| 1. |
- Eriksson, Olof, et al.
(författare)
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The Positron Emission Tomography ligand [11C]5-Hydroxy-Tryptophan can be used as a surrogate marker for the human endocrine pancreas
- 2014
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 63:10, s. 3428-3437
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Tidskriftsartikel (refereegranskat)abstract
- In humans a well-developed serotonin system is localized to the pancreatic islets while being absent in exocrine pancreas. Assessment of pancreatic serotonin biosynthesis could therefore be used to estimate the human endocrine pancreas. Proof of concept was tested in a prospective clinical trial by comparisons of type 1 diabetic (T1D) patients, with extensive reduction of beta cells, with healthy volunteers (HV).C-peptide negative (i.e. insulin-deficient) T1D subjects (n=10) and HV (n=9) underwent dynamic Positron Emission Tomography with the radiolabeled serotonin precursor [(11)C]5-Hydroxy-Tryptophan ([(11)C]5-HTP).A significant accumulation of [(11)C]5-HTP was obtained in the pancreas of the HV, with large inter-individual variation. A substantial and highly significant reduction (66%) in the pancreatic uptake of [(11)C]5-HTP in T1D subjects was observed, and this was most evident in the corpus and caudal regions of the pancreas where beta-cells normally are the major constituent of the islets.[(11)C]5-HTP retention in the pancreas was reduced in T1D compared to non-diabetic subjects. Accumulation of [(11)C]5-HTP in the pancreas of both HV and subjects with T1D were in agreement with previously reported morphological observations on the beta cell volume implying that [(11)C]5-HTP retention is a useful non-invasive surrogate marker for the human endocrine pancreas.
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| 36. |
- Ahlqvist, Emma, et al.
(författare)
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A common variant upstream of the PAX6 gene influences islet function in man.
- 2012
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 55, s. 94-104
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: Impaired glucose tolerance and impaired insulin secretion have been reported in families with PAX6 mutations and it is suggested that they result from defective proinsulin processing due to lack of prohormone convertase 1/3, encoded by PCSK1. We investigated whether a common PAX6 variant would mimic these findings and explored in detail its effect on islet function in man. METHODS: A PAX6 candidate single nucleotide polymorphism (rs685428) was associated with fasting insulin levels in the Diabetes Genetics Initiative genome-wide association study. We explored its potential association with glucose tolerance and insulin processing and secretion in three Scandinavian cohorts (N = 8,897 individuals). In addition, insulin secretion and the expression of PAX6 and transcriptional target genes were studied in human pancreatic islets. RESULTS: rs685428 G allele carriers had lower islet mRNA expression of PAX6 (p = 0.01) and PCSK1 (p = 0.001) than AA homozygotes. The G allele was associated with increased fasting insulin (p (replication) = 0.02, p (all) = 0.0008) and HOMA-insulin resistance (p (replication) = 0.02, p (all) = 0.001) as well as a lower fasting proinsulin/insulin ratio (p (all) = 0.008) and lower fasting glucagon (p = 0.04) and gastric inhibitory peptide (GIP) (p = 0.05) concentrations. Arginine-stimulated (p = 0.02) insulin secretion was reduced in vivo, which was further reflected by a reduction of glucose- and potassium-stimulated insulin secretion (p = 0.002 and p = 0.04, respectively) in human islets in vitro. CONCLUSIONS/INTERPRETATION: A common variant in PAX6 is associated with reduced PAX6 and PCSK1 expression in human islets and reduced insulin response, as well as decreased glucagon and GIP concentrations and decreased insulin sensitivity. These findings emphasise the central role of PAX6 in the regulation of islet function and glucose metabolism in man.
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| 37. |
- Bilal, Ayesha, et al.
(författare)
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Predicting perinatal health outcomes using smartphone-based digital phenotyping and machine learning in a prospective Swedish cohort (Mom2B) : study protocol
- 2022
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Ingår i: BMJ Open. - : BMJ Publishing Group Ltd. - 2044-6055. ; 12:4
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Perinatal complications, such as perinatal depression and preterm birth, are major causes of morbidity and mortality for the mother and the child. Prediction of high risk can allow for early delivery of existing interventions for prevention. This ongoing study aims to use digital phenotyping data from the Mom2B smartphone application to develop models to predict women at high risk for mental and somatic complications.Methods and analysis: All Swedish-speaking women over 18 years, who are either pregnant or within 3 months postpartum are eligible to participate by downloading the Mom2B smartphone app. We aim to recruit at least 5000 participants with completed outcome measures. Throughout the pregnancy and within the first year postpartum, both active and passive data are collected via the app in an effort to establish a participant's digital phenotype. Active data collection consists of surveys related to participant background information, mental and physical health, lifestyle, and social circumstances, as well as voice recordings. Participants' general smartphone activity, geographical movement patterns, social media activity and cognitive patterns can be estimated through passive data collection from smartphone sensors and activity logs. The outcomes will be measured using surveys, such as the Edinburgh Postnatal Depression Scale, and through linkage to national registers, from where information on registered clinical diagnoses and received care, including prescribed medication, can be obtained. Advanced machine learning and deep learning techniques will be applied to these multimodal data in order to develop accurate algorithms for the prediction of perinatal depression and preterm birth. In this way, earlier intervention may be possible.Ethics and dissemination: Ethical approval has been obtained from the Swedish Ethical Review Authority (dnr: 2019/01170, with amendments), and the project fully fulfils the General Data Protection Regulation (GDPR) requirements. All participants provide consent to participate and can withdraw their participation at any time. Results from this project will be disseminated in international peer-reviewed journals and presented in relevant conferences.
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| 38. |
- Eriksson, Emma K.
(författare)
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Effects of Ubiquinone-10 on the Stability and Mechanical Properties of Lipid Membranes
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Ubiquinones are a group of fat-soluble molecules present in many biological membranes. The most abundant version in humans, ubiquinone-10 (Q10), plays an important role in the mitochondrial respiration chain and also functions as a powerful antioxidant. Accumulating evidence suggests that Q10 also could have other functions in the membrane. The aim of this thesis has been to explore Q10’s possible role as a membrane stabilizer.To investigate the potential effect of Q10 in membranes, liposomes with compositions of biological relevance were used as models systems. In lipid systems mimicking that of the inner membrane of the mitochondria, Q10 was found to lower the membrane’s permeability to hydrophilic solutes, render the membrane more resistant to rupturing and promote membrane lipid order. In models mimicking the plasma membrane of E.coli, Q10 was observed to decrease the water permeability and increase the elastic resistance against membrane deformation during osmotic shock. All in all, the results suggest a general membrane stabilizing effect of Q10. The results indicate, however, that the extent of, as well as the mechanisms behind, the membrane stabilizing effects of Q10 vary depending on the membrane lipid composition. Part of the reason for this can likely be traced back to differences in the intermembrane location of Q10.Supplementary experiments, which facilitated the investigations of Q10 membrane effects, revealed that the choice of cuvette material was of importance for liposome leakage experiments with fluorescent hydrophilic dyes. The results of these experiments highlight the need to take liposome-cuvette interactions into account when planning and evaluating spectroscopic studies involving liposomes.
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| 39. |
- Eriksson, Emma S. E., et al.
(författare)
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De novo tertiary structure prediction using RNA123-benchmarking and application to Macugen
- 2014
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Ingår i: Journal of Molecular Modeling. - : Springer Science and Business Media LLC. - 1610-2940 .- 0948-5023. ; 20:8
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Tidskriftsartikel (refereegranskat)abstract
- The present benchmarking study utilizes the RNA123 program for de novo prediction of tertiary structures of a set of 50 RNA molecules for which X-ray/NMR structures are available, based on the nucleic acid sequence only. All molecules contain a hairpin loop motif and a helical structure of canonical and non-canonical base pairs, interrupted by bulges and internal loops to various degrees. RNA molecules with double helices made up purely by canonical base pairing, and molecules containing symmetric internal loops of non-canonical base pairing are, overall, very well predicted. Structures containing bulges and asymmetric internal loops, and more complex structures containing multiple bulges and internal loops in the same molecule, result in larger deviations from their X-ray/NMR predicted structures due to higher degree of flexibility of the nucleotide bases in these regions. In a majority of the molecules included herein, the RNA123 program was, however, able to predict the tertiary structure with a heavy atom RMSD of less than 5 angstrom to the X-ray/NMR structure, and the models were in most cases structurally closer to the X-ray/NMR structures than models predicted by MC-Fold and MC-Sym. A set of RNA molecules containing pseudoknot tertiary structure motifs were included, but neither of the programs was able to predict the folding of the single-stranded stem onto the helix without additional structural input. The RNA123 program was then applied to predict the tertiary structure of the RNA segment of Macugen (R), the first RNA aptamer approved for clinical use, and for which no tertiary structure has yet been solved. Four possible tertiary structures were predicted for this 27-nucleic-acid-long RNA molecule, which will be used in constructing a full model of the PEGylated aptamer and its interaction with the vascular endothelial growth factor target.
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| 40. |
- Eriksson, Emma S. E., et al.
(författare)
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Identifying the sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) as a potential target for hypericin - a theoretical study
- 2012
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Ingår i: Physical Chemistry Chemical Physics. - : Royal Society of Chemistry (RSC). - 1463-9076 .- 1463-9084. ; 14:36, s. 12637-12646
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Tidskriftsartikel (refereegranskat)abstract
- The exact cellular target for the potent anti-cancer agent hypericin has not yet been determined; this thus encourages the application of computational chemistry tools to be employed in order to provide insights that can be employed in further drug development studies. In the present study computational docking and molecular dynamics simulations are applied to investigate possible interactions between hypericin and the Ca2+ pump SERCA as proposed in the literature. Hypericin was found to bind strongly both in pockets within the transmembrane region and in the cytosolic region of the protein, although the two studied isoforms of SERCA differ slightly in their preferred binding sites. The calculated binding energies for hypericin in the four investigated sites were of the same magnitude as for thapsigargin (TG), the most potent SERCA inhibitor, or in the range between TG and di-tert-butylhydroquinone (BHQ), which is also known to possess inhibitory activity. The hydrophobic character of hypericin indicates that the molecule initially binds in the ER membrane from which it diffuses into the transmembrane region of the protein and to binding pockets therein. The transmembrane TG and BHQ binding pockets provide suitable locations for hypericin as they allow for favourable interactions with the lipid tails that surround these. High binding energies were noted for hypericin in these pockets and are expected to constitute highly possible binding sites due to their accessibility from the ER membrane. Hypericin most likely binds to both isoforms of SERCA and acts as an inhibitor or, under light irradiation, as a singlet oxygen generator that in turn degrades the protein or induces lipid peroxidation.
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| 41. |
- Eriksson, Emma S. E., et al.
(författare)
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Permeability of 5-aminolevulinic acid oxime derivatives in lipid membranes
- 2016
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Ingår i: Theoretical Chemistry accounts. - : Springer Science and Business Media LLC. - 1432-881X .- 1432-2234. ; 135:1, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- The endogenous molecule 5-aminolevulinic acid (5ALA) and its methyl ester (Me-5ALA) have been used as prodrugs in photodynamic treatment of actinic keratosis and superficial non-melanoma skin cancers for over a decade. Recently, a novel set of 5ALA derivatives based on introducing a hydrolyzable oxime functionality was proposed and shown to generate considerably stronger onset of the photoactive molecule protoporphyrin IX (PpIX) in the cells. In the current work, we employ molecular dynamics simulation techniques to explore whether the higher intercellular concentration of PpIX caused by the oxime derivatives is related to enhanced membrane permeability, or whether other factors contribute to this. It is concluded that the oximes show overall similar accumulation at the membrane headgroup regions as the conventional derivatives and that the transmembrane permeabilities are in general close to that of 5ALA. The highest permeability of all compounds explored is found for Me-5ALA, which correlates with a considerably lower fee energy barrier at the hydrophobic bilayer center. The high PpIX concentration must hence be sought in other factors, where slow hydrolysis of the oxime functionality is a plausible reason, enabling stronger buildup of PpIX over time.
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| 42. |
- Eriksson, Emma S. E., et al.
(författare)
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Properties and Permeability of Hypericin and Brominated Hypericin in Lipid Membranes
- 2009
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Ingår i: Journal of Chemical Theory and Computation. - : American Chemical Society (ACS). - 1549-9618 .- 1549-9626. ; 5:12, s. 3139-3149
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Tidskriftsartikel (refereegranskat)abstract
- The promising photosensitizing properties of hypericin, a substituted phenanthroperylene quinone naturally found in Saint John's wort, has led to the proposal that it can be utilized in photodynamic therapy, Structurally modified derivatives are at the present time being investigated to generate a more effective hypericin photosensitizer. Neither the detailed mechanism behind the powerful action of hypericin, arising as a result of light excitation, nor the intracellular localization and transportation is still fully understood. In the present work, molecular dynamics simulations have been performed to study the properties and the permeability of hypericin and modifications thereof, substituted with one or four bromine atoms, in a dipalmitoylphosphatidylcholine lipid membrane. The molecules were found to accumulate in the most dense region of the lipids due to competing interactions with the hydrophobic lipid interior and the polar aqueous environment. This was confirmed by analyzing the radial distribution functions and by the density profiles of the system components. Calculated free energy profiles display large negative changes in free energy for the transport process of the molecules into the lipids, which also support this finding. Permeability coefficients show overall fastest diffusion in the membrane system for hypericin containing one bromine.
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| 43. |
- Eriksson, Emma S. E., et al.
(författare)
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Redox and debromination reactions of brominated hypericin
- 2008
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Ingår i: International Journal of Quantum Chemistry. - New York : Wiley. - 0020-7608 .- 1097-461X. ; 108:11, s. 1921-1929
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Tidskriftsartikel (refereegranskat)abstract
- Phototoxic and radical-generating debromination reactions of monobrominated hypericin with bromine at one of four possible positions were investigated using density functional theory. The study was performed on two closely lying conformational isomers, differing in the relative orientations of the two anthracene units of the hypericin core. Calculated adiabatic electron affinities show that the molecules have the ability to, in aqueous solution, extract an electron from the surrounding. The electron might then be passed on to molecular oxygen, forming reactive superoxide radical anions. If electron extraction from the molecule does not occur in this step, the molecule might dissociate, generating a negatively charged bromine as a leaving group and a hypericin radical capable of forming direct binding to biological molecules. This reaction was found possible for those species substituted by Br at two of the four positions, with barriers of 13 kcal/mol in aqueous solution. Debromination was not found energetically possible for neither the neutral ground state compounds nor the bay-deprotonated species.
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| 44. |
- Eriksson, Mattias, et al.
(författare)
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The tree structure : A general framework for food waste quantification in food services
- 2018
-
Ingår i: Resources, Conservation and Recycling. - : Elsevier BV. - 0921-3449 .- 1879-0658. ; 130, s. 140-151
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Tidskriftsartikel (refereegranskat)abstract
- Food waste in the food services industry has been identified as an important unsustainability hotspot, but standardised methods for food waste quantification are lacking. Existing studies on waste quantity assessments have several limitations, such as short and infrequent quantifications times, large methodological variations ranging from physical measurements to visual observations, and lack of comparability across catering unit types. Since lack of comparable waste figures can lead to error-prone analysis, a general framework is needed for waste quantification in food services. This paper presents one such framework that allows data comparisons when overlapping observations are included. The framework was tested in six case studies in professional (public and private) catering units in Sweden. Data were collected from different schools, elderly care homes and hotels and fitted into the framework. The results from these case studies indicate that the framework enables catering units to focus waste quantification on their individual problem areas. It also provides the possibility to extend waste quantification over time without any loss of generalisability. A graphical representation of the framework fits the traditional tree structure and was found to act as a suitable foundation for food waste quantification in food services by structuring collected data. In order to fully utilise the potential of the tree structure, it should be supplemented with precise definitions to create a catering food waste quantification standard.
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| 45. |
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| 46. |
- Jämbeck, Joakim P. M., 1986-, et al.
(författare)
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Molecular Dynamics Studies of Liposomes as Carriers for Photosensitizing Drugs : Development, Validation, and Simulations with a Coarse-Grained Model
- 2014
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Ingår i: Journal of Chemical Theory and Computation. - : American Chemical Society (ACS). - 1549-9618 .- 1549-9626. ; 10:1, s. 5-13
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Tidskriftsartikel (refereegranskat)abstract
- Liposomes are proposed as drug delivery systems and can in principle be designed so as to cohere with specific tissue types or local environments. However, little detail is known about the exact mechanisms for drug delivery and the distributions of drug molecules inside the lipid carrier. In the current work, a coarse-grained (CG) liposome model is developed, consisting of over 2500 lipids, with varying degrees of drug loading. For the drug molecule, we chose hypericin, a natural compound proposed for use in photodynamic therapy, for which a CG model was derived and benchmarked against corresponding atomistic membrane bilayer model simulations. Liposomes with 21-84 hypericin molecules were generated and subjected to 10 microsecond simulations. Distribution of the hypericins, their orientations within the lipid bilayer, and the potential of mean force for transferring a hypericin molecule from the interior aqueous droplet through the liposome bilayer are reported herein.
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| 47. |
- Moberg, Christina, et al.
(författare)
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De unga gör helt rätt när de stämmer staten
- 2022
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Ingår i: Aftonbladet. - 1103-9000.
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Tidskriftsartikel (populärvet., debatt m.m.)abstract
- 1 620 forskare och lärare i forskarvärlden: Vi ställer oss bakom Auroras klimatkrav
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| 48. |
- Patridge, Erik V., et al.
(författare)
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7-Nitro-4-(phenylthio)benzofurazan is a potent generator of superoxide and hydrogen peroxide
- 2012
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Ingår i: Archives of Toxicology. - : Springer Science and Business Media LLC. - 0340-5761 .- 1432-0738. ; 86:10, s. 1613-1625
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Tidskriftsartikel (refereegranskat)abstract
- Here, we report on 7-nitro-4-(phenylthio)benzofurazan (NBF-SPh), the most potent derivative among a set of patented anticancer 7-nitrobenzofurazans (NBFs), which have been suggested to function by perturbing protein-protein interactions. We demonstrate that NBF-SPh participates in toxic redox-cycling, rapidly generating reactive oxygen species (ROS) in the presence of molecular oxygen, and this is the first report to detail ROS production for any of the anticancer NBFs. Oxygraph studies showed that NBF-SPh consumes molecular oxygen at a substantial rate, rivaling even plumbagin, menadione, and juglone. Biochemical and enzymatic assays identified superoxide and hydrogen peroxide as products of its redox-cycling activity, and the rapid rate of ROS production appears to be sufficient to account for some of the toxicity of NBF-SPh (LC50 = 12.1 mu M), possibly explaining why tumor cells exhibit a sharp threshold for tolerating the compound. In cell cultures, lipid peroxidation was enhanced after treatment with NBF-SPh, as measured by 2-thiobarbituric acid-reactive substances, indicating a significant accumulation of ROS. Thioglycerol rescued cell death and increased survival by 15-fold to 20-fold, but pyruvate and uric acid were ineffective protectants. We also observed that the redox-cycling activity of NBF-SPh became exhausted after an average of approximately 19 cycles per NBF-SPh molecule. Electrochemical and computational analyses suggest that partial reduction of NBF-SPh enhances electrophilicity, which appears to encourage scavenging activity and contribute to electrophilic toxicity.
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| 49. |
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| 50. |
- Svensson, Nina, 1988-, et al.
(författare)
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Ride the future – strategisk satsning : fem studier med fokus på autonoma bussar i städer
- 2022
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Fem noga utvalda förstudier har initierats av VTI som en del i den strategiska satsningen ”Ride the future” kopplad till framtidens mobilitetslösningar. Förstudiernas titel är följande: ▪ Databearbetning och visualisering av mobila luftkvalitetsmätningar. ▪ SUMO och Unreal Engine för co-simulering. ▪ Exploring spatio-temporal accessibility in Lambohov: a pre-study. ▪ Vägytans betydelse för vibrationer och komfort i långsamma fordon. ▪ Infrastrukturbehov vid busshållplatser. Föreliggande pm innehåller en kort beskrivning av studierna och den mer utförliga redovisningen återfinns i bilagan.
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