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1.
  • Joffrin, E., et al. (författare)
  • Overview of the JET preparation for deuterium-tritium operation with the ITER like-wall
  • 2019
  • Ingår i: Nuclear Fusion. - : IOP Publishing. - 1741-4326 .- 0029-5515. ; 59:11
  • Forskningsöversikt (refereegranskat)abstract
    • For the past several years, the JET scientific programme (Pamela et al 2007 Fusion Eng. Des. 82 590) has been engaged in a multi-campaign effort, including experiments in D, H and T, leading up to 2020 and the first experiments with 50%/50% D-T mixtures since 1997 and the first ever D-T plasmas with the ITER mix of plasma-facing component materials. For this purpose, a concerted physics and technology programme was launched with a view to prepare the D-T campaign (DTE2). This paper addresses the key elements developed by the JET programme directly contributing to the D-T preparation. This intense preparation includes the review of the physics basis for the D-T operational scenarios, including the fusion power predictions through first principle and integrated modelling, and the impact of isotopes in the operation and physics of D-T plasmas (thermal and particle transport, high confinement mode (H-mode) access, Be and W erosion, fuel recovery, etc). This effort also requires improving several aspects of plasma operation for DTE2, such as real time control schemes, heat load control, disruption avoidance and a mitigation system (including the installation of a new shattered pellet injector), novel ion cyclotron resonance heating schemes (such as the three-ions scheme), new diagnostics (neutron camera and spectrometer, active Alfven eigenmode antennas, neutral gauges, radiation hard imaging systems...) and the calibration of the JET neutron diagnostics at 14 MeV for accurate fusion power measurement. The active preparation of JET for the 2020 D-T campaign provides an incomparable source of information and a basis for the future D-T operation of ITER, and it is also foreseen that a large number of key physics issues will be addressed in support of burning plasmas.
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2.
  • Wuttke, Matthias, et al. (författare)
  • A catalog of genetic loci associated with kidney function from analyses of a million individuals
  • 2019
  • Ingår i: Nature Genetics. - : NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 51:6, s. 957-972
  • Tidskriftsartikel (refereegranskat)abstract
    • Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
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3.
  • Zamora, Juan Carlos, et al. (författare)
  • Considerations and consequences of allowing DNA sequence data as types of fungal taxa
  • 2018
  • Ingår i: IMA Fungus. - : INT MYCOLOGICAL ASSOC. - 2210-6340 .- 2210-6359. ; 9:1, s. 167-185
  • Tidskriftsartikel (refereegranskat)abstract
    • Nomenclatural type definitions are one of the most important concepts in biological nomenclature. Being physical objects that can be re-studied by other researchers, types permanently link taxonomy (an artificial agreement to classify biological diversity) with nomenclature (an artificial agreement to name biological diversity). Two proposals to amend the International Code of Nomenclature for algae, fungi, and plants (ICN), allowing DNA sequences alone (of any region and extent) to serve as types of taxon names for voucherless fungi (mainly putative taxa from environmental DNA sequences), have been submitted to be voted on at the 11th International Mycological Congress (Puerto Rico, July 2018). We consider various genetic processes affecting the distribution of alleles among taxa and find that alleles may not consistently and uniquely represent the species within which they are contained. Should the proposals be accepted, the meaning of nomenclatural types would change in a fundamental way from physical objects as sources of data to the data themselves. Such changes are conducive to irreproducible science, the potential typification on artefactual data, and massive creation of names with low information content, ultimately causing nomenclatural instability and unnecessary work for future researchers that would stall future explorations of fungal diversity. We conclude that the acceptance of DNA sequences alone as types of names of taxa, under the terms used in the current proposals, is unnecessary and would not solve the problem of naming putative taxa known only from DNA sequences in a scientifically defensible way. As an alternative, we highlight the use of formulas for naming putative taxa (candidate taxa) that do not require any modification of the ICN.
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4.
  • Wilking, N., et al. (författare)
  • Long-term follow-up of the SBG 9401 study comparing tailored FEC-based therapy versus marrow-supported high-dose therapy
  • 2007
  • Ingår i: Annals of Oncology. - : Elsevier BV. - 0923-7534 .- 1569-8041. ; 18:4, s. 694-700
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The purpose was to investigate adjuvant marrow-supportive high-dose chemotherapy compared with an equitoxicity-tailored comparator arm. Patients and methods: Five hundred and twenty-five women below theage of 60 years with operated high-risk primary breast cancer were randomised to nine cycles of granulocyte colony-stimulating factor supported and individually tailored FEC (5-fluorouracil, epirubicin, cyclophosphamide), (n = 251) or standard FEC followed by marrow-supported high-dose therapy with CTCb (cyclophosphamide, thiotepa, carboplatin) therapy (n = 274), followed by locoregional radiotherapy and tamoxifen for 5 years. Results: There were 104 breast cancer relapses in the tailored FEC group versus 139 in the CTCb group (double triangular method by Whitehead, P = 0.046), with a median follow-up of all included patients of 60.8 months. The event-free survival demonstrated 121 and 150 events in the tailored FEC- and CTCb group, respectively [P = 0.074, hazard ratio (HR) 0.804, 95% confidence interval (CI) 0.633-1.022]. Ten patients in the tailored FEC regimen developed acute myeloid leukaemia (AML)/myelodysplasia (MDS). One hundred deaths occurred in the tailored FEC group and 121 in the CTCb group (P = 0.287, HR 0.866, 95% CI 0.665-1.129). Conclusion: The update of this study shows an improved outcome linked to the tailored FEC treatment in relation to breast cancer relapse, but also an increased incidence of AML/MDS. © 2007 Oxford University Press.
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5.
  • Claussnitzer, M., et al. (författare)
  • FTO Obesity Variant Circuitry and Adipocyte Browning in Humans
  • 2015
  • Ingår i: New England Journal of Medicine. - 0028-4793. ; 373:10, s. 895-907
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND Genomewide association studies can be used to identify disease-relevant genomic regions, but interpretation of the data is challenging. The FTO region harbors the strongest genetic association with obesity, yet the mechanistic basis of this association remains elusive. We examined epigenomic data, allelic activity, motif conservation, regulator expression, and gene coexpression patterns, with the aim of dissecting the regulatory circuitry and mechanistic basis of the association between the FTO region and obesity. We validated our predictions with the use of directed perturbations in samples from patients and from mice and with endogenous CRISPR-Cas9 genome editing in samples from patients. Our data indicate that the FTO allele associated with obesity represses mitochondrial thermogenesis in adipocyte precursor cells in a tissue-autonomous manner. The rs1421085 T-to-C single-nucleotide variant disrupts a conserved motif for the ARID5B repressor, which leads to derepression of a potent preadipocyte enhancer and a doubling of IRX3 and IRX5 expression during early adipocyte differentiation. This results in a cell-autonomous developmental shift from energy-dissipating beige (brite) adipocytes to energy-storing white adipocytes, with a reduction in mitochondrial thermogenesis by a factor of 5, as well as an increase in lipid storage. Inhibition of Irx3 in adipose tissue in mice reduced body weight and increased energy dissipation without a change in physical activity or appetite. Knockdown of IRX3 or IRX5 in primary adipocytes from participants with the risk allele restored thermogenesis, increasing it by a factor of 7, and overexpression of these genes had the opposite effect in adipocytes from nonrisk-allele carriers. Repair of the ARID5B motif by CRISPR-Cas9 editing of rs1421085 in primary adipocytes from a patient with the risk allele restored IRX3 and IRX5 repression, activated browning expression programs, and restored thermogenesis, increasing it by a factor of 7. Our results point to a pathway for adipocyte thermogenesis regulation involving ARID5B, rs1421085, IRX3, and IRX5, which, when manipulated, had pronounced pro-obesity and anti-obesity effects. (Funded by the German Research Center for Environmental Health and others.)
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6.
  • Chantzichristos, Dimitrios, 1976, et al. (författare)
  • Identification of human glucocorticoid response markers using integrated multi-omic analysis from a randomized crossover trial.
  • 2021
  • Ingår i: eLife. - 2050-084X. ; 10
  • Tidskriftsartikel (refereegranskat)abstract
    • Glucocorticoids are among the most commonly prescribed drugs, but there is no biomarker that can quantify their action. The aim of the study was to identify and validate circulating biomarkers of glucocorticoid action.In a randomized, crossover, single-blind, discovery study, 10 subjects with primary adrenal insufficiency (and no other endocrinopathies) were admitted at the in-patient clinic and studied during physiological glucocorticoid exposure and withdrawal. A randomization plan before the first intervention was used. Besides mild physical and/or mental fatigue and salt craving, no serious adverse events were observed. The transcriptome in peripheral blood mononuclear cells and adipose tissue, plasma miRNAomic, and serum metabolomics were compared between the interventions using integrated multi-omic analysis.We identified a transcriptomic profile derived from two tissues and a multi-omic cluster, both predictive of glucocorticoid exposure. A microRNA (miR-122-5p) that was correlated with genes and metabolites regulated by glucocorticoid exposure was identified (p=0.009) and replicated in independent studies with varying glucocorticoid exposure (0.01 ≤ p≤0.05).We have generated results that construct the basis for successful discovery of biomarker(s) to measure effects of glucocorticoids, allowing strategies to individualize and optimize glucocorticoid therapy, and shedding light on disease etiology related to unphysiological glucocorticoid exposure, such as in cardiovascular disease and obesity.The Swedish Research Council (Grant 2015-02561 and 2019-01112); The Swedish federal government under the LUA/ALF agreement (Grant ALFGBG-719531); The Swedish Endocrinology Association; The Gothenburg Medical Society; Wellcome Trust; The Medical Research Council, UK; The Chief Scientist Office, UK; The Eva Madura's Foundation; The Research Foundation of Copenhagen University Hospital; and The Danish Rheumatism Association.NCT02152553.
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7.
  • Fryk, Emanuel, et al. (författare)
  • Microdialysis and proteomics of subcutaneous interstitial fluid reveals increased galectin-1 in type 2 diabetes patients
  • 2016
  • Ingår i: Metabolism-Clinical and Experimental. - : Elsevier BV. - 0026-0495 .- 1532-8600. ; 65:7, s. 998-1006
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective. To identify a potential therapeutic target for type 2 diabetes by comparing the subcutaneous interstitial fluid from type 2 diabetes patients and healthy men. Methods. Proteomics was performed on the interstitial fluid of subcutaneous adipose tissue obtained by microdialysis from 7 type 2 diabetes patients and 8 healthy participants. 851 proteins were detected, of which 36 (including galectin-1) showed significantly altered expression in type 2 diabetes. We also measured galectin-1 expression in: (1) adipocytes isolated from adipose tissue biopsies from these participants; (2) subcutaneous adipose tissue of 24 obese participants before, during and after 16 weeks on a very low calorie diet (VLCD); and (3) adipocytes isolated from 6 healthy young participants after 4 weeks on a diet and lifestyle intervention to promote weight gain. We also determined the effect of galectin-1 on glucose uptake in human adipose tissue. Results. Galectin-1 protein levels were elevated in subcutaneous dialysates from type 2 diabetes compared with healthy controls (p < 0.05). In agreement, galectin-1 mRNA expression was increased in adipocytes from the type 2 diabetes patients (p < 0.05). Furthermore, galectin-1 mRNA expression was decreased in adipose tissue after VLCD (p < 0.05) and increased by overfeeding (p < 0.05). Co-incubation of isolated human adipocytes with galectin-1 reduced glucose uptake (p < 0.05) but this was independent of the insulin signal. Conclusion. Proteomics of the interstitial fluid in subcutaneous adipose tissue in vivo identified a novel adipokine, galectin-1, with a potential role in the pathophysiology of type 2 diabetes. (C) 2016 Elsevier Inc. All rights reserved.
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8.
  • Jersin, R. A., et al. (författare)
  • Role of the Neutral Amino Acid Transporter SLC7A10 in Adipocyte Lipid Storage, Obesity, and Insulin Resistance
  • 2021
  • Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 70:3, s. 680-695
  • Tidskriftsartikel (refereegranskat)abstract
    • Elucidation of mechanisms that govern lipid storage, oxidative stress, and insulin resistance may lead to improved therapeutic options for type 2 diabetes and other obesity-related diseases. Here, we find that adipose expression of the small neutral amino acid transporter SLC7A10, also known as alanine-serine-cysteine transporter-1 (ASC-1), shows strong inverse correlates with visceral adiposity, insulin resistance, and adipocyte hypertrophy across multiple cohorts. Concordantly, loss of Slc7a10 function in zebrafish in vivo accelerates diet-induced body weight gain and adipocyte enlargement. Mechanistically, SLC7A10 inhibition in human and murine adipocytes decreases adipocyte serine uptake and total glutathione levels and promotes reactive oxygen species (ROS) generation. Conversely, SLC7A10 overexpression decreases ROS generation and increases mitochondrial respiratory capacity. RNA sequencing revealed consistent changes in gene expression between human adipocytes and zebrafish visceral adipose tissue following loss of SLC7A10, e.g., upregulation of SCD (lipid storage) and downregulation of CPT1A (lipid oxidation). Interestingly, ROS scavenger reduced lipid accumulation and attenuated the lipid-storing effect of SLC7A10 inhibition. These data uncover adipocyte SLC7A10 as a novel important regulator of adipocyte resilience to nutrient and oxidative stress, in part by enhancing glutathione levels and mitochondrial respiration, conducive to decreased ROS generation, lipid accumulation, adipocyte hypertrophy, insulin resistance, and type 2 diabetes.
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9.
  • Linnarsson, M K, et al. (författare)
  • Precipitate formation in heavily Al-doped 4H-SiC layers
  • 2001
  • Ingår i: Materials Science Forum, Vols. 353-356. ; , s. 583-586, s. 583-586
  • Konferensbidrag (refereegranskat)abstract
    • Epitaxially grown 4H-SiC structures with several heavily Al doped layers were used. The samples were annealed in Ar atmosphere in a RF-heated furnace between 1500 and 2900 degreesC for 0.5 to 3h. Secondary ion mass spectrometry (SIMS) was used to measure the aluminum concentration versus,depth as well as the lateral distribution (ion images). Transmission electron microscopy (TEM) was employed to study the crystallinity and determine phase composition after heat treatment. A solubility limit of 2x10(20) Al/cm(3) at 2000 degreesC is extracted. Ion images of the lateral Al distribution reveal a pronounced dependence on the Al content. Precipitate formation occurs after heat treatment at 1700 - 2000 degreesC when the Al concentration exceeds 2x10(20) cm(-3) and energy-filtered TEM (EFTEM) shows that the precipitates contain Al.
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10.
  • Ohm, Joel, et al. (författare)
  • Association of Socioeconomic Status With Risk Factor Target Achievements and Use of Secondary Prevention After Myocardial Infarction
  • 2021
  • Ingår i: JAMA Network Open. - : American Medical Association (AMA). - 2574-3805. ; 4:3
  • Tidskriftsartikel (refereegranskat)abstract
    • IMPORTANCE Low socioeconomic status (SES) is associated with poor long-term prognosis after myocardial infarction (MI). Plausible underlying mechanisms have received limited study. OBJECTIVE To assess whether SES is associated with risk factor target achievements or with riskmodifying activities, including cardiac rehabilitation programs, monitoring, and drug therapies, during the first year after MI. DESIGN, SETTING, AND PARTICIPANTS This cohort study included a population-based consecutive sample of 30 191 one-year survivors of first-ever MI who were 18 to 76 years of age, resided in the general community in Sweden, were followed up until their routine 11- to 15-month revisit, and were registered in the national registry SwedishWeb-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART) from 2006 through 2013. Data analyses were performed from January to August 2020. EXPOSURE Individual-level SES by proxy disposable income quintile. Secondary exposures were educational level and marital status. MAIN OUTCOMES AND MEASURES Odds ratios (ORs) with 95% CIs for achieved risk factor targets at the 1-year revisit and for use of guideline-recommended secondary prevention activities. RESULTS The study comprised 30 191 participants ( 72.9% men) with a mean (SD) age of 63.0 (8.6) years. Overall, higher SESwas associated with better target achievements and use of most secondary prevention. The highest (vs lowest) income quintilewas associated with achieved smoking cessation (OR, 2.05; 95% CI, 1.78-2.35), target blood pressure levels (OR, 1.17; 95% CI, 1.07-1.27), and glycated hemoglobin levels (OR, 1.57; 95% CI, 1.19-2.06). The highest-income quintile was associated not only with participation in physical training programs (OR, 2.28; 95% CI, 2.11-2.46) and patient educational sessions (OR, 2.29; 95% CI, 2.12-2.47) in cardiac rehabilitation but also with more monitoring of lipid profiles (OR, 1.20; 95% CI, 1.08-1.33) and intensification of statin therapy (OR, 1.22; 95% CI, 1.11-1.35) during the first year after MI. One year after MI, the highest-income quintile was associated with persistent use of statins (OR, 1.26; 95% CI, 1.10-1.45), high-intensity statins (OR, 1.10; 95% CI, 1.00-1.21), and renin-angiotensin-aldosterone system inhibitors (OR, 1.27; 95% CI, 1.08-1.49). CONCLUSIONS AND RELEVANCE Findings indicated that, in a publicly financed health care system, higher SES was associated with better achievement of most risk factor targets, programs aimed at lifestyle change, and evidence-based drug therapies after MI. Observed differences in secondary prevention activity may be a factor in higher long-term risk of recurrent disease among individuals with low SES.
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11.
  • Ohm, Joel, et al. (författare)
  • Lipid levels achieved after a first myocardial infarction and the prediction of recurrent atherosclerotic cardiovascular disease
  • 2019
  • Ingår i: International Journal of Cardiology. - : ELSEVIER IRELAND LTD. - 0167-5273 .- 1874-1754. ; 296, s. 1-7
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Low density lipoprotein cholesterol (LDL-C) goals post-myocardial infarction (MI) are debated, and the significance of achieved blood lipid levels for predicting a first recurrent atherosclerotic cardiovascular disease (rASCVD) event post-MI is unclear.Methods: This was a cohort study on first-ever MI survivors aged <= 76 years attending 4-14 week revisits throughout Sweden 2005-2013. Personal-level data was collected from SWEDEHEART and linked national registries. Exposures were quintiles of LDL-C, high density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TGs) at the revisit. Group level associations with rASCVD (nonfatal MI or coronary heart disease death or fatal or nonfatal ischemic stroke) were estimated in Cox regression models. Predictive capacity was estimated by differences in C-statistic, integrated discriminatory improvement, and net reclassification improvement when adding each blood lipid to a validated risk prediction model.Results: 25,643 patients, 96.9% on statin therapy, were followed during a mean of 4.1 years. rASCVD occurred in 2173 patients (8.5%). For LDL-C and TC, moderate associations with rASCVD were observed only in the 5th vs. the lowest (referent) quintiles. For TGs and HDL-C increased risks were observed in quintiles 3-5 vs. the lowest. Minor predictive improvements were observed when lipid fractions were added to the risk model but the discrimination overall was poor (C-statistics < 0.6).Conclusions: Our data question the importance of LDL-C levels achieved at first revisit post-MI for decisions on continued treatment intensity considering the weak association with rASCVD observed in this post-MI cohort.
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12.
  • Ohm, Joel, et al. (författare)
  • Socioeconomic Disparities and Mediators for Recurrent Atherosclerotic Cardiovascular Disease Events After a First Myocardial Infarction
  • 2023
  • Ingår i: Circulation. - : Lippincott Williams & Wilkins. - 0009-7322 .- 1524-4539. ; 148:3, s. 256-267
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND:Low socioeconomic status is associated with worse secondary prevention use and prognosis after myocardial infarction (MI). Actions for health equity improvements warrant identification of risk mediators. Therefore, we assessed mediators of the association between socioeconomic status and first recurrent atherosclerotic cardiovascular disease event (rASCVD) after MI.METHODS:In this cohort study on 1-year survivors of first-ever MI with Swedish universal health coverage ages 18 to 76 years, individual-level data from SWEDEHEART (Swedish Web System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies) and linked national registries was collected from 2006 through 2020. Exposure was socioeconomic status by disposable income quintile (principal proxy), educational level, and marital status. The primary outcome was rASCVD and secondary outcomes were cardiovascular and all-cause mortality. We initially assessed the incremental attenuation of hazard ratios with 95% CIs in sequential multivariable models adding groups of potential mediators (ie, previous risk factors, acute presentation and infarct severity, initial therapies, and secondary prevention). Thereafter, the proportion of excess rASCVD associated with a low income mediated through nonparticipation in cardiac rehabilitation, suboptimal statin management, a cardiometabolic risk profile, persistent smoking, and blood pressure above target after MI were calculated using causal mediation analysis.RESULTS:Among 68 775 participants (73.8% men), 7064 rASCVD occurred during a mean 5.7-year follow-up. Income, adjusted for age, sex, and calendar year, was associated with rASCVD (hazard ratio, 1.63 [95% CI, 1.51-1.76] in the lowest versus highest income quintile). Risk attenuated most by adjustment for previous risk factors and by adding secondary prevention variables for a final model (hazard ratio, 1.38 [95% CI, 1.26-1.51]) in the lowest versus highest income quintile. The proportions of the excess 15-year rASCVD risk in the lowest income quintile mediated through nonparticipation in cardiac rehabilitation, cardiometabolic risk profile, persistent smoking, and poor blood pressure control were 3.3% (95% CI 2.1-4.8), 3.9% (95% CI, 2.9-5.5), 15.2% (95% 9.1-25.7), and 1.0% (95% CI 0.6-1.5), respectively. Risk mediation through optimal statin management was negligible.CONCLUSIONS:Nonparticipation in cardiac rehabilitation, a cardiometabolic risk profile, and persistent smoking mediate income-dependent prognosis after MI. In the absence of randomized trials, this causal inference approach may guide decisions to improve health equity.
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13.
  • Ohm, Joel, et al. (författare)
  • Socioeconomic status predicts second cardiovascular event in 29,226 survivors of a first myocardial infarction
  • 2018
  • Ingår i: European Journal of Preventive Cardiology. - : SAGE PUBLICATIONS LTD. - 2047-4873 .- 2047-4881. ; 25:9, s. 985-993
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Risk assessment post-myocardial infarction needs improvement, and risk factors derived from general populations apply differently in secondary prevention. The prediction of subsequent cardiovascular events post-myocardial infarction by socioeconomic status has previously been poorly studied. Design Swedish nationwide cohort study. Methods A total of 29,226 men and women (27%), 40-76 years of age, registered at the standardised one year revisit after a first myocardial infarction in the secondary prevention quality registry of SWEDEHEART 2006-2014. Personal-level data on socioeconomic status measured by disposable income and educational level, marital status, and the primary endpoint, first recurrent event of atherosclerotic cardiovascular disease, defined as non-fatal myocardial infarction or coronary heart disease death or fatal or non-fatal stroke were obtained from linked national registries. Results During the mean 4.1-year follow-up, 2284 (7.8%) first recurrent manifestations of atherosclerotic cardiovascular disease occurred. Both socioeconomic status indicators and marital status were associated with the primary endpoint in multivariable Cox regression models. In a comprehensively adjusted model, including secondary preventive treatment, the hazard ratio for the highest versus lowest quintile of disposable income was 0.73 (95% confidence interval 0.62-0.83). The association between disposable income and first recurrent manifestation of atherosclerotic cardiovascular disease was stronger in men as was the risk associated with being unmarried (tests for interaction P<0.05). Conclusions Among one year survivors of a first myocardial infarction, first recurrent manifestation of atherosclerotic cardiovascular disease was predicted by disposable income, level of education and marital status. The association between disposable income and first recurrent manifestation of atherosclerotic cardiovascular disease was independent of secondary preventive treatment but further study on causal pathways is needed.
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14.
  • Skoglund, Per H., et al. (författare)
  • Amino-Terminal Pro-B-Type Natriuretic Peptide Improves Discrimination for Incident Atherosclerotic Cardiovascular Disease Beyond Ambulatory Blood Pressure in Elderly Men
  • 2015
  • Ingår i: Hypertension. - 0194-911X .- 1524-4563. ; 66:3, s. 681-686
  • Tidskriftsartikel (refereegranskat)abstract
    • Improvement of risk prediction for atherosclerotic cardiovascular disease (ASCVD) is needed. Both ambulatory blood pressure (ABP) and biomarkers amino-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein and cystatin C improve risk prediction but they have not been evaluated in relation to each other. We analyzed whether NT-proBNP, high-sensitivity C-reactive protein, or cystatin C improved risk prediction beyond traditional ASCVD risk factors combined with 24-hour systolic BP (SBP). Secondary aim was to evaluate whether ABP improved risk prediction when compared with models with the biomarkers. We followed up 907 70-year-old men, free of baseline disease, for incident ASCVD defined as fatal or nonfatal myocardial infarction or fatal or nonfatal stroke for a median of 10 years. Cox regression was used to estimate the association between variables in the models and incident ASCVD. Biomarkers were added to a model containing both traditional risk factors and ABP and the models were compared on C-statistics and net reclassification improvement. Twenty-four hour SBP improved discrimination for incident ASCVD when compared with office SBP in a traditional risk factor model (area under the receiver-operating characteristic curve, +2.4%). NT-proBNP further improved reclassification (+18.7%-19.9%; P<0.01) when added to ABP models, whereas high-sensitivity C-reactive protein and cystatin C did not. Twenty-four hour SBP significantly improved net reclassification when added to a traditional risk factor model that included NT-proBNP. The combination of 24-hour SBP and NT-proBNP improved discrimination and net reclassification for incident ASCVD when compared with office SBP in elderly men. NT-proBNP, but not high-sensitivity C-reactive protein or cystatin C, improved risk prediction and discrimination when added to a model that included ABP.
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18.
  • Alavian Ghavanini, Farzan, 1978, et al. (författare)
  • Direct Measurement of the Bending Stiffness of Individual Vertically Aligned Carbon Nanofibers (VACNFs)
  • 2011
  • Ingår i: NT11 International Conference on the Science and Application of Nanotubes University of Cambridge, Cambridge, 10 – 16 July, 2011.
  • Konferensbidrag (refereegranskat)abstract
    • Vertically aligned carbon nanofibers (VACNFs) are synthesized in a plasma-enhanced chemical vapor deposition process (PECVD) in which the position, diameter, length, and alignment of individual nanofibers can be controlled accurately. This has provided an unprecedented opportunity to realize a new bottom-up-engineered material with excellent mechanical and electrical properties which could exploit the third dimension at a reasonable cost. VACNFs have been already employed in a number of applications including electron emitters, gene delivery arrays, and nanoelectromechanical systems. However, no direct measurement of the Young’s modulus of VACNFs has been reported yet. Qi et al. have used nanoindentation method to measure the collective response of a forest of VACNFs with a distribution in length and diameter of the constituent nanofibers. Kaul et al., have reported in situ uniaxial compression tests on individual VACNFs but they have not provided enough information to evaluate the accuracy of their measurements. Indirect estimation of the VACNFs Young’s modulus has also been reported by Eriksson et al. from measurements of the resonance frequency of a nanofiber deposited on top of an excitation electrode. Here, we report on direct measurements of VACNFs Young’s modulus using a piezoresistive atomic force microscope (AFM) cantilever implemented inside a scanning electron microscope (SEM). The VACNFs were grown from Ni catalyst seeds, patterned using electron-beam lithography on top of a stoichiometric TiN underlayer. The VACNFs were grown in a commercially available PECVD chamber (AIXTRON BlackMagic™). The nanofibers were approached from the side and pushed at the tip (resembling a cantilever beam) and force-deflection curves were obtained. By calibrating the AFM sensor the bending stiffness of the nanofiber could be determined. The Young’s modulus was then estimated by taking the nanofibers dimensions into account. The sub-nano Newton force precision provided by the AFM force-sensor together with the fact the individual VACNFs could be observed in the SEM simultaneously during the measurements, has enabled us to measure the nanofibers Young’s modulus with a high precision. Preliminary measurements indicate that VACNFs posses a Young’s modulus between 40 to 100 GPa which is comparable to CVD grown carbon nanotubes of similar diameter.
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19.
  • Almroth, Gabriel, 1953-, et al. (författare)
  • Acute glomerulonephritis associated with streptococcus pyogenes with concomitant spread of streptococcus constellatus in four rural families
  • 2005
  • Ingår i: Upsala Journal of Medical Sciences. - 0300-9734 .- 2000-1967. ; 110:3, s. 217-231
  • Tidskriftsartikel (refereegranskat)abstract
    • We studied history, renal histopathology and microbiology of an epidemic of acute glomerulonephritis associated with throat infections and uncommon culture results in four neighbour families. A 40-year-old man (index patient) was referred to a university hospital for dialysis and kidney biopsy due to a suspected acute glomerulonephritis. An acute tonsillitis had preceded the condition. Penicillin treatment had been started four days before the discovery of renal failure. Throat swabs were positive for β-hemolytic streptococci, group C (GCS). GCS were also found in throat cultures from his wife and two of their children. The bacteria were typed as Streptococcus constellatus. A third child had S. constellatus expressing Lancefield antigen group G. A neighbour and two of his children fell ill the following week with renal involvement. Throat swabs from both these children were positive for S. constellatus. His third child had erythema multiforme and S. constellatus in the throat while a fourth child had β-hemolytic streptococci group A, Streptococcus pyogenes. Kidney biopsies on the index patient and his neighbour showed an acute diffuse prolipherative glomerulonephritis compatible with acute post-streptococcal nephritis and microbiological analysis of renal tissue revealed in both cases S. pyogenes and S. constellatus. The families had had much contact and had consumed unpasteurized milk from our index patient's farm. In four of seven persons in two additional neighbouring families S. constellatus was found in throat swabs during the same month while two persons carried Streptococcus anginosus expressing the Lancefield C antigen. In conclusion spread of S. constellatus coincided with the occurrence of four cases of acute glomerulonephritis. The two biopsied patients had both S. pyogenes and S. constellatus present in renal tissue. The epidemic either suggested that the outbreak of glomerulonephritis was due to S. pyogenes but coincided with the transmission and colonization of S. constellatus or that the S. constellatus strains were highly pathogenic or nephritogenic and that this organism can be transmitted in such cases.
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20.
  • Andersson-Assarsson, Johanna C., 1974, et al. (författare)
  • Evolution of age-related mutation-driven clonal haematopoiesis over 20 years is associated with metabolic dysfunction in obesity
  • 2023
  • Ingår i: Ebiomedicine. - 2352-3964. ; 92
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Haematopoietic clones caused by somatic mutations with >= 2% variant allele frequency (VAF) increase with age and are linked to risk of haematological malignancies and cardiovascular disease. Recent observations suggest that smaller clones (VAF<2%) are also associated with adverse outcomes. Our aims were to determine the prevalence of clonal haematopoiesis driven by clones of variable sizes in individuals with obesity treated by usual care or bariatric surgery (a treatment that improves metabolic status), and to examine the expansion of clones in relation to age and metabolic dysregulation over up to 20 years.Methods Clonal haematopoiesis-driver mutations (CHDMs) were identified in blood samples from participants of the Swedish Obese Subjects intervention study. Using an ultrasensitive assay, we analysed single-timepoint samples from 1050 individuals treated by usual care and 841 individuals who had undergone bariatric surgery, and multiple-timepoint samples taken over 20 years from a subset (n = 40) of the individuals treated by usual care.Findings In this explorative study, prevalence of CHDMs was similar in the single-timepoint usual care and bariatric surgery groups (20.6% and 22.5%, respectively, P = 0.330), with VAF ranging from 0.01% to 31.15%. Clone sizes increased with age in individuals with obesity, but not in those who underwent bariatric surgery. In the multiple-timepoint analysis, VAF increased by on average 7% (range -4% to 24%) per year and rate of clone growth was negatively associated with HDL-cholesterol (R = -0.68, 1.74 E-04).Interpretation Low HDL-C was associated with growth of haematopoietic clones in individuals with obesity treated by usual care.
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21.
  • Andreasson, U., et al. (författare)
  • An enzyme activity as a potential biomarker for Alzheimer's disease.
  • 2010
  • Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5279 .- 1552-5260. ; 6:4, s. 497-498
  • Konferensbidrag (refereegranskat)abstract
    • Background: Six different N-terminal amyloid precursor protein (APP) fragments, with molecular weight ∼12 kDa, have previously been identified in human cerebrospinal fluid (CSF). In a pilot study, both the sum of their concentrations, measured by western blot, and the relative abundance pattern, measured by mass spectrometry, were different in Alzheimer's disease (AD) patients compared to healthy controls. To test if these differences were also reflected in protease activities that possibly give rise to the ∼12 kDa fragments an enzymatic assay was developed and the activity in CSF was investigated for its potential as a biomarker for AD. Methods: The substrate in the protease activity assay was a custom made fluorochrome/quencher labeled peptide that covers the cleavage sites in APP (APP118-APP127) corresponding to the C-termini of the six ∼12 kDa APP fragments. The activity was measured in CSF from 55 AD patients and 17 controls. Results: There was a significant increase in the protease activity in CSF from AD patients compared to the controls (p = 0.001). This is in line with previous results which indicate that the sum of the ∼12 kDa fragments are elevated in AD. Results from inhibition studies strongly suggests that the enzyme responsible for the cleavage of the substrate is an aspartic protease since a sub nM IC50 value was recorded for Pepstatin A while no inhibition was observed for the cysteine protease specific inhibitor E64 at concentrations up to100 nM. Conclusions: There exists an enzymatic activity in CSF capable of cleaving a peptide substrate that spans a portion, close to the N-terminal, of APP. In a pilot study the activity is increased in AD patients compared to controls suggesting that it can be used as a biomarker.
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22.
  • Bergman, Annika, et al. (författare)
  • No germline mutations in supposed tumour suppressor genes SAFB1 and SAFB2 in familial breast cancer with linkage to 19p.
  • 2008
  • Ingår i: BMC Medical Genetics. - : BioMed Central. - 1471-2350. ; 9
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: The scaffold attachment factor B1 and B2 genes, SAFB1/SAFB2 (both located on chromosome 19p13.3) have recently been suggested as tumour suppressor genes involved in breast cancer development. The assumption was based on functional properties of the two genes and loss of heterozygosity of intragenic markers in breast tumours further strengthened the postulated hypothesis. In addition, linkage studies in Swedish breast cancer families also indicate the presence of a susceptibility gene for breast cancer at the 19p locus. Somatic mutations in SAFB1/SAFB2 have been detected in breast tumours, but to our knowledge no studies on germline mutations have been reported. In this study we investigated the possible involvement of SAFB1/SAFB2 on familiar breast cancer by inherited mutations in either of the two genes.RESULTS: Mutation analysis in families showing linkage to the SAFB1/2 locus was performed by DNA sequencing. The complete coding sequence of the two genes SAFB1 and SAFB2 was analyzed in germline DNA from 31 affected women. No missense or frameshift mutations were detected. One polymorphism was found in SAFB1 and eight polymorphisms were detected in SAFB2. MLPA-anlysis showed that both alleles of the two genes were preserved which excludes gene inactivation by large deletions.CONCLUSION: SAFB1 and SAFB2 are not likely to be causative of the hereditary breast cancer syndrome in west Swedish breast cancer families.
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23.
  • Bergman, Jan, et al. (författare)
  • Oxidative Ring Expansion of Spirocyclic Oxindole Derivatives
  • 2014
  • Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 79:19, s. 9065-9073
  • Tidskriftsartikel (refereegranskat)abstract
    • Oxidation of the spirocyclic oxindole derivative, isamic acid 1, led to decarboxylation and ring expansion to quinazolino[4,5-b]quinazoline-6,8-dione 7 rather than, as previously believed, its isomer 6. The structure of 7 was confirmed by X-ray crystallography. Condensation of isatin (indole-2,3-dione) and 2-aminobenzamide led to the spirocyclic molecule, spiro[3H-indole-3,2'(1H)quinazoline]-2,4'(1H,3H)dione 8, which was also identified as an intermediate in the oxidation of isamic acid. Mild hydrolysis of 7 gave the 10-membered molecule 22. Isamic acid could easily be converted to N-nitrosoisamic acid, which when heated in ethanol underwent a ring expansion to a hydroximino derivative, 38, of compound 6. The structure of 38 was confirmed by X-ray crystallography.
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24.
  • Bergman, J., et al. (författare)
  • Thionations using a P4S10-pyridine complex in solvents such as acetonitrile and dimethyl sulfone
  • 2011
  • Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 76:6, s. 1546-1553
  • Tidskriftsartikel (refereegranskat)abstract
    • Tetraphosphorus decasulfide (P 4S 10) in pyridine has been used as a thionating agent for a long period of time. The moisture-sensitive reagent has now been isolated in crystalline form, and the detailed structure has been determined by X-ray crystallography. The thionating power of this storable reagent has been studied and transferred to solvents such as acetonitrile in which it has proven to be synthetically useful and exceptionally selective. Its properties have been compared with the so-called Lawesson reagent (LR). Particularly interesting are the results from thionations at relatively high temperatures (̃165 °C) in dimethyl sulfone as solvent. Under these conditions, for instance, acridone and 3-acetylindole could quickly be transformed to the corresponding thionated derivatives. Glycylglycine similarly gave piperazinedithione. At these temperatures, LR is inefficient due to rapid decomposition. The thionated products are generally cleaner and more easy to obtain because in the crystalline reagent, impurities which invariably are present in the conventional reagents, P 4S 10 in pyridine or LR, have been removed.
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25.
  • Björck, Fredrik, et al. (författare)
  • Outcomes in a Warfarin-Treated Population With Atrial Fibrillation
  • 2016
  • Ingår i: JAMA cardiology. - : American Medical Association (AMA). - 2380-6583 .- 2380-6591. ; 1:2, s. 172-180
  • Tidskriftsartikel (refereegranskat)abstract
    • IMPORTANCE Vitamin K antagonist (eg, warfarin) use is nowadays challenged by the non-vitamin K antagonist oral anticoagulants (NOACs) for stroke prevention in atrial fibrillation (AF). NOAC studies were based on comparisons with warfarin arms with times in therapeutic range (TTRs) of 55.2% to 64.9%, making the results less credible in health care systems with higher TTRs. OBJECTIVES To evaluate the efficacy and safety of well-managed warfarin therapy in patients with nonvalvular AF, the risk of complications, especially intracranial bleeding, in patients with concomitant use of aspirin, and the impact of international normalized ratio (INR) control. DESIGN, SETTING, AND PARTICIPANTS A retrospective, multicenter cohort study based on Swedish registries, especially AuriculA, a quality register for AF and oral anticoagulation, was conducted. The register contains nationwide data, including that from specialized anticoagulation clinics and primary health care centers. A total of 40 449 patients starting warfarin therapy owing to nonvalvular AF during the study period were monitored until treatment cessation, death, or the end of the study. The study was conducted from January 1, 2006, to December 31, 2011, and data were analyzed between February 1 and November 15, 2015. Associating complications with risk factors and individual INR control, we evaluated the efficacy and safety of warfarin treatment in patients with concomitant aspirin therapy and those with no additional antiplatelet medications. EXPOSURES Use of warfarin with and without concomitant therapy with aspirin. MAIN OUTCOMES AND MEASURES Annual incidence of complications in association with individual TTR (iTTR), INR variability, and aspirin use and identification of factors indicating the probability of intracranial bleeding. RESULTS Of the 40 449 patients included in the study, 16 201 (40.0%) were women; mean (SD) age of the cohort was 72.5 (10.1) years, and the mean CHA(2)DS(2)-VASc (cardiac failure or dysfunction, hypertension, age >= 75 years [doubled], diabetes mellitus, stroke [doubled]-vascular disease, age 65-74 years, and sex category [female]) score was 3.3 at baseline. The annual incidence, reported as percentage (95% CI) of all-cause mortality was 2.19% (2.07-2.31) and, for intracranial bleeding, 0.44%(0.39-0.49). Patients receiving concomitant aspirin had annual rates of any major bleeding of 3.07%(2.70-3.44) and thromboembolism of 4.90% (4.43-5.37), and those with renal failure were at higher risk of intracranial bleeding (hazard ratio, 2.25; 95% CI, 1.32-3.82). Annual rates of any major bleeding and any thromboembolism in iTTR less than 70% were 3.81% (3.51-4.11) and 4.41% (4.09-4.73), respectively, and, in high INR variability, were 3.04%(2.85-3.24) and 3.48% (3.27-3.69), respectively. For patients with iTTR 70% or greater, the level of INR variability did not alter event rates. CONCLUSIONS AND RELEVANCE Well-managed warfarin therapy is associated with a low risk of complications and is still a valid alternative for prophylaxis of AF-associated stroke. Therapy should be closely monitored for patients with renal failure, concomitant aspirin use, and poor INR control.
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26.
  • Brice, Heloise, et al. (författare)
  • Stereocontrolled access to optically-enriched oxabispidines
  • 2012
  • Ingår i: Chemical Communications. - : Royal Society of Chemistry (RSC). - 1359-7345 .- 1364-548X. ; 48:40, s. 4836-4838
  • Tidskriftsartikel (refereegranskat)abstract
    • A range of chiral, optically-enriched bicyclic oxabispidines were prepared from (S)-(-)-2,3-epoxypropylphthalimide using an efficient sequence featuring a stereocontrolled intramolecular Mannich reaction as the key transformation.
  •  
27.
  • Briggner, Lars-Erik, et al. (författare)
  • In Silico Solid State Perturbation for Solubility Improvement
  • 2014
  • Ingår i: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 9:4, s. 724-726
  • Tidskriftsartikel (refereegranskat)abstract
    • Solubility is a frequently recurring issue within pharmaceutical industry, and new methods to proactively resolve this are of fundamental importance. Here, a novel methodology is reported for intrinsic solubility improvement, using insilico prediction of crystal structures, by perturbing key interactions in the crystalline solid state. The methodology was evaluated with a set of benzodiazepine molecules, using the two-dimensional molecular structure as the only a priori input. The overall trend in intrinsic solubility was correctly predicted for the entire set of benzodiazepines molecules. The results also indicate that, in drug compound series where the melting point is relatively high (i.e., brick dust compounds), the reported methodology should be very suitable for identifying strategically important molecular substitutions to improve solubility. As such, this approach could be a useful predictive tool for rational compound design in the early stages of drug development.
  •  
28.
  • Briggner, Lars-Erik, et al. (författare)
  • Solid-State Perturbation for Solubility Improvement : A Proof of Concept
  • 2011
  • Ingår i: ChemMedChem. - : Wiley. - 1860-7179. ; 6:1, s. 60-62
  • Tidskriftsartikel (refereegranskat)abstract
    • Simple and rational: The intrinsic solubility of a compound can be systematically improved by perturbing key interactions in its crystal structure. By carefully choosing the perturbation, the end result will be a molecule similar to the original one, but with significantly higher solubility. This methodology is demonstrated on a subset of benzodiazepines, resulting in significant improvement of their solubility.
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29.
  • Cong, Jiayan, et al. (författare)
  • Bis(1,1-bis(2-pyridyl)ethane)copper(i/II) as an efficient redox couple for liquid dye-sensitized solar cells
  • 2016
  • Ingår i: Journal of Materials Chemistry A. - : Royal Society of Chemistry. - 2050-7488 .- 2050-7496. ; 4:38, s. 14550-14554
  • Tidskriftsartikel (refereegranskat)abstract
    • A new redox couple, [Cu(bpye)2]+/2+, has been synthesized, and applied in dye-sensitized solar cells (DSSCs). Overall efficiencies of 9.0% at 1 sun and 9.9% at 0.5 sun were obtained, which are considerably higher than those obtained for cells containing the reference redox couple, [Co(bpy)3]2+/3+. These results represent a record for copper-based complex redox systems in liquid DSSCs. Fast dye regeneration, sluggish recombination loss processes, faster electron self-exchange reactions and suitable redox potentials are the main reasons for the observed increase in efficiency. In particular, the main disadvantage of cobalt complex-based redox couples, charge-transport problems, appears to be resolved by a change to copper complex redox couples. The results make copper complex-based redox couples very promising for further development of highly efficient DSSCs.
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30.
  • Cong, Jiayan, et al. (författare)
  • Bis(1,1-bis(2-pyridyl)ethane)copper(I/II) as an efficient redox couple for liquid dye-sensitized solar cells
  • 2016
  • Ingår i: Journal of Materials Chemistry. - 0959-9428 .- 1364-5501. ; 4:38, s. 14550-14554
  • Tidskriftsartikel (refereegranskat)abstract
    • A new redox couple, [Cu(bpye)2]+/2+, has been synthesized, and applied in dye-sensitized solar cells (DSSCs). Overall efficiencies of 9.0% at 1 sun and 9.9% at 0.5 sun were obtained, which are considerably higher than those obtained for cells containing the reference redox couple, [Co(bpy)3]2+/3+. These results represent a record for copper-based complex redox systems in liquid DSSCs. Fast dye regeneration, sluggish recombination loss processes, faster electron self-exchange reactions and suitable redox potentials are the main reasons for the observed increase in efficiency. In particular, the main disadvantage of cobalt complex-based redox couples, charge-transport problems, appears to be resolved by a change to copper complex redox couples. The results make copper complex-based redox couples very promising for further development of highly efficient DSSCs.
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31.
  • Franck, Niclas, et al. (författare)
  • Identification of adipocyte genes regulated by caloric intake
  • 2011
  • Ingår i: Journal of Clinical Endocrinology and Metabolism. - : Endocrine society. - 0021-972X .- 1945-7197. ; 96:2, s. E413-E418
  • Tidskriftsartikel (refereegranskat)abstract
    • CONTEXT: Changes in energy intake have marked and rapid effects on metabolic functions and some of the effects may be due to changes in adipose tissue gene expression that precede alterations in body weight. OBJECTIVE: To identify genes in adipose tissue regulated by changes in caloric intake independent of changes in body weight. RESEARCH DESIGN AND METHODS: Obese subjects were given a very-low calorie diet (VLCD; 450 kcal/day) for 16 weeks. After the diet, ordinary food was gradually reintroduced during 2 weeks while there were minimal changes in body weight. Adipose tissue gene expression was measured by microarray analysis. First, genes regulated during caloric restriction and in the opposite direction during the weight stable re-feeding phase were identified. To verify opposite regulation to that observed during caloric restriction, identified genes were further analyzed using adipocyte expression profiles from healthy subjects before and after overfeeding. Results were confirmed using real time PCR or immunoassay. RESULTS: Using a significance level of p<0.05 for all comparisons, 52 genes were downregulated and 50 were up-regulated by caloric restriction and regulated in the opposite direction by re-feeding and overfeeding. Among these were genes that affect lipogenesis (ACLY, ACACA, FASN, SCD), protein synthesis (4EBP1, 4EBP2), beta-oxidation (CPT1B), liberation of fatty acids (CIDEA) and glyceroneogenesis (PCK2). Interestingly, several of these are under control of the master regulator mTOR. CONCLUSIONS: The observed transcriptional changes indicate that mTOR plays a central role in the control of diet-regulated adipocyte genes involved in lipogenesis and protein synthesis.
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32.
  • Gao, Jiajia, et al. (författare)
  • Crystallography as Forensic Tool for Understanding Electrolyte Degradation in Dye-sensitized Solar Cells
  • 2017
  • Ingår i: ChemistrySelect. - : WILEY-V C H VERLAG GMBH. - 2365-6549. ; 2:4, s. 1675-1680
  • Tidskriftsartikel (refereegranskat)abstract
    • The precipitation of solid compounds from model electrolytes for liquid dye-sensitized solar cells has a story to tell regarding decomposition processes to be expected in such systems. Of course, the crystal lattice energy for a specific crystalline compounds plays a role in what compound that will eventually precipitate, but the compounds nevertheless serve as indicators for what type of processes that take place in the solar cell electrolytes upon ageing. From the compounds isolated in this study we learn that both ligand exchange processes, double-salt precipitation and oxidation are degradation processes that should not be overlooked when formulating efficient and stable electrolytes for this type of electrochemical system.
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33.
  • Gao, Jiajia, et al. (författare)
  • Light-induced electrolyte improvement in cobalt tris(bipyridine)-mediated dye-sensitized solar cells
  • 2019
  • Ingår i: Journal of Materials Chemistry A. - : Royal Society of Chemistry. - 2050-7488 .- 2050-7496. ; 7:33, s. 19495-19505
  • Tidskriftsartikel (refereegranskat)abstract
    • Lithium-ion-free tris(2,2′-bipyridine) Co(ii/iii)-mediated electrolytes have previously been proposed for long-term stable dye-sensitized solar cells (DSSCs). Such redox systems also offer an impressive DSSC performance improvement under light soaking exposure, manifested by an increase in photocurrent and fill factor without the expense of decreasing photovoltage. Kinetic studies show that charge transfer and ion diffusion at the electrode/electrolyte interface are improved due to the light exposure. Control experiments reveal that the light effect is unambiguously associated with electrolyte components, [Co(bpy)3]3+ and the Lewis-base additive tert-butylpyridine (TBP). Electrochemical and spectroscopic investigation of the [Co(bpy)3]3+/TBP mixtures points out that the presence of TBP, which retards the electrolyte diffusion, however causes an irreversible redox reaction of [Co(bpy)3]3+ upon light exposure that improves the overall conductivity. This discovery not only provides a new strategy to mitigate the typical Jsc-Voc trade-off in Co(ii/iii)-mediated DSSCs but also highlights the importance of investigating the photochemistry of a photoelectrochemical system. 
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34.
  • Glad, Camilla A M, 1981, et al. (författare)
  • Expression of GHR and Downstream Signaling Genes in Human Adipose Tissue-Relation to Obesity and Weight Change.
  • 2019
  • Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 104:5, s. 1459-1470
  • Tidskriftsartikel (refereegranskat)abstract
    • GH is a strong regulator of metabolism. In obesity, both GH secretion and adipose tissue GHR gene expression are decreased. More detailed information on the regulation of GHR, STAT3/5, and downstream-regulated genes in human adipose tissue during diet-induced weight loss and weight gain is lacking.The aim of the present study was to investigate the gene expression patterns of GHR and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway (JAK2, STAT3, STAT5A, and STAT5B) in human subcutaneous adipose tissue in relation to energy restriction and overfeeding.Tissue distribution was analyzed in a data set generated by RNA sequencing containing information on global expression in human tissues. Subcutaneous adipose tissue or adipocyte gene expression (measured by DNA microarrays) was investigated in the following settings: (i) individuals with obesity vs individuals with normal weight; (ii) energy restriction; and (iii) overfeeding.GHR expression was decreased in subjects with obesity compared with subjects with normal weight (P < 0.001). It was increased in response to energy restriction and decreased in response to overfeeding (P = 0.015 and P = 0.030, respectively). STAT3 expression was increased in subjects with obesity (P < 0.001). It was decreased during energy restriction and increased during overfeeding (P = 0.004 and P = 0.006, respectively). STAT3-regulated genes showed an overall view of overexpression in obesity.The results of the present study have shown that GHR, STAT3, and STAT3-regulated genes are dynamically, and reciprocally, regulated at the tissue level in response to energy restriction and overfeeding, suggesting that GH signaling is perturbed in obesity.
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35.
  • Goldberg, Kristin, et al. (författare)
  • Oxadiazole isomers : all bioisosteres are not created equal
  • 2012
  • Ingår i: MedChemComm. - : Royal Society of Chemistry (RSC). - 2040-2503 .- 2040-2511. ; 3:5, s. 600-604
  • Tidskriftsartikel (refereegranskat)abstract
    • Two series of amino-substituted 1,2,4- and 1,3,4-oxadiazole matched compounds were evaluated and found to have significant differences in their various physical and pharmaceutical properties. Experimental and computational techniques suggested that variation in hydrogen bond acceptor and donor strength were responsible for these effects.
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36.
  • Gu, Chungang, et al. (författare)
  • Lipid Peroxide-Mediated Oxidative Rearrangement of the Pyrazinone Carboxamide Core of Neutrophil Elastase Inhibitor AZD9819 in Blood Plasma Samples
  • 2015
  • Ingår i: Drug Metabolism And Disposition. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 0090-9556 .- 1521-009X. ; 43:10, s. 1441-1449
  • Tidskriftsartikel (refereegranskat)abstract
    • This study focused on the mechanistic interpretation of ex vivo oxidation of a candidate drug in blood plasma samples. An unexpected lipid peroxide-mediated epoxidation followed by a dramatic rearrangement led to production of a five-membered oxazole derivative from the original six-membered pyrazinone-carboxamide core of a human neutrophil elastase inhibitor, 6-(1-(4-cyanophenyl)-1H-pyrazol-5-yl)-N-ethyl-5-methyl-3-oxo-4-(3-(trifluoromethyl) phenyl)-3,4-dihydropyrazine-2-carboxamide (AZD9819). The rearranged oxidation product 2-(1-(4-cyanophenyl)-1H-pyrazol-5-yl)-5-(N-ethylacetamido)-N-(3-(trifluoromethyl)phenyl)oxazole-4-carboxamide was characterized by accurate-mass tandem mass spectrometry fragmentations, by two-dimensional NMR and X-ray crystallography of an authentic standard, and by incorporation of an O-18 atom from molecular O-18(2) to the location predicted by our proposed mechanism. The lipid peroxide-mediated oxidation was demonstrated by using human low-density lipoprotein (LDL) in pH 7.4 phosphate buffer and by inhibiting the oxidation with ascorbic acid or L-glutathione, two antioxidants effective in both plasma and the LDL incubation. A nucleophilic mechanism for the epoxidation of AZD9819 by lipid hydroperoxides explains the prevention of its ex vivo oxidation by acidification of the plasma samples. The discovery of the lipid peroxide-dependent oxidation of an analyte and the means of prevention could provide valuable information for biotransformation and bioanalysis.
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37.
  • Guan, Jikui, et al. (författare)
  • Clinical response of the novel activating ALK-I1171T mutation in neuroblastoma to the ALK inhibitor ceritinib.
  • 2018
  • Ingår i: Cold Spring Harbor molecular case studies. - : Cold Spring Harbor Laboratory. - 2373-2873. ; 4:4
  • Tidskriftsartikel (refereegranskat)abstract
    • Tumors with Anaplastic Lymphoma Kinase (ALK) fusion rearrangements, including non-small cell lung cancer and anaplastic large cell lymphoma, are highly sensitive to ALK tyrosine kinase inhibitors (TKIs), underscoring the notion that such cancers are addicted to ALK activity. While mutations in ALK are heavily implicated in childhood neuroblastoma, response to the ALK TKI crizotinib has been disappointing. Embryonal tumors in patients with DNA repair defects such as Fanconi anemia (FA) often have a poor prognosis, due to lack of therapeutic options. Here we report a child with underlying FA and ALK mutant high-risk neuroblastoma responding strongly to precision therapy with the ALK TKI ceritinib. Conventional chemotherapy treatment caused severe, life-threatening toxicity. Genomic analysis of the initial biopsy identified germ-line FANCA mutations as well as a novel ALK-I1171T variant. ALK-I1171T generates a potent gain-of-function mutant, as measured in PC12 cell neurite outgrowth and NIH3T3 transformation. Pharmacological inhibition profiling of ALK-I1171T in response to various ALK TKIs identified an 11-fold improved inhibition of ALK-I1171T with ceritinib when compared with crizotinib. Immunoaffinity-coupled LC-MS/MS phosphoproteomics analysis indicated a decrease in ALK signaling in response to ceritinib. Ceritinib was therefore selected for treatment in this child. Mono-therapy with ceritinib was well tolerated and resulted in normalized catecholamine markers and tumor shrinkage. After 7.5 months treatment, residual primary tumor was surgically removed and exhibited hallmarks of differentiation together with reduced Ki67 levels. Clinical follow-up after 21 months treatment revealed complete clinical remission including all metastatic sites. Therefore, ceritinib presents a viable therapeutic option for ALK-positive neuroblastoma.
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38.
  • Gyllenhammar, Irina, et al. (författare)
  • Diverging temporal trends of human exposure to bisphenols and plastizisers, such as phthalates, caused by substitution of legacy EDCs?
  • 2017
  • Ingår i: Environmental Research. - : Elsevier BV. - 0013-9351. ; 153, s. 48-54
  • Tidskriftsartikel (refereegranskat)abstract
    • Phthalates and phenolic substances were investigated in urine samples from first-time mothers in Uppsala, Sweden, collected between 2009 and 2014. These substances have a comparably fast metabolism and urinary metabolites are predominantly analysed. The main aim was to investigate if measures to decrease production and use of certain phthalates and bisphenol A (BPA) have resulted in decreased human exposure, and to determine if exposures to replacement chemicals have increased. Temporal trends were evaluated for metabolites (n=13) of seven phthalates, a phthalate replacer, four different bisphenols, triclosan, one organophosphate-based flame retardant, and for two pesticides. The results showed downward trends of several phthalates which are in the process of being regulated and phased out. Concomitantly, an increasing trend was seen for a metabolite of the phthalate replacer Di-iso-nonylcyclohexane 1,2-dicarboxylate (DiNCH). Bisphenol A (BPA) showed a downward trend, whereas bisphenol F, identified as one of the substitutes for BPA, showed an increasing trend. The decreasing trend of triclosan is likely due to declining use within the EU. Temporal trend studies of urine samples make it possible to investigate human exposure to rapidly metabolised substances and study how measures taken to regulate and replace problematic chemicals affect human exposure.
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39.
  • Hammarström, Lars G. J., et al. (författare)
  • The Oncolytic Efficacy and in Vivo Pharmacokinetics of [2-(4-Chlorophenyl)quinolin-4-yl](piperidine-2-yl)methanol (Vacquinol-1) Are Governed by Distinct Stereochemical Features
  • 2016
  • Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 59:18, s. 8577-8592
  • Tidskriftsartikel (refereegranskat)abstract
    • Glioblastoma remains an incurable brain cancer. Drugs developed in the past 20 years have not improved the prognosis for patients, necessitating the development of new treatments. We have previously reported the therapeutic potential of the quinoline methanol Vacquinol-1 (1) that targets glioblastoma cells and induces cell death by catastrophic vacuolization. Compound 1 is a mixture of four stereoisomers due to the two adjacent stereogenic centers in the molecule, complicating further development in the preclinical setting. This work describes the isolation and characterization of the individual isomers of 1 and shows that these display stereospecific pharmacokinetic and pharmacodynamic features. In addition, we present a stereoselective synthesis of the active isomers, providing a basis for further development of this compound series into a novel experimental therapeutic for glioblastoma.
  •  
40.
  • Hansson, Caroline, 1981, et al. (författare)
  • Increased plasma levels of neuro-related proteins in patients with stress-related exhaustion: A longitudinal study
  • 2024
  • Ingår i: PSYCHONEUROENDOCRINOLOGY. - 0306-4530 .- 1873-3360. ; 167
  • Tidskriftsartikel (refereegranskat)abstract
    • Exhaustion disorder (ED) is a stress-related disorder characterized by physical and mental symptoms of exhaustion. Recent data suggest that pathophysiological processes in the central nervous system are involved in the biological mechanisms underlying ED. The aims of this study were to investigate if plasma levels of neurorelated proteins differ between patients with ED and healthy controls, and, if so, to investigate if these differences persist over time. Using the Olink Neuro Exploratory panel, we quantified the plasma levels of 92 neuro-related proteins in 163 ED patients at the time of diagnosis (baseline), 149 patients at long-term follow-up (7-12 years later, median follow-up time 9 years and 5 months), and 100 healthy controls. We found that the plasma levels of 40 proteins were significantly higher in the ED group at baseline compared with the control group. Out of these, the plasma levels of 36 proteins were significantly lower in the ED group at follow-up compared with the same group at baseline and the plasma levels of four proteins did not significantly differ between the groups. At followup, the plasma levels of two proteins were significantly lower in the ED group compared with the control group. These data support the hypothesis that pathophysiological processes in the central nervous system are involved in the biological mechanisms underlying ED.
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41.
  • Holmlund, F, et al. (författare)
  • Sympathetic skin vasoconstriction--further evaluation using laser Doppler techniques
  • 2001
  • Ingår i: Clinical Physiology. - : Wiley. - 1365-2281 .- 0144-5979. ; 21:3, s. 287-291
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim of this study was to quantify the reflex sympathetic vasoconstriction in skin at different depths. Twenty healthy subjects were studied. Finger skin blood flow was measured using laser Doppler perfusion imaging (LDPI) and laser Doppler perfusion monitoring (LDPM). In LDPM, a probe with fibres separated 0.25 mm (deep) and 0.14 mm (superficial) from the illuminating fibre was used. Local heating (40 degrees C) was achieved with a Peltier element, and reflex vasoconstriction induced by immersion of the contra-lateral hand and forearm for 3 min in water at 15 degrees C. The change in skin blood flow was measured and a vasoconstriction index (VAC: cooling/before cooling) calculated. VAC indices of LDPI, LDPM-0.25 and LDPM-0.14 were 0.60, 0.59 and 0.60, respectively. The two components of the LDPM perfusion value, blood cell velocity and concentration, were studied separately. Their contributions in LDPM-0.25 were roughly the same, whereas the velocity component dominated in LDPM-0.14, although their relative responses in the two channels were similar. We conclude that sympathetic skin vasoconstriction does not significantly differ in two compartments, as probed with fibres separated by 0.25 and 0.14 mm. Blood cell velocity is influenced in a proportional way, as is concentration.
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42.
  • Håkansson, M., et al. (författare)
  • The crystal structure of staphylococcal enterotoxin H : Implications for binding properties to MHC class II and TcR molecules
  • 2000
  • Ingår i: Journal of Molecular Biology. - : Elsevier BV. - 0022-2836. ; 302:3, s. 527-537
  • Tidskriftsartikel (refereegranskat)abstract
    • The X-ray structure of the superantigen staphylococcal enterotoxin H (SEH) has been determined at 1.69 Å resolution. In this paper we present two structures of zinc-free SEH (apoSEH) and one zinc-loaded form of SEH (ZnSEH). SEH exhibits the conventional superantigen (SAg) fold with two characteristic domains. In ZnSEH one zinc ion per SEH molecule is bound to the C-terminal β-sheet in the region implicated for major histocompatibility complex class II (MHC class II) binding in SEA, SED and SEE. Surprisingly, the zinc ion has only two ligating amino acid residues His206 and Asp208. The other ligands to the zinc ion are two water molecules. An extensive packing interaction between two symmetry-related molecules in the crystal, 834 Å2/molecule, forms a cavity that buries the zinc ions of the molecules. This dimer-like interaction is found in two crystal forms. Nevertheless, zinc-dependent dimerisation is not observed in solution, as seen in the case of SED. A unique feature of SEH as compared to other staphylococcal enterotoxins is a large negatively charged surface close to the Zn2+ site. The interaction of SEH with MHC class II is the strongest known among the staphylococcal enterotoxins. However, SEH seems to lack a SEB-like MHC class II binding site, since the side-chain properties of structurally equivalent amino acid residues in SEH and those in SEB-binding MHC class II differ dramatically. There is also a structural flexibility between the domains of SEH. The domains of two apoSEH structures are related by a 5°rotation leading to at most 3 Å difference in C(α) positions. Since the T-cell receptor probably interacts with both domains, SEH by this rotation may modulate its binding to different TcR Vβ-chains. (C) 2000 Academic Press.
  •  
43.
  • Hägg Samuelsson, Ulrika, 1973, et al. (författare)
  • Gene expression profile and aortic vessel distensibility in voluntarily exercised spontaneously hypertensive rats: potential role of heat shock proteins
  • 2005
  • Ingår i: Physiol Genomics. - 1531-2267 .- 1094-8341. ; 22:3, s. 319-26
  • Tidskriftsartikel (refereegranskat)abstract
    • Physical exercise is considered to be beneficial for cardiovascular health. Nevertheless, the underlying specific molecular mechanisms still remain unexplored. In this study, we aimed to investigate the effects of voluntary exercise on vascular mechanical properties and gene regulation patterns in spontaneously hypertensive rats. By using ultrasound biomicroscopy in an ex vivo perfusion chamber, we studied the distensibility of the thoracic aorta. Furthermore, exercise-induced gene regulation was studied in aortae, using microarray analysis and validated with real-time PCR. We found that distensibility was significantly improved in aortas from exercising compared with control rats (P < 0.0001). Exercising rats demonstrated a striking pattern of coordinated downregulation of genes belonging to the heat shock protein family. In conclusion, voluntary exercise leads to improved vessel wall distensibility and reduced gene expression of heat shock protein 60 and 70, which may indicate decreased oxidative stress in the aortic vascular wall.
  •  
44.
  • Johansson, Per, et al. (författare)
  • Convergence of chromogranin and amyloid metabolism in the brain.
  • 2010
  • Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5279 .- 1552-5260. ; 6:4, s. 511-511
  • Konferensbidrag (refereegranskat)abstract
    • Background: Much is unknown regarding the regulation of amyloid precursor protein (APP) processing in the human central nervous system. It has been hypothesized that amyloidogenic APP-processing preferentially occurs in the regulated secretory pathway of neurons. To test this hypothesis we looked for correlations of APP-derived molecules in CSF with chromogranin (Cg) derived peptides, representing the regulated secretion. Methods: Patients with Alzheimer's disease (AD, N = 32), multiple sclerosis (MS, N = 50) and healthy controls (N = 70) were enrolled. CSF was analyzed for the amyloid peptides Aβ1-42, Aβx-42, Aβx-40, Aβx-38, α-cleaved soluble APP (α-sAPP), β-cleaved soluble APP (β-sAPP), and peptides derived from CgB and SgII (Secretogranin-II, CgC). We investigated CSF levels of the protease BACE1, which processes APP into Aβ, in relation to Cg-levels. Finally, we measured Cg levels in cell media from untreated and BACE1-inhibited SH-SY5Y human neuroblastoma cells. Results: CSF Cg levels correlated to sAPP and Aβ peptides in AD, MS and controls, and to CSF BACE1. Cell medium from BACE1-inhibited cells had decreased CgB levels. Conclusions: These results suggest that a large part of APP in the human central nervous system is processed in the regulated secretory pathway of neurons.
  •  
45.
  •  
46.
  • Johnson, M S, et al. (författare)
  • Characterization and chromosomal localization of rat scavenger receptor class B type I, a high density lipoprotein receptor with a putative leucine zipper domain and peroxisomal targeting sequence.
  • 1998
  • Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 139:1, s. 72-80
  • Tidskriftsartikel (refereegranskat)abstract
    • High density lipoprotein (HDL) participates in reverse cholesterol transport and in the delivery of cholesterol to steroid-producing tissues. Scavenger receptor class B type I (SR-BI) was recently shown to bind HDL and mediate internalization of its cholesterol content. We have cloned the rat homolog of this receptor, determined its chromosomal location, and examined its expression in rat tissues and in a model of follicular development, ovulation, and luteinization. The predicted protein contained two transmembrane domains, a leucine zipper motif, and a peroxisomal targeting sequence. The rat and human SR-BI genes were mapped to a region previously linked between rat and human chromosomes 12. SR-BI gene expression was detected in several rat tissues, with high levels in ovarian tissue, liver, and adrenal cortex, as determined by ribonuclease protection assay and in situ hybridization. A significant increase in SR-BI gene expression was detected in the late phase of corpus luteum formation, and transcripts were abundant in corpus luteum and in thecal cells at all stages of follicular development. In conclusion, the rat SR-BI complementary DNA predicted a protein with several conserved motifs, including a putative leucine zipper and a peroxisomal targeting sequence. The chromosomal locations of the rat and human SR-BI homologs suggest that this gene is a new member of a previously reported, conserved synteny group. SR-BI gene expression was high in steroid-producing tissues and in the liver, consistent with a role of this receptor in the uptake of HDL cholesterol.
  •  
47.
  •  
48.
  • Karpman, D, et al. (författare)
  • The role of lipopolysaccharide and Shiga-like toxin in a mouse model of Escherichia coli O157:H7 infection
  • 1997
  • Ingår i: Journal of Infectious Diseases. - : Oxford University Press (OUP). - 0022-1899 .- 1537-6613. ; 175:3, s. 20-611
  • Tidskriftsartikel (refereegranskat)abstract
    • The role of lipopolysaccharide (LPS) and Shiga-like toxin (SLT) in the pathogenesis of hemolytic uremic syndrome (HUS) was studied in a mouse model. Mice inoculated intragastrically with Escherichia coli O157:H7 developed gastrointestinal, neurologic, and systemic symptoms, necrotic foci in the colon, glomerular and tubular histopathology, and fragmented erythrocytes. LPS-responder (C3H/HeN) mice developed a combination of neurologic and systemic symptoms, whereas LPS-nonresponder (C3H/HeJ) mice had a biphasic course of disease, first developing systemic symptoms and later severe neurologic symptoms. Mice inoculated with SLT-II-positive strains developed severe neurotoxic symptoms and a higher frequency of systemic symptoms and glomerular pathology compared with SLT-II-negative strains. Anti-SLT-II antibodies protected against these symptoms and pathology. These results demonstrate that this model could be used to study aspects of human HUS and that both LPS and SLT are important for disease development.
  •  
49.
  • Kloo, Lars, et al. (författare)
  • On the Intra- and Intermolecular Bonding in Polyiodides
  • 2002
  • Ingår i: European Journal of Inorganic Chemistry. - 1434-1948 .- 1099-1948. ; :5, s. 1203-1209
  • Tidskriftsartikel (refereegranskat)abstract
    • The nature of intra- and intermolecular interactions of poly-iodides has been investigated by means of quantum chemical methods and structural statistical data. In the region of "secondary bonds" the interaction is adequately described in terms of covalent bonding accompanied by dispersion. At greater distances the interaction is dominated by ion-quadrupole interactions between ionic and neutral iodine building blocks of the polyiodide structures.
  •  
50.
  • Koch, Daniel, et al. (författare)
  • 2,2 '-Biindolyl Reactions with Aldehydes
  • 2016
  • Ingår i: European Journal of Organic Chemistry. - : Wiley-VCH Verlag. - 1434-193X .- 1099-0690. ; :7, s. 1389-1396
  • Tidskriftsartikel (refereegranskat)abstract
    • 2,2'-Biindolyl has been condensed with aromatic and aliphatic aldehydes and products featuring 10-membered rings have been obtained. Thus, benzaldehyde gave compound 24a as the primary product, which readily underwent transannular oxidative coupling to 25a. The structures of both compounds were confirmed by X-ray crystallography. The product from 2,2'-biindolyl and formaldehyde under strongly acidic conditions was slightly different leading to compound 11, whose structure also was confirmed by X-ray crystallography. In this case, two molecules of 2,2'-biindolyl reacted with six molecules of formaldehyde.
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