This thesis investigates the anti-leukemic activity of terpenoids isolated from medicinal mushrooms and marine sponges, as well as their possible targets and mechanisms of action. In the first section, we focused on studying the triterpenoidal components of three triterpenoid-enriched medicinal mushrooms Antrodia cinnamomea, Ganoderma lucidum, and Poria cocos, which have been used in folk medicine for centuries and also developed into several contemporary marketed products. We isolated the major and characteristic triterpenoids from these mushrooms, together with six new lanostanoids (II-1–II-6). The anti-leukemic activity of the isolates was evaluated in vitro using MTT proliferative assay and seven of them exhibited potential anti-leukemic effect. The active lead compounds were further subjected to computational analyses utilizing the ChemGPS-NP tool. We established a database for the anti-leukemic relevant chemical space of triterpenoids isolated from these three medicinal mushrooms, which could be used as a reference database for further research on anti-leukemic triterpenoids. Our results indicated that the anti-leukemic effect of the active lead compounds was mediated not only through topoisomerases inhibition but also through inhibiting DNA polymerases. The second and third sections focused on isolation of anti-leukemic sesterterpenoids from sponges. The investigation of Carteriospongia sp. led to the isolation of two new scalarane-type sesterterpenoids (III-1 and III-2) and one known tetraprenyltoluquinol-related metabolite (III-3). All isolates exhibit an apoptotic mechanism of action against Molt 4 cells, found to be mediated through the disruption of the mitochondrial membrane potential (MMP) and inhibition of topoisomerase IIα expression. Detailed investigation of the apoptotic mechanism of action using molecular docking analysis revealed that compound III-1 might target Hsp90 protein. The apoptotic-inducing effect of III-3 was supported by in vivo experiment by suppressing the volume of xenograft tumor growth (47.58%) compared with the control. In the final section of this thesis we studied manoalide and its derivatives, sesterterpenoids isolated from the sponge Luffariella sp.. Manoalide has been studied as a potential anti-inflammatory agent for the last thirty years with more than 200 publications and 40 patents. However, the configurations at positions 24 and 25 were never revealed. In the current study, ten manoalide-type sesterterpenoids (IV-1–IV-10) were isolated from Luffariella sp. and their stereoisomers at positions 24 and 25 were identified and separated for the first time. The configuration at positions 24 and 25 showed to have a significant effect on the anti-leukemic activity of manoalide derivatives, with the 24R,25S-isomer exhibiting the most potent anti-leukemic activity. The apoptotic mechanism of action of compound IV-7 against Molt 4 cells was investigated, and the compound was found to trigger MMP disruption and intracellular reactive oxygen species (ROS) generation. Compound IV-7 also inhibited activity against both human topoisomerases, I and II. The in vivo experiment further supported the anti-leukemic effect of IV-7 with a 66.11% tumor volume suppression compared to the control.

Until now, most metabolomics protocols have been optimized towards high sample throughput and high metabolite coverage, parameters considered to be highly important for identifying influenced biological pathways and to generate as many potential biomarkers as possible. From an analytical point of view this can be troubling, as neither sample throughput nor the number of signals relates to actual quality of the detected signals/metabolites. However, a method’s selectivity for a specific signal/metabolite is often closely associated to the quality of that signal, yet this is a parameter often neglected in metabolomics. This thesis demonstrates the importance of considering selectivity when developing NMR and LC-MS metabolomics methods, and introduces a novel approach for measuring chromatographic and signal selectivity in LC-MS metabolomics. Selectivity for various sample preparations and HILIC stationary phases was compared. The choice of sample preparation affected the selectivity in both NMR and LC-MS. For the stationary phases, selectivity differences related primarily to retention differences of unwanted matrix components, e.g. inorganic salts or glycerophospholipids. Metabolites co-eluting with these matrix components often showed an incorrect quantitative signal, due to an influenced ionization efficiency and/or adduct formation. A novel approach for measuring selectivity in LC-MS metabolomics has been introduced. By dividing the intensity of each feature (a unique mass at a specific retention time) with the total intensity of the co-eluting features, a ratio representing the combined chromatographic (amount of co-elution) and signal (e.g. in-source fragmentation) selectivity is acquired. The calculated co-feature ratios have successfully been used to compare the selectivity of sample preparations and HILIC stationary phases. In conclusion, standard approaches in metabolomics research might be unwise, as each metabolomics investigation is often unique.  The methods used should be adapted for the research question at hand, primarily based on any key metabolites, as well as the type of sample to be analyzed. Increased selectivity, through proper choice of analytical methods, may reduce the risks of matrix-associated effects and thereby reduce the false positive and false negative discovery rate of any metabolomics investigation.

Tuberculosis is an ancient infectious disease and a leading cause of death globally. Preclinical research is important for defining drugs and regimens which should be carried forward to human studies. This thesis aims to characterize the population pharmacokinetics and exposure-response relationships of anti-tubercular drugs alone and in combinations, and to suggest experimental designs for preclinical settings. The population pharmacokinetics of rifampicin, isoniazid, ethambutol and pyrazinamide were described for the first time in two mouse models. This allowed for linking the population pharmacokinetic model to the Multistate Tuberculosis Pharmacometric (MTP) model for biomarker response, which was used to characterize exposure-response relationships in monotherapy. Pharmacodynamic interactions in combination therapies were quantitatively described by linking the MTP model to the General Pharmacodynamic Interaction (GPDI) model, which provided estimates of single drug effects together with a quantitative model-based evaluation framework for evaluation of pharmacodynamic interactions among drugs in combinations. Synergism (more than expected additivity) was characterized between rifampicin and ethambutol, while antagonism (less than expected additivity) was characterized between rifampicin and isoniazid in combination therapies. The new single-dose pharmacokinetic design with enrichened individual sampling was more informative than the original design, in which only one sample was taken from each mouse in the pharmacokinetic studies. The new oral zipper design allows for informative pharmacokinetic sampling in a multiple-dose administration scenario for characterizing pharmacokinetic-pharmacodynamic relationships, with similar or lower bias and imprecision in parameter estimates and with a decreased total number of animals required by up to 7-fold compared to the original design. The optimized design for assessing pharmacodynamic interactions in the combination therapies, which was based on EC20, EC50 and EC80 of the single drug, provided lower bias and imprecision than a conventional reduced four-by-four microdilution checkerboard design at the same total number of samples required, which followed the 3Rs of animal welfare. In summary, in this thesis the population pharmacokinetic-pharmacodynamic models of first-line drugs in mice were characterized through linking each population pharmacokinetic model to the MTP model. Pharmacodynamic interactions were quantitatively illustrated by the MTP-GPDI model. Lastly, experimental designs were optimized and recommended to both pharmacokinetic and pharmacodynamic studies for preclinical settings.

Background Advances in medical treatment during the last 50 years have resulted in more individuals with congenital heart disease (CHD) and Marfan syndrome reaching childbearing age. The substantial physiological changes during pregnancy result in a high-risk situation, and pregnancy is a major concern in women with these conditions. Aims To describe the socio-demographic characteristics, birth characteristics and reproductive patterns of individuals with CHD and women with Marfan syndrome. To investigate obstetric and neonatal outcomes in the firstborn children of individuals with CHD and women with Marfan syndrome. To study long-term cardiovascular outcomes after childbirth in women with Marfan´syndrome. Methods The studies are population-based register studies. The study population in the first paper included all women born between 1973 and 1983 who were alive and resident in Sweden at the age of 13 (494 692 women, of whom 2 216 were women with CHD). In the second paper, the same definition of the study population was chosen, except that it involved all men born between 1973 and 1983 (522 216 men, of whom 2 689 men with CHD). The third and fourth papers involved a study population of all Swedish women born between 1973 and 1993 who were still living in Sweden at age 13. This population consisted of 1 017 538 women, 273 of whom had been diagnosed with Marfan syndrome. Results and conclusions The individuals studied were more often born preterm, and were small-for-gestational age babies. They were more likely to have been born by cesarean section. In women with CHD, these characteristics were repeated in their firstborn children. No increased risks were found in children of men with CHD or in children of women with Marfan syndrome. There was no increased risk of aortic dissection in women with Marfan syndrome during pregnancy compared to women with Marfan syndrome who did not give birth. Higher frequencies of cardiac arrhythmia and valvular heart disease were found after childbirth in women with Marfan syndrome. Pregnancy in women with CHD is a high-risk situation associated with increased risk of adverse neonatal outcomes for the expected child. Pregnancy in women without CHD, but where the father has CHD is not so associated with increased risk of adverse obstetric or neonatal outcomes. Pregnancy in women with Marfan syndrome is not associated with adverse outcomes for the expected child.

Denna studie handlar om hur lärare och elever uppfattar bilder i biologiböcker i grundskolans senare del utifrån ett normkritiskt perspektiv. Mer konkret har jag undersökt på vilket sätt lärare beskriver att de använder bilder i biologiböcker och på vilket sätt elevernas bakgrund påverkar vilken information de utläser ur bilderna. Den metod som användes var semistrukturerade kvalitativa intervjuer med tre lärare i grundskolan samt en enkätundersökning med 59 elever i årskurs nio. Studien visar att lärarna använder bilder i biologiboken med varierande medvetenhet och att de tror att det inte är någon större skillnad i hur de elever som uppfattar sig som tjejer respektive killar tolkar bilderna. Studien visar dock att elevernas uppfattade kön spelar roll. De elever som uppfattar sig som tjejer kan ange fler relevanta ord för bilderna i läroboken och läser in sakliga och negativt laddade begrepp kring män i bilderna för sex och samlevnadskapitlet, medan de som uppfattar sig som killar läser in fler negativt laddade ord kring kvinnor för dessa bilder. När de gäller bilden som föreställer Carl von Linné associerar de elever som uppfattar sig som killar i större utsträckning till naturvetenskapliga forskare eller till historiska manliga personer som inte har koppling till bilden. Överlag tolkar eleverna bilderna bokstavligt samt associerar till ord som inte alltid har med bilden att göra. Slutsatsen är att lärarna är delvis medvetna om behovet av stimulerande bilder för eleverna men att lärarna behöver mer kunskap om hur olika elever uppfattar de bilder som används i undervisningen, så att lärarna kan komplettera bilderna i läroboken med bilder som utmanar heteronormativa begrepp, traditionella könsmönster och synen på biologin som en vetenskap för västerländska män.

Cognitive impairments are an increasing health problem worldwide. In the developed countries, the average life expectancy has dramatically increased over the last decades, and with an elderly population more cases of cognitive impairments appear. Age, genetics, and different medical conditions such as diabetes mellitus, and substance use disorders may all contribute to declined cognitive ability. Physiological functions also decrease with increasing age, as does the activity of the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis. Interestingly, both GH and IGF-1 are recognized for their neuroprotective effects and cognitive enhancement. The overall aim of this thesis was to investigate the impact of the somatotrophic axis (i.e. GH/IGF-1 axis) in rodents with cognitive deficiencies induced by diabetes or long-term drug exposure. For the first time cognitive impairments were characterized in diabetic mice using a spatial learning and memory task called the Barnes maze (BM). In diabetic mice, impaired learning in the BM was associated with decreased expression of the GH receptor (GHR) in the frontal cortex, a region important for e.g. working memory. Treatment with GH reversed certain cognitive impairments seen in diabetic animals. In rats treated with gamma-hydroxybutyrate (GHB), a significant decrease of Igf1 mRNA expression in the frontal cortex was observed. This observation may explain the impaired cognitive function previously seen following GHB administration. Furthermore, rats exposed to chronic morphine delivered in mini-osmotic pumps displayed memory impairments in the Morris water maze (MWM), an effect that seems to be associated with the composition of the N-methyl-d-aspartate (NMDA) receptor complex in the frontal cortex. In conclusion, the result strengthens the evidence for GH being a cognitive enhancer. Moreover, the result within this thesis identifies the frontal cortex as an important brain region, where gene expression related to the somatotrophic system is affected in rodents with cognitive impairments. The thesis especially emphasizes the importance of the local somatotrophic system in the brain with regard to cognitive function.

Vi möts av mängder med bilder av teknik och vetenskap i populärkulturens verk. Dessa bilder kan ses som representationer av vår verklighet och bidrar också till att skapa våra uppfattningar om världen. Denna uppsats fokuserar på att studera just de populärvetenskapliga bilderna av teknik och vetenskap som finns representerade samt hur dessa bilder är en del av sin kontext. Genom att närmare studera filmerna Demolition Man och Sunshine, utifrån frågor om tekniken skildras som ond, god eller neutral, hur vetenskapsmannen gestaltas samt hur förhållandet mellan människa och maskin ser ut, nystar denna uppsats fram de bilder av teknik och vetenskap som återfinns i dessa två verk.

I denna undersökning riktas intresset mot att förstå och belysa sätt att tänka kring utbildningsplanering, undervisningens organisering och utbildningens relevans och betydelse i samtiden och framtiden, och detta under en period från 1957 till 1975. Mer specifikt närmar sig undersökningen den satsning på undervisningsteknologi och utbildningsteknologi som görs inom utbildningssystemet under denna period. I detta närmande används en diskursiv textanalytisk metod, Michel Foucaults arkeologiska angreppssätt, för att söka belysa periodens utbildningsmässiga tänkande, såsom detta tar sig uttryck i relationen mellan utsagor producerade av politiska, fackliga och vetenskapliga aktörer engagerade i utbildning – och mer specifikt i grundskolans utveckling. Jag använder sedan en kritiskt diskursiv teoribildning, med huvudvikten lagd vid Foucaults genealogiska inriktning, för att skapa en förståelse för vad som i denna undersökning berörs som ett u-teknologiskt vetandeobjekt. Här intresserar jag mig för det specifika i ett u-teknologiskt vetande, men även dess plats i en utbildningsdiskursiv praktik där dimensioner som vetenskap, teknik och utveckling är centrala för en förståelse av detta vetande. En mer övergripande linje i denna undersökning är även en diskussion av sättet att tänka kring utbildning igår, idag och imorgon, och detta i perspektivet av det moderna samhällets föränderlighet eller tröghet.

<p>Vi möts av mängder med bilder av teknik och vetenskap i populärkulturens verk. Dessa bilder kan ses som representationer av vår verklighet och bidrar också till att skapa våra uppfattningar om världen.</p><p>Denna uppsats fokuserar på att studera just de populärvetenskapliga bilderna av teknik och vetenskap som finns representerade samt hur dessa bilder är en del av sin kontext. Genom att närmare studera filmerna Demolition Man och Sunshine, utifrån frågor om tekniken skildras som ond, god eller neutral, hur vetenskapsmannen gestaltas samt hur förhållandet mellan människa och maskin ser ut, nystar denna uppsats fram de bilder av teknik och vetenskap som återfinns i dessa två verk.</p>

<p>"Understanding what I write" is a study of university-scientists’ work concerning science-information, with the basis in Pedagogical Theory. The empirical material is collected through an inquiry and several interviews with scinentists at the ten universities of Sweden. This inquiry was done within the timeframe of November 2000 to Janurary 2001. The purpose is to find out wich methods scientists use to spread their knowledge to the society and what possibilities there are to improve these.</p> / <p>"Jag skriver begripligt "är en studie av universitetsforskares arbete med forskningsinformation med utgångspunkt i pedagogisk teori. Det empiriska materialet är insamlat i form av en enkät och ett flertal intervjuer med forskare på Sveriges tio universitet, under tidsperioden första november 2000 till sista januari 2001. Syftet med undersökningen är att ta reda på vilka metoder forskare använder för att sprida sin kunskap till det omgivande samhället och vilka möjligheter det finns att förbättra dessa.</p>