Feedback regulation by Atf3 in the endothelin-1-responsive transcriptome of cardiomyocytes: Egr1 is a principal Atf3 target

Endothelin-1 promotes cardiomyocyte hypertrophy by inducing changes in gene expression. Immediate early genes including activating transcription factor 3 (Atf3), Egr1 and Ptgs2 are rapidly and transiently upregulated by endothelin-1 in cardiomyocytes. Atf3 regulates expression of downstream genes and is implicated in negative feedback regulation of other immediate early genes. To identify Atf3-regulated genes, we knocked down Atf3 expression in cardiomyocytes exposed to endothelin-1 and used microarrays to interrogate the transcriptomic effects. Of upregulated mRNAs, expression of 23 (including Egr1, Ptgs2) was enhanced and expression of 25 was inhibited by Atf3 knockdown. Using quantitative PCR, we determined that knockdown of Atf3 had little effect on upregulation of Egr1 mRNA over 30 min, but abolished the subsequent decline, causing sustained Egr1 mRNA expression and enhanced protein expression. This resulted from direct binding of Atf3 to the Egr1 promoter. Mathematical modelling established that Atf3 can suffice to suppress Egr1 expression. Given the widespread co-regulation of Atf3 with Egr1, we suggest that the Atf3-Egr1 negative feedback loop is of general significance. Loss of Atf3 caused abnormal cardiomyocyte growth, presumably resulting from dysregulation of target genes. Our data therefore identify Atf3 as a nexus in cardiomyocyte hypertrophy required to facilitate the full and proper growth response.

Effects of seed addition on beetle assemblages during the re-creation of species-rich lowland hay meadows

Species-rich lowland hay meadows are of conservation importance for both plants and invertebrates; however, they have declined in area across Europe as a result of conversion to other land uses and management intensification. The re-creation of these grasslands on ex-arable land provides a valuable approach to increasing the extent and conservation value of this threatened habitat. Over a 3-year period a replicated block design was used to test whether introducing seeds promoted the re-creation of both plant and phytophagous beetle assemblages typical of a target hay meadow. Seeds were harvested from local hay meadows, and applied to experimental plots in the form of either green hay or brush harvesting seeds. Green hay spreading achieved the greatest success in re-creating plant and phytophagous beetle assemblages. While re-creation success increased over time for both taxa, for the phytophagous beetles the greatest increase in re-creation success relative to the establishment year also occurred where green hay was applied. We also considered the phytophagous beetles in terms of functional traits that describe host plant specificity, larval feeding location and dispersal. Phytophagous beetle functional trait composition was most similar to the target hay meadow assemblage where some form of seed addition was used, i.e. hay spreading or brush harvested seeds. This study identified the importance of introducing target plant species as a mechanism to promote the re-creation of phytophagous beetle communities. Seed addition methods (e.g. green hay spreading) are crucial to successful hay meadow re-creation.

Causal evidence for frontal involvement in memory target maintenance by posterior brain areas during distracter interference of visual working memory

Dorsolateral prefrontal cortex (DLPFC) is recruited during visual working memory (WM) when relevant information must be maintained in the presence of distracting information. The mechanism by which DLPFC might ensure successful maintenance of the contents of WM is, however, unclear; it might enhance neural maintenance of memory targets or suppress processing of distracters. To adjudicate between these possibilities, we applied time-locked transcranial magnetic stimulation (TMS) during functional MRI, an approach that permits causal assessment of a stimulated brain region's influence on connected brain regions, and evaluated how this influence may change under different task conditions. Participants performed a visual WM task requiring retention of visual stimuli (faces or houses) across a delay during which visual distracters could be present or absent. When distracters were present, they were always from the opposite stimulus category, so that targets and distracters were represented in distinct posterior cortical areas. We then measured whether DLPFC-TMS, administered in the delay at the time point when distracters could appear, would modulate posterior regions representing memory targets or distracters. We found that DLPFC-TMS influenced posterior areas only when distracters were present and, critically, that this influence consisted of increased activity in regions representing the current memory targets. DLPFC-TMS did not affect regions representing current distracters. These results provide a new line of causal evidence for a top-down DLPFC-based control mechanism that promotes successful maintenance of relevant information in WM in the presence of distraction.

The spatial impact of visual distractors on saccade latency

Remote transient changes in the environment, such as the onset of visual distractors, impact on the exe- cution of target directed saccadic eye movements. Studies that have examined the latency of the saccade response have shown conflicting results. When there was an element of target selection, saccade latency increased as the distance between distractor and target increased. In contrast, when target selection is minimized by restricting the target to appear on one axis position, latency has been found to be slowest when the distractor is shown at fixation and reduces as it moves away from this position, rather than from the target. Here we report four experiments examining saccade latency as target and distractor posi- tions are varied. We find support for both a dependence of saccade latency on distractor distance from target and from fixation: saccade latency was longer when distractor is shown close to fixation and even longer still when shown in an opposite location (180°) to the target. We suggest that this is due to inhib- itory interactions between the distractor, fixation and the target interfering with fixation disengagement and target selection.

Why the home region matters: location and regional multinationals

Much of the literature in international business analysing the multinational enterprise uses the country as the relevant environmental parameter. This paper presents both theoretical and empirical evidence to demonstrate that country-level analysis now needs to be augmented by analysis at the ‘regional’ level of the broad triad markets of Europe, North America and the Asia Pacific. The great majority of the world's 500 largest firms concentrate their activities within their home region of the triad. This study uses variance component analysis and finds that this home region effect outperforms the country effect. Together, the regional and industry effects explain most of the geographic expansion of multinational enterprises (MNEs), whereas country, firm and year effects are very minor. The new data and variance component analysis on the activities of large MNEs reported here suggest that new thinking is required about the importance of large regions of the triad as the relevant unit of analysis for business strategy to supplement the conventional focus on the country.

Multi-target out-of-sequence data association: tracking using graphical models

When performing data fusion, one often measures where targets were and then wishes to deduce where targets currently are. There has been recent research on the processing of such out-of-sequence data. This research has culminated in the development of a number of algorithms for solving the associated tracking problem. This paper reviews these different approaches in a common Bayesian framework and proposes an architecture that orthogonalises the data association and out-of-sequence problems such that any combination of solutions to these two problems can be used together. The emphasis is not on advocating one approach over another on the basis of computational expense, but rather on understanding the relationships among the algorithms so that any approximations made are explicit. Results for a multi-sensor scenario involving out-of-sequence data association are used to illustrate the utility of this approach in a specific context.

Multi-target out-of-sequence data association

In data fusion systems, one often encounters measurements of past target locations and then wishes to deduce where the targets are currently located. Recent research on the processing of such out-of-sequence data has culminated in the development of a number of algorithms for solving the associated tracking problem. This paper reviews these different approaches in a common Bayesian framework and proposes an architecture that orthogonalises the data association and out-of-sequence problems such that any combination of solutions to these two problems can be used together. The emphasis is not on advocating one approach over another on the basis of computational expense, but rather on understanding the relationships between the algorithms so that any approximations made are explicit.

The multisensory attentional consequences of tool use: a functional magnetic resonance imaging study

Background: Tool use in humans requires that multisensory information is integrated across different locations, from objects seen to be distant from the hand, but felt indirectly at the hand via the tool. We tested the hypothesis that using a simple tool to perceive vibrotactile stimuli results in the enhanced processing of visual stimuli presented at the distal, functional part of the tool. Such a finding would be consistent with a shift of spatial attention to the location where the tool is used. Methodology/Principal Findings: We tested this hypothesis by scanning healthy human participants' brains using functional magnetic resonance imaging, while they used a simple tool to discriminate between target vibrations, accompanied by congruent or incongruent visual distractors, on the same or opposite side to the tool. The attentional hypothesis was supported: BOLD response in occipital cortex, particularly in the right hemisphere lingual gyrus, varied significantly as a function of tool position, increasing contralaterally, and decreasing ipsilaterally to the tool. Furthermore, these modulations occurred despite the fact that participants were repeatedly instructed to ignore the visual stimuli, to respond only to the vibrotactile stimuli, and to maintain visual fixation centrally. In addition, the magnitude of multisensory (visual-vibrotactile) interactions in participants' behavioural responses significantly predicted the BOLD response in occipital cortical areas that were also modulated as a function of both visual stimulus position and tool position. Conclusions/Significance: These results show that using a simple tool to locate and to perceive vibrotactile stimuli is accompanied by a shift of spatial attention to the location where the functional part of the tool is used, resulting in enhanced processing of visual stimuli at that location, and decreased processing at other locations. This was most clearly observed in the right hemisphere lingual gyrus. Such modulations of visual processing may reflect the functional importance of visuospatial information during human tool use

Bohemian graduates in the UK: disciplines and location determinants for entering creative careers

The human capital and regional economic development literature has become increasingly interested in the role of the ‘Bohemian occupations’ on economic growth. Using UK higher education student micro-data, we investigate the characteristics and location determinants of creative (bohemian) graduates. We examine three specific sub-groups: creative arts & design graduates; creative media graduates; other creative graduates. We find these disciplines influence the ability of graduates to enter creative occupations and be successful in the labour market. We also highlight the role of geography, with London and the South East emerging as hubs for studying and providing Bohemian graduates with more labour market opportunities.

Glycogen synthase kinase 3 (GSK3) in the heart: a point of integration in hypertrophic signalling and a therapeutic target? A critical analysis

Glycogen synthase kinase 3 (GSK3, of which there are two isoforms, GSK3alpha and GSK3beta) was originally characterized in the context of regulation of glycogen metabolism, though it is now known to regulate many other cellular processes. Phosphorylation of GSK3alpha(Ser21) and GSK3beta(Ser9) inhibits their activity. In the heart, emphasis has been placed particularly on GSK3beta, rather than GSK3alpha. Importantly, catalytically-active GSK3 generally restrains gene expression and, in the heart, catalytically-active GSK3 has been implicated in anti-hypertrophic signalling. Inhibition of GSK3 results in changes in the activities of transcription and translation factors in the heart and promotes hypertrophic responses, and it is generally assumed that signal transduction from hypertrophic stimuli to GSK3 passes primarily through protein kinase B/Akt (PKB/Akt). However, recent data suggest that the situation is far more complex. We review evidence pertaining to the role of GSK3 in the myocardium and discuss effects of genetic manipulation of GSK3 activity in vivo. We also discuss the signalling pathways potentially regulating GSK3 activity and propose that, depending on the stimulus, phosphorylation of GSK3 is independent of PKB/Akt. Potential GSK3 substrates studied in relation to myocardial hypertrophy include nuclear factors of activated T cells, beta-catenin, GATA4, myocardin, CREB, and eukaryotic initiation factor 2Bvarepsilon. These and other transcription factor substrates putatively important in the heart are considered. We discuss whether cardiac pathologies could be treated by therapeutic intervention at the GSK3 level but conclude that any intervention would be premature without greater understanding of the precise role of GSK3 in cardiac processes.

Effects of target expansion on selection performance in older computer users

Point and click interactions using a mouse are an integral part of computer use for current desktop systems. Compared with younger users though, older adults experience greater difficulties performing cursor positioning tasks, and this can present limitations to using a computer easily and effectively. Target expansion is a technique for improving pointing performance, where the target dynamically grows as the cursor approaches. This has the advantage that targets conserve screen real estate in their unexpanded state, yet can still provide the benefits of a larger area to click on. This paper presents two studies of target expansion with older and younger participants, involving multidirectional point-select tasks with a computer mouse. Study 1 compares static versus expanding targets, and Study 2 compares static targets with three alternative techniques for expansion. Results show that expansion can improve times by up to 14%, and reduce error rates by up to 50%. Additionally, expanding targets are beneficial even when the expansion happens late in the movement, i.e. after the cursor has reached the expanded target area or even after it has reached the original target area. Participants’ subjective feedback on the target expansion are generally favorable, and this lends further support for the technique.

Location, control and innovation in knowledge-intensive industries

The rising share of intangibles in economies worldwide highlights the crucial role of knowledge-intensive and creative industries in current and future wealth generation. The recognition of this trend has led to intense competition in these industries. At the micro-level, firms from both advanced and emerging economies are globally dispersing their value chains to control costs and leverage capabilities. The geography of innovation is the outcome of a dynamic process whereby firms from emerging economies strive to catch-up with advanced economy competitors, creating strong pressures for continued innovation. However, two distinct strategies can be discerned with regard to the control of the value chain. A vertical integration strategy emphasizes taking advantage of ‘linkage economies’ whereby controlling multiple value chain activities enhances the efficiency and effectiveness of each one of them. In contrast, a specialization strategy focuses on identifying and controlling the creative heart of the value chain, while outsourcing all other activities. The global mobile handset industry is used as the template to illustrate the theory.