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  • 2251.
    Abrahamsson, Sten
    et al.
    Gotland University, School of the Humanities and Social Science.
    Hansson, Jonas
    Högskolan Väst.
    Isaksson, Raine
    Gotland University, School of the Humanities and Social Science.
    Integrated Management Systems: testing a model for integration2011In: 14th Toulon-Verona Conference: Organizational Excellence in Service, 1-3 September, 2011, Alicante, Spain / [ed] Jacques Martin and Claudio Baccarani, University of Alicante and University of Oviedo, Spain , 2011, p. 22-35Conference paper (Other academic)
    Abstract [en]

    Management systems are widely used for creating order, minimising risks and for assuring performance. Management systems are in many occasions integrated since this has been found to be beneficial. In this paper a model for a fully integrated management system (IMS) based on the three axes of level, extent and scope of integration is tested for relevance. The studied system permits the integration of all relevant process dimensions. The research is only in a pilot stage, but the initial results are promising and indicate that there are advantages in using the process view as a base for identifying critical aspects to be managed. A review of the current situation for system integration is studied and the model is subjected to some tests using Sweden as a case. The background study shows that system integration still is limited, especially when comparing with a fully integrated IMS. The feedback from the organisations interviewed is positive and supports continued work with development of the model.

  • 2252.
    Abrahamsson, Sten
    et al.
    Gotland University, School of the Humanities and Social Science.
    Isaksson, Raine
    Gotland University, School of the Humanities and Social Science.
    Adding requirements on customers to current quality models toimprove quality: development of a customer ‐ vendor interaction2010In: 13th QMOD conference on Quality and Service Sciences ICQSS 2010 / [ed] Jens J. Dahlgaard, Linköping University, Sweden, Visby: Gotland University , 2010, p. 1-9Conference paper (Refereed)
    Abstract [en]

    In most descriptions of business development and models for Corporate Governance, contacts between supplier and customer are for the most part focused on the supplier’s responsibility to identify and document customer requirements in order to enable the organization to meet customer requirements (stated and unstated). In the actual contact between customer and supplier it has been observed in several cases that there are aspects of the interaction not described in traditional theoretical quality models. What seems to be missing is a more explicit requirement for customers and for customers' actions. The logic is that a qualified customer performing based on supplier instructions will result in a better performing product. The apparent lack of theoretical models describing this aspect indicates that this is an interesting area for research and development.

    The purpose of this paper is to highlight a seemingly "forgotten" area within quality management, which is the lack of requirements put on customers in quality models.  The first objective is to review existing quality models to explore the extent of requirement on customers included. The second objective is to propose additions to current models that include requirements placed on customers.

    A limited review of the award criteria and the most common models for quality and improvement techniques shows that there is no explicit and documented way to set requirements for customers. Our interpretation is that EFQM is the model closest to our description of “demands on customer” due to their clauses connected to “partnership”.

    The ISO/DIS 26000 is moving the requirements further against the customer for the social responsibility than the quality standards are doing.

    Further research could focus on how requirements on customer will affect the performance of the entire supply chain both from a quality and social point of view.

  • 2253.
    Abrahamsson, Sten
    et al.
    Gotland University, School of the Humanities and Social Science.
    Isaksson, Raine
    Gotland University, School of the Humanities and Social Science.
    Implementing Lean: Discussing Standardization Versus Customization with Focus on National Cultural Dimensions2012In: Management and Production Engineering Review, ISSN 2082-1344, Vol. 3, no 4, p. 4-13Article in journal (Refereed)
    Abstract [en]

    Lean or Toyota Production System (TPS) has more or less successfully been implemented in the Western world’s businesses and organizations for the past 20 years. Several authors have discussed what it is that creates a successful implementation, and several studies have been presented where strategies for implementations have been studied. Culture’s impact and possible mitigation for Western companies have been studied and described by for example Womak & Jones. Proponents of the concept of Lean argue that culture is not a constraint for implementation of Lean. Lean Management is called a philosophy but it is often used as a change strategy in the sense that it is implemented with the view of improving performance. A change strategy could be seen as a product that might have to be customized with the view of improving the effectiveness of the implementation. On the other hand abandoning a standardized approach comes with the risk of severely altering the change strategy, possibly to its detriment. Implementing Lean will have an effect on the company culture. Does it make any sense customizing the implementation to culture if the issue is changing the culture? The purpose of this paper is to highlight and discuss the balance between a customized implementation and a standardized implementation. Which are the main arguments for standardization and customization and how could these be reconciled? A literature study of Lean implementation has been carried out and compared with Lean principles and theories from change management with focus on change drivers and change barriers. Main drivers of Hofstede’s national cultural dimensions are compared with Lean principles to identify possible drivers and barriers in different cultures. The theory synthesis on drivers and barriers is subjected to a first test in a case study on Lean implementation according to a standardized approach. The implementation is made in a small Swedish factory belonging to a worldwide industrial company. Results from the literature review and the case study indicate that both customization and standardization are needed.

  • 2254.
    Abrahamsson, Sten
    et al.
    Gotland University, School of the Humanities and Social Science.
    Isaksson, Raine
    Gotland University, School of the Humanities and Social Science.
    Hansson, Jonas
    University West.
    Integrated Management Systems: advantages, problems and possibilities2010In: 13th Toulon-Verona Conference: Organizational Excellence in Service / [ed] Jacques Martin, Toulon University, 2010, p. 1-12Conference paper (Refereed)
    Abstract [en]

    Effective management in the globalized world requires an effective, efficient and flexible management system. Effective could be interpreted as addressing all relevant stakeholder concerns in a context of Corporate Social Responsibility (CSR). Efficient would mean that it does the job with low resource use. Flexibility requires that changed conditions and new requirements easily can be included. Many organizations are already working with Integrated Management Systems (IMS). Interesting questions are to what extent current integration covers the above mentioned needs and if not what changes are needed. This conceptual paper looks at the advantages and problems of integration. Possibilities for development of fully integrated management systems are studied from the perspective of managing stakeholder needs, with the forthcoming ISO 26000 – “Guidance on social responsibility”, as inspiration. Results show that there are advantages in integration, but that the scope and level of integration often is limited. A conceptual model for integrating all stakeholder needs in value networks is presented.

  • 2255.
    Abrahamsson Söderberg, Sofie
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Business Studies.
    Rällfors, Axel
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Business Studies.
    Upplysningskrav vid värdering till verkligt värde: En studie om hur företag har anpassat sig till upplysningskraven kring verkligt värde och revisorns roll vid granskningen av dess efterlevnad2014Independent thesis Advanced level (degree of Master (One Year)), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    De senaste åren har värderingsmetoden värdering till verkligt värde blivit mycket kritiserad. Bland annat anses värderingsmetoden ge allt för stort utrymme för en företagsledning att manipulera de finansiella rapporterna. Uppsatsen behandlar därför hur väl företag följer upplysningskraven som de ska följa när de värderar tillgångar och skulder till verkligt värde enligt den internationella redovisningsstandarden IFRS 13 (International Financial Reporting Standard) samt revisorns uttalande i revisionsberättelsen gällande företagens efterlevnad av upplysningskraven. Detta görs för att studera om upplysningskraven efterföljs och i de fall då företagen inte följer upplysningskraven huruvida revisorn gör ett modifierat uttalande i revisionsberättelsen. Urvalet för studien är samtliga företag noterade på Stockholmsbörsen, Nasdaq OMX Stockholm, inom skogs-, fastighets- och banksektorn år 2012 och år 2013. Data har insamlats genom bearbetning och analyser av respektive företags årsredovisning. Av studien följer att företagen inte efterlever upplysningskraven fullt ut och att respektive företags revisor inte väljer att göra ett modifierat uttalande trots att ISA (International Standards on Auditing) uppmanar till det. Fastighetsbolagen visar högst efterlevnad av upplysningar, därefter kommer skogsbolagen och sist bankerna.

  • 2256.
    Abrahamsson Söderberg, Sofie
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Business Studies.
    Tunstig, Sanna
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Business Studies.
    En studie av storbankers finansiella ställning: I finanskrisens spår2014Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Finansiella institutioner har en stor samhällspåverkan, något som inte minst tydliggjordes genom den senaste finanskrisen då bankers finansiella ställning ifrågasattes. Studien syftar därför till att skapa en överblick hur bankers finansiella ställning sett ut i samband med finanskrisen år 2008. Undersökningen har genomförts genom att använda en övergripande modell baserad på nyckeltal som anses mäta bankers finansiella ställning, samt en kompletterande information i form av icke-numerisk data. Utifrån resultatet kunde det observeras att den genomsnittliga finansiella ställningen under perioden år 2007-2012 varit svag, samt att den var något svagare år 2012 än år 2007. Slutsatsen som kunde dras var att de europeiska bankerna haft en svag finansiell ställning och att tillgångskvaliteten ofta haft en betydelse för den finansiella ställningen. Studien fann dock några fall då banker haft en låg tillgångskvalitet men hög kapitaltäckning och/eller likviditet.

  • 2257. Abrahmsen-Alami, S
    et al.
    Persson, K
    Stilbs, P
    Alami, E
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical Chemistry.
    Effect of temperature on NMR self-diffusion in aqueous associative polymer solutions1996In: Journal of Physical Chemistry, Vol. 100, no 11, p. 4598-4605Article in journal (Refereed)
    Abstract [en]

    The temperature dependence of polymer self-diffusion rates in aqueous solutions of C12EO200C12 (AP9, Mw = 9300) and C12EO90C12 (AP4, Mw = 4600) and nonmodified analogues PEO10 and PEO4 (Mw = 10 000 and 3400) has been studied. The effect of the hydrophobic end-groups on the self-diffusion of the associative polymer (AP) was found to be proportional to the polymer content and inversely related to the temperature. The variation of the AP self-diffusion coefficient follows an Arrhenius behavior. The resulting apparent activation energies, Ea, increase with polymer content from 15 to 55 kJ/mol in the range 0.5−50 wt % for AP9, whereas the parent PEO10 shows an almost constant Ea of about 25 kJ/mol in the same concentration range. Activation energies derived from self-diffusion and low shear viscosity measurements were found to be quite similar. The distribution of self-diffusion coefficients often observed in AP systems is discussed in terms of distribution of aggregate sizes at low AP content and homogeneity of the network at higher contents. The residence time of an AP monomer in a hydrophobic domain was estimated as 0.1 ms at 25 °C and decreases with temperature. Also included are turbidity measurements on the AP systems.

  • 2258. Abrahmsén-Alami, S
    et al.
    Stilbs, P
    Alami, Elouafi
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical Chemistry.
    Water self-diffusion in aqueous associative polymer solutions1996In: JOURNAL OF PHYSICAL CHEMISTRY, Vol. 100, no 16, p. 6691-6697Article in journal (Refereed)
    Abstract [en]

    Water self-diffusion in aqueous model associative polymer (AP) solutions, hydrophobically end-capped poly(ethylene oxide), C12EO200C12 (AP9,) and C12EO90C12 (AP4), has been studied with the NMR-PGSE method and compared to the diffusion in nonmodified poly(ethylene oxide) PEO. It was found that it decreases monotonically with increasing polymer concentration, giving Di/D0 ≈ 0.2 at 50 wt % (D0 being the water self-diffusion coefficient in the absence of polymer), independently of polymer molecular weight and modification. In further evaluation of the data, the cell-diffusion model was used. Such an analysis suggests that up to a polymer content of about 2 wt % AP9, water diffusion is not significantly affected by the polymer. Above this concentration, up to about 10 water molecules per EO group are affected in AP9 and AP4 solutions. On increasing the temperature, water self-diffusion increases, following an Arrhenius-like equation, with Ea equal to that of pure water at low polymer content (10 wt %). The activation energy increases with polymer content, and at 50 wt %, Ea is about 30 kJ/mol, independently of polymer type. A minor difference in Ea between AP4 and AP9 solutions at intermediate polymer content is likely to originate from the ability of AP4 to form well-developed cubic phase structures. An increase in temperature was found to lead to a slight dehydration of the associative polymer EO monomers closest to the hydrophobic core.

  • 2259. Abramczyk, Olga
    et al.
    Zien, Piotr
    Zielinski, Rafał
    Pilecki, Marek
    Hellman, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Szyszka, Ryszard
    The protein kinase 60S is a free catalytic CK2alpha' subunit and forms an inactive complex with superoxide dismutase SOD12003In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 307, no 1, p. 31-40Article in journal (Refereed)
    Abstract [en]

    The 60S ribosomes from Saccharomyces cerevisiae contain a set of acidic P-proteins playing an important role in the ribosome function. Reversible phosphorylation of those proteins is a mechanism regulating translational activity of ribosomes. The key role in regulation of this process is played by specific, second messenger-independent protein kinases. The PK60S kinase was one of the enzymes phosphorylating P-proteins. The enzyme has been purified from yeast and characterised. Pure enzyme has properties similar to those reported for casein kinase type 2. Peptide mass fingerprinting (PMF) has identified the PK60S as a catalytic alpha(') subunit of casein kinase type 2 (CK2alpha(')). Protein kinase activity is inhibited by SOD1 and by highly specific CK2 inhibitor-4,5,6,7-tetrabromo-benzotriazole (TBBt). The possible mechanism of regulation of CK2alpha(') activity in stress conditions, by superoxide dismutase in regulation of 80S-ribosome activity, is discussed.

  • 2260.
    Abramenkovs, Andris
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Spiegelberg, Diana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Nilsson, Sten
    Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
    Stenerlöw, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    The α-emitter Ra-223 induces clustered DNA damage and significantly reduces cell survivalManuscript (preprint) (Other academic)
    Abstract [en]

    The bone-seeking radiopharmaceutical Xofigo (Radium-223 dichloride) has demonstrated both extended survival and palliative effects in treatment of bone metastases in patients with prostate cancer. The alpha-particle emitter Ra-223, administered as Ra-223 dichloride, targets regions undergoing active bone remodeling and strongly binds hydroxyapatite found in bone. However, the mechanisms mediating toxicity and properties of Ra-223 binding to hydroxyapatite are not fully understood. In the current study, we show that the alpha-particles originating from the Ra-223 decay chain produce a track-like distribution of the DNA damage response proteins 53BP1 and ɣH2AX and induce high amounts of clustered DNA double-strand breaks in prostate cancer cell nuclei. The Ra-223 treatment inhibited growth of prostate cancer cells, grown in 2D- and 3D- models in vitro, independent of prostate cancer cell type and androgen receptor variant 7 (ARv7) expression. The rapid binding with a high affinity of Ra-223 to bone structures was verified in an in silico assay (KD= 19.2 ± 6.5 e-18) and almost no dissociation was detected within 24 hours. Importantly, there was no significant uptake of Ra-223 in cells. Further, we demonstrate the importance of the local dose-distribution of this treatment; there was more than 100-fold increase in cell killing when Ra-223 was attached to the bone-like hydroxyapatite structure, compared to when the radioactivity was distributed in the cell growth media. However, independent of the exposure condition, the high cell killing efficacy of the Ra-223 was attributed to the clustered DNA damaged sites induced by the released α-particles.

  • 2261.
    Abramenkovs, Andris
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Spiegelberg, Diana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Stenerlöw, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Ra223 induced clustered DNA damage reduces cell survival independently of androgen receptor variant 7 expression2018In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 45, p. S634-S635Article in journal (Other academic)
  • 2262.
    Abramenkovs, Andris
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Stenerlöw, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Measurement of DNA-Dependent Protein Kinase Phosphorylation Using Flow Cytometry Provides a Reliable Estimate of DNA Repair Capacity2017In: Radiation Research, ISSN 0033-7587, E-ISSN 1938-5404, Vol. 188, no 6, p. 597-604Article in journal (Refereed)
    Abstract [en]

    Uncontrolled generation of DNA double-strand breaks (DSBs) in cells is regarded as a highly toxic event that threatens cell survival. Radiation-induced DNA DSBs are commonly measured by pulsed-field gel electrophoresis, microscopic evaluation of accumulating DNA damage response proteins (e.g., 53BP1 or gamma-H2AX) or flow cytometric analysis of gamma-H2AX. The advantage of flow cytometric analysis is that DSB formation and repair can be studied in relationship to cell cycle phase or expression of other proteins. However, gamma-H2AX is not able to monitor repair kinetics within the first 60 min postirradiation, a period when most DSBs undergo repair. A key protein in non-homologous end joining repair is the catalytic subunit of DNA-dependent protein kinase. Among several phosphorylation sites of DNA-dependent protein kinase, the threonine at position 2609 (T2609), which is phosphorylated by ataxia telangiectasia mutated (ATM) or DNA-dependent protein kinase catalytic subunit itself, activates the end processing of DSB. Using flow cytometry, we show here that phosphorylation at T2609 is faster in response to DSBs than gamma-H2AX. Furthermore, flow cytometric analysis of T2609 resulted in a better representation of fast repair kinetics than analysis of gamma-H2AX. In cells with reduced ligase IV activity, and wild-type cells where DNA-dependent protein kinase activity was inhibited, the reduced DSB repair capacity was observed by T2609 evaluation using flow cytometry. In conclusion, flow cytometric evaluation of DNA-dependent protein kinase T2609 can be used as a marker for early DSB repair and gives a better representation of early repair events than analysis of gamma-H2AX.

  • 2263.
    Abramenkovs, Andris
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Stenerlöw, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Removal of heat-sensitive clustered damaged DNA sites is independent of double-strand break repair2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 12, article id e0209594Article in journal (Refereed)
    Abstract [en]

    DNA double-strand breaks (DSBs) are the most deleterious lesions that can arise in cells after ionizing radiation or radiometric drug treatment. In addition to prompt DSBs, DSBs may also be produced during repair, evolving from a clustered DNA damaged site, which is composed of two or more distinct lesions that are located within two helical turns. A specific type of cluster damage is the heat-sensitive clustered site (HSCS), which transforms into DSBs upon treatment at elevated temperatures. The actual lesions or mechanisms that mediate the HSCS transformation into DSBs are unknown. However, there are two possibilities; either these lesions are transformed into DSBs due to DNA lesion instability, e.g., transfer of HSCS into single-strand breaks (SSBs), or they are formed due to local DNA structure instability, e.g., DNA melting, where two SSBs on opposite strands meet and transform into a DSB. The importance of these processes in living cells is not understood, but they significantly affect estimates of DSB repair capacity. In this study, we show that HSCS removal in human cells is not affected by defects in DSB repair or inhibition of DSB repair. Under conditions where rejoining of prompt DSBs was almost completely inhibited, heat-sensitive DSBs were successfully rejoined, without resulting in increased DSB levels, indicating that HSCS do not transfer into DSB in cells under physiological conditions. Furthermore, analysis by atomic force microscopy suggests that prolonged heating of chromosomal DNA can induce structural changes that facilitate transformation of HSCS into DSB. In conclusion, the HSCS do not generate additional DSBs at physiological temperatures in human cells, and the repair of HSCS is independent of DSB repair.

  • 2264.
    Abramenkovs, Andris
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Induction and repair of clustered DNA damage sites after exposure to ionizing radiation2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The mechanisms that maintain genomic stability safeguard cells from constant DNA damage produced by endogenous and external stressors. Therefore, this thesis aimed to specifically address questions regarding the requirement and involvement of DNA repair proteins in the repair of various types of radiation-induced DNA damage.

    The first aim was to determine whether the phosphorylation of DNA-PKcs, a major kinase involved in non-homologous end joining pathway, can be utilized to score the DNA double-strand break (DSB) content in cells. DNA-PKcs phosphorylated (pDNA-PKcs) at T2609 was more sensitive to the cellular DSB content than ɣH2AX, as analyzed by flow cytometry. Further, pDNA-PKcs at T2609 could discriminate between DSB repair-compromised and normal cells, confirming that the pDNA-PKcs can be used as a DSB repair marker. In paper II, the DSB repair was assessed in cells with reduced levels of DNA-PKcs. The reduction in DNA-PKcs resulted in decreased cell survival and unaffected DSB repair. These results clearly indicate that DNA-PKcs plays an additional role in promoting cell survival in addition to its function in DSB repair.

    The second part of the thesis focused on the characterization of complex DNA damage. DNA damage was investigated after exposure to α-particles originating from Ra-223. The Ra-223 treatment induced a nonrandom DSB distribution consistent with damage induced by high-linear energy transfer radiation. The exposure to Ra-223 significantly reduced cell survival in monolayers and 3D cell structures. The last paper unraveled the fate of heat-sensitive clustered DNA damage site (HSCS) repair in cells. HSCS repair was independent of DSB repair, and these lesions did not contribute to the generation of additional DSBs during repair. Prolonged heating of DNA at relatively low temperatures induced structural changes in the DNA that contributed to the production of DNA artifacts.

    In conclusion, these results demonstrate that DNA-PKcs can be used to monitor DSB repair in cells after exposure to ionizing radiation. However, the functions of DNA-PKcs are not limited to DSB repair, as it can promote cell survival through other mechanisms. The complexity of the DNA damage produced by high-LET radiation is a major contributor to cell death. However, not all clusters produced in irradiated cells are converted into DSBs during repair.

    List of papers
    1. Measurement of DNA-Dependent Protein Kinase Phosphorylation Using Flow Cytometry Provides a Reliable Estimate of DNA Repair Capacity
    Open this publication in new window or tab >>Measurement of DNA-Dependent Protein Kinase Phosphorylation Using Flow Cytometry Provides a Reliable Estimate of DNA Repair Capacity
    2017 (English)In: Radiation Research, ISSN 0033-7587, E-ISSN 1938-5404, Vol. 188, no 6, p. 597-604Article in journal (Refereed) Published
    Abstract [en]

    Uncontrolled generation of DNA double-strand breaks (DSBs) in cells is regarded as a highly toxic event that threatens cell survival. Radiation-induced DNA DSBs are commonly measured by pulsed-field gel electrophoresis, microscopic evaluation of accumulating DNA damage response proteins (e.g., 53BP1 or gamma-H2AX) or flow cytometric analysis of gamma-H2AX. The advantage of flow cytometric analysis is that DSB formation and repair can be studied in relationship to cell cycle phase or expression of other proteins. However, gamma-H2AX is not able to monitor repair kinetics within the first 60 min postirradiation, a period when most DSBs undergo repair. A key protein in non-homologous end joining repair is the catalytic subunit of DNA-dependent protein kinase. Among several phosphorylation sites of DNA-dependent protein kinase, the threonine at position 2609 (T2609), which is phosphorylated by ataxia telangiectasia mutated (ATM) or DNA-dependent protein kinase catalytic subunit itself, activates the end processing of DSB. Using flow cytometry, we show here that phosphorylation at T2609 is faster in response to DSBs than gamma-H2AX. Furthermore, flow cytometric analysis of T2609 resulted in a better representation of fast repair kinetics than analysis of gamma-H2AX. In cells with reduced ligase IV activity, and wild-type cells where DNA-dependent protein kinase activity was inhibited, the reduced DSB repair capacity was observed by T2609 evaluation using flow cytometry. In conclusion, flow cytometric evaluation of DNA-dependent protein kinase T2609 can be used as a marker for early DSB repair and gives a better representation of early repair events than analysis of gamma-H2AX.

    Place, publisher, year, edition, pages
    RADIATION RESEARCH SOC, 2017
    National Category
    Biophysics
    Identifiers
    urn:nbn:se:uu:diva-343567 (URN)10.1667/RR14693.1 (DOI)000416744600001 ()
    Funder
    Swedish Cancer SocietySwedish Radiation Safety Authority
    Available from: 2018-03-02 Created: 2018-03-02 Last updated: 2019-03-08Bibliographically approved
    2. Suppression of DNA-dependent protein kinase sensitize cells to radiation without affecting DSB repair
    Open this publication in new window or tab >>Suppression of DNA-dependent protein kinase sensitize cells to radiation without affecting DSB repair
    2014 (English)In: Mutation research, ISSN 0027-5107, E-ISSN 1873-135X, Vol. 769, p. 1-10Article in journal (Refereed) Published
    Abstract [en]

    Efficient and correct repair of DNA double-strand break (DSB) is critical for cell survival. Defects in the DNA repair may lead to cell death, genomic instability and development of cancer. The catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) is an essential component of the non-homologous end joining (NHEJ) which is the major DSB repair pathway in mammalian cells. In the present study, by using siRNA against DNA-PKcs in four human cell lines, we examined how low levels of DNA-PKcs affected cellular response to ionizing radiation. Decrease of DNA-PKcs levels by 80-95%, induced by siRNA treatment, lead to extreme radiosensitivity, similar to that seen in cells completely lacking DNA-PKcs and low levels of DNA-PKcs promoted cell accumulation in G2/M phase after irradiation and blocked progression of mitosis. Surprisingly, low levels of DNA-PKcs did not affect the repair capacity and the removal of 53BP1 or gamma-H2AX foci and rejoining of DSB appeared normal. This was in strong contrast to cells completely lacking DNA-PKcs and cells treated with the DNA-PKcs inhibitor NU7441, in which DSB repair were severely compromised. This suggests that there are different mechanisms by which loss of DNA-PKcs functions can sensitize cells to ionizing radiation. Further, foci of phosphorylated DNA-PKcs (T2609 and S2056) co-localized with DSB and this was independent of the amount of DNA-PKcs but foci of DNA-PKcs was only seen in siRNA-treated cells. Our study emphasizes on the critical role of DNA-PKcs for maintaining survival after radiation exposure which is uncoupled from its essential function in DSB repair. This could have implications for the development of therapeutic strategies aiming to radiosensitize tumors by affecting the DNA-PKcs function.

    Keywords
    DNA repair, DNA-PKcs, Ionizing radiation, DNA-PK deficiency, NU7441
    National Category
    Medical Genetics
    Identifiers
    urn:nbn:se:uu:diva-237292 (URN)10.1016/j.mrfmmm.2014.06.004 (DOI)000343625700001 ()
    Available from: 2014-12-03 Created: 2014-12-01 Last updated: 2019-03-08Bibliographically approved
    3. The α-emitter Ra-223 induces clustered DNA damage and significantly reduces cell survival
    Open this publication in new window or tab >>The α-emitter Ra-223 induces clustered DNA damage and significantly reduces cell survival
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    The bone-seeking radiopharmaceutical Xofigo (Radium-223 dichloride) has demonstrated both extended survival and palliative effects in treatment of bone metastases in patients with prostate cancer. The alpha-particle emitter Ra-223, administered as Ra-223 dichloride, targets regions undergoing active bone remodeling and strongly binds hydroxyapatite found in bone. However, the mechanisms mediating toxicity and properties of Ra-223 binding to hydroxyapatite are not fully understood. In the current study, we show that the alpha-particles originating from the Ra-223 decay chain produce a track-like distribution of the DNA damage response proteins 53BP1 and ɣH2AX and induce high amounts of clustered DNA double-strand breaks in prostate cancer cell nuclei. The Ra-223 treatment inhibited growth of prostate cancer cells, grown in 2D- and 3D- models in vitro, independent of prostate cancer cell type and androgen receptor variant 7 (ARv7) expression. The rapid binding with a high affinity of Ra-223 to bone structures was verified in an in silico assay (KD= 19.2 ± 6.5 e-18) and almost no dissociation was detected within 24 hours. Importantly, there was no significant uptake of Ra-223 in cells. Further, we demonstrate the importance of the local dose-distribution of this treatment; there was more than 100-fold increase in cell killing when Ra-223 was attached to the bone-like hydroxyapatite structure, compared to when the radioactivity was distributed in the cell growth media. However, independent of the exposure condition, the high cell killing efficacy of the Ra-223 was attributed to the clustered DNA damaged sites induced by the released α-particles.

    Keywords
    Prostate cancer, ARv7, DNA damage, Ra-223, high-LET
    National Category
    Radiology, Nuclear Medicine and Medical Imaging
    Research subject
    Medical Cell Biology
    Identifiers
    urn:nbn:se:uu:diva-378720 (URN)
    Available from: 2019-03-08 Created: 2019-03-08 Last updated: 2019-03-08
    4. Removal of heat-sensitive clustered damaged DNA sites is independent of double-strand break repair
    Open this publication in new window or tab >>Removal of heat-sensitive clustered damaged DNA sites is independent of double-strand break repair
    2018 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 12, article id e0209594Article in journal (Refereed) Published
    Abstract [en]

    DNA double-strand breaks (DSBs) are the most deleterious lesions that can arise in cells after ionizing radiation or radiometric drug treatment. In addition to prompt DSBs, DSBs may also be produced during repair, evolving from a clustered DNA damaged site, which is composed of two or more distinct lesions that are located within two helical turns. A specific type of cluster damage is the heat-sensitive clustered site (HSCS), which transforms into DSBs upon treatment at elevated temperatures. The actual lesions or mechanisms that mediate the HSCS transformation into DSBs are unknown. However, there are two possibilities; either these lesions are transformed into DSBs due to DNA lesion instability, e.g., transfer of HSCS into single-strand breaks (SSBs), or they are formed due to local DNA structure instability, e.g., DNA melting, where two SSBs on opposite strands meet and transform into a DSB. The importance of these processes in living cells is not understood, but they significantly affect estimates of DSB repair capacity. In this study, we show that HSCS removal in human cells is not affected by defects in DSB repair or inhibition of DSB repair. Under conditions where rejoining of prompt DSBs was almost completely inhibited, heat-sensitive DSBs were successfully rejoined, without resulting in increased DSB levels, indicating that HSCS do not transfer into DSB in cells under physiological conditions. Furthermore, analysis by atomic force microscopy suggests that prolonged heating of chromosomal DNA can induce structural changes that facilitate transformation of HSCS into DSB. In conclusion, the HSCS do not generate additional DSBs at physiological temperatures in human cells, and the repair of HSCS is independent of DSB repair.

    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-374120 (URN)10.1371/journal.pone.0209594 (DOI)000454621900032 ()30592737 (PubMedID)
    Funder
    Swedish Cancer Society, CAN2014/661Swedish Cancer Society, CAN2016/649Swedish Radiation Safety Authority, SSM2017-2374Swedish Radiation Safety Authority, SSM2018-2181
    Available from: 2019-01-23 Created: 2019-01-23 Last updated: 2019-03-08Bibliographically approved
  • 2265.
    Abramian, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Informatics and Media, Information Systems.
    Wedholm, Joel
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Informatics and Media, Information Systems.
    BYOD och Cloud Computing: En vägledande studie för hur BYOD bör bedrivas säkert tillsammans med cloud computing2013Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    The aim of this thesis is to gain a richer insight into how information security is affected by Bring Your Own Device (BYOD) in combination with cloud computing. This study has come to its conclusion by performing interviews and sending out questionaries that has later been analyzed using current theory. A specification has been established out of this and will serve as a guiding contribution for organisations.

  • 2266.
    Abramov, Sergei
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Kazan Fed Univ, Inst Fundamental Med & Biol, Kazan, Russia.
    Kozyrev, Sergey V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Farias, Fabiana H. G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Washington Univ, Genome Inst, Sch Med, St Louis, MO USA.
    Dahlqvist, Johanna
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Leonard, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wilbe, Maria
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Swedish Univ Agr Sci SLU, Dept Anim Breeding & Genet, Uppsala, Sweden.
    Alexsson, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pielberg, Gerli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hansson-Hamlin, H.
    Swedish Univ Agr Sci SLU, Dept Clin Sci, Uppsala, Sweden.
    Andersson, G.
    Swedish Univ Agr Sci SLU, Dept Anim Breeding & Genet, Uppsala, Sweden.
    Tandre, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ronnblom, L.
    Swedish Univ Agr Sci SLU, Dept Clin Sci, Uppsala, Sweden.
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    The risk allele A of rs200395694 associated with SLE in Swedish patients affects on MEF2D gene regulation and alternative splicing2018In: Human Gene Therapy, ISSN 1043-0342, E-ISSN 1557-7422, Vol. 29, no 12, p. A44-A44Article in journal (Other academic)
  • 2267. Abramovic, A.
    et al.
    Pecaric, J.
    Persson, Lars-Erik
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Mathematics, Applied mathematics.
    Varosanec, S.
    General inequalities via isotonic subadditive functionals2007In: Mathematical Inequalities & Applications, ISSN 1331-4343, E-ISSN 1848-9966, Vol. 10, no 1, p. 15-28Article in journal (Refereed)
    Abstract [en]

    In this manuscript a number of general inequalities for isotonic subadditive functionals on a set of positive mappings are proved and applied. In particular, it is pointed out that these inequalities both unify and generalize some general forms of the Hö̈lder, Popoviciu, Minkowski, Bellman and Power mean inequalities. Also some refinements of some of these results are proved.

  • 2268. Abramovitz, T
    et al.
    Berthelsen, A
    Schjoth, F
    Thybo, H
    Balling, N
    Nielsen, L
    Flueh, ER
    Hubinger, S
    Reston, T
    Pedersen, LB
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Geophysics.
    Schmidt, J
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Geophysics.
    England, RW
    Hobbs, RW
    Maguire, PKH
    MONA LISA: Deep seismic investigations of the lithosphere in the southeastern North Sea1997In: TECTONOPHYSICS, ISSN 0040-1951, Vol. 269, no 1-2, p. 1-19Article in journal (Other academic)
    Abstract [en]

    The MONA LISA collaborative project has collected 1112 km of seismic normal-incidence reflection data (recorded to 26 s) and wide-angle data from 26 onshore and 2 offshore locations along 4 profiles in the southeastern North Sea. The seismic data clearly

  • 2269.
    Abramowicz, Sara
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology.
    Online recruitment of cutting-edge users: A user experience study of Ericsson Labs developer portal2010Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    This thesis investigates how to reach and recruit cutting-edge users to user experience studies. The recruitment of cutting-edge users is difficult since these users usually are not registered in recruitment databases. Cutting-edge users are advanced, early-adopters of technology and sometimes referred to as opinion leaders. Telecom research projects performed at Ericsson Research involve products and services 2-3 years ahead of the market; early-adopters and cutting edge users are therefore an important user group.

     

    To test recruitment methods a user experience study was performed of Ericsson Labs developer portal. Ericsson Labs offers Application Programming Interfaces for mobile and web applications development. Internet marketing theories were used to form a recruitment method. Respondents were recruited from the Ericsson Labs user database and they were contacted individually via email. The users were invited to share their thoughts and ideas about the portal to help improve and possibly influence the direction of the site.

     

    This thesis also assessed different online qualitative research methods applied for user experience research. Online focus groups such as bulletin boards were used to interact with users in addition to individual chat and voice interviews. Performing user experience research on the Internet is a cost-efficient way to interact with users in geographically dispersed areas.

     

    The findings from the study show that recruitment is hard; it is especially difficult to recruit active and conversational respondents from a user database. Providing incentives and using personal communication were shown to be successful strategies to convince users to participate in a study.

  • 2270.
    Abramowicz, Sara
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Business Studies.
    Rydman, Maria
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Business Studies.
    Projektverksamhet med samhällsnyttan i fokus: införandeprocessen av SMS-biljetten vid Upplands Lokaltrafik2008Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    The aim of this thesis is to explore possible differences between public and private companies’ way to manage projects. In order to analyze the managerial aspects, we have studied the project of a new payment system implemented at the public-transport organization Upplands Lokaltrafik (UL). The project enables mobile payment by text message (SMS). Most theory concerning the management of projects is developed for private companies. It is therefore of great interest to explore whether that theory is applicable to the SMS-project conducted by a public company. Within the theory of project management, we have chosen to focus on the concept of process orientation in order to describe the project and the parties involved. To specify the different stages of the work process we have used Deming’s cycle. The cycle describes the iterative workflow of a project by the four stages; Plan (Planning the project), Do (Implementing the project), Study(Study the effects of the implementation) and Act (Act upon the results of the feedback). The model’s four stages are represented by equally large shares in the optimal cycle, however, the most common situation for private companies is that the Do part is larger than the other parts and the Study and Act parts are seldom employed. The decision-making process in public companies is more complex due to their organizational structure, which in UL’s case implies that the project process is different to that of private companies. With this in mind, the process of evaluation is more difficult to conduct. The finding of this study is that the public and private companies have somewhat different management techniques, which we have observed in particular while studying the SMS-project. Nevertheless, the SMS-project is run with some similar characteristics to a private company, which we have seen has affected the outcome of the project negatively in the sense that they have failed to use the process orientation fully. UL would therefore benefit from using process-orientation techniques such as evaluation and feedback in a greater extent in upcoming projects.

     

  • 2271. Abrams, P
    et al.
    Cardozo, L
    Fall, M
    Griffiths, D
    Rosier, P
    Ulmsten, U
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Women's and Children's Health.
    Van Kerrebroeck, P
    Victor, A
    Wein, A
    The standardisation of terminology in lower urinary tract function: reportfrom the standardisation sub-committee of the International ContinenceSociety.2003In: Urology, Vol. 61, p. 37-Article in journal (Refereed)
  • 2272. Abrams, P
    et al.
    Cardozo, L
    Fall, M
    Griffiths, D
    Rosier, P
    Ulmsten, U
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Women's and Children's Health.
    van Kerrebroeck, P
    Victor, A
    Wein, A
    The standardisation of terminology of lower urinary tract function: Report from the standardistation sub-committee of the International Continence Society.2002In: Neurourology and Urodynamics, Vol. 21, p. 167-Article in journal (Refereed)
  • 2273. Abrams, Pascale
    et al.
    Boquete, Hugo
    Fideleff, Hugo
    Feldt-Rasmussen, Ulla
    Jonsson, J
    Koltowska-Häggström, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Wilton, Patrick
    Abs, Roger
    GH replacement in hypopituitarism improves lipid profile and quality of life independently of changes in obesity variables2008In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 159, no 6, p. 825-832Article in journal (Refereed)
    Abstract [en]

    Objective: GH deficiency (GHD) in adults is characterized by elevated body mass index (BMI), increased waist girth (WG) and increased fat mass (FM). Information about how these indicators of obesity affect the lipid profile and quality of life (QoL) of GHD subjects is scarce. It is also unclear how changes in these indicators brought about by GH replacement influence lipids and QoL. Design and methods: Adult GHD Subjects from the Pfizer International Metabolic Database were grouped according to BMI (n = 291 with BMI < 25 kg/m(2), n = 372 with BMI 25-30 kg/m(2), n = 279 with BMI > 30 kg/m(2)), WG (n = 508 with normal WG, n = 434 with increased WG) and FM (n = 357) and according to changes in these variables after 1 year of GH replacement. Serum IGF-1 concentrations, lipid concentrations and QoL using the QoL Assessment of GHD in Adults questionnaire were assessed at baseline and after 1 year of treatment. Results: At baseline, total and low-density lipoprotein (LDL) cholesterol were similarly elevated in the BMI and WG groups, but high-density lipoprotein (HDL) cholesterol decreased and triglycerides increased with increasing BMI and WG. QoL was progressively poorer with increasing BMI and WG. After 1 year of GH replacement, total and LDL cholesterol and QoL improved in all BMI, WG and FM groups. Conclusions: Variables of obesity adversely affect the already unfavourable lipid profile in GHD Subjects by decreasing HDL cholesterol, but do not counteract the positive effect of GH replacement on LDL cholesterol. Similarly, QoL is influenced by obesity, but responds equally well to GH treatment independent of BMI, WG and FM.

  • 2274.
    Abramson, Jeff
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry.
    Structural studies on the integral membrane protein, ubiquinol oxidase from Escherichia coli2001Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Heme-copper oxidases are redox-driven proton pumps that couple the reduction of molecular oxygen to water with the vectorial translocation of protons across the membrane. The proton gradient generated by heme-copper oxidases and the other members of the aerobic respiratory chain is ultimately used to drive the synthesis of ATP. There are two main branches of the heme-copper oxidases that are characterized by the electron donating substrate; the cytochrome c oxidases, which use cytochrome c as the electron donor, and the ubiquinol oxidases, which use a lipid-soluble molecule, ubiquinol, as their electron donor. These enzymes share important structural and functional features.

    This thesis presents the procedures that have led to the first crystal structure of a ubiquinol oxidase, cytochrome bo, oxidase from Escherichia coli, at a resolution of 3.5 Å. The overall structure of the enzyme is similar to those of cytochrome c oxidases; however the membrane spanning region of subunit I contains a cluster of polar residues exposed to the interior of the lipid bilayer. No such structural feature is present in cytochrome c oxidases. Mutagenesis studies on residues in this region strongly suggest that this area forms a ubiquinone binding site. A comparison of this region with known ubiquinone binding sites shows remarkable similarities. In light of these findings specific roles for these polar residues is proposed in electron and proton transfer in ubiquinol oxidase.

    A fusion protein of cytochrome bo3-Protein Z was generated in an attempt to increase the hydrophilic surface of the protein, thus extending protein-protein contacts within the crystal lattice structure. Such an approach can be used to facilitate crystallization.

  • 2275. Abramsson, Alexandra
    et al.
    Kurup, Sindhulakshmi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Yamada, Shuhei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lindblom, Per
    Schallmeiner, Edith
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Ledin, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ringvall, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Kjellén, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Bondjers, Göran
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lindahl, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Spillmann, Dorothe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gerhardt, Holger
    Defective N-sulfation of heparan sulfate proteoglycans limits PDGF-BB binding and pericyte recruitment in vascular development2007In: Genes & Development, ISSN 0890-9369, E-ISSN 1549-5477, Vol. 21, no 3, p. 316-331Article in journal (Refereed)
    Abstract [en]

    During vascular development, endothelial platelet-derived growth factor B (PDGF-B) is critical for pericyte recruitment. Deletion of the conserved C-terminal heparin-binding motif impairs PDGF-BB retention and pericyte recruitment in vivo, suggesting a potential role for heparan sulfate (HS) in PDGF-BB function during vascular development. We studied the participation of HS chains in pericyte recruitment using two mouse models with altered HS biosynthesis. Reduction of N-sulfation due to deficiency in N-deacetylase/N-sulfotransferase-1 attenuated PDGF-BB binding in vitro, and led to pericyte detachment and delayed pericyte migration in vivo. Reduced N-sulfation also impaired PDGF-BB signaling and directed cell migration, but not proliferation. In contrast, HS from glucuronyl C5-epimerase mutants, which is extensively N- and 6-O-sulfated, but lacks 2-O-sulfated L-iduronic acid residues, retained PDGF-BB in vitro, and pericyte recruitment in vivo was only transiently delayed. These observations were supported by in vitro characterization of the structural features in HS important for PDGF-BB binding. We conclude that pericyte recruitment requires HS with sufficiently extended and appropriately spaced N-sulfated domains to retain PDGF-BB and activate PDGF receptor β (PDGFRβ) signaling, whereas the detailed sequence of monosaccharide and sulfate residues does not appear to be important for this interaction.

  • 2276.
    Abramsson, Marianne & Borgegård, Lars-Erik
    Uppsala University, Units outside the University, Institute for Housing and Urban Research.
    Välfärd i förändring. Den allmännyttiga bostadsmarknaden i några välfärdsstater (Changing of welfare. The municipal housing market in a number of welfare states)1996Report (Other scientific)
  • 2277.
    Abramsson, Marianne & Borgegård, Lars-Erik
    Uppsala University, Units outside the University, Institute for Housing and Urban Research.
    Välstånd i förändring. Om skilda förutsättningar för olika hushållsgruppers boendekarriär under perioden 1975-1995. (Changing welfare - different conditions for households housing career during the period 1975-1995)1996Report (Other scientific)
  • 2278. Abramsson, Marianne
    et al.
    Andersson, Eva
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Institute for Housing and Urban Research.
    Residential mobility patterns of older people2009Conference paper (Other academic)
  • 2279.
    Abramsson, Marianne
    et al.
    Uppsala University, Units outside the University, Institute for Housing and Urban Research.
    Borgegård, Lars-Erik
    Changing welfare states and social housing: Consequences for spatial segregation - reviewed1998In: Scandinavian Housing & Planning Research, ISSN 0281-5737, Vol. 15, no 3, p. 149-173Article in journal (Refereed)
    Abstract [en]

    Most western countries have reached a peak of welfare and are facing cuts to their welfare programmes. Housing policies and the housing market are similarly going through changes with regard to ownership, rent levels and market prices. The process can be

  • 2280.
    Abramsson, Marianne
    et al.
    Uppsala University, Units outside the University, Institute for Housing and Urban Research.
    Borgegård, Lars-Erik
    Fransson, Urban
    Uppsala University, Units outside the University, Institute for Housing and Urban Research.
    Boendekarriär - att välja bostad (Housing career - a choice of housing)2000In: Bostadsrätten i ett nytt millennium (Cooperative housing in a new millennium), 2000, p. 33-55Chapter in book (Refereed)
  • 2281.
    Abramsson, Marianne
    et al.
    Uppsala University, Units outside the University, Institute for Housing and Urban Research.
    Borgegård, Lars-Erik
    Fransson, Urban
    Housing Careers: Immigrants in Local Swedish Housing Markets2002In: Housing Studies, Vol. 17, no 3, p. 445-464Article in journal (Refereed)
  • 2282.
    Abramsson, Marianne
    et al.
    Uppsala University, Units outside the University, Institute for Housing and Urban Research.
    Borgegård, Lars-Erik
    Uppsala University, Units outside the University, Institute for Housing and Urban Research.
    Fransson, Urban
    Housing Careers of Young Households2002Conference paper (Other scientific)
  • 2283.
    Abramsson, Marianne
    et al.
    Uppsala University, Units outside the University, Institute for Housing and Urban Research.
    Borgegård, Lars-Erik
    Uppsala University, Units outside the University, Institute for Housing and Urban Research.
    Fransson, Urban
    Uppsala University, Units outside the University, Institute for Housing and Urban Research.
    Medelålders och äldres boende (Housing for middle-aged and elderly people)2000In: Bostadsrätten i ett nytt millennium (Cooperative housing in a new millennium), Gävle: Institutet för bostads- och urbanforskning , 2000, p. 113-143Chapter in book (Other (popular science, discussion, etc.))
  • 2284.
    Abramsson, Marianne
    et al.
    Uppsala University, Units outside the University, Institute for Housing and Urban Research.
    Borgegård, Lars-Erik
    Fransson, Urban
    Seniors as actors on the Swedish housing marke2001Conference paper (Other scientific)
  • 2285. Abramsson, Marianne
    et al.
    Borgegård, Lars-Erik
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Institute for Housing and Urban Research.
    Fransson, Urban
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Institute for Housing and Urban Research.
    The first years as independent actors in the housing market: Young households in a Swedish municipality2004In: Journal of Housing and the Built Environment, ISSN 1566-4910, E-ISSN 1573-7772, Vol. 19, no 2, p. 145-168Article in journal (Refereed)
  • 2286. Abramsson, Marianne
    et al.
    Borggård, Lars-Erik
    Uppsala University, Units outside the University, Institute for Housing and Urban Research.
    Fransson, Urban
    Uppsala University, Units outside the University, Institute for Housing and Urban Research.
    Medelålders och äldres boende2000In: Bostadsrätten i ett nytt millenium, 2000Chapter in book (Refereed)
  • 2287.
    Abramsson, Marianne
    et al.
    ISV Institutionen för samhälls- och välfärdsstudier, Linköpings universitet.
    Sandstedt, Eva
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Institute for Housing and Urban Research.
    Bostadsmarknad och bostadsformer för andra halvan av livet2012In: Äldres boende: forskningsperspektiv i Norden / [ed] Catharina Nord & Marianne Abramsson, Stockholm: Studentlitteratur, 2012, 1, p. 157-168Chapter in book (Refereed)
    Abstract [sv]

    I denna antologi diskuteras äldres boendeförhållanden utifrån ett samhälls- och individperspektiv. Äldres boende inkluderar såväl kvarboende i vanliga bostäder som boende i bostäder särskilt avsedda för äldre. I boken behandlas fysiska och sociala aspekter på boendet, äldres bostadsmarknad och boendepreferenser. De olika kapitlen exemplifierar olika sätt att studera äldre och deras boendesituation och visar på den variation av områden inom vilka forskning om äldres boende bedrivs. Tillsammans ger de en bred bild av äldres boendesituation och lyfter fram de frågor som särskilt berör äldre, alltifrån de friska och mer rörliga äldre med stora valmöjligheter till de multisjuka äldre som lever längre med sina sjukdomar. Denna heterogenitet ställer stora krav på äldres bostäder och boendemiljöer.

    Antologin är avsedd att utgöra ett underlag för kurser om äldres boende ur ett samhällsvetenskapligt perspektiv. Den vänder sig också till aktörer i kommunal produktion av bostäder och omsorg samt andra med intresse för  äldres bostadsfrågor.

    Alla författare är medlemmar i Nordiska nätverket för forskning om äldres boende.

  • 2288.
    Abramsson, Mia
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Production and characterization of Acetylcholine Binding Protein2018Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
  • 2289.
    Abramsson Zetterberg, Lilianne
    Uppsala University, Disciplinary Domain of Science and Technology.
    Chromosome aberrations detected by the flow cytometer based micronucleus assay: studies of rodent erythrocytes after exposure to very low doses of ionizing radiation or to chemicals 1997Doctoral thesis, comprehensive summary (Other academic)
  • 2290.
    Abramsson-Zetterberg, L
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Genetics.
    Ascorbic acid is not clastogenic and does not modify the effect of extended low-dose-rate gamma-irradiation in mouse bone marrow1996In: International Journal of Radiation Biology, ISSN 0955-3002, E-ISSN 1362-3095, Vol. 70, no 1, p. 77-81Article in journal (Refereed)
    Abstract [en]

    Ascorbic acid was given to CBA mice in drinking water (5%) a week before and during 35-day exposure to gamma-radiation from 137 Cs at a very low dose-rate (44 mGy/day). The frequency of micronucleated normochromatic erythrocytes (fMNCE) in peripheral blood was monitored by repeated sampling during the exposure. The analyses were made with flow cytometry giving a high resolution because of the large number of cells analysed, about 10(6) for each dose group and sampling occasion. Ascorbic acid in the drinking water did not modify the increase of fMNCE in the gamma-irradiated groups of mice, nor did ascorbic acid influence the fMNCE in the non-irradiated groups of mice.

  • 2291.
    Abramsson-Zetterberg, L
    et al.
    Uppsala University.
    Grawe, J
    Uppsala University.
    Zetterberg, G
    Uppsala University.
    Erythropoiesis and the induction of micronuclei in mouse spleen determined by flow cytometry1997In: MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS, ISSN 1383-5718, Vol. 394, no 1-3, p. 17-28Article in journal (Other scientific)
    Abstract [en]

    Erythrocytes from the spleen of CBA mice have been prepared for analyses by flow cytometry. About 80% of the polychromatic erythrocytes (PCE) in the spleen originate from erythropoiesis in the spleen, while the remaining 20% come from the peripheral blood

  • 2292.
    ABRAMSSONZETTERBERG, L
    et al.
    Uppsala University.
    GRAWE, J
    Uppsala University.
    ZETTERBERG, G
    Uppsala University.
    FLOW CYTOMETRIC ANALYSIS OF MICRONUCLEUS INDUCTION IN MICE BY INTERNAL EXPOSURE TO CS-137 AT VERY-LOW DOSE-RATES1995In: INTERNATIONAL JOURNAL OF RADIATION BIOLOGY, ISSN 0955-3002, Vol. 67, no 1, p. 29-36Article in journal (Other scientific)
    Abstract [en]

    Internal radiation from Cs-137, intraperitoneally injected into mice, induced chromosome damage seen as micronuclei in erythrocytes of peripheral blood harvested 72 h after injection and analysed With flow cytometry. The retention of injected Cs-137 activ

  • 2293.
    AbramssonZetterberg, L
    et al.
    Uppsala University.
    Grawe, J
    Uppsala University.
    Zetterberg, G
    Uppsala University.
    Spontaneous and radiation-induced micronuclei in erythrocytes from four species of wild rodents: a comparison with CBA mice1997In: MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS, ISSN 1383-5718, Vol. 393, no 1-2, p. 55-71Article in journal (Other scientific)
    Abstract [en]

    Almost 100 animals of 4 different species of small wild rodents (bank vole, Clethrionomys glareolus; field vole, Microtus agrestis; yellow-necked mouse, Apodemus flavicollis; and wood mouse, Apodemus sylvaticus) were trapped in central Sweden and used in

  • 2294.
    Abramsson-Zetterberg, L
    et al.
    Uppsala University.
    Grawe, J
    Uppsala University.
    Zetterberg, G
    Uppsala University.
    The micronucleus test in rat erythrocytes from bone marrow, spleen and peripheral blood: the response to low doses of ionizing radiation, cyclophosphamide and vincristine determined by flow cytometry1999In: MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS, ISSN 0027-5107, Vol. 423, no 1-2, p. 113-124Article in journal (Other scientific)
    Abstract [en]

    The frequency of micronucleated polychromatic erythrocytes (fMPCE) was determined in samples from bone marrow, spleen and peripheral blood of rats exposed to low doses of X-rays, cyclophosphamide or vincristine. The fMPCE values were lower in the peripher

  • 2295. Abramsson-Zetterberg, L
    et al.
    Zetterberg, G
    Bergqvist, Michael
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Grawe, J
    Human cytogenetic biomonitoring using flow-cytometric analysis ofmicronuclei in transferrin-positive immature peripheral bloodreticulocytes.2000In: Environ Mol Mutagen, Vol. 36, p. 22-Article in journal (Refereed)
  • 2296.
    AbramssonZetterberg, L
    et al.
    Uppsala University.
    Zetterberg, G
    Uppsala University.
    Grawe, J
    Uppsala University.
    The time-course of micronucleated polychromatic erythrocytes in mouse bone marrow and peripheral blood1996In: MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS, ISSN 0027-5107, Vol. 350, no 2, p. 349-358Article in journal (Other scientific)
    Abstract [en]

    The time-course of micronucleated polychromatic erythrocytes (MPCE) in mouse bone marrow and peripheral blood, induced by an acute 0.1 Gy dose of X-rays, was determined using flow cytometric analysis, which made frequent sampling possible and allowed use

  • 2297.
    Abramsson-Zetterberg, L
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology.
    Zetterberg, G
    Sundell-Bergman, S
    Grawe, J
    Absence of genomic instability in mice following prenatal low dose-rate gamma-irradiation2000In: INTERNATIONAL JOURNAL OF RADIATION BIOLOGY, ISSN 0955-3002, Vol. 76, no 7, p. 971-977Article in journal (Refereed)
    Abstract [en]

    Purpose: To determine whether mice exposed to an extended low dose of gamma-irradiation during most of their prenatal period express increased frequencies-of micronucleated polychromatic erythrocytes (fMPCE) and/or micronucleated normochromatic erythrocyt

  • 2298.
    Abramsson-Zetterberg, Lilianne
    et al.
    National Food Administration, Uppsala.
    Durling, Louise J.K.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Yang-Wallentin, Fan
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Information Science.
    Rytter, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Vessby, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    The impact of folate status and folic acid supplementation on the micronucleus frequency in human erythrocytes2006In: Mutation Research, ISSN 1383-5742, E-ISSN 1388-2139, Vol. 603, no 1, p. 33-40Article in journal (Refereed)
    Abstract [en]

    Folic acid has a well-documented stabilising effect on chromosomes. A correlation between folate status and chromosome stability in humans has been reported in studies that were restricted to certain subpopulations, e.g., folate-deficient persons. The goal of the present investigation was to clarify if there also is a correlation between folate status and chromosome stability among individuals without any folate deficiency.

    The method used here is the recently developed flow cytometry-based micronucleus assay in human transferrin-positive reticulocytes (MN-Trf-Ret). In a blood sample, separation of the very young reticulocytes from the mature erythrocytes makes this micronucleus assay possible.

    This investigation comprises three studies (cross-sectional, giving baseline data), two of which are connected to an intervention study. In the three cross-sectional studies (total number of subjects, 99) the frequency of MN-Trf-Ret (fMN-Trf-Ret) was measured and compared with the serum folate status. In two of the studies also serum homocysteine and Vitamin B12 were measured and compared with the baseline fMN-Trf-Ret. Combining the results from the three cross-sectional studies, a negative correlation between folate status and fMN-Trf-Ret was obtained (p < 0.05).

    The goal of the intervention studies was to clarify if different nutritional supplementations had any effect on the fMN-Trf-Ret and the cell proliferation (percentage polychromatic erythrocytes, PCE). Each of the two studies involved two groups, one placebo and one supplemented group. In one of the studies the supplementation was folic acid, 1000 μg/day during 1 week (n = 30, both sexes); in the other intervention study, folic acid (800 μg/day), B12 (20 μg/day) and B6 (4 mg/day) were taken during 1 week (n = 29, both sexes). No significant difference in %PCE or fMN-Trf-Ret between the two groups was found in either of the two intervention studies.

  • 2299. Abramsson-Zetterberg, Lilianne
    et al.
    Ilbäck, Nils-Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    The synthetic food colouring agent Allura Red AC (E129) is not genotoxic in a flow cytometry-based micronucleus assay in vivo2013In: Food and Chemical Toxicology, ISSN 0278-6915, E-ISSN 1873-6351, Vol. 59, p. 86-89Article in journal (Refereed)
    Abstract [en]

    The safety of several azo colouring agents, used as food additives, has during the years been questioned. Allura Red AC (E129) has in some publications been classified as genotoxic. In fact, in the European Union, Allura Red is permitted as a food additive in human food, but, surprisingly, it was not acceptable as an additive for use in animal feed. In this study we have evaluated whether Allura Red is genotoxic using a flow cytometer-based micronucleus assay in peripheral blood of mice. Male FVB mice were given a single intra-peritoneal injection of various doses of Allura Red and sacrificed at 46 h after treatment. The tested doses were 0, 100, 200, 400, 600, 800, 1000, 1500, and 2000 mg/kg body weight (b.w.). Each dose group constituted three mice, except for in the dose group of 1000 mg/kg b.w., which constituted four mice. Blood samples were collected and the frequency of micronucleated polychromatic erythrocytes (fMNPCE) and the cell proliferation (%PCE) was determined. The analyses did not show any significant difference in the %PCE or in the fMNPCE. Consequently, under the testing circumstances one can conclude that Allura Red is not genotoxic.

  • 2300.
    Abrantes, João A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Jönsson, Siv
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nielsen, Elisabet I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Handling interoccasion variability in model-based dose individualization using therapeutic drug monitoring data.2019In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125Article in journal (Refereed)
    Abstract [en]

    AIMS: This study aims to assess approaches to handle interoccasion variability (IOV) in a model-based therapeutic drug monitoring (TDM) context, using a population pharmacokinetic model of coagulation factor VIII as example.

    METHODS: We assessed five model-based TDM approaches: empirical Bayes estimates (EBEs) from a model including IOV, with individualized doses calculated based on individual parameters either (i) including or (ii) excluding variability related to IOV; and EBEs from a model excluding IOV by (iii) setting IOV to zero, (iv) summing variances of interindividual variability (IIV) and IOV into a single IIV term, or (v) re-estimating the model without IOV. The impact of varying IOV magnitudes (0-50%) and number of occasions/observations was explored. The approaches were compared with conventional weight-based dosing. Predictive performance was assessed with the prediction error (PE) percentiles.

    RESULTS: When IOV was lower than IIV, the accuracy was good for all approaches (50th percentile of the PE [P50] <7.4%), but the precision varied substantially between IOV magnitudes (P97.5 61-528%). Approach (ii) was the most precise forecasting method across a wide range of scenarios, particularly in case of sparse sampling or high magnitudes of IOV. Weight-based dosing led to less precise predictions than the model-based TDM approaches in most scenarios.

    CONCLUSIONS: Based on the studied scenarios and theoretical expectations, the best approach to handle IOV in model-based dose individualisation is to include IOV in the generation of the EBEs, but exclude the portion of unexplained variability related to IOV in the individual parameters used to calculate the future dose.

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