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  • 3701.
    Zhang, Xiaonan
    et al.
    Linkoping Univ, Dept Med & Hlth Sci, SE-58183 Linkoping, Sweden.;Karolinska Inst, Dept Oncol Pathol, SE-17176 Stockholm, Sweden..
    de Milito, Angelo
    Karolinska Inst, Dept Oncol Pathol, SE-17176 Stockholm, Sweden..
    Olofsson, Maria Hagg
    Karolinska Inst, Dept Oncol Pathol, SE-17176 Stockholm, Sweden..
    Gullbo, Joachim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    D'Arcy, Padraig
    Linkoping Univ, Dept Med & Hlth Sci, SE-58183 Linkoping, Sweden.;Karolinska Inst, Dept Oncol Pathol, SE-17176 Stockholm, Sweden..
    Linder, Stig
    Linkoping Univ, Dept Med & Hlth Sci, SE-58183 Linkoping, Sweden.;Karolinska Inst, Dept Oncol Pathol, SE-17176 Stockholm, Sweden..
    Targeting Mitochondrial Function to Treat Quiescent Tumor Cells in Solid Tumors2015Inngår i: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 16, nr 11, s. 27313-27326Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    The disorganized nature of tumor vasculature results in the generation of microenvironments characterized by nutrient starvation, hypoxia and accumulation of acidic metabolites. Tumor cell populations in such areas are often slowly proliferating and thus refractory to chemotherapeutical drugs that are dependent on an active cell cycle. There is an urgent need for alternative therapeutic interventions that circumvent growth dependency. The screening of drug libraries using multicellular tumor spheroids (MCTS) or glucose-starved tumor cells has led to the identification of several compounds with promising therapeutic potential and that display activity on quiescent tumor cells. Interestingly, a common theme of these drug screens is the recurrent identification of agents that affect mitochondrial function. Such data suggest that, contrary to the classical Warburg view, tumor cells in nutritionally-compromised microenvironments are dependent on mitochondrial function for energy metabolism and survival. These findings suggest that mitochondria may represent an Achilles heel for the survival of slowly-proliferating tumor cells and suggest strategies for the development of therapy to target these cell populations.

  • 3702.
    Zhang, Ye
    et al.
    KTH, Skolan för bioteknologi (BIO), Industriell bioteknologi. KTH, Skolan för bioteknologi (BIO), Centra, Centrum för Bioprocessteknik, CBioPT.
    Stobbe, Per
    Silvander, Christian Orrego
    Chotteau, Veronique
    KTH, Skolan för bioteknologi (BIO), Industriell bioteknologi.
    Very high cell density perfusion of CHO cells anchored in a non-woven matrix-based bioreactor2015Inngår i: Journal of Biotechnology, ISSN 0168-1656, E-ISSN 1873-4863, Vol. 213, s. 28-41Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Recombinant Chinese Hamster Ovary (CHO) cells producing IgG monoclonal antibody were cultivated in a novel perfusion culture system CellTank, integrating the bioreactor and the cell retention function. In this system, the cells were harbored in a non-woven polyester matrix perfused by the culture medium and immersed in a reservoir. Although adapted to suspension, the CHO cells stayed entrapped in the matrix. The cell-free medium was efficiently circulated from the reservoir into- and through the matrix by a centrifugal pump placed at the bottom of the bioreactor resulting in highly homogenous concentrations of the nutrients and metabolites in the whole system as confirmed by measurements from different sampling locations. A real-time biomass sensor using the dielectric properties of living cells was used to measure the cell density. The performances of the CellTank were studied in three perfusion runs. A very high cell density measured as 200 pF/cm (where 1 pF/cm is equivalent to 1 x 106 viable cells/mL) was achieved at a perfusion rate of 10 reactor volumes per day (RV/day) in the first run. In the second run, the effect of cell growth arrest by hypothermia at temperatures lowered gradually from 37 C to 29 C was studied during 13 days at cell densities above 100 pF/cm. Finally a production run was performed at high cell densities, where a temperature shift to 31 C was applied at cell density 100 pF/cm during a production period of 14 days in minimized feeding conditions. The IgG concentrations were comparable in the matrix and in the harvest line in all the runs, indicating no retention of the product of interest. The cell specific productivity was comparable or higher than in Erlenmeyer flask batch culture. During the production run, the final harvested IgG production was 35 times higher in the CellTank compared to a repeated batch culture in the same vessel volume during the same time period.

  • 3703.
    Zhang, Yu
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - Ångström, Polymerkemi.
    Rossi, Filippo
    Politecn Milan, Dept Chem Mat & Chem Engn Giulio Natta, Via Mancinelli, I-20131 Milan, Italy..
    Papa, Simonetta
    IRCCS Ist Ric Farmacol Mario Negri, Dept Neurosci, Via La Masa 19, I-20156 Milan, Italy..
    Violatto, Martina Bruna
    IRCCS Ist Ric Farmacol Mario Negri, Dept Biochem & Mol Pharmacol, Via La Masa 19, I-20156 Milan, Italy..
    Bigini, Paolo
    IRCCS Ist Ric Farmacol Mario Negri, Dept Biochem & Mol Pharmacol, Via La Masa 19, I-20156 Milan, Italy..
    Sorbona, Marco
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - Ångström, Polymerkemi.
    Redaelli, Francesca
    Veglianese, Pietro
    IRCCS Ist Ric Farmacol Mario Negri, Dept Neurosci, Via La Masa 19, I-20156 Milan, Italy..
    Hilborn, Jöns
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - Ångström, Polymerkemi.
    Ossipov, Dmitri A.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - Ångström, Polymerkemi.
    Non-invasive in vitro and in vivo monitoring of degradation of fluorescently labeled hyaluronan hydrogels for tissue engineering applications2016Inngår i: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 30, s. 188-198Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Tracking of degradation of hydrogels-based biomaterials in vivo is very important for rational design of tissue engineering scaffolds that act as delivery carriers for bioactive factors. During the process of tissue development, an ideal scaffold should remodel at a rate matching with scaffold degradation. To reduce amount of animals sacrificed, non-invasive in vivo imaging of biomaterials is required which relies on using of biocompatible and in situ gel forming compounds carrying suitable imaging agents. In this study we developed a method of in situ fabrication of fluorescently labeled and injectable hyaluronan (HA) hydrogel based on one pot sequential use of Michael addition and thiol-disulfide exchange reactions for the macromolecules labeling and cross-linking respectively. Hydrogels with different content of HA were prepared and their enzymatic degradation was followed in vitro and in vivo using fluorescence multispectral imaging. First, we confirmed that the absorbance of the matrix-linked near-IR fluorescent IRDye (R) 800CW agent released due to the matrix enzymatic degradation in vitro matched the amount of the degraded hydrogel measured by classical gravimetric method. Secondly, the rate of degradation was inversely proportional to the hydrogel concentration and this structure-degradation relationship was similar for both in vitro and in vivo studies. It implies that the degradation of this disulfide cross-linked hyaluronan hydrogel in vivo can be predicted basing on the results of its in vitro degradation studies. The compliance of in vitro and in vivo methods is also promising for the future development of predictive in vitro tissue engineering models. Statement of significance The need for engineered hydrogel scaffolds that deliver bioactive factors to endogenous progenitor cells in vivo via gradual matrix resorption and thus facilitate tissue regeneration is increasing with the aging population. Importantly, scaffold should degrade at a modest rate that will not be too fast to support tissue growth nor too slow to provide space for tissue development. The present work is devoted to longitudinal tracking of a hydrogel material in vivo from the time of its implantation to the time of complete resorption without sacrificing animals. The method demonstrates correlation of resorption rates in vivo and in vitro for hydrogels with varied structural parameters. It opens the possibility to develop predictive in vitro models for tissue engineered scaffolds and reduce animal studies.

  • 3704.
    Zhang, Zhe
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Kuipers, Grietje
    Niemiec, Lukasz
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Baumgarten, Thomas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Slotboom, Dirk Jan
    de Gier, Jan-Willem
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Hjelm, Anna
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    High-level production of membrane proteins in E-coli BL21(DE3) by omitting the inducer IPTG2015Inngår i: Microbial Cell Factories, ISSN 1475-2859, E-ISSN 1475-2859, Vol. 14, artikkel-id 142Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: For membrane protein production, the Escherichia coli T7 RNA polymerase (T7 RNAP)-based protein production strain BL21(DE3) in combination with T7-promoter based expression vectors is widely used. Cells are routinely cultured in Lysogeny broth (LB medium) and expression of the chromosomally localized t7rnap gene is governed by the isopropyl-beta-D-1-thiogalactopyranoside (IPTG) inducible lacUV5 promoter. The T7 RNAP drives the expression of the plasmid borne gene encoding the recombinant membrane protein. Production of membrane proteins in the cytoplasmic membrane rather than in inclusion bodies in a misfolded state is usually preferred, but often hampered due to saturation of the capacity of the Sec-translocon, resulting in low yields. Results: Contrary to expectation we observed that omission of IPTG from BL21(DE3) cells cultured in LB medium can lead to significantly higher membrane protein production yields than when IPTG is added. In the complete absence of IPTG cultures stably produce membrane proteins in the cytoplasmic membrane, whereas upon the addition of IPTG membrane proteins aggregate in the cytoplasm and non-producing clones are selected for. Furthermore, in the absence of IPTG, membrane proteins are produced at a lower rate than in the presence of IPTG. These observations indicate that in the absence of IPTG the Sec-translocon capacity is not/hardly saturated, leading to enhanced membrane protein production yields in the cytoplasmic membrane. Importantly, for more than half of the targets tested the yields obtained using un-induced BL21(DE3) cells were higher than the yields obtained in the widely used membrane protein production strains C41(DE3) and C43(DE3). Since most secretory proteins reach the periplasm via the Sec-translocon, we also monitored the production of three secretory recombinant proteins in the periplasm of BL21(DE3) cells in the presence and absence of IPTG. For all three targets tested omitting IPTG led to the highest production levels in the periplasm. Conclusions: Omission of IPTG from BL21(DE3) cells cultured in LB medium provides a very cost-and time effective alternative for the production of membrane and secretory proteins. Therefore, we recommend that this condition is incorporated in membrane- and secretory protein production screens.

  • 3705.
    Zhao, Hongxing
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Chen, Maoshan
    Monash Univ, Cent Clin Sch, Australian Ctr Blood Dis, Clayton, Vic, Australia.
    Valdes, Alberto
    Univ Alcala De Henares, Dept Analyt Chem Phys Chem & Chem Engn, Madrid, Spain.
    Lind, Sara
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Pettersson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Transcriptomic and proteomic analyses reveal new insights into the regulation of immune pathways during adenovirus type 2 infection2019Inngår i: BMC Microbiology, ISSN 1471-2180, E-ISSN 1471-2180, Vol. 19, artikkel-id 15Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Human adenovirus (Ad) infection leads to the changes of host cell gene expression and biosynthetic processes. Transcriptomics in adenovirus type 2 (Ad2)-infected lung fibroblasts (IMR-90) cells has previously been studied using RNA sequencing. However, this study included only two time points (12 and 24 hpi) using constrained 76bp long sequencing reads. Therefore, a more detailed study of transcription at different phases of infection using an up-graded sequencing technique is recalled. Furthermore, the correlation between transcription and protein expression needs to be addressed.

    Results: In total, 3556 unique cellular genes were identified as differentially expressed at the transcriptional level with more than 2-fold changes in Ad2-infected cells as compared to non-infected cells by using paired-end sequencing. Based on the kinetics of the gene expression changes at different times after infection, these RNAs fell into 20 clusters. Among them, cellular genes involved in immune response were highly up-regulated in the early phase before becoming down-regulated in the late phase. Comparison of differentially expressed genes at transcriptional and posttranscriptional levels revealed low correlation. Particularly genes involved in cellular immune pathways showed a negative correlation. Here, we highlight the genes which expose inconsistent expression profiles with an emphasis on key factors in cellular immune pathways including NFB, JAK/STAT, caspases and MAVS. Different from their transcriptional profiles with up- and down-regulation in the early and late phase, respectively, these proteins were up-regulated in the early phase and were sustained in the late phase. A surprising finding was that the target genes of the sustained activators failed to show response.

    Conclusion: There were features common to genes which play important roles in cellular immune pathways. Their expression was stimulated at both RNA and protein levels during the early phase. In the late phase however, their transcription was suppressed while protein levels remained stable. These results indicate that Ad2 and the host cell use different strategies to regulate cellular immune pathways. A control mechanism at the post-translational level must thus exist which is under the control of Ad2.

  • 3706.
    Zhao, Yufang
    et al.
    Harbin Inst Technol, Bio X Ctr, Sch Life Sci & Technol, Harbin 150080, Peoples R China..
    Yan, Hongji
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - Ångström, Polymerkemi. Harbin Inst Technol, Bio X Ctr, Sch Life Sci & Technol, Harbin 150080, Peoples R China..
    Qiao, Shupei
    Harbin Inst Technol, Bio X Ctr, Sch Life Sci & Technol, Harbin 150080, Peoples R China..
    Zhang, Long
    Harbin Inst Technol, Bio X Ctr, Sch Life Sci & Technol, Harbin 150080, Peoples R China..
    Wang, Tianran
    Harbin Inst Technol, Bio X Ctr, Sch Life Sci & Technol, Harbin 150080, Peoples R China..
    Meng, Qingyuan
    Chinese Acad Sci, State Key Lab Mol Dev Biol, Inst Genet & Dev Biol, Beijing 100190, Peoples R China..
    Chen, Xiongbiao
    Univ Saskatchewan, Dept Mech Engn, Saskatoon, SK, Canada..
    Lin, Feng-Huei
    Natl Hlth Res Inst, Div Biomed Engn & Nanomed Res, Miaoli, Taiwan.;Natl Taiwan Univ, Inst Biomed Engn, Coll Med, Taipei, Taiwan.;Natl Taiwan Univ, Coll Engn, Taipei, Taiwan..
    Guo, Kai
    Harbin Inst Technol, Bio X Ctr, Sch Life Sci & Technol, Harbin 150080, Peoples R China..
    Li, Chunfeng
    Harbin Inst Technol, Bio X Ctr, Sch Life Sci & Technol, Harbin 150080, Peoples R China..
    Tian, Weiming
    Harbin Inst Technol, Bio X Ctr, Sch Life Sci & Technol, Harbin 150080, Peoples R China.;Harbin Inst Technol, Room 302,Bldg 2E,Sci Pk,2 Yikuang St, Harbin 150080, Heilongjiang, Peoples R China..
    Hydrogels bearing bioengineered mimetic embryonic microenvironments for tumor reversion2016Inngår i: Journal of materials chemistry. B, ISSN 2050-750X, E-ISSN 2050-7518, Vol. 4, nr 37, s. 6183-6191Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Embryonic microenvironments can reverse the metastatic phenotype of aggressive tumors by inhibiting the Nodal signaling pathway. Here, we hypothesize that embryonic microenvironments can be transplanted for the purpose of oncotherapy. We report the development of an injectable bioactive hydrogel system containing the key antagonists of Nodal signaling-Cripto-1 receptor antibodies (2B11)-for the creation of embryonic microenvironments and the examination of their effect on tumor reversion treatment using a mouse model. Our in vitro results show that the hydrogel system can reduce the mitochondrial membrane potential of MDA-MB-231 and MCF-7, promote cell apoptosis, and reduce the invasive ability of cells. Our in vivo results illustrate that the hydrogel system can significantly inhibit tumor growth in both breast cancer and melanoma tumor-bearing mouse models, as well as transform the cell morphology of melanoma B16 cells to melanin-like cells. Furthermore, the results of the up-regulation of tumor suppressor genes and the down-regulation of oncogenes by high-throughput sequencing confirm that the developed system can also selectively turn on some tumor suppressor genes and turn off certain oncogenes so as to prompt the benign reversion of the tumor phenotype. Taken together, our results demonstrate the injectable biomaterial system is able to create an effective microenvironment for melanoma and breast tumor therapy.

  • 3707. Zheng, Zongli
    et al.
    Advani, Abdolreza
    Melefors, Öjar
    Glavas, Steve
    Nordström, Henrik
    Ye, Weimin
    Engstrand, Lars
    Andersson, Anders F.
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Titration-free 454 sequencing using Y adapters2011Inngår i: Nature Protocols, ISSN 1754-2189, E-ISSN 1750-2799, Vol. 6, nr 9, s. 1367-1376Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We describe a protocol for construction and quantification of libraries for emulsion PCR (emPCR)-based sequencing platforms such as Roche 454 or Ion Torrent PGM. The protocol involves library construction using customized Y adapters, quantification using TaqMan-MGB (minor groove binder) probe-based quantitative PCR (qPCR) and calculation of an optimal template-to-bead ratio based on Poisson statistics, thereby avoiding the need for a laborious titration assay. Unlike other qPCR methods, the TaqMan-MGB probe specifically quantifies effective libraries in molar concentration and does not require specialized equipment. A single quality control step prior to emulsion PCR ensures that libraries contain no adapter dimers and have an optimal length distribution. The presented protocol takes similar to 7 h to prepare eight barcoded libraries from genomic DNA into libraries that are ready to use for full-scale emPCR. It will be useful, for example, to allow analyses of precious clinical samples and amplification-free metatranscriptomics.

  • 3708.
    Zhengquan, Yu
    et al.
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan. Linköpings universitet, Hälsouniversitetet.
    Li, Wei
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan. Linköpings universitet, Hälsouniversitetet.
    Brunk, Ulf
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan. Linköpings universitet, Hälsouniversitetet.
    3-Aminopropanal is a lysosomotropic aldehyde that causes oxidative stress and apoptosis by rupturing lysosomes.2003Inngår i: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 111, nr 6, s. 643-652Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    During cerebral ischemia and following trauma, potent cytotoxic polyamine-derived aminoaldehydes form, diffuse, and damage adjacent tissues not directly subjected to the initial insult. One such aldehyde is 3-aminopropanal (3-AP). The mechanisms by which such a small aldehydic compound is excessively cytotoxic have been unclear until recently when we showed that 3-AP, having the structure of a weak lysosomotropic base, concentrates within the acidic vacuolar compartment and causes lysosomal rupture that, in turn, induces caspase activation and apoptotic cell death. Here, using cultured J774 cells and 3-AP as a way to selectively burst lysosomes, we show that moderate lysosomal rupture induces a transient wave of oxidative stress. The start of this oxidative stress period is concomitant with a short period of enhanced mitochondrial membrane potential that later fades and is replaced by a decreased potential before the oxidative stress diminishes. The result of the study suggests that oxidative stress, which has often been described during apoptosis induced by agonists other than oxidative stress per se, may be a consequence of lysosomal rupture with direct and/or indirect effects on mitochondrial respiration and electron transport causing a period of passing enhanced formation of reactive oxygen species.

  • 3709.
    Zhou, Yiwen
    Karlstads universitet, Fakulteten för hälsa, natur- och teknikvetenskap (from 2013), Institutionen för hälsovetenskaper.
    Effect of the exposure to phthalates on phagocytotic activity in non-differentiated and differentiated THP-1 cells2013Independent thesis Basic level (degree of Bachelor), 10 poäng / 15 hpOppgave
  • 3710.
    Zieba, Agata
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Application of Proximity Ligation Assay for Multidirectional Studies on Transforming Growth Factor-β Pathway2012Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    A comprehensive understanding of how the body and all its components function is essential when this knowledge is exploited for medical purposes. The achievements in biological and medical research during last decades has provided us with the complete human genome and identified signaling pathways that governs the cellular processes that facilitates the development and maintenance of higher order organisms. This has brought about the realization that diseases such as cancer is a consequence of genomic aberrations that effects these signaling pathways, endowing cancer cells with the capacity to circumvent homeostasis by acquiring features like self-sustained proliferation and insensitivity to apoptosis. The increased understanding of biology and medicine has been made possible by the development of advanced methods to carry out biological and clinical analyses. The demands of a method often differ regarding in what context it will be applied. It may be acceptable for method to be laborious and time consuming if it is used in basic research, but for medical purposes molecular methods need to be fast and straightforward to perform. Innovative technologies should preferentially address the demands of both researchers and clinicians and provide data not possible to obtain by other methods. An example of such a method is the in situ proximity ligation assay (in situ PLA). In this thesis I have used this method to determine the activity status, at the single-cell level, of the transforming growth factor-β (TGF-β) signaling pathway and activating protein-1 (AP-1) family of transcription factors.  Both of these pathways are frequently involved in cancer development and progression. In addition to this research I herein also present further modifications of in situ PLA, and analyses thereof, to increase the utility and resolution of this assay.

  • 3711.
    Zieba, Agata
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Sjöstedt, Evelina
    KTH Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Olovsson, Matts
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Obstetrik & gynekologi. Uppsala Univ, Dept Womens & Childrens Hlth, S-75185 Uppsala, Sweden..
    Fagerberg, Linn
    KTH Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Hallström, Björn M.
    KTH Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Oskarsson, Linda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Edlund, Karolina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Tolf, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Uhlen, Mathias
    KTH Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Pontén, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    The Human Endometrium-Specific Proteome Defined by Transcriptomics and Antibody-Based Profiling2015Inngår i: Omics, ISSN 1536-2310, E-ISSN 1557-8100, Vol. 19, nr 11, s. 659-668Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The human uterus includes the complex endometrial mucosa, the endometrium that undergoes dynamic, hormone-dependent alterations throughout the life of fertile females. Here we have combined a genome-wide transcriptomics analysis with immunohistochemistry-based protein profiling to analyze gene expression patterns in the normal endometrium. Human endometrial tissues from five women were used for deep sequencing (RNA-Seq). The mRNA and protein expression data from the endometrium were compared to 31 (RNA) and 44 (protein) other normal tissue types, to identify genes with elevated expression in the endometrium and to localize the expression of corresponding proteins at a cellular resolution. Based on the expression levels of transcripts, we could classify all putative human protein coding genes into categories defined by expression patterns and found altogether 101 genes that showed an elevated pattern of expression in the endometrium, with only four genes showing more than five-fold higher expression levels in the endometrium compared to other tissues. In conclusion, our analysis based on transcriptomics and antibody-based protein profiling reports here comprehensive lists of genes with elevated expression levels in the endometrium, providing important starting points for a better molecular understanding of human reproductive biology and disease.

  • 3712.
    Zieba, Agata
    et al.
    Uppsala Univ, Dept Immunol Genet & Pathol, Sci Life Lab, S-75185 Uppsala, Sweden..
    Sjöstedt, Evelina
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Olovsson, Matts
    Uppsala Univ, Dept Womens & Childrens Hlth, S-75185 Uppsala, Sweden..
    Fagerberg, Linn
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Hallström, Björn M.
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Oskarsson, Linda
    Uppsala Univ, Dept Immunol Genet & Pathol, Sci Life Lab, S-75185 Uppsala, Sweden..
    Edlund, Karolina
    Uppsala Univ, Dept Immunol Genet & Pathol, Sci Life Lab, S-75185 Uppsala, Sweden..
    Tolf, Anna
    Uppsala Univ, Dept Immunol Genet & Pathol, Sci Life Lab, S-75185 Uppsala, Sweden..
    Uhlén, Mathias
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Ponten, Fredrik
    Uppsala Univ, Dept Immunol Genet & Pathol, Sci Life Lab, S-75185 Uppsala, Sweden..
    The Human Endometrium-Specific Proteome Defined by Transcriptomics and Antibody-Based Profiling2015Inngår i: Omics, ISSN 1536-2310, E-ISSN 1557-8100, Vol. 19, nr 11, s. 659-668Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The human uterus includes the complex endometrial mucosa, the endometrium that undergoes dynamic, hormone-dependent alterations throughout the life of fertile females. Here we have combined a genome-wide transcriptomics analysis with immunohistochemistry-based protein profiling to analyze gene expression patterns in the normal endometrium. Human endometrial tissues from five women were used for deep sequencing (RNA-Seq). The mRNA and protein expression data from the endometrium were compared to 31 (RNA) and 44 (protein) other normal tissue types, to identify genes with elevated expression in the endometrium and to localize the expression of corresponding proteins at a cellular resolution. Based on the expression levels of transcripts, we could classify all putative human protein coding genes into categories defined by expression patterns and found altogether 101 genes that showed an elevated pattern of expression in the endometrium, with only four genes showing more than five-fold higher expression levels in the endometrium compared to other tissues. In conclusion, our analysis based on transcriptomics and antibody-based protein profiling reports here comprehensive lists of genes with elevated expression levels in the endometrium, providing important starting points for a better molecular understanding of human reproductive biology and disease.

  • 3713.
    Ziegler, Magnus
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Improving Assessments of Hemodynamics and Vascular Disease2019Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Blood vessels are more than simple pipes, passively enabling blood to pass through them. Their form and function are dynamic, changing with both aging and disease. This process involves a feedback loop wherein changes to the shape of a blood vessel affect the hemodynamics, causing yet more structural adaptation. This feedback loop is driven in part by the hemodynamic forces generated by the blood flow, and the distribution and strength of these forces appear to play a role in the initiation, progression, severity, and the outcome of vascular diseases.

    Magnetic Resonance Imaging (MRI) offers a unique platform for investigating both the form and function of the vascular system. The form of the vascular system can be examined using MR-based angiography, to generate detailed geometric analyses, or through quantitative techniques for measuring the composition of the vessel wall and atherosclerotic plaques. To complement these analyses, 4D Flow MRI can be used to quantify the functional aspect of the vascular system, by generating a full time-resolved three-dimensional velocity field that represents the blood flow.

    This thesis aims to develop and evaluate new methods for assessing vascular disease using novel hemodynamic markers generated from 4D Flow MRI and quantitative MRI data towards the larger goal of a more comprehensive non-invasive examination oriented towards vascular disease. In Paper I, we developed and evaluated techniques to quantify flow stasis in abdominal aortic aneurysms to measure this under-explored aspect of aneurysmal hemodynamics. In Paper II, the distribution and intensity of turbulence in the aorta was quantified in both younger and older men to understand how aging changes this aspect of hemodynamics. A method to quantify the stresses generated by turbulence that act on the vessel wall was developed and evaluated using simulated flow data in Paper III, and in Paper V this method was utilized to examine the wall stresses of the carotid artery. The hemodynamics of vascular disease cannot be uncoupled from the anatomical changes the vessel wall undergoes, and therefore Paper IV developed and evaluated a semi-automatic method for quantifying several aspects of vessel wall composition. These developments, taken together, help generate more valuable information from imaging data, and can be pooled together with other methods to form a more comprehensive non-invasive examination for vascular disease.

  • 3714.
    Ziethén, Kristina
    Högskolan Kristianstad, Sektionen för lärande och miljö.
    Validering av turbidimetrisk metod för koncentrationsbestämning av albumin i cerebrospinalvätska2018Independent thesis Basic level (degree of Bachelor), 10 poäng / 15 hpOppgave
    Abstract [sv]

     I denna studie jämfördes två olika metoder för att analysera cerbrospinalvätska (CSF); spinal-protein och spinal-albumin. Syftet med studien var att undersöka om spinal-albumin som baseras på turbidimetri skulle kunna ersätta spinal-protein som baseras på spektrofotometri. Denna används idag som rutinanalys på laboratoriet för klinisk kemi på S Södra Älvsborgs sjukhus (SÄS). 35 prover analyserades, tagna från det CSF -prover som ankom till SÄS. Varje prov kördes två gånger med respektive metod. Studien visade en god korrelation mellan metoderna, dock visade Bland-Altman diagram mindre spridning av värdena som erhölls med albumin-metoden. Resultaten för albumin jämfördes mot Sahlgrenska universitetssjukhus (SU) resultat, då albumin-metoden ingår i deras rutiner.  

    Studien visade också att de dagliga kontrollerna som kördes ej var lämpade för albumin metoden, då både innehåll och koncentration inte var anpassad till spinalprover. Kontrollerna kommer att bytas ut mot andra mer lämpade kontroller. Metoden för spinal-albumin kommer att kunna ersätta total-protein som rutinanalys av CFS.

  • 3715.
    Zimmerman, Linn
    Karlstads universitet, Fakulteten för hälsa, natur- och teknikvetenskap (from 2013), Institutionen för hälsovetenskaper (from 2013).
    Understanding the relationship between indoleamine 2, 3dioxygenase 1 and arginase 1: IDO1 controls Arg1 expression in dendritic cells2016Independent thesis Basic level (degree of Bachelor), 10 poäng / 15 hpOppgave
  • 3716. Zirk, Katrin
    et al.
    Langel, Ülo
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi. University of Tartu, Estonia.
    Vectorization of splice-correcting oligonucleotides with cell-penetrating peptides2013Inngår i: Chimica oggi, ISSN 0392-839X, E-ISSN 1973-8250, Vol. 31, nr 2, s. 12-15Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Personalized medicine approaches based on different gene therapy settings have gained much attention lately. In order to enforce successful gene therapy, genetic material needs to be delivered into cells. Nucleic acids and their analogues are unable to do so and thus require assistance to reach their site of action residing in the cytoplasm or nucleus. Here we give a short review on recent advancements in cell-penetrating peptide mediated delivery of splice-correcting oligonucleotides. We report on different cell-penetrating peptides applied for vectorization of splice-correcting oligonucleotides using both covalent conjugation and non-covalent nanoparticle formation approach. While covalent conjugation has gained extensive interest, there have also been great advances in non-covalent complex formation.

  • 3717.
    Zlatkov, Nikola
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Regulatory mechanisms involved in pathoadaptation of extraintestinal pathogenic Escherichia coli2019Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Establishment of commensal bacteria within a new niche of their host usually promotes the transition from commensalism to pathogenicity. Extraintestinal Pathogenic Escherichia coli (ExPEC) represent different pathovars with biphasic lifestyle – they can reside in the gut as commensals or they can escape and cause diseases elsewhere in the human body. Depending on the disease they are linked to, ExPEC can be divided into Uropathogenic E. coli (UPEC), Newborn Meningitis-causing E. coli (NMEC) and Sepsis-associated E. coli (SEPEC).

    Pathoadaptive mutations linked to c-di-GMP signaling were investigated in the NMEC strain IHE3034 which lacks the main global stress regulator RpoS. We investigated the role of ycgG2 in the lifestyle of NMEC. Deletion of ycgG2, shown by us to encode an YcgG allozyme with c-di-GMP phosphodiesterase (PDE) activity, and the restored RpoS led to a decrease in the S-fimbriae, otherwise robustly produced in artificial urine, hinting that the urinary tract could serve as a habitat for NMEC. We showed that NMEC were capable of aerobic citrate utilization in the presence of a co-substrate - a property that normally does not exist in E. coli. Our data hint that this metabolic upgrade is enhanced by the lack, or reduced activity, of c-di-GMP PDEs. We also found that citrate utilization is a property of ExPEC, since we reconstituted it in E. coli UTI89 (a cystitis isolate) via inactivation of its RpoS, and since a set of pyelonephritis E. coli isolates use citrate aerobically in the presence of glucose. The main reason for this metabolic capability is the absence of RpoS which leads to the production of the citrate transporter CitT. Furthermore, we highlighted the deletion of the fec operon (required for the ferric citrate uptake) in a large group of different ExPEC strains and we showed that NMEC can use CitT for in vitro ferric citrate uptake dependent on YcgG2 as an alternative system.

    Another pathoadaptive mutation which influences the fitness of ExPEC is the clyA (cytolysin A) gene inactivation, resulting from different deletions in different ExPEC genomes. When we restored the clyA+ locus, the UPEC strain 536 displayed increased susceptibility to antimicrobial peptides and urea. We also showed that the ClyA expression in 536 was increased by the presence of the DNA-binding regulator SfaX and another stand-alone PDE similar to YcgG2, called SfaY. The results were further confirmed by ClyA downregulation in NMEC deficient in SfaY and SfaX.

    We also studied the role of sfaY - a gene coding for another stand-alone c-di-GMP PDE. The expression of sfaY is under the regulation of the main promoter of the horizontally acquired sfa gene cluster. The latter is responsible for the regulation and assembly of the virulence-associated S-fimbriae, via which ExPEC bacteria bind to sialylated receptors. We found that NMEC are competent for filamentation because of a c-di-GMP-dependent program under the control of a phase-variation event which selectively turns ‘ON’ the sfa promoter in a subpopulation of bacteria. When SfaY is present, c-di-GMP levels are reduced, thus inducing the SOS stress response via the canonical LexA-RecA pathway. The signaling resulted in an internal differentiation of the bacterial population into a subpopulation exhibiting a filamentous morphotype (bacteria with induced SOS stress response) and a subpopulation of small motile and non-motile bacteria. Hence, this molecular program could serve as a clue to explain the formation of the intracellular bacterial communities observed during urinary tract infection by UPEC.

  • 3718.
    Zlatkov, Nikola
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Uhlin, Bernt Eric
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Absence of Global Stress Regulation in Escherichia coli Promotes Pathoadaptation and Novel c-di-GMP-dependent Metabolic Capability2019Inngår i: Scientific Reports, ISSN 2045-2322, Vol. 9, artikkel-id 2600Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    athoadaptive mutations linked to c-di-GMP signalling were investigated in neonatal meningitis-causing Escherichia coli (NMEC). The results indicated that NMEC strains deficient in RpoS (the global stress regulator) maintained remarkably low levels of c-di-GMP, a major bacterial sessility-motility switch. Deletion of ycgG2, shown here to encode a YcgG allozyme with c-di-GMP phosphodiesterase activity, and the restoration of RpoS led to a decrease in S-fimbriae, robustly produced in artificial urine, hinting that the urinary tract could serve as a habitat for NMEC. We showed that NMEC were skilled in aerobic citrate utilization in the presence of glucose, a property that normally does not exist in E. coli. Our data suggest that this metabolic novelty is a property of extraintestinal pathogenic E. coli since we reconstituted this ability in E. coli UTI89 (a cystitis isolate) via deactivation rpoS; additionally, a set of pyelonephritis E. coli isolates were shown here to aerobically use citrate in the presence of glucose. We found that the main reason for this metabolic capability is RpoS inactivation leading to the production of the citrate transporter CitT, exploited by NMEC for ferric citrate uptake dependent on YcgG2 (an allozyme with c-di-GMP phosphodiesterase activity).

  • 3719.
    Zlatkov, Nikola
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Uhlin, Bernt Eric
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    C-di-GMP-mediated Morphotypic Pathoadaptability of Neonatal Meningitis Escherichia coliManuskript (preprint) (Annet vitenskapelig)
  • 3720.
    Zollbrecht, Christa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden..
    Persson, A. Erik G.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Lundberg, Jon O.
    Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden..
    Weitzberg, Eddie
    Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden..
    Carlström, Mattias
    Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden..
    Nitrite-mediated reduction of macrophage NADPH oxidase activity is dependent on xanthine oxidoreductase-derived nitric oxide but independent of S-nitrosation2016Inngår i: Redox Biology, ISSN 0090-7324, E-ISSN 2213-2317, Vol. 10, s. 119-127Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Inorganic nitrite has shown beneficial effects in cardiovascular and metabolic diseases partly via attenuation of NADPH-oxidase (NOX)-mediated oxidative stress. However, the exact mechanisms are still unclear. Here we investigated the role of S-nitrosation or altered expression of NOX subunits, and the role of xanthine oxidoreductase (XOR) in nitrite-derived nitric oxide (NO) production. Methods: Mouse macrophages were activated with LPS in the presence or absence of nitrite. NOX activity was measured by lucigenin-dependent chemiluminescence. Gene and protein expression of NOX2 subunits and XOR were investigated using qPCR and Western Blot. S-nitrosation of Nox2 and p22phox was studied with a Biotin Switch assay. Uric acid levels in cell culture medium were analyzed as a measure of XOR activity, and NO production was assessed by DAF-FM fluorescence. Results: NOX activity in activated macrophages was significantly reduced by nitrite. Reduced NOX activity was not attributed to decreased NOX gene expression. However, protein levels of p47phox and p67phox subunits were reduced by nitrite in activated macrophages. Protein expression of Nox2 and p22phox was not influenced by this treatment and neither was their S-nitrosation status. Increased uric acid levels after nitrite and diminished NO production during XOR-inhibition with febuxostat suggest that XOR is more active during nitrite-treatment of activated macrophages and plays an important role in the bioactivation of nitrite. Conclusions: Our findings contribute to the mechanistic understanding about the therapeutic effects associated with nitrite supplementation in many diseases. We show that nitrite-mediated inhibition of NOX activity cannot be explained by S-nitrosation of the NOX enzyme, but that changes in NOX2 expression and XOR function may contribute.

  • 3721.
    Zorgati, Habiba
    et al.
    ASTAR, Inst Mol & Cell Biol, Singapore 138673, Singapore;Natl Univ Singapore, Dept Biochem, Singapore 117596, Singapore.
    Larsson, Mårten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. ASTAR, Inst Mol & Cell Biol, Singapore 138673, Singapore.
    Ren, Weitong
    Nanjing Univ, Collaborat Innovat Ctr Adv Microstruct, Dept Phys, Natl Lab Solid State Microstruct, Nanjing 210093, Jiangsu, Peoples R China.
    Sim, Adelene Y. L.
    ASTAR, Bioinformat Inst, Singapore 138671, Singapore.
    Gettemans, Jan
    Univ Ghent, Fac Med & Hlth Sci, Dept Biomol Med, Nanobody Lab, B-9000 Ghent, Belgium.
    Grimes, Jonathan M.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Div Struct Biol, Oxford OX3 7BN, England;Diamond Light Source Ltd, Didcot OX11 ODE, Oxon, England.
    Li, Wenfei
    Nanjing Univ, Collaborat Innovat Ctr Adv Microstruct, Dept Phys, Natl Lab Solid State Microstruct, Nanjing 210093, Jiangsu, Peoples R China.
    Robinson, Robert C.
    ASTAR, Inst Mol & Cell Biol, Singapore 138673, Singapore;Vidyasirimedhi Inst Sci & Technol, Sch Biomol Sci & Engn, Rayong 21210, Thailand;Okayama Univ, Res Inst Interdisciplinary Sci, Okayama 7008530, Japan.
    The role of gelsolin domain 3 in familial amyloidosis (Finnish type)2019Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, nr 28, s. 13958-13963Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In the disease familial amyloidosis, Finnish type (FAF), also known as AGeI amyloidosis (AGeI), the mechanism by which point mutations in the calcium-regulated actin-severing protein gelsolin lead to furin cleavage is not understood in the intact protein. Here, we provide a structural and biochemical characterization of the FAF variants. X-ray crystallography structures of the FAF mutant gelsolins demonstrate that the mutations do not significantly disrupt the calcium-free conformations of gelsolin. Small-angle X-ray-scattering (SAXS) studies indicate that the FAF calcium-binding site mutants are slower to activate, whereas G167R is as efficient as the wild type. Actin-regulating studies of the gelsolins at the furin cleavage pH (6.5) show that the mutant gelsolins are functional, suggesting that they also adopt relatively normal active conformations. Deletion of gelsolin domains leads to sensitization to furin cleavage, and nanobody-binding protects against furin cleavage. These data indicate instability in the second domain of gelsolin (G2), since loss or gain of G2-stabilizing interactions impacts the efficiency of cleavage by furin. To demonstrate this principle, we engineered non-FAF mutations in G3 that disrupt the G2-G3 interface in the calcium-activated structure. These mutants led to increased furin cleavage. We carried out molecular dynamics (MD) simulations on the FAF and non-FAF mutant G2-G3 fragments of gelsolin. All mutants showed an increase in the distance between the center of masses of the 2 domains (G2 and G3). Since G3 covers the furin cleavage site on G2 in calcium-activated gelsolin, this suggests that destabilization of this interface is a critical step in cleavage.

  • 3722.
    Zsigmond, Peter
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neurovetenskap. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Neurokirurgiska kliniken US.
    Nord, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neurovetenskap. Linköpings universitet, Hälsouniversitetet.
    Kullman, Anita
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
    Diczfalusy, Elin
    Linköpings universitet, Institutionen för medicinsk teknik, Biomedicinsk instrumentteknik. Linköpings universitet, Tekniska högskolan.
    Wårdell, Karin
    Linköpings universitet, Institutionen för medicinsk teknik. Linköpings universitet, Tekniska högskolan. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Dizdar (Dizdar Segrell), Nil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neurovetenskap. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Närsjukvården i centrala Östergötland, Neurologiska kliniken.
    Neurotransmitter levels in basal ganglia during levodopa and deep brain stimulation treatment in Parkinson’s disease2014Inngår i: Neurology and Clinical Neuroscience, ISSN 2049-4173, Vol. 2, nr 5, s. 149-155Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background The mechanism by which deep brain stimulation of the nucleus subthalamicus improves Parkinson’s disease symptoms remains unclear. In a previous perioperative study, we showed that there might be alterations of neurotransmitter levels in the globus pallidum interna during deep brain stimulation of the nucleus subthalamicus. Aim In this study, we examined whether deep brain stimulation of the nucleus subthalamicus and levodopa infusion interact and affect the levels of neurotransmitters. Methods Five patients with advanced Parkinson’s disease took part in the study. During subthalamic nucleus surgery, microdialysis catheters were inserted bilaterally in the globus pallidum interna and unilaterally in the right putamen. A study protocol was set up and was followed for 3 days. Levodopa infusion with and without concomitant bilateral deep brain stimulation of the nucleus subthalamicus was also carried out. Results The putaminal dopamine levels increased during deep brain stimulation of the nucleus subthalamicus. In addition, an increase of gamma amino buturic acid concentrations in the globus pallidum interna during deep brain stimulation of the nucleus subthalamicus and during levodopa infusion was found. Conclusions These findings provide evidence that the subthalamic nucleus has a direct action on the substantia nigra pars compacta, and that deep brain stimulation of the nucleus subthalamicus might indirectly release putaminal dopamine. There is also evidence that deep brain stimulation of the nucleus subthalamicus interferes with levodopa therapy resulting in higher levels of levodopa in the brain, explaining why it is possible to decrease levodopa medication after deep brain stimulation surgery.

  • 3723.
    Zsuzsanna Balla, Hajnal
    et al.
    Department of Neurology Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Theodorsson, Elvar
    Department of Clinical Chemistry and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Ström, Jakob O.
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Neurology Faculty of Medicine and Health, Örebro University, Örebro, Sweden; Department of Clinical Chemistry and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Evaluation of commercial, wireless dermal thermometers for surrogate measurements of core temperature2019Inngår i: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Extensive research has been devoted to developing methods for assessing core body temperature, and to determine which method is most accurate. A number of wireless dermal thermometers for home use are presently available, but their relation to core body temperature and suitability for use in clinical research has hitherto not been assessed. The current study aimed to evaluate such thermometers by comparing them to the results of a rectal thermometer. Four wireless dermal thermometers for home use (FeverSmart, iThermonitor, Quest Temp Sitter, and Thermochron iButton) were applied to 15 patients during 24 h, and rectal temperature was measured at four occasions. Pearson correlation revealed moderate correlation for the Feversmart (r = 0.75), iThermonitor (r = 0.79), and Thermochron iButton (r = 0.71) systems. The Quest Temp Sitter system malfunctioned repeatedly, and the correlation (r = 0.29) for this method should therefore be assessed with caution. All dermal thermometers rendered lower average temperatures than Terumo c405 (Feversmart -0.70 ± 0.65 °C; iThermonitor -0.77 ± 0.53 °C, Quest Temp Sitter -1.18 ± 0.66 °C, and Thermochron iButton -0.87 ± 0.65 °C). Sensitivity of the dermal thermometers for detecting core temperatures ≥38.0 °C was low, ranging from 0.33 to 0.6, but improved to 0.60 to 0.80 after adjusting temperatures by the methods' average deviation from rectal temperature. The results from the dermal thermometers tested here showed an insufficient correlation to core temperature to be used for core temperature monitoring in clinical research and practice. Unfortunately, other options for non-invasive temperature measurements are few. The two thermometers with the least unsatisfactory performance profile in our evaluations were the Feversmart and iThermonitor systems.

  • 3724. Zuccarello, Guido
    et al.
    Bouzide, Abderrahim
    Kvarnstrom, Ingemar
    Niklasson, Gunilla
    Svensson, Stefan C. T.
    Brisander, Magnus
    Danielson, Helena
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Nillroth, Ulrika
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Karlen, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Hallberg, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Classon, Björn
    Samuelsson, Bertil
    HIV-1 protease inhibitors based on acyclic carbohydrates1998Inngår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 63, nr 15, s. 4898-4906Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A series of acyclic C2-symmetric HIV protease inhibitors readily accessible from D-mannitol have been developed. Several of the compounds synthesized showed significant in vitro activity against HIV-1 protease.

  • 3725.
    Zulj, Jelena
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Verifiering av metod för analys av tumörmarkörerna CA 125, CA 15-3 och CA 19-9 på Roche Cobas e4112014Independent thesis Basic level (degree of Bachelor), 10 poäng / 15 hpOppgave
    Abstract [sv]

    Tumörmarkörer är substanser som frisätts i kroppsvätskor från cancerceller. Markörerna används inom sjukvården för att upptäcka och följa upp maligna sjukdomar med analyser av markörerna i serum/plasma. Tre av dessa är cancerantigenerna CA 125, CA 15-3 och CA 19-9. Syftet med studien var att verifiera analysmetoden för tumörmarkörerna CA 125, CA 15-3 och CA 19-9 på två Roche Cobas e411 instrument (instrument 1 och 2) inför införandet av dessa vid avdelningen för klinisk kemi och transfusionsmedicin, Lnadstinget Kalmar län. De av företaget rekommenderade cut-off värdena på Roche Cobas e411 (Roche Diagnostics) är för CA 125 <35 kU/l, för CA 15-3 ≤25 kU/l och för CA 19-9 <27 kU/l. Precisionen beräknades med hjälp av statistiska metoder genom analys av den mellanliggande precisionen (mätning av två kontrollnivåer under 5 dagar) och repeterbarheten (analys av två kontrollnivåer i en serie). En korrelationsstudie gjordes med patientprover som erhölls från Aleris Medilab (Abbot Architect i System). Den mellanliggande precisionenn resulterade i högre variationskoefficientvärden (CV %) för samtliga tre markörer i förhållande till ett åsatt CV från Roche Diagnostics. CV värdet skilde även mellan de två Roche Cobas e411 instrumenten. Repeterbarheten bedömdes vara acceptabel för samtliga tre markörer. Korrelationsstudien visade en skillnad i de uppmätta värdena mellan Roche Cobas e411 och Abbot Architect för samtliga tre markörer. Då Roche Cobas e411 tenderade att ge högre uppmätta värden (kU/l) (54 av 85 gånger). Samstämmigheten mellan metoderna var bra då det endast var två prover vid analys av CA 15-3 och två prover vid analys av CA 19-9 som var på skilda sidor om cut-off värdet. Sammanfattningsvis visade studien att den mellanliggande precisisonen (CV-värdet) för alla tre markörerna var högre än Roche Diagnostics angivna CV värde. Olika CV värden erhölls med Roche Cobas e411 jämfört med Abbot Architect. Olika CV värden erhölls också med instrument 1 jämfört med instrument 2. Precisionen anses vara tillräckligt god för införandet av metoderna i rutinbruk.

  • 3726.
    Zuo, Shusheng
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för naturvetenskaplig biokemi.
    Hellman, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Lundahl, Per
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för naturvetenskaplig biokemi.
    On the oligomeric state of the red blood cell glucose transporter GLUT12003Inngår i: Biochimica et Biophysica Acta - Biomembranes, ISSN 0005-2736, E-ISSN 1879-2642, Vol. 1618, nr 1, s. 8-16Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We stripped human red blood cell membranes of cytoskeleton proteins at pH 12 without reductant, partially solubilized the obtained vesicles by use of octaethylene glycol n-dodecyl ether and purified the glucose transporter GLUT1 by anion-exchange chromatography followed by sulfhydryl-affinity chromatography, which removed most of the nucleoside transporter (NT) and the lipids. Eighty percent of the sulfhydryl-bound GLUT1 could be eluted with sodium dodecyl sulfate (SDS) indicating that the bound protein was multimeric. Matrix-assisted laser desorption ionization-time of flight-mass spectrometry (MALDI-ToF-MS) of the trypsinized major SDS-PAGE zone of the purified material identified GLUT1 but no other membrane protein. Transmembrane helices 1 and 8 were among the detected fragments. The reconstituted purified GLUT1 showed glucose transport activity, although only approximately 0.05 high-affinity cytochalasin B (CB) binding sites were present per GLUT1 monomer. The vesicles used as starting material for the purification showed 0.4 CB sites per GLUT1 monomer, similar to vesicles prepared in the presence of dithioerythritol. The data are consistent with the coexistence of monomeric GLUT1 with high-affinity CB-binding activity and preferentially solubilized multimeric GLUT1 with no CB-binding activity in the red blood cell membrane vesicles prepared without reductant.

  • 3727. Zuse, Anne
    et al.
    Prinz, Helge
    Mueller, Klaus
    Prehn, Jochen
    Los, Marek Jan
    BioApplications Enterprises, Winnipeg, MB, Canada; Manitoba Institute of Cell Biology, Cancer Care Manitoba; Manitoba Institute of Child Health; Department of Biochemistry and Medical Genetics; Department of Human Anatomy and Cell Science, University Manitoba, Winnipeg, Canada, .
    Design of novel small molecule inhibitors of tubulin polymerization with high apoptosis-inclucing activity2007Inngår i: Molecular Cancer Therapeutics, ISSN 1535-7163, E-ISSN 1538-8514, Vol. 6, nr 12, s. 3421S-3421SArtikkel i tidsskrift (Fagfellevurdert)
  • 3728.
    Zygmuntowicz, Marcelina
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Biomedicinsk laboratorievetenskap. Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Optimering vid detektion av anti-superoxiddismutas 1 (SOD1) med immunohistokemi: I transgena möss med användning av olika vävnadsförbehandlingsmetoder2016Independent thesis Basic level (professional degree), 10 poäng / 15 hpOppgave
  • 3729.
    Åberg, Gabriel
    Linköpings universitet, Institutionen för fysik, kemi och biologi. Linköpings universitet, Tekniska högskolan.
    Intrinsically Functionalized Silk (Bombyx Mori)2013Independent thesis Advanced level (degree of Master (Two Years)), 20 poäng / 30 hpOppgave
    Abstract [en]

    The goal of the thesis is to incorporate materials with either fluorescent or conductive properties in silk fibers, by feeding silkworms with a diet containing these materials. To achieve this, one would have to breed (rear) silkworm from eggs into larvaes, then to feed the silkworms with this special diet containing fluorescent or conductive materials. Samples of silk were then collected either from spun cocoons or via removing the silk producing organs (silk glands) from the silkworms via dissection. The samples were then analyzed with absorbance spectrometer, spectrofluorometer or via photoluminesecent measurement to determine if any materials had been incorporated into the silk fibers.   Silkworms were successfully reared from eggs up to moths, once the silkworm larvae had grown enough in size their diet were switches from their regular food (silkworm chow) to food containing conjugated molecules or polymers with fluorescent or conductive properties. A total of 14 materials were tested. One material gave a clear positive result and that was from the fluorescent compound Rhodamine B. Other fluorescent materials, Nile red and POWT yielded some results indicating their presence in the silk but the results were not conclusive. The rest of the materials all failed with being incorporated within the silk fibers; this was due to their lethality, size, lack of zwitterionic properties and such.  The properties of the materials are of great importance for the uptake process, where a small zwitterionic molecule has a great change of being taken up and incorporated in the silk fibers. Whereas a big materials such as a polymer without any zwitterionic will in most cases just follow through the food in the digestive track without any uptake. 

  • 3730.
    Åberg, Jonas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Premixed Acidic Calcium Phosphate Cements2012Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Calcium phosphate cements are used in medicine to fill bone defects or give support to screws and plates in fracture fixation. The cements are formed via mixing a powder with water and the mixture harden through a dissolution-precipitation reaction. Today the cement mixing is performed in the operating room and consists of several complicated steps that need to be performed under sterile conditions. This renders the mixing a risk factor, potentially leading to harm for the patient e.g. unsatisfactory healing or infection. To reduce this risk, premixed cements have been developed using glycerol as mixing liquid. The premixed cement sets when it is exposed to body liquids. Therefore, premixed cement can be delivered to the operating room in prefilled syringes ready for use, thus eliminating the mixing step.

    The aim of this thesis is to describe differences between premixed and water-mixed cements and their advantages and drawbacks. The differences will be discussed based on results obtained from bench testing of specific cement properties as function of cement formulations as well as in vitro and in vivo studies.

    Several cement formulations were evaluated e.g. the influence of powder to liquid ratio (P/L), powder particle size and addition of water on key properties. The results showed that premixed cements have excellent handling properties and have mechanical properties similar to water-based cements. Both P/L and particle size can be used to control these properties. It was shown that small amounts of water improve certain cement properties while dry raw materials were important for long shelf life. To better understand the setting of premixed cements new methods for evaluating working time and setting of premixed cements were developed. In vivo studies showed that the formulations developed in this thesis are biocompatible, resorbable and show good tissue response in bone.

    This thesis concludes, that the premixed cements are a promising biomaterial with excellent handling properties and good biological response. The most important challenge for the premixed cements, in order to become commercially successful, is to obtain clinically relevant setting time and shelf life simultaneously. An increasing use of premixed cements in the clinics should shorten operation times and reduce infection rates to the benefit of both patients and medical staff.

  • 3731.
    Åberg, Jonas
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Engstrand, Johanna
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Engqvist, Håkan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Influence of particle size on hardening and handling of a premixed calcium phosphate cement2013Inngår i: Journal of materials science. Materials in medicine, ISSN 0957-4530, E-ISSN 1573-4838, Vol. 24, nr 4, s. 829-835Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Premixed calcium phosphate cements (pCPC) have been developed to circumvent problems related to mixing and transfer of cements in the operating room. In addition, by using pCPC the short working times generally associated with conventional water-mixed cements are avoided. In this work, the influence of particle size on handlingand hardening characteristics of a premixed monetite cement has been assessed. The cements were evaluated with respect to their injectability, setting time and compressive strength. It was found that cements with smaller particle sizes were more difficult to inject and had higher compressive strength. Regarding setting time, no clear trend could be discerned. The addition of granules made the cements easier to inject, but setting time was prolonged and lower strengths were obtained. The main findings of this work demonstrate that particle size can be used to control handling and physical properties ofpremixed cements and that previous knowledge from water-based CPC, regarding effects of particle size, is not directly applicable to premixed CPC.

  • 3732.
    Åberg, Jonas
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Engstrand Unosson, Johanna
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Engqvist, Håkan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Setting mechanisms of an acidic premixed calcium phosphate cement2013Inngår i: Bioceramics Development and Applications, ISSN 2090-5017, E-ISSN 2090-5025, Vol. 3, nr 1, s. 1000070-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Premixed calcium phosphate cements (pCPC), where glycerol is used instead of water as mixing liquid, present better handling characteristics than water-based cements. However, the setting mechanisms of pCPC have not been described thoroughly. The aim of this paper is to increase the understanding of the setting mechanism of pCPC. The investigated cement starts to set when glycerol is exchanged with water via diffusion of glycerol out to the surrounding body fluid and water into the material. To better understand the water-glycerol exchange a method was developed where the setting depth of the cement was measured over time. Thermo gravimetric analysis (TGA) was used to determine the liquid exchange rate during setting. To study the influence of temperature on the crystalline end product, pCPC and water-mixed calcium phosphate cement (wCPC) were set at different temperatures and analyzed with X-ray diffraction (XRD). The setting depth measurements showed that the set layer of the pCPC grew with a speed proportional to t0.51 at 37°C. TGA results furthermore showed that less than 10% of the glycerol remained after 16 hours. Setting of pCPC at different temperatures showed that mainly brushite was formed at 5°C, a mixture of brushite and monetite at 21°C and mainly monetite at 37°C. It furthermore showed that brushite was the main phase after setting of wCPC, but some monetite was present in these cements. The study presents a new method for evaluation of pCPC that increases the understanding of their setting mechanism. Furthermore, the XRD results indicate that storage at 5°C could improve the shelf life of acidic pCPC.

  • 3733.
    Åberg, Jonas
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Henriksson, Helena B
    Dept of Clinical Chemistry and Transfusion Medicine, och Dept of Biomaterials, Sahlgrenska Academy at University of Gothenburg, Göteborg.
    Engqvist, Håkan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Palmquist, Anders
    Dept of Orthopedics, Sahlgrenska University Hospital, Gothenburg University, Göteborg.
    Brantsing, Camilla
    Dept of Clinical Chemistry and Transfusion Medicine, Sahlgrenska Academy at University of Gothenburg, Göteborg.
    Lindahl, Anders
    Dept of Clinical Chemistry and Transfusion Medicine, Sahlgrenska Academy at University of Gothenburg, Göteborg.
    Thomsen, Peter
    Dept of Orthopedics, Sahlgrenska University Hospital, Gothenburg University, Göteborg.
    Brisby, Helena
    Dept. of Biomaterials, Sahlgrenska Academy at University of Gothenburg , Göteborg.
    Biocompatibility and resorption of a radiopaque premixed calcium phosphate cement2012Inngår i: Journal of Biomedical Materials Research. Part A, ISSN 1549-3296, E-ISSN 1552-4965, Vol. 100A, nr 5, s. 1269-1278Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Calcium phosphate cements (CPC) are used as bone void filler in various orthopedic indications; however, there are some major drawbacks regarding mixing, transfer, and injection of traditional CPC. By using glycerol as mixing liquid, a premixed calcium phosphate cement (pCPC), some of these difficulties can be overcome. In the treatment of vertebral fractures the handling characteristics need to be excellent including a high radio-opacity for optimal control during injection. The aim of this study is to evaluate a radiopaque pCPC regarding its resorption behavior and biocompatibility in vivo. pCPC and a water-based CPC were injected into a circle divide 4-mm drilled femur defect in rabbits. The rabbits were sacrificed after 2 and 12 weeks. Cross sections of the defects were evaluated using histology, electron microscopy, and immunohistochemical analysis. Signs of inflammation were evaluated both locally and systemically. The results showed a higher bone formation in the pCPC compared to the water-based CPC after 2 weeks by expression of RUNX-2. After 12 weeks most of the cement had been resorbed in both groups. Both materials were considered to have a high biocompatibility since no marked immunological response was induced and extensive bone ingrowth was observed. The conclusion from the study was that pCPC with ZrO2 radiopacifier is a promising alternative regarding bone replacement material and may be suggested for treatment of, for example, vertebral fractures based on its high biocompatibility, fast bone ingrowth, and good handling properties.

  • 3734.
    Ådemo, Ida
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Biomedicinsk laboratorievetenskap.
    Tid- och temperaturoptimering av lipoproteinlipas-aktivitet: -   en studie på Soleus och Vastus lateralis hos möss2012Independent thesis Basic level (degree of Bachelor), 10 poäng / 15 hpOppgave
  • 3735.
    Ådén, Jörgen
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    NMR studies of protein dynamics and structure2010Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Enzymes are extraordinary molecules that can accelerate chemical reactions by several orders of magnitude. With recent advancements in structural biology together with classical enzymology the mechanism of many enzymes has become understood at the molecular level. During the last ten years significant efforts have been invested to understand the structure and dynamics of the actual catalyst (i. e. the enzyme). There has been a tremendous development in NMR spectroscopy (both hardware and pulse programs) that have enabled detailed studies of protein dynamics. In many cases there exists a strong coupling between enzyme dynamics and function. Here I have studied the conformational dynamics and thermodynamics of three model systems: adenylate kinase (Adk), Peroxiredoxin Q (PrxQ) and the structural protein S16. By developing a novel chemical shift-based method we show that Adk binds its two substrates AMP and ATP with an extraordinarily dynamic mechanism. For both substrate-saturated states the nucleotide-binding subdomains exchange between open and closed states, with the populations of these states being approximately equal. This finding contrasts with the traditional view of enzyme-substrate complexes as static low entropy states. We are also able to show that the individual subdomains in Adk fold and unfold in a non-cooperative manner. This finding is relevant from a functional perspective, since it allows a change in hydrogen bonding pattern upon substrate-binding without provoking global unfolding of the entire enzyme (as would be expected from a two-state folding mechanism). We also studied the structure and dynamics of the plant enzyme PrxQ in both reduced and oxidized states. Experimentally validated structural models were generated for both oxidation states. The reduced state displays unprecedented μs-ms conformational dynamics and we propose that this dynamics reflects local and functional unfolding of an α-helix in the active site. Finally, we solved the structure of S16 from Aquifex aeolicus and propose a model suggesting a link between thermostability and structure for a mesophilic and hyperthermophilic protein pair. A connection between the increased thermostability in the thermophilic S16 and residual structure in its unfolded state was discovered, persistent at high denaturant concentrations, thereby affecting the difference in heat capacity difference between the folded and unfolded state. In summary, we have contributed to the understanding of protein dynamics and to the coupling between dynamics and catalytic activity in enzymes.

  • 3736.
    Ådén, Jörgen
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Wallgren, Marcus
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Storm, Patrik
    Weise, Christoph
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Christiansen, Alexander
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Schröder, Wolfgang
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Funk, Christiane
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Wolf-Watz, Magnus
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Arabidopsis thaliana peroxiredoxin Q is extraordinarily dynamic on the μs-ms timescaleManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Peroxiredoxin Q (PrxQ) isolated from Arabidopsis thaliana belongs to a family of redox enzymes called peroxiredoxins, which are thioredoxin- or glutaredoxin dependent peroxidases acting to reduce peroxides and in particular hydrogen peroxide. PrxQ cycles between an active reduced state and an inactive oxidized state during its catalytic cycle. The catalytic mechanism involves a nucleophilic attack of the catalytic cysteine on hydrogen peroxide to generate a sulfonic acid intermediate with a concerted release of a water molecule. This intermediate is subsequently relaxed by the reaction of a second cysteine, denoted as the resolving cysteine, generating an intermolecular disulphide bond to expel a second water molecule into solution. PrxQ is finally recycled to the active state by a thioredoxin dependent reduction. Previous structural studies of PrxQ homologues have provided the structural basis for the switch between reduced and oxidized conformations. Here we have performed a detailed study of the structure and dynamics of PrxQ in both the oxidized and reduced state. Reliable and experimentally validated structural models of PrxQ in both oxidation states were generated using homology based modeling. Model-free analyses of NMR spin relaxation show that PrxQ is monomeric in both oxidation states. As evident from fast R2 relaxation rates the reduced form of PrxQ undergoes unprecedented dynamics on the slow μs-ms timescale. The ground state of the conformational dynamics is likely the stably folded reduced state as implied by circular dichroism spectroscopy. We speculate that the extensive dynamics is intimately related to the catalytic function of PrxQ.

  • 3737.
    Åhlén, Karina
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Collagen-binding integrin α2β1 activity in vivo and in vitro: Effects of platelet-derived growth factor-BB1998Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The expression of integrins by two cell clones from a rat colon carcinoma was investigated. Cloned cells that gave rise to regressive tumors, but not cells that gave rise to progressive, lethal, tumors, adhered to interstitial collagens through the integrin α2β1, although both cell types expressed it. These data suggest that the apparent activity of α2β1 is important for tumorinvasiveness.

    Inhibition of the α2β1 integrin in rat paw skin lead to a lowering of the interstitial fluid pressure (PIF). an effect that could be overcome by platelet-derived growth factor-BB (PDGF-BB).

    PDGF-BB could stimulate the synthesis of the α2, but not α1, α3 or β1 integrin chains in human AG1518 fibroblasts.

    PDGF-BB also stimulated cell spreading and induced a rapid and transientrelocalization of α2β1 in AG1518 fibroblasts. The relocalization was dependent on phosphatidylinositol 3-kinase (PI3-K) and protein kinase C (PKC), and involved disassembly of focal adhesions as seen in interference reflection microscopy (IRM). The mobility of β1-integrins in the cell membrane was increased in cells stimulated with PDGF-BB.

    PDGF-BB-stimulated collagen gel contraction, as well as the induction of a rise in cytoplasmic free calcium [Ca2+]i were shown to depend on PI3-K. The experimental anti-inflamatory drug α-trinositol induced an increase in [Ca2+]i and could restore PI3-K-dependent chemotaxis towards PDGF-BB as well as the lowering of PIF induced bv inhibitors of PI3K.

    In conclusion: α2β1 is implicated in invasiveness of tumor cells in vivo, and in the maintenance of interstitial fluid pressure (PIF). PDGF-BB is shown to regulate PIF, to stimulate synthesis of the integrin α2 chain, and to modulate cytoskeletal interactions of α1- integrins. The maintenance of PIF, as well as PDGF-BB-stimulation of collagen gel contraction, induction of integrin reorganization from focal adhesions, and induction of a calcium response, was dependent on an activation of PI3-K. PI3-K is hypothesized to mediate these effects at least in part through induction of a rise in [Ca2+]i.

  • 3738. Åkesson, Matilda
    The relationship between abdominal-height, energy consumption and glucose metabolism in obese children and adolescents.2016Independent thesis Basic level (professional degree), 10 poäng / 15 hpOppgave
    Abstract [en]

    Diabetes type-2 and cardiovascular diseases are some of the consequences of obesity. Body Mass Index (BMI) is the most common tool for defining obesity, but measurement of the abdominal-height is something new that might work better for definition of obesity. In this study, the aim was to find out whether there was a relationship between abdominal-height, glucose metabolism and resting energy expenditure in obese children and adolescents. Furthermore, to investigate if the abdominal-height was a more appropriate tool for the definition of obesity than BMI.A retrospective study was made on 43 obese children and adolescents. Several measurements of their body composition was obtained. They had also made an oral glucose tolerance test, an indirect respiratory calorimetry, had their abdominal-height measured and made a Bodpod analysis. The patients were divided into two groups (Group 1 and 2) based on their abdominal-height, and from the same patients, two other groups were made based on their BMI (Group A and B). The patients in Group 1, with the higher abdominal-height than those in Group 2, also in average had a higher age, weight, height, BMI, fat mass and larger waist circumference and hip circumference. Their resting energy expenditure, i.e. RMR and respiratory quotient (RQ) were lower, and so were their fat-free mass. The waist/hip-ratio was very similar in the two groups. During the oral glucose tolerance test, Group 1 had a statistically significant higher number of patients with impaired glucose tolerance than Group 2. Similar differences could be seen between Group A and Group B, where Group A was comparable to Group 1 and Group B to Group 2. However, no statistically significance could be seen comparing the two groups on the impaired glucose tolerance test.

  • 3739.
    Ås, Joel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Active dose selection and dose-response modeling for quantitative high-throughput screening (qHTS)2016Independent thesis Advanced level (professional degree), 20 poäng / 30 hpOppgave
    Abstract [en]

    This master thesis studies the potential benefit of iterative selection of the concentrations

    evaluated when building mathematical dose-response curves (and response surfaces when

    there are two drugs) using experimental measurements. The reference alternative is to use

    a standard two-fold dilution series or ten-fold dilution series measured in replicates. The

    standard 4-parameter Hill dose-response model is used as a reference and for simulations.

    Models to screen for synergy between two different substances are also developed in this thesis.

  • 3740. Åsberg, Marie
    et al.
    Nygren, Åke
    Leopardi, Rosario
    Rylander, Gunnar
    Peterson, Ulla
    Karolinska Institutet.
    Wilczek, Lukas
    Källmén, Håkan
    Ekstedt, Mirjam
    Karolinska Institute.
    Åkerstedt, Torbjörn
    Lekander, Mats
    Ekman, Rolf
    Novel biochemical markers of psychosocial stress in women2009Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 4, nr 1, s. e3590-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Prolonged psychosocial stress is a condition assessed through self-reports. Here we aimed to identify biochemical markers for screening and early intervention in women.

    METHODS: Plasma concentrations of interleukin (IL) 1-alpha, IL1-beta, IL-2, IL-4, IL-6, IL-8, IL-10, interferon-gamma (INF-gamma), tumor necrosis factor-alpha (TNF-alpha), monocyte chemotactic protein-1 (MCP-1), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), thyroid stimulating hormone (TSH), total tri-iodothyronine (TT3), total thyroxine (TT4), prolactin, and testosterone were measured in: 195 women on long-term sick-leave for a stress-related affective disorder, 45 women at risk for professional burnout, and 84 healthy women.

    RESULTS: We found significantly increased levels of MCP-1, VEGF and EGF in women exposed to prolonged psychosocial stress. Statistical analysis indicates that they independently associate with a significant risk for being classified as ill.

    CONCLUSIONS: MCP-1, EGF, and VEGF are potential markers for screening and early intervention in women under prolonged psychosocial stress.

  • 3741.
    Åstrand, Anders
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för tillämpad fysik och elektronik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Centrum för medicinsk teknik och fysik (CMTF).
    Andersson, Britt M
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för tillämpad fysik och elektronik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Centrum för medicinsk teknik och fysik (CMTF).
    Jalkanen, Ville
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för tillämpad fysik och elektronik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Centrum för medicinsk teknik och fysik (CMTF).
    Ljungberg, Börje
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    The first study on whole human prostate ex vivo using a tactile resonance sensor for cancer detectionArtikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    Prostate cancer (PCa) is the most common form of cancer among males in Europe and the USA. A prostatectomy i.e. the removal of the prostate is the most common form of curative treatment. Prostate cancer can be suspected by a blood test for a prostate specific antigen (PSA) and a digital rectal examination (DRE) where a physician palpates the prostate through the rectum and where stiff nodules on the prostate is an indication for PCa. The final diagnosis of PCa is made by microscopic evaluation of ultrasound-guided biopsies taken from suspicious parts of the gland. After a prostatectomy the entire prostate is histopathologically analysed. One area of interest is the superficial part of the prostate gland as tumour growth on the surface suggests that the cancer has spread to other parts of the body.

     

    Tactile resonance sensors can be used to detect areas of different stiffness in soft tissue through a stiffness parameter. It is suggested that tactile resonance sensors can be used to detect prostate cancer since tumours in the human prostate usually is stiffer compared to surrounding healthy glandular tissue.

     

    The aim of the study was to detect tumours on, and beneath the surface, of whole human prostate glands ex vivo using a tactile resonance sensor system (TRSS). Model studies on spherical shaped tissue phantoms made of silicone and porcine tissue were performed to evaluate the ability of the TRSS to detect stiffer volumes at a distance beneath the surface. Finally two resected human prostate glands ex vivo from patients undergoing surgery for prostate cancer were studied.

     

    From the results it was concluded that the clamping force from the rotatable sample holder did not affect the magnitude of the stiffness parameter for the silicone samples. For the porcine muscle samples, the stiffness parameter showed to be affected by clamping forces larger than about 800 mN. The embedded stiff silicone nodules placed about 4 mm under the surface could be detected in both the silicone and biological tissue models with a sensor indentation distance of 0.6 mm. The measurements on resected whole human prostates showed that areas with elevated stiffness parameter values correlated (p < 0.05) with areas where cancer tumours were detected using histolopathological evaluation of the prostate. The tumours were significantly stiffer than the healthy tissue in the dorsal region. This is promising for the development of a clinically useful instrument to detect superficial prostate cancer.

  • 3742.
    Åstrand, Anders P
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för tillämpad fysik och elektronik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Centrum för medicinsk teknik och fysik (CMTF).
    Jalkanen, Ville
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för tillämpad fysik och elektronik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Centrum för medicinsk teknik och fysik (CMTF).
    Andersson, Britt M
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för tillämpad fysik och elektronik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Centrum för medicinsk teknik och fysik (CMTF).
    Lindahl, Olof A
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Centrum för medicinsk teknik och fysik (CMTF).
    Detection of stiff nodules embedded in soft tissue phantoms, mimicking cancer tumours, using a tactile resonance sensor2014Inngår i: Journal of Biomedical Science and Engineering, ISSN 1937-6871, E-ISSN 1937-688X, Vol. 7, s. 181-193Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background

    Prostate cancer (PCa) is the most common form of cancer among males in Europe and in the USA and the most common curative treatment is removal of the prostate, i.e. prostatectomy. After the removal, the prostate is histopathologically analysed. One area of interest is to examine the capsule of the prostate, as tumours on and near the surface can indicate that the PCa has spread to other parts of the body. There are no current methods to examine the surface of the prostate at the time of surgery. Tactile resonance sensors can be used for detecting areas of different stiffness in soft tissue. Human prostate tissue affected by cancer is usually stiffer than healthy tissue, and for this purpose a tactile resonance sensor was developed. The aim of this study was to investigate the depth at which embedded stiffer volumes could be detected, using soft tissue phantoms.

    Methods

    With the tactile resonance sensor used in this study, the shift of the resonance frequency and the force at contact with tissue can be measured, and combined into a tissue stiffness parameter. The detection sensitivity of the sensor at impression depths, 0.4 and 0.8 mm, was measured for detection of an inserted nodules of stiff silicone in softer silicone and in chicken muscle tissue, mimicking prostate tissue with cancer tumours.

    Results

    Measurements on the silicone samples detected the hidden stiffer object at a depth of 1-4 mm with a difference in the stiffness parameter of 80 – 900 mN/kHz (p < 0.028, n = 48). At the depth 5-6 mm the difference was smaller but still significant < 30 mN/kHz (p < 0.05, n = 24). For the measurements on chicken muscle, the detectable depth was 4 mm (p < 0.05, n = 24).

    Conclusion

    This model study suggests that, with only a small impression depth of ≤ 1 mm, the resonance sensor system described here can detect stiffness variations located at least 4 mm in silicone and chicken muscle, mimicking tumours in prostate tissue.

  • 3743.
    Åstrand, Bengt
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    ePrescribing: Studies in Pharmacoinformatics2007Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [sv]

    Det övergripande syftet med den här avhandlingen har varit att, inom området läkemedelsinformatik, studera utvecklingen av elektroniska stöd inom läkemedelsförskrivning; för klinisk praxis, uppföljning och forskning.

    Under århundraden har det handskrivna receptet varit det sätt, med vilket läkare förmedlat sina läkemedelsordinationer till apotekare, vilket också för patienten blivit en informationskälla för hur läkemedel ska användas för att göra bästa nytta. Nu genomgår receptet en förändring från pappersbaserat till elektroniskt meddelande och att anpassa en traditionell process till en ny elektronisk era innebär både möjligheter och utmaningar.

    Studierna som ingår i avhandlingen har visat att exponeringen av förskrivna läkemedel i en allmän befolkning har ökat under de senaste tre decennierna. Risken för potentiella interaktioner mellan läkemedel, varmed avses den risk som finns att olika läkemedel kan påverka varandras effekter och biverkningar, har också visat sig öka starkt desto fler läkemedel som används av en individ. Denna ökade samtidiga användning av flera olika läkemedel, så kallad polyfarmaci, medför att det finns en större anledning för förskrivare och farmacevter att uppmärksamma risken för potentiella interaktioner mellan läkemedel.

    De nyinrättade nationella receptregistren över uthämtad receptförskriven medicin bör användas bland annat för att upptäcka potentiella läkemedelsinteraktioner, såväl i vårdens utövning som inom läkemedelsepidemiologisk forskning. Den svenska läkemedelsförteckningen, som omfattar information om uthämtade receptförskrivna läkemedel för huvuddelen av den svenska befolkningen, bedöms ha en stor klinisk potential. Den enskilde individens historiska information om uthämtade läkemedel är tillgänglig för individen på Internet med hjälp av e-legitimation; även förskrivare och farmacevter på apotek kan ta del av informationen med den enskildes samtycke. Brist på tillgång till enhetliga och säkra autenticeringsmetoder inom hälso- och sjukvården kan dock fördröja tillgången på individuell läkemedelsinformation för förskrivare. I och med att de flesta recepten i Sverige nu skrivs och överförs elektroniskt är det viktigt att kvalitetsmässiga aspekter tas tillvara så att en iakttagen ökad risk för receptförskrivningsfel inte överförs i informationskedjan.

    Avhandlingens slutsats är att e-förskrivning, med kommunikation och användning av lagrad information om receptexpeditioner, möjliggör att läkemedelsbehandling som process kan följas och studeras på ett helt nytt

  • 3744.
    Åstrand, Bengt
    et al.
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Hovstadius, Bo
    Antonov, Karolina
    Petersson, Göran
    Högskolan i Kalmar, eHälsoinstitutet, Högskolan i Kalmar.
    The Swedish National Pharmacy Register2007Inngår i: MEDINFO 2007: Proceedings of the 12th World Congress on Health (Medical) Informatics – Building Sustainable Health Systems, 2007, Vol. 12, nr 1, s. 345-349Konferansepaper (Fagfellevurdert)
  • 3745.
    Åstrand, Bengt
    et al.
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Montelius, Emelie
    Högskolan i Kalmar, Humanvetenskapliga institutionen.
    Petersson, Göran
    Högskolan i Kalmar, Humanvetenskapliga institutionen. Högskolan i Kalmar, eHälsoinstitutet, Högskolan i Kalmar.
    Ekedahl, Anders
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Assessment of ePrescription quality: an observational study at three mail-order pharmacies2009Inngår i: BMC Medical Informatics and Decision Making, ISSN 1472-6947, E-ISSN 1472-6947, Vol. 9, nr 1, s. Article number: 8-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: The introduction of electronic transfer of prescriptions (ETP) or ePrescriptions in ambulatory health care has been suggested to have a positive impact on the prescribing and dispensing processes. Thereby, implying that ePrescribing can improve safety, quality, efficiency, and cost-effectiveness. In December 2007, 68% of all new prescriptions were transferred electronically in Sweden. The aim of the present study was to assess the quality of ePrescriptions by comparing the proportions of ePrescriptions and non-electronic prescriptions necessitating a clarification contact (correction, completion or change) with the prescriber at the time of dispensing.

    Methods: A direct observational study was performed at three Swedish mail-order pharmacies which were known to dispense a large proportion of ePrescriptions (38–75%). Data were gathered on all ePrescriptions dispensed at these pharmacies over a three week period in February 2006. All clarification contacts with prescribers were included in the study and were classified and assessed in comparison with all drug prescriptions dispensed at the same pharmacies over the specified period.

    Results: Of the 31225 prescriptions dispensed during the study period, clarification contacts were made for 2.0% (147/7532) of new ePrescriptions and 1.2% (79/6833) of new non-electronic prescriptions. This represented a relative risk (RR) of 1.7 (95% CI 1.3–2.2) for new ePrescriptions compared to new non-electronic prescriptions. The increased RR was mainly due to 'Dosage and directions for use', which had an RR of 7.6 (95% CI 2.8–20.4) when compared to other clarification contacts. In all, 89.5% of the suggested pharmacist interventions were accepted by the prescriber, 77.7% (192/247) as suggested and an additional 11.7% (29/247) after a modification during contact with the prescriber.

    Conclusion: The increased proportion of prescriptions necessitating a clarification contact for new ePrescriptions compared to new non-electronic prescriptions indicates the need for an increased focus on quality aspects in ePrescribing deployment. ETP technology should be developed towards a two-way communication between the prescriber and the pharmacist with automated checks of missing, inaccurate, or ambiguous information. This would enhance safety and quality for the patient and also improve efficiency and cost-effectiveness within the health care system.

  • 3746.
    Åstrand, Bengt
    et al.
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Åstrand, Emelie
    Uppsala universitet.
    Antonov, Karolina
    Apoteket AB, Stockholm.
    Petersson, Göran
    Högskolan i Kalmar, Humanvetenskapliga institutionen. Högskolan i Kalmar, eHälsoinstitutet, Högskolan i Kalmar.
    Detection of potential drug interactions: a model for a national pharmacy register2006Inngår i: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 62, nr 9, s. 749-756Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective  The widespread use of pharmaceuticals prescribed by different physicians has caused the Swedish government to propose a new legislation with registration of all prescriptions dispensed at the Swedish pharmacies. In the present study, we wanted to examine the frequency, distribution and determinants of potential drug interactions.Methods  The prescriptions from all individuals (n=8,214) with two or more prescriptions during October 2003 to December 2004 were collected from the ongoing Jämtland cohort study of a total of about 11,000 individuals. Potential drug–drug interactions were detected with a computerized interaction detection system and classified according to clinical relevance (types A–D).Results  On average each individual filled 14.6 (men 14.3, women 14.8) prescriptions during the study period. 3.6% of the individuals used more than 15 different drugs. The number of detected potential drug interactions type A–D was 4,941 (men 1,949, women 2,992). The risk of receiving a potential interaction type A–D was estimated as the cumulative incidence 0.26 (2,116/8,214) overall, 0.22 (748/3,467) for men and 0.29 (1,368/4,747) for women during the 15-month study period. The age adjusted risk, RRadj, for women was estimated as 1.30. Excluding sex hormones and modulators of the genital system, the RRadj was 0.96, with no elevated risk for women. For potential interactions type D, that might have serious clinical consequences, 167 (cumulative incidence 0.0203) individuals (72 men, cumulative incidence 0.0208, 95 women cumulative incidence 0.0200) were detected. The risk of receiving a combination of potentially interacting drugs was positively correlated to age and polypharmacy. The cumulative incidence for elderly was estimated as 0.36 (65–84 years) and 0.39 (85 years and above). The relative risk for individuals with 15 drugs or more was estimated as 3.67 (95% CI 3.46–3.90).Conclusion  In a general population there were relatively few severe potential drug interactions. The new Swedish national pharmacy register will provide health care professionals with a powerful tool to systematically review all prescriptions. An alert system should focus on the more potential drug interactions, type C–D, with close monitoring of elderly and patients with polypharmacy.

  • 3747.
    Åstrand, Emelie
    et al.
    Högskolan i Kalmar.
    Åstrand, Bengt
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Antonov, Karolina
    The Association of Pharmaceutical Industry, Stockholm.
    Petersson, Göran
    Högskolan i Kalmar, Humanvetenskapliga institutionen. Högskolan i Kalmar, eHälsoinstitutet, Högskolan i Kalmar.
    Erratum: Potential drug interactions during a three-decade study2007Inngår i: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 63, nr 11, s. 1095-Artikkel i tidsskrift (Fagfellevurdert)
  • 3748.
    Åstrand, Emelie
    et al.
    Högskolan i Kalmar, Naturvetenskapliga institutionen. Högskolan i Kalmar, eHälsoinstitutet, Högskolan i Kalmar.
    Åstrand, Bengt
    Högskolan i Kalmar, Naturvetenskapliga institutionen. Apoteket AB.
    Antonov, Karolina
    The Association of Pharmaceutical IndustryStockholm.
    Petersson, Göran
    Högskolan i Kalmar, Humanvetenskapliga institutionen. Högskolan i Kalmar, eHälsoinstitutet, Högskolan i Kalmar.
    Potential drug interactions during a three-decade study period: a cross-sectional study of a prescription register2007Inngår i: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 63, nr 9, s. 851-859Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objectives  The increased risk of adverse events in patients receiving potentially interacting drugs has long been recognized. The purpose of the present study was to evaluate the change in the risk of receiving potentially interacting drugs during a period covering three decades and to examine the relative risk of actual drug combinations. Methods  The prescriptions from all individuals (about 8,000) with two or more prescriptions during three periods of 15 months, October to December 1983–1984, 1993–1994 and 2003–2004, were collected from an ongoing cohort study in the county of Jämtland, Sweden. The potential interactions were detected by a computerized system. Results  The relative risk (RR) of receiving potentially interacting drugs increased for type C interactions [RR: 1.177, 95% confidence interval (CI): 1.104–1.256] and decreased for type D interactions (RR: 0.714, 95% CI: 0.587–0.868) from the period 1983–1984 to 2003–2004. Polypharmacy for the participants increased by 61%, from 9.05 filled prescriptions per subject in 1983–1984 to 10.6 in 1993–1994 and 14.6 in 2003–2004. The RR was positively correlated to the pronounced increase in polypharmacy; in addition, an exponential relationship was found for the more severe type D interactions. Few interacting drug combinations were responsible for a large proportion of the risk. Conclusion  We conclude that the risk of receiving potentially interacting drugs was strongly correlated to the concomitant use of multiple drugs. The pronounced increase in polypharmacy over time implies a growing reason for prescribers and pharmacists to be aware of drug interactions. Recently established national prescription registers should be evaluated for drug interaction vigilance, both clinically and epidemiologically.

  • 3749.
    Åstrand, Mikael
    KTH, Skolan för bioteknologi (BIO), Proteinteknologi.
    Engineering strategies for ABD-derived affinity proteins for therapeutic and diagnostic applications2016Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Small stable protein domains are attractive scaffolds for engineering affinity proteins due to their high tolerance to mutagenesis without loosing structural integrity. The albuminbinding domain is a 5 kDa three-helix bundle derived from the bacterial receptor Protein G with low-nanomolar affinity to albumin. In this thesis, the albumin-binding domain is explored as a scaffold for engineering novel affinity proteins with the possible benefit of combining a prolonged serum half-life with specific targeting in a single small scaffold protein. Previously, a library was created by randomizing surface-exposed residues in order to engineer affinity to a new target antigen in addition to the inherent albumin affinity. Here, phage display selections were separately performed against the tumor antigens ERBB2 and ERBB3. The ERBB3 selection resulted in a panel of candidates that were found to have varying affinities to ERBB3 in the nanomolar range, while still retaining a high affinity to albumin. Further characterization concluded that the clones also competed for binding to ERBB3 with the natural activating ligand Heregulin. The selections against ERBB2 resulted in sub-nanomolar affinities to ERBB2 where the binding site was found to overlap with the antibody Trastuzumab. The binding sites on ABD to albumin and either target were found in both selections to be mutually exclusive, as increased concentrations of albumin reduced the level of binding to ERBB2 or ERBB3. An affinity-matured ERBB2 binder, denoted ADAPT6, which lacked affinity to albumin was evaluated as a radionuclide-labeled imaging tracer for diagnosing ERBB2-positive tumors. Biodistribution studies in mice showed a high renal uptake consistent with affinity proteins in the same size range and the injected ADAPT quickly localized to the implanted tumor. High contrast images could be generated and ERBB2-expressing tissue could be distinguished from normal tissue with high contrast, demonstrating the feasibility of the scaffold for use as diagnostic tool. In a fourth study, affinity maturation strategies using staphylococcal cell-surface display were evaluated by comparing two replicate selections and varying the stringency. A sub-nanomolar target concentration was concluded to be inappropriate for equilibrium selection as the resulting output was highly variable between replicates. In contrast, equilibrium sorting at higher concentrations followed by kinetic-focused off-rate selection resulted in high output overlap between attempts and a clear correlation between affinity and enrichment.

  • 3750.
    Åström, Jeanette
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Biomedicinsk laboratorievetenskap. Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Att särskilja en stickblödning från subaraknoidal blödning vid likvoranalys: Ett underlag för en korrektionsformel som kan kompensera för bilirubinökning i likvor till följd av en stickblödning2019Independent thesis Basic level (professional degree), 10 poäng / 15 hpOppgave
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