Patents, Ethics and Stem Cell Research : The Case of hESC Innovation in Australia, Europe and the United States

Embryonic stem cells offer potentially a ground-breaking insight into health and diseases and are said to offer hope in discovering cures for many ailments unimaginable few years ago. Human embryonic stem cells are undifferentiated, immature cells that possess an amazing ability to develop into almost any body cell such as heart muscle, bone, nerve and blood cells and possibly even organs in due course. This remarkable feature, enabling embryonic stem cells to proliferate indefinitely in vitro (in a test tube), has branded them as a so-called miracle cure . Their potential use in clinical applications provides hope to many sufferers of debilitating and fatal medical conditions. However, the emergence of stem cell research has resulted in intense debates about its promises and dangers. On the one hand, advocates hail its potential, ranging from alleviating and even curing fatal and debilitating diseases such as Parkinson s, diabetes, heart ailments and so forth. On the other hand, opponents decry its dangers, drawing attention to the inherent risks of human embryo destruction, cloning for research purposes and reproductive cloning eventually. Lately, however, the policy battles surrounding human embryonic stem cell innovation have shifted from being a controversial research to scuffles within intellectual property rights. In fact, the ability to obtain patents represents a pivotal factor in the economic success or failure of this new biotechnology. Although, stem cell patents tend to more or less satisfy the standard patentability requirements, they also raise serious ethical and moral questions about the meaning of the exclusions on ethical or moral grounds as found in European and to an extent American and Australian patent laws. At present there is a sort of a calamity over human embryonic stem cell patents in Europe and to an extent in Australia and the United States. This in turn has created a sense of urgency to engage all relevant parties in the discourse on how best to approach patenting of this new form of scientific innovation. In essence, this should become a highly favoured patenting priority. To the contrary, stem cell innovation and its reliance on patent protection risk turmoil, uncertainty, confusion and even a halt on not only stem cell research but also further emerging biotechnology research and development. The patent system is premised upon the fundamental principle of balance which ought to ensure that the temporary monopoly awarded to the inventor equals that of the social benefit provided by the disclosure of the invention. Ensuring and maintaining this balance within the patent system when patenting human embryonic stem cells is of crucial contemporary relevance. Yet, the patenting of human embryonic stem cells raises some fundamental moral, social and legal questions. Overall, the present approach of patenting human embryonic stem cell related inventions is unsatisfactory and ineffective. This draws attention to a specific question which provides for a conceptual framework for this work. That question is the following: how can the investigated patent offices successfully deal with patentability of human embryonic stem cells? This in turn points at the thorny issue of application of the morality clause in this field. In particular, the interpretation of the exclusions on ethical or moral grounds as found in Australian, American and European legislative and judicial precedents. The Thesis seeks to compare laws and legal practices surrounding patentability of human embryonic stem cells in Australia and the United States with that of Europe. By using Europe as the primary case study for lessons and guidance, the central goal of the Thesis then becomes the determination of the type of solutions available to Europe with prospects to apply such to Australia and the United States. The Dissertation purports to define the ethical implications that arise with patenting human embryonic stem cells and intends to offer resolutions to the key ethical dilemmas surrounding patentability of human embryonic stem cells and other morally controversial biotechnology inventions. In particular, the Thesis goal is to propose a functional framework that may be used as a benchmark for an informed discussion on the solution to resolving ethical and legal tensions that come with patentability of human embryonic stem cells in Australian, American and European patent worlds. Key research questions that arise from these objectives and which continuously thread throughout the monograph are: 1. How do common law countries such as Australia and the United States approach and deal with patentability of human embryonic stem cells in their jurisdictions? These practices are then compared to the situation in Europe as represented by the United Kingdom (first two chapters), the Court of Justice of the European Union and the European Patent Office decisions (Chapter 3 onwards) in order to obtain a full picture of the present patenting procedures on the European soil. 2. How are ethical and moral considerations taken into account at patent offices investigated when assessing patentability of human embryonic stem cell related inventions? In order to assess this part, the Thesis evaluates how ethical issues that arise with patent applications are dealt with by: a) Legislative history of the modern patent system from its inception in 15th Century England to present day patent laws. b) Australian, American and European patent offices presently and in the past, including other relevant legal precedents on the subject matter. c) Normative ethical theories. d) The notion of human dignity used as the lowest common denominator for the interpretation of the European morality clause. 3. Given the existence of the morality clause in form of Article 6(1) of the Directive 98/44/EC of the European Parliament and of the Council of 6 July 1998 on the legal protection of biotechnological inventions which corresponds to Article 53(a) European Patent Convention, a special emphasis is put on Europe as a guiding principle for Australia and the United States. Any room for improvement of the European morality clause and Europe s current manner of evaluating ethical tensions surrounding human embryonic stem cell inventions is examined. 4. A summary of options (as represented by Australia, the United States and Europe) available as a basis for the optimal examination procedure of human embryonic stem cell inventions is depicted, whereas the best of such alternatives is deduced in order to create a benchmark framework. This framework is then utilised on and promoted as a tool to assist Europe (as represented by the European Patent Office) in examining human embryonic stem cell patent applications. This method suggests a possibility of implementing an institution solution. 5. Ultimately, a question of whether such reformed European patent system can be used as a founding stone for a potential patent reform in Australia and the United States when examining human embryonic stem cells or other morally controversial inventions is surveyed. The author wishes to emphasise that the guiding thought while carrying out this work is to convey the significance of identifying, analysing and clarifying the ethical tensions surrounding patenting human embryonic stem cells and ultimately present a solution that adequately assesses patentability of human embryonic stem cell inventions and related biotechnologies. In answering the key questions above, the Thesis strives to contribute to the broader stem cell debate about how and to which extent ethical and social positions should be integrated into the patenting procedure in pluralistic and morally divided democracies of Europe and subsequently Australia and the United States.

Functional expression and subcellular localization of the Cl- cotransporters KCC2 and NKCC1 in rodent hippocampal and neocortical neurons

The work presented here has focused on the role of cation-chloride cotransporters (CCCs) in (1) the regulation of intracellular chloride concentration within postsynaptic neurons and (2) on the consequent effects on the actions of the neurotransmitter gamma-aminobutyric acid (GABA) mediated by GABAA receptors (GABAARs) during development and in pathophysiological conditions such as epilepsy. In addition, (3) we found that a member of the CCC family, the K-Cl cotransporter isoform 2 (KCC2), has a structural role in the development of dendritic spines during the differentiation of pyramidal neurons. Despite the large number of publications dedicated to regulation of intracellular Cl-, our understanding of the underlying mechanisms is not complete. Experiments on GABA actions under resting steady-state have shown that the effect of GABA shifts from depolarizing to hyperpolarizing during maturation of cortical neurons. However, it remains unclear, whether conclusions from these steady-state measurements can be extrapolated to the highly dynamic situation within an intact and active neuronal network. Indeed, GABAergic signaling in active neuronal networks results in a continuous Cl- load, which must be constantly removed by efficient Cl- extrusion mechanisms. Therefore, it seems plausible to suggest that key parameters are the efficacy and subcellular distribution of Cl- transporters rather than the polarity of steady-state GABA actions. A further related question is: what are the mechanisms of Cl- regulation and homeostasis during pathophysiological conditions such as epilepsy in adults and neonates? Here I present results that were obtained by means of a newly developed method of measurements of the efficacy of a K-Cl cotransport. In Study I, the developmental profile of KCC2 functionality during development was analyzed both in dissociated neuronal cultures and in acute hippocampal slices. A novel method of photolysis of caged GABA in combination with Cl- loading to the somata was used in this study to assess the extrusion efficacy of KCC2. We demonstrated that these two preparations exhibit a different temporal profile of functional KCC2 upregulation. In Study II, we reported an observation of highly distorted dendritic spines in neurons cultured from KCC2-/- embryos. During their development in the culture dish, KCC2-lacking neurons failed to develop mature, mushroom-shaped dendritic spines but instead maintained an immature phenotype of long, branching and extremely motile protrusions. It was shown that the role of KCC2 in spine maturation is not based on its transport activity, but is mediated by interactions with cytoskeletal proteins. Another important player in Cl- regulation, NKCC1 and its role in the induction and maintenance of native Cl- gradients between the axon initial segment (AIS) and soma was the subject of Study III. There we demonstrated that this transporter mediates accumulation of Cl- in the axon initial segment of neocortical and hippocampal principal neurons. The results suggest that the reversal potential of the GABAA response triggered by distinct populations of interneurons show large subcellular variations. Finally, a novel mechanism of fast post-translational upregulation of the membrane-inserted, functionally active KCC2 pool during in-vivo neonatal seizures and epileptiform-like activity in vitro was identified and characterized in Study IV. The seizure-induced KCC2 upregulation may act as an intrinsic antiepileptogenic mechanism.

Language universals and linguistic complexity : Three case studies in core argument marking

In this dissertation I study language complexity from a typological perspective. Since the structuralist era, it has been assumed that local complexity differences in languages are balanced out in cross-linguistic comparisons and that complexity is not affected by the geopolitical or sociocultural aspects of the speech community. However, these assumptions have seldom been studied systematically from a typological point of view. My objective is to define complexity so that it is possible to compare it across languages and to approach its variation with the methods of quantitative typology. My main empirical research questions are: i) does language complexity vary in any systematic way in local domains, and ii) can language complexity be affected by the geographical or social environment? These questions are studied in three articles, whose findings are summarized in the introduction to the dissertation. In order to enable cross-language comparison, I measure complexity as the description length of the regularities in an entity; I separate it from difficulty, focus on local instead of global complexity, and break it up into different types. This approach helps avoid the problems that plagued earlier metrics of language complexity. My approach to grammar is functional-typological in nature, and the theoretical framework is basic linguistic theory. I delimit the empirical research functionally to the marking of core arguments (the basic participants in the sentence). I assess the distributions of complexity in this domain with multifactorial statistical methods and use different sampling strategies, implementing, for instance, the Greenbergian view of universals as diachronic laws of type preference. My data come from large and balanced samples (up to approximately 850 languages), drawn mainly from reference grammars. The results suggest that various significant trends occur in the marking of core arguments in regard to complexity and that complexity in this domain correlates with population size. These results provide evidence that linguistic patterns interact among themselves in terms of complexity, that language structure adapts to the social environment, and that there may be cognitive mechanisms that limit complexity locally. My approach to complexity and language universals can therefore be successfully applied to empirical data and may serve as a model for further research in these areas.

Notions of Nation : A Critical Discursive Psychology perspective on the Isle of Man

At the the heart of this study can be seen the dual concern of how the nation is represented as a categorical entity and how this is put to use in everyday social interactions.This can be seen as a reaction to the general approach to categorisation and identity functions that tend to be reified and essentialized within the social sciences. The empirical focus of this study is the Isle of Man, a crown dependency situated geographically central within the British Isles while remaining political outside the United Kingdom. The choice of this site was chosen explicitly as ‘notions of nation’ expressed on the island can be seen as being contested and ephemerally unstable. To get at these ‘notions of nation’ is was necessary to choose specific theoretical tools that were able to capture the wider cultural and representational domain while being capable of addressing the nuanced and functional aspects of interaction. As such, the main theoretical perspective used within this study was that of critical discursive psychology which incorporates the specific theoretical tools interpretative repertoires, ideological dilemmas and subject positions. To supplement these tools, a discursive approach to place was taken in tandem to address the form and function of place attached to nationhood. Two methods of data collection were utilized, that of computer mediated communication and acquaintance interviews. From the data a number of interpretative repertoires were proposed, namely being, essential rights, economic worth, heritage claims, conflict orientation, people-as-nation and place-as-nation. Attached to such interpretative repertoires were the ideological dilemmas region vs. country, people vs. place and individualism vs. collectivism. The subject positions found are much more difficult to condense, but the most significant ones were gender, age and parentage. The final focus of the study, that of place, was shown to be more than just an unreflected on ‘container’ of people but was significant in terms of the rhetorical construction of such places for how people saw themselves and the discursive function of the particular interaction. As such, certain forms of place construction included size, community, temporal, economic, safety, political and recognition. A number of conclusions were drawn from the above which included, that when looking at nation categories we should take into account the specific meanings that people attach to such concepts and to be aware of the particular uses they are put to in interaction. Also, that it is impossible to separate concepts neatly, but it is necessary to be aware of the intersection where concepts cross, and clash, when looking at nationhood.

Functional outcome and health-related quality of life after traumatic brain injury in the framework of the International Classification of Functioning, Disability and Health (ICF)

Traumatic brain injury (TBI) affects people of all ages and is a cause of long-term disability. In recent years, the epidemiological patterns of TBI have been changing. TBI is a heterogeneous disorder with different forms of presentation and highly individual outcome regarding functioning and health-related quality of life (HRQoL). The meaning of disability differs from person to person based on the individual s personality, value system, past experience, and the purpose he or she sees in life. Understanding of all these viewpoints is needed in comprehensive rehabilitation. This study examines the epidemiology of TBI in Finland as well as functioning and HRQoL after TBI, and compares the subjective and objective assessments of outcome. The frame of reference is the International Classification of Functioning, Disability and Health (ICF). The subjects of Study I represent the population of Finnish TBI patients who experienced their first TBI between 1991 and 2005. The 55 Finnish subjects of Studies II and IV participated in the first wave of the international Quality of life after brain injury (QOLIBRI) validation study. The 795 subjects from six language areas of Study III formed the second wave of the QOLIBRI validation study. The average annual incidence of Finnish hospitalised TBI patients during the years 1991-2005 was 101:100 000 in patients who had TBI as the primary diagnosis and did not have a previous TBI in their medical history. Males (59.2%) were at considerably higher risk of getting a TBI than females. The most common external cause of the injury was falls in all age groups. The number of TBI patients ≥ 70 years of age increased by 59.4% while the number of inhabitants older than 70 years increased by 30.3% in the population of Finland during the same time period. The functioning of a sample of 55 persons with TBI was assessed by extracting information from the patients medical documents using the ICF checklist. The most common problems were found in the ICF components of Body Functions (b) and Activities and Participation (d). HRQoL was assessed with the QOLIBRI which showed the highest level of satisfaction on the Emotions, Physical Problems and Daily Life and Autonomy scales. The highest scores were obtained by the youngest participants and participants living independently without the help of other people, and by people who were working. The relationship between the functional outcome and HRQoL was not straightforward. The procedure of linking the QOLIBRI and the GOSE to the ICF showed that these two outcome measures cover the relevant domains of TBI patients functioning. The QOLIBRI provides the patients subjective view, while the GOSE summarises the objective elements of functioning. Our study indicates that there are certain domains of functioning that are not traditionally sufficiently documented but are important for the HRQoL of persons with TBI. This was the finding especially in the domains of interpersonal relationships, social and leisure activities, self, and the environment. Rehabilitation aims to optimize functioning and to minimize the experience of disability among people with health conditions, and it needs to be based on a comprehensive understanding of human functioning. As an integrative model, the ICF may serve as a frame of reference in achieving such an understanding.

Constructing and negotiating entrepreneurial agency : A social psychological approach to entrepreneurship discourse in the farm context

Entrepreneurship, understood as the autonomous, effective pursuit of opportunities regardless of resources, is currently subject to a multitude of interests, expectations, and facilitation efforts. On the one hand, such entrepreneurial agency has broad appeal to individuals in Western market democracies and resonates with their longing for an autonomous, personally tailored, meaningful, and materially rewarding way of life. On the other hand, entrepreneurship represents a tempting and increasingly popular means of governance and policy making, and thus a model for the re-organization of a variety of societal sectors. This study focuses on the diffusion and reception of entrepreneurship discourse in the context of farming and agriculture, where pressures to adopt entrepreneurial orientations have been increasingly pronounced while, on the other hand, the context of farming has historically enjoyed state protection and adhered to principles that seem at odds with aspects of individualistic entrepreneurship discourse . The study presents an interpretation of the psychologically and politically appealing uses of the notion of entrepreneurial agency , reviews the historical and political background of the current situation of farming and agriculture with regard to entrepreneurship, and examines their relationships in four empirical studies. The study follows and develops a social psychological, situated relational approach that guides the qualitative analyses and interpretations of the empirical studies. Interviews with agents from the farm sector aim to stimulate evaluative responses and comments on the idea of entrepreneurship on farms. Analysis of the interview talk, in turn, detects the variety of evaluative responses and argumentative contexts with which the interviewees relate themselves to the entrepreneurship discourse and adopt, use, resist, or reject it. The study shows that despite the pressures towards entrepreneurialism, the diffusion of entrepreneurship discourse and the construction of entrepreneurial agency in farm context encounter many obstacles. These obstacles can be variably related to aspects dealing with the individual agent, the action situation, the characteristics of the action itself, or to the broader social, institutional and cultural context. Many aspects of entrepreneurial agency, such as autonomy, personal initiative and achievement orientation, are nevertheless familiar to farmers and are eagerly related to one s own farming activities. The idea of entrepreneurship is thus rarely rejected outright. The findings highlight the relational and situational preconditions for the construction of entrepreneurial agency in the farm context: When agents demonstrate entrepreneurial agency, they do so by drawing on available and accessed relational resources characteristic of their action context. Likewise, when agents fail or are reluctant to demonstrate entrepreneurial agency, they nevertheless actively account for their situation and demonstrate personal agency by drawing on the relational resources available to them.

From ‘Afflicted’ to Activists: Structural Violence and Climate Change Discourse in the States of Pernambuco and Paraíba in Northeast Brazil

This study approaches the problem of poverty in the hinterlands of Northeast Brazil through the concept of structural violence, linking the environmental threats posed by climate change, especially those related to droughts, to the broader social struggles in the region. When discussions about potentials and rights are incorporated into the problematic of poverty, a deeper insight is obtained regarding the various factors behind the phenomenon. It is generally believed that climate change is affecting the already marginalized and poor more than those of higher social standing, and will increasingly do so in the future. The data for this study was collected during a three month field work in the states of Pernambuco and Paraíba in Northeast Brazil. The main methods used were semi-structured interviews and participant observation, including attending seminars concerning climate change on the field. The focus of the work is to compare both layman and expert perceptions on what climate change is about, and question the assumptions about its effects in the future, mainly that of increased numbers of ‘climate refugees’ or people forced to migrate due to changes in climate. The focus on droughts, as opposed to other manifestations of climate change, arises from the fact that droughts are not only phenomena that develop over a longer time span than floods or hurricanes, but is also due to the historical persistence of droughts in the region, and both the institutional and cultural linkages that have evolved around it. The instances of structural violence that are highlighted in this study; the drought industry, land use, and the social and power relations present in the region, including those between the civil society, the state and the private agribusiness sector, all work against a backdrop of symbolic and moral realms of value production, where relations between the different actors are being negotiated anew with the rise of the climate change discourse. The main theoretical framework of the study consists of Johan Galtung’s and Paul Farmer’s theory of structural violence, Ulrich Beck’s theory of the risk society, and James Scott’s theory of everyday peasant resistance.

Una gramática descriptiva del chabacano de Ternate

This dissertation is a descriptive grammar of Ternate Chabacano, a Spanish-lexifier Creole spoken by 3.000 people in the town of Ternate, Philippines. The dissertation offers an analysis of the phonological, morphological, and syntactic system of the language. It includes an overview of the historical background, the current situation of the speech community and a collection of annotated texts. Ternate Chabacano shares many characteristics with its main adstrate language Tagalog as well as the dialectal varieties of Spanish. At present, English also exerts an influence, nevertheless mainly affecting its lexicon. The description offered is based on fieldwork conducted in Ternate. Spoken language collected through thematic interviews forms the main type of the material analysed. Information regarding the informants and text types is included in the examples. Ternate Chabacano has a five-vowel system and 17 consonant phonemes. The morphology of the language is largely isolating. Clitics are used extensively for expressing adverbial relations. The verbal system is based on the preverbal markers that express the category of tense, modality and aspect, among which aspect is the main dimension. Complex predicates and verbal chains are used in order to further distinguish aspect and modality, as well as changes of voice and valency. Intransitive verbs express motion, states, and reflexive actions, even though the majority of verbs can occur in both intransitive and transitive clauses. Ternate Chabacano is a nominative-accusative type language but the typological configuration of the Philippine languages influences the marking of its constituents. A case in point is constituted by the nominal determination system. The basic constituent order in a clause is VSO. Equative and attibutive clauses are formed by juxtaposition while the locative clauses feature a copula. Indefinite terms are expressed through existential constructions. The negation of existential clauses differs from standard negation but both are intensified in the same way. In spoken discourse, tag-questions are common. Pragmatic elements and social formulas reflect largely the corresponding Tagalog expressions. Coordination and subordination occur typically without overt markers but a variety of markers exists for expressing different relations, especially those made explicit by adverbial clauses. Verbal chains form a continuum from serial verbs to complementation and ultimately to coordination.

Cohésion modale et subordination : Le conditionnel et le jussif finnois au miroir de la valeur sémantique et discursive du subjonctif français

Modal cohesion and subordination. The Finnish conditional and jussive moods in comparison to the French subjunctive This study examines verb moods in subordinate clauses in French and Finnish. The first part of the analysis deals with the syntax and semantics of the French subjunctive, mood occurring mostly in subordinate positions. The second part investigates Finnish verb moods. Although subordinate positions in Finnish grammar have no special finite verb form, certain uses of Finnish verb moods have been compared to those of subjunctives and conjunctives in other languages. The present study focuses on the subordinate uses of the Finnish conditional and jussive (i.e. the third person singular and plural of the imperative mood). The third part of the analysis discusses the functions of subordinate moods in contexts beyond complex sentences. The data used for the analysis include 1834 complex sentences gathered from newspapers, online discussion groups and blog texts, as well as audio-recorded interviews and conversations. The data thus consist of both written and oral texts as well as standard and non-standard variants. The analysis shows that the French subjunctive codes theoretical modality. The subjunctive does not determine the temporal and modal meaning of the event, but displays the event as virtual. In a complex sentence, the main clause determines the temporal and modal space within which the event coded by the subjunctive clause is interpreted. The subjunctive explicitly indicates that the space constructed in the main clause extends its scope over the subordinate clause. The subjunctive can therefore serve as a means for creating modal cohesion in the discourse. The Finnish conditional shares the function of making explicit the modal link between the components of a complex construction with the French subjunctive, but the two moods differ in their semantics. The conditional codes future time and can therefore occur only in non-factual or counterfactual contexts, whereas the event expressed by French subjunctive clauses can also be interpreted as realized. Such is the case when, for instance, generic and habitual meaning is involved. The Finnish jussive mood is used in a relatively limited number of subordinate clause types, but in these contexts its modal meaning is strikingly close to that of the French subjunctive. The permissive meaning, typical of the jussive in main clause positions, is modified in complex sentences so that it entails inter-clausal relation, namely concession. Like the French subjunctive, the jussive codes theoretical modal meaning with no implication of the truth value of the proposition. Finally, the analysis shows that verb moods mark modal cohesion, not only on the syntagmatic level (namely in complexe sentences), but also on the paradigmatic axis of discourse in order to create semantic links over entire segments of talk. In this study, the subjunctive thus appears, not as an empty category without function, as it is sometimes described, but as an open form that conveys the temporal and modal meanings emerging from the context.

Functional regulation of the Neurofibromatosis 2 tumor suppressor merlin

Neurofibromatosis 2 (NF2) is an autosomal dominant disorder manifested by the formation of multiple benign tumors of the nervous system. Affected individuals typically develop bilateral vestibular schwannomas which lead to deafness and balance disorders. The syndrome is caused by inactivation of the NF2 tumor suppressor gene, and mutation or loss of the NF2 product, merlin, is sufficient for tumorigenesis in both hereditary and sporadic NF2-associated tumors. Merlin belongs to the band 4.1 superfamily of cytoskeletal proteins, which also contain the related ezrin, radixin, and moesin (ERM) proteins. The ERM members provide a link between the cell cytoskeleton and membrane by connecting membrane-associated proteins to actin filaments. By stabilizing complexes in the cell cortex, the ERMs modulate morphology, growth, and migration of cells. Despite their structural homology, overlapping subcellular distribution, direct molecular association, and partial overlap of molecular interactions, merlin and ezrin exert opposite effects on cell proliferation. Merlin suppresses cell proliferation, whereas ezrin expression is linked to oncogenic activity. We hypothesized that the regions which differ between the proteins might explain merlin s specificity as a tumor suppressor. We therefore analyzed the regions, which are most diverse between merlin and ezrin; the N-terminal tail and the C-terminus. To determine the properties of the C-terminal region, we studied the two most predominant merlin isoforms together with truncation variants similar to those found in patients. We also focused on the evolutionally conserved C-terminal residues, E545-E547, that harbor disease causing mutations in its corresponding DNA sequence. In addition to inhibiting cell proliferation, merlin regulates cytoskeletal organization. The morphogenic properties of merlin may play a role in tumor suppression, since patient-derived tumor cells demonstrate cytoskeletal abnormalities. We analyzed the mechanisms of merlin-induced extension formation and determined that the C-terminal region of amino acids 538-568 is particularly important for the morphogenic activity. We also characterized the role of C-terminal merlin residues in the regulation of proliferation, phosphorylation, and intramolecular associations. In contrast to previous reports, we demonstrated that both merlin isoforms are able to suppress cell proliferation, whereas C-terminally mutated merlin constructs showed reduced growth inhibition. Phosphorylation serves as a mechanism to regulate the tumor suppressive activity of merlin. The C-terminal serine 518 is phosphorylated in response to both p21-activated kinase (PAK) and protein kinase A (PKA), which inactivates the growth inhibitory function of merlin. However, at least three differentially phosphorylated forms of the protein exist. In this study we demonstrated that also the N-terminus of merlin is phosphorylated by AGC kinases, and that both PKA and Akt phosphorylate merlin at serine 10 (S10). We evaluated the impact of this N-terminal tail phosphorylation, and showed that the phosphorylation state of S10 is an important regulator of merlin s ability to modulate cytoskeletal organization but also regulates the stability of the protein. In summary, this study describes the functional effect of merlin specific regions. We demonstrate that both S10 in the N-terminal tail and residues E545-E547 in the C-terminus are essential for merlin activity and function.

An Efficient Constraint Grammar Parser based on Inward Deterministic Automata

Pappret conceptualizes parsning med Constraint Grammar på ett nytt sätt som en process med två viktiga representationer. En representation innehåller lokala tvetydighet och den andra sammanfattar egenskaperna hos den lokala tvetydighet klasser. Båda representationer manipuleras med ren finite-state metoder, men deras samtrafik är en ad hoc -tillämpning av rationella potensserier. Den nya tolkningen av parsning systemet har flera praktiska fördelar, bland annat det inåt deterministiska sättet att beräkna, representera och räkna om alla potentiella tillämpningar av reglerna i meningen.

Interruption and Uncooperativeness in Academic ELF Group Work : An Application of Linear Unit Grammar

This study addresses the challenge of analyzing interruption in spoken interaction. It begins with my observation of eight hours of academic group work among speakers of English as a lingua franca (ELF) in a university course. Unlike the common findings of ELF research which underscore the cooperative orientation of ELF users, this particular group gave strong impressions of interruption and uncooperativeness as they prepared a scientific group presentation. In the effort to investigate these impressions, I found that no satisfactory method exists for systematically identifying and analyzing interruptions. A useful tool was found in Linear Unit Grammar or LUG (Sinclair & Mauranen 2006), which analyzes spoken interaction prospectively as linear text. In the course of transcribing one of the early group work meetings, I developed a model of LUG-based criteria for identifying individual instances of interruption. With this system in place, I was then able to evaluate the aggregate occurrences of interruption in the group work and identify co-occurring interactive features which further influenced the perception of uncooperativeness. Finally, these aggregate statistics directed a return to the data and a contextually sensitive, qualitative analysis. This research cycle illuminates the interactive features which contributed to my own impressions of uncooperativeness, as well as the group members orientations to their own interruptive practice.

Designing a Dependency Representation and Grammar Definition Corpus for Finnish

We outline the design and creation of a syntactically and morphologically annotated corpora of Finnish for use by the research community. We motivate a definitional, systematic “grammar definition corpus” as a first step in an three-year annotation effort to help create higher-quality, better-documented extensive parsebanks at a later stage. The syntactic representation, consisting of a dependency structure and a basic set of dependency functions, is outlined with examples. Reference is made to double-blind annotation experiments to measure the applicability of the newgrammar definition corpus methodology.