Substitution of pseudokinase domain residue Val-617 by large non-polar amino acids causes activation of JAK2

Explaining the uniqueness of the acquired somatic JAK2 V617F mutation, which is present in more than 95% of polycythemia vera patients, has been a challenge. The V617F mutation in the pseudokinase domain of JAK2 renders the unmutated kinase domain constitutively active. We have performed random mutagenesis at position 617 of JAK2 and tested each of the 20 possible amino acids for ability to induce constitutive signaling in Ba/F3 cells expressing the erythropoietin receptor. Four JAK2 mutants, V617W, V617M, V617I, and V617L, were able to induce cytokine independence and constitutive downstream signaling. Only V617W induced a level of constitutive activation comparable with V617F. Also, only V617W stabilized tyrosine-phosphorylated suppressor of cytokine signaling 3 ( SOCS3), a mechanism by which JAK2 V617F overcomes inhibition by SOCS3. The V617W mutant induced a myeloproliferative disease in mice, mainly characterized by erythrocytosis and megakaryocytic proliferation. Although JAK2 V617W would predictably be pathogenic in humans, the substitution of the Val codon, GTC, by TTG, the codon for Trp, would require three base pair changes, and thus it is unlikely to occur. We discuss how the predicted conformations of the activated JAK2 mutants can lead to better screening assays for novel small molecule inhibitors.

Adjustment to inflammatory bowel disease: The relative influence of illness perceptions and coping

Background: The Common Sense Model (CSM) of illness representations was used in the current study to examine the relative contribution of illness perceptions and coping strategies in explaining adjustment to inflammatory bowel disease (IBD). Methods: Participants were 80 adults consecutively attending an outpatients' clinic with a diagnosis of either Crohn's disease or ulcerative colitis. Respondents completed and returned a questionnaire booklet that assessed illness perceptions, coping, and adjustment. Adjustment was measured from the perspectives of psychological distress, quality of life, and functional independence. Results: Illness perceptions (particularly perception of consequences of IBD) were uniformly the most consistent variables explaining adjustment to IBD. Coping did not significantly add to predicting adjustment once illness perceptions were controlled for and therefore did not mediate the relationship between illness perceptions and adjustment, as proposed in the CSM. Conclusions: The results suggest the importance of addressing illness perceptions in developing appropriate psychological interventions for IBD.

High tech start-ups in University Science Park incubators: The relationship between the start-up’s lifecycle progression and use of the incubator’s resources

University Science Park incubators (USIs) have emerged as a means by which Government, academia and business can develop high technology business firms (spin out HTBFs) from initial conception through to becoming established small firms, which are ready to move beyond the Science Park confines. Although there is considerable literature on how USIs can be improved and developed there is a paucity of studies, which explore how lifecycle development within HTBFs in USIs can affect how they use the unique resources and opportunities of the USI. Moreover, there is a focus on single point in time studies, which do not adequately investigate the longitudinal dynamics of HTBF lifecycle development within USIs. Therefore, the aim of this paper is to explore the longitudinal use of the unique resources of the USI by HTBFs at different lifecycle stages. The research methodology involved 18 HTBFs within two separate USIs. A series of longitudinal interviews and focus groups were conducted with HTBFs and USI staff over a 36-month period. NUD*IST software was used in developing the coding and analysis of transcripts. The results show that a HTBF's propensity to make effective use of the USI's resources and support increases as the lifecycle stage of the company increases and the small-firm searches for independence and autonomy. Therefore, further research is required to investigate the following two outstanding questions; firstly, which usage pattern is associated with the HTBF's ultimate success or failure in the marketplace? And secondly, are there any services missing from the observed array that the USI could provide to enhance the HTBF's degree of ultimate success? © 2007 Elsevier Ltd. All rights reserved.

A framework for managing uncertain inputs: An axiomization of rewarding

The success postulate in belief revision ensures that new evidence (input) is always trusted. However, admitting uncertain input has been questioned by many researchers. Darwiche and Pearl argued that strengths of evidence should be introduced to determine the outcome of belief change, and provided a preliminary definition towards this thought. In this paper, we start with Darwiche and Pearl’s idea aiming to develop a framework that can capture the influence of the strengths of inputs with some rational assumptions. To achieve this, we first define epistemic states to represent beliefs attached with strength, and then present a set of postulates to describe the change process on epistemic states that is determined by the strengths of input and establish representation theorems to characterize these postulates. As a result, we obtain a unique rewarding operator which is proved to be a merging operator that is in line with many other works. We also investigate existing postulates on belief merging and compare them with our postulates. In addition, we show that from an epistemic state, a corresponding ordinal conditional function by Spohn can be derived and the result of combining two epistemic states is thus reduced to the result of combining two corresponding ordinal conditional functions proposed by Laverny and Lang. Furthermore, when reduced to the belief revision situation, we prove that our results induce all the Darwiche and Pearl’s postulates as well as the Recalcitrance postulate and the Independence postulate.

The Area Distribution of Solar Magnetic Bright Points

Magnetic bright points (MBPs) are among the smallest observable objects on the solar photosphere. A combination of G-band observations and numerical simulations is used to determine their area distribution. An automatic detection algorithm, employing one-dimensional intensity profiling, is utilized to identify these structures in the observed and simulated data sets. Both distributions peak at an area of approximate to 45,000 km(2), with a sharp decrease toward smaller areas. The distributions conform with log-normal statistics, which suggests that flux fragmentation dominates over flux convergence. Radiative magneto-convection simulations indicate an independence in the MBP area distribution for differing magnetic flux densities. The most commonly occurring bright point size corresponds to the typical width of inter-granular lanes.

Autopoiesis and the Home Confined Consumer: The Role of Personal Communities

Purpose – The purpose of this paper is to explore the consumption of a personal community and its role in the everyday life of the home-confined consumer. Design/methodology/approach – Using a Radical Constructivist approach, three cases of home confinement were explored in depth over a period of two years. Ongoing “conversations” captured the consumption experiences with personal communities. Findings – In relation to the home-confined context, the ability to attain individuality, empowerment and creativity are all heightened as a result of personal community construction. An underlying concern for home-confined consumers is their removal from independent living to institutionalized living, and, as a result the need to construct, manage and maintain a personal community is of major concern. Research limitations/implications – Although the study addresses a home-confined context, it is nevertheless reflective of concerns that are significant to all consumers, namely the attainment of individuality and independence irrespective of marginalization or not. Practical implications – The importance of a personal community in terms of both self-empowerment and self-identity with respect to marginalized groups and vulnerable individuals should not be underestimated. The supporting role of a personal community provides, in times of uncertainty, a framework to maintain self-identity and independence. Originality/value – This paper provides a better understanding of the role of a personal community in the consumption experiences of those consumers marginalized and vulnerable as a consequence of context. Home-confined consumers are “invisible” in the marketplace and the personal community is a means of redressing this imbalance by empowering such individuals.

Electrical energy storage and Smart Grid technologies to integrate the next generation of Renewable Power Systems

The growth of renewable power sources, distributed generation and the potential for alternative fuelled modes of transport such as electric vehicles has led to concerns over the ability of existing grid systems to facilitate such diverse portfolio mixes in already congested power systems. Internationally the growth in renewable energy sources is driven by government policy targets associated with the uncertainties of fossil fuel supplies, environmental issues and a move towards energy independence. Power grids were traditionally designed as vertically integrated centrally managed entities with fully dispatchable generating plant. Renewable power sources, distributed generation and alternative fuelled vehicles will place these power systems under additional stresses and strains due to their different operational characteristics. Energy storage and smart grid technologies are widely proposed as the tools to integrate these future diverse portfolio mixes within the more conventional power systems. The choice in these technologies is determined not only by their location on the grid system, but by the diversification in the power portfolio mix, the electricity market and the operational demands. This paper presents a high level technical and economic overview of the role and relevance of electrical energy storage and smart grid technologies in the next generation of renewable power systems.