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.

Sivistyksestä sivilisaatioon. Kulttuurikäsitys J. V. Snellmanin historiallisessa ajattelussa

From Bildung to Civilisation. Conception of Culture in J. V. Snellman’s Historical Thinking The research explores Johan Vilhelm Snellman’s (1806–1881) conception of culture in the context of his historical thinking. Snellman was a Finnish, Swedish-speaking journalist, teacher and thinker, who held a central position in the Finnish national discourse during the nineteenth century. He has been considered as one of the leading theorists of a Finnish nation, writing widely about the themes such as the advancement of the national education, Finnish language and culture. Snellman is already a widely studied person in Finnish intellectual history, often characterised as a follower of G. W. F. Hegel’s philosophical system. My own research introduces a new kind of approach on Snellman’s texts, emphasising the conceptual level of his thought. With this approach, my aim is to broaden the Finnish research tradition on conceptual history. I consider my study as a cultural history of concepts, belonging also to the field of intellectual history. My focus is on one hand on the close reading of Snellman’s texts and on the other hand on contextualising his texts to the European intellectual tradition of the time. A key concept of Snellman’s theoretical thinking is his concept of bildning, which can be considered as a Swedish counterpart of the German concept of Bildung. The Swedish word incorporated all the main elements of the German concept. It could mean education or the so-called high culture, but most fundamentally it was about the self-formation of the individual. This is also the context in which Snellman’s concept of bildning has often been interpreted. In the study, I use the concept of bildning as a starting point of my research but I broaden my focus on the cognate concepts such as culture (kultur), spirit (anda) and civilisation. The purpose of my study is thus to illustrate how Snellman used and modified these concepts and from these observations to draw a conclusion about the nature of his conception of culture. Snellman was an early Finnish philosopher of history but also interested in the practice of the writing of history. He did not write any historical presentations himself but followed the publications in the field of history and introduced European historical writing to the Finnish, Swedish-speaking reading audience in his newspapers. The primary source material consists of different types of Snellman’s texts, including philosophical writings, lecture material, newspaper articles and private letters. I’m reading Snellman’s texts in the context of other texts produced both by his Finnish predecessors and contemporaries and by Swedish, German and French writers. Snellman’s principal philosophical works, Versuch einer spekulativen Entwicklung der Idee der Persönlichkeit (1841) and Läran om staten (1842), were both written abroad. Both of the works were contributions to contemporary debates on the international level, especially in Germany and Sweden. During the 1840s and 1850s Snellman had two newspapers of his own, Saima and Litteraturblad, which were directed towards the Swedish-speaking educated class. Both of the newspapers were very popular and their circulations were among the largest of their day in Finland. The topics of his articles and reviews covered literature, poetry, philosophy and education as well as issues concerning the economic, industrial and technical development in Finland. In his newspapers Snellman not only brought forth his own ideas but also spread the knowledge of European events and ideas to his readers. He followed very carefully the cultural and political situation in Western Europe. He also followed European magazines and newspapers and was well acquainted with German, French and also English literature – and of course Swedish literature to with which he had the closest ties. In his newspapers Snellman wrote countless number of literary reviews and critics, introducing his readers to European literature. The study consists of three main chapters in which I explore my research question in three different, yet overlapping contexts. In the first of these chapters, I analyse Snellman’n theoretical thinking and his concepts of bildning, kultur, anda and civilisation in the context of earlier cultural discourse in Finland as well as the tradition of German idealistic philosophy and neo-humanism. With the Finnish cultural discourse I refer to the early cultural discussion in Finland, which emerged after the year 1809, when Finland became an autonomous entity of its own as a Grand Duchy of Russia. Scholars of the Academy of Turku opened a discussion on the themes such as the state of national consciousness, the need for national education and the development of the Finnish language as a national language of Finland. Many of these academics were also Snellman’s teachers in the early years of his academic career and Snellman clearly formulated his own ideas in the footsteps of these Finnish predecessors. In his theoretical thinking Snellman was a collectivist; according to him an individual should always be understood in connection with the society, its values and manners, as well as to the traditions of a culture where an individual belongs to. In his philosophy of the human spirit Snellman was in many ways a Hegelian but his notion of education or ‘bildning’ includes also elements that connect him with the wider tradition of German intellectual history, namely the neo-humanist tradition and, at least to some extent, to the terminology of J. G. Herder or J. G. Fichte, for example. In this chapter, I also explore Snellman’s theory of history. In his historical thinking Snellman was an idealist, believing in the historical development of the human spirit (Geist in German language). One can characterise his theory of history by stating that it is a mixture of a Hegelian triumph of the spirit and Herderian emphasis on humanity (Humanität) and the relative nature of ‘Bildung’. For Snellman, the process of ‘bildning’ or ‘Bildung’ is being realised in historical development through the actions of human beings. Snellman believed in the historical development of the human civilization. Still Snellman himself considered that he had abandoned Hegel’s idea about the process of world history. Snellman – rightly or wrongly – criticised Hegel of emphasising the universal end of history (the realisation of the freedom of spirit) at the expense of the historical plurality and the freedom of each historical era. Snellman accused Hegel of neglecting the value and independency of different historical cultures and periods by imposing the abstract norm, the fulfilment of the freedom of spirit, as the ultimate goal of history. The historicist in Snellman believed in the individuality of each historical period; each historical era or culture had values, traditions and modes of thought of its own. This historicist in Snellman could not accept the talk about one measure or the end of history. On the other hand Snellman was also a universalist. He believed that mankind had a common task and that task was the development of ‘Bildung’, freedom or humanity. The second main chapter consists of two parts. In the first part, I explore the Finnish nationalistic discourse from the cultural point of view by analysing the notions such as a nation, national spirit or national language and showing how Snellman formulated his own ideas in a dialogic situation, participating in the Finnish discourse but also reacting to international discussions on the themes of the nation and nationality. For Snellman nationality was to a great extent the collective knowledge and customs or practices of the nation. Snellman stated that nationality is to be considered as a form of ‘bildning’. This could be seen not simply as affection for the fatherland but also for the mental identity of the nation, its ways of thinking, its practices, national language, customs and laws, the history of the nation. The simplest definition of nationality that Snellman gives is that nationality is the social life of the people. In the second part of the chapter I exam Snellman’s historical thinking and his understanding about historical development, interaction between different nations and cultures in the course of history, as well as the question of historical change; how do cultures or civilisations develop and who are the creators of culture? Snellman did not believe in one dominating culture but understood the course of history as a dialogue between different cultures. On the other hand, his views are very Eurocentric – here he follows the ideas of Hegel or for example the French historian François Guizot – for Snellman Europe represented the virtue of pluralism; in Europe one could see the diversity of cultures which, on the other hand, were fundamentally based on a common Christian tradition. In the third main chapter, my focus is on the writing of history, more precisely on Snellman’s ideas on the nature of history as a science and on the proper way of writing historical presentations. Snellman wrote critics on the works of history and introduced his readers to the writing of history especially in France, Sweden and German-speaking area – in some extend also in Britain. Snellman’s collectivistic view becomes evident also in his reviews on historical writing. For Snellman history was not about the actions of the states and their heads, nor about the records of ruling families and battles fought. He repeatedly stressed that history is a discipline that seeks to provide a total view of a phenomenon. A historian should not only collect information on historical events, since this information touches only the surface of a certain epoch or civilisation; he has to understand an epoch as totality. This required an understanding about the major contours in history, connections between civilisations and an awareness of significant turning points in historical development. In addition, it required a holistic understanding about a certain culture or historical era, including also the so-called inner life of a specific nation, a common people and their ways of life. Snellman wrote explicitly about ‘cultural history’ in his texts, referring to this kind of broad understanding of a society. In historical writing Snellman found this kind of broader view from the works of the French historians such as François Guizot and Jules Michelet. In all of these chapters, I elaborate the conceptual dimension of Snellman’s historical thinking. In my study I argue that Snellman not only adopted the German concepts of Bildung or Kultur in his own thinking but also developed the Swedish concepts in a way that include personal and innovative aspects. Snellman’s concept of bildning is not only a translation from ‘Bildung’ but he uses the Swedish concept in a versatile way that includes both the moral aspect of human development and social dimension of a human life. Along with ‘bildning’ Snellman used also the terms ‘kultur’ and ‘civilisation’ when referring to the totality of a certain nation or historical era, including both the so-called high culture (arts, science, religion) and the modes of thought as well as ways of life of the people as a whole. Unlike many of his Finnish contemporaries, Snellman did not use civilisation as a negative concept, lacking the moral essence of German term ‘Bildung’ or ‘Kultur’. Instead, for Snellman civilisation was a neutral term and here he comes close to the French tradition of using the term. In the study I argue that Snellman’s conception of culture in fact includes a synthesis of the German tradition of ‘Bildung’ and the French tradition of ‘civilisation’.

Negative refractive index materials and propagation

Negative refractive index materials and propagation of electromagnetic waves in them started to draw attention of scientists not so long ago. This review highlights historically important and recent papers on practical and theoretical aspects related to these issues. Namely, basic properties and peculiarities of such materials related to both their design and wave propagation in them, experimental verification of predictions theoretically made for them, possible practical applications and prospects in this area are considered.

Life-related negative customer emotions in real estate agent encounters

The goal of this study was to explore how do customers’ life-related negative emotions affect real estate business. This was divided into two research questions: 1. What life-related negative emotions can be recognised in real estate customer encounters? 2. How do the recognised emotions affect customer encounters and the realtor’s work? 3. How can the realtor take the emotions into account in customer service? The theoretical background consists of two main lines of study: emotions and customer encounters. A wide literary review on emotions research was conducted from a cognitive psychology point of view, focusing on negative emotions. Emotions research was then combined into the field of customer encounters. Qualitative study was chosen as the methodological basis of the study. Empirical material of this study was collected through in-depth interviews with 13 successful Finnish real estate agents. Narrative research was used as a method for the study. Four life-related emotion categories were recognized in real estate customer encounters: sadness, anger, anxiety and shame. These emotions rose from issues varying from death of a close one to divorce and from major changes in life stages to deep emotional attachment to an old home. The study also found that these incidental negative emotions do affect customer encounters and realtors’ work. The emotions affected the decision making of customers and sometimes overshadowed reason. Some emotions made the customer passive and slow to make any decisions, while others made their decision making fast and hasty. Even though the incidental emotions might not have had anything to do with the real estate deal, they could affect the outcome of the customer encounter and the whole real estate deal. Interestingly enough, the study found that not all successful real estate agents knowingly serve customers in an emotional level. The study does, however, suggest that in fact it may be an ethical decision of the customer server to take into account the emotional state of the customer. Attending to the emotional side of customers does not only increase pleasantness of the customer encounter, but may improve and balance customer decision making and prevent hasty decisions possibly leading to improved customer satisfaction. This study also gave practical managerial implications to customer service providers on how negative incidental emotions can be attended to in a customer encounter. This study could be useful not only to real estate agents, but also in other types of customer service, especially with vulnerable populations or other types of home-related business.