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  • 4351.
    Ahlgren, Sara
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Reijmar, Karin
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Edwards, Katarina
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Targeting lipodisks enable selective delivery of anticancer peptides to tumor cells2017In: Nanomedicine: Nanotechnology, Biology and Medicine, ISSN 1549-9634, E-ISSN 1549-9642, Vol. 13, no 7, p. 2325-2328Article in journal (Refereed)
    Abstract [en]

    Issues concerning non-specificity, degradation and hemolysis severely hamper the development of membranolytic amphiphilic peptides into safe and efficient anticancer agents. To increase the therapeutic potential, we have previously developed a strategy based on formulation of the peptides in biocompatible nanosized lipodisks. Studies using melittin as model peptide show that the proteolytic degradation and hemolytic effect of the peptide are substantially reduced upon loading in lipodisks. Here, we explored the possibilities to increase the specificity and boost the cytotoxicity of melittin to tumor cells by use of targeting lipodisk. We demonstrate that small (~20 nm) EGF-targeted lipodisks can be produced and loaded with substantial amounts of peptide (lipid/peptide molar ratio >7) by means of a simple and straightforward preparation protocol. In vitro cell studies confirm specific binding of the peptide-loaded disks to tumor cells and suggest that cellular internalization of the disks results in a significantly improved cell-killing effect.

  • 4352.
    Ahlgren, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Radionuclide molecular imaging using affibody molecules2010In: Current Pharmaceutical Biotechnology, ISSN 1389-2010, E-ISSN 1873-4316, Vol. 11, no 6, p. 581-589Article, review/survey (Refereed)
    Abstract [en]

    The current way to increase efficacy of cancer therapy is the use of molecular recognition of aberrantly expressed gene products for selective treatment. However, only a fraction of the patients have tumors with a particular molecular target. Radionuclide imaging of molecular targets might help to stratify patient for cancer treatment. Affibody molecules are scaffold proteins, which can be selected for high affinity recognition of proteinaceous molecular targets. The capacity to re-fold under physiological conditions allows labeling of Affibody molecules in a broad range of pH and temperatures with preserved binding properties. Peptide synthesis or introduction of a unique cysteine enables site-specific labeling of Affibody molecules, resulting in uniform conjugates with well-defined pharmacological characteristics. The small size (7 kDa) of Affibody molecules provides rapid extravasation, rapid tumor penetration, and rapid clearance of unbound tracer from healthy organs and tissues. In combination with sub-nanomolar affinity, this results in high contrast in vivo imaging a few hours after injection. Excellent targeting has been demonstrated in pre-clinical studies with HER2-targeting Affibody molecules labeled with (99m)Tc and (111)In for single photon computed tomography (SPECT), and (18)F, (64)Cu, (124)I and (68)Ga for positron emission tomography (PET). Pilot clinical data confirm the high potential of Affibody molecules.

  • 4353.
    Ahlgren, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wållberg, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Tran, Thuy A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Widström, Charles
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Section of Medical Physics.
    Hjertman, Magnus
    Affibody AB, Stockholm, Sweden.
    Abrahmsén, Lars
    Affibody AB, Stockholm, Sweden.
    Berndorff, Dietmar
    Global Drug Discovery, Bayer Schering Pharma AG, Berlin, Germany.
    Dinkelborg, Ludger M.
    Global Drug Discovery, Bayer Schering Pharma AG, Berlin, Germany.
    Cyr, John E.
    Global Drug Discovery, Bayer Schering Pharma AG, Berlin, Germany.
    Feldwisch, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Targeting of HER2-expressing tumors with a site-specifically 99mTc-labeled recombinant affibody molecule, ZHER2:2395, with C-terminally engineered cysteine2009In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 50, no 5, p. 781-789Article in journal (Refereed)
    Abstract [en]

    The detection of human epidermal growth factor receptor type 2 (HER2) expression in malignant tumors provides important information influencing patient management. Radionuclide in vivo imaging of HER2 may permit the detection of HER2 in both primary tumors and metastases by a single noninvasive procedure. Small (7 kDa) high-affinity anti-HER2 Affibody molecules may be suitable tracers for SPECT visualization of HER2-expressing tumors. The use of generator-produced (99m)Tc as a label would facilitate the prompt translation of anti-HER2 Affibody molecules into use in clinics. METHODS: A C-terminal cysteine was introduced into the Affibody molecule Z(HER2:342) to enable site-specific labeling with (99m)Tc. Two recombinant variants, His(6)-Z(HER2:342)-Cys (dissociation constant [K(D)], 29 pM) and Z(HER2:2395)-Cys, lacking a His tag (K(D), 27 pM), were labeled with (99m)Tc in yields exceeding 90%. The binding specificity and the cellular processing of Affibody molecules were studied in vitro. Biodistribution and gamma-camera imaging studies were performed in mice bearing HER2-expressing xenografts. RESULTS: (99m)Tc-His(6)-Z(HER2:342)-Cys was capable of targeting HER2-expressing SKOV-3 xenografts in SCID mice, but the liver radioactivity uptake was high. A series of comparative biodistribution experiments indicated that the presence of the His tag caused elevated accumulation in the liver. (99m)Tc-Z(HER2:2395)-Cys, not containing a His tag, showed low uptake in the liver and high and specific uptake in HER2-expressing xenografts. Four hours after injection, the radioactivity uptake values (percentage of injected activity per gram of tissue [%IA/g]) were 6.9 +/- 2.5 (mean +/- SD) %IA/g in LS174T xenografts (moderate level of HER2 expression) and 15 +/- 3 %IA/g in SKOV-3 xenografts (high level of HER2 expression). The corresponding tumor-to-blood ratios were 88 +/- 24 and 121 +/- 24, respectively. Both LS174T and SKOV-3 xenografts were clearly visualized with a clinical gamma-camera 1 h after injection of (99m)Tc-Z(HER2:2395)-Cys. CONCLUSION: The Affibody molecule (99m)Tc-Z(HER2:2395)-Cys is a promising tracer for SPECT visualization of HER2-expressing tumors.

  • 4354. Ahlgrim, C.
    et al.
    Gutermuth, J.
    Onell, A.
    Borres, Magnus P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Schaeffner, I
    Darsow, U.
    Pfab, F.
    Brockow, K.
    Ring, J.
    Behrendt, H.
    Jakob, T.
    Huss-Marp, J.
    Comparison of Molecular Multiplex and Singleplex Analysis of IgE to Grass Pollen Allergens in Untreated German Grass Pollen-Allergic Patients2015In: Journal of investigational allergology & clinical immunology, ISSN 1018-9068, E-ISSN 1698-0808, Vol. 25, no 3, p. 190-195Article in journal (Refereed)
    Abstract [en]

    Background: The ImmunoCAP ISAC 112 platform is the only commercially available molecular allergy IgE multiplex test. Data on the comparison of this rather novel test with the molecular singleplex ImmunoCAP IgE platform are lacking. Objective:To compare the multiplex ISAC 112 platform and the singleplex ImmunoCAP platform in regard to IgE to grass pollen allergens in untreated grass pollen allergic patients in Germany. Methods: Serum samples from 101 adults with grass pollen allergy were analyzed for specific IgE (sIgE) to 8 allergenic molecules from timothy grass pollen and to the 112 allergenic molecules included in the ISAC panel. The results for the multiplex and singleplex tests were subsequently analyzed statistically. Results: Comparison of sIgE to grass pollen allergens detected by ISAC 112 and the singleplex ImmunoCAP assay revealed the following correlation coefficients: 0.88 (rPhl p1), 0.96 (rPhl p2), 0.70 (nPhl p4), 0.94 (rPhl p5b), 0.92 (rPhl p6), 0.85 (rPhl p11), and 0.78 (rPhl p12). Conclusion: Molecular testing with ISAC 112 correlates well with the ImmunoCAP platform for respective molecular timothy grass pollen allergens.

  • 4355.
    Ahlgrimm, Lena
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Educational Sciences, Department of Education.
    Skolbibliotekets funktion: En studie av fyra skolbibliotek 20132014Independent thesis Advanced level (professional degree), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Syftet med denna uppsats är att undersöka och analysera vilken funktion skolbibliotek kan ha i skolorna 2013 i förhållande till skollagen och utifrån frågeställningar där skolbiblioteket analyseras utifrån fyra områden: rummet, medierna och informationssystemet, personalen samt eleverna. Metoderna som används för att genomföra denna studie är kvalitativa. Det innebär att fyra varianter av skolbibliotek undersöktes genom samtalsintervjuer med skolbibliotekspersonal, enkätfrågor till elever i årskurs nio samt enkätfrågor till rektorerna på de aktuella skolorna. Resultaten analyseras och jämförs i förhållande till hur ett skolbibliotek kan definieras. Resultaten visar att det är när områdena ovan är kompletta och sätts samman som skolbiblioteket får den funktion som efterfrågas i skollagen. Studien av de fyra skolbiblioteken visar bristande förståelse för vilka funktioner som bildar ett skolbibliotek och avsaknad av ekonomiska resurser.

  • 4356.
    Ahlholm, Martin
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Physics Didactics.
    Fysikattityder hos gymnasieelever?: Trender bland intresse för fysik och fysikattityder bland svenska gymnasieelever2013Independent thesis Advanced level (professional degree), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Empirical research has shown that there are clear links between the interests, attitudes, and studentsuccess. The aim of the survey, which is the foundation of this report, was to measure how theinterest in physics and attitudes towards physics and physics education differs between the differentyears in upper secondary school. Maryland Physics Expectations (MPEX) Survey has been used tomeasure the attitudes. The questionnaire was answered by 605 respondents from technology andnatural science program from two upper secondary schools in central Sweden. Interest in physics islow on the investigated schools and it tends to become lower through the ages. Overall, there aremore unfavorable responses of the different attitude dimensions in third grade than in first grade. Concept is the dimension that has the most unfavorable response in both the second and third grade.In order to increase the conceptual understanding of upper secondary school students, shouldconceptual understanding be offered a greater part of the teaching. Examining conceptualunderstanding in homework assignments and tests are also preferable.

  • 4357.
    Ahlin, Alexander
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Educational Sciences, Department of Education.
    Analys av framställningen av kommunism i läroböcker - före och efter Sovjetunionens fall2016Independent thesis Advanced level (professional degree), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Detta arbete analyserar innehållet om kommunism i svenska läroböcker i samhällskunskap för gymnasiet. Fyra läroböcker har analyserats. Två läroböcker före Sovjetunionens fall, från 1982 och 1987 och två läroböcker efter Sovjetunionens fall, från 1993 och 1995. Studiens syfte är att analysera hur innehållet om kommunism i läroböckerna förändras efter Sovjetunionens fall, 1991. Studiens teoretiska ramverk utgår ifrån small state-teorin och Staffan Selanders teoretiska begrepp för textanalys av läroböcker. Teorin utgår från att små stater som exempelvis Sverige måste använda sig av strategier i sitt förhållnings sätt stormakter, som exempelvis Sovjetunionen. Strategierna går ut på att en liten stat inte kan vara alltför kritisk, eller okritisk i sitt förhållningssätt gentemot en potentiellt hotande stormakt. En innehållslig idéanalys användes i analysen och frågeställningarna utgick från två teman som skulle verka för att ge en djupare förståelse om vilken bild av kommunism som framställs i läroböckerna. Resultatet visar att det inte finns någon enhetlig bild som förmedlas om kommunism, varken i böckerna som skrevs innan Sovjetunionens fall eller i böckerna som skrevs innan Sovjetunionens fall. Mest anmärkningsvärt i resultatet är att läroboken från 1995 inte framför någon kritik mot det forna kommunistiska Sovjetunionen, boken från 1993 framför däremot kritik mot kommunism som politisk ideologi och Sovjetunionen som kommunistisk stat. Läroboken från 1982 framstår som försiktig i sin framställning av kommunism, dock kan framställningen tolkas som en indirekt kritik mot kommunism och Sovjetunionen. Läroboken från 1987 är starkt kritisk mot Sovjetunionen som i läroboken kallas för en kommunistdiktatur som styrs av en liten elit. 

  • 4358.
    Ahlin, Alexander
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Social and Economic Geography.
    Framställningen av Kina i geografiläroböcker: En kvalitativ textanalys2019Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Syftet med denna studie var att analysera hur en utomeuropeisk kultur, Kina, framställs i läroböcker i geografi för grundskolans senare år. Studien utgick från Edward Saids teori om orientalism. I studien togs tidigare läroboksforskning upp, vars resultat visar på att det förekommer stereotyper, fördomar och förenklingar i läroböcker. I tidigare forskning visas också på hur både elever och lärare ofta uppfattar läroböcker som objektiv faktakälla. För att besvara studiens syfte så skapades frågeställningar om, och i sådant fall på vilket sätt, det gick att se spår av orientalism och traditionell gestaltning av Kina, dess kultur och befolkning i läroböckerna. Studien använde sig av metoden kvalitativ textanalys som innebär en närläsning och tolkning av texterna som är föremål för analysen. Resultaten från analysen visar att det går att tolka spår av orientalism i läroböckerna. Resultaten bekräftar därmed delvis resultat som tidigare forskning visat. Resultaten öppnar för vidare och fortsatt analys av läroböcker, exempelvis i större omfattning eller över andra skolämnen för att avgöra om liknande resultat går att få och att därmed en generalisering av resultaten kan göras av läroböcker i ett större perspektiv. 

  • 4359. Ahlin, Anders
    et al.
    Bark, Carina
    Jansson, Anders
    Malmlöf, Peter
    Knutsson, B
    Persson, L
    Carlqvist, B
    Kjebon, J
    GMMS 3.0: Handbok för utformning av användargränssnitt1997Book (Other academic)
  • 4360.
    Ahlin, Cecilia
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Cyclin A and cyclin E as prognostic factors in early breast cancer2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Breast cancer is one of the most common malignancies in women. Due to early detection and the use of screening programs approximately 60% of all new cases lack lymph node involvement. Today, a substantial proportion of these women will be offered adjuvant systemic chemotherapy. However, better proliferation markers are needed to predict patient outcome and to avoid overtreatment.

    Cyclin A, cyclin E and Ki-67 are all markers for proliferation and involved in the regulation of the cell cycle. Overexpression has been associated with disease recurrence in several studies, but the results have not been consistent. However, none of these studies has investigated aberrant expression of cyclin E (the expression of cyclin E during phases of the cell cycle other than late G1 and early S-phase). Studies have shown that aberrant cyclin E might provide additional prognostic information compared to cyclin E alone.

    The aims of this thesis were 1.to investigate the prognostic value of cyclin A, cyclin E and aberrant cyclin E in early breast cancer. 2.to validate the tissue microarray (TMA) technique for cyclin A and 3.to define the most optimal cut-off values for cyclin A and Ki-67.

    We found that the agreement of TMA and large section results was good with kappa values 0.62-0.75 and that the reproducibility of the two readers’ results was good or even very good, with kappa values 0.71 – 0.87.

    The optimal cut-off value for cyclin A average was 8% and for cyclin A maximum value 11%. The corresponding values for Ki-67 were 15 and 22%.

    Neither cyclin E nor aberrant cyclin E was a prognostic factor in low-risk node negative breast cancer patients.

    Finally, we conclude that cyclin A is a prognostic factor in node negative breast cancer (univariate analysis average value OR=2.9 95% CI 1.8-4.6; maximum value OR=3.7 95% CI 2.3-5.9).

    List of papers
    1. Reliability of cyclin A assessment on tissue microarrays in breast cancer compared to conventional histological slides
    Open this publication in new window or tab >>Reliability of cyclin A assessment on tissue microarrays in breast cancer compared to conventional histological slides
    Show others...
    2006 (English)In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 94, no 11, p. 1697-1702Article in journal (Refereed) Published
    Abstract [en]

    Cyclin A has in some studies been associated with poor breast cancer survival, although all studies have not confirmed this. Its prognostic significance in breast cancer needs evaluation in larger studies. Tissue microarray (TMA) technique allows a simultaneous analysis of large amount of tumours on a single microscopic slide. This makes a rapid screening of molecular markers in large amount of tumours possible. Because only a small tissue sample of each tumour is punched on an array, the question has arisen about the representativeness of TMA when studying markers that are expressed in only a small proportion of cells. For this reason, we wanted to compare cyclin A expression on TMA and on traditional large sections. Two breast cancer TMAs were constructed of 200 breast tumours diagnosed between 1997-1998. TMA slides and traditional large section slides of these 200 tumours were stained with cyclin A antibody and analysed by two independent readers. The reproducibility of the two readers' results was good or even very good, with kappa values 0.71-0.87. The agreement of TMA and large section results was good with kappa value 0.62-0.75. Cyclin A overexpression was significantly (P<0.001) associated with oestrogen receptor and progesterone receptor negativity and high grade both on TMA and large sections. Cyclin A overexpression was significantly associated with poor metastasis-free survival both on TMA and large sections. The relative risks for metastasis were similar on TMA and large sections. This study suggests that TMA technique could be useful to study histological correlations and prognostic significance of cyclin A on breast cancer on a large scale.

    Keywords
    breast cancer, cyclin A, tissue microarray, Biopsy/methods, Breast Neoplasms/*pathology/radiotherapy, Cyclin A/analysis/*genetics, Female, Humans, Reproducibility of Results, Tissue Array Analysis/*methods
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-97138 (URN)10.1038/sj.bjc.6603147 (DOI)16670718 (PubMedID)
    Available from: 2008-04-29 Created: 2008-04-29 Last updated: 2017-12-14Bibliographically approved
    2. Ki67 and cyclin A as prognostic factors in early breast cancer: What are the optimal cut-off values?
    Open this publication in new window or tab >>Ki67 and cyclin A as prognostic factors in early breast cancer: What are the optimal cut-off values?
    Show others...
    2007 (English)In: Histopathology, ISSN 0309-0167, E-ISSN 1365-2559, Vol. 51, no 4, p. 491-498Article in journal (Refereed) Published
    Abstract [en]

    AIMS: To find the optimal cut-off values for cyclin A and Ki67 in early breast cancer tumours and to evaluate their prognostic values. METHODS AND RESULTS: Tissue microarray (TMA) slides were constructed from 570 T1-4 N0-1 M0 breast cancer tumours. The TMA slides were stained for cyclin A and Ki67 using immunohistochemistry with commercial antibodies. To investigate the optimal cut-off values for cyclin A, Ki67 average and maximum values the material was split into two parts at cut-offs defined by dividing it into deciles. For each cut-off value the relative risk (RR) for metastasis-free survival (MFS) and overall survival (OS) was calculated comparing patients with high versus low cyclin A or Ki67 expression. When using a cut-off value around the seventh decile, cyclin A and Ki67 score correlated with the highest RR ratio for MFS in the chemotherapy-naïve subgroup. Among patients having received adjuvant chemotherapy, no statistically significant differences in MFS or OS were found. CONCLUSIONS: The optimal cut-off value for cyclin A average is 8% and for cyclin A maximum value 11%; for Ki67 the corresponding values are 15% and 22%. Additional studies are needed to verify these results.

    Keywords
    breast cancer, cut-off value, cyclin A, Ki67, tissue microarray
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-97139 (URN)10.1111/j.1365-2559.2007.02798.x (DOI)000249661900008 ()17711446 (PubMedID)
    Available from: 2008-04-29 Created: 2008-04-29 Last updated: 2017-12-14Bibliographically approved
    3. Aberrant expression of cyclin E in low-risk node negative breast cancer
    Open this publication in new window or tab >>Aberrant expression of cyclin E in low-risk node negative breast cancer
    Show others...
    2008 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 47, no 8, p. 1539-1545Article in journal (Refereed) Published
    Abstract [en]

    Background. Cyclin E is a cell cycle regulatory protein which occurs in G1, peaks in late G1 and is degraded in early S-phase. Cyclin E overexpression appears to be an independent prognostic factor for overall survival in breast cancer. Material and Methods. Nuclear cyclin A is a reliable marker for S-and G2-phases. Consequently, aberrant expression of cyclin E can be detected by simultaneous immunostainings for cyclin A and cyclin E. Studies have shown that aberrant cyclin E might provide additional prognostic information compared to that of cyclin E alone. This study aimed to investigate cyclin E and aberrant cyclin E expression in low-risk node negative breast cancer. We compared women that died from their breast cancer (n=17) with women free from relapse>8 years after initial diagnosis (n=24). All women had stage I, low risk breast cancer. The groups were matched regarding tumour size, receptor status, adjuvant chemotherapy and tumour differentiation. Tumour samples were analysed regarding expression of cyclin A, cyclin E and double-stained tumour cells using immunoflourescence staining and digital microscopy. Results. No differences were seen regarding expression of cyclin E or aberrant cyclin E in cases compared to controls. Discussion. We conclude that neither cyclin E nor aberrant cyclin E is a prognostic factor in low-risk node negative breast cancer patients.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-97140 (URN)10.1080/02841860701856581 (DOI)000260227700010 ()18607847 (PubMedID)
    Available from: 2008-04-29 Created: 2008-04-29 Last updated: 2017-12-14Bibliographically approved
    4. Is cyclin A a prognostic factor in node negative breast cancer?
    Open this publication in new window or tab >>Is cyclin A a prognostic factor in node negative breast cancer?
    Show others...
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-97141 (URN)
    Available from: 2008-04-29 Created: 2008-04-29 Last updated: 2010-01-13Bibliographically approved
  • 4361.
    Ahlin, Cecilia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Aaltonen, Kirsimari
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Nevanlinna, Heli
    Fjällskog, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Blomqvist, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Ki67 and cyclin A as prognostic factors in early breast cancer: What are the optimal cut-off values?2007In: Histopathology, ISSN 0309-0167, E-ISSN 1365-2559, Vol. 51, no 4, p. 491-498Article in journal (Refereed)
    Abstract [en]

    AIMS: To find the optimal cut-off values for cyclin A and Ki67 in early breast cancer tumours and to evaluate their prognostic values. METHODS AND RESULTS: Tissue microarray (TMA) slides were constructed from 570 T1-4 N0-1 M0 breast cancer tumours. The TMA slides were stained for cyclin A and Ki67 using immunohistochemistry with commercial antibodies. To investigate the optimal cut-off values for cyclin A, Ki67 average and maximum values the material was split into two parts at cut-offs defined by dividing it into deciles. For each cut-off value the relative risk (RR) for metastasis-free survival (MFS) and overall survival (OS) was calculated comparing patients with high versus low cyclin A or Ki67 expression. When using a cut-off value around the seventh decile, cyclin A and Ki67 score correlated with the highest RR ratio for MFS in the chemotherapy-naïve subgroup. Among patients having received adjuvant chemotherapy, no statistically significant differences in MFS or OS were found. CONCLUSIONS: The optimal cut-off value for cyclin A average is 8% and for cyclin A maximum value 11%; for Ki67 the corresponding values are 15% and 22%. Additional studies are needed to verify these results.

  • 4362. Ahlin, Cecilia
    et al.
    Fernö, Mårten
    Amini, Rose-Marie
    Karolinska universitetssjukhuset, Stockholm.
    Tolockiene, Egle
    Blomqvist, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Bergh, Jonas
    Fjällskog, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Ki-67 och cyklin A – prognostiska faktorer vid bröstcancer: Dags att införa proliferationsmarkörer i klinisk rutin2010In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 107, no 10, p. 672-675Article in journal (Refereed)
  • 4363.
    Ahlin, Cecilia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Gruhne, Bettina
    Holmqvist, Marit
    Zetterberg, Anders
    Fjällskog, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Aberrant expression of cyclin E in low-risk node negative breast cancer2008In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 47, no 8, p. 1539-1545Article in journal (Refereed)
    Abstract [en]

    Background. Cyclin E is a cell cycle regulatory protein which occurs in G1, peaks in late G1 and is degraded in early S-phase. Cyclin E overexpression appears to be an independent prognostic factor for overall survival in breast cancer. Material and Methods. Nuclear cyclin A is a reliable marker for S-and G2-phases. Consequently, aberrant expression of cyclin E can be detected by simultaneous immunostainings for cyclin A and cyclin E. Studies have shown that aberrant cyclin E might provide additional prognostic information compared to that of cyclin E alone. This study aimed to investigate cyclin E and aberrant cyclin E expression in low-risk node negative breast cancer. We compared women that died from their breast cancer (n=17) with women free from relapse>8 years after initial diagnosis (n=24). All women had stage I, low risk breast cancer. The groups were matched regarding tumour size, receptor status, adjuvant chemotherapy and tumour differentiation. Tumour samples were analysed regarding expression of cyclin A, cyclin E and double-stained tumour cells using immunoflourescence staining and digital microscopy. Results. No differences were seen regarding expression of cyclin E or aberrant cyclin E in cases compared to controls. Discussion. We conclude that neither cyclin E nor aberrant cyclin E is a prognostic factor in low-risk node negative breast cancer patients.

  • 4364.
    Ahlin, Cecilia
    et al.
    Orebro Univ, Dept Oncol, Orebro, Sweden..
    Lundgren, Claudia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Embretsen-Varro, Elin
    Orebro Univ, Dept Oncol, Orebro, Sweden..
    Jirstrom, Karin
    Lund Univ, Dept Pathol & Oncol, Lund, Sweden..
    Blomqvist, Carl
    Orebro Univ, Dept Oncol, Orebro, Sweden.;Univ Helsinki, Dept Oncol, Helsinki, Finland..
    Fjällskog, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    High expression of cyclin D1 is associated to high proliferation rate and increased risk of mortality in women with ER-positive but not in ER-negative breast cancers2017In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 164, no 3, p. 667-678Article in journal (Refereed)
    Abstract [en]

    Cyclin D1 has a central role in cell cycle control and is an important component of estrogen regulation of cell cycle progression. We have previously shown that high cyclin D expression is related to aggressive features of ER-positive but not ER-negative breast cancer. The aims of the present study were to validate this differential ER-related effect and furthermore explore the relationship between cyclin D overexpression and CCND1 gene amplification status in a node-negative breast cancer case-control study. Immunohistochemical nuclear expression of cyclin D1 (n = 364) and amplification of the gene CCND1 by fluorescent in situ hybridization (n = 255) was performed on tissue microarray sections from patients with T1-2N0M0 breast cancer. Patients given adjuvant chemotherapy were excluded. The primary event was defined as breast cancer death. Breast cancer-specific survival was analyzed in univariate and multivariable models using conditional logistic regression. Expression of cyclin D1 above the median (61.7%) in ER breast cancer was associated with an increased risk for breast cancer death (OR 3.2 95% CI 1.5-6.8) also when adjusted for tumor size and grade (OR 3.1). No significant prognostic impact of cyclin D1 expression was found among ER-negative cases. Cyclin D1 overexpression was significantly associated to high expression of the proliferation markers cyclins A (rho 0.19, p = 0.006) and B (rho 0.18, p = 0.003) in ER-positive tumors, but not in ER-negative cases. There was a significant association between CCND1 amplification and cyclin D1 expression (p = 0.003), but CCND1 amplification was not statistically significantly prognostic (HR 1.4, 95% CI 0.4-4.4). We confirmed our previous observation that high cyclin D1 expression is associated to high proliferation and a threefold higher risk of death from breast cancer in ER-positive breast cancer.

  • 4365.
    Ahlin, Cecilia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Zhou, Wenjing
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Holmqvist, Marit
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Nilsson, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Clinical Research, County of Västmanland.
    Jirström, Karin
    Blomqvist, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Fjällskog, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Cyclin A is a proliferative marker with good prognostic value in node-negative breast cancer2009In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 18, no 9, p. 2501-2506Article in journal (Refereed)
    Abstract [en]

    Background: Proliferative markers are not recommended as prognostic   factors for clinical use in breast cancer due to lack of   standardization in methodology. However, proliferation is driving   several gene expression signatures emphasizing the need for a reliable   proliferative marker IF or clinical use. Studies suggest that cyclin A   is a prognostic marker with satisfying reproducibility. We investigated   cyclin A as a prognostic marker in node-negative breast cancer using   previously defined cutoff values.   Patients and Methods: In a case-control study, we defined 190 women who   died from breast cancer as cases and 190 women alive at the time for   the corresponding case's death as controls. Inclusion criteria were   tumor size <= 50 mm, no lymph node metastases and no adjuvant   chemotherapy. Tumor tissues were immunostained for cyclin A using   commercially available antibodies.   Results: We found a statistically significant association between   expression of cyclin A and breast cancer death in a univariate model:   odds ratio for cyclin A(ave) 2.7 [95% confidence interval (CI),   1.7-4.3] and cyclin A(max) 3.4 (CI, 2.1-5.5). Corresponding odds ratio   for Ki67 were Ki67(ave) 1.9 (CI, 1.2-3.1) and Ki67(max) 1.7 (CI,   1.1-2.7) and for grade 3.1 (CI, 1.8-5.1). Cyclin A was strongly   correlated to Ki67 and grade why a model including all was not   appropriate.   Conclusions: Cyclin A is a prognostic factor for breast cancer death in   node-negative patients using standardized methodology regarding scoring   and cutoff values. Adding cyclin A as a proliferative marker to established clinicopathologic factors will improve the separation of  low and high risk breast cancer.

  • 4366.
    Ahlin, Cecilia
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Zhou, Wenjing
    Holmqvist, Marit
    Jirström, Karin
    Blomqvist, Carl
    Amini, Rose-Marie
    Fjällskog, Marie-Louise
    Is cyclin A a prognostic factor in node negative breast cancer?Manuscript (Other academic)
  • 4367.
    Ahlin, Emma
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Educational Sciences, Department of Education.
    Olofsson, Jana
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Educational Sciences, Department of Education.
    SvEng loss med Charlie: Ett inspirationsmaterial som uppmanar pedagoger och barn till att använda det engelska språket i förskolan2016Independent thesis Basic level (professional degree), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    The starting point of this work is to introduce early language learning of English in preschool. It takes a long time to learn the basics of a foreign language and children are most receptive to learning languages ​​in the preschool age. We have chose to create a product that inspires teachers to use English in preschool and find a curiosity about the language in children aged 3–5 years. The product is built in related subject areas from the preschool curriculum with the main focus on the English language. English is thus the subject integrated and becomes a means to achieve the aspirations of the goals. The topics covered include: maths, language, social interaction, movement and health, creativity and science and technology. The product is presented in six stories about the unisex character Charlie who loves language. For each story, there is a related activity involving a subject area. Finally, there is aesthetic extra-material that can be paired with the stories and deepens the learning of the English language with singing and drama. Overall instructions to the booklet are presented in the beginning. Preparations, materials and other instructions are presented to each activity. The summary booklet consists of 28 pages of text and image. The completed product was distributed to 12 educators in preschool who provided feedback and evaluated the design, use and relevance of the product. The results show that many educators think that English has a place in preschool. The product was well received by all educators and was considered to be good and inspiring base material that urged them to use the English language in preschool. 

  • 4368.
    Ahlin, Erik
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, LUVAL.
    Modellering av dagvattennät utgående från markhöjder2012Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    According to The Swedish Water and Wastewater Association (SWWA), a storm waternetwork must be able to handle a rainfall with a return period of 10 years. In order toevaluate whether a drain system is adequately dimensioned, a storm water model can beestablished. This requires knowledge about the levels at which the conduits are situated,and this information is insufficient in many areas. However, the pipes could largely beassumed to follow the topography and the pipes levels can be estimated from it.Therefore, the aim of this study was to develop a method for how the level of stormwater conduits could be assessed from the ground level, and the significance thismethod had for storm water modeling. A further aim was also to, according to thismethod; assess the storm water systems of the Lidingö community, which lackedinformation on the pipe levels. Furthermore, for the method to be useful it wasimportant to make it easily applicable even to large storm water networks.The method was developed using parts of the storm water network in Sundbyberg,Stockholm. The levels of the conduits were known beforehand, and an analysis of themresulted in a method where the depth of the manhole, which controls the levels of theconduits, was estimated to 2 m. An exception had to be made when the conduits were inreverse slope, in which cases horizontal slope was assumed.When evaluating the impact from the depth assessment on the runoff, the uncertaintyfrom the imperviousness was taken into account by using three different scenarios;unchanged, 30% lower and 30% higher imperviousness. The risk of flooding for eachone of the manholes was weighted from the results of these three scenarios. Thisresulted in a pressure level for each manhole, either above ground, below ground orinconclusive. This was done for the model with both known levels for the conduits, andwith the assessed levels. In order to evaluate how well the method for applying thedepth worked, the status of each manhole was compared between the two models.The conclusion from this study was that the method developed here, more or less gavethe same results as when the levels of the conduits were previously known.Discrepancies arose mainly in ditches, but also for a few landlocked areas and outlets.For the Lidingö storm water network, 18 % of the wells ended up with a pressure levelabove ground when applied to a rain with a 10 year return period. Another 16 % of thewells were inconclusive.

  • 4369. Ahlin, Erik
    et al.
    Elshafei, Amir
    Nur, Musa
    El Safi, Sayda Hassan
    Johan, Rönnelid
    EIghazali, Gehad
    Anti-citrullinated peptide antibodies and rheumatoid factor in Sudanese patients with Leishmania donovani infection2011In: REV BRAS REUMATOL, ISSN 0482-5004, Vol. 51, no 6, p. 572-586Article in journal (Refereed)
    Abstract [en]

    Objective: The present study evaluated the presence of anti-cyclic citrullinated peptides antibodies (anti-CCP), rheumatoid factor (RF), and circulating immune complexes (CIC) in Sudanese patients infected with the Leishmania donovani parasite. Patients and methods: Sera were collected from Leishmania infected patients (n = 116) and healthy Sudanese (n = 93). Nineteen Sudanese anti-CCP+RA patients were included as positive controls. Levels of CIC and anti-CCP were measured by ELISA. Control plate with cyclic control peptides containing arginine instead of citrulline was used to evaluate citrulline specific reactivity. Results: Among Leishmania-infected patients and anti-CCP+RA patients, most were RF positive (86%), while the frequency of CIC positivity was higher among visceral leishmaniasis (VL) patients (VL 38%; anti-CCP+RA 24%). When anti-CCP reactivity was analysed, 12% of VL patients were found to be positive. The levels of anti-CCP among V L patients correlated well with the CIC levels found (r = 0.65, P < 0.0001). In RA group, no association was found between CIC and anti-CCP. The possibility that anti-CCP positivity was due to cross reactions with CIC was experimentally ruled out. Contrary to what was seen in Sudanese RA sera, the CCP reactivity was not restricted to citrulline but reacted equally well with the arginine control peptide. Conclusion: The finding that CCP reactivity was not restricted to citrulline argues that this is more an effect of extensive inflammation and immune activation than a sign of shared pathogenic characteristics with anti-CCP arthritis. Our findings stress the importance to interpret a positive CCP test carefully when evaluated in non-rheumatic conditions or in areas where such infections predominate.

  • 4370. Ahlin, Erik
    et al.
    Elshafei, Amir
    Nur, Musa
    El Safi, Sayda Hassan
    Ronnelid, Johan
    Elghazali, Gehad
    Retraction: Anti-citrullinated peptide antibodies and rheumatoid factor in Sudanese patients with Leishmania donovani infection (vol 51, pg 579, 2011)2014In: Revista Brasileira de Reumatologia, ISSN 0482-5004, E-ISSN 1809-4570, Vol. 54, no 3, p. 255-255Article in journal (Refereed)
  • 4371.
    Ahlin, Fanny
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Government.
    The Legitimacy of the Intervention in Syria: A critical review regarding the intervention in Syria in 2018 executed by the United States of America, Great Britain and France2019Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
  • 4372.
    Ahlin, Gustav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    In vitro and in silico prediction of drug-drug interactions with transport proteins2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Drug transport across cells and cell membranes in the human body is crucial for the pharmacological effect of drugs. Active transport governed by transport proteins plays an important role in this process. A vast number of transport proteins with a wide tissue distribution have been identified during the last 15 years. Several important examples of their role in drug disposition and drug-drug interactions have been described to date. Investigation of drug-drug interactions at the transport protein level are therefore of increasing interest to the academic, industrial and regulatory research communities.

    The gene expression of transport proteins involved in drug transport was investigated in the jejunum, liver, kidney and colon to better understand their influence on the ADMET properties of drugs. In addition, the gene and protein expression of transport proteins in cell lines, widely used for predictions of drug transport and metabolism, was examined.

    The substrate and inhibitor heterogeneity of many transport proteins makes it difficult to foresee whether the transport proteins will cause drug-drug interactions. Therefore, in vitro assays for OCT1 and OATP1B1, among the highest expressed transport proteins in human liver, were developed to allow investigation of the inhibitory patterns of these proteins. These assays were used to investigate two data sets, consisting of 191 and 135 registered drugs and drug-like molecules for the inhibition of OCT1 and OATP1B1, respectively. Numerous new inhibitors of the transport proteins were identified in the data sets and the properties governing inhibition were determined. Further, antidepressant drugs and statins displayed strong inhibition of OCT1 and OATP1B1, respectively. The inhibition data was used to develop predictive in silico models for each of the two transport proteins.

    The highly polymorphic nature of some transport proteins has been shown to affect drug response and may lead to an increased risk of drug-drug interactions, and therefore, the OCT1 in vitro assay was used to study the effect of common genetic variants of OCT1 on drug inhibition and drug-drug interactions. The results indicated that OCT1 variants with reduced function were more susceptible to inhibition. Further, a drug-drug interaction of potential clinical significance in the genetic OCT1 variant M420del was proposed.

    In summary, gene expression of transport proteins was investigated in human tissues and cell lines. In vitro assays for two of the highest expressed liver transport proteins were used to identify previously unknown SLC transport protein inhibitors and to develop predictive in silico models, which may detect previously known drug-drug interactions and enable new ones to be identified at the transport protein level. In addition, the effect of genetic variation on inhibition of the OCT1 was investigated.

    List of papers
    1. Expression of thirty-six drug transporter genes in human intestine, liver, kidney, and organotypic cell lines
    Open this publication in new window or tab >>Expression of thirty-six drug transporter genes in human intestine, liver, kidney, and organotypic cell lines
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    2007 (English)In: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 35, no 8, p. 1333-1340Article in journal (Refereed) Published
    Abstract [en]

    This study was designed to quantitatively assess the mRNA expression of 36 important drug transporters in human jejunum, colon, liver, and kidney. Expression of these transporters in human organs was compared with expression in commonly used cell lines (Caco-2, HepG2, and Caki-1) originating from these organs to assess their value as in vitro transporter system models, and was also compared with data obtained from the literature on expression in rat tissues to assess species differences. Transporters that were highly expressed in the intestine included HPT1, PEPT1, BCRP, MRP2, and MDR1, whereas, in the liver, OCT1, MRP2, OATP-C, NTCP and BSEP were the main transporters. In the kidney, OAT1 was expressed at the highest levels, followed by OAT3, OAT4, MCT5, MDR1, MRP2, OCT2, and OCTN2. The best agreement between human tissue and the representative cell line was observed for human jejunum and Caco-2 cells. Expression in liver and kidney ortholog cell lines was not correlated with that in the associated tissue. Comparisons with rat transporter gene expression revealed significant species differences. Our results allowed a comprehensive quantitative comparison of drug transporter expression in human intestine, liver, and kidney. We suggest that it would be beneficial for predictive pharmacokinetic research to focus on the most highly expressed transporters. We hope that our comparison of rat and human tissue will help to explain the observed species differences in in vivo models, increase understanding of the impact of active transport processes on pharmacokinetics and distribution, and improve the quality of predictions from animal studies to humans.

    Keywords
    Urinary system, Digestive system, Cell line, Established cell line, In vitro, Kidney, Liver, Gut, Human, Genetics, Gene, Carrier protein, Drug
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-11385 (URN)10.1124/dmd.107.014902 (DOI)000248200000013 ()17496207 (PubMedID)
    Available from: 2007-09-11 Created: 2007-09-11 Last updated: 2018-01-12Bibliographically approved
    2. Endogenous Gene and Protein Expression of Drug Transporting Proteins in Cell Lines Routinely used in Drug Discovery Programs
    Open this publication in new window or tab >>Endogenous Gene and Protein Expression of Drug Transporting Proteins in Cell Lines Routinely used in Drug Discovery Programs
    Show others...
    2009 (English)In: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 37, no 12, p. 2275-2283Article in journal (Refereed) Published
    Abstract [en]

    The aim of this study was to investigate the gene and protein expression profiles of important drug transporting proteins in human cell lines commonly used for studies of drug transport mechanisms. Human cell lines used to transiently or stably express single transporters (HeLa, HEK293) and leukaemia cell lines used to study drug resistance by ABC-transporters (HL-60, K562) were investigated, and compared with organotypic cell lines (HepG2, Saos-2, Caco-2 and Caco-2 TC7). For gene expression studies, real-time PCR was used, while monospecific polyclonal antibodies were generated and used to investigate protein expression by immunohistochemistry. Thirty-six transporters were studied for gene expression and nine for protein expression. The antibodies were validated using expression patterns in human tissues. Finally, the function of one ubiquitously expressed transporter, MCT1; SLC16A1 was investigated using 14C-lactic acid as a substrate. In general, the adherent cell lines (HeLa, HEK293) displayed low transporter expression and the expression patterns were barely affected by transfection. The leukaemia cell lines (K562, HL-60) and Saos-2 also had low endogenous transporter expression, while the organotypic cell lines (HepG2 and Caco-2) showed higher expression of some transporters. Comparison of gene and protein expression profiles gave poor correlations, but better agreement was obtained for antibodies with a good validation score, indicating that antibody quality was a significant variable. Importantly, the monocarboxylic acid transporting protein MCT1 was significantly expressed in all, and functional in most of the cell lines, indicating that MCT1 may be a confounding factor when the transport of small anionic drugs is investigated.

    Keywords
    Cell lines, Caco-2, HEK293, HeLa, Saos-2, HL-60, K562, HepG2, Gene expression, Protein expression, MCT1
    National Category
    Pharmaceutical Sciences
    Research subject
    Biopharmaceutics; Pharmaceutics
    Identifiers
    urn:nbn:se:uu:diva-107571 (URN)10.1124/dmd.109.028654 (DOI)000271935200002 ()19741037 (PubMedID)
    Available from: 2009-08-17 Created: 2009-08-17 Last updated: 2018-01-13Bibliographically approved
    3. Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1
    Open this publication in new window or tab >>Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1
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    2008 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 51, no 19, p. 5932-5942Article in journal (Refereed) Published
    Abstract [en]

    The liver-specific organic cation transport protein (OCT1; SLC22A1) transports several cationic drugs including the antidiabetic drug metformin and the anticancer agents oxaliplatin and imatinib. In this study, we explored the chemical space of registered oral drugs with the aim of studying the inhibition pattern of OCT1 and of developing predictive computational models of OCT1 inhibition. In total, 191 structurally diverse compounds were examined in HEK293-OCT1 cells. The assay identified 47 novel inhibitors and confirmed 15 previously known inhibitors. The enrichment of OCT1 inhibitors was seen in several drug classes including antidepressants. High lipophilicity and a positive net charge were found to be the key physicochemical properties for OCT1 inhibition, whereas a high molecular dipole moment and many hydrogen bonds were negatively correlated to OCT1 inhibition. The data were used to generate OPLS-DA models for OCT1 inhibitors; the final model correctly predicted 82% of the inhibitors and 88% of the noninhibitors of the test set.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-86815 (URN)10.1021/jm8003152 (DOI)000259760500010 ()18788725 (PubMedID)
    Available from: 2008-12-08 Created: 2008-12-08 Last updated: 2017-12-14Bibliographically approved
    4. Genotype-dependent effects of inhibitors of the organic cation transporter, OCT1:: predictions of metformin interactions
    Open this publication in new window or tab >>Genotype-dependent effects of inhibitors of the organic cation transporter, OCT1:: predictions of metformin interactions
    Show others...
    2011 (English)In: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150, Vol. 11, no 6, p. 400-411Article in journal (Refereed) Published
    Abstract [en]

    Common genetic variants of the liver-specific human organic cation transporter 1 (OCT1; SLC22A1) have reduced transport capacity for substrates such as the antidiabetic drug metformin. The effect of the reduced OCT1 function on drug interactions associated with OCT1 has not been investigated and was, therefore, the focus of the study presented here. HEK293 cells expressing human OCT1-reference or the variants R61C, V408M, M420del and G465R were first used to study the kinetics and inhibition pattern of the OCT1 substrate 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP(+)). In the second part OCT1-mediated (14)C-metformin uptake was studied in the presence of drugs administered concomitantly with metformin. Transport studies using ASP(+) showed that the function of the variants decreased in the following order: OCT1-reference = V408M = M420del >R61C > >G465R. Variants M420del and R61C were more sensitive to drug inhibition, with IC(50) values up to 23 times lower than those of the OCT1-reference. Uptake studies using (14)C-metformin were in qualitative agreement with those using ASP(+), with the exception that a larger reduction in transport capacity was observed for M420del. Concomitantly administered drugs, such as verapamil and amitriptyline, revealed potential drug-drug interactions at clinical plasma concentrations of metformin for OCT1-M420del.

    Keywords
    OCT1, polymorphism, metformin, drug-drug intaeractions, transport protein
    National Category
    Pharmaceutical Sciences
    Research subject
    Biopharmaceutics; Pharmaceutics
    Identifiers
    urn:nbn:se:uu:diva-107572 (URN)10.1038/tpj.2010.54 (DOI)000297506500003 ()
    Available from: 2009-08-17 Created: 2009-08-17 Last updated: 2018-01-13Bibliographically approved
    5. In Vitro and In Silico Strategies to Identify OATP1B1 Inhibitors and Predict Clinical Drug-Drug Interactions
    Open this publication in new window or tab >>In Vitro and In Silico Strategies to Identify OATP1B1 Inhibitors and Predict Clinical Drug-Drug Interactions
    Show others...
    2012 (English)In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 29, no 2, p. 411-426Article in journal (Other academic) Published
    Abstract [en]

    To establish in vitro and in silico models that predict clinical drug-drug interactions (DDIs) with the OATP1B1 (SLCO1B1) transporter. The inhibitory effect of 146 drugs and drug-like compounds on OATP1B1-mediated transport was studied in HEK293 cells. A computational model was developed to predict OATP1B1 inhibition. Concentration-dependent effects were investigated for six compounds; clinical DDIs were predicted by calculating change in exposure (i.e. R-values) in eight different ways. Sixty-five compounds were identified as OATP1B1 inhibitors at 20 mu M. The computational model predicted the test set with 80% accuracy for inhibitors and 91% for non-inhibitors. In vitro-in vivo comparisons underscored the importance of using drugs with known clinical effects as references. Thus, reference drugs, cyclosporin A, gemfibrozil, and fenofibrate, provided an inhibition interval to which three antiviral drugs, atazanavir, lopinavir, and amprenavir, could be compared and their clinical DDIs with OATP1B1 classified. Twenty-two new OATP1B1 inhibitors were identified, a predictive OATP1B1 inhibition in silico model was developed, and successful predictions of clinical DDIs were obtained with OATP1B1.

    Keywords
    in silico, in vitro-in vivo extrapolation, inhibition, MRP2, OATP1B1
    National Category
    Pharmaceutical Sciences
    Research subject
    Biopharmaceutics; Pharmaceutics
    Identifiers
    urn:nbn:se:uu:diva-107573 (URN)10.1007/s11095-011-0564-9 (DOI)000299506700007 ()
    Available from: 2009-08-17 Created: 2009-08-17 Last updated: 2018-01-13Bibliographically approved
  • 4373.
    Ahlin, Gustav
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Chen, L
    Department of Biopharmaceutical Sciences, University of California San Francisco, San Francisco, California, USA.
    Lazorova, Lucia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Chen, Ying
    Department of Biopharmaceutical Sciences, University of California San Francisco, San Francisco, California, USA.
    Ianculescu, Alexandra G.
    Department of Biopharmaceutical Sciences, University of California San Francisco, San Francisco, California, USA.
    Davis, Robert L.
    3Center for Health Research Southeast, Kaiser Permanente, Atlanta, USA.
    Giacomini, Kathleen M.
    Department of Biopharmaceutical Sciences, University of California San Francisco, San Francisco, California, USA.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Genotype-dependent effects of inhibitors of the organic cation transporter, OCT1:: predictions of metformin interactions2011In: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150, Vol. 11, no 6, p. 400-411Article in journal (Refereed)
    Abstract [en]

    Common genetic variants of the liver-specific human organic cation transporter 1 (OCT1; SLC22A1) have reduced transport capacity for substrates such as the antidiabetic drug metformin. The effect of the reduced OCT1 function on drug interactions associated with OCT1 has not been investigated and was, therefore, the focus of the study presented here. HEK293 cells expressing human OCT1-reference or the variants R61C, V408M, M420del and G465R were first used to study the kinetics and inhibition pattern of the OCT1 substrate 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP(+)). In the second part OCT1-mediated (14)C-metformin uptake was studied in the presence of drugs administered concomitantly with metformin. Transport studies using ASP(+) showed that the function of the variants decreased in the following order: OCT1-reference = V408M = M420del >R61C > >G465R. Variants M420del and R61C were more sensitive to drug inhibition, with IC(50) values up to 23 times lower than those of the OCT1-reference. Uptake studies using (14)C-metformin were in qualitative agreement with those using ASP(+), with the exception that a larger reduction in transport capacity was observed for M420del. Concomitantly administered drugs, such as verapamil and amitriptyline, revealed potential drug-drug interactions at clinical plasma concentrations of metformin for OCT1-M420del.

  • 4374.
    Ahlin, Gustav
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hilgendorf, Constanze
    AstraZeneca R&D, Mölndal.
    Karlsson, Johan
    AstraZeneca R&D, Mölndal, Sweden.
    Al-Khalili Szigyarto, Cristina
    Department of Proteomics, The Royal Institute of Technology, Stockholm, Sweden.
    Uhlén, Mathias
    Department of Proteomics, The Royal Institute of Technology, Stockholm, Sweden.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Endogenous Gene and Protein Expression of Drug Transporting Proteins in Cell Lines Routinely used in Drug Discovery Programs2009In: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 37, no 12, p. 2275-2283Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate the gene and protein expression profiles of important drug transporting proteins in human cell lines commonly used for studies of drug transport mechanisms. Human cell lines used to transiently or stably express single transporters (HeLa, HEK293) and leukaemia cell lines used to study drug resistance by ABC-transporters (HL-60, K562) were investigated, and compared with organotypic cell lines (HepG2, Saos-2, Caco-2 and Caco-2 TC7). For gene expression studies, real-time PCR was used, while monospecific polyclonal antibodies were generated and used to investigate protein expression by immunohistochemistry. Thirty-six transporters were studied for gene expression and nine for protein expression. The antibodies were validated using expression patterns in human tissues. Finally, the function of one ubiquitously expressed transporter, MCT1; SLC16A1 was investigated using 14C-lactic acid as a substrate. In general, the adherent cell lines (HeLa, HEK293) displayed low transporter expression and the expression patterns were barely affected by transfection. The leukaemia cell lines (K562, HL-60) and Saos-2 also had low endogenous transporter expression, while the organotypic cell lines (HepG2 and Caco-2) showed higher expression of some transporters. Comparison of gene and protein expression profiles gave poor correlations, but better agreement was obtained for antibodies with a good validation score, indicating that antibody quality was a significant variable. Importantly, the monocarboxylic acid transporting protein MCT1 was significantly expressed in all, and functional in most of the cell lines, indicating that MCT1 may be a confounding factor when the transport of small anionic drugs is investigated.

  • 4375.
    Ahlin, Gustav
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Karlsson, Johan
    Pedersen, Jenny M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Gustavsson, Lena
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Matsson, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Norinder, Ulf
    Bergström, Christel A S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Structural requirements for drug inhibition of the liver specific human organic cation transport protein 12008In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 51, no 19, p. 5932-5942Article in journal (Refereed)
    Abstract [en]

    The liver-specific organic cation transport protein (OCT1; SLC22A1) transports several cationic drugs including the antidiabetic drug metformin and the anticancer agents oxaliplatin and imatinib. In this study, we explored the chemical space of registered oral drugs with the aim of studying the inhibition pattern of OCT1 and of developing predictive computational models of OCT1 inhibition. In total, 191 structurally diverse compounds were examined in HEK293-OCT1 cells. The assay identified 47 novel inhibitors and confirmed 15 previously known inhibitors. The enrichment of OCT1 inhibitors was seen in several drug classes including antidepressants. High lipophilicity and a positive net charge were found to be the key physicochemical properties for OCT1 inhibition, whereas a high molecular dipole moment and many hydrogen bonds were negatively correlated to OCT1 inhibition. The data were used to generate OPLS-DA models for OCT1 inhibitors; the final model correctly predicted 82% of the inhibitors and 88% of the noninhibitors of the test set.

  • 4376.
    Ahlin, Jacob
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Theology, Department of Theology, Studies in Faith and Ideologies, Systematic Theology and Studies in World Views.
    Spong – reformator eller rotkapare?: – En analys av John Shelby Spongs kristologi och försoningsteologi2017Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
  • 4377.
    Ahlin, Jenny
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Educational Sciences, Department of Education.
    Utbudet av svensk barnlitteratur i översättning: behovet av det och om det används2014Independent thesis Basic level (professional degree), 10 credits / 15 HE creditsStudent thesis
  • 4378.
    Ahlin, Jenny
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Educational Sciences, Department of Education.
    Larsson, Emma
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Educational Sciences, Department of Education.
    Läxstöttning: En statistisk undersökning om föräldrars engagemang och tid2015Independent thesis Advanced level (professional degree), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Under vår verksamhetsförlagda utbildning på Grundlärarprogrammet har vi kunnat urskilja skillnader i vilket stöd eleverna får med läxarbete i hemmet. Utifrån dessa iakttagelser har vi valt att undersöka hur ofta eleverna uppskattar att deras föräldrar ser till att de avsätter tid för att göra sina läxor och hur det påverkar elevernas prestationer. Mycket av den tidigare forskningen tyder på att läxstöttning är väsentligt för hur eleverna presterar i skolan och att det finns stora könsskillnader i hur ofta eleverna får stöttning och också i hur eleverna presterar i skolan. Syftet med studien är att undersöka vilken betydelse föräldrars engagemang och tid till läxstöttning har för elevernas prestationer och huruvida det existerar könsskillnader gällande stöttning i hemmet. Vi har frågat oss hur ofta eleverna och föräldrarna skattar att föräldrarna ser till att eleverna avsätter tid för att göra sina hemläxor. Genom att använda oss av data från TIMSS 2011 har vi kunnat göra våra analyser med hjälp av statistikprogrammet SPSS. Analyserna visar att hur ofta eleverna uppskattar att deras föräldrar ansvarar för att tid avsätts för läxläsning ger marginella skillnader i deras testresultat i TIMSS 2011. Det framkom däremot att det fanns stora skillnader i hur ofta eleverna uppskattade att deras föräldrar ser till att de avsätter tid för att göra sina läxor. Det visade sig också att det inte fanns några större könsskillnader varken i hur ofta eleverna uppskattar att föräldrarna ser till att de avsätter tid för att göra sina läxor eller i relation till deras testresultat i TIMSS 2011. Slutligen kunde vi konstatera att elevernas och föräldrarnas uppskattning om hur ofta detta typ av stöd förekommer i hemmet inte överensstämmer med varandra.

  • 4379.
    Ahlin, Larisa
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Business Studies.
    Verksamhetsstyrning inom en offentlig organisation: En fallstudie av styrningens utformning och praktiska tillämpning2014Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Abstract

    The purpose of this research is to analyze how management is applied practically within selected public sector administrations of Gotland Region and determine what congruence is applied between different management models.

    Empirical data has been collected through semi-structured interviews and together with analysis of Gotland Region governing documents. Firstly the aim was to interview a wide selection of different public sector managers. However, ten representatives from four different administrations were finally interviewed.

    The results of the study show that a balanced management takes a central place in Gotland Region Management Control Systems Package. The complexity of the organization causes difficulties in applying the model to the whole organization. Balanced scorecard is mostly used for goal setting and monitoring. Only in one of four administrations practical application and implementation of balanced scorecard on management level taking place. Implementation of balanced scorecards within organizations with strong cultural governance requires committed managers at all levels, support from the top managers and time for cultural transformation. This study reviled did not find major contradiction between different models of management. However, contradictions may occur within administrative control. Should a conflict between economic aspects and balanced scorecard occur, economy takes control. This rule is clearly stated in the governing documents.

  • 4380.
    Ahlin, Malin
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Business Studies.
    Pettersson, Julia
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Business Studies.
    Fastighetsbolagens val att redovisa till verkligt värde eller anskaffningsvärde: En studie om vilka faktorer som påverkar företag i deras val av redovisningsmetod 2010Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

     

    IAS 40 allows two methods of valuation for investment properties, fair value model and cost model. The purpose of this paper is to investigate what drive property companies to disclose their investment properties at fair value. In order to understand their choice, we use accounting choice theory and the three factors this theory describes, information asymmetry, allowing opportunism and agency costs. To answer our purpose, we have from a qualitative approach performed semi-structured interviews with respondents from five of the largest listed property companies in Sweden. The results suggest that firms have chosen the method that is most effective in the valuation of investment properties. But also that the three factors that accounting choice theory includes: information asymmetry, allowing opportunism and agency costs, reflected in their choice to choose one model over the other.

  • 4381.
    Ahlin, Åsa
    Uppsala University, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Faculty of Social Sciences, Department of Economics.
    1. Individual Demand for Local Public Schooling: Evidence from Swedish Survey Data. 2. Does School Competition Matter? Effects of a Large-Scale School Choice Reform on Student Performance.2002Licentiate thesis, monograph (Other scientific)
  • 4382.
    Ahlin, Åsa
    Uppsala University, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Faculty of Social Sciences, Department of Economics.
    Compulsory Schooling in a Decentralized Setting: Studies of the Swedish Case2004Doctoral thesis, monograph (Other academic)
    Abstract [en]

    Essay 1 (with Eva Johansson) investigates the demand for local public schooling using survey data, a method previously never applied to Sweden. Estimating a demand specification corresponding to that in U.S. studies, more elastic demand than in the U.S. is found. In an alternative specification, a more inelastic demand is indicated, in line with earlier findings on demand for total local spending in Sweden. Support for the hypothesis that municipal employees tend to have higher preferences for local public school spending than other employees is found. The differences in elasticities are, however, not statistically significant.

    Essay 2 investigates school competition and its implications for student performance. Using a value added specification, increased local school competition is shown to have positive effects on average performance in mathematics, but no significant effects in English or Swedish test performance. Immigrant pupils and those in need of special education tend to gain more from increased school competition, while adverse effects on students from low education families are found in terms of English and Swedish performance. Quantile regressions indicate homogeneous effects on low and high performing students.

    Essay 3 (with Eva Mörk) investigates the extent to which grants, local tax base, preferences and structural characteristics affected local school resources in connection with the decentralization of compulsory schooling in Sweden, using municipal panel data covering 1989-1995. The main arguments against decentralization are not supported by our findings. First, school spending as well as teacher density is found to be more equally distributed across municipalities following decentralization. Second, local tax capacity is not found to influence local school resources more in the decentralized than in the centralized regime. Furthermore, targeted grants have a significant impact on resources while general grants have not.

    Essay 4 examines teacher mobility in Sweden. Particular attention is paid to the role of working conditions. Various school attributes are used to proxy for teachers’ working conditions, including the average student performance, school resources and student composition. The results indicate a link, in the expected direction, between school attributes and the probability that a teacher will leave her teaching position in favour of another school. Also, teachers with higher wages tend to have a lower propensity of leaving their school. In contrast to previous US findings, the estimated impact of wages are not sensitive to whether or not controls for school attributes are included.

  • 4383.
    Ahlin, Åsa
    Uppsala University, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Faculty of Social Sciences, Department of Economics.
    Does school competition matter?: Effects of a large-scale school choice reform on student performance2003Report (Other academic)
    Abstract [en]

    The effect of a general school choice reform on student performance is studied in a Swedish institutional setting. A rich set of individual level data allows estimation of a value added specification, mitigating problems with omission of relevant variables. Increased school competition is shown to have statistically significant positive effects on student performance in mathematics, but no significant effects in English and Swedish. Interacting school competition with student characteristics, the results indicate that immigrant students and those in need of special education tend to gain more from increased school competition than others, while adverse effects on students from low education families are found in terms of English and Swedish performance. However, quantile regressions indicate homogeneous effects on low and high performing students.

  • 4384.
    Ahlin, Åsa
    Uppsala University, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Faculty of Social Sciences, Department of Economics.
    Does School Competition Matter? Effects of a Large-Scale School Choice Reform on Student Performance2003Report (Other scientific)
  • 4385.
    Ahlin, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Economics.
    Johansson, Eva
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Economics.
    Demand for local public schooling: another brick in the wall2000Report (Other academic)
    Abstract [en]

    In this paper we investigate the demand for local public school expenditures in Sweden. By using survey data, a method previously never applied to Swedish data, the paper provides an additional piece of evidence on individual demand for publicly provided local services. Estimating a linear demand specification, we find that the demand is inelastic with respect to income and tax, much in line with previous Swedish findings in a median voter framework. Estimation of a log-linear demand specification indicates more elastic demand. Testing the hypothesis that municipal employees tend to have a higher demand for public spending than others, we conclude that income, as well as taxprice, enters the demand function differently for the two groups of employees. We find no evidence of Tiebout sorting.

  • 4386.
    Ahlin, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Economics.
    Johansson, Eva
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Economics.
    Individual Demand for Local Public Schooling: Evidence from Swedish Survey Data2001In: International Tax and Public Finance, ISSN 0927-5940, E-ISSN 1573-6970, Vol. 8, no 4, p. 331-352Article in journal (Refereed)
  • 4387.
    Ahlin, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Economics.
    Mörk, Eva
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Economics. Uppsala University, Units outside the University, Office of Labour Market Policy Evaluation.
    Effects of Decentralization on School Resources2005Report (Other (popular science, discussion, etc.))
  • 4388.
    Ahlin, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Economics.
    Mörk, Eva
    Uppsala University, Units outside the University, Office of Labour Market Policy Evaluation.
    Effects of decentralization on school resources2008In: Economics of Education Review, ISSN 0272-7757, E-ISSN 1873-7382, Vol. 27, no 3, p. 276-284Article in journal (Refereed)
    Abstract [en]

    Sweden has undertaken major national reforms of its school sector, which, consequently, has been classified as one of the most decentralized ones in the OECD. This paper investigates whether local tax base, grants, and preferences affected local school resources differently as decentralization took place. We find that municipal tax base affects per pupil spending in the same way regardless of whether the school sector is centralized or decentralized, but has a smaller effect on teacher–pupil ratio after the reforms. The less-targeted grants are the fewer teachers per pupil do the municipalities employ. The results for local preferences are less clear-cut.

  • 4389.
    Ahlin, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Economics.
    Mörk, Eva
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Economics.
    Effects Of Decentralization On School Resources: Sweden 1989-20022007Report (Other academic)
    Abstract [en]

    Sweden has undertaken major national reforms of its school sector which, con- sequently, has been classified as one of the most decentralized ones in the OECD. This paper investigates whether school resources became more un- equally distributed across municipalities in connection with the reforms and if local tax base, grants, and preferences affected local school resources differently as decentralization took place. Using municipal data the paper studies how per pupil spending and the teacher-pupil ratio has evolved over the period 1989– 2002, separating between three different waves of decentralization. As nothing much has happened with per pupil spending, the teacher-pupil ratio has become more evenly distributed across municipalities. Municipal tax base affects per pupil spending in the same way regardless of whether the school sector is cen- tralized or decentralized, but has a smaller effect on teacher-pupil ratio after the reforms. The less targeted grants are, the fewer teachers per pupil do the mu- nicipalities employ. The results for local preferences are less clear cut.

  • 4390.
    Ahlinder, Linnea
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences. Totalförsvarets forskningsinstitut.
    Raman Spectroscopy and Hyperspectral Analysis of Living Cells Exposed to Nanoparticles2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Nanoparticles, i.e. particles with at least one dimension smaller than 100 nm, are present in large quantities in ambient air and can also be found in an increasing amount of consumer products. It is known that many nanomaterials have physicochemical properties that differ from physicochemical properties of the same material in bulk size. It is therefore important to characterize nanoparticles and to evaluate their toxicity. To understand mechanisms behind nanotoxicity, it is important to study the uptake of nanoparticles, and how they are accumulated. For these purposes model studies of cellular uptake are useful. In this thesis metal oxide and carbon-based nanoparticles have been studied in living cells using Raman spectroscopy. Raman spectroscopy is a method that facilitates a non-destructive analysis without using any fluorescent labels, or any other specific sample preparation. It is possible to collect Raman images, i.e. images where each pixel corresponds to a Raman spectrum, and to use the spectral information to detect nanoparticles, and to identify organelles in cells. In this thesis the question whether or not nanoparticles can enter the cell nucleus of lung epithelial cells has been addressed using hyperspectral analysis. It is shown that titanium dioxide nanoparticles and iron oxide nanoparticles are taken up by cells, and also in the cell nucleus. In contrast, graphene oxide nanoparticles are mainly found attached on the outside of the cell membrane and very few nanoparticles are found in the cell, and none have been detected in the nucleus. It is concluded that graphene oxide nanoparticles are not cytotoxic. However, a comparison of Raman spectra of biomolecules in cells exposed to graphene oxide, unexposed cells and apoptotic cells, shows that the graphene oxide nanoparticles do affect lipid and protein structures. In this thesis, several multivariate data analysis methods have been used to analyze Raman spectra and Raman images. In addition, super-resolution algorithms, which originally have been developed to improve the resolution in photographic images, were optimized and applied to Raman images of cells exposed to submicron polystyrene particles in living cells.

    List of papers
    1. Large Uptake of Titania and Iron Oxide Nanoparticles in the Nucleus of Lung Epithelial Cells as Measured by Raman Imaging and Multivariate Classification
    Open this publication in new window or tab >>Large Uptake of Titania and Iron Oxide Nanoparticles in the Nucleus of Lung Epithelial Cells as Measured by Raman Imaging and Multivariate Classification
    2013 (English)In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 105, no 2, p. 310-319Article in journal (Refereed) Published
    Abstract [en]

    It is a challenging task to characterize the biodistribution of nanoparticles in cells and tissue on a subcellular level. Conventional methods to study the interaction of nanoparticles with living cells rely on labeling techniques that either selectively stain the particles or selectively tag them with tracer molecules. In this work, Raman imaging, a label-free technique that requires no extensive sample preparation, was combined with multivariate classification to quantify the spatial distribution of oxide nanoparticles inside living lung epithelial cells (A549). Cells were exposed to TiO2 (titania) and/or alpha-FeO(OH) (goethite) nanoparticles at various incubation times (4 or 48 h). Using multivariate classification of hyperspectral Raman data with partial least-squares discriminant analysis, we show that a surprisingly large fraction of spectra, classified as belonging to the cell nucleus, show Raman bands associated with nanoparticles. Up to 40% of spectra from the cell nucleus show Raman bands associated with nanoparticles. Complementary transmission electron microscopy data for thin cell sections qualitatively support the conclusions.

    National Category
    Engineering and Technology
    Research subject
    Engineering Science with specialization in Solid State Physics
    Identifiers
    urn:nbn:se:uu:diva-206593 (URN)10.1016/j.bpj.2013.06.017 (DOI)000321941700006 ()
    Available from: 2013-09-02 Created: 2013-09-02 Last updated: 2017-12-06Bibliographically approved
    2. Super-resolution Raman mapping of living cells exposed to submicron polystyrene particles
    Open this publication in new window or tab >>Super-resolution Raman mapping of living cells exposed to submicron polystyrene particles
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Engineering and Technology
    Identifiers
    urn:nbn:se:uu:diva-251333 (URN)
    Available from: 2015-04-15 Created: 2015-04-15 Last updated: 2015-05-18
    3. Evidence of nuclear uptake and increased DNA damage in human lung epithelial cells after low dose exposure to reactive titanium dioxide nanoparticles
    Open this publication in new window or tab >>Evidence of nuclear uptake and increased DNA damage in human lung epithelial cells after low dose exposure to reactive titanium dioxide nanoparticles
    (English)Manuscript (preprint) (Other academic)
    National Category
    Engineering and Technology
    Identifiers
    urn:nbn:se:uu:diva-251336 (URN)
    Available from: 2015-04-15 Created: 2015-04-15 Last updated: 2015-05-18
    4. Graphene oxide nanoparticle attachment and its toxicity on living lung epithelial cells
    Open this publication in new window or tab >>Graphene oxide nanoparticle attachment and its toxicity on living lung epithelial cells
    Show others...
    2015 (English)In: RSC Advances, ISSN 2046-2069, E-ISSN 2046-2069, Vol. 5, no 73, p. 59447-59457Article in journal (Refereed) Published
    Abstract [en]

    Since its discovery, graphene and its oxidized form, graphene oxide (GO), have attracted interest in a wide range of technical applications. Concerns about their potential toxicity calls for scrutinized studies, but hitherto conflicting results have been reported which partly may be due to variations of synthesis and exposure procedures. Here we report on the attachment and toxicity of contamination-free graphene oxide nanoparticles (GONP) in living lung epithelial cells. The synthesis of chemically pure GONP was made by an improvement of the Hummer's method based on graphene exfoliated from graphite using high-intensity ultrasonication, resulting in two dimensional sheets with a lateral dimension in the range 200 nm to 3 mu m and thickness of 0.9 nm. Confocal Raman spectroscopy combined with multivariate analysis was used to study the interaction of GONP and living cells. It is shown that overlapping Raman bands due to GONPs and biomolecules in the cells can clearly be separated with this approach. Orthogonal partial least squares discriminant analysis was used to compare spectral data collected from cells exposed to GONP with spectral data collected from non-exposed control cells, and spectral data from cells exposed to a surfactant known to induce apoptosis. Our analyses show that GONP readily attach to the cells, forming sheets which cover a large fraction of the cell surfaces, and induce small chemical changes. In particular, chemical modifications of proteins and lipids in lung epithelial cells are inferred. GONPs do not, however, decrease cell viability. In contrast, enhanced cell proliferation is observed. Our results shed new light on the interactions of GO, and in contrast to some previous reports, suggest that GO is not toxic. The hyperspectral Raman spectroscopy analysis employed here should be applicable for other fields in nanomedicine as a label-free non-perturbing analytical method.

    Place, publisher, year, edition, pages
    Royal Society of Chemistry, 2015
    National Category
    Other Engineering and Technologies
    Identifiers
    urn:nbn:se:uu:diva-251338 (URN)10.1039/C5RA09351A (DOI)000357961800060 ()
    Available from: 2015-04-15 Created: 2015-04-15 Last updated: 2017-12-04Bibliographically approved
    5. Polymorph and size dependent uptake and toxicity of TiO2 nanoparticles in living lung epithelial cells
    Open this publication in new window or tab >>Polymorph and size dependent uptake and toxicity of TiO2 nanoparticles in living lung epithelial cells
    Show others...
    2011 (English)In: Small, ISSN 1613-6810, Vol. 7, no 4, p. 514-523Article in journal (Refereed) Published
    Abstract [en]

    The cellular uptake and distribution of five types of well-characterized anatase and rutile TiO(2) nanoparticles (NPs) in A549 lung epithelial cells is reported. Static light scattering (SLS), in-vitro Raman microspectroscopy (mu-Raman) and transmission electron spectroscopy (TEM) reveal an intimate correlation between the intrinsic physicochemical properties of the NPs, particle agglomeration, and cellular NP uptake. It is shown that mu-Raman facilitates chemical-, polymorph-, and size-specific discrimination of endosomal-particle cell uptake and the retention of particles in the vicinity of organelles, including the cell nucleus, which quantitatively correlates with TEM and SLS data. Depth-profiling mu-Raman coupled with hyperspectral data analysis confirms the location of the NPs in the cells and shows that the NPs induce modifications of the biological matrix. NP uptake is found to be kinetically activated and strongly dependent on the hard agglomeration size-not the primary particle size-which quantitatively agrees with the measured intracellular oxidative stress. Pro-inflammatory responses are also found to be sensitive to primary particle size.

    National Category
    Engineering and Technology
    Research subject
    Engineering Science with specialization in Solid State Physics
    Identifiers
    urn:nbn:se:uu:diva-139730 (URN)10.1002/smll.201001832 (DOI)000288080400013 ()
    Available from: 2010-12-29 Created: 2010-12-29 Last updated: 2016-04-19Bibliographically approved
  • 4391.
    Ahlinder, Linnea
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Solid State Physics.
    Ekstrand-Hammarstrom, Barbro
    Geladi, Paul
    Österlund, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Solid State Physics.
    Large Uptake of Titania and Iron Oxide Nanoparticles in the Nucleus of Lung Epithelial Cells as Measured by Raman Imaging and Multivariate Classification2013In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 105, no 2, p. 310-319Article in journal (Refereed)
    Abstract [en]

    It is a challenging task to characterize the biodistribution of nanoparticles in cells and tissue on a subcellular level. Conventional methods to study the interaction of nanoparticles with living cells rely on labeling techniques that either selectively stain the particles or selectively tag them with tracer molecules. In this work, Raman imaging, a label-free technique that requires no extensive sample preparation, was combined with multivariate classification to quantify the spatial distribution of oxide nanoparticles inside living lung epithelial cells (A549). Cells were exposed to TiO2 (titania) and/or alpha-FeO(OH) (goethite) nanoparticles at various incubation times (4 or 48 h). Using multivariate classification of hyperspectral Raman data with partial least-squares discriminant analysis, we show that a surprisingly large fraction of spectra, classified as belonging to the cell nucleus, show Raman bands associated with nanoparticles. Up to 40% of spectra from the cell nucleus show Raman bands associated with nanoparticles. Complementary transmission electron microscopy data for thin cell sections qualitatively support the conclusions.

  • 4392.
    Ahlinder, Linnea
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Solid State Physics.
    Henych, Jiří
    Wiklund Lindström, Susanne
    Ekstrand-Hammarström, Barbro
    Stengl, Václav
    Österlund, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Solid State Physics.
    Graphene oxide nanoparticle attachment and its toxicity on living lung epithelial cells2015In: RSC Advances, ISSN 2046-2069, E-ISSN 2046-2069, Vol. 5, no 73, p. 59447-59457Article in journal (Refereed)
    Abstract [en]

    Since its discovery, graphene and its oxidized form, graphene oxide (GO), have attracted interest in a wide range of technical applications. Concerns about their potential toxicity calls for scrutinized studies, but hitherto conflicting results have been reported which partly may be due to variations of synthesis and exposure procedures. Here we report on the attachment and toxicity of contamination-free graphene oxide nanoparticles (GONP) in living lung epithelial cells. The synthesis of chemically pure GONP was made by an improvement of the Hummer's method based on graphene exfoliated from graphite using high-intensity ultrasonication, resulting in two dimensional sheets with a lateral dimension in the range 200 nm to 3 mu m and thickness of 0.9 nm. Confocal Raman spectroscopy combined with multivariate analysis was used to study the interaction of GONP and living cells. It is shown that overlapping Raman bands due to GONPs and biomolecules in the cells can clearly be separated with this approach. Orthogonal partial least squares discriminant analysis was used to compare spectral data collected from cells exposed to GONP with spectral data collected from non-exposed control cells, and spectral data from cells exposed to a surfactant known to induce apoptosis. Our analyses show that GONP readily attach to the cells, forming sheets which cover a large fraction of the cell surfaces, and induce small chemical changes. In particular, chemical modifications of proteins and lipids in lung epithelial cells are inferred. GONPs do not, however, decrease cell viability. In contrast, enhanced cell proliferation is observed. Our results shed new light on the interactions of GO, and in contrast to some previous reports, suggest that GO is not toxic. The hyperspectral Raman spectroscopy analysis employed here should be applicable for other fields in nanomedicine as a label-free non-perturbing analytical method.

  • 4393.
    Ahlinder, Linnea
    et al.
    Swedish Def Res Agcy, FOI, Cementvagen 20, SE-90182 Umea, Sweden..
    Lindstrom, Susanne Wiklund
    Swedish Def Res Agcy, FOI, Cementvagen 20, SE-90182 Umea, Sweden..
    Lejon, Christian
    Swedish Def Res Agcy, FOI, Cementvagen 20, SE-90182 Umea, Sweden..
    Geladi, Paul
    Swedish Univ Agr Sci, Dept Forest Biomat & Technol, SE-90183 Umea, Sweden..
    Österlund, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Solid State Physics.
    Noise Removal with Maintained Spatial Resolution in Raman Images of Cells Exposed to Submicron Polystyrene Particles2016In: NANOMATERIALS, ISSN 2079-4991, Vol. 6, no 5, article id UNSP 83Article in journal (Refereed)
    Abstract [en]

    The biodistribution of 300 nm polystyrene particles in A549 lung epithelial cells has been studied with confocal Raman spectroscopy. This is a label-free method in which particles and cells can be imaged without using dyes or fluorescent labels. The main drawback with Raman imaging is the comparatively low spatial resolution, which is aggravated in heterogeneous systems such as biological samples, which in addition often require long measurement times because of their weak Raman signal. Long measurement times may however induce laser-induced damage. In this study we use a super-resolution algorithm with Tikhonov regularization, intended to improve the image quality without demanding an increased number of collected pixels. Images of cells exposed to polystyrene particles have been acquired with two different step lengths, i.e., the distance between pixels, and compared to each other and to corresponding images treated with the super-resolution algorithm. It is shown that the resolution after application of super-resolution algorithms is not significantly improved compared to the theoretical limit for optical microscopy. However, to reduce noise and artefacts in the hyperspectral Raman images while maintaining the spatial resolution, we show that it is advantageous to use short mapping step lengths and super-resolution algorithms with appropriate regularization. The proposed methodology should be generally applicable for Raman imaging of biological samples and other photo-sensitive samples.

  • 4394.
    Ahlinder, Linnea
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences.
    Wiklund Lindström, Susanne
    Lejon, Christian
    Geladi, Paul
    Österlund, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences.
    Super-resolution Raman mapping of living cells exposed to submicron polystyrene particlesManuscript (preprint) (Other academic)
  • 4395. Ahlinder, Linnea
    et al.
    Österlund, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Solid State Physics.
    Hyperspektral analys av celler och vävnad exponerade för luftburna partiklar2010Report (Refereed)
  • 4396.
    Ahlinder, Linnea
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Solid State Physics.
    Österlund, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Solid State Physics.
    Wiklund Lindström, Susanne
    Raman mapping and hyperspectral data analysis2010Report (Refereed)
  • 4397.
    Ahlkrona, Josefin
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Scientific Computing. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Numerical Analysis.
    Computational Ice Sheet Dynamics: Error control and efficiency2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Ice sheets, such as the Greenland Ice Sheet or Antarctic Ice Sheet, have a fundamental impact on landscape formation, the global climate system, and on sea level rise. The slow, creeping flow of ice can be represented by a non-linear version of the Stokes equations, which treat ice as a non-Newtonian, viscous fluid. Large spatial domains combined with long time spans and complexities such as a non-linear rheology, make ice sheet simulations computationally challenging. The topic of this thesis is the efficiency and error control of large simulations, both in the sense of mathematical modelling and numerical algorithms. In the first part of the thesis, approximative models based on perturbation expansions are studied. Due to a thick boundary layer near the ice surface, some classical assumptions are inaccurate and the higher order model called the Second Order Shallow Ice Approximation (SOSIA) yields large errors. In the second part of the thesis, the Ice Sheet Coupled Approximation Level (ISCAL) method is developed and implemented into the finite element ice sheet model Elmer/Ice. The ISCAL method combines the Shallow Ice Approximation (SIA) and Shelfy Stream Approximation (SSA) with the full Stokes model, such that the Stokes equations are only solved in areas where both the SIA and SSA is inaccurate. Where and when the SIA and SSA is applicable is decided automatically and dynamically based on estimates of the modeling error. The ISCAL method provides a significant speed-up compared to the Stokes model. The third contribution of this thesis is the introduction of Radial Basis Function (RBF) methods in glaciology. Advantages of RBF methods in comparison to finite element methods or finite difference methods are demonstrated.

    List of papers
    1. A numerical study of scaling relations for non-Newtonian thin-film flows with applications in ice sheet modelling
    Open this publication in new window or tab >>A numerical study of scaling relations for non-Newtonian thin-film flows with applications in ice sheet modelling
    2013 (English)In: Quarterly Journal of Mechanics and Applied Mathematics, ISSN 0033-5614, E-ISSN 1464-3855, Vol. 66, p. 417-435Article in journal (Refereed) Published
    National Category
    Computational Mathematics
    Identifiers
    urn:nbn:se:uu:diva-205727 (URN)10.1093/qjmam/hbt009 (DOI)000327457200001 ()
    Projects
    eSSENCE
    Available from: 2013-08-09 Created: 2013-08-22 Last updated: 2017-12-06Bibliographically approved
    2. Accuracy of the zeroth- and second-order shallow-ice approximation: numerical and theoretical results
    Open this publication in new window or tab >>Accuracy of the zeroth- and second-order shallow-ice approximation: numerical and theoretical results
    2013 (English)In: Geoscientific Model Development, ISSN 1991-959X, E-ISSN 1991-9603, Vol. 6, p. 2135-2152Article in journal (Refereed) Published
    National Category
    Computational Mathematics
    Identifiers
    urn:nbn:se:uu:diva-213571 (URN)10.5194/gmd-6-2135-2013 (DOI)000329050500017 ()
    Projects
    eSSENCE
    Available from: 2013-12-19 Created: 2013-12-28 Last updated: 2017-12-06Bibliographically approved
    3. Dynamically coupling the non-linear Stokes equations with the shallow ice approximation in glaciology: Description and first applications of the ISCAL method
    Open this publication in new window or tab >>Dynamically coupling the non-linear Stokes equations with the shallow ice approximation in glaciology: Description and first applications of the ISCAL method
    2016 (English)In: Journal of Computational Physics, ISSN 0021-9991, E-ISSN 1090-2716, Vol. 308, p. 1-19Article in journal (Refereed) Published
    National Category
    Computational Mathematics
    Identifiers
    urn:nbn:se:uu:diva-269822 (URN)10.1016/j.jcp.2015.12.025 (DOI)000369086700001 ()
    Projects
    eSSENCE
    Available from: 2015-12-17 Created: 2015-12-18 Last updated: 2017-12-01Bibliographically approved
    4. The ISCAL method and the grounding line: Combining the Stokes equations with the Shallow Ice Approximation and Shelfy Stream Approximation
    Open this publication in new window or tab >>The ISCAL method and the grounding line: Combining the Stokes equations with the Shallow Ice Approximation and Shelfy Stream Approximation
    2016 (English)Report (Other academic)
    Series
    Technical report / Department of Information Technology, Uppsala University, ISSN 1404-3203 ; 2016-006
    National Category
    Computational Mathematics
    Identifiers
    urn:nbn:se:uu:diva-283438 (URN)
    Projects
    eSSENCE
    Available from: 2016-04-19 Created: 2016-04-13 Last updated: 2016-05-16Bibliographically approved
    5. A meshfree approach to non-Newtonian free surface ice flow: Application to the Haut Glacier d'Arolla
    Open this publication in new window or tab >>A meshfree approach to non-Newtonian free surface ice flow: Application to the Haut Glacier d'Arolla
    2016 (English)Report (Other academic)
    Series
    Technical report / Department of Information Technology, Uppsala University, ISSN 1404-3203 ; 2016-005
    National Category
    Computational Mathematics
    Identifiers
    urn:nbn:se:uu:diva-283437 (URN)
    Projects
    eSSENCE
    Available from: 2016-04-19 Created: 2016-04-13 Last updated: 2016-05-16Bibliographically approved
  • 4398.
    Ahlkrona, Josefin
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Scientific Computing.
    Implementing Higher Order Dynamics into the Ice Sheet Model SICOPOLIS2011Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Ice sheet modeling is an important tool both for reconstructing past ice sheets and predicting their future evolution, but is complex and computationally costly. It involves modeling a system including the ice sheet, ice shelves and ice streams, which all have different dynamical behavior. The governing equations are non-linear, and to capture a full glacial cycle more than 100,000 years need to be simulated. To reduce the problem size, approximations of the equations are introduced. The most common approximation, the Shallow Ice Approximation (SIA), works well in the ice bulk but fails in e.g. the modeling of ice streams and the ice sheet/ice shelf coupling. In recent years more accurate models, so-called higher order models, have been constructed to address these problems. However, these models are generally constructed in an ad hoc fashion, lacking rigor. In this thesis, so-called Second Order Shallow Ice Approximation (SOSIA) equations for pressure, vertical shear stress and velocity are implemented into the ice sheet model SICOPOLIS. The SOSIA is a rigorous model derived by Baral in 1999 [3]. The numerical solution for a simple model problem is compared to an analytical solution, and benchmark experiments, comparing the model to other higher order models, are carried out. The numerical and analytical solution agree well, but the results regarding vertical shear stress and velocity differ from other models. It is concluded that there are problems with the model implemented, most likely in the treatment of the relation between stress and strain rate.

     

  • 4399.
    Ahlkrona, Josefin
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Scientific Computing. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Numerical Analysis.
    The ISCAL method and the grounding line: Combining the Stokes equations with the Shallow Ice Approximation and Shelfy Stream Approximation2016Report (Other academic)
  • 4400.
    Ahlkrona, Josefin
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Scientific Computing. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Numerical Analysis.
    Kirchner, Nina
    Lötstedt, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Scientific Computing. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Numerical Analysis.
    A numerical study of scaling relations for non-Newtonian thin-film flows with applications in ice sheet modelling2013In: Quarterly Journal of Mechanics and Applied Mathematics, ISSN 0033-5614, E-ISSN 1464-3855, Vol. 66, p. 417-435Article in journal (Refereed)
85868788899091 4351 - 4400 of 252434
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