Mechanistic Studies On the Role of Polyamines and Microvesicles in Tumor Growth and Hypoxia-mediated Angiogenesis

Solid tumors are composed of cancer cells, as well as resident or infiltrating non-malignant cells that contribute to the malignant state in an ecosystem generally accepted as the tumor microenvironment. Microenvironmental tumor hypoxia is the foremost leading cause of angiogenesis, i.e. the formation of new blood vessels from pre-existing vasculature, and its correlation to tumor growth and aggressiveness has included hypoxia-induced angiogenesis into the hallmarks of cancer. Accordingly, anti-angiogenic therapy was developed for the treatment of cancer patients; however, clinical studies have shown benefit only for a small group of patients, thus challenging the preceding expectations on anti-angiogenic targeting of tumors and underscoring the complex biology of human cancer disease. This thesis aims at investigating mechanistic roles of polyamines and microvesicles in tumor biology and hypoxia-mediated angiogenesis. We considered the option of inhibiting cancer cell proliferation by the combination of polyamine synthesis inhibition with phage display-derived antibodies targeting the polyamine uptake system. Further, we found a novel role of polyamines in the hypoxic stress response of cancer cells. The findings resulted in a strategy for enhancing the sensitivity of polyamine biosynthesis inhibition in experimental glioblastoma, i.e. highly aggressive brain tumors, through simultaneous anti-angiogenic induction of tumor hypoxia. We have elucidated the role of protease-activated receptors in the hypoxic responses of endothelial cells, and found a specific role of protease activated receptor-2. We show that hypoxic coagulation system activation in glioblastoma cell derived microvesicles elicits pro-angiogenic signaling in hypoxic endothelial cells through protease activated receptor-2. Further studies investigated the uptake mechanism of glioblastoma cell-derived microvesicles, and present the still hypothetical possibility of multicellular transfer of complex, molecular information through microvesicles. In conclusion, further studies aim at understanding the limitations of current anti-angiogenic treatments as well as identifying new targets or combinations of therapies. Data presented in this thesis identify new pathways of hypoxia-mediated tumor development with possible implications for therapeutic intervention

Med alla barn i fokus - om förskolans roll i flerspråkiga barns språkutveckling

I denna artikel står flerspråkiga barns språkliga situation i förskolan i fokus och syftet är att lyfta fram och diskutera hur förskollärare kan stödja dessa barns möjligheter att utveckla sitt ordförråd

Varumärkets mening: den offentliga organisationens vision och värden ur medarbetarens perspektiv

Ett framgångsrikt varumärkesarbete förutsätter att medarbetaren förstår och uttrycker organisationens vision och värden, samtidigt är medarbetaren åsidosatt inom forskningsfältet varumärkeskommunikation. Den här studien lyfter därför fram medarbetarens perspektiv i den komplexa offentliga organisationens varumärkesarbete. Syftet är att genom kvalitativa intervjuer skapa en djupare förståelse för medarbetarens meningsskapande kring vision och värden. För att få en så detaljrik bild som möjligt av medarbetarens meningsskapande i den offentliga organisationen har vi gjort en fallstudie av Skatteverket. Vi ser i studien att medarbetaren använder moral som tolkningsram för att skapa mening kring vision och värden i såväl det praktiska arbetet som i organisationens strategi. Medarbetarna skapar även mening utifrån berättelser som från olika perspektiv dramatiserar och förklarar vision och värden. Vår uppfattning är att den icke- konkurrensutsatta offentliga organisationen kan gynnas av att arbeta med visioner och värden som är generella snarare än unika och som tillsammans bildar en helhet.Although successful branding requires that co-workers comprehend and express the vision and core values of the organization, the co-worker is neglected during the brand research phase. Therefore, this study highlights the co-worker perspective in the complex work with branding within a public organization. Through qualitative interviews, the purpose is to create a more detailed understanding of how co-workers make sense of visions and core values. To form as detailed a picture as possible regarding co-workers’ sensemaking in a public organization, we conducted a case study on the Swedish Tax Agency (Skatteverket). In this study, we find that co-workers use morals as their interpretive framework for giving meaning to vision and core values – both in terms of practice, as well regarding the strategy of the organization. Co-workers’ sensemaking is also based on stories that dramatize and explain vision and core values from different perspectives. Our understanding is that the non-competitive, public organization would benefit from working on visions and core values that are general rather than specific, that together form a whole

Methodological concepts for integrated assessment of agricultural and environmental policies in SEAMLESS-IF

Agricultural and Food Policy, Environmental Economics and Policy, Farm Management, Land Economics/Use,

Ice-core data used for the construction of the Greenland Ice-Core Chronology 2005 and 2021 (GICC05 and GICC21)

We here describe, document, and make available a wide range of data sets used for annual-layer identification in ice cores from DYE-3, GRIP, NGRIP, NEEM, and EGRIP. The data stem from detailed measurements performed both on the main deep cores and shallow cores over more than 40 years using many different setups developed by research groups in several countries and comprise both discrete measurements from cut ice samples and continuous-flow analysis data. The data series were used for counting annual layers 60 000 years back in time during the construction of the Greenland Ice-Core Chronology 2005 (GICC05) and/or the revised GICC21, which currently only reaches 3800 years back. Now that the underlying data are made available (listed in Table 1) we also release the individual annual-layer positions of the GICC05 timescale which are based on these data sets. We hope that the release of the data sets will stimulate further studies of the past climate taking advantage of these highly resolved data series covering a large part of the interior of the Greenland ice sheet

PTER is a N-acetyltaurine hydrolase that regulates feeding and obesity.

Taurine is a conditionally essential micronutrient and one of the most abundant amino acids in humans1-3. In endogenous taurine metabolism, dedicated enzymes are involved in the biosynthesis of taurine from cysteine and in the downstream metabolism of secondary taurine metabolites4,5. One taurine metabolite is N-acetyltaurine6. Levels of N-acetyltaurine are dynamically regulated by stimuli that alter taurine or acetate flux, including endurance exercise7, dietary taurine supplementation8 and alcohol consumption6,9. So far, the identities of the enzymes involved in N-acetyltaurine metabolism, and the potential functions of N-acetyltaurine itself, have remained unknown. Here we show that the body mass index associated orphan enzyme phosphotriesterase-related (PTER)10 is a physiological N-acetyltaurine hydrolase. In vitro, PTER catalyses the hydrolysis of N-acetyltaurine to taurine and acetate. In mice, PTER is expressed in the kidney, liver and brainstem. Genetic ablation of Pter in mice results in complete loss of tissue N-acetyltaurine hydrolysis activity and a systemic increase in N-acetyltaurine levels. After stimuli that increase taurine levels, Pter knockout mice exhibit reduced food intake, resistance to diet-induced obesity and improved glucose homeostasis. Administration of N-acetyltaurine to obese wild-type mice also reduces food intake and body weight in a GFRAL-dependent manner. These data place PTER into a central enzymatic node of secondary taurine metabolism and uncover a role for PTER and N-acetyltaurine in body weight control and energy balance

A role for the cell-wall protein silacidin in cell size of the diatom Thalassiosira pseudonana

Diatoms contribute 20% of global primary production and form the basis of many marine food webs. Although their species diversity correlates with broad diversity in cell size, there is also an intraspecific cell-size plasticity due to sexual reproduction and varying environmental conditions. However, despite the ecological significance of the diatom cell size for food-web structure and global biogeochemical cycles, our knowledge about genes underpinning the size of diatom cells remains elusive. Here, a combination of reverse genetics, experimental evolution and comparative RNA8 sequencing analyses enabled us to identify a previously unknown genetic control of cell size in the diatom Thalassiosira pseudonana. In particular, the targeted deregulation of the expression of the cell-wall protein silacidin caused a significant increase in valve diameter. Remarkably, the natural downregulation of the silacidin gene transcript due to experimental evolution under low temperature also correlated with cell-size increase. Our data give first evidence for a genetically controlled regulation of cell size in Thalassiosira pseudonana and possibly other centric diatoms as they also encode the silacidin gene in their genomes