NOS3 gene polymorphisms are associated with risk markers of cardiovascular disease, and interact with omega-3 polyunsaturated fatty acids

Objective Omega-3 polyunsaturated fatty acids (n-3 PUFA) may protect against the development of cardiovascular disease (CVD). Genotype at key genes such as nitric oxide synthase (NOS3) may determine responsiveness to fatty acids. Gene–nutrient interactions may be important in modulating the development of CVD, particularly in high-risk individuals with the metabolic syndrome (MetS). Methods Biomarkers of CVD risk, plasma fatty acid composition, and NOS3 single nucleotide polymorphism (SNP) genotype (rs11771443, rs1800783, rs1800779, rs1799983, rs3918227, and rs743507) were determined in 450 individuals with the MetS from the LIPGENE dietary intervention cohort. The effect of dietary fat modification for 12 weeks on metabolic indices of the MetS was determined to understand potential NOS3 gene–nutrient interactions. Results Several markers of inflammation and dyslipidaemia were significantly different between the genotype groups. A significant gene–nutrient interaction was observed between the NOS3 rs1799983 SNP and plasma n-3 PUFA status on plasma triacylglycerol (TAG) concentrations. Minor allele carriers (AC + AA) showed an inverse association with significantly higher plasma TAG concentrations in those with low plasma n-3 PUFA status and vice versa but the major allele homozygotes (CC) did not. Following n-3 PUFA supplementation, plasma TAG concentrations of minor allele carriers of rs1799983 were considerably more responsive to changes in plasma n-3 PUFA, than major allele homozygotes. Conclusions Carriers of the minor allele at rs1799983 in NOS3 have plasma TAG concentrations which are more responsive to n-3 PUFA. This suggests that these individuals might show greater beneficial effects of n-3 PUFA consumption to reduce plasma TAG concentrations.

Interpretation of infant facial expression in the context of maternal postnatal depression

Postnatal maternal depression is associated with difficulties in maternal responsiveness. As most signals arising from the infant come from facial expressions one possible explanation for these difficulties is that mothers with postnatal depression are differentially affected by particular infant facial expressions. Thus, this study investigates the effects of postnatal depression on mothers’ perceptions of infant facial expressions. Participants (15 controls, 15 depressed and 15 anxious mothers) were asked to rate a number of infant facial expressions, ranging from very positive to very negative. Each face was shown twice, for a short and for a longer period of time in random order. Results revealed that mothers used more extreme ratings when shown the infant faces (i.e. more negative or more positive) for a longer period of time. Mothers suffering from postnatal depression were more likely to rate negative infant faces shown for a longer period more negatively than controls. The differences were specific to depression rather than an effect of general postnatal psychopathology—as no differences were observed between anxious mothers and controls. There were no other significant differences in maternal ratings of infant faces showed for short periods or for positive or neutral valence faces of either length. The findings that mothers with postnatal depression rate negative infant faces more negatively indicate that appraisal bias might underlie some of the difficulties that these mothers have in responding to their own infants signals.

ApoE polymorphism and fish oil supplementation in subjects with an antherogenic lipoprotein phenotype

The study assessed the efficacy of fish oil supplementation in counteracting the classic dyslipidemia of the atherogenic lipoprotein phenotype (ALP). In addition, the impact of the common apolipoprotein E (apoE) polymorphism on the fasting and postprandial lipid profile and on responsiveness to the dietary intervention was established. Fifty-five ALP males (aged 34 to 69 years, body mass index 22 to 35 kg/m2, triglyceride [TG] levels 1.5 to 4.0 mmol/L, high density lipoprotein cholesterol [HDL-C] <1.1 mmol/l, and percent low density lipoprotein [LDL]-3 >40% total LDL) completed a randomized placebo-controlled crossover trial of fish oil (3.0 g eicosapentaenoic acid/docosahexaenoic acid per day) and placebo (olive oil) capsules with the 6-week treatment arms separated by a 12-week washout period. In addition to fasting blood samples, at the end of each intervention arm, a postprandial assessment of lipid metabolism was carried out. Fish oil supplementation resulted in a reduction in fasting TG level of 35% (P<0.001), in postprandial TG response of 26% (TG area under the curve, P<0.001), and in percent LDL-3 of 26% (P<0.05). However, no change in HDL-C levels was evident (P=0.752). ANCOVA showed that baseline HDL-C levels were significantly lower in apoE4 carriers (P=0.035). The apoE genotype also had a striking impact on lipid responses to fish oil intervention. Individuals with an apoE2 allele displayed a marked reduction in postprandial incremental TG response (TG incremental area under the curve, P=0.023) and a trend toward an increase in lipoprotein lipase activity relative to non-E2 carriers. In apoE4 individuals, a significant increase in total cholesterol and a trend toward a reduction in HDL-C relative to the common homozygous E3/E3 profile was evident. Our data demonstrate the efficacy of fish oil fatty acids in counteracting the proatherogenic lipid profile of the ALP but also that the apoE genotype influences responsiveness to this dietary treatment.

Identification of potential mechanisms of toxicity after di-(2-ethylhexyl)-phthalate (DEHP) adult exposure in the liver using a systems biology approach

Phthalates are industrial additives widely used as plasticizers. In addition to deleterious effects on male genital development, population studies have documented correlations between phthalates exposure and impacts on reproductive tract development and on the metabolic syndrome in male adults. In this work we investigated potential mechanisms underlying the impact of DEHP on adult mouse liver in vivo. A parallel analysis of hepatic transcript and metabolic profiles from adult mice exposed to varying DEHP doses was performed. Hepatic genes modulated by DEHP are predominantly PPARalpha targets. However, the induction of prototypic cytochrome P450 genes strongly supports the activation of additional NR pathways, including Constitutive Androstane Receptor (CAR). Integration of transcriptomic and metabonomic profiles revealed a correlation between the impacts of DEHP on genes and metabolites related to heme synthesis and to the Rev-erbalpha pathway that senses endogenous heme level. We further confirmed the combined impact of DEHP on the hepatic expression of Alas1, a critical enzyme in heme synthesis and on the expression of Rev-erbalpha target genes involved in the cellular clock and in energy metabolism. This work shows that DEHP interferes with hepatic CAR and Rev-erbalpha pathways which are both involved in the control of metabolism. The identification of these new hepatic pathways targeted by DEHP could contribute to metabolic and endocrine disruption associated with phthalate exposure. Gene expression profiles performed on microdissected testis territories displayed a differential responsiveness to DEHP. Altogether, this suggests that impacts of DEHP on adult organs, including testis, could be documented and deserve further investigations.

Utopia and education in the seventeenth century: Bacon’s 'Salomon’s House' and its influence

New Worlds Reflected provides a significant contribution both to the history of utopian literature and travel, and to the wider cultural and intellectual history of the time, assembling original essays from scholars interested in representations of the globe and new and ideal worlds in the period from the sixteenth to eighteenth centuries, and in the imaginative reciprocal responsiveness of utopian and travel writing. Chapter 7 looks at the influence of Salomon’s House in Francis Bacon’s New Atlantis (1627) on later seventeenth-century educational utopias.

Inertia in Japanese organizations: knowledge management routines and failure to innovate

This paper argues that features of Japanese organizations, previously held to be the foundations of innovation, change and flexibility, can equally be significant barriers to change, innovation and adaptation in turbulent economic environments. This paper draws on two in-depth case studies of Japanese organizations. It shows how, in both cases, these firms displayed specific weaknesses in the ways in which they integrate and bundle knowledge, in particular around their research and development (R&D) functions. Despite the adoption of strategies of technological innovation and internationalization, the data suggest that the pursuit of both strategies is beset by barriers of inertia. Embedded internal network connections and knowledge-sharing routines between central R&D and other divisions are inappropriate for the revised strategy. Existing external connections, with preferred suppliers and customers within keiretsu structures, and close relationships with existing R&D partners retard these firms' strategic flexibility. With a limited variety of latent routines, knowledge, capabilities and agency to draw on when needed, these firms have limited organizational responsiveness and high levels of path-dependency.

Housing supply and planning delay in the South of England

There is growing international interest in the impact of regulatory controls on the supply of housing The UK has a particularly restrictive planning regime and a detailed and uncertain process of development control linked to it. This paper presents the findings of empirical research on the time taken to gain planning permission for selected recent major housing projects from a sample of local authorities in southern England. The scale of delay found was far greater than is indicated by average official data measuring the extent to which local authorities meet planning delay targets. If these results are representative of the country as a whole, they indicate that planning delay could be a major cause of the slow responsiveness of British housing supply.

Firm size and competition: a comparison of the housebuilding industries in Australia, the UK and the USA

Housebuilding is frequently viewed as an industry full of small firms. However, large firms exist in many countries. Here, a comparative analysis is made of the housebuilding industries in Australia, Britain and the USA. Housebuilding output is found to be much higher in Australia and the USA than in Britain when measured on a per capita basis. At the same time, the degree of market concentration in Australia and the USA is relatively low but in Britain it is far greater, with a few firms having quite substantial market shares. Investigation of the size distribution of the top 100 or so firms ranked by output also shows that the decline in firm size from the largest downwards is more rapid in Britain than elsewhere. The exceptionalism of the British case is put down to two principal reasons. First, the close proximity of Britain’s regions enables housebuilders to diversify successfully across different markets. The gains from such diversification are best achieved by large firms, because they can gain scale benefits in any particular market segment. Second, land shortages induced by a restrictive planning system encourage firms to takeover each other as a quick and beneficial means of acquiring land. The institutional rules of planning also make it difficult for new entrants to come in at the bottom end of the size hierarchy. In this way, concentration grows and a handful of large producers emerge. These conditions do not hold in the other two countries, so their industries are less concentrated. Given the degree of rivalry between firms over land purchases and takeovers, it is difficult to envisage them behaving in a long-term collusive manner, so that competition in British housebuilding is probably not unduly compromised by the exceptional degree of firm concentration. Reforms to lower the restrictions, improve the slow responsiveness and reduce the uncertainties associated with British planning systems’ role in housing supply are likely to greatly improve the ability of new firms to enter housebuilding and all firms’ abilities to increase output in response to rising housing demand. Such reforms would also probably lower overall housebuilding firm concentration over time.

Obesity and body fat classification in the metabolic syndrome: impact on cardiometabolic risk metabotype

Obesity is a key factor in the development of the metabolic syndrome (MetS), which is associated with increased cardiometabolic risk. We investigated whether obesity classification by body mass index (BMI) and body fat percentage (BF%) influences cardiometabolic profile and dietary responsiveness in 486 MetS subjects (LIPGENE dietary intervention study). Anthropometric measures, markers of inflammation and glucose metabolism, lipid profiles, adhesion molecules and haemostatic factors were determined at baseline and after 12 weeks of 4 dietary interventions (high saturated fat (SFA), high monounsaturated fat (MUFA) and 2 low fat high complex carbohydrate (LFHCC) diets, 1 supplemented with long chain n-3 polyunsaturated fatty acids (LC n-3 PUFAs)). 39% and 87% of subjects classified as normal and overweight by BMI were obese according to their BF%. Individuals classified as obese by BMI (± 30 kg/m2) and BF% (± 25% (men) and ± 35% (women)) (OO, n = 284) had larger waist and hip measurements, higher BMI and were heavier (P < 0.001) than those classified as non-obese by BMI but obese by BF% (NOO, n = 92). OO individuals displayed a more pro-inflammatory (higher C reactive protein (CRP) and leptin), pro-thrombotic (higher plasminogen activator inhibitor-1 (PAI-1)), pro-atherogenic (higher leptin/adiponectin ratio) and more insulin resistant (higher HOMA-IR) metabolic profile relative to the NOO group (P < 0.001). Interestingly, tumour necrosis factor alpha (TNF-α) concentrations were lower post-intervention in NOO individuals compared to OO subjects (P < 0.001). In conclusion, assessing BF% and BMI as part of a metabotype may help identify individuals at greater cardiometabolic risk than BMI alone.

Farmer experience of pluralistic agricultural extension, Malawi

Purpose: Malawi’s current extension policy supports pluralism and advocates responsiveness to farmer demand. We investigate whether smallholder farmers’ experience supports the assumption that access to multiple service providers leads to extension and advisory services that respond to the needs of farmers. Design/methodology/approach: Within a case study approach, two villages were purposively selected for in-depth qualitative analysis of available services and farmers’ experiences. Focus group discussions were held separately with male and female farmers in each village, followed by semi-structured interviews with 12 key informants selected through snowball sampling. Transcripts were analysed by themes and summaries of themes were made from cross case analysis. Findings: Farmers appreciate having access to a variety of sources of technical advice and enterprise specific technology. However, most service providers continue to dominate and dictate what they will offer. Market access remains a challenge, as providers still emphasize pushing a particular technology to increase farm productivity rather than addressing farmers’ expressed needs. Although farmers work in groups, providers do not seek to strengthen these to enable active interaction and to link them to input and produce markets. This limits farmers’ capacity to continue with innovations after service providers pull out. Poor coordination between providers limits exploitation of potential synergies amongst actors. Practical implications: Services providers can adapt their approach to engage farmers in discussion of their needs and work collaboratively to address them. At a system level, institutions that have a coordination function can play a more dynamic role in brokering interaction between providers and farmers to ensure coverage and responsiveness. Originality/value: The study provides a new farmer perspective on the implementation of extension reforms.

Managing the duality of IHRM: unravelling the strategy and perceptions of key actors in South Korean MNCs

This research aims to extend our understanding of the duality between global integration and local responsiveness in multinational corporations (MNCs) by exploring the perceptions of corporate HR actors regarding the intra-organisational factors that alter the balance between these pressures. It examines the perceptions and actions of key actors in the context of two Korean MNCs. The study shows the importance attributed to a range of socio-procedural factors by corporate actors and which, therefore, inform the practical management of the dual forces, notably: HR expertise, social ties, trustworthy relationships and co-involvement in decision processes.

Terrestrial biogeochemical feedbacks in the climate system

The terrestrial biosphere is a key regulator of atmospheric chemistry and climate. During past periods of climate change, vegetation cover and interactions between the terrestrial biosphere and atmosphere changed within decades. Modern observations show a similar responsiveness of terrestrial biogeochemistry to anthropogenically forced climate change and air pollution. Although interactions between the carbon cycle and climate have been a central focus, other biogeochemical feedbacks could be as important in modulating future climate change. Total positive radiative forcings resulting from feedbacks between the terrestrial biosphere and the atmosphere are estimated to reach up to 0.9 or 1.5 W m−2 K−1 towards the end of the twenty-first century, depending on the extent to which interactions with the nitrogen cycle stimulate or limit carbon sequestration. This substantially reduces and potentially even eliminates the cooling effect owing to carbon dioxide fertilization of the terrestrial biota. The overall magnitude of the biogeochemical feedbacks could potentially be similar to that of feedbacks in the physical climate system, but there are large uncertainties in the magnitude of individual estimates and in accounting for synergies between these effects.

Trafficking and signaling of G protein-coupled receptors in the nervous system: implications for disease and therapy

G protein-coupled receptors (GPCRs) are expressed throughout the nervous system where they regulate multiple physiological processes, participate in neurological diseases, and are major targets for therapy. Given that many GPCRs respond to neurotransmitters and hormones that are present in the extracellular fluid and which do not readily cross the plasma membrane, receptor trafficking to and from the plasma membrane is a critically important determinant of cellular responsiveness. Moreover, trafficking of GPCRs throughout the endosomal system can initiate signaling events that are mechanistically and functionally distinct from those operating at the plasma membrane. This review discusses recent advances in the relationship between signaling and trafficking of GPCRs in the nervous system. It summarizes how receptor modifications influence trafficking, discusses mechanisms that regulate GPCR trafficking to and from the plasma membrane, reviews the relationship between trafficking and signaling, and considers the implications of GPCR trafficking to drug development.

Endothelin-converting enzyme-1 degrades internalized somatostatin-14

Agonist-induced internalization of somatostatin receptors (ssts) determines subsequent cellular responsiveness to peptide agonists and influences sst receptor scintigraphy. To investigate sst2A trafficking, rat sst2A tagged with epitope was expressed in human embryonic kidney cells and tracked by antibody labeling. Confocal microscopical analysis revealed that stimulation with sst and octreotide induced internalization of sst2A. Internalized sst2A remained sequestrated within early endosomes, and 60 min after stimulation, internalized sst2A still colocalized with beta-arrestin1-enhanced green fluorescence protein (EGFP), endothelin-converting enzyme-1 (ECE-1), and rab5a. Internalized (125)I-Tyr(11)-SST-14 was rapidly hydrolyzed by endosomal endopeptidases, with radioactive metabolites being released from the cell. Internalized (125)I-Tyr(1)-octreotide accumulated as an intact peptide and was released from the cell as an intact peptide ligand. We have identified ECE-1 as one of the endopeptidases responsible for inactivation of internalized SST-14. ECE-1-mediated cleavage of SST-14 was inhibited by the specific ECE-1 inhibitor, SM-19712, and by preventing acidification of endosomes using bafilomycin A(1). ECE-1 cleaved SST-14 but not octreotide in an acidic environment. The metallopeptidases angiotensin-1 converting enzyme and ECE-2 did not hydrolyze SST-14 or octreotide. Our results show for the first time that stimulation with SST-14 and octreotide induced sequestration of sst2A into early endosomes and that endocytosed SST-14 is degraded by endopeptidases located in early endosomes. Furthermore, octreotide was not degraded by endosomal peptidases and was released as an intact peptide. This mechanism may explain functional differences between octreotide and SST-14 after sst2A stimulation. Moreover, further investigation of endopeptidase-regulated trafficking of neuropeptides may result in novel concepts of neuropeptide receptor inactivation in cancer diagnosis.

The Life of Galileo and Brechtian television drama

Bertolt Brecht's dramaturgy was as influential upon the development of British drama on television between the 1950s and the 1970s as it was in the theatre. His influence was made manifest through the work of writers, directors and producers such as Tony Garnett, Ken Loach, John McGrath and Dennis Potter, whose attempts to create original Brechtian forms of television drama were reflected in the frequent reference to Brecht in contemporary debate concerning the political and aesthetic direction and value of television drama. While this discussion has been framed thus far around how Brechtian techniques and theory were applied to the newer media of television, this article examines these arguments from another perspective. Through detailed analysis of a 1964 BBC production of The Life of Galileo, I assess how the primary, canonical sources of Brecht's stage plays were realised on television during this period, locating Brecht's drama in the wider context of British television drama in general during the 1960s and 1970s. I pay particular attention to the use of the television studio as a site that could replicate or reinvent the theatrical space of the stage, and the responsiveness of the television audience towards Brechtian dramaturgy.