DiVA - Academic Archive On-line

Working Together : Exploring Relational Tensions in Swedish Academia

Thu, 19 Aug 2010 10:11:35 +0200

This study explores the basic social conditions for high-quality university research, and focuses on research in science and technology in Sweden. Swedish research policy has adopted more of a market perspective on academic research and its role in society. This has meant the promotion of competition between researchers, increased focus on efficiency at universities, and attempts to make academia harmonize more with industry and other actors. How do such policies affect the variety of perspectives within the academic system? How do they affect the positions and identities of individual academics? These issues are discussed through the concept of "relational tensions". Relational tensions refer to social strains arising when interacting actors have different perspectives. Relational tensions can stimulate creativity, but may also cause unproductive conflicts. The discussion is underpinned by interviews with university researchers and a case study of Uppsala BIO-X, a program to commercialize university research in biotechnology. Typical cases of relational tensions are identified. These concern both interpersonal relations and differences between organized science and industry. A notable observation concerns potential frustration of individual academics, as competition and efficiency tends to make their positions and identities more contested. Researchers cope with relational tensions in three identified ways: socialization, seclusion, and lateral authority. Socialization is natural and often necessary, but reduces the variety of perspectives. Seclusion serves to retain variety and independence, but reduces interaction with others. Lateral authority is to formally or informally lend a researcher more authority, which improves the chance of maintaining a variety of perspectives without reducing interaction. The sustained usefulness of academic research arguably depends on its ability to foster and communicate a variety of perspectives. Hence, (i) promoting lateral authority seems fruitful within academia and in relations between academia and industry, and (ii) encouraging competition and efficiency may to some extent be counterproductive.

T Regulatory Cells – Friends or Foes?

Thu, 19 Aug 2010 09:55:16 +0200

T regulatory cells (Tregs) have been extensively studied in patients with cancer or autoimmunity. These cells hamper the immune system’s ability to clear tumor cells in cancer patients. In autoimmune diseases, on the other hand, they are not able to restrain autoreactive immune responses. If we manage to understand Tregs and their role in health and diseases we may be able to develop better immunomodulatory therapies.

Early studies demonstrated that tolerance was maintained by a subset of CD25⁺ T-cells. CD25 was the earliest marker for Tregs and is still often used to define these cells. Several Treg-associated markers have been suggested throughout the years. However, these markers can be upregulated by activated T-cells as well. The most specific marker for Tregs is currently the transcription factor forkhead box P3 (FoxP3).

In this thesis, we investigated the presence of CD25^- Tregs in patients with B-cell malignancies and in patients with autoimmunity. These cells were identified in both patient groups. Further, patients with B-cell malignancies often have high levels of soluble CD25 (sCD25) in the periphery. In our patient cohorts, the level of peripheral Tregs correlated with the level of sCD25 in patients with lymphoma. Tregs were shown to release sCD25 in vitro and sCD25 had a suppressive effect on T-cell proliferation. These data show that Tregs may release CD25 to hamper T-cell proliferation and that this may be an immune escape mechanism in cancer patients.

Previous studies have demonstrated that an increased infiltration of FoxP3⁺ cells into lymphoma-affected lymph nodes is associated with a better patient outcome. This is in contrast to studies from non-hematological cancers where an increased presence of Tregs is associated with a poor prognosis. Since previous studies have shown that Tregs are able to kill B-cells, we wanted to investigate if Tregs are cytotoxic in patients with B-cell tumors. In the subsequent studies, Tregs from patients with B-cell lymphoma and B-cell chronic lymphocytic leukemia (CLL) were phenotyped to investigate the presence of cytotoxic markers on these cells. FoxP3-expressing T-cells from both patients with CLL and B-cell lymphoma displayed signs of cytotoxicity by upregulation of FasL and the degranulation marker CD107a. Tregs from CLL patients could further kill their autologous B-cells in in vitro cultures.

Taken together the studies in this thesis have demonstrated two possible new functions of Tregs in patients with B-cell malignancies and the presence of CD25^- Tregs in both cancer and autoimmunity.

Psychological and Behavioral Aspects of Receiving Genetic Counseling for Hereditary Cancer

Fri, 20 Aug 2010 11:59:00 +0200

The overall aims of this thesis were to investigate psychological and behavioral effects of receiving cancer genetic counseling for breast, ovarian and colorectal cancer and/or with a family history of these cancer types and to determine whether counselees’ informational needs were met.

Study I was performed 3-7 years post-counseling. Participants (n=214) reported a relatively high level of anxiety but a low level of depression compared to cancer patients in general. However, there was no indication that the distress experienced was due to the counseling. Moderate changes in life and family relations, high level of adherence to recommended controls and satisfaction was reported. Study II was a randomized control trial (RCT) intervention study which involved 147 counselees. An increase in the level of knowledge and correct estimation of personal risk was reported in both the intervention and control groups, although this increase declined at later follow-up. Enhanced information led to significantly greater satisfaction with the given information, and the way of informing relatives. Most counselees had shared information with their at-risk relatives. Study III focused on sharing information with at-risk relatives among participants in study II and their relatives (n=81). Counselees were interviewed and answered a questionnaire, whilst their relatives only answered the questionnaire. Counselees reported positive/neutral feelings about communicating genetic information and mostly interpreted their relatives’ reactions as positive/ neutral. Also, approximately 50% of relatives reported positive/neutral reactions and were generally satisfied with the received information. Study IV was conducted in Sweden and Norway based on 235 counselees. Counselees expected counselors to be skillful and thoughtful, take them seriously and provide risk estimations and medical information. Most important issues to counselees were satisfactorily addressed by the counselors. Analyzing importance rankings resulted in five categories of needs: a need for facts, caring communication and medical information, need for understanding and support in sharing genetic information, practical care and medical/practical information.

In conclusion, no adverse psychological or behavioral effect on counselees was observed. Apparently, genetic counseling is managed properly and counselors successfully address counselees’ needs. Providing extended information does not seem necessary, however, tailoring information to individual counselees needs may create a more effective counseling.

Application of Padlock Probe Based Nucleic Acid Analysis In Situ

Fri, 20 Aug 2010 09:22:37 +0200

The great variation displayed by nucleic acid molecules in human cells, and the continuous discovery of their impact on life, consequently require continuous refinements of molecular analysis techniques. Padlock probes and rolling circle amplification offer single nucleotide discrimination in situ, a high signal-to-noise ratio and localized detection within cells and tissues.

In this thesis, in situ detection of nucleic acids with padlock probes and rolling circle amplification was applied for detection of DNA in the single cell gel electrophoresis assay to detect nuclear and mitochondrial DNA. This assay is used to measure DNA damage and repair. The behaviour of mitochondrial DNA in the single cell gel electrophoresis assay has earlier been controversial, but it was shown herein that mitochondrial DNA diffuses away early in the assay. In contrast, Alu repeats remain associated with the nuclear matrix throughout the procedure. A new twelve gel approach was also developed with increased throughput of the single cell gel electrophoresis assay. DNA repair of three genes OGG1, XPD and HPRT and of Alu repeats after H₂O₂ induced damage was further monitored. All three genes and Alu repeats were repaired faster than total DNA. Finally, padlock probes and rolling circle amplification were applied for detection of the single stranded RNA virus Crimean Congo hemorrhagic fever virus. The virus was detected by first reverse transcribing RNA into cDNA.. The virus RNA together with its complementary RNA and the nucleocapsid protein were detected in cultured cells.

The work presented here enables studies of gene specific damage and repair as well as viral infections in situ. Detection by ligation offers high specificity and makes it possible to discriminate even between closely related molecules. Therefore, these techniques will be useful for a wide range of applications within research and diagnostics.

Ion Beam Analysis of First Wall Materials Exposed to Plasma in Fusion Devices

Thu, 19 Aug 2010 11:05:30 +0200

One major step needed for fusion to become a reliable energy source is the development of materials for the extreme conditions (high temperature, radioactivity and erosion) caused by hot plasmas. The main goal of the present study is to use and optimise ion beam methods (lateral resolution and sensitivity) to characterise the distribution of hydrogen isotopes that act as fuel. Materials from the test reactors JET (Joint European Torus), TEXTOR (Tokamak Experiment for Technology Oriented Research) and Tore Supra have been investigated.

Deuterium, beryllium and carbon were measured by elastic recoil detection analysis (ERDA) and nuclear reaction analysis (NRA). To ensure high 3D spatial resolution a nuclear microbeam (spot size <10 µm) was used with ³He and ²⁸Si beams. The release of hydrogen caused by the primary ion beam was monitored and accounted for.

Large variations in surface (top 10 µm) deuterium concentrations in carbon fibre composites (CFC) from Tore Supra and TEXTOR was found, pointing out the importance of small pits and local fibre structure in understanding fuel retention. At deeper depths into the CFC limiter tiles from Tore Supra, deuterium rich bands were observed confirming the correlation between the internal material structure and fuel storage in the bulk.

Sample cross sections from thick deposits on the JET divertor showed elemental distributions that were dominantly laminar although more complex structures also were observed. Depth profiles of this kind elucidate the plasma-wall interaction and material erosion/deposition processes in the reactor vessel.

The information gained in this thesis will improve the knowledge of first wall material for the next generation fusion reactors, concerning the fuel retention and the lifetime of the plasma facing materials which is important for safety as well as economical reasons.

Krislärande – konfliktfylld anpassning : Pedagogik för samverkan inför samhällskriser

Tue, 17 Aug 2010 10:32:31 +0200

A societal crisis is an emergency that affects many people and large parts of society, threatening life, health, safety and basic values. In a societal crisis, there is a need for coordination between various bodies in the society. Coordination in societal crises has previously been studied mainly from a management perspective. Learning perspectives have been studied to a lesser extent.

The main purpose of this thesis is to increase knowledge about the conditions for developing consensus and establish a common understanding of synergy-effects, a surplus value, for knowledge meetings between individuals from different organizations when they cooperate in the emergency management system. The study seeks to understand to the following questions: 1) What images and ideas do participants bring into the coordination group about societal crisis, how have they developed and changed? 2) How do the participants act when they have different pictures and meet? 3) Can the basic ideas of the research circle be used for knowledge building at knowledge meetings in the emergency management-system? 4) Can the basic ideas of the research circle be used to develop consensus and establish a common understanding of synergy-effects before societal crises happen?

The main study consists of three case studies in three different-sized municipalities. It is based on 36 semi-structured interviews with participants in local crisis management coordination groups, observations during exercises and meetings, document studies and an experiment with the so-called knowledge meeting. The results are compared with complementary studies from two knowledge meetings and two coordination exercises based on observation, questionnaires and evaluations. The individuals, organizations, and structures have been identified as frame factors for coordination groups. The results show that the participants have different images of societal crisis and that coordination is a time-consuming approach requiring cross-perspective learning, interaction, as well as dialogue and reflection skills. The participants eventually develop their crisis learning, i.e. conflict-filled adaptation. A system's opened nature is important for individual learning.

Geographies of the Japanese Cultural Economy : Innovation and Creative Consumption

Thu, 19 Aug 2010 10:12:29 +0200

日本の文化経済に関する地理学的考察：イノベーションと創造的消費に着目して今日、日本のポップカルチャーはますます世界中で親しまれるようになった。マンガやアニメ、特にデジタル・ゲームは若者を中心に人気を集めている。日本文化の世界的展開を前にして、西欧諸国の人々が以下のような関心を抱くことも自然であろう。これらの文化的表現は一体どこで生まれ、また、誰によって制作されているのか。本研究の目的は文化経済の地理的現象について、新たなトレンドや製品を生み出し、解釈し、そして発展させる人々およびその空間について探求することである。もっとも、ここでは、定評のある作家・クリエーターや製品開発者、企業、さらには産業動態といった、一般的に文化経済研究において注目される観点に重きを置いていない。本研究を構成する三つの論考において、特定の空間と商取引や学習、創造性、革新性との関係を描き、検証することを課題としている。その方法として、解釈的アプローチ並びに現象学より着想を得た定性的分析を採用した。分析データについては、主に2007年から2009年の間に日本において行ったフィールドワークより収集したものを用いている。第一論文では、日本の玩具およびゲーム産業における製品開発を題材としている。物語や映像を展開する手段として、それらを様々なメディア形態へと配信していくことが一般的である。メディア媒体の混合を通じて、ブランドを創出し、根強い顧客を確保していく。西欧諸国において人気の高い二つの日本のキャラクターを検証して明らかとなったことは、メディア・ミックスの全体性を作り出す際の製品ユーザーの重要性である。その役割は必ずしも製品競争力に直結するようなライセンス取得者や作家・クリエーター、もしくは特定の企業であるとは限らない。むしろ、連結された体験こそがユーザーにとって重要である。新たな映像や物語が取り込まれるにつれてメディア・ミックスは発展する。その強さを促進する原動力はしばしばユーザーの手中にある。第二論文では東京都秋葉原を分析地域とした。この地域は家電製品やハイテク機器の商店が立ち並ぶ日本有数の電気屋街として知られている。近年では、デジタル・ゲームやマンガに関連した商品など、大衆文化の一大消費拠点でもある。秋葉原が知識やアイディアを交換する空間へと変化した結果、流行ならびに新たな文化的現象が創出され、評価され、そして発展していく場となっている。この過程において、秋葉原という特定の空間とその人々こそが重要であり、消費および消費者の諸活動が文化的イノベーションと競争力のある文化的表現を育てる。従って、本論考は、一般的なビジネスパークや産業クラスターの諸研究とは異なる観点からの、イノベーションおよびクリエイティブ・ミリュー論への貢献と位置づけられよう。第三論文ではコミックマーケットを分析対象としている。コミックマーケットは、参加者達のアイディアや物語、専門的技法といった情報交換の場として40年もの間に進化を遂げてきた。著名な作家・クリエーターにとって、本イベントは新たな読者・愛好家へと作品を広めるような開放的な空間をもつ大規模な催しへと発展した。そこで展示もしくは頒布される同人誌は挑発的であり挑戦的でもある。また、「コスプレ」を代表として、その他の多くの文化的現象も見られる。本イベントにおける創造的活動や遊びは、しばしば日本の文化経済に影響を与えるような新たなトレンドの契機となる。世界中にも消費者とクリエーターが出会い、触れ合うような同様のイベントは少なくない。本稿の事例は、大々的な催しを必要とするような、イベントを基礎とした経済活動の一例である。他方で、関連省庁やメディア・コングロマリットとは異なるような、ボトムアップ型で成功的に発展してきた文化経済の制度的催しの一例ともいえよう。以上のように、本研究では文化と経済過程の関係が相互的かつ互恵的となるような社会科学のアプローチを提示している。特定の場とユーザーは、大衆消費が確立され、大衆文化が発展するような空間において、文化的イノベーションを生み出す上で最も重要な役割を果たしている。従って、これらの空間は文化産業の競争力を間接的に左右している。今日、有力企業による大規模投資や高額な展示方法などに続き、消費者は文化経済の鍵となるイノベーターとして認識されよう。その理由の一つとして、文化的商品の価値が流行や誇張された宣伝のような偶然的要因によって決定される点と無関係ではない。これらはファンと創造的な消費者が有する独特の消費文化の中で開花することが多い。本稿が探求してきた点は、この消費と空間、延いては現代文化経済の理解についてである。文化産業に関する今後の研究は、制作プロセスに関与する積極的な主体として、ますます消費者に着目する必要があろう。

Electronic and Molecular Surface Structures of Dye-Sensitized TiO₂ Interfaces

Fri, 20 Aug 2010 10:14:07 +0200

The dye-sensitized solar cell is a promising solar cell technology. In these systems the key process for light to electricity conversion is molecular in nature and is initiated in dye molecules adsorbed at a semiconducting surface. This thesis focuses on the electronic and molecular surface structure of the dye/TiO₂ interface, and the experimental results were obtained from surface sensitive X-ray based electron spectroscopic methods.

Two families of dyes, triarylamine based organic dyes and ruthenium based inorganic dyes, were investigated. The effect of dye structural modications on the interfacial properties was studied, such as the surface concentrations, dye molecular surface orientation, molecular interactions, and energy level matching. Also, the impact of additional parameters such as the incorporation of coadsorbents and the solvents used for dye sensitization were studied and complementary photoelectrochemical characterization was used to demonstrate functional properties corresponding to changes in the molecular layers.

The experiments provided information on how specic structural modications change the frontier electronic structure. The results also showed that the adsorption of the organic dye leads to submolecular electronic changes, and that the dye surface orientations in general favor effcient energy conversion. Moreover, effects of solvents and coadsorbents, on both energy level matching between the dye and the TiO₂ substrate and the surfacemolecular structure were quantied.

Regulation of TGF-β Signaling by Post-Translational Modifications

Fri, 20 Aug 2010 11:57:20 +0200

Transforming growth factor-β (TGF-β) signaling is initiated when the ligand binds to type II and type I serine/threonine kinase receptors at the cell surface. Activated TGF-β type I receptors phosphorylate R-Smads which relocate, together with co-Smads, to the cell nucleus and regulate transcription. Enhancement or repression of Smad-specific gene targets leads to intracellular protein compositions which organize functional complexes and thus govern cellular processes such as proliferation, migration and differentiation.

TGF-β/Smad signaling relays are regulated by various post-translational modifications. From receptors to gene promoters, intricate interplays between phosphorylation, acetylation, ubiquitination and numerous other modifications, control Smad signaling initiation and duration. However, many steps in the cascade, including receptor internalization, Smad nuclear shuttling and transcriptional termination, still remain elusive. The open gaps in our understanding of these mechanisms most likely involve additional post-translational regulations. Thus, the aim of the present investigation was to identify novel modulators of TGF-β/Smad signaling.

In the first part of this thesis, we show the importance of ADP-ribosylation in Smad-mediated transcription. We identified poly(ADP-ribose) polymerase 1 (PARP-1) as a Smad interacting protein. Our work revealed that PARP-1 forms direct interactions with Smad3/4, and PARylates residues in their MH1 domains. This modification restricts Smads from binding to DNA and attenuates Smad-activated transcription. PARylation is reversed by the glycohydrolase PARG. We provide evidence that PARG can de-ADP-ribosylate Smads, which enhances Smad-promoted gene regulation.

In the second part, we examine a Smad-dependent gene target of TGF-β signaling, salt inducible kinase 1 (SIK). After induction, SIK cooperates with Smad7 and Smurf2 to downregulate the TGF-β type I receptor. The mechanism relies on both the kinase and UBA domain of SIK as well as the E3-ligase activity of Smurf2.

In summary, we have unveiled two enzyme-dependent TGF-β/Smad modulatory mechanisms; SIK promoted receptor turnover and PARP-1/PARG-regulated Smad signaling.

Human Papilloma Virus, Epstein-Barr Virus, and Herpes Simplex Virus Type-1 in Oral Squamous Cell Carcinomas from Three Populations

Wed, 25 Aug 2010 13:20:47 +0200

Most oral squamous cell carcinoma (OSCC) is believed to develop via a multistep process of cumulative gene damage in epithelial cells. Increasing incidence of OSCC and evidence that traditional risk factors may not be responsible directed us to investigate the prevalence of virus in pre- and malignant samples.The integration of the DNA from human papillomavirus (HPV), Epstein-Barr virus (EBV), and Herpes simplex (HSV) into the human genome is associated with the expression of oncogenes and the down-regulation of tumor-suppressor genes in OSCC carcinogenesis. This thesis compared samples from India and Sudan, two countries on two continents having a documented high incidence of oral cancer, with specimens from Sweden, with its known low incidence of oral cancer. Each region has, in addition to smoking, a unique non-smoked tobacco habits with documented carcinogenic effects. These countries also typify areas of low and high socioeconomic living conditions with their expected impact on disease development. The study populations were selected from tobacco users and nonusers with OSCC, oral sub-mucous fibrosis (India), oral lichen planus (Sweden), oral leukoplakia with and without dysplasia and snuff-induced lesions (Sweden and Sudan). An expedient method was developed for extracting DNA from old formalin-fixed and paraffin-embedded biopsies. The prevalence of HPV, EBV, and HSV was investigated using PCR/DNA sequencing and southern blot hybridization analysis. We found HPV and EBV to be most prevalent in samples of tissue characterized as normal, with decreasing prevalence in dysplastic and malignant lesions. This intriguing finding that prevalence decreases as neoplastic development proceeds warrants further investigation. Our data do not at first sight support the conclusion that viruses and tobacco use jointly interact with cell mechanisms in the development of oral cancer.

Entrepreneurs and Small-Scale Enterprises : Self Reported Health, Work Conditions, Work Environment Management and Occupational Health Services

Tue, 17 Aug 2010 14:47:44 +0200

This thesis focused on factors contributing to improved work environment in small-scale enterprises and sustainable health for the entrepreneurs.

In Study I, implementation of the provision of Systematic Work Environment Management (SWEM) with and without support was investigated. Two implementation methods were used, supervised and network method. The effect of the project reached the employees faster in the enterprises with the supervised method. In general, the work environment improved in all enterprises. However, extensive support to small-scale enterprises in terms of advice and networking aimed at fulfilling SWEM regulations had limited effect – especially considering the cost of applying these methods.

Studies II, III, and IV focused on entrepreneurs’ health, work conditions, strategies for maintaining good health, and utilisation of Occupational Health Service (OHS). A closed cohort of entrepreneurs in ten different trades responded to two self-administered questionnaires on health and work conditions, with five years between the surveys: at baseline, 496 entrepreneurs responded, and 251 entrepreneurs responded at follow-up. Differences were tested by Chi²-test, and associations estimated with logistic regression analyses. Qualitative interviews on entrepreneurs’ strategies for maintaining good health were included. In Study II, the most frequently reported complaints, musculoskeletal pain and mental health problems, were associated with poor job satisfaction and poor physical work environment. In Study III, consistent self-reported good health, i.e. good health both at baseline and at follow up, was associated with self-valued good social life when adjusted for physical work conditions and job satisfaction. Entrepreneurs’ strategies for maintaining good health included good planning and control over work, flexibility at work, good social contact with family, friends and other entrepreneurs, and regular physical exercise.

Study IV concerned entrepreneur’s utilisation of OHS. Entrepreneurs affiliated to OHS had either better or more adverse work conditions than non-affiliated entrepreneurs. Medical care and health check-ups were the services most utilised. Affiliation to OHS correlated with use of specific information sources and active work environment management. The entrepreneurs were not consistently affiliated to OHS over the five-year-period.

Emotional Empathy, Facial Reactions, and Facial Feedback

Mon, 16 Aug 2010 10:20:04 +0200

The human face has a fascinating capability to express emotions. The facial feedback hypothesis suggests that the human face not only expresses emotions but is also able to send feedback to the brain and modulate the ongoing emotional experience. It has furthermore been suggested that this feedback from the facial muscles could be involved in empathic reactions. This thesis explores the concept of emotional empathy and relates it to two aspects concerning activity in the facial muscles. First, do people high versus low in emotional empathy differ in regard to in what degree they spontaneously mimic emotional facial expressions? Second, is there any difference between people with high as compared to low emotional empathy in respect to how sensitive they are to feedback from their own facial muscles? Regarding the first question, people with high emotional empathy were found to spontaneously mimic pictures of emotional facial expressions while people with low emotional empathy were lacking this mimicking reaction. The answer to the second question is a bit more complicated. People with low emotional empathy were found to rate humorous films as funnier in a manipulated sulky facial expression than in a manipulated happy facial expression, whereas people with high emotional empathy did not react significantly. On the other hand, when the facial manipulations were a smile and a frown, people with low as well as high emotional empathy reacted in line with the facial feedback hypothesis. In conclusion, the experiments in the present thesis indicate that mimicking and feedback from the facial muscles may be involved in emotional contagion and thereby influence emotional empathic reactions. Thus, differences in emotional empathy may in part be accounted for by different degree of mimicking reactions and different emotional effects of feedback from the facial muscles.

Molecular Studies of Diamond-Blackfan Anemia and Congenital Nail Dysplasia

Fri, 27 Aug 2010 09:28:22 +0200

The aim of this thesis is to investigate the effect of genetic mutations on the pathophysiology of two human disorders: Diamond-Blackfan Anemia (DBA) and isolated congenital nail dysplasia.

The first part of this thesis (Paper I-III) investigates the mechanism associated with DBA. DBA is a rare bone marrow failure syndrome characterized by the absence or decrease of erythroid precursor cells. The disease is further associated with growth retardation, malformations, predisposition to malignant disease and heterozygous mutations in ribosomal protein (RP) genes. The second part of this thesis (Paper IV) investigates the genetic basis of isolated autosomal recessive nail dysplasia characterized by pachyonychia and onycholysis of both finger- and toenails. It further dissects the molecular mechanisms regulating nail development.

In the first study, we investigated the previously reported RPS19/PIM-1 interaction by generating a combined Rps19/Pim-1 knockout mouse model. We found that allelic Rps19 insufficiency and Pim-1 deficiency have a cooperative effect on murine hematopoiesis resulting in increased myeloid cellularity associated with cell cycle alterations and reduced apoptosis. In the second study, we analyzed primary fibroblasts from DBA patients with truncating mutations in RPS19 or RPS24 and observed a marked delay in cellular growth associated with specific cell cycle defects. In the third study, we discovered that recombinant RPS19 binds its own mRNA and that the binding is altered when two DBA-associated RPS19 mutations are introduced. In the fourth study, we identified mutations in the WNT signaling receptor Frizzled 6 (FZD6). We observed that the nonsense mutant fails to interact with the first downstream effector Dishevelled. Fzd6 mutant mice displayed claw malformations and we detected a transient Fzd6 expression in the distal digits at the embryonic time point for nail development.

In summary, this thesis elucidates several mechanisms in the etiology of DBA and congenital nail dysplasia and mechanisms regulating nail development.

Functional Diversification among MADS-Box Genes and the Evolution of Conifer Seed Cone Development

Thu, 26 Aug 2010 14:27:37 +0200

MADS-box genes are important regulators of reproductive development in seed plants, including both flowering plants and conifers. In this thesis the evolution of the AGAMOUS subfamily of MADS-box genes, and what the ancestral function of this group of genes might have been in the early seed plants about 300 million years ago, was addressed by the discovery of two novel conifer genes, both basal to all previously known AGAMOUS subfamily genes. DAL20, the most basal of these genes, was exclusively expressed in roots, unlike all previously known AGAMOUS subfamily genes. I also studied the evolutionary mechanisms leading to functional diversification of duplicated genes in two different subfamilies of MADS-box genes; the AGAMOUS and AGL6 subfamilies. Focus was on studying changes in gene expression pattern, representing changes in the transcriptional regulation between the genes, and on comparing the functional properties of the gene products, representing changes in the protein-coding sequence between the genes. Duplicated genes in the AGL6 subfamily were found to have evolved by both mechanisms. In the AGAMOUS subfamily I found duplicated spruce genes; DAL2 and DAL20, that appear to have functionally diversified mainly by changes in the transcriptional regulation. Conifer AGAMOUS subfamily genes were also used in a comparative developmental-genetics approach to evaluate hypotheses, based on the morphology of fossil and extant conifer seed cones, on the identity of the female reproductive organ, the ovuliferous scale, and the evolution of seed cone morphology in the conifer families Pinaceae, Taxodiaceae and Cupressaceae. Seed cones in these families have been hypothesized to have homologous ovule-bearing organs, but I found substantial differences in the expression patterns of orthologous AGAMOUS subfamily genes in seed cones of these families that are not compatible with this hypothesis, indicating that the evolutionary history of conifer seed cones is more diverse than previously thought.

Aspects of Optical Coherence Tomography (OCT) in Healthy Eyes and Eyes with Retinal Diseases

Fri, 27 Aug 2010 13:09:51 +0200

Optical coherence tomography (OCT) is a technique in which cross-sectional images from intraocular tissue can be obtained. The quantitative and qualitative examinations are used for evaluating retinal diseases. Conventional OCT (Stratus) is mainly used, but the new Spectral domain (Cirrus) OCT, which has improved technology, may provide more reliable measurements.

The aim of the study was to collect normal values of macular thickness in children and adults and to evaluate the effect of age and/or gender, to compare measurement variability in healthy eyes and eyes with age-related macular degeneration (AMD), to compare Stratus and Cirrus OCT and to study the effect of cataract surgery on macula.

Sixty-seven healthy adults and 56 children, 30 patients with AMD, 34 patients with diabetes and cataract and 35 healthy controls were included. The quantitative maps in Stratus and Cirrus were used and manual correction of foveal location was evaluated. Qualitative OCT was compared to fluorescein angiography (FA) after cataract surgery.

The mean values of macular thickness in Stratus OCT were 207µm in adults and 204 µm in children. The measurement variability was low. Macular thickness decreased with age in adults, but not in children. No correlation with gender was found. In eyes with wet AMD, there were small differences in measurement variability comparing Stratus and Cirrus OCT. After manual correction in Cirrus OCT, the coefficients of repeatability were improved to values close to the repeatability in normal eyes. Two thirds of the diabetic and half of the control eyes showed leakage on FA after cataract surgery. Qualitative OCT corresponded poorly to FA in diabetic eyes. A thicker macula, assessed with OCT, was often observed without any obvious effect on visual acuity. OCT was as good as FA in revealing clinically relevant changes in macula after surgery, and was the technique recommended for follow-up.

Marqueurs corrélatifs en français et en suédois : Étude sémantico-fonctionnelle de d’une part… d’autre part, d’un côté… de l’autre et de non seulement… mais en contraste

Mon, 30 Aug 2010 10:46:56 +0200

This thesis deals with the correlative markers d’une part… d’autre part, d’un côté… de l’autre and non seulement… mais in French and their Swedish counterparts dels… dels, å ena sidan… å andra sidan and inte bara… utan. These markers are composed of two separate parts generally occurring together, and announce a serial of at least two textual units to be considered together.

The analyses of the use of these three French and three Swedish markers are based upon two corpora of non-academic humanities texts. The first, principal corpus, is composed only of original French and Swedish texts. The second, complementary corpus, is composed of source texts in the two languages and their translations in the other language. By the combination of these two corpora, this study is comparative as well as contrastive.

Through application of the Geneva model of discourse analysis and the Rhetorical Structure Theory, a semantic and functional approach to correlative markers and their text-structural role is adopted. The study shows similarities as well as differences between the six markers, both within each language and between the languages. D’une part… d’autre part and dels… dels principally mark a conjunctive relation, whereas d’un côté… de l’autre and å ena sidan… å andra sidan more often are used in a contrastive relation, even though they all can be used for both kinds of relations. Non seulement… mais and inte bara… utan mark a conjunctive relation, but can also indicate that the second argument is stronger than the first one. By the use of these two markers, the language users also present the first one as given and the second one as new information. In general, the French correlative markers appear to have a more argumentative function, whereas the text-structural function is demonstrated to be the most important in Swedish.

Characterisation of Members of the HD-Zip I and DREB/ERF Transcription Factor Families and their Functions in Plant Stress Responses

Wed, 1 Sep 2010 13:33:20 +0200

Plants have to adapt to various environmental conditions. In comparison with other eukaryotes, plant genomes encode relatively many transcription factors, and have families of transcription factors only found in plants, two such are the large AP2/ERF (APETALA2/Ethylene Responsive Factor) and HD-Zip (Homeodomain leucine zipper) families. Members of these families play roles in plant development, responses to stress and other environmental stimuli. This thesis describes the functions of members of both these families. Two AP2/ERF proteins of the DREB/ERF (Drought Responsive Element Binding/Ethylene Responsive Factor) subfamily, AtERF38 and AtERF39 show a negative effect on growth in transgenic over-expression lines. They are regulated by stress and confer stress tolerance, which suggests a function as negative growth regulators during stress. The 14 Oryza sativa (rice) HD-Zip I genes were described and a phylogenetic analysis of the HD-Zip I genes in Arabidopsis thaliana, rice and Craterostigma plantagineum defined four clades that were conserved between mono and dicots, but also showed that four clades had most likely been lost in either lineage. The phylogeny was supported by conserved intron/exon patterning and the duplication history of the rice genome. The expression patterns in different organs indicate a non-conserved regulation of genes within and between clades. Drought stress regulation was conserved within two clades, but not between the clades. Further analysis on the function of four HD-Zip I genes in Arabidopsis, ATHB5, -6, -7 and -12 showed an involvement in the transcriptional regulation of ABA receptors and signalling components. These are the first described direct target genes for ATHB7 and ATHB12. It was also shown that there exists a direct cross-regulation between these four HD-Zips. The effect of ATHB5, -6, -7 and -12 would be as negative regulators of ABA signalling, desensitising the plant to constant levels of ABA, and enabling sensitivity to changes in stress level.

Coal and Oil: The Dark Monarchs of Global Energy : Understanding Supply and Extraction Patterns and their Importance for Future Production

Fri, 3 Sep 2010 11:33:20 +0200

The formation of modern society has been dominated by coal and oil, and together these two fossil fuels account for nearly two thirds of all primary energy used by mankind. This makes future production a key question for future social development and this thesis attempts to answer whether it is possible to rely on an assumption of ever increasing production of coal and oil. Both coal and oil are finite resources, created over long time scales by geological processes. It is thus impossible to extract more fossil fuels than geologically available. In other words, there are limits to growth imposed by nature.

The concept of depletion and exhaustion of recoverable resources is a fundamental question for the future extraction of coal and oil. Historical experience shows that peaking is a well established phenomenon in production of various natural resources. Coal and oil are no exceptions, and historical data shows that easily exploitable resources are exhausted while more challenging deposits are left for the future.

For oil, depletion can also be tied directly to the physical laws governing fluid flows in reservoirs. Understanding and predicting behaviour of individual fields, in particularly giant fields, are essential for understanding future production. Based on comprehensive databases with reserve and production data for hundreds of oilfields, typical patterns were found. Alternatively, depletion can manifest itself indirectly through various mechanisms. This has been studied for coal.

Over 60% of the global crude oil production is derived from only around 330 giant oilfields, where many of them are becoming increasingly mature. The annual decline in existing oil production has been determined to be around 6% and it is unrealistic that this will be offset by new field developments, additional discoveries or unconventional oil. This implies that the peak of the oil age is here.

For coal a similar picture emerges, where 90% of the global coal production originates from only 6 countries. Some of them, such as the USA show signs of increasing maturity and exhaustion of the recoverable amounts. However, there is a greater uncertainty about the recoverable reserves and coal production may yield a global maximum somewhere between 2030 and 2060.

This analysis shows that the global production peaks of both oil and coal can be expected comparatively soon. This has significant consequences for the global energy supply and society, economy and environment. The results of this thesis indicate that these challenges should not be taken lightly.

Clinical Studies in the Acute Phase of Subarachnoid Haemorrhage

Thu, 2 Sep 2010 13:25:52 +0200

Patients admitted in similar clinical condition after spontaneous SAH can develop very different clinical courses. This could depend on the severity of the initial global ischemic brain injury at ictus. In the present study, we explored relations between clinical and radiological parameters at admission that indicate a more severe initial impact, and the following days hormone levels and brain metabolism.

Early global cerebral oedema (GCE) on computed tomography occurred in 57 % of SAH patients and was associated with a more severe clinical condition. The brain’s glucose metabolism, measured with intracerebral microdialysis (MD), changed the first days. MD-glucose was initially high and MD-pyruvate low. MD-glucose gradually decreased and MD-pyruvate and MD-lactate increased, suggesting a transition to a hyperglycolytic state. This was more pronounced in patients with GCE. Similar patterns were seen for interstitial non-transmitter amino acids. From initial low concentrations, they gradually increased in parallel with MD-pyruvate. The amino acid concentrations were higher for patients admitted in better clinical condition. Insulin lowered MD-glucose and MD-pyruvate even when plasma glucose values remained high. P-ACTH and S-cortisol were elevated early after SAH. GCE was associated with higher S-cortisol acutely. Urine cortisol excretion, indicating levels of free cortisol, were higher in patients in a better clinical condition. Suppressed P-ACTH occurred in periods of brain ischemia.

We suggest that GCE on the first CT scan is a warning sign indicating increased vulnerability if the patient is exposed to compromised energy supply or increased energy demand. Reduction of blood glucose after SAH should be done with caution. The temporal change of the glucose metabolism and the amino acid concentrations probably reflect activated repair mechanisms. This should be considered in the intensive care treatment of SAH patients. Finally, our results support earlier observations that the response of the hypothalamic-pituitary-adrenal system is important in critical care.

In vivo Pharmacokinetic Interactions of Finasteride and Identification of Novel Metabolites

Fri, 3 Sep 2010 10:48:07 +0200

The general aim of this thesis was to improve the understanding of the in vivo pharmacokinetics and, in particular, the metabolism of finasteride, a 5α-reductase inhibitor used in the treatment of enlarged prostate glands and male pattern baldness. CYP3A4 has been identified as the major enzyme involved in the sequential metabolism of finasteride to ω-OH finasteride (M1) and ω-COOH finasteride (M3). The consequences of induced and inhibited metabolism on the pharmacokinetics of finasteride and its metabolites were investigated in humans and pigs. Both studies included bile collection. The collected human and pig samples were used for the metabolite identification.

As expected, induced metabolism led to reduced plasma exposure of finasteride and inhibited metabolism had the opposite effect. The interactions were investigated in detail and included examination of the biliary pharmacokinetics of finasteride and its metabolites. In pigs, the study included monitoring of the hepatic extraction over time, deconvolution and the development of a semi-physiological model for comparison of the effects on the gut wall and liver metabolism. For M3, the concentration ratios of bile to plasma and the renal clearance indicated that carrier-mediated processes are involved in the biliary and urinary excretion. This was not, however, the case for finasteride.

The metabolite, M1, could not be quantified either in humans or pigs. Instead, two other OH metabolites, M1 isomers, were identified in humans. These metabolites were found to undergo glucuronide conjugation. In humans, one glucuronide was identified intact and in pigs, both glucuronides were identified intact in bile and in urine. In addition, a glucuronide of M3 was identified in human bile.

In conclusion, advances have been made in the understanding of the pharmacokinetics of finasteride, in particular in relation to the metabolism. Hopefully, the findings of this comprehensive investigation can be applied to other drugs and novel chemical entities.

Applications of Four-Colour Fluorescent Primer Extension Technology for SNP Analysis and Discovery

Fri, 3 Sep 2010 14:10:59 +0200

Studies on genetic variation can reveal effects on traits and disease, both in humans and in model organisms. Good technology for the analysis of DNA sequence variations is critical. Currently the development towards assays for large-scale and parallel DNA sequencing and genotyping is progressing rapidly. Single base primer extension (SBE) is a robust reaction principle based on four-colour fluorescent terminating nucleotides to interrogate all four DNA nucleotides in a single reaction. In this thesis, SBE methods were applied to the analysis and discovery of single nucleotide polymorphism (SNP) in the model organism Drosophila melanogaster and in humans.

The tag-array minisequencing system in a microarray format is convenient for intermediate sized genotyping projects. The system is scalable and flexible to adapt to specialized and novel applications. In Study I of the thesis a tool was established to automate quality control of clustered genotype data. By calculating “Silhouette scores”, the SNP genotype assignment can be evaluated by a single numeric measure. Silhouette scores were then applied in Study I to compare the performance of four DNA polymerases and in Study III to evaluate freeze-dried reagents in the tag-array minisequencing system.

The characteristics of the tag-array minisequencing system makes it suitable for inexpensive genome-wide gene mapping in the fruit fly. In Study II a high-resolution SNP map, and 293 genotyping assays, were established across the X, 2^nd and 3^rd chromosomes to distinguish commonly used Drosophila strains. A database of the SNP markers and a program for automatic allele calling and identification of map positions of mutants was also developed. The utility of the system was demonstrated by rapid mapping of 14 genes that disrupt embryonic muscle patterning.

In Study III the tag-array minisequencing system was adapted to a lab-on-a-chip format for diagnostic testing for mutations in the TP53 gene. Freeze-drying was evaluated for storing reagents, including thermo-sensitive enzymes, on the microchip to reduce the complexity of the integrated test. Correct genotyping results were obtained using freeze-dried reagents in each reaction step of the genotyping protocol, both in test tubes and in single polymer test chambers. The results showed the potential of the approach to be implemented in fully integrated systems.

The four-colour chemistry of SBE has been developed further to allow massively parallel sequencing (MPS) of short DNA fragments as in the Genome Analyzer system (Solexa/Illumina). In Study IV MPS was used to compare Nimblegen arrays and the SureSelect solution-based system for targeted enrichment of 56 continuous human candidate-gene regions totalling 3.1 Mb in size. Both methods detected known SNPs and discovered novel SNPs in the target regions, demonstrating the feasibility for complexity reduction of sequencing libraries by hybridization methods.

The Nucleosome as a Signal Carrying Unit : From Experimental Data to Combinatorial Models of Transcriptional Control

Fri, 3 Sep 2010 08:37:36 +0200

The human genome consists of over 3 billion nucleotides and would be around 2 meters long if uncoiled and laid out. Each human somatic cell contains all this in their nucleus which is only around 5 µm across. This extreme compaction is largely achieved by wrapping the DNA around a histone octamer, the nucleosome. Still, the DNA is accessible to the transcriptional machinery and this regulation is highly dynamic and change rapidly with, e.g. exposure to drugs. The individual histone proteins can carry specific modifications such as methylations and acetylations. These modifications are a major part of the epigenetic status of the DNA which contributes significantly to the transcriptional status of a gene - certain modifications repress transcription and others are necessary for transcription to occur. Specific histone methylations and acetylations have also been implicated in more detailed regulation such as inclusion/exclusion of individual exons, i.e. splicing. Thus, the nucleosome is involved in chromatin remodeling and transcriptional regulation – both directly from steric hindrance but also as a signaling platform via the epigenetic modifications.

In this work, we have developed tools for storage (Paper I) and normalization (Paper II) of next generation sequencing data in general, and analyzed nucleosome locations and histone modification in particular (Paper I, III and IV). The computational tools developed allowed us as one of the first groups to discover well positioned nucleosomes over internal exons in such wide spread organisms as worm, mouse and human. We have also provided biological insight into how the epigenetic histone modifications can control exon expression in a combinatorial way. This was achieved by applying a Monte Carlo feature selection system in combination with rule based modeling of exon expression. The constructed model was validated on data generated in three additional cell types suggesting a general mechanism.

Lars Levi Læstadius' spiritualitet

Wed, 1 Sep 2010 14:14:57 +0200

The purpose of this study has been to be able to discern the core characteristics of the spirituality of Lars Levi Læstadius (1800-1861), minister of the Church of Sweden and originator of a large revival movement that carries his name. His spirituality is analysed as reflected in his mostly Finnish language sermons, out of which 466 are preserved. It is maintained that an adequate interpretation of the sermons can only be achieved through an understanding of their linguistic and rhetorical style and their principles of biblical exegesis. Accordingly, the initial focus of the study is on these three aspects, after which follows an analysis of the content. The very first chapter, however, investigates the biographical background of Læstadius’ spirituality, in particular the character of his spiritual breakthrough in 1844.

The study shows that Sámi oral culture, in which Læstadius was deeply rooted, is an important factor behind the style and principals of exegesis in his sermons. The sermons are metaphorical and narrative to a large degree. The rhetoric is oriented towards “the spiritual heart” and addresses the emotional life more than the intellectual life. The principals of exegesis have their closest parallel in patristic times, not in the 1800-s. A typological interpretation of the Bible based on a mimetic strategy of reading is dominant.

The study shows that the imagery of the sermons constitutes a cohesive ‘metaphorical universe’. The imagery is organised in ‘constellations of interplay’ in which the Christ figure of the gospels or a metaphor for God, and metaphorical role models for the listeners are depicted. Hermeneutical methods are employed in combination with statistical analysis to determine what constellations are central and how they are used. The four most central constellations are analyzed in detail; they are “the Saviour”, “the Heavenly Parent”, “the Shepherd” and “the Light”, designated according to their name for the triune God. However, “The Heavenly Parent” is Læstadius’ most frequent metaphor for God, and the image of God from which it springs determines his theology and spirituality. ‘Reconciliation’ with ones “Heavenly Parent” is his key concern, and this requires a humble attitude. The study shows that humility is the basic common quality of his prime role models, which means that this quality stands out as the most important ideal of his spirituality. The constellations of interplay show that a mystical experience of reconciliation and of being in God’s presence is Læstadius’ highest aim for his listeners, and thus a prominent characteristic of his spirituality.

As a whole, the study shows that Sámi culture was more important for Læstadius’ spirituality than has hitherto been acknowledged, and that the imagery of his sermons is not a poetic or sentimental expression, but one in which both biblical theology and mystical experience are involved.

Essays on Valuation of Environmental Attributes

Tue, 31 Aug 2010 13:06:06 +0200

This thesis consists of three self-contained essays.

Essay 1. Radon is a radioactive gas which may occur in buildings and originates mainly from radioactive bedrock and radioactive building materials. In this paper we examine the willingness-to-pay for mitigation of residential radon. A rich data set, from the municipality of Stockholm (Sweden) for the period 1994 - 1996, enables estimation of models accounting for spatial correlation. Our estimate of the marginal willingness-to-pay is approximately SEK 58 200. Our results show that failure to account for the spatial structure inherent in the data, tend to over-estimate the marginal willingness-to-pay for mitigation of residential radon.

Essay 2. This study examines the impact of a refinery on property values. The objective was to study the impact of the non-aesthetic view, the odor, and the impact of the reduced quality of coastal amenities in the surrounding area. To carry out the analysis, a spatial hedonic house price model was applied to transaction data enriched with a measure of visibility of the refinery determined by site inspection. The results indicate that all property values increase with distance to the refinery, but at more than twice the rate in the upwind direction, suggesting a negative effect of odor on property prices. In the proximity of the refinery, a view of the refinery tends to have a negative effect on property values, for example at 1 000 m the estimated effect is -24.5 %. At larger distances, as other positive objects in the view become dominant, the effect turns positive. At 2 000 m the effect is 0.8 %. To study the impact of the reduced quality of coastal amenities, we examined the premiums paid for properties with a sea front and sea view. The results show large differences in premiums and the estimated premium for a sea front (view) in a non-adjacent parish is 139.4 % (69.0 %) and in an adjacent parish 47.7 % (23.7 %), suggesting that a lower quality of coastal amenities could have a strong negative effect on property values.

Essay 3. In this paper we conduct a choice experiment to assess aesthetic improvements in the neighborhood of a refinery located on the Swedish west coast. Considered improvements are: a reduction of vessels operating the refinery jetty, elimination of the odor of crude oil, and removal of the chimneys. We find that respondents marginal willingness-to-pay for an elimination of the odor of crude oil amounts to SEK 3 075. The marginal willingness-to-pay for removal of the chimneys is estimated to SEK 2 082. We find no support for preferences in favour of a reduction of vessels operating the refinery jetty. We also examine if the preferences for the aesthetic improvements differ between permanent residents and second-home owners. The results suggest that both groups have the same preferences regarding the proposed improvements in the environment surrounding the refinery.

Surface and Interface Studies of ZnO using Reactive Dynamics Simulation

Thu, 2 Sep 2010 14:34:48 +0200

About 90% of all chemicals are produced with the help of catalysts, substances with the ability to accelerate reactions without being consumed. Metal oxides play a prominent role in catalysis, since they are able to act reversibly in many chemical processes. Zink oxide (ZnO) is used to catalyse a number of industrially important reactions. For many of these reactions water is present as a reactant, product, or byproduct. The surface structure has a significant impact on the catalytic activity. However, currently, no experimental method simultaneously offers the spatial and temporal resolution to directly follow a catalytic process.

This thesis explores surface structure dependent dynamical behavior for ZnO surfaces, nanoparticles, and water interfaces, using the computational chemistry method Molecular Dynamics, which enables detailed studies of structural and dynamical processes. Quantum mechanical (QM) calculations have been performed to obtain the energetics of the materials as a function of structure. This data has been used to parametrize reactive force-fields (ReaxFF), since the catalytic processes require both far larger and longer simulations than the capabilities of QM calculations on current computers.

The simulations show that when steps are present on the surface, during crystal growth of ZnO, the creation of energetically favorable structures is accelerated. At the ZnO - water interface, structures that favor hydrogen bonding is promoted. At low, monolayer, coverage water adsorbs both molecularly and dissociatively, whereas at high coverage dissociated adsorption is favored. During evaporation from the monolayers, the ratio of dissociated and molecular water is preserved. Surface steps stabilizes the dissociated state as well as increases the rate of dissociation. The dynamical properties of ZnO nanoparticles were explored using Raman measurements and simulation. In both simulation and experiment certain vibrations were suppressed in the nanoparticles, compared to bulk. The simulations show that a narrow surface region lack the bulk-specific vibrations.

When Cheap is Good : Cost-Effective Parent and Teacher Interventions for Children with Externalizing Behavior Problems

Fri, 3 Sep 2010 14:36:56 +0200

There is strong empirical support for behavioral parent training (BPT) as an intervention for children with externalizing behavior problems (EBP). However, there is a lack of studies that have investigated the effectiveness of BPT in routine care. Furthermore, most families in need of service do not gain access to it. Another issue of concern is that a sizable portion of children who take part in BPT does not show clinical significant improvement. With regard to behavioral teacher training (BTT) for students with EBP, there is a paucity of intervention trials using randomized design. The training procedures have rarely been standardized, which have resulted in interventions that are dependent upon heavy involvement of external consultants. To improve the accessibility to service for students with EBP, intervention models that are feasible for typical school personnel need to be developed.

Study I investigated the effects of BPT in routine care. The participants were randomized to BPT with full practitioner support (BPT-P), self-administered BPT with minimal practitioner support (BPT-S), or a waitlist control group (WL). The study showed that BPT implemented by briefly trained social service employees (BPT-P) resulted in at least as large effects as previous efficacy studies. PMT-S also showed significant effects compared to the WL, but was less effective than PMT-P. Improvements in child behaviors were mediated by improved parenting behaviors. Study II investigated the effects of an enhanced version of the BPT-program from study I. The program targeted families with risk factors for non-response that were referred to service within the social services. The results showed strong intervention effects on child EBP and parent anxiety/depression for enhanced BPT compared to regular BPT. Study III used a randomized design to evaluate the effects of a standardized and feasible BTT program. At both posttest and follow-up, significant effects favoring the BTT-group over the active control group were found on student EBP, teacher behavior management, and peer problems. The study also showed that the effect on student EBP was mediated by change in teacher behavior management.

Success as Science but Burden for Business? : On the difficult relationship between scientific advancement and innovation

Fri, 27 Aug 2010 14:48:15 +0200

Today, a general policy and investment recipe for economic growth and innovation, on both a national and an international level, is to base commercial ventures on novel scientific solutions. From this perspective, scientific research is seen as an untapped source of innovation, and the ambition is to make new scientific knowledge more easily transferable to business settings, where it is supposed to generate direct economic benefits. Since the instigation of the Human Genome Organisation Project in 1990, which set out to map the entire genetic composition of the average human being, great expectations have been put on biotechnology, and it has been viewed as the new gold mine for both scientific and business advancement. Through research it is expected to deliver new scientific knowledge primarily about previously untreatable illnesses and, as an industry, it is expected to produce new technical solutions realising this knowledge. This expectation has directed large amounts of investment capital to biotechnology in the pursuit of capitalising on new scientific discoveries through their commercialisation. This investigation is an empirically based process study of one such innovation process. With a network approach, focusing particularly on resource combinations, this study aims to create a better understanding of what is involved in trying to achieve innovation based on new scientific solutions. The specific case of the commercialisation of pyrosequencing, a new method for the analysis of genetic material, demonstrates the difficulty of making a scientific breakthrough into a useful business resource. The innovation process is investigated from several perspectives. By looking at the development of something new, at its large-scale production, and widespread use, this study shows how these aspects represent vastly different economic logics. It also demonstrates how great a challenge it can be for these to function together in the attempt of achieving successful innovation.

The Cyanobacterial Uptake Hydrogenase : Regulation, Maturation and Function

Fri, 3 Sep 2010 11:30:04 +0200

With accellerating global warming and pollution problems a change of energy regime is necessary. Solar energy offers a clean and unlimited energy source of enormous potential. Due to it’s intermittenet nature solar energy must be stored - ideally in the chemical bond of a carrier molecule. Hydrogen gas, H₂, an energy carrier with water as only emission when used in a fuel cell, is considered to be the choise for the future. In this context cyanobacteria show promising potential as future H₂ factories since they can produce H₂ from solar energy and water. The main enzymes directly involved in cyanobacterial hydrogen metabolism are nitrogenases and hydrogenases. Cyanobacterial hydrogenases are either uptake hydrogenases or bidirectional hydrogenases and their maturation requires assistance of six maturation proteins and two hydrogenase specific proteases. In this thesis the transcriptional regulation, maturation and function of the cyanobacterial uptake hydrogenases were investigated in the filamentous, heterocyst forming strains Nostoc punctiforme ATCC 29133 and Nostoc sp. strain PCC 7120. Five genes, encoding proteins putatively involved in the maturation of the uptake hydrogenase were identified upstream the known maturation genes. Two transcription factors, CalA and CalB, were found interacting with the stretch of DNA forming the upstream regions of the uptake hydrogenase structural genes and the novel maturation genes. The expression of the uptake hydrogenase were heterocysts specific and the specificity mapped to a short promoter region starting -57 bp upstream the transcription start point. In addition, the function of the uptake hydrogenase was inserted in a metabolic context. Among the proteases, a conserved region was discovered possibly involved in determining the hydrogenase specificity. This thesis has given valuable information about the transcriptional regulation, maturation and function of the uptake hydrogenase in filamentous, heterocystous cyanobacteria and identified new targets for bioengineering of mutant strains with higher H₂ production rates.

Modeling of Electron Cooling : Theory, Data and Applications

Fri, 3 Sep 2010 09:15:23 +0200

The Vlasov technique is used to model the electron cooling force. Limitations of the applicability of the method is obtained by considering the perturbations of the electron plasma. Analytical expressions of the electron cooling force, valid beyond the Coulomb logarithm approximation, are derived and compared to numerical calculations using adaptive Monte Carlo integration. The calculated longitudinal cooling force is veriﬁed with measurements in CELSIUS.

Transverse damping rates of betatron oscillations for a nonlinear cooling force is explored. Experimental data of the transverse monochromatic instability is used to determine the rms angular spread due to solenoid ﬁeld imperfections in CELSIUS. The result, θ_rms= 0.16 ± 0.02 mrad, is in agreement with the longitudinal cooling force measurements. This veriﬁes the internal consistency of the model and shows that the transverse and longitudinal cooling force components have different velocity dependences. Simulations of electron cooling with applications to HESR show that the momentum reso- lution ∆p/p smaller than 10⁻⁵ is feasible, as needed for the charmonium spectroscopy in the experimental program of PANDA. By deﬂecting the electron beam angle to make use of the monochromatic instability, a reasonable overlap between the circulating antiproton beam and the internal target can be maintained. The simulations also indicate that the cooling time is considerably shorter than expected.

Long-term Effects of Opioids in the Treatment of Chronic Pain : Investigation of Problems and Hazards on Clinical, Biochemical, Cellular and Genetic Levels

Thu, 2 Sep 2010 14:25:08 +0200

After two decades of liberal prescribing of opioids, there has been an increasing recognition of problems connected to the prolonged use of opioids for chronic pain.

The aim of my thesis was to explore some consequences of long-term opioid treatment for chronic pain such as problematic opioid use, endocrine disorders, tolerance and genetic variations in pain and opioid response.

Sixty patients with severe pain and problematic opioid use were treated with a structured methadone programme. Risk factors were musculoskeletal pain, psychiatric co-morbidity and previous addiction. Treatment resulted in good pain relief and improved quality of life, but function was impaired by side effects indicating endocrine dysregulation.

The possibility of opioid-induced endocrine dysfunction was explored in the second paper, where 40 pain patients treated with strong opioids and 20 pain patients without treatment of strong opioids were investigated. The opioid-treated patients had significantly higher incidence of endocrine disturbance affecting gonadal and adrenal function and prolactin levels.

The functionality of the μ-receptor after long-term treatment with morphine, saline and naloxone was explored in a cell-line expressing the μ-receptor. After one and four weeks of treatment the binding was tested with morphine, methadone, fentanyl and DAMGO and function measured by GTP γ-assay. The binding of DAMGO was significantly diminished after 4 weeks in cells treated with morphine compared with saline and naloxone.

Genetic variation in three genes with functional impact on opioid response and pain sensitivity was investigated in 80 patients with chronic low-back pain and differential opioid sensitivity and in 56 healthy controls. The results indicated a higher incidence of opioid-related side effects and gender differences in patients with the minor allele of the ABCB1 gene, a correlation between increased opioid sensitivity and the major CACNA2D2 allele and a possible relationship between intrinsic protection against chronic pain and the minor allele of OPRM1.

Long Noncoding RNA Mediated Regulation of Imprinted Genes

Thu, 2 Sep 2010 10:27:24 +0200

Genomic imprinting is an epigenetic phenomenon that causes a subset of mammalian genes to be expressed from only one allele in a parent-of-origin manner. The defects in the imprinting regulation result in disorders that affect development, growth and metabolism. We have used the Kcnq1 imprinted cluster as a model to understand the mechanism of imprinted gene regulation. The imprinting at the Kcnq1 locus is regulated by a long noncoding RNA, Kcnq1ot1, whose transcription on the paternal chromosome is associated with the silencing of at least eight neighboring genes.

By destabilizing Kcnq1ot1 in an episomal system, we have conclusively shown that it is the RNA and not the process of transcription that is required for the gene silencing in cis. Kcnq1ot1 RNA interacts with the chromatin modifying enzymes such as G9a and Ezh2 and recruits them to imprinted genes to establish repressive chromatin compartment and gene silencing.

Using the episomal system, we have identified an 890 bp silencing domain (SD) at the 5’ end of Kcnq1ot1 RNA, which is required for silencing of neighboring reporter genes. The deletion of the SD in the mouse resulted in the relaxation of imprinting of ubiquitously imprinted genes (Cdkn1c, Kcnq1, Slc22a18, and Phlda2) as well as reduced DNA methylation over the somatic DMRs associated with the ubiquitously imprinted genes. Moreover, Kcnq1ot1 RNA interacts with Dnmt1 and recruits to the somatic DMRs and this recruitment was significantly affected in the SD mutant mice.

By using a transgenic mouse, we have conditionally deleted Kcnq1ot1 promoter at different developmental stages and demonstrated that Kcnq1ot1 maintains imprinting of the ubiquitously imprinted genes by regulating DNA methylation over the somatic DMRs. Kcnq1ot1 is dispensable for the maintenance of repressive histone marks and the imprinting of placental-specific imprinted genes (Tssc4 and Osbpl5).

In conclusion, we have described the mechanisms by which Kcnq1ot1 RNA establishes and maintains expression of multiple imprinted genes in cis.

Evolution of the Neuropeptide Y and Opioid Systems and their Genomic Regions

Thu, 9 Sep 2010 08:35:32 +0200

Two whole genome duplications (2R) occurred early in vertebrate evolution. By using combined information from phylogenetic analyses and chromosomal location of genes, this thesis delineates the evolutionary history of two receptor-ligand systems that expanded by these large scale events. A third whole genome duplication (3R) took place in the teleost fish lineage and has also contributed to the complexity of the gene families.

New members of neuropeptide Y (NPY) peptide and receptor families were generated in 2R and 3R. Evolutionary comparisons show that the ancestral teleost fish had four peptides; subsequently, differential losses of the peptide genes occurred. In zebrafish the peptides and receptors display differences in tissue distribution and have evolved binding preferences. In the frog Silurana tropicalis three peptides and six receptors werev identified, also displaying some differences in tissue distribution and receptor-ligand preferences. The findings in these experimental animals highlight both evolutionary conservation and lineage-specific features of the NPY system.

The opioid system consists of four receptors and several peptides originating from four precursors. These results show that the receptor family was formed in 2R and 3R and that 2R together with one local duplication gave rise to the peptide family. The ancestral receptor and peptide genes were located on the same chromosome, suggesting coevolution. The Hox gene clusters, important in early development, provided the first strong evidence for 2R. Several neighboring gene families were analyzed and found to have expanded in 2R and 3R. In depth analyses of insulin-like growth factor binding protein (IGFBP) and voltage-gated sodium channel (SCN) gene families illustrates the importance of local duplications in combination with whole genome duplications in the formation of gene families.

These findings provide additional strong evidence for two genome duplications in early vertebrate evolution and show that these events generated many new genes that could evolve new or more specialized functions.

"VEM är jag?" : Det lyriska subjektet och dess förklädnader i Tomas Tranströmers författarskap

Mon, 30 Aug 2010 13:04:21 +0200

The aim of this dissertation is to examine how the lyrical subject is presented in Tomas Tranströmer’s poetry and prose. Crucial concepts such as the lyrical subject, autobiography, and the memoir are thoroughly discussed and defined based on modern research.

The first chapter is devoted entirely to Tranströmer’s prose. Unlike previous studies, this dissertation seeks to establish the genre to which the poet’s memoirs belong. The comparative analysis I use in my dissertation enables us to see both the differences and the similarities in the way that Tranströmer presents the lyrical subject in his prose and poetry. I have taken into account the motifs used by Tranströmer in his memoirs as well as in his poetry.

The next chapter discusses the Swedish reception of modernism, a literary movement, which also according to Tranströmer himself, greatly influenced his literary debut in Sweden in the 1950s.

The subsequent chapters of my dissertation are devoted to an analysis of Tomas Tranströmer’s poems, which I classify on the basis of how they express the lyrical subject. I analyze both the way the lyrical subject is expressed and its place in the poem. Even though Tomas Tranströmer often uses his own experiences in his works, he transforms them in order to make them more universal. Thus, the lyrical subject is not identical with the poet himself. At the same time, the way the lyrical subject is expressed in a poem highlights its personal character.

In the conclusion of the dissertation it is argued that further research is needed to establish whether the selection of Tomas Tranströmer's poems made by the editors of various anthologies may have influenced the reception of his poetry as being objective and impersonal.

Health-Related Quality of Life in Asthma

Wed, 8 Sep 2010 12:38:01 +0200

Health-related quality of life (HRQL) has become an important outcome in asthma, since traditional outcomes, such as respiratory symptoms and pulmonary function, might not entirely express the patient’s perception of the limitations caused by the disease. The aim of this thesis was to study HRQL in asthma and to analyse if HRQL was related to asthma onset and prognosis. Other aims were to identify determinants of low HRQL in clinically-verified asthmatics, and to study whether low HRQL was a predictor of mortality.

In 1990, a self-administered questionnaire was completed by 12,560 individuals from three age groups (16, 30-39, and 60-69 years) in two counties of Sweden. In a second phase, all subjects who reported a history of obstructive respiratory symptoms (n = 1,851) and 600 randomly-selected controls were invited to a clinical investigation including spirometry, allergy testing, and assessment of HRQL with the Gothenburg Quality of Life instrument. In 2003, the eligible subjects in the cohort (n=11,282) were sent a new questionnaire. Mortality data in the cohort was followed up during 1990–2008 using data from the National Board of Health and Welfare Mortality Database.

The 616 subjects with clinically-verified asthma 1990 had significantly lower HRQL than subjects without asthma. In the 2003 follow-up, the 305 subjects with persistent asthma had a lower HRQL than the 155 subjects who showed improvement in asthma during the follow-up. Subjects who had developed asthma by the follow-up had a significantly lower HRQL at baseline than those who did not develop asthma. Significant determinants of quality of life in asthma were female sex, smoking habits, higher airway responsiveness to irritants, respiratory symptom severity, positive skin prick test, and absenteeism from work or school. Low HRQL was related to increased mortality, but this association was not found when analyzing the asthmatic group alone.

In conclusion, measurements of HRQL are of value for evaluating both the impact and progression of asthma.

Att leva tillsammans : En studie i kristen och feministisk sexualetik

Mon, 30 Aug 2010 11:40:12 +0200

There is an ongoing change in our society within the fields of sexual relationships. Along with new experiences there is a need for a shifting Christian ethical and theological reflection. The first aim of the dissertation is to analyze four models of Christian sexual ethics, all with an ambition to be reconstructive towards more traditional sexual ethics. The second aim is to criticize the models and make constructive proposals to a Christian and feminist sexual ethics. The theoretical outlook of the study is feminist theology with inspiration from the work of Michel Foucault on sexuality and Anthony Giddens on relationship.

Lisa Sowle Cahill provides and argues for a sexual ideal from a Catholic tradition. By observing the functions of the body she distinguishes an ideal of heterosexual and fertile sexual relationships in a context of equality. Margaret Farley, representing the second model, is with Cahill arguing for a feminist view. Farley though turns to the norm of justice and puts the questions of just relationship in the center of her sexual ethical reflection. The third model is from the work of the Anglican theologian Adrian Thatcher. He puts the love of Christ and a life for others in focus. Mark Jordan is the last model and is working with the Christian tradition from a queer perspective. The work and life of eros, together with sexual pleasure, is what should govern sexual relations.

My main objections are the idea of an essence of sexuality and a supposed connection between the same essence of sexuality and norms for relationships. Instead I suggest a strategic understanding of sexuality, where the norm of right relationships should decide how sexuality should be understood. What I propose in the constructive part of the dissertation is that a person should be understood as both having authority and responsibility. What is of importance is to pay attention and criticize social structures that prevent people to act with authority and responsibility in their intimate affairs. From the norms of Margaret Farley, I draw the importance of commitment, making authority as well as responsibility possible within relationships.

Querying Data Providing Web Services

Mon, 30 Aug 2010 09:25:18 +0200

Web services are often used for search computing where data is retrieved from servers providing information of different kinds. Such data providing web services return a set of objects for a given set of parameters without any side effects. There is need to enable general and scalable search capabilities of data from data providing web services, which is the topic of this Thesis.

The Web Service MEDiator (WSMED) system automatically provides relational views of any data providing web service operations by reading the WSDL documents describing them. These views can be queried with SQL. Without any knowledge of the costs of executing specific web service operations the WSMED query processor automatically and adaptively finds an optimized parallel execution plan calling queried data providing web services.

For scalable execution of queries to data providing web services, an algebra operator PAP adaptively parallelizes calls in execution plans to web service operations until no significant performance improvement is measured, based on monitoring the flow from web service operations without any cost knowledge or extensive memory usage.

To comply with the Everything as a Service (XaaS) paradigm WSMED itself is implemented as a web service that provides web service operations to query and combine data from data providing web services. A web based demonstration of the WSMED web service provides general SQL queries to any data providing web service operations from a browser.

WSMED assumes that all queried data sources are available as web services. To make any data providing system into a data providing web service WSMED includes a subsystem, the web service generator, which generates and deploys the web service operations to access a data source. The WSMED web service itself is generated by the web service generator.

Influence of chemical interaction at the lattice-mismateched h-BN/Rh(111) and h-BN/Pt(111) interfaces on the overlayer morphology

Tue, 7 Sep 2010 15:03:00 +0200

The atomic and electronic structure of the lattice-mismatched h-BN/Pt(111) and h-BN/Rh(111) interfaces formed by pyrolitic reactions with vaporized borazine has been studied by low-energy electron diffraction, scanning tunneling microscopy, x-ray-absorption spectroscopy, and core-level and valence-band photoemission. It has been found that on Pt(111), h-BN forms a nearly flat monolayer, insignificantly corrugated across the supercell. On Rh(111), h-BN grows in form of a nanomesh, as originally observed by Corso [Science 303, 217 (2004)]. The structural difference between the h-BN/Pt(111) and h-BN/Rh(111) interfaces is associated with the strength of chemical interaction between h-BN and the substrate surface. A stronger orbital hybridization on Rh(111) results in a stronger attraction of the monolayer to the metal surface at favorable adsorption sites resulting in a highly corrugated structure (nanomesh). It has been shown that the electronic structure of the outer (elevated) and inner (attracted to the surface) nanomesh sites is very different as a result of different chemical bonding to the substrate (weak and strong, respectively).