Towards New Therapeutic Targets: Identification of Novel Tumor Markers in Chronic Lymphocytic Leukemia

Chronic Lymphocytic Leukemia (CLL) is the most common leukemia in the Western world and is caused by an abnormal accumulation of B lymphocytes in peripheral blood, bone marrow and lymphoid organs. It is a disease mainly of adults. The clinical outcome of CLL may differ significantly. Some patients have an indolent leukemia with long survival, while others experience an aggressive disease, with an acute need for treatment. At present, no treatment regimen can be considered curative. Novel therapeutic approaches are required. Those aimed at directing the body’s natural defense system against the tumor cells require well characterized targets that are exclusively expressed by the tumor cells. In 2001, microarray studies revealed FMOD, a member of the Small Leucine Rich Proteoglycan family (SLRP) and ROR1, a member of the Receptor Tyrosine Kinase (RTK) family, as two genes being overexpressed in CLL compared to healthy controls. SLRPs are normally expressed and secreted into the extracellular matrix of collagen-rich tissues. They interact with collagen and participate in signaling regulation by the interaction with integrins, growth factors and their receptors. RTKs are transmembrane receptors for growth factors, cytokines and hormones and play important roles in cellular processes including proliferation, differentiation, migration, metabolism and survival. The ectopic expression of FMOD and ROR1 in CLL was unexpected and was the prelude to this thesis. FMOD is located on chromosome 1 adjacent to two other members of the SLRP family; PRELP and OPTC. In this project, we investigated FMOD, PRELP, OPTC and ROR1 at the gene as well as protein levels and their expression in CLL compared to healthy individuals and other hematological malignancies. We also investigated the effect of siRNA silencing of FMOD and ROR1 in CLL and normal control cells. FMOD, PRELP, OPTC and ROR1 were expressed in all CLL patients but not in normal controls. ROR1 was detected on the surface of CLL cells, which corresponds to the natural ROR1 localization. PRELP and OPTC, on the other hand, seemed to be abnormally retained within the CLL cells, rather than secreted. The PRELP and OPTC proteins expressed in CLL were further investigated and found to be differentially glycosylated compared to their normal counterparts. The molecular weight of the detected PRELP and OPTC corresponded to completely unglycosylated core proteins. PRELP was detected in the cytosol of CLL cells, while CLL OPTC was found in the nucleus and endoplasmic reticulum. Using siRNA technology, FMOD and ROR1 were efficiently downregulated which resulted in apoptosis of CLL cells but not of B cells from healthy donors. This suggests that FMOD and ROR1 may be important for the survival of CLL cells. In conclusion, four genes, FMOD, PRELP, OPTC and ROR1, were found to be ectopically expressed by CLL cells. At least two of these genes, FMOD and ROR1, may be important for CLL cell survival. The reason for the aberrant expressions is not yet known, but once elucidated it may contribute to the understanding of the pathogenesis of CLL. Also, these novel markers might be suitable targets for future immunotherapy in CLL

Pilgrimage as post-secular therapy

This article describes the institutionalized pilgrim role and then turns to the therapeutic discourse which is so prominent in the modern pilgrimage to Santiago de Compostela. Both the role and the discourse can be related to the concept of post-secularity, demonstrating that complex cultural fields such as religion and therapy, become intertwined in new ways through modern pilgrimage. This article also shows that churches cooperating in this type of pilgrimage are adapting to the post-secular age, finding a new sort of raison d’être in a multi-religious, international world. Here the author refers to the Church of Norway and its role in Norwegian pilgrimage. The latter is modelled upon the Santiago example

Short Attosecond Pulse Trains at High Repetition Rates for Novel Pump-Probe and Coincidence Studies

This work aims at studying photoionization dynamics from atoms and surfaces at attose time scales. The work was based on development and applications of a high repetition rate High-order Harmonic Generation (HHG) light source that utilizes Optical Parametric Amplification (OPA) laser technology. The laser system delivers few-cycle pulses in the near infrared (IR) at a repetition rate of 200 kHz. Through the use of advanced pulse characterization techniques, the pulse quality was kept high in order to ensure efficient HHG at relatively low pulse energies. In the HHG process, a short extreme ultraviolet (XUV) light pulse of attosecond duration is produced with every half cycle of the driving field.When performing HHG with driving pulses in the few-cycle regime, a short attosecond pulse train consisting of only a handful pulses is generated. The spectral properties and temporal structure of the HHG radiation was explained in terms of interference between attosecond pulses. The number of pulses can be controlled with the Carrier-to-Envelope Phase (CEP). The short pulse trains were used together with a weak IR field for two-color photoionization, measured with a 3D momentum imaging spectrometer. The angle-resolved photoionization spectra are found to be asymmetric, and behave distinctly different depending primarily on the number of pulses that are used for ionization. In the case when two pulses are used, the electron peaks are shifted, but when the number is increased to three, additional peaks appear. This was explained using an attosecond time-slit interference model.The coincidence capabilities of the photoelectron spectrometer were utilized to measure single-photon double-ionization of helium for the first time with an HHG source. This challenging measurement combines the coincidence and imaging properties of the spectrometer with the efficient generation of high harmonics, and is only possible due to the high repetition rate of the source. The full Triple Differential Cross Section (TDCS) was obtained for a range of energies. Additionally, the IR light source was used for surface science applications, which benefit strongly from a high repetition rate. Light-wave driven currents in semiconductor materials were measured at a higher repetition rate and with longer pulses than reported previously. Plasmon dynamics in gold nanosponges and induced at the edges of thin layers of the Transition Metal Dichalcogenide (TMD) WSe2 were studied

Caminoization at Sea: The Fjord Pilgrim route in Norway

Based on official church and public-sector documents and texts related to the Fjord Pilgrim Route, we discuss how a process of Caminoization is expressed in Norway, both in relation to how this new invention relates to the medieval pilgrimage culture of the country, and how it inspires developments in the so-called pilgrimage renaissance in modern, Protestant Norway. The new construction of the Fjord Route demonstrates not only the Camino’s influence on contemporary pilgrimage in Europe, but also its scope for innovation in a broad field that encompasses state, church, country, and tourist organization actors. Focusing on the role of history and heritage in the Fjord Pilgrim Route, we argue that Caminoization, traditionalization, and heritagization are key factors that affected the establishment of the new Fjord Route and Norwegian pilgrim culture.acceptedVersio

Ground Water and Surface Water Influence on the Water Quality in the Antequera River basin, Bolivia : A Minor Field Study

The Antequera Basin of 150 km2 is a sub-basin to Lake Poopó, located at an altitude of 3800 meters above sea level on the Bolivian high plateau. Lake Poopó is a terminal lake with high salinity and heavy pollution from centuries of extensive mining activity. The climate is semiarid-cold with an average precipitation of 450 mm/year and potential evaporation of 1700 mm/year. Almost all rain falls during December to March and the temperature varies from -2 to 18°C during the summer and from -10 to 14°C during the winter. Antequera River is seasonal, only carrying water during the rainy season. The social situation is marked by poverty and scarcity of water. The sub-basin Antequera has a population of about 4300 inhabitants. The inhabitants of lower part of the basin mainly earn their living from agriculture and livestock and in the upper part mining activity is important. The water quality is fairly good in the uppermost part of the basin while there are problems with pollution due to mining activity further down. This study aims to investigate the ground water and surface water system in River Antequera and how the water quality changes along the river. Also to find out if anthropogenic and natural influences affect the surface water quality. A field study was done at the end of the rainy season, in the beginning of March 2008, to collect water samples and measure river flow, pH and TDS. The samples were analyzed regarding concentrations of Ca2+, Mg2+, Na+, K+, SO42-, NO3-, Cl- and alkalinity. The water quality and flow was compared along the river to find out if anthropogenic influence and ground water affect the surface water quality. In the uppermost part of Antequera basin the river water quality is of fairly good quality except in regards of nitrate. A bit further downstream the area is full of old mine residue and active and deserted mines surround the river. pH in the river drops to around 2-3 here and remains low throughout its course. All concentrations of analyzed ions increase significantly in the reach through the mine district due to extensive weathering. Further south a tributary is connecting and this result in dilution. As the river approaches the low land all ion concentrations increase which indicates intrusion of shallow ground water. Sodium and chloride keeps increasing toward the saline Lake Poopó. Measurements of total dissolved solids (TDS) in wells show ground water becoming more saline close to the lake

Färgen mellan husen

Färg finns överallt omkring oss och är avgörande för vårt seende och hur vi visuellt uppfattar och förstår vår omgivning. Färg har också fysiologisk och psykologisk effekt på människor och påverkar våra känslor, vårt mående och beteende. Uppsatsen undersöker hur forskning om färgs påverkan på människor kan användas inom landskapsarkitektur för att skapa levande och trivsamma platser i staden. För att sätta färgforskning i en landskapsarkitekturkontext, används arkitekten Jan Gehls forskning om hur vi bör utforma städer och offentliga rum med den enskilda människans behov och upplevelse av stadsrummet som utgångspunkt. Genom litteraturstudie undersöks färgforsknings relevans för landskapsarkitektur i perspektiv av Jan Gehls etablerade och välanvända teorier om stadsbyggande. Studien visar att forskning om färg ur ett miljöpsykologiskt perspektiv kan komplettera delar av Jan Gehls teorier och visar på aspekter där färg kan användas som ett gestaltningsverktyg för att skapa attraktiva stadsrum.Colour is everywhere around us and is crucial to our vision and how we visually perceive and understand our surroundings. Colour also has a physiological and psychological effect on people and affects our emotions, mood and behavior. The thesis examines how research on the impact of colours on people can be used in landscape architecture to create lively and pleasant places in the city. To put colour research in a context of landscape architecture, the architect Jan Gehl's research on how we should design cities and public spaces with the needs and experience of the urban space as a starting point, is used. Through a literature study, the relevance of colour research to landscape architecture is examined in the perspective of Jan Gehl's established and well-used theories on urban design. The study shows that research on colour from an environmental psychology perspective can complement parts of Jan Gehl's theories and shows aspects where colour can be used as a design tool to create attractive urban spaces

Gjenfødsel på caminoen til Santiago de Compostela

Caminoen til Santiago de Compostela er i dag Europas viktigste pilegrimsvei. Den tiltrekker seg reisende fra store deler av verden med ulik religiøs og livssynsmessig bakgrunn. Artikkelen fokuserer på oppfatninger av caminoen som et liminalt, transformativt rom. Kildene er vandringsberetninger og refleksjoner i tidsskriftet Pilegrimen, medlemsbladet til Pilegrimsfellesskapet St. Jakob. Hensikten er å vise noe av variasjonen i hvordan vandrere opplever fornyelse og gjenfødsel ved å gå caminoen, og hvordan bladets formidling gjenspeiler en forskyvning mot individualisert, kroppsorientert åndelighet, som mange forskere hevder er karakteristisk for senmoderne religionsutvikling

Alternative oxidase respiration in the mycorrhizal fungus Laccaria bicolor

The temperature on Earth is rising, and one of the main drivers is anthropogen-ic greenhouse gases such as carbon dioxide (CO2). The world’s forests act as carbon sinks, binding carbon into their biomass. The net carbon assimilation is determined by the uptake and release of CO2 through the processes of photo-synthesis and respiration. Respiration in plants and most fungi can proceed via two pathways. The most frequently used pathway ends with the terminal com-plex Cytochrome C oxidase (COX), but it can also follow a less efficient alter-native pathway, which ends with Alternative oxidase (AOX). The rate by which plants and other organisms use the alternative pathway affects their carbon use efficiency. Both enzymes use atmospheric oxygen as their substrate, but they discrimi-nate differently against the isotope 18O. In this study, the presence of AOX in the mycorrhizal fungus Laccaria bicolor was proven, using isotope ratio mass spectrometry (IRMS). Based on the 18O discrimination of the mycelium in the presence of pathway specific inhibitors, the electron partitioning to each path-way in untreated mycelium (i.e. without inhibitors) was estimated. As found in previous studies on plants, the discrimination was found to be affected by the water content of the sample. Since this effect was probably derived from diffusion limitation, all discrimination values were normalized to correspond to the mean water content, 94.4%. The 18O discrimination of L. bicolor was found to be 18.8±0.9, which is comparable to COX values previ-ously found in plants and to discrimination values of baker’s yeast, Saccar-omyces cerevisiae, which lacks AOX. This indicated that the use of AOX in young mycelium of L. bicolor was negligible. However, a correlation was dis-covered between AOX contribution and age, suggesting that AOX plays an increasingly important role in ageing mycelium. The oxygen isotope discrimination method is currently the only reliable way of measuring AOX/COX partitioning during respiration. However, despite numerous studies in various species, this is the first time it has been applied to fungal mycelium, and as such it represents an important step towards a greater understanding of fungal respiration. Further studies of fungal AOX under natu-ral conditions, in combination with estimations of fungal biomass, has a great potential to improve the accuracy of carbon sequestration models.Temperaturen på Jorden stiger, och en av de främsta orsakerna är antropogena växthusgaser som koldioxid (CO2). Världens skogar fungerar som kolsänkor, då de binder in kol i sin biomassa. Den totala mängd kol som lagras in bestäms av upptag och avgång av CO2 under fotosyntes och respiration. Respiration i växter och de flesta svampar kan ske via två olika vägar. Den mest använda avslutas med enzymet cytokrom C (COX), medan den alternativa och mindre effektiva vägen slutar med enzymet alternativt oxidas (AOX). Användandet av AOX påverkar hur effektivt organismen använder kolet den tar upp. Båda enzymerna använder sig av syre från atmosfären som substrat, men de diskriminerar olika starkt mot syreisotopen 18O. I den här studien visas att en-zymet AOX finns i mykorrizasvampen Laccaria bicolor, och dess användning mäts med hjälp av masspektrometri av isotopiska förhållanden (IRMS). Dis-krimineringen av syreisotopen 18O uppskattades för varje enzym med hjälp av inhibitorer och användes sedan för att räkna ut elektrondelningen mellan de olika respirationsvägarna i obehandlat mycel, d.v.s. utan tillsatta inhibitorer. Liksom i tidigare studier visade sig diskrimineringen vara påverkad av pro-vets vatteninnehåll. Eftersom denna effekt troligtvis uppkommit på grund av diffusionsbegränsning av substratet normaliserades alla diskrimineringsvärden till det som motsvarade det genomsnittliga vatteninnehållet, 94,4%. Diskrimi-neringen av 18O i L. bicolor var 18,8±0,9, vilket är jämförbart med de värden som presenterats för växter och jästsvampen Saccaromyces cerevisiae, vilken saknar AOX. Detta indikerade att användandet av AOX är försumbart i ungt mycel. Dock kunde ett samband påvisas mellan AOX-användning och ålder, vilket antyder att AOX spelar en allt viktigare roll allt eftersom mycelet åldras. IRMS är den enda tillförlitliga metoden för mätning av elektronfördelning mellan AOX och COX. Ändå, trots otaliga studier i olika arter, är detta första gången som denna metod används i svampmycel. Arbetet som sådant utgör därför ett viktigt steg mot en större förståelse av svampars respiration. Vidare studier av AOX i svamp under naturliga förhållanden, i kombination med uppskattningar av svampars biomassa, har stor potential att ytterligare förbättra säkerheten i kolinlagringsmodeller

Structural and biophysical studies of pneumococcal capsular surface proteins

Streptococcus pneumoniae (pneumococcus) is a major human pathogen and a leading cause of morbidity and mortality worldwide, especially in children and the elderly. The casualties due to respiratory infections are estimated to be over 4 million per year, where pneumococcus is the predominant species. Moreover, the increasing number of antibiotic-resistant strains and the suboptimal clinical efficacy of available vaccines confines control of this pathogen. In view of this situation, substantial attention has focused on novel virulence-related pneumococcal proteins as potential targets for future drug targets. One such target is the pneumococcal serine-rich repeat protein (PsrP), an important virulence factor present in a majority of the strains capable of causing invasive pneumococcal disease (IPD). The functional binding region (BR) of this protein binds to keratin-10 (KRT10) and also promotes biofilm formation through self-oligomerization. The crystal structure of the KRT10-binding region of PsrP (BR187-385) reveals an extended β -sheet on one side of a compressed two-sided β-barrel presents a basic groove that could accommodate the acidic helical rod domain of KRT10. Well-ordered loop regions distort the other side of the barrel and form a papercliplike sub-structure for more specific interaction with KRT10. In vitro alanine substitution of residues localized within this paperclip structure efficiently disrupted BR187-385/KRT10 complex formation. Within the work of this thesis we also found that BR187-385, which lacks the putative oligomerization region, forms stable oligomers in vitro. Small angle X-ray scattering and circular dichroism experiments revealed a non-globular and possibly disordered structure of the N-terminal region. A comparative analysis of the long (BR120-395) and short (BR187-385) domain constructs even suggested an inhibitory role for the N-terminal BR122-166 domain in oligomerization. Indeed, we could show that the N-terminal region is released by cleavage through the human furin protease that specifically recognizes a sequence localized between the globular BR187-385 domain and the disordered N-terminal part. The crystal structure of the dimer of the KRT10-binding domain of PsrP reveals a domain swap mechanism for dimerization, this process, although energetically costly, is probable when PsrP is involved in biofilm formation. The minor ancillary pilus protein RrgC is believed to anchor the pneumococcal pilus to the cell wall, and until recently very little was known about its structure. In this work we have evaluated the structure of the protein in solution with SAXS, and shown that the protein is a multidomain protein with flexible linkers and adopts extended conformations in solution. Through this work we have proposed a more specific interaction between PsrP and KRT10 than previously reported, as well as shown that oligomerization is possible despite the removal of the N-terminal region. These findings are very important for a deeper understanding of the details in PsrP’s role in pneumococcal invasion. The structural studies of RrgC provide a platform for future studies. The results presented within this thesis will hopefully aid in the future development of novel drugs and vaccines

Traktstorlek före och efter omarrondering i Dalarnas län -frågor kring Lantmäteriets båtnadsberäkning

Land consolidation is a major problem in many countries in Europe. In Sweden, mainly the state of Dalarna, there is a strong consolidation of forestland, probably the strongest in all of Europe. The consolidation is a big obstacle for forest management and ownership questions due to the often long and narrow strips of land. One of the main reasons for land consolidation in Dalarna results from the heritage procedure, were land is divided between all of the inheritors. To improve the consolidation large surveys in the consolidated villages in Dalarna are carried out. Many laws have to be followed due to the survey. Three types of criteria have to be achieved before the survey can start, these three criterias are: The cost-income criteria, the improvement criteria and the opinion criteria. The main question with this work is to investigate the cost-income criteria. There is a calculation done before the survey can start, to show if the income is larger than the cost of the improvement of the consolidation, if that’s the case the survey can be carried out. Tract sizes and the grade of cooperation in forest work is a main question that is used in the calculation. These two things have been investigated. The investigated area has been Djura parish in Leksand´s municipality and Gagnef´s- and Mockfjärd´s parishes in Gagnef´s municipality over the years between 1991 to 1993 and 2010 to 2011. The work has been carried out at the Private forest owner association, Mellanskog. The results point to an increase of tract sizes and a decrease of cooperation after the survey has taken place