations of maximal proliferative response on migratory and invasive properties using three oestrogen-responsive human breast cancer cell lines (MCF-7, T-47-D, ZR-75-1). Cells were maintained short-term (1 week) or long-term (20±2 weeks) in phenol-red-free medium containing 5% charcoal-stripped serum with no addition, 10-8M 17-oestradiol, 1-5x10-4M methylparaben, 10-5M n-propylparaben or 10-5M n-butylparaben. Long-term exposure (20±2 weeks) of MCF-7 cells to methylparaben, n-propylparaben or n-butylparaben increased migration as measured using a scratch assay, time-lapse microscopy and xCELLigence technology: invasive properties were found to increase in matrix degradation assays and migration through matrigel on xCELLigence. Western immunoblotting showed an associated downregulation of E-cadherin and -catenin in the long-term paraben-exposed cells which could be consistent with a mechanism involving epithelial to mesenchymal transition. Increased migratory activity was demonstrated also in long-term paraben-exposed T-47-D and ZR-75-1 cells using a scratch assay and time-lapse microscopy. This is the first report that in vitro, parabens can influence not only proliferation but also migratory and invasive properties of human breast cancer cells.

Multivalency in healable supramolecular polymers: the effect of supramolecular cross-link density on the mechanical properties and healing of noncovalent polymer networks

Polymers with the ability to heal themselves could provide access to materials with extended lifetimes in a wide range of applications such as surface coatings, automotive components and aerospace composites. Here we describe the synthesis and characterisation of two novel, stimuli-responsive, supramolecular polymer blends based on π-electron-rich pyrenyl residues and π-electron-deficient, chain-folding aromatic diimides that interact through complementary π–π stacking interactions. Different degrees of supramolecular “cross-linking” were achieved by use of divalent or trivalent poly(ethylene glycol)-based polymers featuring pyrenyl end-groups, blended with a known diimide–ether copolymer. The mechanical properties of the resulting polymer blends revealed that higher degrees of supramolecular “cross-link density” yield materials with enhanced mechanical properties, such as increased tensile modulus, modulus of toughness, elasticity and yield point. After a number of break/heal cycles, these materials were found to retain the characteristics of the pristine polymer blend, and this new approach thus offers a simple route to mechanically robust yet healable materials.

Impact of the enhanced permeability and retention (EPR) effect and cathepsins levels on the activity of polymer-drug conjugates

Polymer-drug conjugates have demonstrated clinical potential in the context of anticancer therapy. However, such promising results have, to date, failed to translate into a marketed product. Polymer-drug conjugates rely on two factors for activity: (i) the presence of a defective vasculature, for passive accumulation of this technology into the tumour tissue (enhanced permeability and retention (EPR) effect) and (ii) the presence of a specific trigger at the tumour site, for selective drug release (e.g., the enzyme cathepsin B). Here, we retrospectively analyse literature data to investigate which tumour types have proved more responsive to polymer-drug conjugates and to determine correlations between the magnitude of the EPR effect and/or expression of cathepsin B. Lung, breast and ovarian cancers showed the highest response rate (30%, 47% and 41%, respectively for cathepsin-activated conjugates and 31%, 43%, 40%, across all conjugates). An analysis of literature data on cathepsin content in various tumour types showed that these tumour types had high cathepsin content (up to 3835 ng/mg for lung cancer), although marked heterogeneity was observed across different studies. In addition, these tumour types were also reported as having a high EPR effect. Our results suggest that a pre-screening of patient population could bring a more marked clinical benefit.

Revisiting the 'modern' multinational enterprise theory: an emerging-market multinational perspective

Using Triad-based multinational enterprises as their empirical setting, influential scholars in international management uncovered key organizational characteristics needed to create globally integrated and locally responsive multinationals. They proposed a “modern” theory of multinationals' organization (Hedlund, 1994). But recently, a new generation of multinationals from emerging markets has appeared. Little is known about their organizational choices and some scholars even doubt that they leverage organizational capabilities altogether. Does the “modern” theory still hold in their case? This exploratory study of three emerging-market multinationals (EMNEs) discloses that for reasons related to their origin in emerging economies and to the competitive specificities of these economies, EMNEs approach the global and local conundrum in ways which are both similar – and vastly different – from recommendations of the “modern” theory. We inductively develop a new theory that accounts for the evolution of organizational capabilities in EMNEs to reconcile global integration and local responsiveness. We discuss its implications for the executives of both emerging and Triad-based multinationals.

The interaction between the physical environments and people

Buildings affect people in various ways. They can help us to work more effectively; they also present a wide range of stimuli for our senses to react to. Intelligent buildings are designed to be aesthetic in sensory terms not just visually appealing but ones in which occupants experience delight, freshness, airiness, daylight, views out and social ambience. All these factors contribute to a general aesthetic which gives pleasure and affects one’s mood. If there is to be a common vision, it is essential for architects, engineers and clients to work closely together throughout the planning, design, construction and operational stages which represent the conception, birth and life of the building. There has to be an understanding of how patterns of work are best suited to a particular building form served by appropriate environmental systems. A host of technologies are emerging that help these processes, but in the end it is how we think about achieving responsive buildings that matters. Intelligent buildings should cope with social and technological changes and also be adaptable to short-term and long-term human needs. We live through our senses. They rely on stimulation from the tasks we are focused on; people around us but also the physical environment. We breathe air and its quality affects the olfactory system; temperature is felt by thermoreceptors in the skin; sound enters our ears; the visual scene is beheld by our eyes. All these stimuli are transmitted along the sensory nervous system to the brain for processing from which physiological and psychological reactions and judgments are formed depending on perception, expectancies and past experiences. It is clear that the environmental setting plays a role in this sensory process. This is the essence of sensory design. Space plays its part as well. The flow of communication is partly electronic but also largely by people meeting face to face. Our sense of space wants different things at different times. Sometimes privacy but other times social needs have to be satisfied besides the organizational requirement to have effective human communications throughout the building. In general if the senses are satisfied people feel better and work better.

Investigating preferences for dynamic electricity tariffs: the effect of environmental and system benefit disclosure

Dynamic electricity pricing can produce efficiency gains in the electricity sector and help achieve energy policy goals such as increasing electric system reliability and supporting renewable energy deployment. Retail electric companies can offer dynamic pricing to residential electricity customers via smart meter-enabled tariffs that proxy the cost to procure electricity on the wholesale market. Current investments in the smart metering necessary to implement dynamic tariffs show policy makers’ resolve for enabling responsive demand and realizing its benefits. However, despite these benefits and the potential bill savings these tariffs can offer, adoption among residential customers remains at low levels. Using a choice experiment approach, this paper seeks to determine whether disclosing the environmental and system benefits of dynamic tariffs to residential customers can increase adoption. Although sampling and design issues preclude wide generalization, we found that our environmentally conscious respondents reduced their required discount to switch to dynamic tariffs around 10% in response to higher awareness of environmental and system benefits. The perception that shifting usage is easy to do also had a significant impact, indicating the potential importance of enabling technology. Perhaps the targeted communication strategy employed by this study is one way to increase adoption and achieve policy goals.

Perylene as an electron-rich moiety in healable, complementary π–π stacked, supramolecular polymer systems

A two-component, supramolecular polymer blend has been designed using a novel π-electron rich bisperylene- terminated polyether. This polymer is able to self-assemble through electronically complementary π–π stacking interactions with a π-electron-deficient chain-folding polydiimide to afford thermally healable polymer blends. Model compounds were developed to assess the suitability of the deep green complexes formed between perylene residues and chain-folding bis-diimides for use in polymer blends. The polymer blends thus synthesised were elastomeric in nature and demonstrated healable properties as demonstrated by scanning electron microscopy. Healing was observed to occur rapidly at ca. 75 degC, and excellent healing efficiencies were found by tensometric and rheometric analyses. These tuneable, stimuli-responsive, supramolecular polymer blends are compared to related healable blends featuring pyrene-terminated oligomers.

Molecular and phenotypic characterization of the alternative seasonal growth habit and flowering time in barley (Hordeum vulgare ssp. vulgare L.)

Barley can be classified into three major agronomic types, based on its seasonal growth habit (SGH): spring, winter and alternative. Winter varieties require exposure to vernalization to promote subsequent flowering and are autumn-sown. Spring varieties proceed to flowering in the absence of vernalization and are sown in the spring. The ‘alternative’ (also known as ‘facultative’) SGH is only loosely defined and can be sown in autumn or spring. Here, we investigate the molecular genetic basis of alternative barley. Analysis of the major barley vernalization (VRN-H1, VRN-H2) and photoperiod (PPD-H1, PPD-H2) response genes in a collection of 386 varieties found alternative SGH to be characterized by specific allelic combinations. Spring varieties possessed spring loci at one or both of the vernalization response loci, combined with long-day non-responsive ppd-H1 alleles and wild-type alleles at the short-day photoperiod response locus, PPD-H2. Winter varieties possessed winter alleles at both vernalization loci, in combination with the mutant ppd-H2 allele conferring delayed flowering under short-day photoperiods. In contrast, all alternative varieties investigated possessed a single spring allele (either at VRN-H1 or at VRN-H2) combined with mutant ppd-H2 alleles. This allelic combination is found only in alternative types and is diagnostic for alternative SGH in the collection studied. Analysis of flowering time under controlled environment found alternative varieties flowered later than spring control lines, with the difference most pronounced under short-day photoperiods. This work provides genetic characterization of the alternative SGH phenotype, allowing precise manipulation of SGH and flowering time within breeding programmes, and provides the molecular tools for classification of all three SGH categories within national variety registration processes.