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| 2. |
- Kindbom, Karin, et al.
(author)
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Trends in air concentration and deposition at background monitoring sites in Sweden : Major inorganic compounds, heavy metals and ozone
- 2001
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Reports (other academic/artistic)abstract
- This report describes concentrations in air of sulphur compounds, soot, nitrogen compounds andozone in Sweden between 1985-1998. Time trends of concentration in precipitation and depositionof sulphate, nitrate, ammonium, acidity, base cations and chloride in six different regions coveringSweden are evaluated during the period 1983-1998. Trends of heavy metals in precipitation havebeen analysed for the period 1983-1998 and the change in heavy metal concentration, 1975-1995, inmosses is described.Data used in the trend analyses originates from measurements performed at six Swedish EMEPstations and from approximately 25 stations within the national Precipitation Chemistry Network.Two different statistical methods, linear regression and the non-parametric Mann Kendall test, havebeen used to evaluate changes in annual mean values.
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- Almstedt, Karin, 1980-, et al.
(author)
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Unfolding a folding disease: folding, misfolding and aggregation of the marble brain syndrome-associated mutant H107Y of human carbonic anhydrase II
- 2004
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In: Journal of Molecular Biology. - Oxford : Elsevier. - 0022-2836 .- 1089-8638. ; 342:2, s. 619-633
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Journal article (peer-reviewed)abstract
- Most loss-of-function diseases are caused by aberrant folding of important proteins. These proteins often misfold due to mutations. The disease marble brain syndrome (MBS), known also as carbonic anhydrase II deficiency syndrome (CADS), can manifest in carriers of point mutations in the human carbonic anhydrase II (HCA II) gene. One mutation associated with MBS entails the His107Tyr substitution. Here, we demonstrate that this mutation is a remarkably destabilizing folding mutation. The loss-of-function is clearly a folding defect, since the mutant shows 64% of CO2 hydration activity compared to that of the wild-type at low temperature where the mutant is folded. On the contrary, its stability towards thermal and guanidine hydrochloride (GuHCl) denaturation is highly compromised. Using activity assays, CD, fluorescence, NMR, cross-linking, aggregation measurements and molecular modeling, we have mapped the properties of this remarkable mutant. Loss of enzymatic activity had a midpoint temperature of denaturation (Tm) of 16 °C for the mutant compared to 55 °C for the wild-type protein. GuHCl-denaturation (at 4 °C) showed that the native state of the mutant was destabilized by 9.2 kcal/mol. The mutant unfolds through at least two equilibrium intermediates; one novel intermediate that we have termed the molten globule light state and, after further denaturation, the classical molten globule state is populated. Under physiological conditions (neutral pH; 37 °C), the His107Tyr mutant will populate the molten globule light state, likely due to novel interactions between Tyr107 and the surroundings of the critical residue Ser29 that destabilize the native conformation. This intermediate binds the hydrophobic dye 8-anilino-1-naphthalene sulfonic acid (ANS) but not as strong as the molten globule state, and near-UV CD reveals the presence of significant tertiary structure. Notably, this intermediate is not as prone to aggregation as the classical molten globule. As a proof of concept for an intervention strategy with small molecules, we showed that binding of the CA inhibitor acetazolamide increases the stability of the native state of the mutant by 2.9 kcal/mol in accordance with its strong affinity. Acetazolamide shifts the Tm to 34 °C that protects from misfolding and will enable a substantial fraction of the enzyme pool to survive physiological conditions.
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| 4. |
- Björgvinsdottir, Helga, et al.
(author)
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Efficient Oncoretroviral Transduction of Extended Long-Term Culture-Initiating Cells and NOD/SCID Repopulating Cells: Enhanced Reconstitution with Gene-Marked Cells Through an Ex Vivo Expansion Approach.
- 2002
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In: Human Gene Therapy. - 1043-0342. ; 13:9, s. 1061-1073
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Journal article (peer-reviewed)abstract
- Recent developments of surrogate assays for human hematopoietic stem cells (HSC) have facilitated efforts at improving HSC gene transfer efficiency. Through the use of xenograft transplantation models, such as nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice, successful oncoretroviral gene transfer to transplantable hematopoietic cells has been achieved. However, because of the low frequency and/or homing efficiency of SCID repopulating cells (SRC) in bone marrow (BM), studies have primarily focused on cord blood (CB). The recently developed extended (> 60 days) long-term culture-initiating cell (ELTC-IC) assay detects an infrequent and highly quiescent candidate stem cell population in BM as well as CB of the CD34(+)CD38(-) phenotype. Although these characteristics suggest that ELTC-IC and SRC might be closely related, attempts to oncoretrovirally transduce ELTC-IC have been unsuccessful. Here, recently developed conditions (high concentrations of SCF + FL + Tpo in serum-free medium) supporting expansion of BM CD34(+)CD38(-) 12 week ELTC-IC promoted efficient oncoretroviral transduction of BM and CB ELTC-IC. Although SRC can be transduced with oncoretroviral vectors, this is frequently associated with loss of reconstituting activity, posing a problem for development of clinical HSC gene therapy. However, previous attempts at expanding transduced HSC posttransduction resulted in compromised rather than improved gene marking. Utilizing conditions promoting cell divisions and transduction of ELTC-IC we show that although 5 days of ex vivo culture is sufficient to obtain maximum gene transfer efficiency to SRC, extension of the expansion period to 12 days significantly enhances multilineage reconstitution activity of transduced SRC, supporting the feasibility of improving gene marking through ex vivo expansion.
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| 5. |
- Björnström Karlsson, Karin, 1971-
(author)
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Cellular mechanisms of anaesthetic agents
- 2003
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Doctoral thesis (other academic/artistic)abstract
- Anaesthesia is given to approximate 5% of the Swedish population annually, with the great advantage of painless surgery, but it also has side effects such as depression of blood pressure that might give a heart infarction. Exactly how anaesthetic agents cause anaesthesia is poorly known. Most anaesthetics have been shown to interact with the GABAA receptor, whose endogenous ligand GABA causes down-regulation of the brain and sleep. To further explore the cellular signal system used by anaesthetics this study was performed.First, two different malignant cell lines, PC-12 and SH-SY5Y, were tested, to evaluate if they could replace animal cells; however, they did not respond with increased intracellular calcium [Ca2+]i upon stimulation with propofol, as the normal rat neurons do. This is probably due to differences in the intracellular signaling systems in these malignant cells. Therefore, the studies in this thesis were performed on rat neurons.Propofol, an intravenous anaesthetic, was shown to cause a bicucullin insensitive increase in [Ca2+]i, where the release from intracellular stores was dependent on a tyrosine kinase. Sevoflurane, a volatile anaesthetic, also caused an ilrunediate increase in [Ca2+]i, but not nitrous oxide. Increased [Ca2+], is supposed to augment the influx of chloride ions through the GABAA receptor, hence hyperpolarising the neuron, and thereby make it anaesthetised.Tyrosine phosphorylation of the GABAA receptor is necessary for its function. Propofol tyrosine phosphorylates another ß2 subunit in the membrane then GABA. Propofol, but not GABA, also caused a tyrosine phosphorylation of actin in both the cytoskeletal and cell membrane fraction. Together these changes might explain the difference between sleep and anaesthesia. Isoflurane, sevoflurane and nitrous oxide all tyrosine phosphmylate a protein, suggested to be the GABAA receptor ß subunit, in different cellular compartments. This might explain their different clinical effects.Propofol and sevoflurane, but not GABA, causes actin rings to be formed in the cell, and for propofol the signal goes via rhoA and rho kinase, that also are involved in the translocation of actin to the cellular membrane. An unl~own 160 kDa protein is tyrosine phosphorylated by propofol, is part of the rho signalling pathway and is regulated by rho, This unknown protein might be involved in the actin reorganisation.
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| 6. |
- Boström, Curt-Åke, et al.
(author)
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Luftkvalitetsmätningar i ett antal tätorter i sydöstra Sverige tre vintersäsonger -98/99, 99/00 & 00/01
- 2003
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Reports (other academic/artistic)abstract
- I föreliggande rapport redovisas mätningar av luftkvaliteten avseende trafikrelaterade luftföroreningar, kväveoxider (NOX som NO+NO2), ozon (O3) samt lättflyktiga kolväten (VOC) i ett antal tätorter i regionen (Blekinge, Jönköpings, Kalmar, Kronobergs och Östergötlands län). I varje ort har mätningar skett i två punkter (98/99), i ett hårt trafikbelastat gaturum resp. i urban bakgrund. Mätningarna vintersäsongen 00/01 utökades med ytterligare en trafikbelastad mätpunkt Mätningarna har visat att med diffusionsprovtagare och en samordnad strategi kan man få ett jämförelsematerial användbart för bedömning av luftföroreningssituationen i många tätorter och trafikmiljöer. Mätningarna har även visat på vilken skillnad som kan förväntas i halt mellan förmodade hårt belastade miljöer och den urbana bakgrunden. Även i mindre tätorter kan halterna av trafikrelaterade luftföroreningar bli relativt höga i förhållande till gräns-/riktvärden och miljökvalitetsnor
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| 9. |
- Ekström, Karin M., 1959, et al.
(author)
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Customer Oriented Product Development? An exploratory study of four Swedish SME's
- 2001
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Reports (other academic/artistic)abstract
- The purpose of this study was to investigate the degree of customer orientation in a small sample of Swedish SME's. In-depth interviews were carried out with product developers in four companies from three different product areas. The questions posed concerned the company's overall strategy, ways of managing the external dialogue (i.e. the dialogue between the company and the customer), and ways of managing the internal dialogue (i.e. the dialogue between the product development team members, and between the product development team and the company). The study indicates some ambiguities regarding key issues in customer orientation. All companies claimed to be customer-oriented, however, the meanings of the concept varied slightly between offering the customer what the customer wants' to understanding and solving customer problems'. The study also showed that the companies had difficulties defining their customer. While customer-orientation in general seems to imply a consumer-orientation, the customer can also be the middleman or the distributor. The latter was the case in three of the four companies and had clear implications on overall strategy. Also, the direct dialogue between the manufacturer and the end customers, i.e. consumers was rather limited, even though such a dialogue was considered and needed.
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