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International audience; This paper explores the strategic goals behind actors’ involvement in emerging technological innovation systems (TISs) for sustainable technologies and the way they contribute to the development of the TIS functions. Based on six expert interviews with firms within the biorefinery sector in Germany, we observe four different strategic goals driving firm-actors’ involvement: (1) exploiting new markets and businesses, (2) learning about the potential of new markets and businesses, (3) developing new technologies and (4) building up new market applications. We also differentiate between three firm-actor types: (1) a leading type of incumbent firm highly contributing to the TIS functions; (2) a learning type of incumbent firm with lower contribution; and (3) a ‘fill the gap’ type of SME or start-up producing complementary knowledge or connecting other TIS actors.

International audience; This paper aims to elucidate how companies can innovate their business model to strengthen their resilience and timely respond to current ecosystem challenges, like the emergence of new cross-industry value chains in the circular economy. The adoption of new sustainable technologies leads to the disruption of current linear settings and to the need of business model innovation. This study draws upon a case study from the circular economy rooted in by-product valorisation and presents an innovative bio-based process enabling phosphate recovery from rapeseed oil press-cakes. Incumbent actors of established (linear) value chains have been interviewed to highlight potential business model innovation. To this end, an inductive theory-building case study approach has been applied. Results reveal that a business model redesign is needed in order to build novel circular value chains, but it depends on chain actors’ capacity to adapt to change, namely to be resilient. The new value proposition needs to reach new customer targets more sensitive to sustainability issues and/or to enhance the awareness towards bio-based technological solutions into extant customers. Value creation and capture highly depend on the coordinating role of the chain actor willing to invest in the new bio-based technology, which becomes the focal company within the emergent value chain. Two scenarios are open, according to who is playing this role: if the new recovery and release process is carried out by an incumbent, the new process requires exploratory, transformative and exploitative learning together with extra investments in highly specific assets and the establishment of new cross-industry relationships to complement missing assets and knowledge about such technological breakthroughs available on the market. If a new actor enters the emerging value chain, business model innovation is mediated and moderated by a company owning both tangible and intangible resources, thus catalysing technology implementation.

Systems thinking (ST) represents an important cognitive paradigm for the transition towards a circular bio-economy, as greater awareness of the environmental impact of fossil-based products may lead to a switch to sustainable alternatives produced from secondary biomass which is not used as feed or food. However, the relationship between ST and the adoption of bio-based products, as well as the general mechanism of how ST affects environmental behavior, is not yet well-understood. The present study therefore aims to close these research gaps by conducting a survey-based experiment with a ST-motivated treatment, in which participants are asked to list as many consequences of their consumption behavior as possible (N=446 US consumers). Our findings suggest that the treatment is able to slightly activate a ST perspective, along with indirectly affecting consumer intentions to buy bio-based products by means of ST. Subsequent mediation analyses further reveal that an ecological worldview as well as variables from the norm-activation model function as mediators of the relationship between ST and purchase intention.

The receptor for the luteinizing hormone (LH-R) is aberrantly over expressed in cancers of the reproductive system. To uncover whether LH-R over expression has a causative role in cancer, we generated a transgenic (TG) mouse which overexpresses the human LH-R (hLH-R) in the female reproductive tract, under the control of the oviduct-specific glycoprotein (OGP) mouse promoter (mogp-1). The transgene was highly expressed in the uterus, ovary and liver, but only in the uterus morphological and molecular alterations (increased proliferation and trans-differentiation in the endometrial layer) were detected. A transcriptomic analysis on the uteri of young TG mice showed an up regulation of genes involved in cell cycle control and a down regulation of genes related to the immune system and the metabolism of xenobiotics. Aged TG females developed tumor masses in the uteri, which resembled an Endometrial Cancer (EC). Microarray and immunohistochemistry data indicated the deregulation of signaling pathways which are known to be altered in human ECs. The analysis of a cohort of 126 human ECs showed that LH-R overexpression is associated with early-stage tumors. Overall, our data led support to conclude that LH-R overexpression may directly contribute to trigger the neoplastic transformation of the endometrium.

A transition towards a bio-based economy is accompanied by a growing demand for biomass resources as fossil fuels need to be replaced for the more sustainable production of consumer goods, chemicals and energy. To increase the supply of renewable biomass and avoid a conflict with food production, currently underutilized by-products (i.e. leaves, stems) from horticultural production could be valorised as feedstock. The success of this approach depends on farmers' willingness to adopt novel practices like the collection and treatment of plant leaves. However, literature on factors influencing farmers' decisions to adopt novel practices aimed to foster the Bioeconomy is limited. This paper addresses this gap by exploring drivers of farmers' interest in the valorisation of by-products. To this aim, the Value-Belief-Norm theory was used and expanded by contextual factors, such as the perceived market demand for biomass and future environmental policies. A survey with German fruit and vegetable farmers (N = 96) has been carried out and data have been analysed with a Structural Equation Model. Findings suggest that the Value-Belief-Norm theory is a relevant framework for the agricultural domain to predict farmers' interest in the valorisation of horticultural by-products. Results further indicate that an internal ecological worldview is potentially relevant for farmers' perception of contextual conditions aimed to foster the Bioeconomy. These outcomes could have managerial and policy implications associated with the identification of potential lead users to trigger the diffusion of innovative sustainable practices and generally foster the Bioeconomy.

The Na+/K+/Cl- cotransporter-1 (NKCC1) and the K+/Cl- cotransporter-2 (KCC2) set the transmembrane Cl- gradient in the brain, and are implicated in epileptogenesis. We studied the postnatal distribution of NKCC1 and KCC2 in wild-type (WT) mice, and in a mouse model of sleep-related epilepsy, carrying the mutant β2-V287L subunit of the nicotinic acetylcholine receptor (nAChR). In WT neocortex, immunohistochemistry showed a wide distribution of NKCC1 in neurons and astrocytes. At birth, KCC2 was localized in neuronal somata, whereas at subsequent stages it was mainly found in the somatodendritic compartment. The cotransporters' expression was quantified by densitometry in the transgenic strain. KCC2 expression increased during the first postnatal weeks, while the NKCC1 amount remained stable, after birth. In mice expressing β2-V287L, the KCC2 amount in layer V of prefrontal cortex (PFC) was lower than in the control littermates at postnatal day 8 (P8), with no concomitant change in NKCC1. Consistently, the GABAergic excitatory to inhibitory switch was delayed in PFC layer V of mice carrying β2-V287L. At P60, the amount of KCC2 was instead higher in mice bearing the transgene. Irrespective of genotype, NKCC1 and KCC2 were abundantly expressed in the neuropil of most thalamic nuclei since birth. However, KCC2 expression decreased by P60 in the reticular nucleus, and more so in mice expressing β2-V287L. Therefore, a complex regulatory interplay occurs between heteromeric nAChRs and KCC2 in postnatal forebrain. The pathogenetic effect of β2-V287L may depend on altered KCC2 amounts in PFC during synaptogenesis, as well as in mature thalamocortical circuits.

Ion channels regulate cell proliferation, differentiation, and migration in normal and neoplastic cells through cell-cell and cell-extracellular matrix (ECM) transmembrane receptors called integrins. K+ flux through the human ether-a-go-go-related gene 1 (hERG1) channel shapes action potential firing in excitable cells such as cardiomyocytes. Its abundance is often aberrantly high in tumors, where it modulates integrin-mediated signaling. We found that hERG1 interacted with the beta(1) integrin subunit at the plasma membrane of human cancer cells. This interaction was not detected in cardiomyocytes because of the presence of the hERG1 auxiliary subunit KCNE1 (potassium voltage-gated channel subfamily E regulatory subunit 1), which blocked the beta(1) integrin-hERG1 interaction. Although open hERG1 channels did not interact as strongly with beta(1) integrins as did closed channels, current flow through hERG1 channels was necessary to activate the integrin-dependent phosphorylation of Tyr(397) in focal adhesion kinase (FAK) in both normal and cancer cells. In immunodeficient mice, proliferation was inhibited in breast cancer cells expressing forms of hERG1 with impaired K+ flow, whereas metastasis of breast cancer cells was reduced when the hERG1/beta(1) integrin interaction was disrupted. We conclude that the interaction of beta(1) integrins with hERG1 channels in cancer cells stimulated distinct signaling pathways that depended on the conformational state of hERG1 and affected different aspects of tumor progression.

// Elena Lastraioli 1 , Tiziano Lottini 1 , Jessica Iorio 1 , Giancarlo Freschi 2 , Marilena Fazi 2 , Claudia Duranti 1 , Laura Carraresi 3 , Luca Messerini 1 , Antonio Taddei 2 , Maria Novella Ringressi 2 , Marianna Salemme 4 , Vincenzo Villanacci 4 , Carla Vindigni 5 , Anna Tomezzoli 6 , Roberta La Mendola 7 , Maria Bencivenga 7 , Bruno Compagnoni 8 , Mariella Chiudinelli 9 , Luca Saragoni 10 , Ilaria Manzi 11 , Giovanni De Manzoni 7 , Paolo Bechi 2 , Luca Boni 12, * , Annarosa Arcangeli 1, * 1 Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy 2 Department of Surgery and Translational Medicine, University of Florence, 50134 Florence, Italy 3 DI.V.A.L Toscana Srl, 50019 Sesto Fiorentino, Italy 4 Institute of Pathology, Spedali Civili, 25123 Brescia, Italy 5 Pathology Division, Azienda Ospedaliero-Universitaria Senese, 53100 Siena, Italy 6 Pathology Division, Borgo Trento Hospital, 37134 Verona, Italy 7 Division of Surgery, University of Verona, 37134 Verona, Italy 8 Surgery Division, Esine Hospital, ASL Vallecamonica Sebino, 25040 Esine (BS), Italy 9 Pathology Division, Esine Hospital, ASL Vallecamonica Sebino, 25040 Esine (BS), Italy 10 Pathology Division, Morgagni-Pierantoni Hospital, 47121 Forli, Italy 11 Gastroenterology and Endoscopy Unit, Morgagni-Pierantoni Hospital, 47121 Forli, Italy 12 Clinical Trials Coordinating Center, Azienda Ospedaliero-Universitaria Careggi/Istituto Toscano Tumori, 50134 Florence, Italy * These authors contributed equally to this work Correspondence to: Annarosa Arcangeli, email: annarosa.arcangeli@unifi.it Keywords: hERG1, Barrett’s esophagus, adenocarcinoma progression, surveillance, optical imaging Received: March 13, 2016 Accepted: July 09, 2016 Published: August 09, 2016 ABSTRACT Barrett’s esophagus (BE) is the only well-known precursor lesion of esophageal adenocarcinoma (EA). The exact estimates of the annual progression rate from BE to EA vary from 0.07% to 3.6%. The identification of BE patients at higher risk to progress to EA is hence mandatory, although difficult to accomplish. In search of novel BE biomarkers we analyzed the efficacy of hERG1 potassium channels in predicting BE progression to EA. Once tested by immunohistochemistry (IHC) on bioptic samples, hERG1 was expressed in BE, and its expression levels increased during progression from BE to esophageal dysplasia (ED) and EA. hERG1 was also over-expressed in the metaplastic cells arising in BE lesions obtained in different BE mouse models, induced either surgically or chemically. Furthermore, transgenic mice which over express hERG1 in the whole gastrointestinal tract, developed BE lesions after an esophago-jejunal anastomosis more frequently, compared to controls. A case-control study was performed on 104 bioptic samples from newly diagnosed BE patients further followed up for at least 10 years. It emerged a statistically significant association between hERG1 expression status and risk of progression to EA. Finally, a novel fluorophore- conjugated recombinant single chain variable fragment antibody (scFv-hERG1-Alexa488) was tested on freshly collected live BE biopsies: it could recognize hERG1 positive samples, perfectly matching IHC data. Overall, hERG1 can be considered a novel BE biomarker to be exploited for a novel endoscopic surveillance protocol, either in biopsies or through endoscopy, to identify those BE patients with higher risk to progress to EA.

The purpose of this paper is to evaluate the marketing management capabilities of SMEs producing traditional food products, in order to analyse the market orientation of SMEs in the food industry. Following the theoretical approach of Market Orientation, our analysis is based on an assessment of the marketing management process. The methodology refers to a survey developed through a questionnaire published on the web, and a sample of 371 firms based in Belgium, Italy, Spain, the Czech Republic and Hungary was used in the analysis. Cluster analysis was applied to find the different levels of market orientation of the firms. The results revealed a certain lack of appropriate skills in marketing management in the firms of the sample, confirming the evidence found in economic literature concerning SMEs. Nevertheless, cluster analysis outlined a group of firms with good marketing capabilities and market oriented, and these represent a great part of the sample (40%). With regard to the stages of the marketing management process, the most problematic are those of planning and implementation, and control and evaluation, highlighting the difficulties SMEs encounter in carrying out coordinated marketing; which appears to be generally characterised by poor organisational capacity.