Dominant-Negative Effects of Adult-Onset Huntingtin Mutations Alter the Division of Human Embryonic Stem Cells-Derived Neural Cells.

Mutations of the huntingtin protein (HTT) gene underlie both adult-onset and juvenile forms of Huntington's disease (HD). HTT modulates mitotic spindle orientation and cell fate in mouse cortical progenitors from the ventricular zone. Using human embryonic stem cells (hESC) characterized as carrying mutations associated with adult-onset disease during pre-implantation genetic diagnosis, we investigated the influence of human HTT and of an adult-onset HD mutation on mitotic spindle orientation in human neural stem cells (NSCs) derived from hESCs. The RNAi-mediated silencing of both HTT alleles in neural stem cells derived from hESCs disrupted spindle orientation and led to the mislocalization of dynein, the p150Glued subunit of dynactin and the large nuclear mitotic apparatus (NuMA) protein. We also investigated the effect of the adult-onset HD mutation on the role of HTT during spindle orientation in NSCs derived from HD-hESCs. By combining SNP-targeting allele-specific silencing and gain-of-function approaches, we showed that a 46-glutamine expansion in human HTT was sufficient for a dominant-negative effect on spindle orientation and changes in the distribution within the spindle pole and the cell cortex of dynein, p150Glued and NuMA in neural cells. Thus, neural derivatives of disease-specific human pluripotent stem cells constitute a relevant biological resource for exploring the impact of adult-onset HD mutations of the HTT gene on the division of neural progenitors, with potential applications in HD drug discovery targeting HTT-dynein-p150Glued complex interactions.

Negative Regulation of Receptor Tyrosine Kinases by T-cell Protein Tyrosine Phosphatase

Protein tyrosine phosphorylation controls a wide array of cellular responses such as growth, migration, proliferation, differentiation, metabolism and cytoskeletal organisation. Tyrosine phosphorylation is a dynamic process involving the competing activities of protein tyrosine kinases and protein tyrosine phosphatases. The protein tyrosine kinases are further divided into non-receptor- and receptor tyrosine kinases. The latter are transmembrane glycoproteins activated by the binding of specific ligands, mostly growth factors, to their extracellular domain, transmitting different signals to the cell. Growth factor receptors such as the epidermal growth factor receptor, vascular endothelial growth factor receptor 2 and platelet-derived growth factor receptor β, belong to the receptor tyrosine kinases, the signalling of which is often disturbed in various diseases, including cancer. This has led to the development of receptor tyrosine kinase antagonists for use as anti-cancer drugs. As the receptor tyrosine kinases, also the protein tyrosine phosphatases can be divided into receptor- and non-receptor types. The protein tyrosine phosphatases have attained much less attention than the receptor tyrosine kinases partly because they were identified later. However, accumulating evidence shows that the protein tyrosine phosphatases have important roles as specific and active regulators of tyrosine phosphorylation in cells and of physiological processes. Consequently, the protein tyrosine phosphatases are receiving arising interest as novel drug targets. The aim of this work was to elucidate the negative regulation of receptor tyrosine kinases by one non-receptor protein tyrosine phosphatase, T-cell protein tyrosine phosphatase TCPTP. The results show that TCPTP activated by cell adhesion receptor integrin α1 functions as a negative regulator of the epidermal growth factor receptor. It was also found that TCPTP affects vascular endothelial growth factor receptor 2 signalling and angiogenesis. Lastly, a High-throughput screen with 64,280 compounds was performed to identify novel TCPTP activators, resulting in identification of one small molecule compound capable of exerting similar effects on TCPTP signalling as integrin α1. This compound is shown to downregulate signalling of epidermal growth factor receptor and platelet-derived growth factor receptor β, as well as to inhibit cell proliferation and angiogenesis. Our results suggest that a suitable small-molecule TCPTP activator could be utilized in the development of novel anti-cancer drugs.

Customer reference marketing and utilization of social media as an integral part of customer references

The objective of this Bachelor's Thesis is to find out the role of social media in the B-to-B marketing environment of the information technology industry and to discover how IT-firms utilize social media as a part of their customer reference marketing. To reach the objectives the concepts of customer reference marketing and social media are determined. Customer reference marketing can be characterized as one of the most practically relevant but academically relatively overlooked ways in which a company can leverage its customers and delivered solutions and use them as references in its marketing activities. We will cover which external and internal functions customer references have, that contribute to the growth and performance of B-to-B firms. We also address the three mechanisms of customer reference marketing which are 'status transfer', 'validation through testimonials' and 'demonstration of experience and prior performance'. The concept of social media stands for social interaction and creation of user-based content which exclusively occurs through Internet. The social media are excellent tools for networking because of the fast and easy access, easy interaction and vast amount of multimedia attributes. The allocation of social media is determined. The case company helps clarify the specific characteristics of social media usage as part of customer-reference-marketing activities. For IT-firms the best channels to utilize social media in their customer reference marketing activities are publishing and distribution services of content and networking services.

SOCIAL MEDIA IN INTERNATIONAL BRAND COMMUNICATION OF SMES - A multiple case study of small Finnish design-intensive companies

Social media is a rather new phenomenon which has revolutionised the world of online communication. However, academic research on how companies can benefit from social media is lacking. The research objective of this thesis was to examine the use of social media in international brand communication of small Finnish design-intensive companies. Therefore, this research contributes also to the research gap in SME branding. The focus was on communication targeted at consumers. The research was carried out as a mixed methods research employing the questionnaire and multiple case study methods. The questionnaire was used to gather preliminary information on Finnish design-intensive companies and to provide an eligible list of companies for deeper examination. Then, four case companies were studied in more depth. The empirical evidence of the case companies was mainly gathered through theme interviews. The results of the questionnaire shed light on the internationalisation of small Finnish designintensive companies. On average, the companies had internationalised rather quickly after they had been founded. However, the share of exports was rather low in most of the companies. The results revealed also that social media was already used widely in the exporting companies and the use can be expected to grow in future. The findings of the multiple case study suggest that branding activities in small Finnish designintensive companies are constrained by limited resources and skills. In addition, the branding activities are strongly guided by the vision and values of the entrepreneur(s) rather than extensive marketing research. The brand structure was simple in all case companies and they aimed at having a standardised brand image across markets. However, all case companies had faced a need for some adaptation of their international brand communication. Internationally important brand communication channels were international fairs, the internet, word-of-mouth and social media. Social media offered a cost-effective brand communication channel for the case companies. It was used for various purposes, such as creating brand awareness and affecting how the brand is perceived. The entrepreneurs found the use of social media to be rather easy and the case companies had not faced any major challenges. However, the companies had recognised that communication in social media requires consistency and planning. The planning was rather informal and stayed on a general level. Overall, the utilisation of social media in the case companies was limited by a lack of resources. It seemed to affect especially the follow-up of brand communication in social media which stayed rather superficial.

Backpacker 2.0 - Contemporary backpackers and their use of social media as an information and communication platform

Long-term independent budget travel to countries far away has become increasingly common over the last few decades, and backpacking has now entered the tourism mainstream. Nowadays, backpackers are a very important segment of the global travel market. Backpacking is a type of tourism that involves a lot of information search activities. The Internet has become a major source of information as well as a platform for tourism business transactions. It allows travelers to gain information very effortlessly and to learn about tourist destinations and products directly from other travelers in the form of electronic word-of-mouth (eWOM). Social media has penetrated and changed the backpacker market, as now modern travelers can stay connected to people at home, read online recommendations, and organize and book their trips very independently. In order to create a wider understanding on modern-day backpackers and their information search and share behavior in the Web 2.0 era, this thesis examined contemporary backpackers and their use of social media as an information and communication platform. In order to achieve this goal, three sub-objectives were identified: 1. to describe contemporary backpacker tourism 2. to examine contemporary backpackers’ travel information search and share behavior 3. to explore the impacts of new information and communications technologies and Web 2.0 on backpacker tourism The empirical data was gathered with an online survey, thus the method of analysis was mainly quantitative, and a qualitative method was used for a brief analysis of open questions. The research included both descriptive and analytical approaches, as the goal was to describe modern-day backpackers, and to examine possible interdependencies between information search and share behavior and background variables. The interdependencies were tested for statistical significance with the help of five research hypotheses. The results suggested that backpackers no longer fall under the original backpacker definitions described some decades ago. Now, they are mainly short-term travelers, whose trips resemble more those of mainstream tourists. They use communication technologies very actively, and particularly social media. Traditional information sources, mainly guide books and recommendations from friends, are of great importance to them but also eWOM sources are widely used in travel decision making. The use of each source varies according to the stage of the trip. All in all, Web 2.0 and new ICTs have transformed the backpacker tourism industry in many ways. Although the experience has become less authentic in some travelers’ eyes, the backpacker culture is still recognizable.

Planning and implementation of entrepreneurial marketing processes in SMEs

Entrepreneurial marketing is newly established term and there is need for more specific studies in order to understand the concept fully. SMEs have entrepreneurial marketing elements more visible in their marketing and therefore provide more fruitful insights for this research. SMEs marketing has gained more recognition during the past years and in some cases innovative characteristics can be identified despite constraints such as lack of certain resources. The purpose of this research is to study entrepreneurial marketing characteristics and SME processes in order to wider understanding and gain more insights of entrepreneurial marketing. In addition, planning and implementation of entrepreneurial marketing processes is examined in order to gain full coverage of SMEs marketing activities. The research was conducted as a qualitative research and data gathering was based on semi-structured interview survey, which involved nine company interviews. Multiple case research was used to analyze data so that focus and clarity could be maintained in organized manner. Case companies were chosen from different business fields so that more variation and insights could be identified. The empirical results suggest that two examined processes networking and word-of-mouth communication are very important processes for case companies which supports the previous researches. However, the entrepreneurial marketing characteristics had variation some were more visible and recognizable than others. Examining more closely the processes companies did not fully understand that networking or word-of-mouth marketing could be used as efficiently as other conventional marketing methods.

Letters from the War of Ecosystems – An Analysis of Independent Software Vendors in Mobile Application Marketplaces

The recent emergence of a new generation of mobile application marketplaces has changed the business in the mobile ecosystems. The marketplaces have gathered over a million applications by hundreds of thousands of application developers and publishers. Thus, software ecosystems—consisting of developers, consumers and the orchestrator—have emerged as a part of the mobile ecosystem. This dissertation addresses the new challenges faced by mobile application developers in the new ecosystems through empirical methods. By using the theories of two-sided markets and business ecosystems as the basis, the thesis assesses monetization and value creation in the market as well as the impact of electronic Word-of-Mouth (eWOM) and developer multihoming— i. e. contributing for more than one platform—in the ecosystems. The data for the study was collected with web crawling from the three biggest marketplaces: Apple App Store, Google Play and Windows Phone Store. The dissertation consists of six individual articles. The results of the studies show a gap in monetization among the studied applications, while a majority of applications are produced by small or micro-enterprises. The study finds only weak support for the impact of eWOM on the sales of an application in the studied ecosystem. Finally, the study reveals a clear difference in the multi-homing rates between the top application developers and the rest. This has, as discussed in the thesis, an impact on the future market analyses—it seems that the smart device market can sustain several parallel application marketplaces.

Effects of lead and/or zinc exposure during the second stage of rapid postnatal brain growth on delta-aminolevulinate dehydratase and negative geotaxis of suckling rats

Lead has been shown to produce cognitive and motor deficits in young rats that could be mediated, at least in part, by inhibition of the zinc-containing heme biosynthetic enzyme delta-aminolevulinate dehydratase (ALA-D). In the present study we investigated the effects of lead and/or zinc treatment during the second stage of rapid postnatal brain development on brain, kidney and blood ALA-D specific activity, as well as the negative geotaxis behavior of rats. Eight-day-old Wistar rats were injected intraperitoneally with saline, lead acetate (8 mg/kg) and/or zinc chloride (2 mg/kg) daily for five consecutive days. Twenty-four hours after treatment, ALA-D activity was determined in the absence and presence of DL-dithiothreitol (DTT). The negative geotaxis behavior was assessed in 9- to 13-day-old rats. Treatment with lead and/or zinc did not affect body, brain or kidney weights or brain- or kidney-to-body weight ratios of the animals. In spite of the absence of effect of any treatment on ALA-D specific activity in brain, kidney and blood, the reactivation index with DTT was higher in the groups treated with lead or lead + zinc than in the control group, in brain, kidney and blood (mean ± SEM; brain: 33.33 ± 4.34, 38.90 ± 8.24, 13.67 ± 3.41; kidney: 33.50 ± 2.97, 37.60 ± 2.67, 15.80 ± 2.66; blood: 63.95 ± 3.73, 56.43 ± 5.93, 31.07 ± 4.61, respectively, N = 9-11). The negative geotaxis response behavior was not affected by lead and/or zinc treatment. The results indicate that lead and/or zinc treatment during the second stage of rapid postnatal brain growth affected ALA-D, but zinc was not sufficient to protect the enzyme from the effects of lead in brain, kidney and blood.

How to increase brand quality perception with audiovisual content? : Exploring the role of emotions in B2C and B2B contexts

This study discusses how audiovisual content can influence brand quality perceptions. The purpose of this study is to explore how audiovisual content creation can increase brand quality perceptions. This research problem is addressed with three sub questions, which aim at clarifying the role of emotions between content marketing and brand quality perception, explaining how different functions of audiovisual content can increase brand quality perception, and by identifying and comparing the key differences in content creation in business-to-consumer and business-to-businesscontexts. The theoretical background of the study is in brand personality, consumer emotions, consumerbrand relationships, content marketing and B2B branding literature. The empirical research part includes a single-case study. The case company was a Swiss startup that wished to build a highquality brand for both B2C and B2B segments. The empirical data was collected in September 2014. Eight interviews were conducted; seven with target segment representatives and one with an existing customer of the case company. The empirical findings were analyzed with thematic analysis and finally a 5-stage framework was created based on the findings of the research, offering a guideline for high-quality content creation. This study finds that emotions play an important role in brand quality perceptions. Psychological processes, emotion, cognition and conation, influence the engagement process of the target segment which ultimately can lead to activation and electronic word-of-mouth. Brand quality perception is the result of the overall emotion of the brand. The overall emotion derives from brand personality, brand concept, product attributes and utilitarian benefits of the brand. The entertaining and educational functions of the audiovisual content can target and evoke these emotional processes, and result in increased quality perceptions. In the B2B context, emotions are found to play a relatively smaller role in the quality perception processes. However, the significance of emotions cannot be ignored, since they can emphasize the value for the buying organization, and build on the trust and loyalty among the potential customers. The final framework presents five stages of content creation that ultimately improve brand quality perceptions. These stages help marketers to design and implement their content and evoke positive emotions in their target segment as part of a quality-based marketing strategy. Further research is warranted to quantitatively test the generalizability of the framework. Further research is also suggested to make the framework adaptable to different stages of the brand life cycle.

Alleviating Negative Spillover of a Brand-Harm Crisis: Sensegiving vs. Sensehiding in a Competitor’s Denial Response Strategy

A brand-harm crisis not only affects the scandalized brand, but may also influence competing brands. Thus, marketers of competing brands need to develop response strategies for reducing negative spillover effects. This research takes a competitor’s perspective and introduces two types of response strategies used to convey a sense of denial: sensegiving and sensehiding. It also investigates how the effects of response strategies are contingent upon brand relatedness and individual thinking styles. The results from three experimental studies show that using a sensegiving strategy reduces negative spillover effects more than using a sensehiding strategy. Additionally, the studies suggest that the observed difference in the effects of response strategy tends to be greater when the level of brand relatedness is high than when it is low. However, individual thinking styles (holistic vs. analytic) seem to have little impact on consumers’ responses to the two denial strategies. This research contributes to the brand-harm crisis literature and provides novel insights into a competitor’s response to potential negative spillover effects.

The voice of the consumer speaks forcefully in brand identity: user-generated content forces smart marketers to listen

User-generated content (UGC) is attracting a great deal of interest - some of it effective, some misguided. This article reviews the marketing-related factors that gave rise to UGC, tracing the relevant development of market orientation, social interaction, word of mouth, brand relationships, consumer creativity, co-creation, and customization, largely through the pages of the Journal of Advertising Research over the last 40 (or so) of its 50 years. The authors then discuss the characteristic features of UGC and how they differ from (and are similar to) these concepts. The insights thus gained will help practitioners and researchers understand what UGC is (and is not) and how it should (and should not) be used.

The negative regulation of platelet function: extending the role of the ITIM

The central role of immune-receptorlike signaling mechanisms in the activation of platelets at sites of vascular injury is well established. Of equal importance to the regulatory systems that control the activation of platelets are those systems that negatively regulate platelets and thereby prevent inappropriate platelet activation and thrombosis. Recent reports have identified a new mechanism through which this may be achieved, which involves signaling via a receptor that contains an immunoreceptor tyrosine-based inhibitory motif (ITIM). The role of ITIMs in the control of platelet function is the subject of this review.

MICAL-1 is a negative regulator of MST-NDR kinase signaling and apoptosis.

MICALs (molecules interacting with CasL) are atypical multidomain flavoenzymes with diverse cellular functions. The molecular pathways employed by MICAL proteins to exert their cellular effects remain largely uncharacterized. Via an unbiased proteomics approach, we identify MICAL-1 as a binding partner of NDR (nuclear Dbf2-related) kinases. NDR1/2 kinases are known to mediate apoptosis downstream of the mammalian Ste-20-like kinase MST1, and ablation of NDR1 in mice predisposes the mice to cancer as a result of compromised apoptosis. MST1 phosphorylates NDR1/2 kinases at their hydrophobic motif, thereby facilitating full NDR kinase activity and function. However, if and how this key phosphorylation event is regulated are unknown. Here we show that MICAL-1 interacts with the hydrophobic motif of NDR1/2 and that overexpression or knockdown of MICAL-1 reduces or augments NDR kinase activation or activity, respectively. Surprisingly, MICAL-1 is a phosphoprotein but not an NDR or MST1 substrate. Rather, MICAL-1 competes with MST1 for NDR binding and thereby antagonizes MST1-induced NDR activation. In line with this inhibitory effect, overexpression or knockdown of MICAL-1 inhibits or enhances, respectively, NDR-dependent proapoptotic signaling induced by extrinsic stimuli. Our findings unveil a previously unknown biological role for MICAL-1 in apoptosis and define a novel negative regulatory mechanism of MST-NDR signaling.

A word of caution on calculating market-based minimum capital risk requirements

This paper demonstrates that the use of GARCH-type models for the calculation of minimum capital risk requirements (MCRRs) may lead to the production of inaccurate and therefore inefficient capital requirements. We show that this inaccuracy stems from the fact that GARCH models typically overstate the degree of persistence in return volatility. A simple modification to the model is found to improve the accuracy of MCRR estimates in both back- and out-of-sample tests. Given that internal risk management models are currently in widespread usage in some parts of the world (most notably the USA), and will soon be permitted for EC banks and investment firms, we believe that our paper should serve as a valuable caution to risk management practitioners who are using, or intend to use this popular class of models.

The efficacy of shopping value in predicting destination loyalty

Recognizing the importance of tourism's experiential aspects, this research examines how hedonic and utilitarian values relate to tourist's overall shopping experience satisfaction and destination loyalty. Study findings suggest both hedonic and utilitarian shopping values are strongly linked to overall shopping satisfaction. Overall shopping satisfaction fully mediates utilitarian shopping value's effect on destination repatronage intention (DRI), destination word-of-mouth (DWoM), and partially mediates hedonic shopping value's (HSV) effect on DRI and DWoM. Study results advance consumer behavior theory and offer managerial implications for retailers operating in a rapidly maturing tourism destination in Turkey's Mediterranean region.