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  • 1. Bergander, L
    et al.
    Wahlström, Niklas
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institutet.
    Alsberg, T
    Bergman, Jan
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institutet.
    Rannug, A
    Rannug, U
    Characterization of in vitro metabolites of the aryl hydrocarbon receptor ligand 6-formylindolo[3,2-b] carbazole by liquid chromatography-mass spectrometry and NMR.2003In: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 31, no 2, p. 233-241Article in journal (Refereed)
    Abstract [en]

    The tryptophan photoproduct 6-formylindolo[3,2-b] carbazole (FICZ) exhibits the highest aryl hydrocarbon receptor (AhR) binding affinity reported so far. In different cells, in vitro, both extracts of UV-irradiated tryptophan and the synthesized pure compound FICZ induce a rapid and transient expression of AhR-regulated genes. The transient induction suggests that the biotransformation gene battery induced by AhR activation takes part in a metabolic degradation of the ligand, whereby a low steady-state level is regained. The down-regulation of AhR-regulated gene expression was previously shown to be dependent on cytochrome P450 1A1 (CYP1A1). Metabolism of FICZ generates five major metabolites, which appeared as three peaks (M1-M3) in the high performance liquid chromatography. The aim of the present study was to use rat liver S9 from Aroclor-pretreated rats to produce large enough quantities of FICZ metabolites for structure characterization and to determine their product precursor relationship. NMR analysis of large combined fractions of the metabolites indicated that M3 and M2 contained 2 isomers, respectively. By means of liquid chromatography-mass spectrometry (negative ion electrospray mode) and NMR spectroscopy (by H-1-NMR, correlation spectroscopy, and nuclear Overhauser effect spectroscopy techniques) five metabolites of FICZ were identified, and their structures were elucidated. The molecular weights of the two M3 isomers were 300 and both M2 and M1 compounds demonstrated molecular weights of 316, corresponding to addition of one (M3) and of two oxygen (M2 and M1), respectively. The structures were assigned as 2- and 8-hydroxy (M3), 2,10- and 4,8-dihydroxy (M2) and 2,8-dihydroxy derivatives of indolo[3,2-b] carbazole-6-carboxaldehyde (6-formylindolo[ 3,2-b] carbazole).

  • 2. Granhall, Ulf
    et al.
    Welsh, Allana
    Throbäck, Ingela Noredal
    Hjort, Karin
    Södertörn University, School of Life Sciences, Molecular biology.
    Hansson, Mikael
    Hallin, Sara
    Bacterial community diversity in paper mills processing recycled paper2010In: Journal of Industrial Microbiology & Biotechnology, ISSN 1367-5435, E-ISSN 1476-5535, Vol. 37, no 10, p. 1061-1069Article in journal (Refereed)
    Abstract [en]

    Paper mills processing recycled paper suffer from biofouling causing roblems both in the mill and final product. The total bacterial ommunity composition and identification of specific taxa in the process ater and biofilms at the stock preparation and paper machine areas in a ill with recycled paper pulp was described by using a DNA-based pproach. Process water in a similar mill was also analyzed to nvestigate if general trends can be found between mills and over time. acterial community profiles, analyzed by terminal-restriction fragment ength polymorphism (T-RFLP), in process water showed that the dominant eaks in the profiles were similar between the two mills, although the verall composition was unique for each mill. When comparing process ater and biofilm at different locations within one of the mills, we bserved a separation according to location and sample type, with the iofilm from the paper machine being most different. 16S rRNA gene clone ibraries were generated and 404 clones were screened by RFLP analysis. rouping of RFLP patterns confirmed that the biofilm from the paper achine was most different. A total of 99 clones representing all RFLP atterns were analyzed, resulting in sequences recovered from nine acterial phyla, including two candidate phyla. Bacteroidetes epresented 45% and Actinobacteria 23% of all the clones. Sequences with imilarity to organisms implicated in biofouling, like Chryseobacterium pp. and Brevundimonas spp., were recovered from all samples even though he mill had no process problems during sampling, suggesting that they re part of the natural paper mill community. Moreover, many sequences howed little homology to as yet uncultivated bacteria implying that aper mills are interesting for isolation of new organisms, as well as or bioprospecting.

  • 3.
    Khihon Rokhas, Maria
    Södertörn University College, School of Life Sciences.
    Development of an assay for screening drug candidates for mechanism-based inhibition of human CYP3A42008Independent thesis Advanced level (degree of Master (Two Years))Student thesis
    Abstract [en]

    Cytochrome P450 (CYP) constitutes a superfamily of heme- containing enzymes that catalyze the oxidative biotransformation of structurally diverse xenobiotics including pharmaceuticals and drugs. Cytochrome P450 3A4 is not only the most abundant isoform in human liver but is also responsible for metabolizing approximately 60% of therapeutic drugs. This feature makes CYP3A4 highly susceptible to both reversible and irreversible, such as mechanism-based, inhibition. Mechanism-based inhibition is characterized by being time dependent as well as NADPH and concentration dependent, when some drugs are converted by CYPs to reactive metabolites. The inactivation of CYP3A4 can be due to chemical modification of the heme, the protein, or both by covalent binding of modified heme to the protein. Compared to reversible inhibition, mechanism-based inhibition of CYP3A4 more frequently causes unfavourable drug- drug interactions (DDI), as the inactivated CYP3A4 has to be replaced by newly synthesized CYP3A4 protein. DDI can lead to higher exposure of co-administered drugs, sometimes leading to toxicity. For these reasons, drug metabolism groups within pharmaceutical companies need a well established screening assay to assess mechanism-based inactivation of major human P450 enzymes by new chemical substances that are being developed by the company. Historically, adverse drug interactions were found in clinical trials or after the drugs were commercially released. That caused pharmaceutical companies large economical losses, since a large portion of development cost was in vain.Medivir AB is a small pharmaceutical company that would like to set up a screening method to be used to test candidate drugs for CYP3A4 mechanism-based inhibition. The central aim of this master degree project was to set up a screening assay to test irreversible inhibition of CYP3A4 and validate it with known inhibitors. Using the validated assay, a number of in-house project compounds will be measured for inhibition potential and the results analyzed for structure-activity correlations. Relationships between some functional groups and mechanism-based inhibition can provide insight for improvement of drug candidates and inhibition liability. The assay was based on microsomes containing recombinant human CYP3A4 and activity measured by conversion of the substrate dibenzylfluorescein into a fluorescent product. The product was quantified by measurement of fluorescence in a 96-well plate reader. Optimization was achieved by determining the reaction linearity with time and enzyme concentration. When possible the Km for the probe substrate was also determined. The effect of different backgrounds was studied to settle on a compensation for the enzyme activity. The effect of DMSO on CYP3A4 mediated metabolism of the substrate was studied to determine the acceptable solvent concentration. The concentration responsible for 50% inhibition (IC50) was also determined for several known inhibitors and compared with literature data.

  • 4.
    Nugent, Rebecca L.
    et al.
    University of Southern California.
    Johnsson, Anna
    Södertörn University, School of Life Sciences, Molecular biology. Karolinska Intitutet.
    Fleharty, Brian
    Stowers Institute for Medical Research.
    Gogol, Madelaine
    Stowers Institute for Medical Research.
    Xue-Franzen, Yongtao
    Södertörn University, School of Life Sciences, Molecular biology. Karolinska Institutet.
    Seidel, Chris
    Stowers Institute for Medical Research.
    Wright, Anthony P. H.
    Södertörn University, School of Life Sciences, Molecular biology. Karolinska Institutet.
    Forsburg, Susan L.
    University of Southern California.
    Expression profiling of S. pombe acetyltransferase mutants identifies redundant pathways of gene regulation2010In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 11, article id 59Article in journal (Refereed)
    Abstract [en]

    Background: Histone acetyltransferase enzymes (HATs) are implicated in egulation of transcription. HATs from different families may overlap in arget and substrate specificity. esults: We isolated the elp3(+) gene encoding the histone cetyltransferase subunit of the Elongator complex in fission yeast and haracterized the phenotype of an Delta elp3 mutant. We examined genetic nteractions between Delta elp3 and two other HAT mutants, Delta mst2 nd Delta gcn5 and used whole genome microarray analysis to analyze heir effects on gene expression. onclusions: Comparison of phenotypes and expression profiles in single, ouble and triple mutants indicate that these HAT enzymes have verlapping functions. Consistent with this, overlapping specificity in istone H3 acetylation is observed. However, there is no evidence for verlap with another HAT enzyme, encoded by the essential mst1(+) gene.

  • 5.
    Sandås, Therese
    et al.
    Södertörn University College, School of Business Studies.
    Karlström, Micaela
    Södertörn University College, School of Business Studies.
    Distansuppföljning av ICD-patienter: En hälsoekonomisk utvärdering2009Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [sv]

    Uppsatsens syfte är att undersöka vilka ekonomiska effekter införandet av distansuppföljning för ICD-patienter har ur ett samhällsperspektiv. Delsyftet är att identifiera ekonomiska argument och kvalitativa aspekter för och emot införandet av tjänsten distansuppföljning.

    Författarna har kommit fram till ett antal slutsatser. Att införa distansuppföljning som uppföljningsmetod för ICD-patienter istället för konventionella återbesök på sjukhus innebär stora kostnadsbesparingar. Nettonuvärdet uppgår till drygt 268 miljoner kronor efter femton år. Vid tidsperiodens slut erhålls en kostnadsbesparing på cirka 35,6 procent. De ekonomiska fördelarna överstiger kostnaderna redan efter ett år, och hela investeringskostnaden återfås efter sju år. Kvalitativa argument som talar för distansuppföljning är tidsbesparingar, förenklad uppföljning, bättre övervakning och att patienterna upplever en större trygghet.

  • 6.
    Svenaeus, Fredrik
    Södertörn University, School of Culture and Communication, Centre for Studies in Practical Knowledge.
    Phenomenology listens to Prozac: analyzing the SSRI revolution2007In: Medical technologies and the life world: the social construction of normality / [ed] Sonja Olin Lauritzen, Lars-Christer Hydén, Abingdon, Oxon, UK: Routledge, 2007, p. 164-183Chapter in book (Other academic)
    Abstract [en]

    Focuses on the ways new health technologies intervene into our lives. This book explores: how new health technologies are understood by lay people and patients; how the outcomes of these technologies are communicated in various clinical settings; and, how these technologies can alter our notions of health and illness and create 'new illness'.

  • 7.
    Weinryb, Noomi
    et al.
    Uppsala universitet.
    Bubela, Tania
    Univ Alberta, Sch Publ Hlth, Edmonton, AB T6G 1C9, Canada..
    Stepping Into and Out of the Void: Funding Dynamics of Human Embryonic Stem Cell Research in California, Sweden, and South Korea2016In: Stem Cell Reviews, ISSN 1550-8943, E-ISSN 1558-6804, Vol. 12, no 1, p. 8-14Article in journal (Refereed)
    Abstract [en]

    Nonprofit organizations and philanthropists stepped into a funding void caused by controversies over public funding of human embryonic stem cell (hESC) research. Based on interviews of 83 representatives of 53 funders, we examine the motivations and accountability structures of public agencies, corporations, fundraising dependent nonprofit organizations and philanthropic organizations that funded hESC research in three jurisdictions: California, Sweden, and South Korea. While non-traditional forms of funding are essential in the early stages of research advancement, they are unreliable for the long timeframes necessary to advance cell therapies. Such funding sources may enter the field based on high expectations, but may exit just as rapidly based on disappointing rates of progress.

  • 8.
    Xue-Franzen, Yongtao
    et al.
    Södertörn University, School of Life Sciences, Molecular biology. Karolinska Institutet.
    Johnsson, Anna
    Södertörn University, School of Life Sciences, Molecular biology. Karolinska Intitutet.
    Brodin, David
    Karolinska Institutet.
    Henriksson, Johan
    Södertörn University, School of Life Sciences, Molecular biology. Karolinska Institutet.
    Bürglin, Thomas R.
    Södertörn University, School of Life Sciences, Molecular biology. Karolinska Institutet.
    Wright, Anthony P. H.
    Södertörn University, School of Life Sciences, Molecular biology. Karolinska Institutet.
    Genome-wide characterisation of the Gcn5 histone acetyltransferase in budding yeast during stress adaptation reveals evolutionarily conserved and diverged roles2010In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 11, article id 200Article in journal (Refereed)
    Abstract [en]

    Background: Gcn5 is a transcriptional coactivator with histone cetyltransferase activity that is conserved with regard to structure as ell as its histone substrates throughout the eukaryotes. Gene egulatory networks within cells are thought to be evolutionarily iverged. The use of evolutionarily divergent yeast species, such as S. erevisiae and S. pombe, which can be studied under similar nvironmental conditions, provides an opportunity to examine the nterface between conserved regulatory components and their cellular pplications in different organisms. esults: We show that Gcn5 is important for a common set of stress esponses in evolutionarily diverged yeast species and that the activity f the conserved histone acetyltransferase domain is required. We define group of KCl stress response genes in S. cerevisiae that are pecifically dependent on Gcn5. Gcn5 is localised to many Gcn5-dependent enes including Gcn5 repressed targets such as FLO8. Gcn5 regulates ivergent sets of KCl responsive genes in S. cerevisiae and S. pombe. enome-wide localization studies showed a tendency for redistribution of cn5 during KCl stress adaptation in S. cerevisiae from short genes to he transcribed regions of long genes. An analogous redistribution was ot observed in S. pombe. onclusions: Gcn5 is required for the regulation of divergent sets of Cl stress-response genes in S. cerevisiae and S. pombe even though it s required a common group of stress responses, including the response o KCl. Genes that are physically associated with Gcn5 require its ctivity for their repression or activation during stress adaptation, roviding support for a role of Gcn5 as a corepressor as well as a oactivator. The tendency of Gcn5 to re-localise to the transcribed egions of long genes during KCl stress adaptation suggests that Gcn5 lays a specific role in the expression of long genes under adaptive onditions, perhaps by regulating transcriptional elongation as has been een for Gcn5 in S. pombe. Interestingly an analogous redistribution of cn5 is not seen in S. pombe. The study thus provides important new nsights in relation to why coregulators like Gcn5 are required for the orrect expression of some genes but not others.

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