Identifying Individual T Cell Receptors of Optimal Avidity for Tumor Antigens.

Cytotoxic T cells recognize, via their T cell receptors (TCRs), small antigenic peptides presented by the major histocompatibility complex (pMHC) on the surface of professional antigen-presenting cells and infected or malignant cells. The efficiency of T cell triggering critically depends on TCR binding to cognate pMHC, i.e., the TCR-pMHC structural avidity. The binding and kinetic attributes of this interaction are key parameters for protective T cell-mediated immunity, with stronger TCR-pMHC interactions conferring superior T cell activation and responsiveness than weaker ones. However, high-avidity TCRs are not always available, particularly among self/tumor antigen-specific T cells, most of which are eliminated by central and peripheral deletion mechanisms. Consequently, systematic assessment of T cell avidity can greatly help distinguishing protective from non-protective T cells. Here, we review novel strategies to assess TCR-pMHC interaction kinetics, enabling the identification of the functionally most-relevant T cells. We also discuss the significance of these technologies in determining which cells within a naturally occurring polyclonal tumor-specific T cell response would offer the best clinical benefit for use in adoptive therapies, with or without T cell engineering.

Graduating 4th year radiology residents' perception of optimal imaging modalities for neoplasm and trauma: a pilot study from four U.S. universities

OBJECTIVE: Our purpose was to assess 4th year radiology residents' perception of the optimal imaging modality to investigate neoplasm and trauma. MATERIALS AND METHODS: Twenty-seven 4th year radiology residents from four residency programs were surveyed. They were asked about the best imaging modality to evaluate the brain and spine, lungs, abdomen, and the musculoskeletal system. Imaging modalities available were MRI, CT, ultrasound, PET, and X-ray. All findings were compared to the ACR appropriateness criteria. RESULTS: MRI was chosen as the best imaging modality to evaluate brain, spine, abdominal, and musculoskeletal neoplasm in 96.3%, 100%, 70.4%, and 63% of residents, respectively. CT was chosen by 88.9% to evaluate neoplasm of the lung. Optimal imaging modality to evaluate trauma was CT for brain injuries (100%), spine (92.6%), lung (96.3%), abdomen (92.6%), and major musculoskeletal trauma (74.1%); MRI was chosen for sports injury (96.3%). There was agreement with ACR appropriateness criteria. CONCLUSION: Residents' perception of the best imaging modalities for neoplasm and trauma concurred with the appropriateness criteria by the ACR.

Unambiguous assessments of reaction paths for selected pericyclic reactions

Four commonplace concerted reactions are examined using (i) correlation diagrams, (ii) frontier molecular orbital analyses for transition states, (iii) Zimmerman-Dewar analyses for transition states and (iv) modified Zimmerman-Dewar analyses for transition states. Only the latter approach is consistently satisfactory.

Capital Structure of Finnish SMEs and Financial Constraints

This thesis studies capital structure of Finnish small and medium sized enterprises. The specific object of the study is to test whether financial constraints have an effect on capital structure. In addition influences of several other factors were studied. Capital structure determinants are formulated based on three capital structure theories. The tradeoff theory and the agency theory concentrate on the search of optimal capital structure. The pecking order theory concerns favouring on financing source over another. The data of this study consists of financial statement data and results of corporate questionnaire. Regression analysis was used to find out the effects of several determinants. Regression models were formed based on the presented theories. Short and long term debt ratios were considered separately. The metrics of financially constrained firms was included in all models. It was found that financial constrains have a negative and significant effect to short term debt ratios. The effect was negative also to long term debt ratio but not statistically significant. Other considerable factors that influenced debt ratios were fixed assets, age, profitability, single owner and sufficiency of internal financing.

In search of true friendship

The present text proposes a discussion on the concept of true friendship. The argument is grounded mostly on Aristotle's Nicomachean Ethics, Owen Flanagan's ethics as human ecology, and on contemporary authors' works about the Greek philosopher's concept of friendship. Given that human beings flourish through 1) exercising capacities, 2) being moral, and 3) having true friendships, difficulties to establish the level of trust required by true friendships turns the search itself (for them) morally valid.

In search of Lost Childhood

The article is located at the Daily Sun's editorial section's subsection "Post-Log."

In search of information systems value : a case study of the EHR benefits realisation efforts of three Swedish hospitals.

The Swedish public health care organisation could very well be undergoing its most significant change since its specialisation during the late 19th and early 20th century. At the heart of this change is a move from using manual patient journals to electronic health records (EHR). EHR are complex integrated organisational wide information systems (IS) that promise great benefits and value as well as presenting great challenges to the organisation. The Swedish public health care is not the first organisation to implement integrated IS, and by no means alone in their quest for realising the potential benefits and value that it has to offer. As organisations invest in IS they embark on a journey of value-creation and capture. A journey where a costbased approach towards their IS-investments is replaced with a value-centric focus, and where the main challenges lie in the practical day-to-day task of finding ways to intertwine technology, people and business processes. This has however proven to be a problematic task. The problematic situation arises from a shift of perspective regarding how to manage IS in order to gain value. This is a shift from technology delivery to benefits delivery; from an ISimplementation plan to a change management plan. The shift gives rise to challenges related to the inability of IS and the elusiveness of value. As a response to these challenges the field of IS-benefits management has emerged offering a framework and a process in order to better understand and formalise benefits realisation activities. In this thesis the benefits realisation efforts of three Swedish hospitals within the same county council are studied. The thesis focuses on the participants of benefits analysis projects; their perceptions, judgments, negotiations and descriptions of potential benefits. The purpose is to address the process where organisations seek to identify which potential IS-benefits to pursue and realise, this in order to better understand what affects the process, so that realisation actions of potential IS-benefits could be supported. A qualitative case study research design is adopted and provides a framework for sample selection, data collection, and data analysis. It also provides a framework for discussions of validity, reliability and generalizability. Findings displayed a benefits fluctuation, which showed that participants’ perception of what constituted potential benefits and value changed throughout the formal benefits management process. Issues like structure, knowledge, expectation and experience affected perception differently, and this in the end changed the amount and composition of potential benefits and value. Five dimensions of benefits judgment were identified and used by participants when finding accommodations of potential benefits and value to pursue. Identified dimensions affected participants’ perceptions, which in turn affected the amount and composition of potential benefits. During the formal benefits management process participants shifted between judgment dimensions. These movements emerged through debates and interactions between participants. Judgments based on what was perceived as expected due to one’s role and perceived best for the organisation as a whole were the two dominant benefits judgment dimensions. A benefits negotiation was identified. Negotiations were divided into two main categories, rational and irrational, depending on participants’ drive when initiating and participating in negotiations. In each category three different types of negotiations were identified having different characteristics and generating different outcomes. There was also a benefits negotiation process identified that displayed management challenges corresponding to its five phases. A discrepancy was also found between how IS-benefits are spoken of and how actions of IS benefits realisation are understood. This was a discrepancy between an evaluation and a realisation focus towards IS value creation. An evaluation focus described IS-benefits as well-defined and measurable effects and a realisation focus spoke of establishing and managing an on-going place of value creation. The notion of valuescape was introduced in order to describe and support the understanding of IS value creation. Valuescape corresponded to a realisation focus and outlined a value configuration consisting of activities, logic, structure, drivers and role of IS.

Westerners in search of the legendary potion : ayahuasca travel in the borderland between tourism and pilgrimage

The thesis examines the phenomenon most commonly known as “ayahuasca tourism” – i.e. the practice of westerners traveling to South America and partaking in ceremonies in which a powerful entheogenic brew, ayahuasca, is consumed. While this popular phenomenon has been steadily increasing during the last decades, it has, however, been insufficiently studied by scholars. An important question which has not been properly addressed in earlier studies is how ayahuasca tourism relates to the wider occurrence of travel and how it should be perceived with reference to the theoretical frameworks on the subject of travel. Drawing on theories regarding pilgrimage and tourism, the main purpose of this thesis is to examine the relationship between ayahuasca tourism and the broader spectrum of travel. In particular, the study tests the designations “pilgrimage”, “religious tourism” and “spiritual tourism” with reference to ayahuasca tourism. Utilizing earlier literature as well as ayahuasca tourists‟ reports obtained from an Internet forum as a basis for analysis, I search for a suitable terminology to be used for the phenomenon. The study lays special emphasis on the protagonists‟ motivations, experiences and outcomes in order to take note of various aspects of the wide-ranging occurrence of ayahuasca tourism. Key findings indicate that ayahuasca tourism is best understood as a combination of pilgrimage and tourism. On the basis of the analysis I argue that ayahuasca tourism should be labeled as “pilgrimage” and/or “spiritual tourism”, and the tourists respectively as “pilgrims” and/or “spiritual tourists”. The category of “religious tourism/tourist”, on the other hand, turns out to be an inappropriate designation when describing the phenomenon. In general, through my study I show that the results are consistent with the present trend in the study of travel to perceive pilgrimage and tourism as theoretically similar phenomena. The study of ayahuasca tourism serves thus as living proof of contemporary travel, in which the categories of pilgrimage and tourism are often indistinguishable. I suggest that ayahuasca tourism is by no means exceptional on this point, but can rather be used as an illustration of modern travel forms on a general level. Thus, the present study does not only add to the research of ayahuasca tourism, but also provides additional insights into the study of travel.

Genetics of inherited small vessel diseases – in search of a novel small vessel disease and modifiers of the clinical course of CADASIL

The genetic and environmental risk factors of vascular cognitive impairment are still largely unknown. This thesis aimed to assess the genetic background of two clinically similar familial small vessel diseases (SVD), CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) and Swedish hMID (hereditary multi-infarct dementia of Swedish type). In the first study, selected genetic modifiers of CADASIL were studied in a homogenous Finnish CADASIL population of 134 patients, all carrying the p.Arg133Cys mutation in NOTCH3. Apolipoprotein E (APOE) genotypes, angiotensinogen (AGT) p.Met268Thr polymorphism and eight NOTCH3 polymorphisms were studied, but no associations between any particular genetic variant and first-ever stroke or migraine were seen. In the second study, smoking, statin medication and physical activity were suggested to be the most profound environmental differences among the monozygotic twins with CADASIL. Swedish hMID was for long misdiagnosed as CADASIL. In the third study, the CADASIL diagnosis in the Swedish hMID family was ruled out on the basis of genetic, radiological and pathological findings, and Swedish hMID was suggested to represent a novel SVD. In the fourth study, the gene defect of Swedish hMID was then sought using whole exome sequencing paired with a linkage analysis. The strongest candidate for the pathogenic mutation was a 3’UTR variant in the COL4A1 gene, but further studies are needed to confirm its functionality. This study provided new information about the genetic background of two inherited SVDs. Profound knowledge about the pathogenic mutations causing familial SVD is also important for correct diagnosis and treatment options.

In search of good relationships to music : understanding aspiration and challenge in developing music school teacher practices

This study focuses on teacher practices in publicly funded music schools in Finland. As views on the aims of music education change and broaden, music schools across Europe share the challenge of developing their activities in response. In public and scholarly debate, there have been calls for increased diversity of contents and concepts of teaching. In Finland, the official national curriculum for state-funded music schools builds on the ideal that teaching and learning should create conditions which promote ‘a good relationship to music’. The meaning of this concept has been deliberately left open in order to leave room for dialogue, flexibility, and teacher autonomy. Since what is meant by ‘good’ is not defined in advance, the notion of ‘improving’ practices is also open to discussion. The purpose of the study is to examine these issues from teachers’ point of view by asking what music school teachers aim to accomplish as they develop their practices. Methodologically, the study introduces a suggestion for building empirical research on Alperson’s ‘robust’ praxial approach to music education, a philosophical theory which is strongly committed to practitioner perspectives and musical diversity. A systematic method for analysing music education practices, interpretive practice analysis, is elaborated with support from interpretive research methods originally used in policy analysis. In addition, the research design shows how reflecting conversations (a collaborative approach well-known in Nordic social work) can be fruitfully applied in interpretive research and combined with teacher inquiry. Data have been generated in a collaborative project involving five experienced music school teachers and the researcher. The empirical material includes transcripts from group conversations, data from teacher inquiry conducted within the project, and transcripts from follow-up interviews. The teachers’ aspirations can be understood as strivings to reinforce the connection between musical practices and various forms of human flourishing such that music and flourishing can sustain each other. Examples from their practices show how the word ‘good’ receives its meaning in context. Central among the teachers’ concerns is their hope that students develop a free and sustainable interest in music, often described as inspiration. I propose that ‘good relationships to music’ and ‘inspiration’ can be understood as philosophical mediators which support the transition from an indeterminate ‘interest in music’ towards specific ways in which music can become a (co-)constitutive part of living well in each person’s particular circumstances. Different musical practices emphasise different aspects of what is considered important in music and in human life. Music school teachers consciously balance between a variety of such values. They also make efforts to resist pressure which might threaten the goods they think are most important. Such goods include joy, participation, perseverance, solid musical skills related to specific practices, and a strong sense of vitality. The insights from this study suggest that when teachers are able to create inspiration, they seem to do so by performing complex work which combines musical and educational aims and makes general positive contributions to their students’ lives. Ensuring that teaching and learning in music schools remain as constructive and meaningful as possible for both students and teachers is a demanding task. The study indicates that collaborative, reflective and interdisciplinary work may be helpful as support for development processes on both individual and collective levels of music school teacher practices.

In search of the interrelatedness of innovation and internationalisation processes in entrepreneurial life science companies

This study is motivated by the question how resource scarce innovative entrepreneurial companies seek and leverage global resources. This study takes a resource-seeking perspective a step forward and suggests that resources that enable the entrepreneurial internationalisation are largely accrued from the early stages of entrepreneurial life; that is from the innovation development. Consequently, this study seeks to explain how innovation and internationalisation processes are interrelated in the entrepreneurial internationalisation. This main objective is approached through three research questions, (1) What role do inter-organisational relationships in innovation have in the entrepreneurial internationalisation process? (2) What kind of inward–outward links do inter-organisational relationships create in the resource-seeking-based entrepreneurial internationalisation process? (3) What kind of capability to collaborate forms in the interaction of inter-organisational relationship deployment? The research design is a mixed methods design that consists of quantitative pilot study and qualitative multiple case study of five entrepreneurial life science companies from Finland and Austria. The findings show that innovation and internationalisation processes are tightly interwoven in pre-internationalisation state. The findings also reveal that the more experienced companies are able to take advantage of complexcross-border inter-organisational relationship structures better than the starting companies. However, very minor evidence was found on inward links translating into outward links in the entrepreneurial internationalisation process, despite the expectation to observe more of these links in the data. Combined intangible-tangible resource-seeking was the most preferred to build links between inward–outward internationalisation but also to develop competence to collaborate. By adopting a resource- instead of market-seeking approach, this study illustrated that internationalisation extends to early stages of innovative companies, and that in high-technology companies’ potentially significant cross-border relationships have started to form long before incorporation. Therefore, these observations justified the firmer inclusion of pre-company history in innovative entrepreneurship studies. The study offers a conceptualisation of entrepreneurial internationalisation that is perceived as a process. The main theoretical contributions are in the areas of international entrepreneurship and in the behavioural process studies of entrepreneurial internationalisation and resource-based internationalisation. The inclusion of the innovation-based discussion, namely the innovation process, in the internationalisation process theories has clearly contributed to the understanding of entrepreneurial internationalisation in the context of international entrepreneurship. Innovation development is a central act of entrepreneurial companies, and neglecting innovation process investigation from entrepreneurial internationalisation leaves potentially influential mechanisms unexplored.

In Search of Convergence: A Co-citation Analysis of Three Sport Management Journals

Responding to a series of articles in sport management literature calling for more diversity in terms of areas of interest or methods, this study warns against the danger of excessively fragmenting this field of research. The works of Kuhn (1962) and Pfeffer (1993) are taken as the basis of an argument that connects convergence with scientific strength. However, being aware of the large number of counterarguments directed at this line of reasoning, a new model of convergence, which focuses on clusters of research contributions with similar areas of interest, methods, and concepts, is proposed. The existence of these clusters is determined with the help of a bibliometric analysis of publications in three sport management journals. This examination determines that there are justified reasons to be concerned about the level of convergence in the field, pointing out to a reduced ability to create large clusters of contributions in similar areas of interest.

In search of the Holy Grail : how viable is John Rawls' purely political conception of justice?

Please consult the paper edition of this thesis to read. It is available on the 5th Floor of the Library at Call Number: Z 9999 P65 Y68 1995