Are transgenic mice the 'alkahest' to understanding myocardial hypertrophy and failure?

Murine transgenesis using cardioselective promoters has become increasingly common in studies of cardiac hypertrophy and heart failure, with expression mediated by pronuclear microinjection being the commonest format. Without wishing to decry their usefulness, in our view, such studies are not necessarily as unambiguous as sometimes portrayed and clarity is not always their consequence. We describe broadly the types of approach undertaken in the heart and point out some of the drawbacks. We provide three arbitrarily-chosen examples where, in spite of a number of often-independent studies, no consensus has yet been achieved. These include glycogen synthase kinase 3, the extracellular signal-regulated kinase pathway and the ryanodine receptor 2. We believe that the transgenic approach should not be viewed in an empyreal light and, depending on the questions asked, we suggest that other experimental systems provide equal (or even more) valuable outcomes.

Conditional transgenic expression of fibroblast growth factor 9 in the adult mouse heart reduces heart failure mortality after myocardial infarction

BACKGROUND: Fibroblast growth factor 9 (FGF9) is secreted from bone marrow cells, which have been shown to improve systolic function after myocardial infarction (MI) in a clinical trial. FGF9 promotes cardiac vascularization during embryonic development but is only weakly expressed in the adult heart. METHODS AND RESULTS: We used a tetracycline-responsive binary transgene system based on the α-myosin heavy chain promoter to test whether conditional expression of FGF9 in the adult myocardium supports adaptation after MI. In sham-operated mice, transgenic FGF9 stimulated left ventricular hypertrophy with microvessel expansion and preserved systolic and diastolic function. After coronary artery ligation, transgenic FGF9 enhanced hypertrophy of the noninfarcted left ventricular myocardium with increased microvessel density, reduced interstitial fibrosis, attenuated fetal gene expression, and improved systolic function. Heart failure mortality after MI was markedly reduced by transgenic FGF9, whereas rupture rates were not affected. Adenoviral FGF9 gene transfer after MI similarly promoted left ventricular hypertrophy with improved systolic function and reduced heart failure mortality. Mechanistically, FGF9 stimulated proliferation and network formation of endothelial cells but induced no direct hypertrophic effects in neonatal or adult rat cardiomyocytes in vitro. FGF9-stimulated endothelial cell supernatants, however, induced cardiomyocyte hypertrophy via paracrine release of bone morphogenetic protein 6. In accord with this observation, expression of bone morphogenetic protein 6 and phosphorylation of its downstream targets SMAD1/5 were increased in the myocardium of FGF9 transgenic mice. CONCLUSIONS: Conditional expression of FGF9 promotes myocardial vascularization and hypertrophy with enhanced systolic function and reduced heart failure mortality after MI. These observations suggest a previously unrecognized therapeutic potential for FGF9 after MI.

The changing nature of UK construction professional service firms

Professional services firms (PSFs) have been the subject of much attention in the literature in recent years, ranging across a number of distinct but related disciplines including economics, sociology, organization and management studies. Analysis has tended to concentrate on law and accounting firms in particular, and although there is a growing academic interest in construction/built environment professional services firms (CPSFs), these have received much less scrutiny. However, many of the changes taking place among PSFs – in particular, growth in firm size, moves towards external ownership and greater service/geographical diversification – are also taking place among the larger CPSFs. The CPSF sector is not especially well documented and there is little understanding of the motives for, and implications of, these changes in the firms, their clients and wider society. CPSFs are reviewed in the context of the more general PSF literature and a set of questions is posed for future research on CPSFs. These questions include the need to understand the implications of firm type on performance, the form of ownership that might confer the greatest financial benefits for different stakeholder groups, and the wider societal consequences of continuing growth in size and diversification of CPSFs.

Generic strategies and performance: evidence from manufacturing firms

Purpose – The purpose of this study is to examine the relationship between business-level strategy and organisational performance and to test the applicability of Porter's generic strategies in explaining differences in the performance of organisations. Design/methodology/approach – The study was focussed on manufacturing firms in the UK belonging to the electrical and mechanical engineering sectors. Data were collected through a postal survey using the survey instrument from 124 organisations and the respondents were all at CEO level. Both objective and subjective measures were used to assess performance. Non-response bias was assessed statistically and it was not found to be a major problem affecting this study. Appropriate measures were taken to ensure that common method variance (CMV) does not affect the results of this study. Statistical tests indicated that CMV problem does not affect the results of this study. Findings – The results of this study indicate that firms adopting one of the strategies, namely cost-leadership or differentiation, perform better than “stuck-in-the-middle” firms which do not have a dominant strategic orientation. The integrated strategy group has lower performance compared with cost-leaders and differentiators in terms of financial performance measures. This provides support for Porter's view that combination strategies are unlikely to be effective in organisations. However, the cost-leadership and differentiation strategies were not strongly correlated with the financial performance measures indicating the limitations of Porter's generic strategies in explaining performance heterogeneity in organisations. Originality/value – This study makes an important contribution to the literature by identifying some of the gaps in the literature through a systematic literature review and addressing those gaps.

Catch-up strategies in the Indian auto components industry: domestic firms’ responses to market liberalization

Market liberalization in emerging-market economies and the entry of multinational firms spur significant changes to the industry/institutional environment faced by domestic firms. Prior studies have described how such changes tend to be disruptive to the relatively backward domestic firms, and negatively affect their performance and survival prospects. In this paper, we study how domestic supplier firms may adapt and continue to perform, as market liberalization progresses, through catch-up strategies aimed at integrating with the industry's global value chain. Drawing on internalization theory and the literatures on upgrading and catch-up processes, learning and relational networks, we hypothesize that, for continued performance, domestic supplier firms need to adapt their strategies from catching up initially through technology licensing/collaborations and joint ventures with multinational enterprises (MNEs) to also developing strong customer relationships with downstream firms (especially MNEs). Further, we propose that successful catch-up through these two strategies lays the foundation for a strategy of knowledge creation during the integration of domestic industry with the global value chain. Our analysis of data from the auto components industry in India during the period 1992–2002, that is, the decade since liberalization began in 1991, offers support for our hypotheses.

Rheology of discrete failure regimes of anisotropic sea ice

A rheological model of sea ice is presented that incorporates the orientational distribution of ice thickness in leads embedded in isotropic floe ice. Sea ice internal stress is determined by coulombic, ridging and tensile failure at orientations where corresponding failure criteria are satisfied at minimum stresses. Because sea ice traction increases in thinner leads and cohesion is finite, such failure line angles are determined by the orientational distribution of sea ice thickness relative to the imposed stresses. In contrast to the isotropic case, sea ice thickness anisotropy results in these failure lines becoming dependent on the stress magnitude. Although generally a given failure criteria type can be satisfied at many directions, only two at most are considered. The strain rate is determined by shearing along slip lines accompanied by dilatancy and closing or opening across orientations affected by ridging or tensile failure. The rheology is illustrated by a yield curve determined by combining coulombic and ridging failure for the case of two pairs of isotropically formed leads of different thicknesses rotated with regard to each other, which models two events of coulombic failure followed by dilatancy and refreezing. The yield curve consists of linear segments describing coulombic and ridging yield as failure switches from one lead to another as the stress grows. Because sliding along slip lines is accompanied by dilatancy, at typical Arctic sea ice deformation rates a one-day-long deformation event produces enough open water that these freshly formed slip lines are preferential places of ridging failure.

Modeling Coulombic failure of sea ice with leads

[1] Sea ice failure under low-confinement compression is modeled with a linear Coulombic criterion that can describe either fractural failure or frictional granular yield along slip lines. To study the effect of anisotropy we consider a simplified anisotropic sea ice model where the sea ice thickness depends on orientation. Accommodation of arbitrary deformation requires failure along at least two intersecting slip lines, which are determined by finding two maxima of the yield criterion. Due to the anisotropy these slip lines generally differ from the standard, Coulombic slip lines that are symmetrically positioned around the compression direction, and therefore different tractions along these slip lines give rise to a nonsymmetric stress tensor. We assume that the skewsymmetric part of this tensor is counterbalanced by an additional elastic stress in the sea ice field that suppresses floe spin. We consider the case of two leads initially formed in an isotropic ice cover under compression, and address the question of whether these leads will remain active or new slip lines will form under a rotation of the principal compression direction. Decoupled and coupled models of leads are considered and it is shown that for this particular case they both predict lead reactivation in almost the same way. The coupled model must, however, be used in determining the stress as the decoupled model does not resolve the stress asymmetry properly when failure occurs in one lead and at a new slip line.

Controlling market power of vertically integrated firms in electricity networks: demand response of aggregator agents

This article reports the results of an experiment that examined how demand aggregators can discipline vertically-integrated firms - generator and distributor-retailer holdings-, which have a high share in wholesale electricity market with uniform price double auction (UPDA). We initially develop a treatment where holding members redistribute the profit based on the imposition of supra-competitive prices, in equal proportions (50%-50%). Subsequently, we introduce a vertical disintegration (unbundling) treatment with holding-s information sharing, where profits are distributed according to market outcomes. Finally, a third treatment is performed to introduce two active demand aggregators, with flexible interruptible loads in real time. We found that the introduction of responsive demand aggregators neutralizes the power market and increases market efficiency, even beyond what is achieved through vertical disintegration.

Adaptive behavior by single-product and multiproduct price setting firms in experimental markets

We focus on the learning dynamics in multiproduct price-setting markets, where firms use past strategies and performance to adapt to the corresponding equilibrium.

Automatic ability attribution after failure: a dual process view of achievement attribution

Causal attribution has been one of the most influential frameworks in the literature of achievement motivation, but previous studies considered achievement attribution as relatively deliberate and effortful processes. In the current study, we tested the hypothesis that people automatically attribute their achievement failure to their ability, but reduce the ability attribution in a controlled manner. To address this hypothesis, we measured participants’ causal attribution belief for their task failure either under the cognitive load (load condition) or with full attention (no-load condition). Across two studies, participants attributed task performance to their ability more in the load than in the no-load condition. The increased ability attribution under cognitive load further affected intrinsic motivation. These results indicate that cognitive resources available after feedback play crucial roles in determining causal attribution belief, as well as achievement motivations. (PsycINFO Database Record (c) 2013 APA, all rights reserved)(journal abstract)

Management compensation systems in MNCs and domestic firms. Cross-national empirical evidence

• This is a study of the relationship between institutional settings and managerial compensation systems, based on extensive cross-national survey evidence. • We compare differences in practices between Multinational Corporations (MNCs) and domestic firms across a range of capitalist archetypes. • We find that MNCs are more likely to promote compensation systems that incentivise managers in line with organisational performance compared to domestic firms. Our findings also reveal persistent diversity reflecting firm type and institutional setting. We find that the gap between MNCs and domestic firms in terms of the usage of incentive-related compensation is less pronounced in Liberal Market Economies than in other settings. This suggests that it is a combination of being an MNC and the specific home locale that moulds approaches to managerial compensation. This reflects considerable hybridisation of practices within and between settings.

Modelling methodology and forecast failure

We analyse by simulation the impact of model-selection strategies (sometimes called pre-testing) on forecast performance in both constant-and non-constant-parameter processes. Restricted, unrestricted and selected models are compared when either of the first two might generate the data. We find little evidence that strategies such as general-to-specific induce significant over-fitting, or thereby cause forecast-failure rejection rates to greatly exceed nominal sizes. Parameter non-constancies put a premium on correct specification, but in general, model-selection effects appear to be relatively small, and progressive research is able to detect the mis-specifications.

The outsourcing strategy of local and multinational firms: A supply base perspective

Firms outsource through connecting to local and global supply bases and making such connections produces costs of search and evaluation, which are a function of transaction characteristics and firm capabilities. We argue that firms outsource more when those costs are low. Hence, domestic subsidiaries of multinational firms, with low cost access to both local and global supply bases, outsource more than either domestic firms or foreign subsidiaries, as confirmed by evidence from a large data panel. We also propose that among foreign subsidiaries, distance from the home country co-determines search and evaluation costs such that subsidiaries from more distant countries outsource less. This is confirmed for geographic distance, but a positive effect is found for political distance and a mixed effect for cultural distance.