HIF-driven SF3B1 induces KHK-C to enforce fructolysis and heart disease.

Fructose is a major component of dietary sugar and its overconsumption exacerbates key pathological features of metabolic syndrome. The central fructose-metabolising enzyme is ketohexokinase (KHK), which exists in two isoforms: KHK-A and KHK-C, generated through mutually exclusive alternative splicing of KHK pre-mRNAs. KHK-C displays superior affinity for fructose compared with KHK-A and is produced primarily in the liver, thus restricting fructose metabolism almost exclusively to this organ. Here we show that myocardial hypoxia actuates fructose metabolism in human and mouse models of pathological cardiac hypertrophy through hypoxia-inducible factor 1α (HIF1α) activation of SF3B1 and SF3B1-mediated splice switching of KHK-A to KHK-C. Heart-specific depletion of SF3B1 or genetic ablation of Khk, but not Khk-A alone, in mice, suppresses pathological stress-induced fructose metabolism, growth and contractile dysfunction, thus defining signalling components and molecular underpinnings of a fructose metabolism regulatory system crucial for pathological growth.

Non-invasive prenatal testing for aneuploidy and beyond: challenges of responsible innovation in prenatal screening.

This paper contains a joint ESHG/ASHG position document with recommendations regarding responsible innovation in prenatal screening with non-invasive prenatal testing (NIPT). By virtue of its greater accuracy and safety with respect to prenatal screening for common autosomal aneuploidies, NIPT has the potential of helping the practice better achieve its aim of facilitating autonomous reproductive choices, provided that balanced pretest information and non-directive counseling are available as part of the screening offer. Depending on the health-care setting, different scenarios for NIPT-based screening for common autosomal aneuploidies are possible. The trade-offs involved in these scenarios should be assessed in light of the aim of screening, the balance of benefits and burdens for pregnant women and their partners and considerations of cost-effectiveness and justice. With improving screening technologies and decreasing costs of sequencing and analysis, it will become possible in the near future to significantly expand the scope of prenatal screening beyond common autosomal aneuploidies. Commercial providers have already begun expanding their tests to include sex-chromosomal abnormalities and microdeletions. However, multiple false positives may undermine the main achievement of NIPT in the context of prenatal screening: the significant reduction of the invasive testing rate. This document argues for a cautious expansion of the scope of prenatal screening to serious congenital and childhood disorders, only following sound validation studies and a comprehensive evaluation of all relevant aspects. A further core message of this document is that in countries where prenatal screening is offered as a public health programme, governments and public health authorities should adopt an active role to ensure the responsible innovation of prenatal screening on the basis of ethical principles. Crucial elements are the quality of the screening process as a whole (including non-laboratory aspects such as information and counseling), education of professionals, systematic evaluation of all aspects of prenatal screening, development of better evaluation tools in the light of the aim of the practice, accountability to all stakeholders including children born from screened pregnancies and persons living with the conditions targeted in prenatal screening and promotion of equity of access.

Long-Lasting Metabolic Imbalance Related to Obesity Alters Olfactory Tissue Homeostasis and Impairs Olfactory-Driven Behaviors.

Obesity is associated with chronic food intake disorders and binge eating. Food intake relies on the interaction between homeostatic regulation and hedonic signals among which, olfaction is a major sensory determinant. However, its potential modulation at the peripheral level by a chronic energy imbalance associated to obese status remains a matter of debate. We further investigated the olfactory function in a rodent model relevant to the situation encountered in obese humans, where genetic susceptibility is juxtaposed on chronic eating disorders. Using several olfactory-driven tests, we compared the behaviors of obesity-prone Sprague-Dawley rats (OP) fed with a high-fat/high-sugar diet with those of obese-resistant ones fed with normal chow. In OP rats, we reported 1) decreased odor threshold, but 2) poor olfactory performances, associated with learning/memory deficits, 3) decreased influence of fasting, and 4) impaired insulin control on food seeking behavior. Associated with these behavioral modifications, we found a modulation of metabolism-related factors implicated in 1) electrical olfactory signal regulation (insulin receptor), 2) cellular dynamics (glucorticoids receptors, pro- and antiapoptotic factors), and 3) homeostasis of the olfactory mucosa and bulb (monocarboxylate and glucose transporters). Such impairments might participate to the perturbed daily food intake pattern that we observed in obese animals.

Innovation process management of complex consumer products and services in new innovation paradigm – case location based business

Innovation is the word of this decade. According to innovation definitions, without positive sales impact and meaningful market share the company’s product or service has not been an innovation. Research problem of this master thesis is to find out what is the innovation process of complex new consumer products and services in new innovation paradigm. The objective is to get answers to two research questions: 1) What are the critical success factors what company should do when it is implementing the paradigm change in mass markets consumer business with complex products and services? 2) What is the process or framework one firm could follow? The research problem is looked from one company’s innovation creation process, networking and organization change management challenges point of views. Special focus is to look the research problem from an existing company perspective which is entering new business area. Innovation process management framework of complex new consumer products and services in new innovation paradigm has been created with support of several existing innovation theories. The new process framework includes the critical innovation process elements companies should take into consideration in their daily activities when they are in their new business innovation implementing process. Case company location based business implementation activities are studied via the new innovation process framework. This case study showed how important it is to manage the process, look how the target market and the competition in it is developing during company’s own innovation process, make decisions at right time and from beginning plan and implement the organization change management as one activity in the innovation process. In the end this master thesis showed that all companies need to create their own innovation process master plan with milestones and activities. One plan does not fit all, but all companies can start their planning from the new innovation process what was introduced in this master thesis.

Management Control for Corporate Sustainability Execution: The Role of Employee Compensation

The research described in this thesis examines the characteristics, the benefits and the challenges associated with the implementation of management accounting systems in the field of Corporate Social Responsibility (CSR). Applied to the CSR context, management accounting relates to the identification, elaboration and communication of information about an organization's interactions with the society and the environment. Based on this information, firms are able to make decisions to achieve social and environmental objectives and provide evidence justifying the benefits and the costs of such actions. The study begins by focusing on green management and exploring the characteristics of Environmental Management Accounting (EMA) systems within firms. The first chapter informs the reader about the growing body of EMA research and reveals unexplored relevant aspects that need to be further investigated. The work also emphasizes the importance of developing new theoretical hypotheses and appropriate research designs to empirically tackle new aspects of EMA and gain understanding on the use of these practices. Subsequently, given the acknowledged importance of control systems in influencing the behaviour of individuals within organizations, the remaining two chapters of the dissertation focus on the functioning of CSR-linked incentives assigned to employees in the form of compensation plans. The second chapter examines the determinants influencing corporate provision of incentives for the attainment of environmental targets. Empirical analysis of a sample of international firms reveals that companies are likely to use green incentives as mechanisms to increase the efficacy in contracting with their employees as well as to respond to social influences. Finally, the third chapter investigates the effectiveness of contracting associated with the use of CSR-linked executive compensation. Empirical analysis of a sample of US-based companies shows that corporate choice to tie senior executives' pay to CSR targets promotes the firm's CSR performance. Cette thèse examine les caractéristiques, avantages et défis associés à l'utilisation des systèmes de contrôle de gestion dans le domaine de la Responsabilité Sociale des Entreprises (RSE). Dans le contexte de la RSE, les activités du contrôle de gestion impliquent l'identification, l'élaboration et la communication d'informations qui concernent les interactions des organisations avec la société et l'environnement. Avec ces informations les entreprises sont en mesure de prendre des décisions visant à atteindre les objectifs sociaux et environnementaux de l'organisation et de documenter les bénéfices et coûts de ces actions. Dès le début, la thèse se concentre sur les caractéristiques des systèmes de contrôle de gestion environnementale au sein des entreprises. Le premier chapitre passe en revue la littérature existante et révèle des aspects inexplorés. Pour ce faire, le travail suggère le développement de nouvelles théories ainsi que l'utilisation de méthodes appropriées. Ces dernières doivent permettre d'aborder empiriquement de nouveaux aspects des systèmes de contrôle environnemental et faciliter la compréhension sur l'utilisation de ces pratiques. Considérant l'importance des systèmes de contrôle pour influencer le comportement des individus au sein des organisations, la suite du travail se concentre sur le fonctionnement des contrats de rémunération des employées liées aux résultats de la RSE. Plus particulièrement, le deuxième chapitre examine les facteurs qui influencent la décision des entreprises d'assigner des objectifs environnementaux aux employées. L'analyse empirique d'un échantillon d'entreprises internationales montre que les entreprises sont susceptibles d'utiliser des mécanismes incitatifs écologiques pour augmenter l'efficacité des contrats ainsi que pour répondre aux influences sociales. Finalement, le troisième chapitre analyse l'efficacité des contrats de rémunération des dirigeants liés aux résultats de la RSE. L'analyse empirique d'un échantillon de sociétés américaines indique que le choix de l'entreprise de lier la rémunération des dirigeants à des objectifs de la RSE favorise la performance RSE de l'organisation.

Webdatanet : Innovation and quality in web-based data collection

The article discusses the development of WEBDATANET established in 2011 which aims to create a multidisciplinary network of web-based data collection experts in Europe. Topics include the presence of 190 experts in 30 European countries and abroad, the establishment of web-based teaching and discussion platforms and working groups and task forces. Also discussed is the scope of the research carried by WEBDATANET. In light of the growing importance of web-based data in the social and behavioral sciences, WEBDATANET was established in 2011 as a COST Action (IS 1004) to create a multidisciplinary network of web-based data collection experts: (web) survey methodologists, psychologists, sociologists, linguists, economists, Internet scientists, media and public opinion researchers. The aim was to accumulate and synthesize knowledge regarding methodological issues of web-based data collection (surveys, experiments, tests, non-reactive data, and mobile Internet research), and foster its scientific usage in a broader community.

Fluctuation-Driven Neural Dynamics Reproduce Drosophila Locomotor Patterns.

The neural mechanisms determining the timing of even simple actions, such as when to walk or rest, are largely mysterious. One intriguing, but untested, hypothesis posits a role for ongoing activity fluctuations in neurons of central action selection circuits that drive animal behavior from moment to moment. To examine how fluctuating activity can contribute to action timing, we paired high-resolution measurements of freely walking Drosophila melanogaster with data-driven neural network modeling and dynamical systems analysis. We generated fluctuation-driven network models whose outputs-locomotor bouts-matched those measured from sensory-deprived Drosophila. From these models, we identified those that could also reproduce a second, unrelated dataset: the complex time-course of odor-evoked walking for genetically diverse Drosophila strains. Dynamical models that best reproduced both Drosophila basal and odor-evoked locomotor patterns exhibited specific characteristics. First, ongoing fluctuations were required. In a stochastic resonance-like manner, these fluctuations allowed neural activity to escape stable equilibria and to exceed a threshold for locomotion. Second, odor-induced shifts of equilibria in these models caused a depression in locomotor frequency following olfactory stimulation. Our models predict that activity fluctuations in action selection circuits cause behavioral output to more closely match sensory drive and may therefore enhance navigation in complex sensory environments. Together these data reveal how simple neural dynamics, when coupled with activity fluctuations, can give rise to complex patterns of animal behavior.

Innovation and Regulation in ICT. Keys for Development

The expansion of broadband speed and coverage over IP technology, which extend over transport and terminal access networks, has increased the demand for applications and content which by being provided over it, uniformly give rise to convergence. These shifts in technologies and enterprise business models are giving rise to the necessity for changing the perspective and scope of the Universal Service and of the regulation frameworks, with this last one based in the same principles as always but varying its application. Several aspects require special and renewed attention, such as the definition of relevant markets and dominant operators, the role of packages, interconnection of IP networks, network neutrality, the use of the spectrum with a vision of value for the citizenship, the application of the competition framework, new forms of licensing, treatment of the risk in the networks, changes in the regulatory authorities, amongst others. These matters are treated from the perspective of the actual trends in the world and its conceptual justification.

The local configuration of a science and innovation policy : a city into the nanoworld

Local trajectories and arrangements play a significant role because the development of a research field, such as nanoscience and nanotechnology, requires substantial investments in human and instrumental resources. But why are there often concentrated in a limited number of places? What dynamics lead to such concentration? The hypothesis is that there is an assemblage of heterogeneous resources through the action of local actors. The chapter will explore, from an Actor Network Theory (ANT) perspective, how the local emergence of research dynamics from: the revival of local traditions, the local and national action of institutional entrepreneurs, controversial dynamics, and researchers' arrangements to involve other actors. It will examine how they connect up with each other and mutually commit themselves to the development of new technologies. It will focus on the role of narratives in this assembling: how were the local narratives of the past mobilized and to what effect.

Productivity and innovation spillovers: Micro evidence from Spain

This article analyses the impact that innovation expenditure and intrasectoral and intersectoral externalities have on productivity in Spanish firms. While there is an extensive literature analysing the relationship between innovation and productivity, in this particular area there are far fewer studies that examine the importance of sectoral externalities, especially with the focus on Spain. One novelty of the study, which covers the industrial and service sectors, is that we also consider jointly the technology level of the sector in which the firm operates and the firm size. The database used is the Technological Innovation Panel, PITEC, which includes 12,813 firms for the year 2008 and has been little used in this type of study. The estimation method used is Iteratively Reweighted Least Squares method, IRLS, which is very useful for obtaining robust estimations in the presence of outliers. The results confirm that innovation has a positive effect on productivity, especially in high-tech and large firms. The impact of externalities is more heterogeneous because, while intrasectoral externalities have a poitive and significant effect, especially in low-tech firms independently of size, intersectoral externalities have a more ambiguous effect, being clearly significant for advanced industries in which size has a positive effect.

A relational approach to the geography of innovation: a typology of regions

The aim of this study was to devise a method for computing a composite indicator that measures the regional degree of exposure to external knowledge sources. On the basis of this indicator, we propose a typology of regions according to their potential capacity to access extra-local items of knowledge, which might help them to recombine complementary elements of such an asset to produce a higher number of new ideas. Building on various research streams that have been relatively independent to date, we summarize a non-exhaustive instrumental list of recent studies that motivates our approach and the construction of our complex indicator, which can be used to appraise the extent to which each region is in an optimal position to access external innovative resources.

Research networks and inventors’ mobility as drivers of innovation evidence from Europe

We investigate the importance of the labour mobility of inventors, as well as the scale, extent and density of their collaborative research networks, for regional innovation outcomes. To do so, we apply a knowledge production function framework at the regional level and include inventors’ networks and their labour mobility as regressors. Our empirical approach takes full account of spatial interactions by estimating a spatial lag model together, where necessary, with a spatial error model. In addition, standard errors are calculated using spatial heteroskedasticity and autocorrelation consistent estimators to ensure their robustness in the presence of spatial error autocorrelation and heteroskedasticity of unknown form. Our results point to the existence of a robust positive correlation between intraregional labour mobility and regional innovation, whilst the relationship with networks is less clear. However, networking across regions positively correlates with a region’s innovation intensity.

Growth factor- and cytokine-driven pathways governing liver stemness and differentiation.

Liver is unique in its capacity to regenerate in response to injury or tissue loss. Hepatocytes and other liver cells are able to proliferate and repopulate the liver. However, when this response is impaired, the contribution of hepatic progenitors becomes very relevant. Here, we present an update of recent studies on growth factors and cytokine-driven intracellular pathways that govern liver stem/progenitor cell expansion and differentiation, and the relevance of these signals in liver development, regeneration and carcinogenesis. Tyrosine kinase receptor signaling, in particular, c-Met, epidermal growth factor receptors or fibroblast growth factor receptors, contribute to proliferation, survival and differentiation of liver stem/progenitor cells. Different evidence suggests a dual role for the transforming growth factor (TGF)-β signaling pathway in liver stemness and differentiation. On the one hand, TGF-β mediates progression of differentiation from a progenitor stage, but on the other hand, it contributes to the expansion of liver stem cells. Hedgehog family ligands are necessary to promote hepatoblast proliferation but need to be shut off to permit subsequent hepatoblast differentiation. In the same line, the Wnt family and β-catenin/T-cell factor pathway is clearly involved in the maintenance of liver stemness phenotype, and its repression is necessary for liver differentiation during development. Collectively, data indicate that liver stem/progenitor cells follow their own rules and regulations. The same signals that are essential for their activation, expansion and differentiation are good candidates to contribute, under adequate conditions, to the paradigm of transformation from a pro-regenerative to a pro-tumorigenic role. From a clinical perspective, this is a fundamental issue for liver stem/progenitor cell-based therapies.