| 1. |
- Albrecht, Inka, et al.
(författare)
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Development of autoantibodies against muscle-specific FHL1 in severe inflammatory myopathies
- 2015
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Ingår i: Journal of Clinical Investigation. - : AMER SOC CLINICAL INVESTIGATION INC. - 0021-9738 .- 1558-8238. ; 125:12, s. 4612-4624
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Tidskriftsartikel (refereegranskat)abstract
- Mutations of the gene encoding four-and-a-half LIM domain 1 (FHL1) are the causative factor of several X-linked hereditary myopathies that are collectively termed FHL1-related myopathies. These disorders are characterized by severe muscle dysfunction and damage. Here, we have shown that patients with idiopathic inflammatory myopathies (IIMs) develop autoimmunity to FHL1, which is a muscle-specific protein. Anti-FHL1 autoantibodies were detected in 25% of IIM patients, while patients with other autoimmune diseases or muscular dystrophies were largely anti-FHL1 negative. Anti-FHL1 reactivity was predictive for muscle atrophy, dysphagia, pronounced muscle fiber damage, and vasculitis. FHL1 showed an altered expression pattern, with focal accumulation in the muscle fibers of autoantibody-positive patients compared with a homogeneous expression in anti-FHL1-negative patients and healthy controls. We determined that FHL1 is a target of the cytotoxic protease granzyme B, indicating that the generation of FHL1 fragments may initiate FHL1 autoimmunity. Moreover, immunization of myositis-prone mice with FHL1 aggravated muscle weakness and increased mortality, suggesting a direct link between anti-FHL1 responses and muscle damage. Together, our findings provide evidence that FHL1 may be involved in the pathogenesis not only of genetic FHL1-related myopathies but also of autoimmune IIM. Importantly, these results indicate that anti-FHL1 autoantibodies in peripheral blood have promising potential as a biomarker to identify a subset of severe IIM.
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| 2. |
- Andersson, Asa, et al.
(författare)
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Vitamin D intake and status in immigrant and native Swedish women : a study at a primary health care centre located at 60 degrees N in Sweden
- 2013
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Ingår i: Food & Nutrition Research. - : SNF Swedish Nutrition Foundation. - 1654-6628 .- 1654-661X. ; 57, s. UNSP 20089-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Immigration to Sweden from lower latitude countries has increased in recent years. Studies in the general population in other Nordic countries have demonstrated that these groups are at risk of developing vitamin D deficiency, but studies in primary health care patients are rare. Objectives: The aim of this study is to examine possible differences in plasma-25(OH)-vitamin D levels and intake of vitamin D between Swedish and immigrant female patients in a primary health care centre located at 60 degrees N, where half of the inhabitants have an immigrant background. Another objective was to estimate what foods contribute with most vitamin D. Design: Thirty-one female patients from the Middle East and Africa and 30 from Sweden were recruited. P-25(OH)D was measured and intake of vitamin D was estimated with a modified food frequency questionnaire (FFQ). Results: Vitamin D deficiency (plasma-25(OH)D<25 nmol/L) was common among immigrant women (61%). One immigrant woman and half of the Swedish women had optimal levels (plasma-25(OH)D>50 nmol/L). There was a positive correlation between the intake of vitamin D from food and plasma-25(OH) D. Only three women, all Swedish, reached the recommended intake of vitamin D from food. The immigrant women had lower intake compared to Swedish women (median: 3.1 vs. 5.1 mu g/day). The foods that contributed with most vitamin D were fatty fish, fortified milk and margarine. Immigrant women consumed less fortified milk and margarine but more meat. Irrespective of origin, patients with plasma-25(OH)D<25 nmol/L consumed less margarine but more meat. Conclusion: Vitamin D deficiency was common in the immigrant patients and their intake of vitamin D was lower. This highlights the need to target information about vitamin D to immigrant women in order to decrease the risk for vitamin D deficiency. The FFQ was well adapted to its purpose to estimate intake of vitamin D.
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| 3. |
- Andersson-Sköld, Yvonne, 1957-, et al.
(författare)
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Development of the SUNRA Tool to Improve Regional and Local Sustainability of the Transportation Sector
- 2022
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Ingår i: Sustainability. - : MDPI AG. - 2071-1050. ; 14:18, s. 11275-
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Tidskriftsartikel (refereegranskat)abstract
- To fulfil the global sustainable development goals (SDGs), achieving sustainable development is becoming urgent, not least in the transportation sector. In response to this, the sustainability framework Sustainability National Road Administrations (SUNRA) was developed to contribute to improving the sustainability performance of national road administrations across Europe. In the present study, the framework has been tested, applied and further developed to be applicable for target setting and follow-up at the project level at both the Swedish Transport Administration (STA) and at municipal levels. The aim was a framework relevant for investment, re-investments, maintenance and operation projects and also to make it more user applicable. The study also investigated how the framework can contribute to sustainability, identified drivers and barriers for applying the framework and examined whether the framework can be applied and adapted to projects of different complexities. The adaptations and developments were done in collaboration between researchers and practitioners. The results show that the framework could easily be used and adapted for investment, re-investment, maintenance and operation projects in the planning stage, as well as for small municipal establishments, construction or reconstruction of residential areas and frequent maintenance. The framework contributes to increased awareness on sustainability, and it provides a common structure and transparency on how infrastructure project goals/targets are set and fulfilled. The framework can also be applied to follow the fulfilment of the goals/targets and thereby adapt the project to better fulfil the goals. Identified barriers include the lack of obligations and lack of experience in using sustainability frameworks.
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| 4. |
- Bohman, Anton, et al.
(författare)
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Heredity of nasal polyps
- 2015
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Ingår i: Rhinology. - 0300-0729 .- 1996-8604. ; 53:1, s. 25-28
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Tidskriftsartikel (refereegranskat)abstract
- Background: Nasal polyps is a common disease but little is known about its' pathogenesis. Our hypothesis was that there are genetic factors involved in the development of this disease. The aim of this study was to examine close relatives of patients with nasal polyps and comparing them with a general population with regard to prevalence of polyps. Methodology: Patients with nasal polyps who attended the clinic were recruited to the study and were asked whether they had any close adult relatives (siblings, parents or children). We intended to recruit two relatives per patient, one of each gender, for nasal endoscopy. The prevalence of nasal polyps in these relatives was compared with the prevalence of nasal polyps in a general population. Results: During a 4-year period, 368 patients and 410 relatives were recruited to the study. Although we were unable to recruit two close relatives for every patient, we were able to calculate nasal polyp prevalence within families as being 19.2%. Compared with the prevalence of nasal polyps among individuals in a general Swedish population from the same geographical area, the relative risk for polyps among relatives was almost five times higher. Conclusion: This study strongly indicates that heredity is a factor of importance for development of nasal polyps.
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| 5. |
- Campbell, PJ, et al.
(författare)
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Pan-cancer analysis of whole genomes
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
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Tidskriftsartikel (refereegranskat)abstract
- Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1–3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10–18.
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| 6. |
- Carlsson Tedgren, Åsa, et al.
(författare)
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Experience from long-term monitoring of RAKR ratios in Ir-192 brachytherapy
- 2008
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Ingår i: Radiotherapy and Oncology. - : Elsevier BV. - 0167-8140 .- 1879-0887. ; 89:2, s. 217-221
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Tidskriftsartikel (refereegranskat)abstract
- Background: Ratios of values of brachytherapy source strengths, as measured by hospitals and vendors, comprise constant differences as, e.g., systematic errors in ion chamber calibration factors and measurement setup. Such ratios therefore have the potential to reveal the systematic changes in routines or calibration services at either the hospital or the vendor laboratory, which could otherwise be hidden by the uncertainty in the source strength values. Methods: The RAKR of each new source in 13 afterloading units at five hospitals were measured by well-type ion chambers and compared to values for the same source stated on vendor certificates. Results: Differences from unity in the ratios of RAKR values determined by hospitals and vendors are most often small and stable around their mean values to within +/- 11.5%. Larger deviations are rare but occur. A decreasing ratio, seen at two hospitals for the same source, was useful in detecting an erroneous pressure gauge at the vendors site. Conclusions: Establishing a mean ratio of RAKR values, as measured at the hospital and supplied on the vendor certificate, and monitoring this as a function of time are an easy way for the early detection of problems with equipment or routines at either the hospital or the vendor site.
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| 7. |
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| 8. |
- Harnek, Jan, et al.
(författare)
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The 2011 outcome from the Swedish Health Care Registry on Heart Disease (SWEDEHEART)
- 2013
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Ingår i: Scandinavian Cardiovascular Journal. - : Informa UK Limited. - 1401-7431 .- 1651-2006. ; 47, s. 1-10
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Tidskriftsartikel (refereegranskat)abstract
- Objectives. The Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART) collects data to support the improvement of care for heart disease. Design. SWEDEHEART collects on-line data from consecutive patients treated at any coronary care unit n = (74), followed for secondary prevention, undergoing any coronary angiography, percutaneous coronary intervention, percutaneous valve or cardiac surgery. The registry is governed by an independent steering committee, the software is developed by Uppsala Clinical Research Center and it is funded by The Swedish national health care provider independent of industry support. Approximately 80,000 patients per year enter the database which consists of more than 3 million patients. Results. Base-line, procedural, complications and discharge data consists of several hundred variables. The data quality is secured by monitoring. Outcomes are validated by linkage to other registries such as the National Cause of Death Register, the National Patient Registry, and the National Registry of Drug prescriptions. Thanks to the unique social security number provided to all citizens follow-up is complete. The 2011 outcomes with special emphasis on patients more than 80 years of age are presented. Conclusion. SWEDEHEART is a unique complete national registry for heart disease.
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| 9. |
- Hjelmervik, Trond Ove R., et al.
(författare)
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The influence of the NOD Nss1/Idd5 loci on sialadenitis and gene expression in salivary glands of congenic mice
- 2007
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Ingår i: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 9:5
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Tidskriftsartikel (refereegranskat)abstract
- The nonobese diabetic ( NOD) Nss1 and Idd5 loci have been associated with sialadenitis development in mice. In this study the NOD Nss1 and Idd5 loci were backcrossed onto the healthy control strain B10. Q by using the speed congenic breeding strategy, resulting in three congenic strains: B10. Q. Nss1, B10. Q. Nss1/Idd5 heterozygous and B10. Q. Nss1/Idd5 homozygous. We investigated the effects of the Nss1 and Idd5 loci on sialadenitis and gene expression in NOD congenic mice. One submandibular salivary gland from each mouse was used for histological analysis of sialadenitis, whereas the contralateral salivary gland was used for gene expression profiling with the Applied Biosystems Mouse Genome Survey chip v. 1.0. The results were validated using quantitative reverse transcriptase PCR. The NOD Nss1 and Idd5 loci had clear influence on the onset and progression of sialadenitis in congenic mice. Double congenic mice exhibited the most severe phenotype. We successfully identified several genes that are located in the NOD congenic regions to be differentially expressed between the congenic strains and the control strain. Several of these were found to be co-regulated, such as Stat1, complement component C1q genes and Tlr12. Also, a vast contingency of interferon-regulated genes ( such as Ltb, Irf7 and Irf8) and cytokine and chemokine genes ( such as Ccr7 and Ccl19) were differentially expressed between the congenic strains and the control strain. Over-representation of inflammatory signalling pathways was observed among the differentially expressed genes. We have found that the introgression of the NOD loci Nss1 and Idd5 on a healthy background caused sialadenitis in NOD congenic mouse strains, and we propose that genes within these loci are important factors in the pathogenesis. Furthermore, gene expression profiling has revealed several differentially expressed genes within and outside the NOD loci that are similar to genes found to be differentially expressed in patients with Sjogren's syndrome, and as such are interesting candidates for investigation to enhance our understanding of disease mechanisms and to develop future therapies.
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| 10. |
- Igl, Wilmar, et al.
(författare)
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Animal source food intake and association with blood cholesterol, glycerophospholipids and sphingolipids in a northern Swedish population
- 2013
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Ingår i: International Journal of Circumpolar Health. - : Informa UK Limited. - 1239-9736 .- 2242-3982. ; 72, s. 421-427
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Tidskriftsartikel (refereegranskat)abstract
- Background. The high intake of game meat in populations with a subsistence-based diet may affect their blood lipids and health status. Objective. To examine the association between diet and circulating levels of blood lipid levels in a northern Swedish population. Study design. We compared a group with traditional lifestyle (TLS) based on reindeer herding (TLS group) with those from the same area with a non-traditional lifestyle (NTLS) typical of more industrialized regions of Sweden (NTLS group). The analysis was based on self-reported intake of animal source food (i.e. non-game meat, game meat, fish, dairy products and eggs) and the serum blood level of a number of lipids [total cholesterol (TC), low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), triglycerides (TG), glycerophospholipids and sphingolipids]. Results. The TLS group had higher cholesterol, LDL and HDL levels than the reference group. Of the TLS group, 65% had cholesterol levels above the threshold for increased risk of coronary heart disease (>= 240 mg/dl), as compared to 38% of the NTLS group. Self-reported consumption of game meat was positively associated with TC and LDL. Conclusions. The high game meat consumption of the TLS group is associated with increased cholesterol levels. High intake of animal protein and fat and low fibre is known to increase the risk of cardiovascular disease, but other studies of the TLS in northern Sweden have shown comparable incidences of cardiovascular disease to the reference (NTLS) group from the same geographical area. This indicates that factors other than TC influence disease risk. One such possible factor is dietary phospholipids, which are also found in high amounts specifically in game meat and have been shown to inhibit cholesterol absorption.
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| 11. |
- Johansson, Anna, et al.
(författare)
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A stroma targeted therapy enhances castration effects in a transplantable rat prostate cancer model.
- 2007
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Ingår i: The Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 100, s. 6-6
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Castration results in a major involution of the normal prostate gland. This process is initiated by effects in the prostate stroma and vasculature. Castration-induced regression of androgen sensitive prostate tumors is however less prominent and hypothetically this could be related to a limited stromal/vascular response. We therefore used animal tumor models to explore the importance of stroma and vascular effects, and if castration effects could be enhanced by a simultaneous therapy targeting the tumor stroma. METHODS: Using rats with Dunning PAP and H tumors, stereological methods, immunohistochemistry, and Western blotting, we studied the tumor response 7 and 28 days after castration and after the addition of stroma targeted therapies. RESULTS: In the normal ventral prostate (VP) nuclear androgen receptors (AR) were rapidly downregulated after castration. In contrast, the Dunning tumors downregulated the AR in the cancerous epithelium, but not in the surrounding stroma. Vascular regulators such as the angiopoietins, tie 2, and PDGF-Rbeta were not decreased in the stroma after castration, as observed in the VP, creating an environment that prevents vascular involution. When a tumor stroma targeted therapy inhibiting the tie 2 receptor and the PDGF-Rbeta simultaneously was added to castration it resulted in a decreased vascular density, increased tumor cell apoptosis and decreased tumor growth compared to castration alone. CONCLUSIONS: The stroma in highly differentiated androgen sensitive Dunning tumors is apparently androgen insensitive. If this unresponsive stroma is targeted the effects of castration can be enhanced.
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| 12. |
- Johansson, Asa, et al.
(författare)
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Linkage disequilibrium between microsatellite markers in the Swedish Sami relative to a worldwide selection of populations
- 2005
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Ingår i: Human Genetics. - : Springer Science and Business Media LLC. - 0340-6717 .- 1432-1203. ; 116:1-2, s. 105-13
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Tidskriftsartikel (refereegranskat)abstract
- The pattern of linkage disequilibriurn (LD) is affected by a number of factors, including population dernography. High LD is seen in populations with a relatively limited and constant size, presurnably due to genetic drift. We have examined the extent of LD arnong over 300 genome-wide pattern microsatellite loci in 29 populations from around the world. The pattern of LD vari ed between populations, with larger extent of LO in populations with limited size relative to larger populations. In addition, the LD between 88 less spaced microsatellite ffiarkers from 10 different genornic regions were examined in the Sami compared to the general Swedish population. For the se ffiarkers increased LD extending up to 5 Mb was detected in the Sami. The arnount of LD also differed between the chrornosornal regions. The arnount of LD in the Sami makes this population suited for mapping ofcornplex genetic traits
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| 13. |
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| 14. |
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| 15. |
- Johansson, Per-Ola, et al.
(författare)
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Design and synthesis of potent inhibitors of the malaria aspartyl proteases plasmepsin I and II : Use of solid-phase synthesis to explore novel statine motifs
- 2004
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 47:13, s. 3353-3366
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Tidskriftsartikel (refereegranskat)abstract
- Picomolar to low nanomolar inhibitors of the two aspartic proteases plasmepsin (Plm) I and II, from the malaria parasite Plasmodium falciparum, have been identified from sets of libraries containing novel statine-like templates modified at the amino and carboxy terminus. The syntheses of the novel statine templates were carried out in solution phase using efficient synthetic routes and resulting in excellent stereochemical control. The most promising statine template was attached to solid support and diversified by use of parallel synthesis. The products were evaluated for their Plm I and II inhibitory activity as well as their selectivity over cathepsin D. Selected inhibitors were, in addition, evaluated for their inhibition of parasite growth in cultured infected human red blood cells. The most potent inhibitor in this report, compound 16, displays Ki values of 0.5 and 2.2 nM for Plm I and II, respectively. Inhibitor 16 is also effective in attenuating parasite growth in red blood cells showing 51% inhibition at a concentration of 5 μM. Several inhibitors have been identified that exhibit Ki values between 0.5 and 74 nM for both Plm I and II. Some of these inhibitors also show excellent selectivity vs cathepsin D.
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| 16. |
- Kirwan, Gemma M, et al.
(författare)
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Building Multivariate Systems Biology Models
- 2012
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Ingår i: Analytical Chemistry. - Washington : American Chemical Society (ACS). - 0003-2700 .- 1520-6882. ; 84:16, s. 7064-7071
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Tidskriftsartikel (refereegranskat)abstract
- Systems biology methods using large-scale "omics" data sets face unique challenges: integrating and analyzing near limitless data space, while recognizing and removing systematic variation or noise. Herein we propose a complementary multivariate analysis workflow to both integrate "omics" data from disparate sources and analyze the results for specific and unique sample correlations. This workflow combines principal component analysis (PCA), orthogonal projections to latent structures discriminate analysis (OPLS-DA), orthogonal 2 projections to latent structures (O2PLS), and shared and unique structures (SUS) plots. The workflow is demonstrated using data from a study in which ApoE3Leiden mice were fed an atherogenic diet consisting of increasing cholesterol levels followed by therapeutic intervention (fenofibrate, rosuvastatin, and LXR activator T-0901317). The levels of structural lipids (lipidomics) and free fatty acids in liver were quantified via liquid chromatography-mass spectrometry (LC-MS). The complementary workflow identified diglycerides as key hepatic metabolites affected by dietary cholesterol and drug intervention. Modeling of the three therapeutics for mice fed a high-cholesterol diet further highlighted diglycerides as metabolites of interest in atherogenesis, suggesting a role in eliciting chronic liver inflammation. In particular, O2PLS-based SUS2 plots showed that treatment with T-0901317 or rosuvastatin returned the diglyceride profile in high-cholesterol-fed mice to that of control animals.
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| 17. |
- Lazarevic, Vladimir, et al.
(författare)
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Failure matters : unsuccessful cytogenetics and unperformed cytogenetics are associated with a poor prognosis in a population-based series of acute myeloid leukaemia
- 2015
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Ingår i: European Journal of Haematology. - Hoboken, USA : Wiley-Blackwell. - 0902-4441 .- 1600-0609. ; 94:5, s. 419-423
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Tidskriftsartikel (refereegranskat)abstract
- Unsuccessful cytogenetics (UC) in patients with acute myeloid leukaemia (AML) treated on different SWOG trials was recently reported to be associated with increased age and dismal outcome. To ascertain whether this holds true also in unselected patients with AML, we retrieved all cytogenetic reports in cases from the population-based Swedish AML Registry. Between 1997 and 2006, 1737 patients below 80 yr of age without myelosarcoma or acute promyelocytic leukaemia received intensive treatment. The frequencies of UC and unperformed cytogenetics (UPC) were 2.1% and 20%, respectively. The early death rates differed between the cytogenetic subgroups (P = 0.006) with the highest rates in patients with UC (14%) and UPC (12%) followed by high-risk (HR) AML, intermediate risk (IR) and standard risk (SR) cases successfully karyotyped (8.6%, 5.9%, and 5.8%, respectively). The complete remission rate was lower in UC and UPC and HR compared with the other risk groups (P < 0.001). The overall five-year survival rates were 25% for UC and 22% for UPC, whereas the corresponding frequencies for SR, IR and HR AML patients without UC and UPC were 64%, 31% and 15%, respectively. In conclusion, lack of cytogenetic data translates into a poor prognosis.
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| 18. |
- Lazarevic, Vladimir, et al.
(författare)
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Prognostic significance of high hyperdiploid and triploid/tetraploid adult acute myeloid leukemia
- 2015
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Ingår i: American Journal of Hematology. - : WILEY-BLACKWELL. - 0361-8609 .- 1096-8652. ; 90:9, s. 800-805
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Tidskriftsartikel (refereegranskat)abstract
- To ascertain the clinical implications of high hyperdiploid (HH; 49-65 chromosomes) and triploid/tetraploid (TT; greater than65 chromosomes) adult acute myeloid leukemia (AML), all such cases were retrieved from the Swedish AML Registry. Of the 3,654 cytogenetically informative cases diagnosed between January 1997 and May 2014, 68 (1.9%) were HH (n=50)/TT (n=18). Patients with HH/TT were older than those with intermediate risk (IR) AML (median 71 years vs. 67 years; P=0.042) and less often had de novo AML (63% vs. 79%; P=0.004); no such differences were observed between HH/TT and complex karyotype (CK) AML. The overall survival (OS) was similar between patients with HH/TT and CK AML (median 0.9 years vs. 0.6 years; P=0.082), whereas OS was significantly longer (median 1.6 years; P=0.028) for IR AML. The OS was shorter for cases with HH than with TT (median 0.6 years vs. 1.4 years; P=0.032) and for HH/TT AMLs with adverse abnormalities (median 0.8 years vs. 1.1 years; P=0.044). In conclusion, HH/TT AML is associated with a poor outcome, but chromosome numbers greater than65 and absence of adverse aberrations seem to translate into a more favorable prognosis. Thus, HH/TT AMLs are clinically heterogeneous and should not automatically be grouped as high risk.Am. J. Hematol. 90:800-805, 2015. (c) 2015 Wiley Periodicals, Inc.
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| 19. |
- Liu, Yanling, et al.
(författare)
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Western Blotting via Proximity Ligation for High Performance Protein Analysis
- 2011
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Ingår i: Molecular & Cellular Proteomics. - 1535-9476 .- 1535-9484. ; 10:11, s. O111.011031-
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Tidskriftsartikel (refereegranskat)abstract
- Western blotting is a powerful and widely used method, but limitations in detection sensitivity and specificity, and dependence upon high quality antibodies to detect targeted proteins, are hurdles to overcome. The in situ proximity ligation assay, based on dual antibody recognition and powerful localized signal amplification, offers increased detection sensitivity and specificity, along with an ability to identify complex targets such as phosphorylated or interacting proteins. Here we have applied the in situ proximity ligation assay mechanism in Western blotting. This combination allowed the use of isothermal rolling circle amplification of DNA molecules formed in target-specific ligation reaction, for 16-fold or greater increase in detection sensitivity. The increased specificity because of dual antibody recognition ensured highly selective assays, detecting the specific band when combinations of two cross-reactive antitubulin antibodies were used (i.e. both producing distinct nonspecific bands in traditional Western blotting). We also demonstrated detection of phosphorylated platelet-derived growth factor receptor beta by proximity ligation with one antibody directed against the receptor and another directed against the phosphorylated tyrosine residue. This avoided the need for stripping and re-probing the membrane or aligning two separate traditional blots. We demonstrate that the high-performance in situ proximity ligation-based Western blotting described herein is compatible with detection via enhanced chemiluminescence and fluorescence detection systems, and can thus be readily employed in any laboratory.
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| 20. |
- Moayyeri, Alireza, et al.
(författare)
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Genetic determinants of heel bone properties : genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium
- 2014
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:11, s. 3054-3068
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Tidskriftsartikel (refereegranskat)abstract
- Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 x 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 x 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 x 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.
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| 21. |
- Pelaseyed, Thaher, 1979, et al.
(författare)
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Unfolding dynamics of the mucin SEA domain probed by force spectroscopy suggest that it acts as a cell-protective device.
- 2013
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Ingår i: The FEBS journal. - : Wiley. - 1742-4658 .- 1742-464X. ; 280:6, s. 1491-501
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Tidskriftsartikel (refereegranskat)abstract
- MUC1 and other membrane-associated mucins harbor long, up to 1 μm, extended highly glycosylated mucin domains and sea urchin sperm protein, enterokinase and agrin (SEA) domains situated on their extracellular parts. These mucins line luminal tracts and organs, and are anchored to the apical cell membrane by a transmembrane domain. The SEA domain is highly conserved and undergoes a molecular strain-dependent autocatalytic cleavage during folding in the endoplasmic reticulum, a process required for apical plasma membrane expression. To date, no specific function has been designated for the SEA domain. Here, we constructed a recombinant protein consisting of three SEA domains in tandem and used force spectroscopy to assess the dissociation force required to unfold individual, folded SEA domains. Force-distance curves revealed three peaks, each representing unfolding of a single SEA domain. Fitting the observed unfolding events to a worm-like chain model yielded an average contour length of 32 nm per SEA domain. Analysis of forces applied on the recombinant protein revealed an average unfolding force of 168 pN for each SEA domain at a loading rate of 25 nN·s(-1). Thus, the SEA domain may act as a breaking point that can dissociate before the plasma membrane is breached when mechanical forces are applied to cell surfaces.
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| 22. |
- Peolsson, Anneli, et al.
(författare)
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Effects of neck-specific exercise with or without a behavioural approach in addition to prescribed physical activity for individuals with chronic whiplash-associated disorders: a prospective randomised study
- 2013
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Ingår i: BMC Musculoskeletal Disorders. - : BioMed Central. - 1471-2474. ; 14:311
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Tidskriftsartikel (refereegranskat)abstract
- Background: Up to 50% of chronic whiplash associated disorders (WAD) patients experience considerable pain and disability and remain on sick-leave. No evidence supports the use of physiotherapy treatment of chronic WAD, although exercise is recommended. Previous randomised controlled studies did not evaluate the value of adding a behavioural therapy intervention to neck-specific exercises, nor did they compare these treatments to prescription of general physical activity. Few exercise studies focus on patients with chronic WAD, and few have looked at patients ability to return to work and the cost-effectiveness of treatments. Thus, there is a great need to develop successful evidence-based rehabilitation models. The study aim is to investigate whether neck-specific exercise with or without a behavioural approach (facilitated by a single caregiver per patient) improves functioning compared to prescription of general physical activity for individuals with chronic WAD. less thanbrgreater than less thanbrgreater thanMethods/Design: The study is a prospective, randomised, controlled, multi-centre study with a 2-year follow-up that includes 216 patients with chronic WAD (andgt;6 months and andlt;3 years). The patients (aged 18 to 63) must be classified as WAD grade 2 or 3. Eligibility will be determined with a questionnaire, telephone interview and clinical examination. The participants will be randomised into one of three treatments: (A) neck-specific exercise followed by prescription of physical activity; (B) neck-specific exercise with a behavioural approach followed by prescription of physical activity; or (C) prescription of physical activity alone without neck-specific exercises. Treatments will be performed for 3 months. We will examine physical and psychological function, pain intensity, health care consumption, the ability to resume work and economic health benefits. An independent, blinded investigator will perform the measurements at baseline and 3, 6, 12 and 24 months after inclusion. The main study outcome will be improvement in neck-specific disability as measured with the Neck Disability Index. All treatments will be recorded in treatment diaries and medical records. less thanbrgreater than less thanbrgreater thanDiscussion: The study findings will help improve the treatment of patients with chronic WAD.
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| 23. |
- Rask-Andersen, Mathias, 1979-, et al.
(författare)
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Modification of Heritability for Educational Attainment and Fluid Intelligence by Socioeconomic Deprivation in the UK Biobank
- 2021
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Ingår i: American Journal of Psychiatry. - : American Psychiatric Association Publishing. - 0002-953X .- 1535-7228. ; 178:7, s. 625-634
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Socioeconomic factors have been suggested to influence the effect of education- and intelligence-associated genetic variants. However, results from previous studies on the interaction between socioeconomic status and education or intelligence have been inconsistent. The authors sought to assess these interactions in the UK Biobank cohort of 500,000 participants.METHODS: The authors assessed the effect of socioeconomic deprivation on education- and intelligence-associated genetic variants by estimating the single-nucleotide polymorphism (SNP) heritability for fluid intelligence, educational attainment, and years of education in subsets of UK Biobank participants with different degrees of social deprivation, using linkage disequilibrium score regression. They also generated polygenic scores with LDpred and tested for interactions with social deprivation.RESULTS: SNP heritability increased with socioeconomic deprivation for fluid intelligence, educational attainment, and years of education. Polygenic scores were also found to interact with socioeconomic deprivation, where the effects of the scores increased with increasing deprivation for all traits.CONCLUSIONS: These results indicate that genetics have a larger influence on educational and cognitive outcomes in more socioeconomically deprived U.K. citizens, which has serious implications for equality of opportunity.
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| 24. |
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| 25. |
- Skottheim Honn, John, et al.
(författare)
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Regulation of twin of eyeless during Drosophila development
- 2016
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Ingår i: Gene Expression Patterns. - : Elsevier BV. - 1567-133X .- 1872-7298. ; 20:2, s. 120-129
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Tidskriftsartikel (refereegranskat)abstract
- The Pax-6 protein is vital for eye development in all seeing animals, from sea urchins to humans. Either of the Pax6 genes in Drosophila (twin of eyeless and eyeless) can induce a gene cascade leading to formation of entire eyes when expressed ectopically. The twin of eyeless (toy) gene in Drosophila is expressed in the anterior region of the early fly embryo. At later stages it is expressed in the brain, ventral nerve cord and (eventually) the visual primordium that gives rise to the eye-antennal imaginal discs of the larvae. These discs subsequently form the major part of the adult head, including compound eyes. We have searched for genes that are required for normal toy expression in the early embryo to elucidate initiating events of eye organogenesis. Candidate genes identified by mutation analyses were subjected to further knock-out and miss-expression tests to investigate their interactions with toy. Our results indicate that the head-specific gap gene empty spiracles can act as a repressor of Toy, while ocelliless (oc) and spalt major (salm) appear to act as positive regulators of toy gene expression. (C) 2016 Elsevier B.V. All rights reserved.
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