Nongenomic signaling of the retinoid X receptor through binding and inhibiting Gq in human platelets

Retinoid X receptors (RXRs) are important transcriptional nuclear hormone receptors, acting as either homodimers or the binding partner for at least one fourth of all the known human nuclear receptors. Functional nongenomic effects of nuclear receptors are poorly understood; however, recently peroxisome proliferator-activated receptor (PPAR) gamma, PPAR beta, and the glucocorticoid receptor have all been found active in human platelets. Human platelets express RXR alpha, and RXR beta. RXR ligands inhibit platelet aggregation and TXA(2) release to ADP and the TXA(2) receptors, but only weakly to collagen. ADP and TXA(2) both signal via the G protein, Gq. RXR rapidly binds Gq but not Gi/z/o/t/gust in a ligand-dependent manner and inhibits Gq-induced Rac activation and intracellular calcium release. We propose that RXR ligands may have beneficial clinical actions through inhibition of platelet activation. Furthermore, our results demonstrate a novel nongenomic mode for nuclear receptor action and a functional cross-talk between G-protein and nuclear receptor signaling families. (C) 2007 by The American Society of Hematology.

Phytohormones and plant-herbivore-pathogen interactions: integrating the molecular with the ecological

Current research into indirect phytopathogen–herbivore interactions (i.e., interactions mediated by the host plant) is carried out in two largely independent directions: ecological/mechanistic and molecular. We investigate the origin of these approaches and their strengths and weaknesses. Ecological studies have determined the effect of herbivores and phytopathogens on their host plants and are often correlative: the need for long-term manipulative experiments is pressing. Molecular/cellular studies have concentrated on the role of signaling pathways for systemic induced resistance, mainly involving salicylic acid and jasmonic acid, and more recently the cross-talk between these pathways. This cross-talk demonstrates how interactions between signaling mechanisms and phytohormones could mediate plant–herbivore–pathogen interactions. A bridge between these approaches may be provided by field studies using chemical induction of defense, or investigating whole-organism mechanisms of interactions among the three species. To determine the role of phytohormones in induced resistance in the field, researchers must combine ecological and molecular methods. We discuss how these methods can be integrated and present the concept of “kaleidoscopic defense.” Our recent molecular-level investigations of interactions between the herbivore Gastrophysa viridula and the rust fungus Uromyces rumicis on Rumex obtusifolius, which were well studied at the mechanistic and ecological levels, illustrate the difficulty in combining these different approaches. We suggest that the choice of the right study system (possibly wild relatives of model species) is important, and that molecular studies must consider the environmental conditions under which experiments are performed. The generalization of molecular predictions to ecologically realistic settings will be facilitated by “middle-ground studies” concentrating on the outcomes of the interactions.

Subcontract and supply enquiries in the tender process of contractors

In the tender process, contractors often rely on subcontract and supply enquiries to calculate their bid prices. However, this integral part of the bidding process is not empirically articulated in the literature. Over 30 published materials on the tendering process of contractors that talk about enquiries were reviewed and found to be based mainly on experiential knowledge rather than systematic evidence. The empirical research here helps to describe the process of enquiries precisely, improve it in practice, and have some basis to support it in theory. Using a live participant observation case study approach, the whole tender process was shadowed in the offices of two of the top 20 UK civil engineering construction firms. This helped to investigate 15 research questions on how contractors enquire and obtain prices from subcontractors and suppliers. Forty-three subcontract enquiries and 18 supply enquiries were made across two different projects with average value of 7m. An average of 15 subcontract packages and seven supply packages was involved. Thus, two or three subcontractors or suppliers were invited to bid in each package. All enquiries were formulated by the estimator, with occasional involvement of three other personnel. Most subcontract prices were received in an average of 14 working days; and supply prices took five days. The findings show 10 main activities involved in processing enquiries and their durations, as well as wasteful practices associated with enquiries. Contractors should limit their enquiry invitations to a maximum of three per package, and optimize the waiting time for quotations in order to improve cost efficiency.

Regulation of cell cycle and stress responses to hydrostatic pressure in fission yeast

We have investigated the cellular responses to hydrostatic pressure by using the fission yeast Schizosaccharomyces pombe as a model system. Exposure to sublethal levels of hydrostatic pressure resulted in G2 cell cycle delay. This delay resulted from Cdc2 tyrosine-15 (Y-15) phosphorylation, and it was abrogated by simultaneous disruption of the Cdc2 kinase regulators Cdc25 and Wee1. However, cell cycle delay was independent of the DNA damage, cytokinesis, and cell size checkpoints, suggesting a novel mechanism of Cdc2-Y15 phosphorylation in response to hydrostatic pressure. Spc1/Sty1 mitogen-activated protein (MAP) kinase, a conserved member of the eukaryotic stress-activated p38, mitogen-activated protein (MAP) kinase family, was rapidly activated after pressure stress, and it was required for cell cycle recovery under these conditions, in part through promoting polo kinase (Plo1) phosphorylation on serine 402. Moreover, the Spc1 MAP kinase pathway played a key role in maintaining cell viability under hydrostatic pressure stress through the bZip transcription factor, Atf1. Further analysis revealed that prestressing cells with heat increased barotolerance, suggesting adaptational cross-talk between these stress responses. These findings provide new insight into eukaryotic homeostasis after exposure to pressure stress.

Recalled relationships with parents and perceptions of professional support in mothers of infants treated for cleft lip

This study examined whether individual differences in perception of the quality of professional support available at a time of stress may be associated with security of attachment. We developed a new measure of parents' perceptions of emotional and practical support provided by a wide range of professionals involved in the treatment of infants with cleft lip. it showed good internal reliability and stability over 4 months. Mothers of 102 infants with cleft lip, with or without cleft palate, completed the measure at 2 and 6 months, together with the Parental Bonding Instrument and the General Health Questionnaire. Mean scores reflecting how much they could trust or talk frankly, or share their worst fears, with professionals, and the extent to which they saw them as a source of useful information or practical help, were lower among mothers with recollections of low maternal care in childhood, or high control. This was the case at 2 and 6 months, and there were some indications of an increasing contribution of low maternal care from 2 to 6 months. The associations were not explained by current depression. Further research is needed to clarify the role of attachment processes in parents' responses to serious medical conditions in their children, and into the implications for the way professionals in paediatric services provide support.

Psychological response to later life widowhood: coping and the effects of gender

The study examined the effects of psychological response and gender on coping with late life widowhood. Forty-six men and 46 women (55 years +) were interviewed about their experiences of widowhood. Participants were classified as to whether they were coping well or less well. Data were analyzed using grounded theory, content. analysis, and three-way loglinear analyses. Loglinear analyses revealed three-way interactions for Gender, Coping, and Response. Men who report feeling upset or selfish are more likely to be coping, as are women who report being comfortable alone. There were two-way interactions between Coping and Response and Gender and Response. Participants who talk to their dead spouse are more Rely to be coping than those who do not. Those who "keep themselves to themselves" are more likely not to be coping than those who do not. Gender differences, were found in psychological response. Differences were also found between those who coped and those who coped less well. The study has enabled the synthesis of quantitative and qualitative data to present a more complete view of late life widowhood than has previously been possible. In addition, the article draws attention to the importance of distinguishing between the effects of bereavement and those of widowhood.

Bacterial, SCFA and gas profiles of a range of food ingredients following in vitro fermentation by human colonic microbiota.

It is now apparent that there is a strong link between health and nutrition and this can be seen clearly when we talk of obesity. The food industry is trying to capitalise on this by adapting high sugar/fat foods to become healthier alternatives. In confectionery food ingredients can be used for a range of purposes including sucrose replacement. Many of these ingredients may also evade digestion in the upper gut and be fermented by the gut microbiota upon entering the colon. This study was designed to screen a range of ingredients and their activities on the gut microbiota. In this study we screened a range of these ingredients in triplicate batch culture fermentations with known prebiotics as controls. Changes in bacteriology were monitored using FISH. SCFA were measured by GC and gas production was assessed during anaerobic batch fermentations. Bacterial enumeration showed significant increases (P ≤ 0.05) in bifidobacteria and lactobacilli with polydextrose and most polyols with no significant increases in Clostridium histolyticum/perfringens. SCFA and gas formation indicated that the substrates added to the fermenters were being utilised by the gut microbiota. It therefore appears these ingredients exert some prebiotic activity in vitro. Further studies, particularly in human volunteers, are necessary.

Using objects to coordinate design activity in interaction

The coordination of design is a multi-faceted problem in construction. In design interactions in particular the real-time coordination of design activity is a persistent concern. The use of objects to coordinate the activity of design is studied as this happens in interactions between an architect and a building user group, in a setting where maintaining awareness of the design situation is important. An account of ways in which this was accomplished and how design activity is coordinated through interactional practices is provided. The empirical analyses examine design interaction from an ethnomethodological/conversation analysis (EM/CA) informed perspective to examine: ways in which mutual orientation to design issues are accomplished, how objects can provide a resource for the recognition of the activities of others and ways in which objects might be observable as momentarily intelligible. Subtle interactional practices involving talk, gesture and gaze were some of the small ways in which mutual orientation to the design actions of others became observable. The production of actions sequentially, in response to another's action, marked the real-time coordination of design moves in this setting. The relevance of accounts of micro-interaction to develop understanding of design activity and how it is coordinated are considered.

Land re-use, complexity and actor-networks: a framework for research

This paper will present a conceptual framework for the examination of land redevelopment based on a complex systems/networks approach. As Alvin Toffler insightfully noted, modern scientific enquiry has become exceptionally good at splitting problems into pieces but has forgotten how to put the pieces back together. Twenty-five years after his remarks, governments and corporations faced with the requirements of sustainability are struggling to promote an ‘integrated’ or ‘holistic’ approach to tackling problems. Despite the talk, both practice and research provide few platforms that allow for ‘joined up’ thinking and action. With socio-economic phenomena, such as land redevelopment, promising prospects open up when we assume that their constituents can make up complex systems whose emergent properties are more than the sum of the parts and whose behaviour is inherently difficult to predict. A review of previous research shows that it has mainly focused on idealised, ‘mechanical’ views of property development processes that fail to recognise in full the relationships between actors, the structures created and their emergent qualities. When reality failed to live up to the expectations of these theoretical constructs then somebody had to be blamed for it: planners, developers, politicians. However, from a ‘synthetic’ point of view the agents and networks involved in property development can be seen as constituents of structures that perform complex processes. These structures interact, forming new more complex structures and networks. Redevelopment then can be conceptualised as a process of transformation: a complex system, a ‘dissipative’ structure involving developers, planners, landowners, state agencies etc., unlocks the potential of previously used sites, transforms space towards a higher order of complexity and ‘consumes’ but also ‘creates’ different forms of capital in the process. Analysis of network relations point toward the ‘dualism’ of structure and agency in these processes of system transformation and change. Insights from actor network theory can be conjoined with notions of complexity and chaos to build an understanding of the ways in which actors actively seek to shape these structures and systems, whilst at the same time are recursively shaped by them in their strategies and actions. This approach transcends the blame game and allows for inter-disciplinary inputs to be placed within a broader explanatory framework that does away with many past dichotomies. Better understanding of the interactions between actors and the emergent qualities of the networks they form can improve our comprehension of the complex socio-spatial phenomena that redevelopment comprises. The insights that this framework provides when applied in UK institutional investment into redevelopment are considered to be significant.

Molecular mechanisms of oestrogen action on growth of human breast cancer cells in culture

Growth responses to oestrogen can be reproducibly obtained using a selection of oestrogen-receptor-containing human breast cancer cell lines, and molecular mechanisms have been shown to include modulation to growth factor/receptor/signalling pathways, cell-cycle proteins, apoptosis, differentiation, adhesion, motility and migration. Considerable progress has been made in understanding the molecular basis of oestrogen action on gene expression through the ligand-activated transcription factors human oestrogen receptor α (ERα) and ERβ and the resulting effects on global gene expression patterns, but the full profile of coordination of the alterations, which brings about changes in cell growth through genomic and non-genomic mechanisms remain to be fully elucidated. Oestrogen regulation of cell growth involves a complex cross-talk between oestrogen receptor and growth factor signalling pathways such that inhibition of one pathway may lead to stimulation of another, which may explain the remarkable ability of human breast cancer cells to escape from any mode of imposed growth inhibition be it oestrogen deprivation or administration of antioestrogen. Although studies on cell growth have focused to date on the effects of physiological oestrogens, many hundreds of environmental chemicals with oestrogenic properties have now been measured in the human breast. Whether or not the weight of evidence eventually establishes any causal link of complex mixtures of environmental oestrogenic chemicals with breast cancer, the presence of so many oestrogenic chemicals in the breast must influence resulting oestrogenic responses, and the impact of this additional oestrogenic burden needs to be taken into account in future studies on growth regulation of human breast cancer cells.

Turing, Kasparov and the future

The 'Turing 100' Conference in Manchester was the main event of the Turing Centenary Year in 2012. This is a report and reflection on Kasparov's popular talk. Within it, he explained how Turing and influenced computer chess, his career and the chess community. Kasparov also played Chessbase's 'TURING' emulation of Turing's second paper chess engine, here labelled 'AT2'. Quasi Turing-tests, computer contributions to world championship chess, and suspected cheating in chess are also mentioned.