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  • 1.
    Agmo Hernández, Víctor
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi, Fysikalisk kemi.
    Karlsson, Göran
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi, Fysikalisk kemi.
    Edwards, Katarina
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi, Fysikalisk kemi.
    Intrinsic Heterogeneity in Liposome Suspensions Caused by the Dynamic Spontaneous Formation of Hydrophobic Active Sites in Lipid Membranes2011Inngår i: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 27, nr 8, s. 4873-4883Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The spontaneous, dynamic formation of hydrophobic active sites in lipid bilayer membranes is studied and characterized. It is shown that the rates of formation and consumption of these active sites control at least two important properties of liposomes: their affinity for hydrophobic surfaces and the rate by which they spontaneously release encapsulated molecules. The adhesion and spreading of liposomes onto hydrophobic polystyrene nanoparticles and the spontaneous leakage of an encapsulated fluorescent dye were monitored for different liposome compositions employing Cryo-TEM, DLS, and fluorescence measurements. It was observed that an apparently homogeneous, monodisperse liposome suspension behaves as if composed by two different populations: a fast leaking population that presents affinity for the hydrophobic substrate employed, and a slow leaking population that does not attach immediately to it. The results reported here suggest that the proportion of liposomes in each population changes over time until a dynamic equilibrium is reached. It is shown that this phenomenom can lead to irreproducibility in, for example, spontaneous leakage experiments, as extruded liposomes leak much faster just after preparation than 24 h afterward. Our findings account for discrepancies in several experimental results reported in the literature. To our knowledge, this is the first systematic study addressing the issue of an existing intrinsic heterogeneity of liposome suspensions.

  • 2.
    Alexander, Michelle
    et al.
    Univ York, York YO10 5DD, N Yorkshire, England.;Univ Aberdeen, Sch Geosci, Dept Archaeol, Aberdeen AB24 3UF, Scotland..
    Ho, Simon Y. W.
    Univ Sydney, Sch Biol Sci, Sydney, NSW 2006, Australia..
    Molak, Martyna
    Polish Acad Sci, Museum & Inst Zool, PL-00679 Warsaw, Poland..
    Barnett, Ross
    Palaeogen & Bioarchaeol Res Network, Res Lab Archaeol, Oxford OX1 3QY, England..
    Carlborg, Örjan
    Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Dorshorst, Ben
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Virginia Tech, Dept Anim & Poultry Sci, Blacksburg, VA 24061 USA..
    Honaker, Christa
    Virginia Tech, Dept Anim & Poultry Sci, Blacksburg, VA 24061 USA..
    Besnier, Francois
    Inst Marine Res, Sect Populat Genet, N-5024 Bergen, Norway..
    Wahlberg, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Dobney, Keith
    Univ Aberdeen, Sch Geosci, Dept Archaeol, Aberdeen AB24 3UF, Scotland..
    Siegel, Paul
    Virginia Tech, Dept Anim & Poultry Sci, Blacksburg, VA 24061 USA..
    Andersson, Leif
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Swedish Univ Agr Sci, Dept Anim Breeding & Genet, S-75007 Uppsala, Sweden..
    Larson, Greger
    Palaeogen & Bioarchaeol Res Network, Res Lab Archaeol, Oxford OX1 3QY, England..
    Mitogenomic analysis of a 50-generation chicken pedigree reveals a rapid rate of mitochondrial evolution and evidence for paternal mtDNA inheritance2015Inngår i: Biology Letters, ISSN 1744-9561, E-ISSN 1744-957X, Vol. 11, nr 10, artikkel-id 20150561Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mitochondrial genomes represent a valuable source of data for evolutionary research, but studies of their short-term evolution have typically been limited to invertebrates, humans and laboratory organisms. Here we present a detailed study of 12 mitochondrial genomes that span a total of 385 transmissions in a well-documented 50-generation pedigree in which two lineages of chickens were selected for low and high juvenile body weight. These data allowed us to test the hypothesis of time-dependent evolutionary rates and the assumption of strict maternal mitochondrial transmission, and to investigate the role of mitochondrial mutations in determining phenotype. The identification of a non-synonymous mutation in ND4L and a synonymous mutation in CYTB, both novel mutations in Gallus, allowed us to estimate a molecular rate of 3.13 x 10(-7) mutations/site/year (95% confidence interval 3.75 x 10(-8)-1.12 x 10(-6)). This is substantially higher than avian rate estimates based upon fossil calibrations. Ascertaining which of the two novel mutations was present in an additional 49 individuals also revealed an instance of paternal inheritance of mtDNA. Lastly, an association analysis demonstrated that neither of the point mutations was strongly associated with the phenotypic differences between the two selection lines. Together, these observations reveal the highly dynamic nature of mitochondrial evolution over short time periods.

  • 3.
    Alinaghizadeh, Hassan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Radioactive fall-out from the Chernobyl nuclear power plant accident in 1986 and cancer rates in Sweden, a 25-year follow up2019Licentiatavhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Aim: The current research aimed to study the association between exposure to low-dose radiation fallout after the Chernobyl accident in 1986 and the incidence of cancer in Sweden.

    Methods: A nationwide study population, selecting information from nine counties out of 21 in Sweden for the period from 1980 – 2010.

    In the first study, an ecological design was defined for two closed cohorts from 1980 and 1986. A possible exposure response pattern between the exposure to 137Cs on the ground and the cancer incidence after the Chernobyl nuclear power plant accident was investigated in the nine northernmost counties of Sweden (n=2.2 million). The activity of 137Cs at the county, municipality and parish level in 1986 was retrieved from the Swedish Radiation Safety Authority (SSI) and used as a proxy for received dose of ionizing radiation. Information about diagnoses of cancer (ICD-7 code 140-209) from 1958 – 2009 were received from the Swedish Cancer Registry, National Board of Health and Welfare (368,244 cases were reported for the period 1958 to 2009). The incidence rate ratios were calculated by using Poisson Regression for pre-Chernobyl (1980 – 1986) and post-Chernobyl (1986 – 2009) using average deposition of 137Cs at three geographical levels: county (n=9), municipality (n=95), and parish level (n=612). Also, a time trend analysis with age standardized cancer incidence in the study population and in the general Swedish population was drawn from 1980 – 2009.

    In the second study, a closed cohort was defined as all individuals living in the three most contaminated counties in mid-Sweden in 1986. Fallout of 137Cs was retrieved as a digital map from the Geological Survey of Sweden, demographic data from Statistics Sweden, and cancer diagnosis from the Swedish Cancer Registry, National Board of Health and Welfare. Individuals were assigned an annual 137Cs exposure based on their place of residence (1986 through 1990), from which 5-year cumulative 137Cs exposures were calculated, accounting for the physical decay of 137Cs and changing residencies. Hazard ratios for having cancer during the follow-up period, adjusted for age, sex, rural/non-rural residence, and pre-Chernobyl total cancer incidence, were calculated.

    Results: No obvious exposure-response pattern in the age-standardized total cancer incidence rate ratios could be seen in the first study. However, a spurious association between the fallout and cancer incidence was present, where areas with the lowest incidence of cancer before the accident coincidentally had the lowest fallout of cesium-137. Increasing the geographical resolution of exposure from the average values of nine counties to the average values of 612 parishes resulted in two to three times higher degree of variance explanation by regression model. There was a secular trend, with an increase in age standardized incidence of cancer from 1980 – 2009. This trend was stronger in the general Swedish population compared to the nine counties of the present study.

    In the second study, 734,537 people identified were divided into three exposure categories: the first quartile was low exposure (0.0 to 45.4 kBq/m2), the second and third quartiles were intermediate exposure (45.41 to 118.8 kBq/m2), and the fourth quartile was highest exposure (118.81 to 564.71 kBq/m2). Between 1991 and 2010, 82,495 cancer cases were registered in the three counties. Adjusted HRs (95% CI) were 1.03 (1.01 to 1.05) for intermediate exposure, and 1.05 (1.03 to 1.07) for the highest exposure, when comparing to the reference exposure.

    Conclusion: Using the ecological data, there was no exposure response trend; however, after refining the data to the individual level of exposure, there was an overall exposure response pattern. Nonetheless, due to the time dependency, these results were restricted to the age group of 25 – 49 among males. Using register-based data only, for determining the association between low-dose exposure to radiation and the risk of developing cancer, is difficult since we cannot control for other significant factors that are associated with cancer.

    Delarbeid
    1. Cancer incidence in northern Sweden before and after the Chernobyl nuclear power plant accident
    Åpne denne publikasjonen i ny fane eller vindu >>Cancer incidence in northern Sweden before and after the Chernobyl nuclear power plant accident
    2014 (engelsk)Inngår i: Radiation and Environmental Biophysics, ISSN 0301-634X, E-ISSN 1432-2099, Vol. 53, nr 3, s. 495-504Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Sweden received about 5 % of the total release of Cs-137 from the Chernobyl nuclear power plant accident in 1986. The distribution of the fallout mainly affected northern Sweden, where some parts of the population could have received an estimated annual effective dose of 1-2 mSv per year. It is disputed whether an increased incidence of cancer can be detected in epidemiological studies after the Chernobyl nuclear power plant accident outside the former Union of Soviet Socialist Republics. In the present paper, a possible exposure-response pattern between deposition of Cs-137 and cancer incidence after the Chernobyl nuclear power plant accident was investigated in the nine northernmost counties of Sweden (2.2 million inhabitants in 1986). The activity of Cs-137 from the fallout maps at 1986 was used as a proxy for the received dose of ionizing radiation. Diagnoses of cancer (ICD-7 code 140-209) from 1980 to 2009 were received from the Swedish Cancer Registry (273,222 cases). Age-adjusted incidence rate ratios, stratified by gender, were calculated with Poisson regression in two closed cohorts of the population in the nine counties 1980 and 1986, respectively. The follow-up periods were 1980-1985 and 1986-2009, respectively. The average surface-weighted deposition of Cs-137 at three geographical levels; county (n = 9), municipality (n = 95) and parish level (n = 612) was applied for the two cohorts to study the pre- and the post-Chernobyl periods separately. To analyze time trends, the age-standardized total cancer incidence was calculated for the general Swedish population and the population in the nine counties. Joinpoint regression was used to compare the average annual percent change in the general population and the study population within each gender. No obvious exposure-response pattern was seen in the age-adjusted total cancer incidence rate ratios. A spurious association between fallout and cancer incidence was present, where areas with the lowest incidence of cancer before the accident coincidentally had the lowest fallout of Cs-137. Increasing the geographical resolution of exposure from nine county averages to 612 parish averages resulted in a two to three times higher value of variance in the regression model. There was a secular trend with an increase in age-standardized incidence of cancer in both genders from 1980 to 2009, but significant only in females. This trend was stronger and statistically significant for both genders in the general Swedish population compared to the nine counties. In conclusion, using both high quality cancer registry data and high resolution exposure maps of Cs-137 deposition, it was not possible to distinguish an effect of Cs-137 on cancer incidence after the Chernobyl nuclear power plant accident in Sweden.

    Emneord
    Cancer, Cesium-137, Chernobyl, Ecological study, Environment, Epidemiology, Ionizing radiation, Nuclear accident, Radiation, Sweden
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-231289 (URN)10.1007/s00411-014-0545-6 (DOI)000339898300003 ()24811728 (PubMedID)
    Tilgjengelig fra: 2014-09-08 Laget: 2014-09-07 Sist oppdatert: 2019-03-28bibliografisk kontrollert
    2. Total cancer incidence in relation to 137Cs fallout in the most contaminated counties in Sweden after the Chernobyl nuclear power plant accident: a register-based study
    Åpne denne publikasjonen i ny fane eller vindu >>Total cancer incidence in relation to 137Cs fallout in the most contaminated counties in Sweden after the Chernobyl nuclear power plant accident: a register-based study
    2016 (engelsk)Inngår i: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 6, nr 12, artikkel-id e011924Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    OBJECTIVES: To determine the total cancer incidence in relation to a 5-year exposure to caesium-137 ((137)Cs) from the 1986 Chernobyl nuclear power plant accident.

    METHODS: A closed cohort was defined as all individuals living in the three most contaminated counties in mid-Sweden in 1986. Fallout of (137)Cs was retrieved as a digital map from the Geological Survey of Sweden, demographic data from Statistics Sweden, and cancer diagnosis from the National Board of Health and Welfare. Individuals were assigned an annual (137)Cs exposure based on their place of residence (1986-1990), from which 5-year cumulative (137)Cs exposures were calculated, accounting for the physical decay of (137)Cs and changing residencies. HRs were adjusted for age, sex, rural/non-rural residence and pre-Chernobyl total cancer incidence.

    RESULTS: The 734 537 people identified were categorised by exposure: the first quartile was low exposure (0.0-45.4 kBq/m(2)), the second and third quartiles were intermediate exposure (45.41-118.8 kBq/m(2)), and the fourth quartile was the highest exposure (118.81-564.71 kBq/m(2)). Between 1991 and 2010, 82 495 cancer cases were registered in the 3 counties. Adjusted HRs (95% CI) were 1.03 (1.01 to 1.05) for intermediate exposure and 1.05 (1.03 to 1.07) for the highest exposure compared to the reference exposure.

    CONCLUSIONS: We found a small overall exposure-response pattern of the total cancer incidence related to (137)Cs after adjustment for age, sex, rural residence and pre-Chernobyl cancer incidence.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-311895 (URN)10.1136/bmjopen-2016-011924 (DOI)000391303600003 ()27998898 (PubMedID)
    Tilgjengelig fra: 2017-01-03 Laget: 2017-01-03 Sist oppdatert: 2019-03-28bibliografisk kontrollert
  • 4.
    Almgren, Mats
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi.
    Garamus, Vasil M
    Nordstierna, Lars
    Luc-Blin, Jean
    Stébé, Marie-José
    Nonideal mixed micelles of fluorinated and hydrogenous surfactants in aqueous solution: NMR and SANS studies of anionic and nonionic systems.2010Inngår i: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 26, nr 8, s. 5355-5363Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Contrast variation SANS and (19)F chemical shifts were measured for three mixed equimolar micelle systems: sodium perfluorooctanoate (SPFO) and sodiumdecylsulfate (SDeS) in 200 mM NaCl, lithium perfluorononanate (LiPFN) and lithium dodecylsulfate (LiDS) in 200 mM LiCl, and a nonionic system C(8)F(17)C(2)H(4)(OC(2)H(4))(9) and C(12)H(25)(OC(2)H(4))(8) in water, all at 25 degrees C. The chemical shift measurements allow the calculation of the average fraction of nearest neighbors of each kind around the reporter group (the trifluoromethyl group). A preference for like neighbors were found in all systems, smallest in the SDeS/SPFO system and largest in the nonionic system, but in all cases substantially smaller than expected at critical conditions. From the SANS measurements the width of the micelle composition distribution was obtained. For the ionic systems similar values were obtained, showing a broadening compared to ideal mixtures, but not broad enough for demixing or clearly bimodal distributions. In the nonionic system the width was estimated as sigma = 0.18 and 0.22 using two different evaluation methods. These values suggest that the system is close to critical conditions. The lower value refers to a direct modeling of the system, assuming an ellipsoidal shape and a Gaussian composition distribution. The modeling showed the nonionic mixed micelles to be prolate ellipsoids with axial ratio 2.2 and an aggregation number larger than 100, whereas the two ionic systems fitted best to oblate shapes (axial ratios 0.8 and 0.65 for SDeS/SPFO and LiDS/LiPFN, respectively) and aggregation numbers of 60 for both.

  • 5.
    Ammar, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Immunohistochemical studies on small arteries from women with polycystic ovary syndrome: Focus on makers for endothelial dysfunction2012Independent thesis Basic level (degree of Bachelor), 10 poäng / 15 hpOppgave
    Abstract [en]

    Women with polycystic ovary syndrome (PCOS) have an increased risk of developing cardiovascular disease (CVD). Metabolic syndrome predominate which may lead to impaired insulin sensitivity and development of type II diabetes and hypertension. Endothelial dysfunction together with pro-inflammatory, pro-thrombotic and pro-oxidant environment serves as initial phase for CVD complications. The research group performs functional studies on isolated arteries with focus on endothelium dependent relaxation from PCOS women and age matched controls and the aim of the presented project was to compare markers for endothelial dysfunction using immunohistochemistry (IHC). Small arteries were isolated from subcutaneous fat biopsies from patients and controls and fixed in O.C.T. compound (-70C dry ice). The biopsies were sectioned in 8µm thin slices for further staining with primary antibodies, DAB as a chromogen and Mayer´s Hematoxylin. The primary antibody was selected for endothelial cell adhesion molecules PECAM-1, P-selectin, vWF and VCAM-1.    There was a tendency for stronger expression of P-selectin in arteries from PCOS women compared with controls, while in the controls a tendency was seen towards stronger expression of VCAM-1 and a weaker staining for vWF if compared with PCOS. There was no obvious difference for other stained markers between the groups. There were differences between tested markers in control groups and the PCOS women whit IHC staining as well as earlier functional tests. Tested markers reflected that endothelial dysfunction were expressed in the endothelium of isolated arteries from PCOS and control women, however further functional studies and IHC studies were warranted to quantify their contribution.

  • 6.
    Andaloussi, Mounir
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Henriksson, Lena M.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Wieckowska, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Lindh, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Björkelid, Christofer
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Larsson, Anna M.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Suresh, Surisetti
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Iyer, Harini
    Srinivasa, Bachally R.
    Bergfors, Terese
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Unge, Torsten
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Mowbray, Sherry L.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Jones, T. Alwyn
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Karlén, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Design, Synthesis, and X-ray Crystallographic Studies of alpha-Aryl Substituted Fosmidomycin Analogues as Inhibitors of Mycobacterium tuberculosis 1-Deoxy-D-xylulose 5-Phosphate Reductoisomerase2011Inngår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 54, nr 14, s. 4964-4976Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The natural antibiotic fosmidomycin acts via inhibition of 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR), an essential enzyme in the non-mevalonate pathway of isoprenoid biosynthesis. Fosmidomycin is active on Mycobacterium tuberculosis DXR (MtDXR), but it lacks antibacterial activity probably because of poor uptake. alpha-Aryl substituted fosmidomycin analogues have more favorable physicochemical properties and are also more active in inhibiting malaria parasite growth. We have solved crystal structures of MtDXR in complex with 3,4-dichlorophenyl substituted fosmidomycin analogues; these show important differences compared to our previously described forsmidomycin-DXR complex. Our best inhibitor has an IC(50) = 0.15 mu M on MtDXR but still lacked activity in a mycobacterial growth assay (MIC > 32 mu g/mL). The combined results, however, provide insights into how DXR accommodates the new inhibitors and serve as an excellent starting point for the design of other novel and more potent inhibitors, particularly against pathogens where uptake is less of a problem, such as the malaria parasite.

  • 7.
    Andersson, Ken G.
    et al.
    KTH Royal Inst Technol, Div Prot Technol, SE-10691 Stockholm, Sweden.
    Oroujeni, Maryam
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Garousi, Javad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Mitran, Bogdan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    Ståhl, Stefan
    KTH Royal Inst Technol, Div Prot Technol, SE-10691 Stockholm, Sweden.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    Löfblom, John
    KTH Royal Inst Technol, Div Prot Technol, SE-10691 Stockholm, Sweden.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Feasibility of imaging of epidermal growth factor receptor expression with ZEGFR: 2377 affibody molecule labeled with 99mTc using a peptide-based cysteine-containing chelator2016Inngår i: International journal of oncology, ISSN 1791-2423, Vol. 49, nr 6, s. 2285-2293Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The epidermal growth factor receptor (EGFR) is overexpressed in a number of malignant tumors and is a molecular target for several specific anticancer antibodies and tyrosine kinase inhibitors. The overexpression of EGFR is a predictive biomarker for response to several therapy regimens. Radionuclide molecular imaging might enable detection of EGFR overexpression by a non-invasive procedure and could be used repeatedly. Affibody molecules are engineered scaffold proteins, which could be selected to have a high affinity and selectivity to predetermined targets. The anti-EGFR ZEGFR:2377 affibody molecule is a potential imaging probe for EGFR detection. The use of the generator-produced radionuclide 99mTc should facilitate clinical translation of an imaging probe due to its low price, availability and favorable dosimetry of the radionuclide. In the present study, we evaluated feasibility of ZEGFR:2377 labeling with 99mTc using a peptide-based cysteine-containing chelator expressed at the C-terminus of ZEGFR:2377. The label was stable in vitro under cysteine challenge. In addition, 99mTc-ZEGFR:2377 was capable of specific binding to EGFR-expressing cells with high affinity (274 pM). Studies in BALB/C nu/nu mice bearing A431 xenografts demonstrated that 99mTc-ZEGFR:2377 accumulates in tumors in an EGFR-specific manner. The tumor uptake values were 3.6±1 and 2.5±0.4% ID/g at 3 and 24 h after injection, respectively. The corresponding tumor-to-blood ratios were 1.8±0.4 and 8±3. The xenografts were clearly visualized at both time-points. This study demonstrated the potential of 99mTc-labeled ZEGFR:2377 for imaging of EGFR in vivo.

  • 8. Aquilante, Francesco
    et al.
    Barone, V
    Roos, B O
    A theoretical investigation of valence and Rydberg electronic states of acrolein.2003Inngår i: Journal of Chemical Physics, ISSN 0021-9606, E-ISSN 1089-7690, Vol. 119, nr 23, s. 12323-12334Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The main features of the ultraviolet spectrum of acrolein have been studied by a multireference perturbative treatment and by a time dependent density functional approach. The valence and Rydberg transition energies have been calculated and the assignment of the experimental bands has been clarified. The different relaxation trends of the three lowest singlet and triplet excited states have been analyzed by unconstrained geometry optimizations. This has allowed, in particular, the characterization of a twisted (3)(pipi*) state, which is crucial for the interesting photophysics and photochemistry of the acrolein molecule and, more generally, of the alpha,beta-enones. Solvatochromic shifts in aqueous solution have been investigated using a combined discrete/continuum approach based on the so called polarizable continuum model. The experimental trends are well reproduced by this approach and a closer degeneracy in the triplet manifold has been detected in solution with respect to gas phase.

  • 9. Aquilante, Francesco
    et al.
    Cossi, M
    Crescenzi, O
    Scalmani, G
    Barone, V
    Computation of the acetone ultraviolet spectrum in gas phase and in aqueous solution by a mixed discrete/continuum model.2003Inngår i: Molecular Physics, ISSN 0026-8976, E-ISSN 1362-3028, Vol. 101, nr 13, s. 1945-1953Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The ultraviolet spectrum of acetone in vacuum and in aqueous solution has been computed by different quantum mechanical methods coupled to the polarizable continuum model (PCM) for describing bulk solvent effects. The results in vacuo show that the time-dependent density functional theory (TDDFT) approach using the PBE0 functional reproduces quite well the result obtained at the CASPT2 level. Supermolecule computations confirm that water molecules belonging to the first shell of polar groups ( here the carbonyl oxygen) must be explicitly included in the quantum mechanical treatment, whereas the effect of other solvent molecules ( which is far from being negligible) can be reliably described by the PCM. Moreover, statistical averaging effects have been taken into account by performing canonical molecular dynamics (MD) simulations followed by TDDFT quantum mechanical computations on representative clusters of increasing dimensions immersed in a polarizable continuum. The results show that the combined MD/DFT/PCM approach is reliable and effective, although the performances of the force field used in the MD simulations must be further investigated.

  • 10. Aquilante, Francesco
    et al.
    De Vito, Luca
    Ferré, Nicolas
    Chigo, Giovanni
    Malmqvist, Per-Åke
    Neogrády, Pavel
    Pedersen, Tjomas Bono
    Pitoňák, Michak
    Reiher, Markus
    Roos, Björn O
    Serrano-Andrés, Luis
    Miroslav, Urban
    Veryazov, Valera
    Lindh, Roland
    Department of Theoretical Chemistry, Lund University.
    Software news and update MOLCAS 7: The Next Generation2010Inngår i: Journal of Computational Chemistry, ISSN 0192-8651, E-ISSN 1096-987X, Vol. 31, nr 1, s. 224-247Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Some of the new unique features of the MOLCAS quantum chemistry package version 7 are presented in this report. In particular, the Cholesky decomposition method applied to some quantum chemical methods is described. This approach is used both in the context of a straight forward approximation of the two-electron integrals and in the generation of so-called auxiliary basis sets. The article describes how the method is implemented for most known wave functions models: self-consistent field, density functional theory, 2nd order perturbation theory, complete-active space self-consistent field multiconfigurational reference 2nd order perturbation theory, and coupled-cluster methods. The report further elaborates on the implementation of a restricted-active space self-consistent field reference function in conjunction with 2nd order perturbation theory. The average atomic natural orbital basis for relativistic calculations, covering the whole periodic table, are described and associated unique properties are demonstrated. Furthermore, the use of the arbitrary order Douglas-Kroll-Hess transformation for one-component relativistic calculations and its implementation are discussed. This section especially focuses on the implementation of the so-called picture-change-free atomic orbital property integrals. Moreover, the ElectroStatic Potential Fitted scheme, a version of a quantum mechanics/molecular mechanics hybrid method implemented in MOLCAS, is described and discussed. Finally, the report discusses the use of the MOLCAS package for advanced studies of photo chemical phenomena and the usefulness of the algorithms for constrained geometry optimization in MOLCAS in association with such studies.

  • 11. Aquilante, Francesco
    et al.
    Jensen, K. P.
    Roos, Björn O.
    The allyl radical revisited: a theoretical study of the electronic spectrum.2003Inngår i: Chemical Physics Letters, ISSN 0009-2614, E-ISSN 1873-4448, Vol. 380, nr 5-6, s. 689-698Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In this Letter, we report the electronic spectrum of the allyl radical, obtained with multiconfigurational perturbation theory (MS-CASPT2). The assignment of the spectrum is in accordance with experiment to within 0.2 eV. We have computed the complete first Rydberg series and the beginning of the second Rydberg series. A new valence-excited B-2(1) state has been found which has hitherto been hidden by Rydberg transitions. A rationalisation of the electronic spectrum is provided in terms of resonance forms in ground and excited states. This model shows that while a multiconfigurational wavefunction is necessary to qualitatively model the system, the large ionic character of the valence electronic states makes an accurate treatment of the dynamical correlation necessary for a quantitative description of the spectrum.

  • 12. Aquilante, Francesco
    et al.
    Malmqvist, Per-Åke
    Pedersen, Thomas Bondo
    Ghosh, Abhik
    Roos, Björn Olof
    Cholesky decomposition-based multiconfiguration second-order perturbation theory (CD-CASPT2): application to the spin-state energetics of Co-III(diiminato)(NPh).2008Inngår i: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 4, nr 5, s. 694-702Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The electronic structure and low-lying electronic states of a Co-III(diiminato)(NPh) complex have been studied using mulficonfigurational wave function theory (CASSCF/CASPT2) The results have been compared to those obtained with density functional theory. The best agreement with ab initio results is obtained with a modified B3LYP functional containing a reduced amount (15%) of Hartree-Fock exchange. A relativistic basis set with 869 functions has been employed in the most extensive ab initio calculations, where a Cholesky decomposition technique was used to overcome problems arising from the large size of the two-electron integral matrix. It is shown that this approximation reproduces results obtained with the full integral set to a high accuracy, thus opening the possibility to use this approach to perform multiconfigurational wave-function-based quantum chemistry on much larger systems relative to what has been possible until now.

  • 13. Aquilante, Francesco
    et al.
    Pedersen, Thomas Bondo
    Quartic scaling evaluation of canonical scaled opposite spin second-order Moller-Plesset correlation energy using Cholesky decompositions.2007Inngår i: Chemical Physics Letters, ISSN 0009-2614, E-ISSN 1873-4448, Vol. 449, nr 4-6, s. 354-357Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The scaled opposite spin second-order Moller-Plesset (SOS-MP2) energy expression is reformulated using Cholesky decomposition of the amplitude matrix. The resulting algorithm requires an auxiliary basis or Cholesky representation of the two-electron integrals and shows fourth-order scaling with system size. Based on an analysis of operation counts, we estimate that the present approach is computationally advantageous compared to the analogous fourth-order algorithms that employ Laplace transforms.

  • 14. Aquilante, Francesco
    et al.
    Pedersen, Thomas Bondo
    Sanchez de Meras, Alfredo
    Koch, Henrik
    Fast noniterative orbital localization for large molecules.2006Inngår i: Journal of Chemical Physics, ISSN 0021-9606, E-ISSN 1089-7690, Vol. 125, nr 17Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We use Cholesky decomposition of the density matrix in atomic orbital basis to define a new set of occupied molecular orbital coefficients. Analysis of the resulting orbitals (”Cholesky molecular orbitals”) demonstrates their localized character inherited from the sparsity of the density matrix. Comparison with the results of traditional iterative localization schemes shows minor differences with respect to a number of suitable measures of locality, particularly the scaling with system size of orbital pair domains used in local correlation methods. The Cholesky procedure for generating orthonormal localized orbitals is noniterative and may be made linear scaling. Although our present implementation scales cubically, the algorithm is significantly faster than any of the conventional localization schemes. In addition, since this approach does not require starting orbitals, it will be useful in local correlation treatments on top of diagonalization-free Hartree-Fock optimization algorithms.

  • 15.
    Baleani, Massimiliano
    et al.
    Laboratorio di Tecnologia Medica, Istituto Ortopedico Rizzoli, Bologna, Italy.
    Fognani, Roberta
    Laboratorio di Tecnologia Medica, Istituto Ortopedico Rizzoli, Bologna, Italy.
    Feresini, Chiara
    Centro Ceramico Bologna, Bologna, Italy.
    Öhman, Caroline
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Spagnolo, Claudia
    Laboratorio di Tecnologia Medica, Istituto Ortopedico Rizzoli, Bologna, Italy.
    Baruffaldi, Fabio
    Laboratorio di Tecnologia Medica, Istituto Ortopedico Rizzoli, Bologna, Italy.
    Real wet density of bone tissue: Does it depend on tissue type and subject?2014Inngår i: Proceedings of 7th World Congress of Biomechanics, 2014, 2014Konferansepaper (Fagfellevurdert)
  • 16.
    Beckman Sundh, Ulla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Studies on Phosphohistidine Phosphatase 1: What? Where? Why?2012Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Phosphohistidine phosphatase 1 (PHPT1) is a small protein, consisting of 125 amino acids, that catalyzes the dephosphorylation of histidine but does not have any activity towards other phosphorylated amino acids. PHPT1 was identified in 2002, and is so far the only mammalian histidine phosphatase known, but still little is known about its physiological role. No mammalian histidine kinases have hitherto been identified.

    Phosphorylation is one of the most important ways in which the structure and activity of a protein may be changed after translation. Proteins are phosphorylated on the side chain of amino acid residues. When a hydroxyl is phosphorylated the result is a phosphoester and when a nitrogen is phosphorylated the result is a phosphoamidate. Histidine may be phosphorylated on either of the two nitrogens of the imidazole ring of the side chain. The resulting phosphoamidate bond is labile and rich in energy, which makes histidine phosphorylation highly reversible and flexible. However, histidine phosphorylation is less studied than that of the phosphoesters due to the acid lability of the phosphoamidate bond.

    The work described in this thesis was focused on further elucidating the physiological role of PHPT1. Amino acid residues of importance for the activity of PHPT1 were identified, and mutants with decreased phosphatase activity were produced. These mutants have been used in studies on the function of PHPT1. By using immunohistochemical methodology the localization of PHPT1 in both mouse and human tissues was determined, with mainly similar results. A general finding was that expression of PHPT1 was high in epithelial cells with short turnover time, indicating that PHPT1 may have an important role in proliferating cells. We have also developed a comparatively fast and simple screening method for determination of PHPT1 activity. Since research in this field has been hampered by the lack of efficient and practical methodology, hopefully this new method will be an asset in search of inhibitors for PHPT1, which in turn may be used for detection of the elusive mammalian histidine kinases, the finding of which may give major breakthroughs in the field.

    Delarbeid
    1. Mutational study of human phosphohistidine phosphatase: effect on enzymatic activity.
    Åpne denne publikasjonen i ny fane eller vindu >>Mutational study of human phosphohistidine phosphatase: effect on enzymatic activity.
    Vise andre…
    2005 (engelsk)Inngår i: Biochem Biophys Res Commun, ISSN 0006-291X, Vol. 337, nr 3, s. 887-91Artikkel i tidsskrift (Fagfellevurdert) Published
    Emneord
    Amino Acid Sequence, Amino Acid Substitution, Binding Sites, Enzyme Activation, Evolution; Molecular, Humans, Molecular Sequence Data, Mutagenesis; Site-Directed, Mutation, Phosphoprotein Phosphatase/analysis/*chemistry/genetics/*metabolism, Protein Binding, Recombinant Proteins/analysis/chemistry/metabolism, Research Support; Non-U.S. Gov't, Sequence Homology; Amino Acid, Structure-Activity Relationship, Substrate Specificity
    Identifikatorer
    urn:nbn:se:uu:diva-80308 (URN)16219293 (PubMedID)
    Tilgjengelig fra: 2006-05-05 Laget: 2006-05-05 Sist oppdatert: 2012-05-30
    2. Immunohistochemical localization of phosphohistidine phosphatase PHPT1 in mouse and human tissues
    Åpne denne publikasjonen i ny fane eller vindu >>Immunohistochemical localization of phosphohistidine phosphatase PHPT1 in mouse and human tissues
    Vise andre…
    2009 (engelsk)Inngår i: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 114, nr 2, s. 65-72Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Protein histidine phosphorylation accounts for about 6% of the total protein phosphorylation in eukaryotic cells; still details concerning histidine phosphorylation and dephosphorylation are limited. A mammalian 14-kDa phosphohistidine phosphatase, also denominated PHPT1, was found 6 years ago that provided a new tool in the study of phosphohistidine phosphorylation. The localization of PHPT1 mRNA by Northern blot analysis revealed high expression in heart and skeletal muscle. The main object of the present study was to determine the PHPT1 expression on protein level in mouse tissues in order to get further information on the physiological role of the enzyme. Tissue samples from adult mice and 14.5-day-old mouse embryos were processed for immunostaining using a PHPT1-specific polyclonal antibody. The same antibody was also provided to the Swedish human protein atlas project (HPR) (http://www.proteinatlas.org/index.php). The results from both studies were essentially consistent with the previously reported expression of mRNA of a few human tissues. In addition, several other tissues, including testis, displayed a high protein expression. A salient result of the present investigation was the ubiquitous expression of the PHPT1 protein and its high expression in continuously dividing epithelial cells.

    Emneord
    Phosphohistidine phosphatase, PHPT1, PHP, phosphohistidine, dephosphorylation, HPR-project
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-119851 (URN)10.1080/03009730802642337 (DOI)000265454800001 ()19396692 (PubMedID)
    Tilgjengelig fra: 2010-03-02 Laget: 2010-03-02 Sist oppdatert: 2017-12-12bibliografisk kontrollert
    3.
    Posten ble ikke funnet. Det kan skyldes at posten ikke lenger er tilgjengelig eller det er feil id i adressefeltet.
  • 17.
    Berggren, Gustav
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fotokemi och molekylärvetenskap.
    Mimicking Nature – Synthesis and Characterisation of Manganese Complexes of Relevance to Artificial Photosynthesis2009Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The development of efficient catalyst for water oxidation is of paramount importance to artificial photosynthesis, but before this can be achieved a deeper understanding of this reaction is essential. In nature this reaction occurs in a tetranuclear Mn-cluster which serves as the work-horse of oxygenic photosynthesis. This thesis summarises my efforts at developing molecular systems capable of mimicking this complex employing a biomimetic approach.

    Three different approaches towards this goal are described here-in. The first section describes a screening study, in which a number of manganese complexes were tested to see whether or not they were capable of catalysing the formation of dioxygen when treated with different oxidants (Papers I). For those reactions in which dioxygen formation was observed the reactions were repeated in labelled water and the incorporation of labelled O-atoms was studied by mass spectrometry. This allowed us to determine to what extent water was the source of the evolved dioxygen (Papers II-III).

    In Chapter three a reported catalyst and a derivative thereof is studied in depth. The influence of changes to the ligand on the oxygen–oxygen bond forming reaction could unfortunately not be reliably addressed, because of the instability of the complexes under “catalytic” conditions. Nevertheless, the study allowed us to revise the “carboxylate shift”-mechanism suggested in the literature (Papers IV-V).

    Chapter four describes the continuation of my work on ligands featuring the carboxylate ligand motif first introduced in Chapter three. In this study ligands containing multiple binding pockets were designed and synthesised (Paper VI).

    A better understanding of the mechanism in the natural water oxidising enzyme will facilitate the design of biomimetic complexes, this is discussed in Chapter five. In this work model complexes (Paper VII) are used to study the mechanism by which natures own water oxidising catalyst performs this reaction.

    Delarbeid
    1. Formation of stoichiometrically O-18-labelled oxygen from the oxidation of O-18-enriched water mediated by a dinuclear manganese complex: a mass spectrometry and EPR study
    Åpne denne publikasjonen i ny fane eller vindu >>Formation of stoichiometrically O-18-labelled oxygen from the oxidation of O-18-enriched water mediated by a dinuclear manganese complex: a mass spectrometry and EPR study
    Vise andre…
    2008 (engelsk)Inngår i: Energy & Environmental Science, ISSN 1754-5692, E-ISSN 1754-5706, Vol. 1, nr 6, s. 668-676Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Oxygen formation was detected for the oxidations of various multinuclear manganese complexes by oxone (HSO5-) in aqueous solution. To determine to what extent water was the source of the evolved O-2, (H2O)-O-18 isotope-labelling experiments coupled with membrane inlet mass spectrometry (MIMS) were carried out. We discovered that during the reaction of oxone with [Mn-2(OAc)(2)(bpmp)](+) (1), stoichiometrically labelled oxygen (O-18(2)) was formed. This is the first example of a homogeneous reaction mediated by a synthetic manganese complex where the addition of a strong chemical oxidant yields O-18(2) with labelling percentages matching the theoretically expected values for the case of both O-atoms originating from water. Experiments using lead acetate as an alternative oxidant supported this finding. A detailed investigation of the reaction by EPR spectroscopy, MIMS and Clark-type oxygen detection enabled us to propose potential reaction pathways.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-108518 (URN)10.1039/b811806j (DOI)000263888600006 ()1754-5692 (ISBN)
    Tilgjengelig fra: 2009-09-21 Laget: 2009-09-21 Sist oppdatert: 2017-12-13
    2. Sodium [1,2-bis(2-methyl-2-oxopropanamido)-benzene](tetrahydrofuran) manganese(III) methanol solvate
    Åpne denne publikasjonen i ny fane eller vindu >>Sodium [1,2-bis(2-methyl-2-oxopropanamido)-benzene](tetrahydrofuran) manganese(III) methanol solvate
    Vise andre…
    2005 (engelsk)Inngår i: Acta Crystallographica Section E-Structure Reports Online, Vol. 61, s. M1169-Artikkel i tidsskrift (Fagfellevurdert) Published
    Identifikatorer
    urn:nbn:se:uu:diva-75924 (URN)
    Tilgjengelig fra: 2006-02-24 Laget: 2006-02-24 Sist oppdatert: 2011-01-11
    3. Two tetranuclear Mn-complexes as biomimetic models of the oxygen evolving complex in Photosystem II. A synthesis, characterisation and reactivity study
    Åpne denne publikasjonen i ny fane eller vindu >>Two tetranuclear Mn-complexes as biomimetic models of the oxygen evolving complex in Photosystem II. A synthesis, characterisation and reactivity study
    Vise andre…
    2009 (engelsk)Inngår i: Dalton Transactions, ISSN 1477-9226, E-ISSN 1477-9234, nr 45, s. 10044-10054Artikkel i tidsskrift (Fagfellevurdert) Published
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-108451 (URN)10.1039/b906175d (DOI)
    Tilgjengelig fra: 2009-09-21 Laget: 2009-09-18 Sist oppdatert: 2017-12-13
    4. Mechanistic Studies on the Water-Oxidizing Reaction of Homogeneous Manganese-Based Catalysts: Isolation and Characterization of a Suggested Catalytic Intermediate
    Åpne denne publikasjonen i ny fane eller vindu >>Mechanistic Studies on the Water-Oxidizing Reaction of Homogeneous Manganese-Based Catalysts: Isolation and Characterization of a Suggested Catalytic Intermediate
    Vise andre…
    2011 (engelsk)Inngår i: Inorganic Chemistry, ISSN 0020-1669, E-ISSN 1520-510X, Vol. 50, nr 8, s. 3425-3430Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The synthesis, isolation, and characterization of two high-valent manganese dimers with isomeric ligands are reported. The complexes are synthesized and crystallized from solutions of low-valent precursors exposed to tert-butyl hydroperoxide. The crystal structures display centrosymmetric complexesconsisting of Mn2 IV,IV(μ-O)2 cores, with one ligand coordinating to each manganese. The ligands coordinate with the diaminoethane backbone, the carboxylate, and one of the two pyridines, while the second pyridine is noncoordinating. The activity of these complexes, under water oxidation conditions, is discussed in light of a proposed mechanism for water oxidation, in which this type of complexes have been suggested as a key intermediate.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-108524 (URN)10.1021/ic102336a (DOI)000290457700034 ()21428420 (PubMedID)
    Tilgjengelig fra: 2009-09-21 Laget: 2009-09-21 Sist oppdatert: 2017-12-13
    5. Synthesis and characterisation of low valent Mn-complexes as models for Mn-catalases
    Åpne denne publikasjonen i ny fane eller vindu >>Synthesis and characterisation of low valent Mn-complexes as models for Mn-catalases
    Vise andre…
    2010 (engelsk)Inngår i: Dalton Transactions, ISSN 1477-9226, E-ISSN 1477-9234, Vol. 39, nr 45, s. 11035-11044Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    In this work we report the synthesis of two novel manganese complexes, [L1(3)Mn(6)(II)](ClO4)(6) (1 center dot(ClO4)(6)) and [L2Mn(2)(II)(mu-OAc)(mu-Cl)](ClO4)(2) (2 center dot(ClO4)(2)), where L1(2-) is the 2,2'-(1,3-phenylenebis(methylene))bis-((2-(bis(pyridin-2-ylmethyl)amino)ethyl)azanediyl)diacetic acid anion and L2 is N1,N1'-(1,3-phenylenebis(methylene))bis(N2,N2'-bis(pyridin-2-ylmethyl)ethane-1,2-diamine). The ligands Na(2)L1 and L2 are built on the same backbone, L2 only contains nitrogen donors, while two carboxylate arms have been introduced in Na(2)L1. The two complexes have been characterized by single-crystal X-ray diffraction, magnetic susceptibility, EPR spectroscopy, and electrochemistry. X-Ray crystallography revealed that 1 is a manganese(II) hexamer and 2 is a manganese(II) dimer featuring an unprecedented mono-mu-acetato, mono-mu-chlorido bridging motif. The ability of the complexes to catalyse H2O2 disproportionation, thereby acting as models for manganese catalases, has been investigated and compared to the activity of two other related manganese complexes. The introduction of carboxylate donors in the ligands, leading to increased denticity, resulted in a drop in H2O2 disproportionation activity.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-108525 (URN)10.1039/c0dt00165a (DOI)000284066100028 ()
    Tilgjengelig fra: 2009-09-21 Laget: 2009-09-21 Sist oppdatert: 2017-12-13
    6. Oxygen evolving reactions catalysed by synthetic manganese complexes: A systematic screening
    Åpne denne publikasjonen i ny fane eller vindu >>Oxygen evolving reactions catalysed by synthetic manganese complexes: A systematic screening
    2007 (engelsk)Inngår i: Dalton Transactions, ISSN 1477-9226, E-ISSN 1477-9234, nr 38, s. 4258-4261Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    A set of six multinuclear manganese complexes was screened for the ability to catalyse reactions yielding O(2) under coherent experimental conditions; we identify a much larger number of manganese compounds than previously known that catalyse oxygen formation.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-11551 (URN)10.1039/b710761g (DOI)000249705100004 ()17893814 (PubMedID)
    Tilgjengelig fra: 2007-09-27 Laget: 2007-09-27 Sist oppdatert: 2017-12-11
    7. Oxygen Evolving Reactions by Synthetic Manganese Complexes
    Åpne denne publikasjonen i ny fane eller vindu >>Oxygen Evolving Reactions by Synthetic Manganese Complexes
    Vise andre…
    2008 (engelsk)Inngår i: Photosynthesis. Energy from the Sun: 14th International Congress on Photosynthesis, Springer, Netherlands , 2008Kapittel i bok, del av antologi (Annet (populærvitenskap, debatt, mm))
    sted, utgiver, år, opplag, sider
    Springer, Netherlands, 2008
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-108452 (URN)978-1-4020-6707-5 (ISBN)
    Tilgjengelig fra: 2009-09-21 Laget: 2009-09-18 Sist oppdatert: 2015-04-24
  • 18.
    Bergström, Gunnel
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk och fysiologisk kemi.
    Ek, Pia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk och fysiologisk kemi.
    Dahlqvist, Ulla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk och fysiologisk kemi.
    Humble, Elisabet
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk och fysiologisk kemi.
    Engström, Lorentz
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk och fysiologisk kemi.
    Subtilisin-catalyzed removal of phosphorylated site of pig liver pyruvate kinase without inactivation of the enzyme1975Inngår i: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 56, nr 2, s. 288-291Artikkel i tidsskrift (Fagfellevurdert)
  • 19.
    Bergström, Gunnel
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk och fysiologisk kemi.
    Ekman, Pia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk och fysiologisk kemi.
    Humble, Elisabet
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk och fysiologisk kemi.
    Engström, Lorentz
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk och fysiologisk kemi.
    Proteolytic modification of pig and rat liver pyruvate kinase including the phosphorylatable site1978Inngår i: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 532, nr 2, s. 259-267Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The phosphorylated or phosphate-accepting site of pyruvate kinase from pig and rat liver was removed without inactivation by incubation with subtilisin. At different time intervals the subtilisin was inactivated with phenylmethylsulfonyl fluoride and the amount of remaining phosphorylatable or phosphorylated sites of pyruvate kinase estimated by incubation with an excess of [32P]-ATP and protein kinase. It was found that to get the same rate of modification the subtilisin concentration required to modify unphosphorylated pyruvate kinase was approximately ten times higher than that used for removal of the phosphorylated site of phosphorylated site of phosphorylated enzyme. It was shown that the proteolytically-modified pyruvate kinase had an increased apparent Km for phosphoenolpyruvate without a change in V, when compared to unmodified unphosphorylated and phosphorylated pyruvate kinase. The removal of the phosphorylated site was not associated with loss of the allosteric sites for ATP and Fru-1,6-P2. The possibility that phosphorylation of the pyruvate kinase increases its degradation rate in vivo is briefly discussed.

  • 20.
    Blom, Elisabeth
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Karimi, Farhad
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Eriksson, Olof
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Hall, Håkan
    Långström, Bengt
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Synthesis and in vitro evaluation of 18F-β-carboline alkaloids as PET ligands2008Inngår i: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 51, nr 6, s. 277-282Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A one-step 18F-labelling strategy was used to prepare four 18F-labelled analogues of 7-methoxy-1-methyl-9H-β-carboline (harmine): 7-(2-[18F]fluoroethoxy)-1-methyl-9H-β-carboline (5), 7-(3-[18F]fluoro-propoxy)-1-methyl-9H-β-carboline (6), 7-[2-(2-[18F]fluoroethoxy)ethoxy]-1-methyl-9H-β-carboline (7), and 7-{2-[2-(2-[18F]fluoroethoxy)ethoxy]-ethoxy}-1-methyl-9H-β-carboline (8). These were synthesized as potential PET ligands for monoamine oxidase A. A solution of pure labelled compound in buffer was obtained in < 70 min from end of radionuclide production, with a decay-corrected yield of up to 23%. The average specific binding to MAO-A in rat brain, determined by autoradiography experiments, was highest for compounds 7 and 8 (89 ± 2 and 96 ± 1% respectively), which was obtained at < 1 nM radioligand concentration.

  • 21.
    Blom, Elisabeth
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Karimi, Farhad
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Långström, Bengt
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    [F-18]/F-19 exchange in fluorine containing compounds for potential use in F-18-labelling strategies2009Inngår i: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 52, nr 12, s. 504-511Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Exchange of [F-18]fluoride with F-19 in various organofluorine compounds in concentrations ranging from 0.06 to 56 mM was explored. We aimed to explore whether exchange reactions can be a potential useful labelling strategy, when there are no requirement of high specific radioactivity. Parameters such as solvents, temperature, conventional vs microwave heating, and the degree of fluorine load in some aromatic and alkyl compounds were investigated with regard to radiochemical yield and specific radioactivity. A series of fluorobenzophenones (1-6), 1-(4-fluorophenyl)ethanone (7), various activated and deactivated fluoro benzenes (8-16), N-(pentafluorophenyl)benzamide (17), (pentafluorophenyl)formamide (18), (tridecafluorohexyl) benzene (19) and tetradecafluorohexane (20) were subjected to [F-18]/F-19 exchange. To test this strategy to label biologically active molecules containing fluorine atoms in an aryl group, two analogues of WAY-100635 (21-22), Lapatinib (23), 2,5,6,7,8-pentafluoro-3-methyinaphthoquinone (24) and 1-(2,4-difluorophenyl)-3-(4-fluorophenyl)propan-l-one (25) were investigated. The multi-fluorinated molecules containing an electron-withdrawing group were successfully labelled at room temperature, whereas the monofluorinated, as well as those containing an electron-donating group, required heating for the exchange reaction to take place.

  • 22. Bradley, Jean-Claude
    et al.
    Guha, Rajarshi
    Lang, Andrew
    Lindenbaum, Pierre
    Neylon, Cameron
    Williams, Antony
    Willighagen, Egon
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Beautifying Data in the Real World2009Inngår i: Beautiful Data: The Stories Behind Elegant Data Solutions / [ed] Toby Segaran & Jeff Hammerbacher, Sebastol, USA: O'Reilly , 2009, 1, s. 259-278Kapittel i bok, del av antologi (Annet (populærvitenskap, debatt, mm))
  • 23.
    Brännström, Nikolina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Comparison of the natural variation of Tripeptidyl peptidase II activity in blood samples among healthy subjects2011Independent thesis Basic level (degree of Bachelor), 10 poäng / 15 hpOppgave
    Abstract [en]

    Tripeptidyl peptidase II (TPPII) is a very large enzyme complex with a molecular weight of 5-6MDa and it has broad substrate specificity. It is located in the cytosol in most eukaryotic cells. TPPII which is an amino peptidase has exopeptidase activity, it removes tripeptides from the free N-terminus of oligopeptides and it is acting downstream of the proteasome. TPPII participates in a number of important processes in the cell: protein degradation, antigen presentation and apoptosis. In some tumor cells an increased expression of TPPII has been found which raise the question if TPPII can be used as a tumor marker in blood. The aim of this study was to compare the natural variation of the enzyme activity in blood samples among healthy subjects and also to see if the specific activity changed dependent on how the samples were stored after sampling. To do this an activity assay was used to measure the TPPII enzyme activity and the method of Bradford. Western blot was used to ensure that the right product, TPPII protein was detected. Finally qPCR was used to evaluate the feasibility of detecting TPPII mRNA in blood samples and to determine if mRNA levels correlated to the TPPII protein amount. The result showed a variation in enzyme activity among healthy subjects, a high activity in erythrocyte fractions compared to plasma and leukocyte fractions and also that storing the samples as lysate in -80C gave the least change in relative specific activity in comparison to the fresh blood cell fractions.

  • 24.
    Carlsson, Jörgen
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Bohl Kullberg, Erika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Kemiska institutionen.
    Capala, Jacek
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Sjöberg, Stefan
    Edwards, Katarina
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Fysikalisk-kemiska institutionen.
    Gedda, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Ligand liposomes and boron neutron capture therapy2003Inngår i: Journal of Neuro-Oncology, Vol. 62, s. 47-Artikkel i tidsskrift (Fagfellevurdert)
  • 25.
    Chi, Celestine N.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Bach, Anders
    University of Copenhagen.
    Gottschalk, Marie
    University of Copenhagen.
    Kristensen, S. Anders
    University of Copenhagen.
    Strømgaard, Kristian
    University of Copenhagen.
    Jemth, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Deciphering the kinetic binding mechanism of dimeric ligands, using a potent plasma-stable dimeric inhibitor of postsynaptic density protein-95 as an example2010Inngår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 285, nr 36, s. 28252-28260Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Dimeric ligands can be potent inhibitors of protein-protein or enzyme-substrate interactions. They have increased affinity and specificity towards their targets due to their ability to bind simultaneously to two binding sites and are therefore very attractive in drug design. However, few studies have addressed the kinetic mechanism of interaction of such bivalent ligands. We have investigated the binding interaction of a recently identified potent plasma-stable dimeric pentapeptide of PDZ1-2 of PSD-95 using protein engineering in combination with fluorescence polarisation, isothermal titration calorimetry and stopped-flow fluorimetry. Our experiments demonstrate that binding occurs via a two-step process, where an initial binding to either one of the two PDZ domains is followed by an intramolecular step, which produces the bidentate complex. We have determined all rate constants involved in the binding reaction and we also find evidence for a conformational transition of the complex. Our data demonstrate the importance of a slow dissociation for a successful dimeric ligand, but also highlight the possibility of optimizing the intramolecular association rate. The results may therefore aid the design of dimeric inhibitors in general.

  • 26. Chung, L. W.
    et al.
    Hayashi, S.
    Lundberg, Marcus
    Kyoto University.
    Nakatsu, T.
    Kato, H.
    Morokuma, K.
    Mechanism of efficient firefly bioluminescence via adiabatic transition state and seam of sloped conical intersection.2008Inngår i: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 130, nr 39, s. 12880-12881Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Firefly emission is a well-known efficient bioluminescence. However, the mystery of the efficient thermal generation of electronic excited states in firefly still remains unsolved, particularly at the atomic and molecular levels. We performed SA-CASSCF(12,12)/6-31G* and CASPT2(12,12)/6-31G*//SA-CASSCF(12,12)/6-31G* calculations to elucidate the reaction mechanism of bioluminescence from the firefly dioxetanone in the gas phase. Adiabatic transition state (TS) for the O-O bond cleavage and the minimum energy conical intersection (MECI) were located and characterized. The unique topology of MECI featuring a seam of a sloped conical intersection for the firefly dioxetanone, which was uncovered for the first time, emerges along the reaction pathway to provide a widely extended channel to diabatically access the excited-state from the ground state.

  • 27.
    Co, Michelle
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi, Analytisk kemi.
    Pressurised Fluid Extraction of Bioactive Species in Tree Barks: Analysis using Hyphenated Electrochemical Mass Spectrometric Detection2010Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Analytical chemistry has developed throughout time to meet current needs. At present, the interest in biorefinery is growing, due to environmental awareness and the depletion of fossil resources. Biomass from agricultural and forestry industries has proven to be excellent raw material for different processes. Biorefinering valuable species such as bioactive species from biomass, without compromising the primary process of the biomass is highly desirable. Pressurised fluid extraction (PFE) using water and ethanol as a solvent was developed for extracting betulin from birch (Betula pendula) bark. Apart from betulin, stilbene glucosides such as astringin, isorhapontin and picied were also extracted from spruce (Picea abies) using PFE. PFE is an advanced technique that extracts at temperatures above the solvent’s atmospheric boiling point. The applied pressure in PFE is mainly to maintain the liquid state of the extraction solvent. Parameters such as type of solvent, temperature, and time affect the extraction selectivity and efficiency. Therefore it is necessary to comprehend these parameters in order to optimise extraction. The DPPH (1,1-diphenyl-2-picrylhydrazyl) assay was used to determine the antioxidant capacity and activity of the obtained bioactive species. The results showed high antioxidant capacity in bioactive species that were extracted at an elevated temperature, 180°C. Extraction and degradation occur simultaneously during the extraction. Hence, it is crucial to separate these two processes in order to obtain the actual value.

    An online hyphenated system of chromatographic separation electrochemical mass spectrometric detection was developed (LC-DAD-ECD-MS/MS). The electrochemical detector facilitates real-time monitoring of the antioxidant capacity and activity of each antioxidant and its oxidation products. This developed LC-DAD-ECD-MS/MS method enabled rapid screening of antioxidants and created a fingerprint map for their oxidation products. Characterisation and molecular elucidation of bioactive species were also performed. Degradation of bioactive species was investigated with the said online system and birch bark extract was compared with birch bark extracts that were hydrothermally treated. The obtained results showed some degradation of antioxidants at 180°C.

    In summary, the aim of this thesis was to develop analytical methods integrated with sustainable chemistry for extraction of bioactive species in biomass from the forestry industry. A novel online system using selective and sensitive detectors such as diode-array, electrochemical, and tandem mass spectrometry was developed to rapidly determine the antioxidant capacity and activity of antioxidants. Furthermore, tandem mass spectrometry enables identification of unknown bioactive species without the need of reference samples.

    Delarbeid
    1. Pressurized liquid extraction of betulin and antioxidants from birch bark
    Åpne denne publikasjonen i ny fane eller vindu >>Pressurized liquid extraction of betulin and antioxidants from birch bark
    Vise andre…
    2009 (engelsk)Inngår i: Green Chemistry, ISSN 1463-9262, E-ISSN 1463-9270, Vol. 11, nr 5, s. 668-674Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Pressurized hot (subcritical) water and ethanol were used to extract betulin and antioxidants from birch bark. Betulin was found to be the major compound (around 26% (w/w)), which was able to be extracted with ethanol (120 degrees C, 50 bar, 15 minutes) but not with water at any of the temperatures tested (40-180 degrees C, 50 bar). The obtained extraction result for betulin is supported by theoretical solvation parameter calculations. Furthermore, high antioxidant activity of the extract was obtained using both ethanol and water as solvent. The antioxidant activity, as determined by a DPPH (2,2-diphenyl-1-picrylhydrazyl) assay, was found to be highest for the water extract of finely ground bark and it markedly increased with elevated extraction temperatures (90-180 degrees C). To elucidate if this was due to increased extraction efficiency or chemical reactions, a set of experiments was performed in which the samples were pre-treated with water at different temperatures before extraction. Results from liquid chromatography showed some differences in molecular composition between samples pre-treated at ambient and 180 degrees C, respectively. However, more detailed studies have to be performed to distinguish between hot-water extraction and reaction kinetics.

    sted, utgiver, år, opplag, sider
    The Royal Society of Chemistry, 2009
    HSV kategori
    Forskningsprogram
    Analytisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-106795 (URN)10.1039/b819965e (DOI)000266004400012 ()
    Tilgjengelig fra: 2009-07-03 Laget: 2009-07-03 Sist oppdatert: 2017-12-13bibliografisk kontrollert
    2. Extraction of Antioxidants from Spruce (Picea abies) Bark using Eco-Friendly Solvents
    Åpne denne publikasjonen i ny fane eller vindu >>Extraction of Antioxidants from Spruce (Picea abies) Bark using Eco-Friendly Solvents
    Vise andre…
    2012 (engelsk)Inngår i: Phytochemical Analysis, ISSN 0958-0344, E-ISSN 1099-1565, Vol. 23, nr 1, s. 1-11Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Introduction-Antioxidants are known to avert oxidation processes and they are found in trees and other plant materials. Tree bark is a major waste product from paper pulp industries; hence it is worthwhile to develop an extraction technique to extract the antioxidants.

    Objective- To develop a fast and environmentally sustainable extraction technique for the extraction of antioxidants from bark of spruce (Picea abies) and also to identify the extracted antioxidants that are abundant in spruce bark.

    Methodology- A screening experiment that involved three different techniques, was conducted to determine the best technique to extract antioxidants.The antioxidant capacity of the extracts was determined with DPPH (2,2-diphenyl-2’-picrylhydrazyl) assay. Pressurised fluid extraction (PFE) turned out to be the best technique and a response surface design was therefore utilised to optimise PFE. Furthermore, NMR and HPLC-DAD-MS/MS were applied to identify the extracted antioxidants.

    Results- PFE using water and ethanol as solvent at 160 and 180°C, respectively, gave extracts of the highest antioxidant capacity. Stilbene glucosides such as isorhapontin, piceid and astringin were identified in the extracts.

    Conclusion-The study has shown that PFE is a fast and environmentally sustainable technique, using water and ethanol as solvent for the extraction of antioxidants from spruce bark.

    sted, utgiver, år, opplag, sider
    Wiley-Blackwell, 2012
    Emneord
    Accelerated solvent extraction, antioxidant, DPPH, ethanol, Picea abies, pressurised fluid extraction, supercritical fluid extraction, water
    HSV kategori
    Forskningsprogram
    Analytisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-133267 (URN)10.1002/pca.1316 (DOI)000298260100001 ()
    Forskningsfinansiär
    Swedish Research Council
    Tilgjengelig fra: 2010-11-04 Laget: 2010-11-04 Sist oppdatert: 2018-01-12bibliografisk kontrollert
    3. Identification and Characterization of Polyphenolic Antioxidants Using On-Line Liquid Chromatography, Electrochemistry, and Electrospray Ionization Tandem Mass Spectrometry
    Åpne denne publikasjonen i ny fane eller vindu >>Identification and Characterization of Polyphenolic Antioxidants Using On-Line Liquid Chromatography, Electrochemistry, and Electrospray Ionization Tandem Mass Spectrometry
    Vise andre…
    2009 (engelsk)Inngår i: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 81, nr 21, s. 8968-8977Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    It is demonstrated that electrochemistry (EC) coupled to liquid chromatography (LC) and electrospray ionization tandem mass spectrometry (LC/EC/ESI-MS/MS) can be used to rapidly obtain information about the antioxidant activity (i.e., oxidation potential) and capacity (i.e., amount) of polyphenolic compounds, including catechin, kaempferol, resveratrol, quercetin, and quercetin glucosides. The described on-line LC/EC/ESI-MS/MS method facilitates the detection and characterization of individual antioxidants based on a combination of the obtained m/z values for the antioxidants and their oxidation products, the potential dependences for the ion intensities, and correlations between the retention times in the LC, EC, and MS chromatograms. As these results provide patterns that can be used in rapid screening for antioxidants in complex samples, the method should be a valuable complement to chemical assays commonly used to determine the total antioxidant capacity of samples. It is shown that the antioxidant capacity for a mixture of polyphenolic compounds depends on the redox potential employed in the evaluation, and this should consequently be taken into account when comparing results from different total antioxidant capacity assays. It is also demonstrated that the inherent antioxidant capacities of phenolic compounds increase with an increasing number of hydroxyl groups and that the potential needed to oxidize the remaining hydroxyl groups increases successively upon oxidation of the compound. Unlike chemical assays, which generally do not provide any information about the identities of the compounds on the molecular level, the present screening method can be used to identify individual antioxidants, rank compounds with respect to their ease of oxidation, and to study the antioxidant capacity at any redox potential of interest.

    HSV kategori
    Forskningsprogram
    Analytisk kemi; Oorganisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-99328 (URN)10.1021/ac901397c (DOI)000276191900046 ()
    Tilgjengelig fra: 2009-03-12 Laget: 2009-03-12 Sist oppdatert: 2018-06-26bibliografisk kontrollert
    4. Degradation effects in the extraction of antioxidants from birch bark using water at elevated temperature and pressure
    Åpne denne publikasjonen i ny fane eller vindu >>Degradation effects in the extraction of antioxidants from birch bark using water at elevated temperature and pressure
    Vise andre…
    2012 (engelsk)Inngår i: Analytica Chimica Acta, ISSN 0003-2670, E-ISSN 1873-4324, Vol. 716, s. 40-48Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Experiments with birch bark samples have been carried to enable a distinction between extraction and degradation effects during pressurised hot water extraction. Two samples, E80 and El 80, contained birch bark extracts obtained after extraction at 80 and 180 degrees C for up to 45 min, respectively. Two other samples, P80 and P180, were only extracted for 5 min at the two temperatures and were thereafter filtered and hydrothermally treated at 80 and 180 degrees C, respectively. During the latter treatment, samples were collected at different times to assess the stability of the extracted compounds. An offline DPPH (2,2-diphenyl-1-picrylhydrazyl) assay, as well as a high performance liquid chromatographic separation coupled to an electrochemical detector, were used to determine the antioxidant capacity of the processed samples. The results obtained with the different techniques were compared to assess the yield of the extraction and degradation processes. In addition, an online hyphenated system comprising high performance liquid chromatography coupled to diode-array; electrochemical; and tandem mass spectrometric detection (HPLC-DAD-ECD-MS/MS) was used to study the compositions of the extracts in more detail. The results for the samples processed at 80 degrees C showed that the extraction reached a steady-state already after 5 min, and that the extracted compounds were stable throughout the entire extraction process. Processing at 180 degrees C, on the other hand, gave rise to partly degraded extracts with a multitude of peaks in both the diode array and electrochemical detectors, and a higher antioxidant capacity compared to for the extracts obtained at 80 degrees C. It is concluded that HPLC-DAD-ECD is a more appropriate technique for the determination of antioxidants than the DPPH assay. The mass spectrometric results indicate that one of the extracted antioxidants, catechin, was isomerised to its diastereoisomers; (+)-catechin, (-)-catechin, (+)-epicatechin, and (-)-epicatechin.

     

    Emneord
    Degradation, Pressurised fluid extraction, Antioxidants, DPPH assay, Electrochemical detection, Diode-array detection, Tandem mass spectrometry, Elevated temperature, Birch bark
    HSV kategori
    Forskningsprogram
    Analytisk kemi; Kemi med inriktning mot oorganisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-132344 (URN)10.1016/j.aca.2011.04.038 (DOI)000301092900008 ()
    Tilgjengelig fra: 2010-11-04 Laget: 2010-10-18 Sist oppdatert: 2017-12-12bibliografisk kontrollert
  • 28.
    Co, Michelle
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi, Analytisk kemi.
    Fagerlund, Amelie
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Sunnerheim, Kerstin
    Department of Natural Sciences, Engineering and Mathematics, Mid Sweden University.
    Sjöberg, Per J. R
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi, Analytisk kemi.
    Turner, Charlotta
    Dept of Organic Chemistry, Lund University.
    Extraction of Antioxidants from Spruce (Picea abies) Bark using Eco-Friendly Solvents2012Inngår i: Phytochemical Analysis, ISSN 0958-0344, E-ISSN 1099-1565, Vol. 23, nr 1, s. 1-11Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction-Antioxidants are known to avert oxidation processes and they are found in trees and other plant materials. Tree bark is a major waste product from paper pulp industries; hence it is worthwhile to develop an extraction technique to extract the antioxidants.

    Objective- To develop a fast and environmentally sustainable extraction technique for the extraction of antioxidants from bark of spruce (Picea abies) and also to identify the extracted antioxidants that are abundant in spruce bark.

    Methodology- A screening experiment that involved three different techniques, was conducted to determine the best technique to extract antioxidants.The antioxidant capacity of the extracts was determined with DPPH (2,2-diphenyl-2’-picrylhydrazyl) assay. Pressurised fluid extraction (PFE) turned out to be the best technique and a response surface design was therefore utilised to optimise PFE. Furthermore, NMR and HPLC-DAD-MS/MS were applied to identify the extracted antioxidants.

    Results- PFE using water and ethanol as solvent at 160 and 180°C, respectively, gave extracts of the highest antioxidant capacity. Stilbene glucosides such as isorhapontin, piceid and astringin were identified in the extracts.

    Conclusion-The study has shown that PFE is a fast and environmentally sustainable technique, using water and ethanol as solvent for the extraction of antioxidants from spruce bark.

  • 29. Cox, Nicholas
    et al.
    Ho, Felix M.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fotokemi och molekylärvetenskap.
    Pewnim, Naray
    Steffen, Ronald
    Smith, Paul J.
    Havelius, Kajsa G. V.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fotokemi och molekylärvetenskap.
    Hughes, Joseph L.
    Debono, Lesley
    Styring, Stenbjörn
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fotokemi och molekylärvetenskap, Molekylär biomimetik.
    Krausz, Elmars
    Pace, Ron J.
    The S-1 split signal of photosystem II: a tyrosine-manganese coupled interaction2009Inngår i: Biochimica et Biophysica Acta - Bioenergetics, ISSN 0005-2728, E-ISSN 1879-2650, Vol. 1787, nr 7, s. 882-889Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Detailed optical and EPR analyses of states induced in dark-adapted PS II membranes by cryogenic illumination permit characterization and quantification of all pigment derived donors and acceptors, as well as optically silent (in the visible, near infrared) species which are EPR active. Near complete turnover formation of Q(A)(-) is seen in all centers, but with variable efficiency, depending on the donor species. In minimally detergent-exposed PS II membranes, negligible (<5%) oxidation of chlorophyll or carotenoid centers occurs for illumination temperatures 5-20 K. An optically silent electron donor to P680(+) is observed with the same decay kinetics as the S-1 split signal. Cryogenic donors to P680(+) seen are: (i) transient (t(1/2)similar to 150 s) tyrosine related species, including 'split signals' (similar to 15% total centers), (ii) reduced cytochrome b(559) (similar to 30-50% centers), and (iii) an organic donor, possibly an amino acid side chain, (similar to 30% centers).

  • 30.
    Dahlqvist, Ulla
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk och fysiologisk kemi.
    Ek, Pia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk och fysiologisk kemi.
    Engström, Lorentz
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk och fysiologisk kemi.
    Endogenous substrates of protein kinase in rat liver cell sap under different dietary conditions1978Inngår i: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 540, nr 1, s. 13-23Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Liver cell sap from normally fed rats, rats fed with a high-carbohydrate diet and fasted rats was chromatographed on DEAE-cellulose (pH 7.0). The chromatogram from each diet group was analyzed for pyruvate kinase activity and endogenous substrates of cyclic AMP-stimulated protein kinase. The materials were pooled into five phosphorylatable fractions, in each of which phosphate incorporation at 0.1 mM and 1.0 mM [32P]ATP in the presence of cyclic AMP and protein kinase was determined. For characterization of the phosphorylatable components, thin-layer gel chromatography on Sephadex G-200 and polyacrylamide gel electrophoresis in detergent were used for determination of native and minimal molecular weights, respectively. Except for pyruvate kinase, eight components which incorporated at least 0.05 nmol of [32P]phosphate/g of liver were detected. The phosphorylation of four of them was stimulated by cyclic AMP. Their minimal molecular weights were 42000, 21000, 52000 and 49000. The component with a minimal molecular weight of 42000 seemed to have a native molecular weight of 160000. Both the 21000 and the 52000 component had a native molecular weight of about 110000-120000. The protein with a minimal molecular weight of 49000 could not be correlated with certainty to a native molecular weight. The proteins whose phosphorylation was not stimulated by cyclic AMP had minimal molecular weights of 54000, 39000, 34000 and 22000.

  • 31.
    Danfors, Torsten
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurologi.
    Sörensen, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET.
    Lubberink, Mark
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Avdelningen för sjukhusfysik.
    Kumlien, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurologi.
    Relative Cerbral Blood Flow Measurement using dynamic Flumazenil-PET may Replace Fluorodeoxyglucose-PET in Epilepsy Surgical Investigations2012Artikkel i tidsskrift (Annet vitenskapelig)
  • 32.
    Diesen, Jarle Sidney
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Kemiska institutionen, Avdelningen för organisk kemi.
    Asymmetric Hydrogenations of Imines, Vinyl Fluorides, Enol Phosphinates and Other Alkenes Using N,P-Ligated Iridium Complexes2008Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The research described in this thesis is directed toward the efficient, enantioselective synthesis of chiral products that have useful functionality. This goal was pursued through catalytic asymmetric hydrogenation, a reaction class that selectively introduces one or two stereocenters into a molecule in an atom-efficient step. This reaction uses a small amount (often <1 mol%) of a chiral catalyst to impart stereoselectivity to the product formed. Though catalytic asymmetric hydrogenation is not a new reaction type, there remain many substrate classes for which it is ineffective. The present thesis describes efforts to extend the reaction to some of these substrates classes. Some of the products synthesized in these studies may eventually find use as building blocks for the production of chiral pharmaceuticals, agrochemicals, or flavouring or colouring agents. However, the primary and immediate aim of this thesis was to develop and demonstrate new catalysts that are rapid and effective in the asymmetric hydrogenation of a broad range of compounds.

    Paper I describes the design and construction of two new, related chiral iridium compounds that are catalysts for asymmetric hydrogenation. They each contain an N,P-donating phosphinooxazoline ligand that is held together by a rigid bicyclic unit. One of these iridium compounds catalyzed the asymmetric hydrogenation of acyclic aryl imines, often with very good enantioselectivities. This is particularly notable because acyclic imines are difficult to reduce with useful enantioselectivity. The second catalyst was useful for the asymmetric hydrogenation of two aryl olefins. In Paper II, the class of catalysts introduced into Paper I is expanded to include many more related compounds, and these are also applied to the asymmetric hydrogenation of prochiral imines and olefins. By studying a range of related catalysts that differ in a single attribute, we were able to probe how different parts of the catalyst affect the yield and selectivity of the hydrogenation reactions.

    Whereas iridium catalysts had been applied to the asymmetric hydrogenation of imines and largely unfunctionalized olefins prior to this work (with varied degrees of success), they had not been used to reduce fluoroolefins. Their hydrogenation, which is discussed in Paper III, was complicated by concomitant defluorination to yield non-halogenated alkanes. To combat this problem, several iridium-based hydrogenation catalysts were applied to the reaction. Two catalysts stood out for their ability to produce chiral fluoroalkanes in good enantioselectivity while minimizing the defluorination reaction, and one of these bore a phosphinooxazoline ligand of the type described in Papers I and II.

    Enol phosphinates are another class of olefins that had not previously been subjected to iridium-catalyzed asymmetric hydrogenation. They do, however, constitute an attractive substrate class, because the product chiral alkyl phosphinates can be transformed into chiral alcohols or chiral phosphines with no erosion of enantiopurity. Iridium complexes of the phosphinooxazoline ligands described in Papers I and II were extremely effective catalysts for the asymmetric hydrogenation of enol phosphinates. They produced alkyl phosphinates from di- and trisubstituted enol phosphinate, β-ketoester-derived enol phosphinates, and even purely alkyl-substituted enol phopshinates, in very high yields and enantioselectivities.

    Delarbeid
    1. Application of Phosphine-Oxazoline Ligands in Ir-Catalyzed Asymmetric Hydrogenation of Acyclic Aromatic N-Arylimines
    Åpne denne publikasjonen i ny fane eller vindu >>Application of Phosphine-Oxazoline Ligands in Ir-Catalyzed Asymmetric Hydrogenation of Acyclic Aromatic N-Arylimines
    2004 Inngår i: Organic Letters, Vol. 6, nr 21, s. 3825-3827Artikkel i tidsskrift (Fagfellevurdert) Published
    Identifikatorer
    urn:nbn:se:uu:diva-97350 (URN)
    Tilgjengelig fra: 2008-05-13 Laget: 2008-05-13bibliografisk kontrollert
    2. Hydrogenation of Imines and Olefins Using Phosphine-Oxazoline Iridium Complexes as Catalysts
    Åpne denne publikasjonen i ny fane eller vindu >>Hydrogenation of Imines and Olefins Using Phosphine-Oxazoline Iridium Complexes as Catalysts
    2006 Inngår i: Chemistry-A European Journal, Vol. 12, nr 8, s. 2318-2328Artikkel i tidsskrift (Fagfellevurdert) Published
    Identifikatorer
    urn:nbn:se:uu:diva-97351 (URN)
    Tilgjengelig fra: 2008-05-13 Laget: 2008-05-13bibliografisk kontrollert
    3. Iridium-Catalyzed Asymmetric Hydrogenation of Fluorinated Olefins Using N,P-Ligands: A struggle with hydrogenolysis and selectivity
    Åpne denne publikasjonen i ny fane eller vindu >>Iridium-Catalyzed Asymmetric Hydrogenation of Fluorinated Olefins Using N,P-Ligands: A struggle with hydrogenolysis and selectivity
    2007 (engelsk)Inngår i: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 129, nr 15, s. 4536-4537Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    To broaden the substrate scope of asymmetric iridium-catalyzed hydrogenation, fluorine-functionalized olefins were synthesized and hydrogenated with iridium complexes. Preliminary results showed high levels of fluorine elimination together with low selectivity. The loss of vinylic fluorine at first seemed difficult to handle, but further studies revealed that a catalyst with an azanorbornyl scaffold in the ligand gave more promising results. With this in mind, a new ligand was developed. This gave among the best results published to date for fluorine asymmetric hydrogenation, yielding high conversion and very high ee's with very little fluorine elimination. Further increasing the selectivity, the trials also revealed that tetrasubstituted fluorine-containing olefins can be hydrogenated with high ee's, despite that this class of compounds has usually shown low reactivity in this reaction type.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-97352 (URN)10.1021/ja0686763 (DOI)000245739700016 ()17375924 (PubMedID)
    Tilgjengelig fra: 2008-05-13 Laget: 2008-05-13 Sist oppdatert: 2017-12-14bibliografisk kontrollert
    4. Asymmetric Hydrogenation of Di and Trisubstituted Enol Phosphinates with N,P-Ligated Iridium Complexes
    Åpne denne publikasjonen i ny fane eller vindu >>Asymmetric Hydrogenation of Di and Trisubstituted Enol Phosphinates with N,P-Ligated Iridium Complexes
    2008 (engelsk)Inngår i: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 130, nr 16, s. 5595-5599Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The iridium-catalyzed asymmetric hydrogenation of various di- and trisubstituted enol phosphinates has been studied. Excellent enantioselectivities (up to >99% ee) and full conversion were observed for a range of substrates with both aromatic and aliphatic side chains. Enol phosphinates are structural analogues of enol acetates, and the hydrogenated alkyl phosphinate products can easily be transformed into the corresponding alcohols with conservation of stereochemistry. We have also hydrogenated, in excellent ee, several purely alkyl-substituted enol phosphinates, producing chiral alcohols that are difficult to obtain highly enantioselectively from ketone hydrogenations.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-97722 (URN)10.1021/ja711372c (DOI)000255041400050 ()
    Tilgjengelig fra: 2008-11-11 Laget: 2008-11-11 Sist oppdatert: 2017-12-14bibliografisk kontrollert
  • 33.
    Dinér, Peter
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi, Organisk kemi.
    Catalytic asymmetric chiral lithium amide-promoted epoxide rearrangement: a NMR spectroscopic and kinetic investigation2010Inngår i: Tetrahedron: asymmetry, ISSN 0957-4166, E-ISSN 1362-511X, Vol. 21, nr 21-22, s. 2733-2739Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The lithium amide derived from the chiral diamine (1R,3S,4S)-3-(1-pyrrolidinyl)methyl-2-azabicyclo[2.2.1]heptane, has been reported to catalytically deprotonate cyclohexene oxide and other epoxides, yielding chiral allylic alcohols in excellent enantiomeric excess. In this work, 6Li, 1H and 13 C NMR spectroscopy have been used to study the aggregation of the chiral lithium amide in THF and the influence on the aggregation by the addition of additives, such as 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU). The activated complex under catalytic deprotonation of cyclohexene oxide, that is, with excess Li-DBU and free DBU, is built from one monomer of the chiral lithium amide, one molecule of epoxide and one additional molecule of DBU. The reaction order (0.97) obtained for the bulk base Li-DBU shows an inverse dependence on the concentration, suggesting a deaggregation of the initial mixed dimer to a monomer-based transition state containing a monomer of the lithium amide.

  • 34.
    Dubois, Louise
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Andersson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Asplund, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Björkelund, Hanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Evaluating real-time immunohistochemistry on multiple tissue samples, multiple targets and multiple antibody labeling methods2013Inngår i: BMC Research Notes, ISSN 1756-0500, E-ISSN 1756-0500, Vol. 6, s. 542-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background

    Immunohistochemistry (IHC) is a well-established method for the analysis of protein expression in tissue specimens and constitutes one of the most common methods performed in pathology laboratories worldwide. However, IHC is a multi-layered method based on subjective estimations and differences in staining and interpretation has been observed between facilities, suggesting that the analysis of proteins on tissue would benefit from protocol optimization and standardization. Here we describe how the emerging and operator independent tool of real-time immunohistochemistry (RT-IHC) reveals a time resolved description of antibody interacting with target protein in formalin fixed paraffin embedded tissue. The aim was to understand the technical aspects of RT-IHC, regarding generalization of the concept and to what extent it can be considered a quantitative method.

    Results

    Three different antibodies labeled with fluorescent or radioactive labels were applied on nine different tissue samples from either human or mouse, and the results for all RT-IHC analyses distinctly show that the method is generally applicable. The collected binding curves showed that the majority of the antibody-antigen interactions did not reach equilibrium within 3 hours, suggesting that standardized protocols for immunohistochemistry are sometimes inadequately optimized. The impact of tissue size and thickness as well as the position of the section on the glass petri dish was assessed in order for practical details to be further elucidated for this emerging technique. Size and location was found to affect signal magnitude to a larger extent than thickness, but the signal from all measurements were still sufficient to trace the curvature. The curvature, representing the kinetics of the interaction, was independent of thickness, size and position and may be a promising parameter for the evaluation of e.g. biopsy sections of different sizes.

    Conclusions

    It was found that RT-IHC can be used for the evaluation of a number of different antibodies and tissue types, rendering it a general method. We believe that by following interactions over time during the development of conventional IHC assays, it becomes possible to better understand the different processes applied in conventional IHC, leading to optimized assay protocols with improved sensitivity.

  • 35.
    Edlund, Bror
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk och fysiologisk kemi.
    Andersson, Jill
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk och fysiologisk kemi.
    Titanji, Vincent
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk och fysiologisk kemi.
    Dahlqvist, Ulla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk och fysiologisk kemi.
    Ek, Pia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk och fysiologisk kemi.
    Zetterqvist, Örjan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk och fysiologisk kemi.
    Engström, Lorentz
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk och fysiologisk kemi.
    Amino acid sequence at the phosphorylated site of rat liver pyruvate kinase1975Inngår i: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 67, nr 4, s. 1516-1521Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    One dominating peptic phosphopeptide, Asx-Thr-Lys-Gly-Pro-Glx-Ile-Glx-Thr-Gly-Val-Leu-Arg-Arg-Ala-(32P)SerP-Val-Ala-Glx-Leu, was obtained from rat liver pyruvate kinase (type L) phosphorylated by cyclic 3′,5′-AMP-stimulated protein kinase from the same tissue. The sequence around the phosphorylated serine residue is similar to that of a corresponding but smaller peptic phosphopeptide previously isolated from pig liver (type L) pyruvate kinase, Leu-Arg-Arg-Ala-(32P)SerP-Leu.

  • 36.
    Edlund, Karolina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Molecular Characterisation and Prognostic Biomarker Discovery in Human Non-Small Cell Lung Cancer2012Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Non-small cell lung cancer (NSCLC) constitutes a clinically, histologically, and genetically heterogeneous disease entity that represents a major cause of cancer-related death. Early-stage patients, who undergo surgery with curative intent, experience high recurrence rates and the effect of adjuvant treatment is modest. Prognostic biomarkers would be of particular relevance to guide intensified treatment depending on expected outcome and moreover often infer a biological role in tumourigenesis.

    This thesis presents a translational study approach to establish a well-characterised NSCLC frozen-tissue cohort and to obtain a profile of each specimen with regard to genome-wide copy number alterations, global gene expression levels and somatic mutations in selected cancer-related genes. Furthermore, the generation of a formalin-fixed, paraffin-embedded tissue microarray enabled validation of findings on the protein level using immunohistochemistry. The comprehensive molecular characterisation, combined with data on clinical parameters, enabled the analysis of biomarkers linked to disease outcome. In Paper I, single nucleotide polymorphism arrays were applied to assess copy number alterations in NSCLC and associations with overall survival in adenocarcinoma and squamous cell carcinoma were described. In Paper II, we evaluated expression levels of selected stromal proteins in NSCLC using immunohistochemistry and the adhesion molecule CD99 was identified as an outcome-related biomarker in two independent cohorts. Paper III presents a strategy for prognostic biomarker discovery based on gene expression profiling, meta-analysis, and validation of protein expression on tissue microarrays, and suggests the putative tumour suppressor CADM1 as a candidate biomarker. In Paper IV, we propose a prognostic role for tumour-infiltrating IGKC-expressing plasma cells in the local tumour microenvironment, indicating an involvement of the humoral immune response in anti-tumor activity. In Paper V, we combined next-generation deep sequencing with statistical analysis of the TP53 database to define novel parameters for database curation.

    In summary, this thesis exemplifies the benefits of a translational study approach, based on a comprehensive tumour characterisation, and describes molecular markers associated with clinical outcome in NSCLC.

    Delarbeid
    1. Gene Copy Number Aberrations Are Associated with Survival in Histologic Subgroups of Non-small Cell Lung Cancer
    Åpne denne publikasjonen i ny fane eller vindu >>Gene Copy Number Aberrations Are Associated with Survival in Histologic Subgroups of Non-small Cell Lung Cancer
    Vise andre…
    2011 (engelsk)Inngår i: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 6, nr 11, s. 1833-1840Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Introduction:

    Non-small cell lung cancer (NSCLC) is characterized by a multitude of genetic aberrations with unknown clinical impact. In this study, we aimed to identify gene copy number changes that correlate with clinical outcome in NSCLC. To maximize the chance to identify clinically relevant events, we applied a strategy involving two prognostically extreme patient groups.

    Methods:

    Short-term (<20 month; n = 53) and long-term survivors (>58 month; n = 47) were selected from a clinically well-characterized NSCLC patient cohort with available fresh frozen tumor specimens. The samples were analyzed using high-resolution single-nucleotide polymorphism array technology to assess gene copy number variations and array-based gene expression profiling. The molecular data were combined with information on clinical parameters.

    Results:

    Genetic aberrations were strongly associated with tumor histology. In adenocarcinoma (n = 50), gene copy number gains on chromosome 8q21-q24.3 (177 genes) were more frequent in long-term than in short-term survivors. In squamous cell carcinoma (n = 28), gains on chromosome 14q23.1-24.3 (133 genes) were associated with shorter survival, whereas losses in a neighboring region, 14q31.1-32.33 (110 genes), correlated with favorable outcome. In accordance with copy number gains and losses, messenger RNA expression levels of corresponding genes were increased or decreased, respectively.

    Conclusion:

    Comprehensive tumor profiling permits the integration of genomic, histologic, and clinical data. We identified gene copy number gains and losses, with corresponding changes in messenger RNA levels that were associated with prognosis in adenocarcinoma and squamous cell carcinoma of the lung.

    Emneord
    Lung cancer, Prognosis, SNP array, CGH, Gene expression profile
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-162455 (URN)10.1097/JTO.0b013e3182295917 (DOI)000296700400008 ()
    Tilgjengelig fra: 2011-12-01 Laget: 2011-11-30 Sist oppdatert: 2018-02-01bibliografisk kontrollert
    2. CD99 is a novel prognostic stromal marker in non-small cell lung cancer
    Åpne denne publikasjonen i ny fane eller vindu >>CD99 is a novel prognostic stromal marker in non-small cell lung cancer
    Vise andre…
    2012 (engelsk)Inngår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 131, nr 10, s. 2264-2273Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The complex interaction between cancer cells and the microenvironment plays an essential role in all stages of tumourigenesis. Despite the significance of this interplay, alterations in protein composition underlying tumour-stroma interactions are largely unknown. The aim of this study was to identify stromal proteins with clinical relevance in non-small cell lung cancer (NSCLC). A list encompassing 203 stromal candidate genes was compiled based on gene expression array data and available literature. The protein expression of these genes in human NSCLC was screened using the Human Protein Atlas. Twelve proteins were selected that showed a differential stromal staining pattern (BGN, CD99, DCN, EMILIN1, FBN1, PDGFRB, PDLIM5, POSTN, SPARC, TAGLN, TNC, VCAN). The corresponding antibodies were applied on tissue microarrays, including 190 NSCLC samples, and stromal staining was correlated with clinical parameters. Higher stromal expression of CD99 was associated with better prognosis in the univariate (p=0.037) and multivariate (p=0.039) analysis. The association was independent from the proportion of tumour stroma, the fraction of inflammatory cells, and clinical and pathological parameters like stage, performance status and tumour histology. The prognostic impact of stromal CD99 protein expression was confirmed in an independent cohort of 240 NSCLC patients (p=0.008). Furthermore, double-staining confocal fluorescence microscopy showed that CD99 was expressed in stromal lymphocytes as well as in cancer associated fibroblasts. Based on a comprehensive screening strategy the membrane protein CD99 was identified as a novel stromal factor with clinical relevance. The results support the concept that stromal properties have an important impact on tumour progression.

    HSV kategori
    Forskningsprogram
    Patologi
    Identifikatorer
    urn:nbn:se:uu:diva-170991 (URN)10.1002/ijc.27518 (DOI)000309185300007 ()22392539 (PubMedID)
    Merknad

    Karolina Edlund and Cecilia Lindskog are shared first authors.

    Tilgjengelig fra: 2012-03-14 Laget: 2012-03-14 Sist oppdatert: 2018-02-01
    3. Biomarker discovery in non-small cell lung cancer: integrating gene expression profiling, meta-analysis and tissue microarray validation
    Åpne denne publikasjonen i ny fane eller vindu >>Biomarker discovery in non-small cell lung cancer: integrating gene expression profiling, meta-analysis and tissue microarray validation
    Vise andre…
    2013 (engelsk)Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 19, nr 1, s. 194-204Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Background:

    Global gene expression profiling has been widely used in lung cancer research to identify clinically relevant molecular subtypes as well as to predict prognosis and therapy response. So far, the value of these multi-gene signatures in clinical practice is unclear and the biological importance of individual genes is difficult to assess as the published signatures virtually do not overlap

    Methods:

    Here we describe a novel single institute cohort, including 196 non-small lung cancers (NSCLC) with clinical information and long-term follow-up. Gene expression array data was used as a training set to screen for single genes with prognostic impact. The top 450 probe sets identified using a univariate Cox regression model (significance level p<0.01) were tested in a meta-analysis including five publicly available independent lung cancer cohorts (n=860).

    RESULTS:

    The meta-analysis revealed 14 genes that were significantly associated with survival (p<0.001) with a false discovery rate <1%. The prognostic impact of one of these genes, the cell adhesion molecule 1 (CADM1), was confirmed by use of immunohistochemistry on tissue microarrays from two independent NSCLC cohorts, altogether including 617 NSCLC samples. Low CADM1 protein expression was significantly associated with shorter survival, with particular influence in the adenocarcinoma patient subgroup.

    CONCLUSIONS:

    Using a novel NSCLC cohort together with a meta-analysis validation approach, we have identified a set of single genes with independent prognostic impact. One of these genes, CADM1, was further established as an immunohistochemical marker with a potential application in clinical diagnostics.

    HSV kategori
    Forskningsprogram
    Patologi
    Identifikatorer
    urn:nbn:se:uu:diva-183399 (URN)10.1158/1078-0432.CCR-12-1139 (DOI)000313051100021 ()23032747 (PubMedID)
    Tilgjengelig fra: 2012-10-25 Laget: 2012-10-25 Sist oppdatert: 2018-02-01bibliografisk kontrollert
    4. The prognostic relevance of tumour-infiltrating plasma cells and immunoglobulin kappa C indicates an important role of the humoral immune response in non-small cell lung cancer
    Åpne denne publikasjonen i ny fane eller vindu >>The prognostic relevance of tumour-infiltrating plasma cells and immunoglobulin kappa C indicates an important role of the humoral immune response in non-small cell lung cancer
    Vise andre…
    2013 (engelsk)Inngår i: Cancer Letters, ISSN 0304-3835, E-ISSN 1872-7980, Vol. 333, nr 2, s. 222-228Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    A prognostic impact of immunoglobulin kappa C (IGKC) expression has been described in cancer. We analysed the influence of B-cell and plasma cell markers, as well as IGKC expression, in non-small lung cancer (NSCLC) using immunohistochemistry on a tissue microarray. IGKC protein expression was independently associated with longer survival, with particular impact in the adenocarcinoma subgroup. Moreover, a correlation was seen with CD138+ cells, but not with CD20. CD138 expression revealed a comparable association with survival. In conclusion, IGKC expression in stroma–infiltrating plasma cells is a prognostic marker in NSCLC, supporting emerging treatment concepts that exploit the humoral immune response.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-181908 (URN)10.1016/j.canlet.2013.01.036 (DOI)000318838700011 ()
    Tilgjengelig fra: 2012-10-01 Laget: 2012-10-01 Sist oppdatert: 2018-02-01bibliografisk kontrollert
    5. Data-driven unbiased curation of the TP53 tumor suppressor gene mutation database and validation by ultradeep sequencing of human tumors
    Åpne denne publikasjonen i ny fane eller vindu >>Data-driven unbiased curation of the TP53 tumor suppressor gene mutation database and validation by ultradeep sequencing of human tumors
    Vise andre…
    2012 (engelsk)Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, nr 24, s. 9551-9556Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Cancer mutation databases are expected to play central roles in personalized medicine by providing targets for drug development and biomarkers to tailor treatments to each patient. The accuracy of reported mutations is a critical issue that is commonly overlooked, which leads to mutation databases that include a sizable number of spurious mutations, either sequencing errors or passenger mutations. Here we report an analysis of the latest version of the TP53 mutation database, including 34,453 mutations. By using several data-driven methods on multiple independent quality criteria, we obtained a quality score for each report contributing to the database. This score can now be used to filter for high-confidence mutations and reports within the database. Sequencing the entire TP53 gene from various types of cancer using next-generation sequencing with ultradeep coverage validated our approach for curation. In summary, 9.7% of all collected studies, mostly comprising numerous tumors with multiple infrequent TP53 mutations, should be excluded when analyzing TP53 mutations. Thus, by combining statistical and experimental analyses, we provide a curated mutation database for TP53 mutations and a framework for mutation database analysis.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-175985 (URN)10.1073/pnas.1200019109 (DOI)000305511300070 ()22628563 (PubMedID)
    Tilgjengelig fra: 2012-06-14 Laget: 2012-06-14 Sist oppdatert: 2018-02-01bibliografisk kontrollert
  • 37.
    Ek, Pia
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Dahlqvist, Ulla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Humble, Elisabet
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Engström, Lorentz
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Comparative kinetic studies on the L-type pyruvate kinase from rat liver and the enzyme phosphorylated by cyclic 3´, 5´-AMP-stimulated protein kinase1976Inngår i: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 429, nr 2, s. 374-382Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The kinetics of rat liver L-type pyruvate kinase (EC 2.7.1.40), phosphorylated with cyclic AMP-stimulated protein kinase from the same source, and the unphosphorylated enzyme have been compared. The effects of pH and various concentrations of substrates, Mg2+, K+ and modifiers were studied. In the absence of fructose 1, 6-diphosphate at pH 7.3, the phosphorylated pyruvate kinase appeared to have a lower affinity for phosphoenolpyruvate (K0.5=0.8 mM) than the unphosphorylated enzyme (K0.5=0.3 mM). The enzyme activity vs. phosphoenolpyruvate concentration curve was more sigmoidal for the phosphorylated enzyme with a Hill coefficient of 2.6 compared to 1.6 for the unphosphorylated enzyme. Fructose 1, 6-diphosphate increased the apparent affinity of both enzyme forms for phosphoenolpyruvate. At saturating concentrations of this activator, the kinetics of both enzyme forms were transformed to approximately the same hyperbolic curve, with a Hill coefficient of 1.0 and K0.5 of about 0.04 mM for phosphoenolpyruvate. The apparent affinity of the enzyme for fructose 1, 6-diphosphate was high at 0.2 mM phosphoenolpyruvate with a K0.5=0.06 muM for the unphosphorylated pyruvate kinase and 0.13 muM for the phosphorylated enzyme. However, in the presence of 0.5 mM alanine plus 1.5 mM ATP, a higher fructose 1, 6-diphosphate concentration was needed for activation, with K0.5 of 0.4 muM for the unphosphorylated enzyme and of 1.4 muM for the phosphorylated enzyme. The results obtained strongly indicate that phosphorylation of pyruvate kinase may also inhibit the enzyme in vivo. Such an inhibition should be important during gluconeogenesis.

  • 38.
    Ekman, Pia
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk och fysiologisk kemi.
    Hermansson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk och fysiologisk kemi.
    Bergström, Gunnel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk och fysiologisk kemi.
    Engström, Lorentz
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk och fysiologisk kemi.
    Rapid proteolytic removal of phosphopeptides and phosphorylatable sites from proteins in rat liver cell sap1978Inngår i: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 86, nr 2, s. 250-254Artikkel i tidsskrift (Fagfellevurdert)
  • 39.
    Elhamili, Anisa
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi, Analytisk kemi.
    Development of Capillary Electrophoresis Methods Coupled to Mass Spectrometry for Biomedical and Pharmaceutical Analysis2011Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The analysis of large intact proteins and complex biological samples containing drug molecules is a common complicated task for many scientists. However, due to the importance of these molecules, there is a growing interest in pharmaceutical and medicinal research to develop rapid, highly sensitive and efficient analytical techniques. The advantages of capillary electrophoresis (CE) in combination with mass spectrometry (MS) provide a powerful analytical tool. However, further improvement and development of these techniques are required to extend their utility and to meet the challenges of selected analytes. Thus, the scope of this thesis deals with the development of novel analytical methods to achieve efficient and high performance analysis of peptides, intact proteins, digests of complex samples and basic pharmaceutical drug compounds in biological matrices.

    Implementation of CE for routine analysis of proteins and complex samples is constrained by the partial adsorption to the capillary wall. Consequently, the use of surface modified capillaries is required to control the surface properties and prevent analyte adsorption. In this thesis, analyte adsorption was successfully prevented using tailored covalent cationic (M7C4I) and electrostatic cationic (PVPy-Me) coatings. Rapid and efficient separations of peptides, proteins and digests of complex samples such as cerebrospinal fluids were obtained with these coatings. The M7C4I coating showed a distinct ability to handle large intact proteins with a molecular size of over 0.5 MDa. The highest peak efficiencies and surprisingly high peak stacking effects were obtained by adding salts to the protein samples. The effect of salt additives on peak efficiencies of intact proteins was further demonstrated and compared using different surface modified capillaries. Additionally, rapid CE-ESI-MS quantification of pharmaceutical drug molecules in human plasma was performed after a SCX-SPE sample preparation method using the M7C4I coating. In conclusion, the results presented in this thesis show the strong potential of CE in combination with MS using electrospray ionization (ESI) for the analysis of peptides and large intact proteins and the applicability for clinical monitoring of the levels of pharmaceutical drug molecules in human plasma with high sensitivity and efficiency.

    Delarbeid
    1. Rapid capillary electrophoresis time-of-flight mass spectrometry separations of peptides and proteins using a monoquaternarized piperazine compound (M7C4l) for capillary coatings
    Åpne denne publikasjonen i ny fane eller vindu >>Rapid capillary electrophoresis time-of-flight mass spectrometry separations of peptides and proteins using a monoquaternarized piperazine compound (M7C4l) for capillary coatings
    Vise andre…
    2008 (engelsk)Inngår i: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 29, nr 8, s. 1619-1625Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    A monoquaternarized piperazine, 1-(4-iodobutyl) 4-aza-1-azoniabicyclo[2,2,2] octane iodide (M7C4I), has been evaluated as a surface derivatization reagent for CE in combination with TOF MS for the analysis of proteins, peptides, and protein digests. The M7C4I piperazine, at alkaline pH, forms a covalent bond via alkylation of the ionized silanols producing a cationic surface with a highly stable and reversed EOF. The obtained surface yields rapid separations (less than 5 min) of peptides and proteins at acidic pH with high separation efficiencies (up to 1.1 X 10(6) plates/m for peptides and up to 1.8 x 10(6) plates/m for proteins) and no observed bleeding of the coating reagent into the mass spectrometer. The simplicity of the coating procedure also enables fast (2 min) regeneration of the surface, if necessary. This is useful in the analysis of complex samples in order to prevent possible memory effects. The potential of using M7C4I-coated capillaries for MS analysis of complex samples is demonstrated by the separation of peptides, proteins, and protein digests. Even more, the spectacular thing in which large intact proteins with molecular masses over 0.5 MDa could be separated. The coating showed good ability to handle these large proteins with high efficiency and retained peak shape as demonstrated by separation of IgG(1) (150 kDa) and thyroglobulin (669 kDa).

    Emneord
    Capillary electrophoresis, M7C4l, Peptides, Proteins, Protein digests, Time-of-flight
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-16217 (URN)10.1002/elps.200700737 (DOI)000255703100005 ()
    Tilgjengelig fra: 2008-05-13 Laget: 2008-05-13 Sist oppdatert: 2017-12-08bibliografisk kontrollert
    2. Analysis of peptides using N-methylpolyvinylpyridium as silica surface modifier for CE-ESI-MS
    Åpne denne publikasjonen i ny fane eller vindu >>Analysis of peptides using N-methylpolyvinylpyridium as silica surface modifier for CE-ESI-MS
    Vise andre…
    2010 (engelsk)Inngår i: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 31, nr 7, s. 1151-1156Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    In this study, the N-methylpolyvinylpyridinuim polymer has for the first time been used as a silica surface modifier for CE in combination with ESI MS (CE-ESI-MS). The compatibility for ESI-MS was demonstrated by the analysis of peptides and protein digests. The N-methylpolyvinylpyridium surface interacts electrostatically with the ionized silanol groups, giving a cationic surface with a reversed EOF. The surface modifier gave rapid and repeatable separations of peptides, proteins and protein digests at acidic pH for more than 4 h of continuous use. The CE separation yielded peak efficiencies of up to 4.3 x 10(5) plates/m. The surface coating is highly compatible with ESI and facilitates the separation and analysis of complex peptide mixtures as shown by the analysis of BSA digests.

    Emneord
    CE, ESI, MS, N-methylpolyvinylpyridinuim, peptides
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-125809 (URN)10.1002/elps.200900536 (DOI)000276811000005 ()20209570 (PubMedID)
    Tilgjengelig fra: 2010-05-28 Laget: 2010-05-28 Sist oppdatert: 2017-12-12bibliografisk kontrollert
    3. The effect of sample salt additives on capillary electrophoresis analysis of intact proteins using surface modified capillaries.
    Åpne denne publikasjonen i ny fane eller vindu >>The effect of sample salt additives on capillary electrophoresis analysis of intact proteins using surface modified capillaries.
    Vise andre…
    2009 (engelsk)Inngår i: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1216, nr 17, s. 3613-3620Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The effect of adding alkali salts to protein samples for capillary electrophoretic (CE) analysis of intact proteins was studied. A high degree of peak stacking, even for large proteins, was found to occur when alkali salts were added to the sample. The addition of salt to the protein sample promotes a strong improvement in the peak efficiency of individual proteins giving up to 2.1 x 10(6) apparent plates/m. The concentration of salt required in the sample to reach optimal peak efficiency show dependency on both the molecular weight and molar concentration of the protein. However, adding salt will, at a sufficiently high concentration, cause a mixture of proteins to co-migrate to one very sharp peak. The observed sample stacking effect was obtained with a number of different surface modified silica capillaries indicating a general phenomenon and not surface coating specific.

    Emneord
    Capillary electrophoresis, alkali salt, intact protein analysis, coated capillary, stacking effect
    HSV kategori
    Forskningsprogram
    Analytisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-100628 (URN)10.1016/j.chroma.2008.12.037 (DOI)000265467200004 ()19150070 (PubMedID)
    Tilgjengelig fra: 2009-04-03 Laget: 2009-04-03 Sist oppdatert: 2017-12-13bibliografisk kontrollert
    4. Optimizing the extraction, separation and quantification of tricyclic antidepressant drugs in human plasma with CE-ESI-TOF-MS using cationic coated capillaries
    Åpne denne publikasjonen i ny fane eller vindu >>Optimizing the extraction, separation and quantification of tricyclic antidepressant drugs in human plasma with CE-ESI-TOF-MS using cationic coated capillaries
    2011 (engelsk)Inngår i: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 32, nr 6-7, s. 647-658Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    In this study, the extraction and CE-ESI-TOF-MS analysis of tricyclic antidepressant (TCA) drugs imipramine, desipramine, clomipramine and norclomipramine in human plasma has been optimized. The CE capillaries were modified with ω-iodo-alkyl ammonium salt (M7C4I coating) to reduce analyte adsorption to the silica wall. The use of a strong cation exchange (SCX) solid-phase extraction (SPE) column specifically designed for the extraction of basic drug species from biofluids gave very clean extracts with high and reproducible recoveries. The extraction recoveries were ranging between 87 and 91% with % RSD values of 0.5-1.7% (n=3). The obtained strong cation exchange-SPE extracts of the TCA in human plasma only contained the analytes of interest. The optimized CE separation conditions were obtained by adding ACN and acetic acid to the sample while using an aqueous BGE. The CE-ESI-TOF-MS analysis was performed within 6min for all TCA analytes under the optimized condition with peak efficiencies up to 1.4×105plates/m and an average % RSD of the migration times of the analytes of 0.3% (n=5). The presented method can readily be used for the extraction and quantification of basic drug species in human biological fluids and in pharmaceutical formulations.

    Emneord
    Capillary electrophoresis, Mass spectrometry, Tricyclic Antidepressant Drugs, Quantification, Human plasma
    HSV kategori
    Forskningsprogram
    Analytisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-143784 (URN)10.1002/elps.201000566 (DOI)000288602000001 ()21341290 (PubMedID)
    Tilgjengelig fra: 2011-01-25 Laget: 2011-01-25 Sist oppdatert: 2018-01-12bibliografisk kontrollert
    5. A method for quantitative analysis of an anticancer drug in human plasma with CE-ESI-TOF-MS
    Åpne denne publikasjonen i ny fane eller vindu >>A method for quantitative analysis of an anticancer drug in human plasma with CE-ESI-TOF-MS
    2011 (engelsk)Inngår i: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 32, nr 13, s. 1778-1785Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    In this study, the extraction recoveries of an anticancer drug (Imatinib) from human plasma using a common liquid-liquid extraction (LLE) method and a new strong cation exchange (SCX) solid-phase extraction (SPE) column was investigated. The extracts were analyzed with CE coupled on-line to electrospray ionization (ESI) time-of-flight mass spectrometry (TOF-MS) using a monoquaternarized piperazine compound (M7C4I) for capillary coatings. Clean extracts with high and reproducible extraction recoveries ranging between 85 and 91% with % RSD values of 2.5% (n = 3) were obtained using the SCX-SPE columns. This can be compared with the recoveries obtained with the LLE method ranging between 30 and 35%. The CE-ESI-TOF-MS analysis was performed in = 0.997 and % RSD values of 0.5% (n = 3). The intra-day and inter-day assay variations were lower than 8%. The presented CE-ESI-TOF-MS method with the use of SCX-SPE columns yielded rapid, efficient and high extraction recoveries together with high sensitivity (LOD 5 ng/mL), selectivity and good linearity. Accordingly, the method can readily be used for accurate determination and therapeutic monitoring of the Imatinib blood levels for more effective patient treatment. In addition, it can be applied for the extraction, quantification and clinical assessments of metabolites of Imatinib and other basic pharmaceutical drug molecules in biological fluids or pharmaceutical dosage forms.

    Emneord
    Capillary electrophoresis, Human plasma, Imatinib, Mass spectrometry, Quantification, Theraputic drug monitoring.
    HSV kategori
    Forskningsprogram
    Analytisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-143791 (URN)10.1002/elps.201100121 (DOI)000292971000027 ()
    Tilgjengelig fra: 2011-01-25 Laget: 2011-01-25 Sist oppdatert: 2018-01-12bibliografisk kontrollert
  • 40.
    Elhamili, Anisa
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi, Analytisk kemi.
    Bergquist, Jonas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi, Analytisk kemi.
    A method for quantitative analysis of an anticancer drug in human plasma with CE-ESI-TOF-MS2011Inngår i: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 32, nr 13, s. 1778-1785Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In this study, the extraction recoveries of an anticancer drug (Imatinib) from human plasma using a common liquid-liquid extraction (LLE) method and a new strong cation exchange (SCX) solid-phase extraction (SPE) column was investigated. The extracts were analyzed with CE coupled on-line to electrospray ionization (ESI) time-of-flight mass spectrometry (TOF-MS) using a monoquaternarized piperazine compound (M7C4I) for capillary coatings. Clean extracts with high and reproducible extraction recoveries ranging between 85 and 91% with % RSD values of 2.5% (n = 3) were obtained using the SCX-SPE columns. This can be compared with the recoveries obtained with the LLE method ranging between 30 and 35%. The CE-ESI-TOF-MS analysis was performed in = 0.997 and % RSD values of 0.5% (n = 3). The intra-day and inter-day assay variations were lower than 8%. The presented CE-ESI-TOF-MS method with the use of SCX-SPE columns yielded rapid, efficient and high extraction recoveries together with high sensitivity (LOD 5 ng/mL), selectivity and good linearity. Accordingly, the method can readily be used for accurate determination and therapeutic monitoring of the Imatinib blood levels for more effective patient treatment. In addition, it can be applied for the extraction, quantification and clinical assessments of metabolites of Imatinib and other basic pharmaceutical drug molecules in biological fluids or pharmaceutical dosage forms.

  • 41.
    Elhamili, Anisa
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi, Analytisk kemi.
    Samuelsson, Jörgen
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi, Analytisk kemi.
    Bergquist, Jonas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi, Analytisk kemi.
    Wetterhall, Magnus
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi, Analytisk kemi.
    Optimizing the extraction, separation and quantification of tricyclic antidepressant drugs in human plasma with CE-ESI-TOF-MS using cationic coated capillaries2011Inngår i: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 32, nr 6-7, s. 647-658Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In this study, the extraction and CE-ESI-TOF-MS analysis of tricyclic antidepressant (TCA) drugs imipramine, desipramine, clomipramine and norclomipramine in human plasma has been optimized. The CE capillaries were modified with ω-iodo-alkyl ammonium salt (M7C4I coating) to reduce analyte adsorption to the silica wall. The use of a strong cation exchange (SCX) solid-phase extraction (SPE) column specifically designed for the extraction of basic drug species from biofluids gave very clean extracts with high and reproducible recoveries. The extraction recoveries were ranging between 87 and 91% with % RSD values of 0.5-1.7% (n=3). The obtained strong cation exchange-SPE extracts of the TCA in human plasma only contained the analytes of interest. The optimized CE separation conditions were obtained by adding ACN and acetic acid to the sample while using an aqueous BGE. The CE-ESI-TOF-MS analysis was performed within 6min for all TCA analytes under the optimized condition with peak efficiencies up to 1.4×105plates/m and an average % RSD of the migration times of the analytes of 0.3% (n=5). The presented method can readily be used for the extraction and quantification of basic drug species in human biological fluids and in pharmaceutical formulations.

  • 42.
    Enweji, Nizar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Dynamics of Resistant Plasmodium falciparum Parasites2014Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Persistence of drug resistant Plasmodium falciparum is a major problem to management and control malaria in endemic areas. The focus of this thesis was to study the dynamics of resistant P. falciparum parasites. The study was performed in two African countries: 1) Sudan: Asar village in eastern Sudan, here we examined the persistence of drug sensitive and resistant P. falciparum genotypes among individuals with single-clone and multiple clones infection during the dry season. We genotyped microsatellite loci in the vicinity of the dihydrofolate reductase gene (dhfr) and the dihydropteroate synthase gene (dhps). Microsatellite investigation showed that asymptomatic parasitemia persisted in some patients for several months throughout the dry season and into the next transmission season. In some samples mixed infections were detected, and we noted several cases where the microsatellite haplotype varied from month to month, suggesting turnover of different parasite populations in the blood. This demonstrates that even during asymptomatic infections there can be dynamics within the parasite population in an individual. In addition, we calculated the parasite density throughout the dry season to the next transmission season by using allele-specific quantitative PCR. Parasite density during the dry season fluctuated, but was generally lower than in the first transmission season. A significant difference (P<0.05) between dry and first transmission season was found in regard to the parasite density, whereas no significant difference was observed when dry and second transmission season were compared (P>0.05). 2) Ethiopia: West Arsi zone, one of the malaria endemic zones of the Oromia region. In the first study we determined the prevalence of asymptomatic malaria carriages from November-December 2012. According to PCR the prevalence of sub-microscopic P. falciparum carriage was 19.2%, microscopy-based prevalence was 3.7% while the prevalence was 6.9% using RDT. Based on this, PCR was considered a better tool for measuring Plasmodium prevalence than microscopy and RDT. A second study addressed the genetic diversity of chloroquine resistance (CQR) in P. falciparum by analysing four microsatellite markers in and around the pfcrt gene. Although CQ was withdrawn for more than a decade, 100% of the parasites still carried the Pfcrt K76T mutation. Only the CVIET haplotype was identified. Based on combinations of MS markers, seven different Ethiopian CQR variants (E1-E7) were identified. Both intronic and MS flanking the pfcrt gene showed low levels of diversity.

    Delarbeid
    1. Dynamics of asymptomatic malaria infections as revealed by microsatellite typing
    Åpne denne publikasjonen i ny fane eller vindu >>Dynamics of asymptomatic malaria infections as revealed by microsatellite typing
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Forskningsprogram
    Molekylär genetik
    Identifikatorer
    urn:nbn:se:uu:diva-230219 (URN)
    Tilgjengelig fra: 2014-08-20 Laget: 2014-08-20 Sist oppdatert: 2015-01-22bibliografisk kontrollert
    2. Real-time quantitative PCR for determining Plasmodium falciparum parasite density in patients with asymptomatic infection in a seasonal transmission area.
    Åpne denne publikasjonen i ny fane eller vindu >>Real-time quantitative PCR for determining Plasmodium falciparum parasite density in patients with asymptomatic infection in a seasonal transmission area.
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-230222 (URN)
    Tilgjengelig fra: 2014-08-20 Laget: 2014-08-20 Sist oppdatert: 2015-01-22
    3. Detection of a substantial number of sub-microscopic Plasmodium falciparum infections by polymerase chain reaction: a potential threat to malaria control and diagnosis in Ethiopia
    Åpne denne publikasjonen i ny fane eller vindu >>Detection of a substantial number of sub-microscopic Plasmodium falciparum infections by polymerase chain reaction: a potential threat to malaria control and diagnosis in Ethiopia
    Vise andre…
    2013 (engelsk)Inngår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 12, s. 352-Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Background: Prompt and effective malaria diagnosis not only alleviates individual suffering, but also decreases malaria transmission at the community level. The commonly used diagnostic methods, microscopy and rapid diagnostic tests, are usually insensitive at very low-density parasitaemia. Molecular techniques, on the other hand, allow the detection of low-level, sub-microscopic parasitaemia. This study aimed to explore the presence of sub-microscopic Plasmodium falciparum infections using polymerase chain reaction (PCR). The PCR-based parasite prevalence was compared against microscopy and rapid diagnostic test (RDT). Methods: This study used 1,453 blood samples collected from clinical patients and sub-clinical subjects to determine the prevalence of sub-microscopic P. falciparum carriages. Subsets of RDT and microscopy negative blood samples were tested by PCR while all RDT and microscopically confirmed P. falciparum-infected samples were subjected to PCR. Finger-prick blood samples spotted on filter paper were used for parasite genomic DNA extraction. Results: The prevalence of sub-microscopic P. falciparum carriage was 19.2% (77/400) (95% CI = 15.4-23.1). Microscopy-based prevalence of P. falciparum infection was 3.7% (54/1,453) while the prevalence was 6.9% (100/1,453) using RDT alone. Using microscopy and PCR, the estimated parasite prevalence was 20.6% if PCR were performed in 1,453 blood samples. The prevalence was estimated to be 22.7% if RDT and PCR were used. Of 54 microscopically confirmed P. falciparum-infected subjects, PCR detected 90.7% (49/54). Out of 100 RDT-confirmed P. falciparum infections; PCR detected 80.0% (80/100). The sensitivity of PCR relative to microscopy and RDT was, therefore, 90.7% and 80%, respectively. The sensitivity of microscopy and RDT relative to PCR was 16.5 (49/299) and 24.2% (80/330), respectively. The overall PCR-based prevalence of P. falciparum infection was 5.6- and 3.3 fold higher than that determined by microscopy and RDT, respectively. None of the sub-microscopic subjects had severe anaemia, though 29.4% had mild anaemia (10-11.9 g/dl). Conclusions: Asymptomatic, low-density malaria infection was common in the study area and PCR may be a better tool for measuring Plasmodium prevalence than microscopy and RDT. The inadequate sensitivity of the diagnostic methods to detect substantial number of sub-microscopic parasitaemia would undoubtedly affect malaria control efforts, making reduction of transmission more difficult. RDT and microscopy-based prevalence studies and subsequent reports of reduction in malaria incidence underestimate the true pictures of P. falciparum infections in the community. PCR, on the other hand, seems to have reasonable sensitivity to detect a higher number of infected subjects with low and sub-microscopic parasite densities than RDTs or microscopy.

    Emneord
    Sub-microscopic carriage, Asymptomatic malaria, Microscopy, RDT, PCR, Ethiopia
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-216887 (URN)10.1186/1475-2875-12-352 (DOI)000329097000001 ()
    Tilgjengelig fra: 2014-01-27 Laget: 2014-01-27 Sist oppdatert: 2017-12-06bibliografisk kontrollert
    4. High prevalence of pfcrt-CVIET haplotype in isolates from asymptomatic and symptomatic patients in south-central Oromia, Ethiopia
    Åpne denne publikasjonen i ny fane eller vindu >>High prevalence of pfcrt-CVIET haplotype in isolates from asymptomatic and symptomatic patients in south-central Oromia, Ethiopia
    Vise andre…
    2014 (engelsk)Inngår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 13, s. 120-Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Background: As a result of extensive chloroquine resistance (CQR) in Plasmodium falciparum in late 1990s, Ethiopia replaced CQ with sulphadoxine-pyrimethamine (SP) as first-line drug, which in turn was replaced by artemisinin combination therapy in 2004. Plasmodium falciparum resistance to CQ is determined by the mutation at K76T of the P. falciparum chloroquine resistance transporter (pfcrt) gene. Understanding diversity in the P. falciparum genome is crucial since it has the potential to influence important phenotypes of the parasite such as drug resistance. Limited data is available regarding the type of pfcrt mutant allelic type, the effect of CQ withdrawal and diversity of the parasite population in south-central Oromia, Ethiopia. Methods: Finger-pricked blood spotted on Whatman 3MM filter papers were collected from falciparum malaria patients. Parasite DNA was extracted from individual blood spots on the filter papers. The presence of K76T mutations was determined using nested PCR for all isolates. Complete sequencing of mutations in pfcrt 72-76 was done for a set of randomly selected resistant isolates. Four microsatellite (MS) markers were analysed to determine the heterozygosity. Results: Although CQ was withdrawn for more than a decade, 100% of the parasites still carried the pfcrt K76T mutation. All isolates were mutant at the K76T polymorphism. Based on combinations of MS markers, seven different Ethiopian CQR variants (E1-E7) were identified. Heterozygosity (He) for MS flanking the pfcrt chloroquine resistance allele ranged from 0.00 (mscrt -29, -29.268 kb) to 0.21 (mscrt -2, -2.814 kb). H-e ranged from 0.00 (msint 3, 0 kb) to 0.19 (msint 2, 0 kb) for MS within the pfcrt gene. Both intronic and MS flanking the pfcrt gene showed low levels of diversity. Conclusion: pfcrt CQR allele seems to be fixed in the study area. Of the different haplotypes associated with CQR, only the CVIET genotype was identified. No reversal to the wild-type has occurred in Ethiopia unlike in many Africa countries where CQR parasites declined after cessation of CQ use. Decreased diversity in CQR isolates surrounding pfcrt suggests CQ selection and homogenization among CQR parasite population. While mutation in msint 3 and mscrt -29 of the mutant pfcrt allele is being fixed, it seems that mutations in msint 2 and mscrt -2 are still evolving and may indicate the start of re-diversification of the population from a fixed 76 T population.

    Emneord
    pfcrt, Wild type, Drug resistance, Chloroquine, Plasmodium falciparum, Mutations, Heterozygosity, Microsatellite, Ethiopia
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-225094 (URN)10.1186/1475-2875-13-120 (DOI)000334807900004 ()
    Merknad

    Golassa and Enweji contributed equally to this work.

    Tilgjengelig fra: 2014-05-27 Laget: 2014-05-27 Sist oppdatert: 2017-12-05bibliografisk kontrollert
  • 43.
    Eriksson, Olof
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Carlsson, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Blom, Elisabeth
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Fysikalisk-organisk kemi.
    Sundin, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Långström, Bengt
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Fysikalisk-organisk kemi.
    Korsgren, Olle
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Velikyan, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Preclinical evaluation of a 68Ga-labeled biotin analogue for applications in islet transplantation2012Inngår i: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 39, nr 3, s. 415-421Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    INTRODUCTION:

    Islet transplantation is a promising treatment for type 1 diabetes mellitus, but the fate of the cells after intraportal infusion is unclear. It is therefore imperative to develop novel techniques for noninvasive imaging and quantification of events following islet transplantation.

    METHODS:

    Small islet-like microbeads, avidin-covered agarose resins (AARs), were used as a model system for islet transplantation. Capability for specific [(68)Ga]Ga-DOTA-(PEG)(2)-biotin uptake and retention for either AARs or human islets conjugated with avidin by means of a heparin scaffold was studied in vitro. Biodistribution of the novel positron emission tomography (PET) tracer [(68)Ga]Ga-DOTA-(PEG)(2)-biotin was evaluated in mice treated by intraportal transplantation of AARs by μPET/computed tomography and ex vivo organ distribution and compared with control mice.

    RESULTS:

    AARs had high capability to bind [(68)Ga]Ga-DOTA-(PEG)(2)-biotin, close to 50% of administrated tracer/μl in vitro (>0.25 MBq/μl). Avidin-tagged human islets could bind on average 2.2% of administered tracer/μl. Specificity (>90%) and retention (>90% after 1 h) were high for both AARs and avidin-tagged islets. Hepatic tracer uptake and retention were increased in mice transplanted with AARs [standardized uptake value (SUV)=2.6] compared to the untreated group (SUV=1.4). In vivo uptake of tracer to AARs was blocked by preadministration of unlabeled biotin.

    CONCLUSIONS:

    Avidin-tagged islet-like objects can be tracked in hepatic volume after intraportal transplantation by using [(68)Ga]Ga-DOTA-(PEG)(2)-biotin and PET.

  • 44.
    Eriksson, Olof
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Espes, Daniel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Selvaraju, Ram K
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Jansson, Emma
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Antoni, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Sörensen, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET.
    Lubberink, Mark
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET.
    Biglarnia, Alireza
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Transplantationskirurgi.
    Eriksson, Jan W
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Sundin, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Ahlström, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Eriksson, Barbro
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Johansson, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Carlsson, Per-Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Transplantation och regenerativ medicin.
    Korsgren, Olle
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    The Positron Emission Tomography ligand [11C]5-Hydroxy-Tryptophan can be used as a surrogate marker for the human endocrine pancreas2014Inngår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 63, nr 10, s. 3428-3437Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In humans a well-developed serotonin system is localized to the pancreatic islets while being absent in exocrine pancreas. Assessment of pancreatic serotonin biosynthesis could therefore be used to estimate the human endocrine pancreas. Proof of concept was tested in a prospective clinical trial by comparisons of type 1 diabetic (T1D) patients, with extensive reduction of beta cells, with healthy volunteers (HV).C-peptide negative (i.e. insulin-deficient) T1D subjects (n=10) and HV (n=9) underwent dynamic Positron Emission Tomography with the radiolabeled serotonin precursor [(11)C]5-Hydroxy-Tryptophan ([(11)C]5-HTP).A significant accumulation of [(11)C]5-HTP was obtained in the pancreas of the HV, with large inter-individual variation. A substantial and highly significant reduction (66%) in the pancreatic uptake of [(11)C]5-HTP in T1D subjects was observed, and this was most evident in the corpus and caudal regions of the pancreas where beta-cells normally are the major constituent of the islets.[(11)C]5-HTP retention in the pancreas was reduced in T1D compared to non-diabetic subjects. Accumulation of [(11)C]5-HTP in the pancreas of both HV and subjects with T1D were in agreement with previously reported morphological observations on the beta cell volume implying that [(11)C]5-HTP retention is a useful non-invasive surrogate marker for the human endocrine pancreas.

  • 45.
    Eskhult, Jonas
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för materialkemi.
    Ulrich, Christian
    Björefors, Fredrik
    Nyholm, Leif
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för materialkemi.
    Current oscillations during chronoamperometric and cyclic voltammetric measurements in alkaline Cu(II)-citrate solutions2008Inngår i: Electrochimica Acta, ISSN 0013-4686, E-ISSN 1873-3859, Vol. 53, nr 5, s. 2188-2197Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    It is demonstrated that current oscillations can be observed during chronoamperometric and cyclic voltammetric experiments in solutions containing 0.4 M CuSO4 and 1.2 M citrate at pH 11 and 50 degrees C. The oscillations, which are shown to originate from local variations in the pH, result in the deposition of nanostructured Cu and Cu2O materials. It is concluded that the current oscillations are analogous to the previously described potential oscillations obtained under controlled current conditions in alkaline Cu(II)-lactate, -tartrate and -citrate solutions. Rotating disk electrode results clearly show that the reduction of the Cu(II)-complexes is kinetically controlled and that the rate of the reduction increases with increasing pH and temperature. It is also shown that the presence of a cathodic peak on the anodic scan in the cyclic voltammograms can be used to identify the experimental conditions leading to the spontaneous current (or potential) oscillations. Electrochemical quartz crystal microbalance results indicate that the cathodic peak stems from an increased rate of the reduction of the Cu(II)-citrate complexes due to a rapid increase in the local pH. This causes Cu2O rather than Cu to be deposited which, however, results in a decrease in the local pH and a decreasing current. In situ ellipsometry data confirm that Cu2O deposition replaces that of Cu in the potential region of the cathodic peak. The present findings should facilitate syntheses of nanolayered materials based on spontaneous potential or current oscillations.

  • 46.
    Fagerlund, Amelie
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Kemiska institutionen, Avdelningen för organisk kemi.
    Sunnerheim, Kerstin
    Dimberg, Lena H.
    Radical-scavenging and antioxidant activity of avenanthramides2009Inngår i: Food Chemistry, ISSN 0308-8146, E-ISSN 1873-7072, Vol. 113, nr 2, s. 550-556Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Avenanthramides are amides of cinnamoyl-anthranilic acids and, among cereals, are exclusively found in oats. This study investigated the structure-antioxidant activities of 15 avenanthramides with different substitution patterns in the two aromatic rings, seven of which were new avenanthramides synthesised and characterised in this study. Radical-scavenging activity was tested as reactivity towards 1,1-diphenyl-2-picrylhydrazyl (DPPH-). The activity increased with the number of radical-stabilising groups ortho to the phenolic hydroxy group. Both aromatic rings were independently important for activity, while conjugation across the amide bond was of minor importance. Antioxidant activity was determined as inhibition of linoleic acid oxidation. In contrast to the radical-scavenging activity, antioxidant activity was observed for most avenanthramides, and also for compounds with only one hydroxy group in either of the aromatic rings. Compared with alpha-tocopherol, the avenanthramides protected linoleic acid from oxidation to a smaller extent initially, but the effect lasted for a longer time.

  • 47.
    Ferraz, Natalia
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi, Ytbioteknik.
    Effect of Surface Nanotopography on Blood-Biomaterial Interactions2010Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Biologically inspired materials are being developed with the aim of improving the integration of medical implants and minimizing non-desirable host reactions. A promising strategy is the design of topographically patterned surfaces that resemble those found in the extracellular environment.

    Nanoporous alumina has been recognized as a potential biomaterial and as an important template for the fabrication of nanostructures.

    In this thesis in vitro studies were done to elucidate the role of alumina nanoporosity on the inflammatory response. Specifically, by comparing alumina membranes with two pore sizes (20 and 200 nm in diameter). Complement and platelet activation were evaluated as well as monocyte/macrophage behaviour.

    Whole blood was incubated with the alumina membranes and thereafter the biomaterial surfaces were evaluated in terms of protein and platelet adhesion as well as procoagulant properties. The fluid phase was analyzed for complement activation products and platelet activation markers. Besides, human mononuclear cells were cultured on the alumina membranes and cell adhesion, viability, morphology and release of pro-inflammatory cytokines were evaluated.

    The results indicated that nanoporous alumina with 200 nm pores promotes higher complement activation than alumina with 20 nm pores.

    In addition, platelet response to nanoporous alumina was found to be highly dependent on the material porosity, as reflected by differences in adhesion, PMP generation and procoagulant characteristics.

    A clear difference in monocyte/macrophage adhesion and activation was found between the two pore size alumina membranes. Few but highly activated cells adhered to the 200 nm membrane in contrast to many but less activated monocytes/macrophages on the 20 nm surface.

    The outcome of this work emphasizes that nanotopography plays an important role in the host response to biomaterials.

    Better understanding of molecular interactions on nano-level will undoubtedly play a significant role in biomaterial implant development and will contribute to design strategies for controlling specific biological events.

    Delarbeid
    1. Nanoporesize affects complement activation
    Åpne denne publikasjonen i ny fane eller vindu >>Nanoporesize affects complement activation
    2008 (engelsk)Inngår i: Journal of biomedical materials research. Part A, ISSN 1552-4965, Vol. 87, nr 3, s. 575-81Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    In the present study, we have shown the vast importance of biomaterial nanotexture when evaluating inflammatory response. For the first time in an in vitro whole blood system, we have proven that a small increase in nanoporesize, specifically 180 nm (from 20 to 200 nm), has a huge effect on the complement system. The study was done using nanoporous aluminiumoxide, a material that previously has been evaluated for potential implant use, showing good biocompatibility. This material can easily be manufactured with different pore sizes making it an excellent candidate to govern specific protein and cellular events at the tissue-material interface. We performed whole blood studies, looking at complement activation after blood contact with two pore size alumina membranes (pore diameters, 20 and 200 nm). The fluid phase was analyzed for complement soluble components, C3a and sC5b-9. In addition, surface adsorbed proteins were eluted and dot blots were performed to detect IgG, IgM, C1q, and C3. All results point to the fact that 200 nm pore size membranes are more complement activating. Significantly, higher values of complement soluble components were found after whole blood contact with 200 nm alumina and all studied proteins adsorbed more readily to this membrane than to the 20 nm pore size membrane. We hypothesize that the difference in complement activation between our two test materials is caused by the type and the amount of adsorbed proteins, as well as their conformation and orientation. The different protein patterns created on the two alumina membranes are most likely a consequence of the material topography.

    Emneord
    nanotopography, nanoporous alumina, complement, whole blood, protein adsorption
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-88357 (URN)10.1002/jbm.a.31818 (DOI)000260984800002 ()18186072 (PubMedID)
    Tilgjengelig fra: 2009-01-30 Laget: 2009-01-29 Sist oppdatert: 2009-07-13bibliografisk kontrollert
    2. Influence of nanoporesize on platelet adhesion and activation
    Åpne denne publikasjonen i ny fane eller vindu >>Influence of nanoporesize on platelet adhesion and activation
    2008 (engelsk)Inngår i: Journal of materials science. Materials in medicine, ISSN 0957-4530, E-ISSN 1573-4838, Vol. 19, nr 9, s. 3115-21Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    In this study we have evaluated the influence of biomaterial nano-topography on platelet adhesion and activation. Nano-porous alumina membranes with pore diameters of 20 and 200 nm were incubated with whole blood and platelet rich plasma. Platelet number, adhesion and activation were determined by using a coulter hematology analyzer, scanning electron microscopy, immunocytochemical staining in combination with light microscopy and by enzyme immunoassay. Special attention was paid to cell morphology, microparticle generation, P-selectin expression and beta-TG production. Very few platelets were found on the 200 nm alumina as compared to the 20 nm membrane. The platelets found on the 20 nm membrane showed signs of activation such as spread morphology and protruding filipodia as well as P-selectin expression. However no microparticles were detected on this surface. Despite the fact that very few platelets were found on the 200 nm alumina in contrast to the 20 nm membrane many microparticles were detected on this surface. Interestingly, all microparticles were found inside circular shaped areas of approximately 3 mum in diameter. Since this is the approximate size of a platelet we speculate that this is evidence of transient, non-adherent platelet contact with the surface, which has triggered platelet microparticle generation. To the authors knowledge, this is the first study that demonstrates how nanotexture can influence platelet microparticle generation. The study highlights the importance of understanding molecular and cellular events on nano-level when designing new biomaterials.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-88354 (URN)10.1007/s10856-008-3449-7 (DOI)000256964300016 ()18414999 (PubMedID)
    Tilgjengelig fra: 2009-01-30 Laget: 2009-01-29 Sist oppdatert: 2017-12-14bibliografisk kontrollert
    3. Procoagulant behavior and platelet microparticle generation on nanoporous alumina
    Åpne denne publikasjonen i ny fane eller vindu >>Procoagulant behavior and platelet microparticle generation on nanoporous alumina
    2010 (engelsk)Inngår i: Journal of biomaterials applications, ISSN 0885-3282, E-ISSN 1530-8022, Vol. 24, nr 8, s. 675-692Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    In the present work, we have investigated platelet microparticle(PMP) generation in whole blood after contact with nanoporous alumina.Alumina membranes with pore sizes of 20 and 200nm in diameter were incubated with whole blood and the number of PMP in the fluid phase was determined by flow cytometry. The role of the complement system in PMP generation was investigated using an analog of the potent complement inhibitor compstatin. Moreover, the procoagulant activity of the two pore size membranes were compared by measuring thrombin formation. Results indicated that PMP were not present in the fluid phase after whole blood contact with either of the alumina membranes. However, scanning electron microscope micrographs clearly showed the presence of PMP clusters on the 200nm pore size alumina, while PMP were practically absent on the 20nm membrane. We probed no influence of complement activation in PMP generation and adhesion and we hypothesize that other specific material-related protein–platelet interactions are taking place. A clear difference in procoagulant activity between the membranes could also be seen, 20nm alumina showed 100% higher procoagulant activity than 200nm membrane. By combining surface evaluation and flow cytometry analyses of the fluid phase, we are able to conclude that 200nm pore size alumina promotes PMP generation and adhesion while the 20nm membrane does not appreciably cause any release or adhesion of PMP, thus indicating a direct connection between PMP generation and nanoporosity.

    sted, utgiver, år, opplag, sider
    SAGE, 2010
    Emneord
    nanoporous alumina, nanotopography, platelets, platelet microparticles, procoagulant activity, compstatin
    HSV kategori
    Forskningsprogram
    Immunologi; Materialvetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-130496 (URN)10.1177/0885328209338639 (DOI)000277806100001 ()19581322 (PubMedID)
    Tilgjengelig fra: 2010-09-08 Laget: 2010-09-08 Sist oppdatert: 2017-12-12bibliografisk kontrollert
    4. Time sequence of blood activation by nanoporous alumina: Studies on platelets and complement system
    Åpne denne publikasjonen i ny fane eller vindu >>Time sequence of blood activation by nanoporous alumina: Studies on platelets and complement system
    2010 (engelsk)Inngår i: Microscopy research and technique (Print), ISSN 1059-910X, E-ISSN 1097-0029, Vol. 73, nr 12, s. 1101-1109Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    In the present work the time sequence of blood activation by alumina membranes with different porosities (20 and 200 nm in diameter) was studied. The membranes were incubated with whole blood from 2 min to 4 h. Platelet adhesion and activation in addition to complement activation were monitored at different time points. Evaluation of platelet adhesion and activation was done by determining the change in platelet number and the levels of thrombospondin-1 in the fluid phase. Scanning electron microscopy studies were done to further evaluate platelet adhesion and morphology. Immunocytochemical staining was used to evaluate the presence of CD41 and CD62P antigens on the material surface. Complement activation was monitored by measuring C3a and sC5b-9 in plasma samples by means of enzyme immunoassays. Both alumina membranes displayed similar complement activation time profiles, with levels of C3a and sC5b-9 increasing with incubation time. A statistically significant difference between the membranes was found after 60 min of incubation. Platelet activation characteristics and time profile were different between the two membranes. Platelet adhesion increased over time for the 20 nm surface, while the clusters of microparticles on the 200 nm surface did not appreciably change during the course of the experiment. The release of thrombospondin-1 increased with time for both membranes, however much later for the 200 nm alumina (240 min) as compared to the 20 nm membrane (60 min). The surface topography of the alumina most probably influence protein transition rate, which in turn affects material-platelet activation kinetics.

    sted, utgiver, år, opplag, sider
    Wiley-Liss Inc., 2010
    Emneord
    nanotopography, biomaterial, whole blood, thrombospondin-1, platelet microparticles
    HSV kategori
    Forskningsprogram
    Immunologi; Materialvetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-110620 (URN)10.1002/jemt.20854 (DOI)000284063800005 ()
    Tilgjengelig fra: 2009-11-18 Laget: 2009-11-18 Sist oppdatert: 2018-01-12bibliografisk kontrollert
    5. Nanoporosity of alumina surfaces induces different patterns of activation in adhering monocytes/macrophages
    Åpne denne publikasjonen i ny fane eller vindu >>Nanoporosity of alumina surfaces induces different patterns of activation in adhering monocytes/macrophages
    2010 (engelsk)Inngår i: International Journal of Biomaterials, ISSN 1687-8787, E-ISSN 1687-8795, Vol. 2010, s. 402715-Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The present study shows that alumina nanotopography affects monocyte/macrophage behaviour. Human mononuclear cells cultured on alumina membranes with pore diameters of 20 and 200 nm were evaluated in terms of cell adhesion, viability, morphology and release of pro-inflammatory cytokines. After 24 hours, cell adhesion was assessed by means of light microscopy and cell viability by measuring LDH release. The inflammatory response was evaluated by quantifying interleukin-1ß and tumour necrosis factor-α. Finally, scanning electron microscopy was used to study cell morphology. Results showed pronounced differences in cell number, morphology and cytokine release depending on the nanoporosity. Few but highly activated cells were found on the 200 nm porous alumina, while relatively larger number of cells was found on the 20 nm porous surface. However, despite their larger number, the cells adhering on the 20 nm surface exhibited reduced pro-inflammatory activity. It can be speculated that the difference in surface topography may lead to distinct protein adsorption patterns and therefore to different degree of cell activation. The data of this paper emphasize the role played by the material nanotexture in dictating cell responses and implies that nanotopography could be exploited for controlling the inflammatory response to implants.

    Emneord
    macrophages, nanoporous alumina, biomaterials, nanotopography, inflammatory response
    HSV kategori
    Forskningsprogram
    Immunologi
    Identifikatorer
    urn:nbn:se:uu:diva-110623 (URN)10.1155/2010/402715 (DOI)21234322 (PubMedID)
    Tilgjengelig fra: 2009-11-18 Laget: 2009-11-18 Sist oppdatert: 2018-01-12bibliografisk kontrollert
  • 48.
    Ferraz, Natalia
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi, Ytbioteknik.
    Hong, Jaan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för klinisk immunologi.
    Santin, Matteo
    School of Pharmacy & Biomolecualr Sciences, University of Brighton.
    Karlsson Ott, Marjam
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi, Ytbioteknik.
    Nanoporosity of alumina surfaces induces different patterns of activation in adhering monocytes/macrophages2010Inngår i: International Journal of Biomaterials, ISSN 1687-8787, E-ISSN 1687-8795, Vol. 2010, s. 402715-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The present study shows that alumina nanotopography affects monocyte/macrophage behaviour. Human mononuclear cells cultured on alumina membranes with pore diameters of 20 and 200 nm were evaluated in terms of cell adhesion, viability, morphology and release of pro-inflammatory cytokines. After 24 hours, cell adhesion was assessed by means of light microscopy and cell viability by measuring LDH release. The inflammatory response was evaluated by quantifying interleukin-1ß and tumour necrosis factor-α. Finally, scanning electron microscopy was used to study cell morphology. Results showed pronounced differences in cell number, morphology and cytokine release depending on the nanoporosity. Few but highly activated cells were found on the 200 nm porous alumina, while relatively larger number of cells was found on the 20 nm porous surface. However, despite their larger number, the cells adhering on the 20 nm surface exhibited reduced pro-inflammatory activity. It can be speculated that the difference in surface topography may lead to distinct protein adsorption patterns and therefore to different degree of cell activation. The data of this paper emphasize the role played by the material nanotexture in dictating cell responses and implies that nanotopography could be exploited for controlling the inflammatory response to implants.

  • 49.
    Ferraz, Natalia
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi, Ytbioteknik.
    Karlsson Ott, Marjam
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi, Ytbioteknik.
    Hong, Jaan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för klinisk immunologi.
    Time sequence of blood activation by nanoporous alumina: Studies on platelets and complement system2010Inngår i: Microscopy research and technique (Print), ISSN 1059-910X, E-ISSN 1097-0029, Vol. 73, nr 12, s. 1101-1109Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In the present work the time sequence of blood activation by alumina membranes with different porosities (20 and 200 nm in diameter) was studied. The membranes were incubated with whole blood from 2 min to 4 h. Platelet adhesion and activation in addition to complement activation were monitored at different time points. Evaluation of platelet adhesion and activation was done by determining the change in platelet number and the levels of thrombospondin-1 in the fluid phase. Scanning electron microscopy studies were done to further evaluate platelet adhesion and morphology. Immunocytochemical staining was used to evaluate the presence of CD41 and CD62P antigens on the material surface. Complement activation was monitored by measuring C3a and sC5b-9 in plasma samples by means of enzyme immunoassays. Both alumina membranes displayed similar complement activation time profiles, with levels of C3a and sC5b-9 increasing with incubation time. A statistically significant difference between the membranes was found after 60 min of incubation. Platelet activation characteristics and time profile were different between the two membranes. Platelet adhesion increased over time for the 20 nm surface, while the clusters of microparticles on the 200 nm surface did not appreciably change during the course of the experiment. The release of thrombospondin-1 increased with time for both membranes, however much later for the 200 nm alumina (240 min) as compared to the 20 nm membrane (60 min). The surface topography of the alumina most probably influence protein transition rate, which in turn affects material-platelet activation kinetics.

  • 50.
    Fondell, Amelie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Two-Step Targeting for Effective Radionuclide Therapy: Preclinical Evaluation of 125I-labelled Anthracycline Delivered by Tumour Targeting Liposomes2011Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    For the treatment of cancer, Auger-electron emitting radionuclides are strongly dependent on their close proximity to DNA to utilize the local therapeutic potential of the Auger electrons. This thesis investigates a two-step targeting approach that uses targeting liposomes for the delivery of an Auger-electron emitter, 125I, coupled to a DNA-binding compound, Comp1, to the tumour-cell DNA. In the first step the liposome targets overexpressed cell-surface receptors. Receptors belonging to epidermal growth factor receptor (EGFR) family are overexpressed in a number of different cancers and are therefore suitable targets. The second step is transportation of the radionuclide to the cell nucleus utilizing a DNA-binding compound. The DNA-binder used in this thesis is a daunorubicin derivative called Comp1. Papers I and II are in vitro characterizations of the targeting liposomes. Both EGFR- and HER2-targeting liposomes delivered 125I-Comp1 receptor specifically to tumour cells, and were efficient in decreasing growth of cultured tumour cells. Paper II also included a biodistribution of 125I-Comp1 delivered by HER2-targeting liposomes in tumour-bearing mice. The results gave a time-dependent uptake in tumours differed from when non-targeting liposomes encapsulating 125I-Comp1 were given. Paper III investigates the therapeutic effect of 125I-Comp1 delivered by HER2-targeting liposomes, in an animal model that mimics a situation of disseminated tumour cells in the abdomen. 125I-Comp1 delivered by HER2-targeting liposomes effectively prolonged survival of the mice in a dose-dependent relation. Several mice in the groups receiving the highest doses were tumour-free at the end of the study. Paper IV compares different lipid compositions of the liposomes with respect to leakage, cellular uptake and therapeutic efficacy of delivered 125I-Comp1on cultured cells. Liposomes containing sphingomyelin or dihydrosphingomyelin retained drug more efficiently and exhibited more receptor specific delivery properties than distearoylglycerophosphatidylcholine (DSPC) containing liposomes. However, it was the DSPC-containing liposomes that displayed best growth inhibition on cultured tumour cells. The thesis concludes that 125I-Comp1 delivered by targeting liposomes is a promising candidate for effective radionuclide therapy.

    Delarbeid
    1. Nuclisome: a novel concept for radionuclide therapy using targeting liposomes
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