| 1. |
- Bergman, Ebba, 1977-, et al.
(författare)
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Effect of a Single Gemfibrozil Dose on the Pharmacokinetics of Rosuvastatin in Bile and Plasma in Healthy Volunteers
- 2010
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Ingår i: Journal of clinical pharmacology. - : Wiley. - 0091-2700 .- 1552-4604. ; 50:9, s. 1039-1049
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Tidskriftsartikel (refereegranskat)abstract
- The effect of a single intrajejunal dose of gemfibrozil (600 mg) on the plasma pharmacokinetics and biliary excretion of a single intrajejunal dose of rosuvastatin (20 mg) was investigated by using a multichannel catheter positioned in the distal duodenum/proximal jejunum in eight healthy volunteers. Bile and plasma samples were collected every 20 min for 200 min, with additional plasma samples being withdrawn for up to 48 hrs. Gemfibrozil did not affect the bioavailability of rosuvastatin, although it increased the apparent absorption phase during the initial 200 minutes (AUC0-200) by 1.56-fold (95%CI: 1.14-2.15). The interaction was less pronounced in this single dose study than in a previous report when gemfibrozil was administered repeatedly, nevertheless, the interaction coincided with the highest exposure to gemfibrozil. The plausible reason why the interaction in this investigation was only minor is the low exposure to gemfibrozil (and its metabolites), suggesting that the total plasma concentration of gemfibrozil needs to be above 20 µM in order to affect the disposition of rosuvastatin. This study demonstrates the value of monitoring the plasma pharmacokinetics of the inhibitor, and not only the drug under investigation, to improve the mechanistic interpretation.
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| 2. |
- Lewandowicz, Andrzej, et al.
(författare)
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Chlorine kinetic isotope effects on the haloalkane dehalogenase reaction
- 2001
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 123:19, s. 4550-4555
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Tidskriftsartikel (refereegranskat)abstract
- We have found chlorine kinetic isotope effects on the dehalogenation catalyzed by haloalkane dehalogenase from Xanthobacter autotrophicus GJ10 to be 1.0045 ± 0.0004 for 1,2-dichloroethane and 1.0066 ± 0.0004 for 1-chlorobutane. The latter isotope effect approaches the intrinsic chlorine kinetic isotope effect for the dehalogenation step. The intrinsic isotope effect has been modeled using semiempirical and DFT theory levels using the ONIOM QM/QM scheme. Our results indicate that the dehalogenation step is reversible; the overall irreversibility of the enzyme-catalyzed reaction is brought about by a step following the dehalogenation.
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| 3. |
- Matsson, Hans, et al.
(författare)
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Polymorphisms in DCDC2 and S100B associate with developmental dyslexia.
- 2015
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Ingår i: Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1434-5161 .- 1435-232X. ; 60:7, s. 399-401
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Tidskriftsartikel (refereegranskat)abstract
- Genetic studies of complex traits have become increasingly successful as progress is made in next-generation sequencing. We aimed at discovering single nucleotide variation present in known and new candidate genes for developmental dyslexia: CYP19A1, DCDC2, DIP2A, DYX1C1, GCFC2 (also known as C2orf3), KIAA0319, MRPL19, PCNT, PRMT2, ROBO1 and S100B. We used next-generation sequencing to identify single-nucleotide polymorphisms in the exons of these 11 genes in pools of 100 DNA samples of Finnish individuals with developmental dyslexia. Subsequent individual genotyping of those 100 individuals, and additional cases and controls from the Finnish and German populations, validated 92 out of 111 different single-nucleotide variants. A nonsynonymous polymorphism in DCDC2 (corrected P = 0.002) and a noncoding variant in S100B (corrected P = 0.016) showed a significant association with spelling performance in families of German origin. No significant association was found for the variants neither in the Finnish case-control sample set nor in the Finnish family sample set. Our findings further strengthen the role of DCDC2 and implicate S100B, in the biology of reading and spelling.
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| 4. |
- Matsson, Mikael, et al.
(författare)
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Carboxin resistance in Paracoccus denitrificans conferred by a mutation in the membrane-anchor domain of succinate:quinone oxidoreductase (Complex II)
- 1998
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Ingår i: Archives of Microbiology. - : Springer Science and Business Media LLC. - 0302-8933 .- 1432-072X. ; 170:1, s. 27-37
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Tidskriftsartikel (refereegranskat)abstract
- Succinate:quinone reductase is a membrane-bound enzyme of the citric acid cycle and the respiratory chain. Carboxin is a potent inhibitor of the enzyme of certain organisms. The bacterium Paracoccus denitrificans was found to be sensitive to carboxin in vivo, and mutants that grow in the presence of 3'-methyl carboxin were isolated. Membranes of the mutants showed resistant succinate:quinone reductase activity. The mutation conferring carboxin resistance was identified in four mutants. They contained the same missense mutation in the sdhD gene, which encodes one of two membrane-intrinsic polypeptides of the succinate:quinone reductase complex. The mutation causes an Asp to Gly replacement at position 89 in the SdhD polypeptide. P. denitrificans strains that overproduced wild-type or mutant enzymes were constructed. Enzymic properties of the purified enzymes were analyzed. The apparent K-m for quinone (DPB) and the sensitivity to thenoyltrifluoroacetone was normal for the carboxin-resistant enzyme, but the succinate:quinone reductase activity was lower than for the wild-type enzyme. Mutations conferring carboxin resistance indicate the region on the enzyme where the inhibitor binds. A previously reported His to Leu replacement close to the [3Fe-4S] cluster in the iron-sulfur protein of Ustilago maydis succinate:quinone reductase confers resistance to carboxin and thenoyltrifluoroacetone. The Asp to Gly replacement in the P. denitrificans SdhD polypeptide, identified in this study to confer resistance to carboxin but not to thenoyltrifluoroacetone, is in a predicted cytoplasmic loop connecting two transmembrane segments. It is likely that this loop is located in the neighborhood of the [3Fe-4S] cluster.
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| 5. |
- Matsson, Mikael, et al.
(författare)
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Intervallträningen som ger guld
- 2012
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Ingår i: Svensk Idrottsforskning. - 1103-4629. ; :2, s. 44-49
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 6. |
- Matsson, Mikael
(författare)
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Quinone reduction sites and the role of heme in succinate:quinone reductase. Studies in Bacillus subtilis and Paracoccus denitrificans
- 2000
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Succinate:quinone reductase (SQR) is an enzyme in the respiratory system of aerobic cells. SQR catalyzes two reactions, the oxidation of succinate to fumarate and the reduction of quinone to quinol. These reactions are coupled by electron transfer within the enzyme from the site of succinate oxidation to the site of quinone reduction. Some enzymes reduce ubiquinone (exergonic reaction) whereas others reduce menaquinone (endergonic reaction). SQR is composed of one membrane-peripheral domain and one membrane-anchor domain. Succinate is oxidized on the peripheral domain which is attached to the electronegative side of the respiratory membrane. This domain consists of two polypeptides, one covalently bound FAD group, one [2Fe-2S] cluster, one [4Fe-4S] cluster and one [3Fe-4S] cluster. The anchor domain harbors the quinone reduction site(s) and is, depending on the organism, composed of one or two polypeptides and one or two b-type hemes. Succinate:menaquinone reductases contain two heme groups, one proximal heme (heme bP) located close to the negative side of the membrane and one distal heme (heme bD) located close to the positive side of the membrane. Succinate:ubiquinone reductases contain only heme bP. Electron transfer from succinate to quinone occurs in a linear pathway including the FAD, the [2Fe-2S] cluster, the [4Fe-4S] cluster, the [3Fe-4S] cluster and sometimes heme as electron carriers in the given order. I have studied SQR from two evolutionary very distant bacteria, Bacillus subtilis and Paracoccus denitrificans. B. subtilis SQR reduces menaquinone whereas P. denitrificans SQR reduces ubiquinone. The combined experimental results support the following model. In succinate:ubiquinone reductases the quinone reduction site is located close to the [3Fe-4S] cluster on the negative side of the membrane. Heme is not required as an electron carrier in these enzymes. Ubiquinone reduction by succinate is not dependent on the transmembrane electrochemical potential. In succinate:menaquinone reductases the quinone reduction site is located close to the positive side of the membrane. Heme bP and heme bD mediate transmembrane electron transfer from the [3Fe-4S] cluster to menaquinone. The transmembrane electrochemical potential provides driving force for the endergonic reduction of menaquinone by succinate.
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| 7. |
- Matsson, Mikael, et al.
(författare)
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The carboxin-binding site on Paracoccus denitrificans succinate:quinone reductase identified by mutation and structure comparison
- 2001
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Ingår i: Journal of Bioenergetics and Biomembranes. - 1573-6881. ; 33, s. 99-105
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Tidskriftsartikel (refereegranskat)abstract
- Succinate:quinone reductase catalyzes electron transfer from succinate to quinone in aerobic respiration. Carboxin is a specific inhibitor of this enzyme from several different organisms. We have isolated mutant strains of the bacterium Paracoccus denitrificans that are resistant to carboxin due to mutations in the succinate:quinone reductase. The mutations identify two amino acid residues, His228 in SdhB and Asp89 in SdhD, that most likely constitute part of a carboxin-binding site. This site is in the same region of the enzyme as the proposed active site for ubiquinone reduction. From the combined mutant data and structural information derived from Escherichia coli and Wolinella succinogenes quinol:fumarate reductase, we suggest that carboxin acts by blocking binding of ubiquinone to the active site. The block would be either by direct exclusion of uhiquinone from the active site or by occlusion of a pore that leads to the active site.
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| 8. |
- Matsson, Mikael, et al.
(författare)
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The distal heme center in Bacillus subtilis succinate:menaquinone reductase is crucial for electron transfer to menaquinone
- 2000
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Ingår i: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 39, s. 8617-8624
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Tidskriftsartikel (refereegranskat)abstract
- Succinate:quinone reductases are membrane-bound enzymes that catalyze electron transfer from succinate to quinone. Some enzymes in vivo reduce ubiquinone (exergonic reaction) whereas others reduce menaquinone (endergonic reaction). The succinate:menaquinone reductases all contain two heme groups in the membrane anchor of the enzyme: a proximal heme (heme b(P)) located close to the negative side of the membrane and a distal heme (heme b(D)) located close to the positive side of the membrane. Heme b(D) is a distinctive feature of the succinate:menaquinone reductases, but the role of this heme in electron transfer to quinone has not previously been analyzed. His28 and His113 are the axial ligands to heme b(D) in Bacillus subtilis succinate:menaquinone reductase. We have individually replaced these His residues with Leu and Met, respectively, resulting in assembled membrane- bound enzymes. The H28L mutant enzyme lacks succinate:quinone reductase activity probably due to a defective quinone binding site. The H113M mutant enzyme contains heme b(D) with raised midpoint potential and is impaired in electron transfer to menaquinone. Our combined experimental data show that the heme b(D) center, into which we include a quinone binding site, is crucial for succinate:menaquinone reductase activity. The results support a model in which menaquinone is reduced on the positive side of the membrane and the transmembrane electrochemical potential provides driving force for electron transfer from succinate via heme b(P) and heme b(D) to menaquinone.
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| 9. |
- Sonesson, Mikael, et al.
(författare)
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Minor salivary gland secretion in children and adults
- 2003
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Ingår i: Archives of Oral Biology. - : Elsevier. - 0003-9969 .- 1879-1506. ; 48:7, s. 535-539
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Tidskriftsartikel (refereegranskat)abstract
- The minor salivary glands are of great importance in the physiology and pathology of the oral cavity. So far, studies of the minor glands have concentrated on adults. In the present study, minor salivary gland secretion was studied in the buccal and labial mucosa of 3-year-old children, adolescents and young adults. In addition, the number of glands per surface area was assessed in the labial mucosa. A total of 90 individuals were included, 30 in each age-group. Saliva was collected on filter paper discs and the salivary secretion rate was measured using a Periotron 8000. The number of secreting labial glands was assessed on PAS-stained filter paper discs under a microscope. Salivary secretion in the buccal mucosa was found to be age-related, with a statistically significant lower rate of secretion (P=0.003) in the 3-year-olds (mean 7.7 microl x cm(-2) x min(-1)) compared with the young adults (11.9 microl x cm(-2) x min(-1)). No significant differences between the sexes were noted. For the labial glands, no age- or sex-related differences were found. In all age-groups, salivary secretion was significantly higher in the buccal than in the labial mucosal area. A statistically significant difference in number of secreting glands was found between all age-groups, with a decreasing number of glands per surface unit with age. The number of glands was significantly lower in males compared with females in the group of adults. The lower rate of buccal salivary secretion in the young children may imply that the oral mucosa is more vulnerable to external injury and that caries protection on the buccal molar surfaces is lower. Previous studies indicate that adults with a reduced rate of minor salivary gland secretion are more susceptible to caries.
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| 10. |
- Sonesson, Mikael, et al.
(författare)
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Mucins MUC5B and MUC7 in minor salivary gland secretion of children and adults
- 2008
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Ingår i: Archives of Oral Biology. - : Elsevier BV. - 0003-9969 .- 1879-1506. ; 53:6, s. 523-527
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The study was designed to investigate the relative amount of MUC5B and MUC7 in minor salivary glands in children and adults, in order to test the hypothesis that secretion of salivary mucins changes between childhood and adulthood. METHODS: Ninety individuals in the age-groups 3-year-olds, 14-year-olds, and young adults 20-25 year-olds were recruited. Sialopapers were applied on the labial and the buccal mucosa and then placed in the Periotron 8000 (Proflowtrade mark) for calculation of the amount of saliva. The assessment of MUC5B and MUC7 was carried out in an ELISA using the LUM5B-2 and the LUM7-1 antiserum, respectively. RESULTS: MUC5B and MUC7 were detected in the labial minor gland saliva in all age groups. In buccal gland saliva, only a few individuals in each age group showed detectable amounts of the mucins. In the labial area, a significantly lower level of MUC7 was noted in 3-year-olds compared with adults. CONCLUSION: The results indicate a site-dependent difference in minor gland mucin secretion and an age-related difference in the labial gland secretion of MUC7.
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