| 1. |
- Cunningham, Janet L., et al.
(författare)
-
Agreement between physicians' and patients' ratings on the Montgomery-Asberg Depression Rating Scale
- 2011
-
Ingår i: Journal of Affective Disorders. - : Elsevier BV. - 0165-0327 .- 1573-2517. ; 135:1-3, s. 148-153
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Self-rating scales developed for monitoring depression severity are potentially informative and cost effective tools. There is an increasing tendency to use the Montgomery-Asberg Depression Rating Scale (MADRS) and the self-rating version (MADRS-S) interchangeably. Methods: 400 patients with major depressive disorder were included. Concordance between patient and physician ratings was measured by means of repeated MADRS and MADRS-S ratings during a six-month drug trial and one-year follow-up. Results: Overall scores from patients and physicians show the same trends and both are sensitive to improvements. Our results, however, show only moderate to good agreement between patient and physician ratings. Intraclass coefficients ranged from 0.47 to 0.75 with highest agreement at week 8. Limitations: Generalizability is restricted to outpatients in general practice with moderate to severe depression. MADRS-S and MADRS scale definitions are similar but not identical concerning language and are scaled differently, 0-6 vs. 0-3, respectively, which may have influenced the results. The exclusion criteria restricted the range of values for the item Suicidal thoughts/Zest for life, which may have reduced the correlations. Conclusions: MADRS-S is a suitable tool for following patients' symptoms on a regular basis over time and may also be used to compensate for bias in physicians' ratings in drug trials.
|
|
| 2. |
- Cunningham, Janet L., et al.
(författare)
-
Predicting disagreement between physicians and patients on depression response and remission
- 2013
-
Ingår i: International Clinical Psychopharmacology. - 0268-1315 .- 1473-5857. ; 28:3, s. 134-140
-
Tidskriftsartikel (refereegranskat)abstract
- Demographic, personality, and disease-related factors all contribute when patients disagree with physicians on the severity of subjective symptoms. This study aims to create a model, on the basis of patient factors at treatment initiation, for longitudinal prediction of disagreement on treatment response and remission in depressed patients. Four hundred patients with major depressive disorder were studied during a clinical drug trial. Repeated assessments with the Montgomery-Asberg Depression Rating Scale (MADRS) and the self-rating version (MADRS-S) were used to indicate response or remission. Factors at baseline and week 2 were tested for inclusion in a model for the prediction of discordance on remission and response between patients and physicians at week 8. The models were then tested, in the same population, at weeks 12, 16, and 24. Model AUCs ranged from 0.71 to 0.74 for week 8. The models that were validated at weeks 12, 16, and 24 indicated stability in the predictive value of the models. The risk for longitudinal disagreement in the evaluation of depression treatment response and remission in clinical practice and drug trials can be predicted using factors at study initiation and at week 2.
|
|
| 3. |
- Anderberg, Peter, et al.
(författare)
-
Older people’s use and nonuse of the internet in Sweden
- 2020
-
Ingår i: International Journal of Environmental Research and Public Health. - : MDPI. - 1661-7827 .- 1660-4601. ; 17:23, s. 1-11
-
Tidskriftsartikel (refereegranskat)abstract
- The use of the internet has considerably increased over recent years, and the importance of internet use has also grown as services have gone online. Sweden is largely an information society like other countries with high reported use amongst European countries. In line with digitalization development, society is also changing, and many activities and services today take place on the internet. This development could potentially lead to those older persons who do not use the internet or do not follow the development of services on the internet finding it difficult to take part in information and activities that no longer occur in the physical world. This has led to a digital divide between groups, where the older generations (60+), in particular, have been affected. In a large study of Sweden’s adult population in 2019, 95 percent of the overall population was said to be internet users, and the corresponding number for users over 66 years of age was 84%. This study shows that the numbers reported about older peoples’ internet use, most likely, are vastly overestimated and that real use is significantly lower, especially among the oldest age groups. We report that 62.4% of the study subjects are internet users and that this number most likely also is an overestimation. When looking at nonresponders to the questionnaire, we find that they display characteristics generally attributed to non-use, such as lower education, lower household economy, and lower cognitive functioning.
|
|
| 4. |
- Andrade, Jorge, et al.
(författare)
-
Applications of grid computing in genetics and proteomics
- 2007
-
Ingår i: Applied Parallel Computing. - Berlin, Heidelberg : Springer Berlin Heidelberg. - 9783540757542 ; , s. 791-798
-
Konferensbidrag (refereegranskat)abstract
- The potential for Grid technologies in applied bioinformatics is largely unexplored. We have developed a model for solving computationally demanding bioinformatics tasks in distributed Grid environments, designed to ease the usability for scientists unfamiliar with Grid computing. With a script-based implementation that uses a strategy of temporary installations of databases and existing executables on remote nodes at submission, we propose a generic solution that do not rely on predefined Grid runtime environments and that can easily be adapted to other bioinformatics tasks suitable for parallelization. This implementation has been successfully applied to whole proteome sequence similarity analyses and to genome-wide genotype simulations, where computation time was reduced from years to weeks. We conclude that computational Grid technology is a useful resource for solving high compute tasks in genetics and proteomics using existing algorithms.
|
|
| 5. |
- Andrade, Jorge, et al.
(författare)
-
Using Grid Technology for Computationally Intensive Applied Bioinformatics Analyses
- 2006
-
Ingår i: In Silico Biology. - 1386-6338. ; 6:6, s. 495-504
-
Tidskriftsartikel (refereegranskat)abstract
- For several applications and algorithms used in applied bioinformatics, a bottle neck in terms of computational time may arise when scaled up to facilitate analyses of large datasets and databases. Re-codification, algorithm modification or sacrifices in sensitivity and accuracy may be necessary to accommodate for limited computational capacity of single work stations. Grid computing offers an alternative model for solving massive computational problems by parallel execution of existing algorithms and software implementations. We present the implementation of a Grid-aware model for solving computationally intensive bioinformatic analyses exemplified by a blastp sliding window algorithm for whole proteome sequence similarity analysis, and evaluate the performance in comparison with a local cluster and a single workstation. Our strategy involves temporary installations of the BLAST executable and databases on remote nodes at submission, accommodating for dynamic Grid environments as it avoids the need of predefined runtime environments (preinstalled software and databases at specific Grid-nodes). Importantly, the implementation is generic where the BLAST executable can be replaced by other software tools to facilitate analyses suitable for parallelisation. This model should be of general interest in applied bioinformatics. Scripts and procedures are freely available from the authors.
|
|
| 6. |
|
|
| 7. |
|
|
| 8. |
- Awla, Darbaz, et al.
(författare)
-
NFATc3 Regulates Trypsinogen Activation, Neutrophil Recruitment, and Tissue Damage in Acute Pancreatitis in Mice.
- 2012
-
Ingår i: Gastroenterology. - : Elsevier BV. - 1528-0012 .- 0016-5085. ; 143:5, s. 1352-1352
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: The signaling mechanisms that regulate trypsinogen activation and inflammation in acute pancreatitis (AP) are unclear. We explored the involvement of the calcium- and calcineurin-dependent transcription factor nuclear factor of activated T-cells (NFAT) in development of AP in mice. METHODS: We measured levels of myeloperoxidase and macrophage inflammatory protein-2 (CXCL2), trypsinogen activation, and tissue damage in the pancreas 24 h after induction of AP by retrograde infusion of taurocholate into the pancreatic ducts of wild-type, NFAT luciferase reporter (NFAT-luc), and NFATc3-deficient mice. We isolated acinar cells and measured NFAT nuclear accumulation, trypsin activity, and expression of NFAT-regulated genes. RESULTS: Infusion of taurocholate increased the transcriptional activity of NFAT in the pancreas, aorta, lung, and spleen of NFAT-luc mice. Inhibition of NFAT with A-285222 blocked taurocholate-induced activation of NFAT in all organs. A-285222 also reduced taurocholate-induced increases in levels of amylase, myeloperoxidase and CXCL2; activation of trypsinogen; necrosis of acinar cells; edema; leukocyte infiltration; and hemorrhage in the pancreas. NFATc3-deficient mice were protected from these effects of taurocholate. Similar results were obtained using an L-arginine-induced model of AP. Reverse transcriptase PCR and confocal immunofluorescence analyses showed that NFATc3 is expressed by acinar cells. NFATc3 expression was activated by stimuli that increase intracellular calcium; activation was prevented by the calcineurin blocker cyclosporine A or A-285222. Activation of trypsinogen by secretagogues in acinar cells was prevented by pharmacologic inhibition of NFAT signaling or lack of NFATc3. A-285222 also reduced expression of inflammatory cytokines such as CXCL2 in acinar cells. CONCLUSIONS: NFATc3 regulates trypsinogen activation, inflammation, and pancreatic tissue damage during development of AP in mice, and might be a therapeutic target.
|
|
| 9. |
- Axén, Anna, 1984-, et al.
(författare)
-
Loneliness in Relation to Social Factors and Self-Reported Health Among Older Adults : A Cross-Sectional Study
- 2023
-
Ingår i: Journal of Primary Care & Community Health. - : Sage Publications. - 2150-1319 .- 2150-1327. ; 14
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Loneliness is described as a public health problem and can be both a consequence of aging and a cause of ill health. Lonely older adults tend to have difficulties making new social connections, essential in reducing loneliness. Loneliness often varies over time, but established loneliness tends to persist. Maintaining good health is fundamental throughout the life course. Social connections change with aging, which can contribute to loneliness. AIM: This study aimed to investigate loneliness in relation to social factors and self-reported health among older adults. METHOD: A cross-sectional research design was used based on data from the Swedish National Study on Aging and Care, Blekinge (SNAC-B), from February 2019 to April 2021. Statistical analysis consisted of descriptive and inferential analysis. RESULTS: Of n = 394 participants, 31.7% (n = 125) stated loneliness. Close emotional connections were necessary for less loneliness. Loneliness was more common among those who did not live with their spouse or partner and met more rarely. Furthermore, seeing grandchildren and neighbors less often increased loneliness, and a more extensive social network decreased loneliness. CONCLUSION: This study underlined the importance of social connections and having someone to share a close, emotional connection with to reduce loneliness.
|
|
| 10. |
- Bahrami, Alireza, et al.
(författare)
-
Important Criteria for Swedish Construction Companies to Choose Environmentally Friendly Concrete
- 2023
-
Ingår i: Civil Engineering Journal. - : CEJ. - 2676-6957 .- 2476-3055. ; 9:1, s. 197-207
-
Tidskriftsartikel (refereegranskat)abstract
- Today, ordinary Portland cement-based concrete is one of the most important building materials and is widely used in new building construction, which is an environmental problem, as cement production accounts for 5%-8% of the world's carbon dioxide emissions. Thus, the need for using more environmentally friendly concrete (EFC) is growing. However, it is stated that Swedish construction companies are reluctant to change and adopt new construction methods and materials. This research aims to map the important criteria for Swedish construction companies to choose EFC for use in their projects. The study is carried out based on a literature study and a questionnaire survey. The questionnaire is designed considering the significant criteria of EFC derived from the literature study. The respondents from the Swedish construction companies were asked to rate these various criteria. The collected results are presented with bar graphs. The results show that the highest valued criterion by the respondents for the use of EFC in the projects is its long-term properties, while the lowest one is the possibility of introducing a specific ceiling for greenhouse gas emissions by the companies.
|
|
| 11. |
- Berglund, Lisa, et al.
(författare)
-
A genecentric Human Protein Atlas for expression profiles based on antibodies
- 2008
-
Ingår i: Molecular & Cellular Proteomics. - 1535-9476 .- 1535-9484. ; 7:10, s. 2019-2027
-
Forskningsöversikt (refereegranskat)abstract
- An attractive path forward in proteomics is to experimentally annotate the human protein complement of the genome in a genecentric manner. Using antibodies, it might be possible to design protein-specific probes for a representative protein from every protein-coding gene and to subsequently use the antibodies for systematical analysis of cellular distribution and subcellular localization of proteins in normal and disease tissues. A new version (4.0) of the Human Protein Atlas has been developed in a genecentric manner with the inclusion of all human genes and splice variants predicted from genome efforts together with a visualization of each protein with characteristics such as predicted membrane regions, signal peptide, and protein domains and new plots showing the uniqueness (sequence similarity) of every fraction of each protein toward all other human proteins. The new version is based on tissue profiles generated from 6120 antibodies with more than five million immunohistochemistry-based images covering 5067 human genes, corresponding to approximately 25% of the human genome. Version 4.0 includes a putative list of members in various protein classes, both functional classes, such as kinases, transcription factors, G-protein-coupled receptors, etc., and project-related classes, such as candidate genes for cancer or cardiovascular diseases. The exact antigen sequence for the internally generated antibodies has also been released together with a visualization of the application-specific validation performed for each antibody, including a protein array assay, Western blot analysis, immunohistochemistry, and, for a large fraction, immunofluorescence-based confocal microscopy. New search functionalities have been added to allow complex queries regarding protein expression profiles, protein classes, and chromosome location. The new version of the protein atlas thus is a resource for many areas of biomedical research, including protein science and biomarker discovery.
|
|
| 12. |
- Berglund, Lisa, et al.
(författare)
-
A whole-genome bioinformatics approach to selection of antigens for systematic antibody generation
- 2008
-
Ingår i: Proteomics. - : Wiley. - 1615-9853 .- 1615-9861. ; 8:14, s. 2832-2839
-
Tidskriftsartikel (refereegranskat)abstract
- Here, we present an antigen selection strategy based on a whole-genome bioinformatics approach, which is facilitated by an interactive visualization tool displaying protein features from both public resources and in-house generated data. The web-based bioinformatics platform has been designed for selection of multiple, non-overlapping recombinant protein epitope signature tags by display of predicted information relevant for antigens, including domain- and epitope sized sequence similarities to other proteins, transmembrane regions and signal peptides. The visualization tool also displays shared and exclusive protein regions for genes with multiple splice variants. A genome-wide analysis demonstrates that antigens for approximately 80% of the human protein-coding genes can be selected with this strategy.
|
|
| 13. |
- Berglund, Lisa, et al.
(författare)
-
Generation of validated antibodies towards the human proteome
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Here we show the results from a large effort to generate antibodies towards the human proteome. A high-throughput strategy was developed based on cloning and expression of antigens as recombitant protein epitope signature tags (PrESTs) Affinity purified polyclonal antibodies were generated, followed by validation by protein microarrays, Western blotting and microarray-based immunohistochemistry. PrESTs were selected based on sequence uniqueness relative the proteome and a bioinformatics analysis showed that unique antigens can be found for at least 85% of the proteome using this general strategy. The success rate from antigen selection to validated antibodies was 31%, and from protein to antibody 55%. Interestingly, membrane-bound and soluble proteins performed equally and PrEST lengths between 75 and 125 amino acids were found to give the highest yield of validated antibodies. Multiple antigens were selected for many genes and the results suggest that specific antibodies can be systematically generated to most human proteibs.
|
|
| 14. |
- Berglund, Lisa, et al.
(författare)
-
Glucose-Dependent Insulinotropic Polypeptide (GIP) Stimulates Osteopontin Expression in the Vasculature via Endothelin-1 and CREB.
- 2016
-
Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 65:1, s. 239-254
-
Tidskriftsartikel (refereegranskat)abstract
- Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone with extrapancreatic effects beyond glycemic control. Here we demonstrate unexpected effects of GIP signaling in the vasculature. GIP induces the expression of the pro-atherogenic cytokine osteopontin (OPN) in mouse arteries, via local release of endothelin-1 (ET-1) and activation of cAMP response element binding protein (CREB). Infusion of GIP increases plasma OPN levels in healthy individuals. Plasma ET-1 and OPN levels are positively correlated in patients with critical limb ischemia. Fasting GIP levels are higher in individuals with a history of cardiovascular disease (myocardial infarction, stroke) when compared to controls. GIP receptor (GIPR) and OPN mRNA levels are higher in carotid endarterectomies from patients with symptoms (stroke, transient ischemic attacks, amaurosis fugax) than in asymptomatic patients; and expression associates to parameters characteristic of unstable and inflammatory plaques (increased lipid accumulation, macrophage infiltration and reduced smooth muscle cell content). While GIPR expression is predominantly endothelial in healthy arteries from human, mouse, rat and pig; remarkable up-regulation is observed in endothelial and smooth muscle cells upon culture conditions yielding a "vascular disease-like" phenotype. Moreover, a common variant rs10423928 in the GIPR gene associated with increased risk of stroke in type 2 diabetes patients.
|
|
| 15. |
- Berglund, Lisa, et al.
(författare)
-
NFAT regulates the expression of AIF-1 and IRT-1: Yin and yang splice variants of neointima formation and atherosclerosis.
- 2012
-
Ingår i: Cardiovascular Research. - : Oxford University Press (OUP). - 1755-3245 .- 0008-6363. ; 93, s. 414-423
-
Tidskriftsartikel (refereegranskat)abstract
- Aims Alternative transcription and splicing of the allograft inflammatory factor-1 (AIF-1) gene results in the expression of two different proteins: AIF-1 and interferon responsive transcript-1 (IRT-1). Here we explore the impact of AIF-1 and IRT-1 on vascular smooth muscle cell (VSMC) activation and neointima formation, the mechanisms underlying their alternative splicing, and associations of AIF-1 and IRT-1 mRNA with parameters defining human atherosclerotic plaque phenotype.Methods and results Translation of AIF-1 and IRT-1 results in different products with contrasting cellular distribution and functions. Overexpression of AIF-1 stimulates migration and proliferation of human VSMCs, whereas IRT-1 exerts opposite effects. Adenoviral infection of angioplasty-injured rat carotid arteries with AdAIF-1 exacerbates intima hyperplasia, whereas infection with AdIRT-1 reduces neointima. Expression of these variants is modulated by changes in nuclear factor of activated T-cells (NFAT) activity. Pharmacological inhibition of NFAT or targeting of NFATc3 with siRNA lowers the AIF-1/IRT-1 ratio and favors an anti-proliferative outcome. NFAT acts as a repressor on the IRT-1 transcriptional start site, which is also sensitive to interferon-γ stimulation. Expression of AIF-1 mRNA in human carotid plaques associates with less extracellular matrix and a more pro-inflammatory plaque and plasma profile, features that may predispose to plaque rupture. In contrast, expression of IRT-1 mRNA associates with a less aggressive phenotype and less VSMCs at the most stenotic region of the plaque.Conclusions Inhibition of NFAT signaling, by shifting the AIF-1/IRT-1 ratio, may be an attractive target to regulate the VSMC response to injury and manipulate plaque stability in atherosclerosis.
|
|
| 16. |
- Berglund, Lisa, et al.
(författare)
-
Novel blocker of NFAT activation inhibits IL-6 production in human myometrial arteries and reduces vascular smooth muscle cell proliferation
- 2007
-
Ingår i: American Journal of Physiology: Cell Physiology. - : American Physiological Society. - 1522-1563 .- 0363-6143. ; 292:3, s. 1167-1178
-
Tidskriftsartikel (refereegranskat)abstract
- The calcineurin/nuclear factor of activated T cells ( NFAT) signaling pathway has been found to play a role in regulating growth and differentiation in several cell types. However, the functional significance of NFAT in the vasculature is largely unclear. Here we show that NFATc1, NFATc3, and NFATc4 are expressed in human myometrial arteries. Confocal immunofluorescence and Western blot analysis revealed that endothelin-1 efficiently increases NFATc3 nuclear accumulation in native arteries. Endothelin-1 also stimulates NFAT-dependent transcriptional activity, as shown by a luciferase reporter assay. Both the agonist-induced NFAT nuclear accumulation and transcriptional activity were prevented by the calcineurin inhibitor CsA and by the novel NFAT blocker A-285222. Chronic inhibition of NFAT significantly reduced IL-6 production in intact myometrial arteries and inhibited cell proliferation in vascular smooth muscle cells cultured from explants from the same arteries. Furthermore, by using small interfering RNA-mediated reduction of NFATc3, we show that this isoform is involved in the regulation of cell proliferation. Protein synthesis in intact arteries was investigated using autoradiography of [S-35] methionine incorporation in serum-free culture. Inhibition of NFAT signaling did not affect overall protein synthesis or specifically the synthesis rates of major proteins associated with the contractile/cytoskeletal system. An intact contractile phenotype under these conditions was also shown by unchanged force response to depolarization or agonist stimulation. Our results demonstrate NFAT expression and activation in native human vessels and point out A-285222 as a powerful pharmacological blocker of NFAT signaling in the vasculature.
|
|
| 17. |
- Berglund, Lisa, et al.
(författare)
-
Nuclear Factor of Activated T Cells Regulates Osteopontin Expression in Arterial Smooth Muscle in Response to Diabetes-Induced Hyperglycemia
- 2010
-
Ingår i: ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY. - Baltimore : Lippincott Williams & Wilkins. - 1079-5642. ; 30, s. 154-218
-
Tidskriftsartikel (refereegranskat)abstract
- Objective-Hyperglycemia is a recognized risk factor for cardiovascular disease in diabetes. Recently, we reported that high glucose activates the Ca2+/calcineurin-dependent transcription factor nuclear factor of activated T cells (NFAT) in arteries ex vivo. Here, we sought to determine whether hyperglycemia activates NFAT in vivo and whether this leads to vascular complications. Methods and Results-An intraperitoneal glucose-tolerance test in mice increased NFATc3 nuclear accumulation in vascular smooth muscle. Streptozotocin-induced diabetes resulted in increased NFATc3 transcriptional activity in arteries of NFAT-luciferase transgenic mice. Two NFAT-responsive sequences in the osteopontin (OPN) promoter were identified. This proinflammatory cytokine has been shown to exacerbate atherosclerosis and restenosis. Activation of NFAT resulted in increased OPN mRNA and protein in native arteries. Glucose-induced OPN expression was prevented by the ectonucleotidase apyrase, suggesting a mechanism involving the release of extracellular nucleotides. The calcineurin inhibitor cyclosporin A or the novel NFAT blocker A-285222 prevented glucose-induced OPN expression. Furthermore, diabetes resulted in higher OPN expression, which was significantly decreased by in vivo treatment with A-285222 for 4 weeks or prevented in arteries from NFATc3(-/-) mice. Conclusions-These results identify a glucose-sensitive transcription pathway in vivo, revealing a novel molecular mechanism that may underlie vascular complications of diabetes.
|
|
| 18. |
- Berglund, Lisa, et al.
(författare)
-
Nuclear factor of activated T-cells transcription factors in the vasculature: the good guys or the bad guys?
- 2008
-
Ingår i: Current Opinion in Lipidology. - 1473-6535. ; 19:5, s. 483-490
-
Tidskriftsartikel (refereegranskat)abstract
- PURPOSE OF REVIEW: The nuclear factor of activated T-cells (NFAT) proteins are a family of Ca/calcineurin-dependent transcription factors that were first characterized in T-lymphocytes as inducers of cytokine gene expression. Since then, NFAT proteins have been shown to play varied roles outside of the immune system, including in the cardiovascular system. Cells in the vessel wall display a diverse array of Ca signaling modalities, which are subject to change during disease. The fact that NFAT proteins are able to decode and translate these signals into changes in gene expression makes them potential regulators of vascular pathogenesis. RECENT FINDINGS: It is now clear that NFAT signaling is required for normal vascular patterning during embryogenesis and for vascular endothelial growth factor-induced angiogenesis. The overall role of NFAT signaling in the vasculature, however, is less clear during adult life. This review aims to give an update on mechanisms that regulate NFAT activation in vascular cells, with an emphasis on the role of mitochondria and of upstream activators such as lipids and glucose. It also addresses recent work implicating NFAT proteins as mediators of vascular disease. SUMMARY: A better understanding of the NFAT-signaling pathway in the vasculature may open up an unexplored area for the development of new therapeutic approaches for treating vascular disease.
|
|
| 19. |
|
|
| 20. |
- Berglund, Lisa
(författare)
-
Role of NFAT (nuclear factor of activated T cells) in vascular smooth muscle
- 2009
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The calcium-dependent transcription factor NFAT was first described as a key player in immune cell regulation. Since then, NFAT signaling has been shown to be crucial for normal vascular development during embryogenesis. This pathway is also an important regulator of cell growth and differentiation in various cell types, however, the functional significance of NFAT in the vasculature is largely unclear. Here, we show for the first time that NFAT is expressed in human arteries and that the novel NFAT blocker A-285222 prevents NFAT activation in this tissue. While NFAT inhibition had only minor effects on vascular contractility and expression of proteins associated with the contractile/cytoskeletal system, it resulted in decreased interleukin-6 production in intact arteries. We provide evidence demonstrating that the NFATc3 isoform has an essential role in the regulation of vascular smooth muscle cell (VSMC) proliferation. NFAT affects VSMC proliferation via splicing of the allograft inflammatory factor-1 (AIF-1) gene. AIF-1 and interferon response transcript-1 (IRT-1) are alternative transcripts encoded from the AIF-1 gene and over expression of AIF-1 led to increased migration and proliferation of VSMCs, whereas IRT-1 over expression had the opposite effect. Moreover, AIF-1 over expression resulted in increased balloon injury-induced neointima formation in rat carotid arteries, whereas over expression of the anti-proliferative IRT-1 yielded less neointima. This suggests that the NFAT signaling pathway may be important for the VSMC response to injury. We further show that a modest elevation in extracellular glucose concentrations led to increased NFAT activity. The mechanism by which glucose acts is via local release of extracellular nucleotides that activate P2Y receptors and increase calcium influx, and via inhibition of GSK-3b and JNK, which oppose NFAT activation. Incubation of arteries in high glucose led to increased expression of the pro-inflammatory cytokine osteopontin (OPN) in an NFAT-dependent manner. Furthermore, streptozotocin-induced diabetes was associated with increased NFAT activation and OPN expression in vivo. Diabetes-induced upregulation of OPN was effectively prevented by pharmacological inhibition of NFAT with A-285222, or in mice lacking NFATc3. In summary, by responding to discrete elevations in blood glucose, NFAT may be of importance for the vascular response to hyperglycemia in diabetes. Combined with the described role for NFAT in the regulation of VSMC proliferation and cytokine expression, inhibition of NFAT signaling with A-285222 is a potential therapeutic target for preventing diabetic vascular complications.
|
|
| 21. |
- Berglund, Lisa, 1978-
(författare)
-
Selection of antigens for antibody-based proteomics
- 2008
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The human genome is predicted to contain ~20,500 protein-coding genes. The encoded proteins are the key players in the body, but the functions and localizations of most proteins are still unknown. Antibody-based proteomics has great potential for exploration of the protein complement of the human genome, but there are antibodies only to a very limited set of proteins. The Human Proteome Resource (HPR) project was launched in August 2003, with the aim to generate high-quality specific antibodies towards the human proteome, and to use these antibodies for large-scale protein profiling in human tissues and cells. The goal of the work presented in this thesis was to evaluate if antigens can be selected, in a high-throughput manner, to enable generation of specific antibodies towards one protein from every human gene. A computationally intensive analysis of potential epitopes in the human proteome was performed and showed that it should be possible to find unique epitopes for most human proteins. The result from this analysis was implemented in a new web-based visualization tool for antigen selection. Predicted protein features important for antigen selection, such as transmembrane regions and signal peptides, are also displayed in the tool. The antigens used in HPR are named protein epitope signature tags (PrESTs). A genome-wide analysis combining different protein features revealed that it should be possible to select unique, 50 amino acids long PrESTs for ~80% of the human protein-coding genes. The PrESTs are transferred from the computer to the laboratory by design of PrEST-specific PCR primers. A study of the success rate in PCR cloning of the selected fragments demonstrated the importance of controlled GC-content in the primers for specific amplification. The PrEST protein is produced in bacteria and used for immunization and subsequent affinity purification of the resulting sera to generate mono-specific antibodies. The antibodies are tested for specificity and approved antibodies are used for tissue profiling in normal and cancer tissues. A large-scale analysis of the success rates for different PrESTs in the experimental pipeline of the HPR project showed that the total success rate from PrEST selection to an approved antibody is 31%, and that this rate is dependent on PrEST length. A second PrEST on a target protein is somewhat less likely to succeed in the HPR pipeline if the first PrEST is unsuccessful, but the analysis shows that it is valuable to select several PrESTs for each protein, to enable generation of at least two antibodies, which can be used to validate each other.
|
|
| 22. |
- Berglund, Lisa, et al.
(författare)
-
The epitope space of the human proteome
- 2008
-
Ingår i: Protein Science. - : Wiley. - 0961-8368 .- 1469-896X. ; 17:4, s. 606-613
-
Tidskriftsartikel (refereegranskat)abstract
- In the post-genome era, there is a great need for protein-specific affinity reagents to explore the human proteome. Antibodies are suitable as reagents, but generation of antibodies with low cross-reactivity to other human proteins requires careful selection of antigens. Here we show the results from a proteomewide effort to map linear epitopes based on uniqueness relative to the entire human proteome. The analysis was based on a sliding window sequence similarity search using short windows (8, 10, and 12 amino acid residues). A comparison of exact string matching (Hamming distance) and a heuristic method (BLAST) was performed, showing that the heuristic method combined with a grid strategy allows for whole proteome analysis with high accuracy and feasible run times. The analysis shows that it is possible to find unique antigens for a majority of the human proteins, with relatively strict rules involving low sequence identity of the possible linear epitopes. The implications for human antibody-based proteomics efforts are discussed.
|
|
| 23. |
- Berglund, M., et al.
(författare)
-
On Human Terms – A First Evaluation of a Massive Open Online Course (MOOC) in Ergonomics
- 2019
-
Ingår i: Advances in Intelligent Systems and Computing. - Cham : Springer International Publishing. - 2194-5365 .- 2194-5357. - 9783319960791 ; 821, s. 530-538
-
Konferensbidrag (refereegranskat)abstract
- The Massive Open Online Course (MOOC) ‘Work and Technology on Human Terms’ (www.onhumanterms.org ) was launched in July 2017 with the aim to contribute to safer and healthier workplaces by increasing the knowledge about how products, systems, and work organizations can be designed on human terms. The purpose of this paper is to present the results of a first evaluation of the MOOC. The online course was used in four different university courses in Ergonomics in Sweden, two given at Chalmers University of Technology in Gothenburg and two given at Linköping University. The MOOC material was used in different ways in the courses: (1) suggested voluntary, alternative material for the students’ self-studies, (2) scheduled activity for self-studies with appointed chapters, and (3) mandatory, selected course material being discussed in follow-up seminars. Data for the evaluation was collected through questionnaires and semi-structured interviews with students and teachers. The results showed that the MOOC served as a repetition of lectured material and gave increased understanding of the theories. The recorded interviews with practitioners and researchers in the MOOC highlighted the importance of the subject in real working life. The knowledge tests were appreciated as rehearsal of understanding. However, the MOOC in parallel with the other course material was also considered to be too much work by some students. A recommendation is to carefully consider how to use and integrate the MOOC as a meaningful, individual, theoretical learning activity for the students. Thereby the lectures in classroom could focus more on discussions and problem-solving regarding the topics and less on basic theory.
|
|
| 24. |
- Birney, Ewan, et al.
(författare)
-
Prepublication data sharing
- 2009
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 461:7261, s. 168-170
-
Tidskriftsartikel (refereegranskat)abstract
- Rapid release of prepublication data has served the field of genomics well. Attendees at a workshop in Toronto recommend extending the practice to other biological data sets.
|
|
| 25. |
- Bjurhager, Ingela, et al.
(författare)
-
State of degradation in archeological oak from the 17th century vasa ship : Substantial strength loss correlates with reduction in (holo)cellulose molecular weight
- 2012
-
Ingår i: Biomacromolecules. - : American Chemical Society (ACS). - 1525-7797 .- 1526-4602. ; :8, s. 2521-2527
-
Tidskriftsartikel (refereegranskat)abstract
- In 1628, the Swedish warship Vasa capsized on her maiden voyage and sank in the Stockholm harbor. The ship was recovered in 1961 and, after polyethylene glycol (PEG) impregnation, it was displayed in the Vasa museum. Chemical investigations of the Vasa were undertaken in 2000, and extensive holocellulose degradation was reported at numerous locations in the hull. We have now studied the longitudinal tensile strength of Vasa oak as a function of distance from the surface. The PEG-content, wood density, and cellulose microfibril angle were determined. The molar mass distribution of holocellulose was determined as well as the acid and iron content. A good correlation was found between the tensile strength of the Vasa oak and the average molecular weight of the holocellulose, where the load-bearing cellulose microfibril is the critical constituent. The mean tensile strength is reduced by approximately 40%, and the most affected areas show a reduction of up to 80%. A methodology is developed where variations in density, cellulose microfibril angle, and PEG content are taken into account, so that cell wall effects can be evaluated in wood samples with different rate of impregnation and morphologies.
|
|
| 26. |
- Blanco, Fabiana, et al.
(författare)
-
In vivo inhibition of nuclear factor of activated T-cells leads to atherosclerotic plaque regression in IGF-II/LDLR -/-ApoB100/100 mice
- 2018
-
Ingår i: Diabetes and Vascular Disease Research. - : SAGE Publications. - 1752-8984 .- 1479-1641. ; 15:4, s. 302-313
-
Tidskriftsartikel (refereegranskat)abstract
- AIMS: Despite vast clinical experience linking diabetes and atherosclerosis, the molecular mechanisms leading to accelerated vascular damage are still unclear. Here, we investigated the effects of nuclear factor of activated T-cells inhibition on plaque burden in a novel mouse model of type 2 diabetes that better replicates human disease.METHODS & RESULTS: IGF-II/LDLR-/-ApoB100/100mice were generated by crossbreeding low-density lipoprotein receptor-deficient mice that synthesize only apolipoprotein B100 (LDLR-/-ApoB100/100) with transgenic mice overexpressing insulin-like growth factor-II in pancreatic β cells. Mice have mild hyperglycaemia and hyperinsulinaemia and develop complex atherosclerotic lesions. In vivo treatment with the nuclear factor of activated T-cells blocker A-285222 for 4 weeks reduced atherosclerotic plaque area and degree of stenosis in the brachiocephalic artery of IGF-II/LDLR-/-ApoB100/100mice, as assessed non-invasively using ultrasound biomicroscopy prior and after treatment, and histologically after termination. Treatment had no impact on plaque composition (i.e. muscle, collagen, macrophages). The reduced plaque area could not be explained by effects of A-285222 on plasma glucose, insulin or lipids. Inhibition of nuclear factor of activated T-cells was associated with increased expression of atheroprotective NOX4 and of the anti-oxidant enzyme catalase in aortic vascular smooth muscle cells.CONCLUSION: Targeting the nuclear factor of activated T-cells signalling pathway may be an attractive approach for the treatment of diabetic macrovascular complications.
|
|
| 27. |
- Bränström, Robert, et al.
(författare)
-
Electrical short-circuit in β-cells from a patient with non-insulinoma pancreatogenous hypoglycemic syndrome (NIPHS) : a case report
- 2010
-
Ingår i: Journal of Medical Case Reports. - : Springer Science and Business Media LLC. - 1752-1947. ; 4:1, s. 315-
-
Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Non-insulinoma pancreatogenous hypoglycemic syndrome is a rare disorder among adults, and, to our knowledge, only about 40 cases have been reported in the literature. CASE PRESENTATION: The patient is a previously healthy 35-year-old Caucasian man. His symptoms began four years ago when he suddenly felt weakness in his legs and started sweating for unknown reasons. The symptoms worsened, and laboratory tests revealed hypoglycemia and hyperinsulinemia at the time of the symptoms. All diagnostics attempts using magnetic resonance imaging, computed tomography, and endoscopic ultrasound did not reveal any abnormalities. At this stage, surgical intervention was planned, and a distal 80% pancreatectomy was performed. The histopathologic and immunohistochemical investigations of the pancreas showed an increased number of islets of different sizes, more or less evenly distributed in the gland, but no insulinoma. Patch-clamp recordings from isolated pancreatic β-cells showed that, even at a low glucose concentration (3 mmol/L), the β-cell membrane was depolarized, and action potentials were seen. Surprisingly, in patch-clamp experiments, the addition of diazoxide had a marked effect on K-ATP channel activity and membrane potential, but no effect on insulin levels in vivo before surgery. CONCLUSION: This case report adds new information on the pathogenesis of non-insulinoma pancreatogenous hypoglycemic syndrome, as we performed an electrophysiologic characterization of isolated islet cells. We show, for the first time, that β-cells isolated from a non-insulinoma pancreatogenous hypoglycemic syndrome patient are constantly depolarized, even at low glucose levels, but display normal K-ATP channel physiology.
|
|
| 28. |
- Byström, P., et al.
(författare)
-
An explorative study on the clinical utility of baseline and serial serum tumour marker measurements in advanced upper gastrointestinal cancer
- 2010
-
Ingår i: Oncology Reports. - : Spandidos Publications. - 1021-335X .- 1791-2431. ; 24:6, s. 1645-1652
-
Tidskriftsartikel (refereegranskat)abstract
- The value of early tumour marker changes during palliative chemotherapy in patients with upper gastrointestinal adenocarcinoma (UGIA) is unclear. Seventy-three patients with advanced UGIA were randomised to receive 45 mg/m2 docetaxel or 180 mg/m2 irinotecan with 5-FU/leucovorin. After every 2nd course the patients were crossed over to the other regimen. Serum was sampled before start of chemotherapy and every 2nd week during 8 weeks for CEA, TPA, TPS, CA72-4, CA19-9 and CA242 measurements. Eighteen patients (25%) had partial response (PR) and 21 patients had stable disease for at least 4 months (SD4). All baseline marker levels, except CA72-4, correlated with time to progression and survival. Patients with normal levels, except CA72-4, also had more clinical responses (PR+SD4) than patients with elevated values. Tumour marker changes early during treatment provided modest predictive information for tumour response and survival. A model combining baseline level, the change and the interaction between them gave the best prediction of outcome, however, insignificantly better than baseline level for all markers except CA242. Baseline tumour marker levels provide prognostic information for patients with UGIA on palliative chemotherapy. Early changes generally failed to provide accurate information for tumour response and survival.
|
|
| 29. |
- Byström, Per, et al.
(författare)
-
Evaluation of predictive markers for patients with advanced colorectal cancer
- 2012
-
Ingår i: Acta Oncologica. - 0284-186X .- 1651-226X. ; 51:7, s. 849-859
-
Tidskriftsartikel (refereegranskat)abstract
- Background.To evaluate the predictive and prognostic value of serum and plasma tumor markers, in comparison with clinical and biomedical parameters for response rate (RR), progression-free survival (PFS) and overall survival (OS) among patients with metastatic colorectal cancer (mCRC) treated with combination chemotherapy.Material and methods.One-hundred and six patients with mCRC from three centers, part of a multicenter study, received irinotecan with the Nordic bolus 5-fluorouracil (5-FU) and folinic acid schedule (FLIRI) or the de Gramont schedule (Lv5FU2-IRI). Blood samples for CEA, CA19-9, TPA, TIMP-1, SAA, transthyretin and CRP were taken at baseline and after two, four and eight weeks of treatment. Tumor marker levels at baseline and longitudinally were compared with responses evaluated (CT/MRI) after two and four months of treatment. The correlations to RR, PFS and OS were evaluated with regression analyses.Results.A significant correlation to OS was seen for baseline levels of all markers. In multivariate analyses with clinical parameters, TPA, CRP, SAA and TIMP-1 provided independent information. The baseline values of CEA, TPA and TIMP-1 were also significantly correlated to PFS and TPA to RR. Changes during treatment, i.e. the slope gave with the exception of CA19-9 for OS less information about outcomes. The best correlation to response was seen for CEA, CA19-9 and TPA with AUC values of 0.78, 0.83 and 0.79, respectively, using a combined model based upon an interaction between the slope and the baseline value.Conclusions.Baseline tumor markers together with clinical parameters provide prognostic information about survival in patients with mCRC. The ability of the individual tumor markers to predict treatment response and PFS is limited. Changes in marker levels during the first two months of treatment are less informative of outcome.
|
|
| 30. |
- Christiansen, Line, et al.
(författare)
-
Associations Between Mobile Health Technology use and Self-rated Quality of Life : A Cross-sectional Study on Older Adults with Cognitive Impairment
- 2021
-
Ingår i: Gerontology and geriatric medicine. - : Sage Publications. - 2333-7214. ; 7, s. 1-8
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Quality of life (QoL) is affected even at early stages in older adults with cognitive impairment. The use of mobile health (mHealth) technology can offer support in daily life and improve the physical and mental health of older adults. However, a clarification of how mHealth technology can be used to support the QoL of older adults with cognitive impairment is needed. Objective: To investigate factors affecting mHealth technology use in relation to self-rated QoL among older adults with cognitive impairment. Methods: A cross-sectional research design was used to analyse mHealth technology use and QoL in 1,082 older participants. Baseline data were used from a multi-centered randomized controlled trial including QoL, measured by the Quality of Life in Alzheimer’s Disease (QoL-AD) Scale, as the outcome variable. Data were analyzed using logistic regression models. Results: Having moderately or high technical skills in using mHealth technology and using the internet via mHealth technology on a daily or weekly basis was associated with good to excellent QoL in older adults with cognitive impairment. Conclusions: The variation in technical skills and internet use among the participants can be interpreted as an obstacle for mHealth technology to support QoL. © The Author(s) 2021.
|
|
| 31. |
- Christiansen, Line, et al.
(författare)
-
Health-related quality of life and related factors among a sample of older people with cognitive impairment
- 2019
-
Ingår i: Nursing Open. - : Wiley-Blackwell Publishing Inc.. - 2054-1058. ; 6:3, s. 849-859
-
Tidskriftsartikel (refereegranskat)abstract
- Aim: This study aimed to identify factors affecting health-related quality of life (HRQoL) of older adults with cognitive impairment and to describe the association of these factors with different components of HRQoL. Design: A cross-sectional, descriptive research design was used. Methods: Data were collected from 247 individuals aged 60 years and older from a Swedish longitudinal cohort study. The Short-Form Health Survey-12 (SF-12) and EuroQol (EQ-5D) were used to assess HRQoL. The data were analysed using descriptive and comparative statistics. Results: The present study identified several factors that influenced HRQoL of older adults with cognitive impairment. The results of a multiple logistic regression analysis revealed that the following factors were associated with physical and mental HRQoL: dependency in activities of daily living (ADL), receiving informal care and feelings of loneliness and pain. © 2019 The Authors. Nursing Open published by John Wiley & Sons Ltd.
|
|
| 32. |
- Christiansen, Line, et al.
(författare)
-
Using Mobile Health and the Impact on Health-Related Quality of Life : Perceptions of Older Adults with Cognitive Impairment
- 2020
-
Ingår i: International Journal of Environmental Research and Public Health. - : MDPI. - 1661-7827 .- 1660-4601. ; 17:8
-
Tidskriftsartikel (refereegranskat)abstract
- Digital health technologies such as mobile health (mHealth) are considered to have the potential to support the needs of older adults with cognitive impairment. However, the evidence for improving health with the use of mHealth applications is of limited quality. Few studies have reported on the consequences of technology use concerning the older adults' quality of life. The purpose of this study was to describe perceptions of mHealth and its impact on health-related quality of life (HRQoL) among older adults with cognitive impairment. The study was conducted using a qualitative design with a phenomenographic approach. A total of 18 older participants with cognitive impairment were interviewed. The interviews were analyzed in order to apply phenomenography in a home-care context. The results showed variations in the older adults' perceptions that were comprised within three categories of description; Require technology literacy, Maintain social interaction, and Facilitate independent living. In conclusion, the development and design of mHealth technologies need to be tailored based on older adults´ needs in order to be understood and perceived as useful in a home-care context. For mHealth to support HRQoL, healthcare should be provided in a way that encourages various forms of communication and interaction.
|
|
| 33. |
- Christiansen, Line, 1986-
(författare)
-
Using Mobile Health Technology to Support Health-related Quality of Life : From the Perspective of Older Adults with Cognitive Impairment
- 2022
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The prevalence of cognitive impairment and illness increases with age. For older adults, maintaining or improving health-related quality of life (HRQoL) in the early stages of cognitive impairment is important to prevent consequences related to the progression of the condition. This thesis aims to identify factors affecting HRQoL and describe how mHealth technology can support HRQoL in older adults with cognitive impairment.Four studies were conducted using quantitative and qualitative approaches. A cross-sectional design was used to identify factors affecting older adults’ HRQoL (Study I) and investigate the relationship between mHealth technology use and self-rated quality of life (QoL) (Study III). A phenomenographical design was used to describe variations in older adults’ perceptions of mHealth technology and its impact on HRQoL (Study II). A prospective longitudinal design was used to examine older adults’ HRQoL changes over time (Study IV).Participants were selected from two longitudinal population studies using a purposive sampling strategy to include those aged 55 years and above with mild cognitive impairment or mild dementia. Data were obtained from questionnaires and semi-structured interviews. Data from the quantitative studies were analysed using statistical analysis, including descriptive and comparative analysis and regression analysis, while data from the qualitative study were examined using phenomenographical analysis in consecutive steps.The results showed that most older adults experienced good HRQoL with regard to both physical and mental health. The likelihood of having good-to-excellent QoL increased with age and was higher among males and those with higher education levels. Those diagnosed with dementia reported poorer HRQoL. Factors associated with low HRQoL included dependency in activities of daily living, receiving informal care and feelings of loneliness and pain. The use of mHealth technology was perceived as supportive in maintaining social interactions and facilitating independent living. The technology literacy levels among the study sample varied significantly. Those who reported having moderate-to-high technical skills and using the internet regularly via mHealth technology had higher odds of experiencing good-to-excellent QoL. No significant changes were observed in the older adults’ HRQoL over time in relation to the non-use and use of a customized mHealth application.The indicators of HRQoL are clinically relevant for the secondary prevention of dementia to help maintain good HRQoL in older adults with incipient cognitive impairment. The technology-related differences reflect the risk of digital exclusion. To improve preconditions for being digitally involved in society, societal initiatives that aim to empower the technology literacy level of older adults are needed.
|
|
| 34. |
|
|
| 35. |
- Danielsson, Henrik, et al.
(författare)
-
A Systematic Review of Longitudinal Trajectories of Mental Health Problems in Children with Neurodevelopmental Disabilities
- 2024
-
Ingår i: Journal of Developmental and Physical Disabilities. - : Springer. - 1056-263X .- 1573-3580. ; 36, s. 203-242
-
Forskningsöversikt (refereegranskat)abstract
- To review the longitudinal trajectories - and the factors influencing their development - of mental health problems in children with neurodevelopmental disabilities. Systematic review methods were employed. Searches of six databases used keywords and MeSH terms related to children with neurodevelopmental disabilities, mental health problems, and longitudinal research. After the removal of duplicates, reviewers independently screened records for inclusion, extracted data (outcomes and influencing factors), and evaluated the risk of bias. Findings were tabulated and synthesized using graphs and a narrative. Searches identified 94,662 unique records, from which 49 publications were included. The median publication year was 2015. Children with attention deficit hyperactivity disorder were the most commonly included population in retrieved studies. In almost 50% of studies, trajectories of mental health problems changed by < 10% between the first and last time point. Despite multiple studies reporting longitudinal trajectories of mental health problems, greater conceptual clarity and consideration of the measures included in research is needed, along with the inclusion of a more diverse range of populations of children with neurodevelopmental disabilities.
|
|
| 36. |
- Daskoulidou, Nikoleta, et al.
(författare)
-
High glucose enhances store-operated calcium entry by upregulating ORAI/STIM via calcineurin-NFAT signalling
- 2015
-
Ingår i: Journal of Molecular Medicine. - : Springer Science and Business Media LLC. - 1432-1440 .- 0946-2716. ; 93:5, s. 511-521
-
Tidskriftsartikel (refereegranskat)abstract
- ORAI and stromal interaction molecule (STIM) are storeoperated channel molecules that play essential roles in human physiology through a coupling mechanism of internal Ca2+ store to Ca2+ influx. However, the roles of ORAI and STIMin vascular endothelial cells under diabetic conditions remain unknown. Here, we investigated expression and signalling pathways of ORAI and STIM regulated by high glucose or hyperglycaemia using in vitro cell models, in vivo diabetic mice and tissues from patients. We found that ORAI1-3 and STIM1-2 were ubiquitously expressed in human vasculatures. Their expression was upregulated by chronic treatment with high glucose (HG, 25 mM D-glucose), which was accompanied by enhanced store-operated Ca2+ influx in vascular endothelial cells. The increased expression was also observed in the aortae from genetically modified Akita diabetic mice (C57BL/6-Ins2(Akita)/J) and streptozocin-induced diabetic mice, and aortae from diabetic patients. HG-induced upregulation of ORAI and STIM genes was prevented by the calcineurin inhibitor cyclosporin A and NFATc3 siRNA. Additionally, in vivo treatment with the nuclear factor of activated T cells (NFAT) inhibitor A-285222 prevented the gene upregulation in Akita mice. However, HG had no direct effects on ORAI1-3 currents and the channel activation process through cytosolic STIM1 movement in the cells coexpressing STIM1-EYFP/ORAIs. We concluded that upregulation of STIM/ORAI through Ca2+-calcineurin-NFAT pathway is a novel mechanism causing abnormal Ca2+ homeostasis and endothelial dysfunction under hyperglycaemia.
|
|
| 37. |
- Einarsdottir, Berglind Osk, 1979, et al.
(författare)
-
A patient-derived xenograft pre-clinical trial reveals treatment responses and a resistance mechanism to karonudib in metastatic melanoma
- 2018
-
Ingår i: Cell Death & Disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 9:8
-
Tidskriftsartikel (refereegranskat)abstract
- Karonudib (TH1579) is a novel compound that exerts anti-tumor activities and has recently entered phase I clinical testing. The aim of this study was to conduct a pre-clinical trial in patient-derived xenografts to identify the possible biomarkers of response or resistance that could guide inclusion of patients suffering from metastatic melanoma in phase II clinical trials. Patient-derived xenografts from 31 melanoma patients with metastatic disease were treated with karonudib or a vehicle for 18 days. Treatment responses were followed by measuring tumor sizes, and the models were categorized in the response groups. Tumors were harvested and processed for RNA sequencing and protein analysis. To investigate the effect of karonudib on T-cell-mediated anti-tumor activities, tumor-infiltrating T cells were injected in mice carrying autologous tumors and the mice treated with karonudib. We show that karonudib has heterogeneous anti-tumor effect on metastatic melanoma. Thus, based on the treatment responses, we could divide the 31 patient-derived xenografts in three treatment groups: progression group (32%), suppression group (42%), and regression group (26%). Furthermore, we show that karonudib has anti-tumor effect, irrespective of major melanoma driver mutations. Also, we identify high expression of ABCB1, which codes for p-gp pumps as a resistance biomarker. Finally, we show that karonudib treatment does not hamper T-cell-mediated anti-tumor responses. These findings can be used to guide future use of karonudib in clinical use with a potential approach as precision medicine.
|
|
| 38. |
- Eisele, Frederik, et al.
(författare)
-
An Hsp90 co-chaperone links protein folding and degradation and is part of a conserved protein quality control
- 2021
-
Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 35:13
-
Tidskriftsartikel (refereegranskat)abstract
- In this paper, we show that the essential Hsp90 co-chaperone Sgt1 is a member of a general protein quality control network that links folding and degradation through its participation in the degradation of misfolded proteins both in the cytosol and the endoplasmic reticulum (ER). Sgt1-dependent protein degradation acts in a parallel pathway to the ubiquitin ligase (E3) and ubiquitin chain elongase (E4), Hul5, and overproduction of Hul5 partly suppresses defects in cells with reduced Sgt1 activity. Upon proteostatic stress, Sgt1 accumulates transiently, in an Hsp90- and proteasome-dependent manner, with quality control sites (Q-bodies) of both yeast and human cells that co-localize with Vps13, a protein that creates organelle contact sites. Misfolding disease proteins, such as synphilin-1 involved in Parkinson's disease, are also sequestered to these compartments and require Sgt1 for their clearance. © 2021 The Author(s)
|
|
| 39. |
- Eivazzadeh, Shahryar, 1975-, et al.
(författare)
-
Ethical Challenges of Evaluating Health Information Systems
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- BackgroundEvaluating and researching health information systems are interventions of their kind and might lead to ethical complexities and challenges. Most of those challenges are inherited from the more general fields of research and evaluation, health studies, and information systems studies. Beyond those challenges, this field has its particular traits, regarding the involved stakeholders, required values or qualities, or the process which can raise field-specific or context-specific ethical challenges.ObjectivesThis paper reports and discusses some of the challenges of evaluating and researching health information systems by taking a systematic approach in finding, postulating, and analyzing them.MethodThrough a scoping review, a set of ethical challenges, regarding the evaluation and research of health information systems, were extracted. From the same set of articles, the acting entities, including stakeholders and artefacts, were identified. From a sample of seven cases of health information systems, a set of demanded impact qualities were extracted. From the literature, the evaluation stages were elicited. The acting entities, required qualities, and the evaluation stages were combined to create a three-dimensional space. The space contained the ethical challenges extracted from the scoping review and helped to postulate more items.ResultsThe final list of identified items contains 20 possible ethical challenges that can be caused or raised by evaluating or researching health information systems and technologies. The ethical challenges are discussed, based on their probable stage of occurrence. The three-dimensional space and the method of populating it is proposed as an effective method in similar cases of discovering ethical challenges.ConclusionEvaluating or researching health information systems can raise ethical challenges, that we have identified 20 of them in this article. All the challenges were discussed, such as the actual value of evaluation, breach of privacy, risks for safety, problems with usability and accessibility, conflict of interests, problems with the informed consent, and miscommunication. The novel approach for elicitation of the ethical challenges introduced in this article might be applied in other similar studies.
|
|
| 40. |
|
|
| 41. |
- Ellison, Stephen, et al.
(författare)
-
Attenuation of Experimental Atherosclerosis by Interleukin-19.
- 2013
-
Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1524-4636. ; 33:10, s. 2316-2324
-
Tidskriftsartikel (refereegranskat)abstract
- Interleukin-19 (IL-19) is a putative Th2, anti-inflammatory interleukin. Its expression and potential role in atherogenesis are unknown. IL-19 is not detected in normal artery and is expressed to a greater degree in plaque from symptomatic versus asymptomatic patients, suggesting a compensatory counter-regulatory function. We tested whether IL-19 could reduce atherosclerosis in susceptible mice and identified plausible mechanisms.
|
|
| 42. |
- Fagerberg, Linn, et al.
(författare)
-
Prediction of the human membrane proteome
- 2010
-
Ingår i: Proteomics. - : Wiley. - 1615-9853 .- 1615-9861. ; 10:6, s. 1141-1149
-
Tidskriftsartikel (refereegranskat)abstract
- Membrane proteins are key molecules in the cell, and are important targets for pharmaceutical drugs. Few three-dimensional structures of membrane proteins have been obtained, which makes computational prediction of membrane proteins crucial for studies of these key molecules. Here, seven membrane protein topology prediction methods based on different underlying algorithms, such as hidden Markov models, neural networks and support vector machines, have been used for analysis of the protein sequences from the 21 416 annotated genes in the human genome. The number of genes coding for a protein with predicted cc-helical transmembrane region(s) ranged from 5508 to 7651, depending on the method used. Based on a majority decision method, we estimate 5539 human genes to code for membrane proteins, corresponding to approximately 26% of the human protein-coding genes. The largest fraction of these proteins has only one predicted transmembrane region, but there are also many proteins with seven predicted transmembrane regions, including the G-protein coupled receptors. A visualization tool displaying the topologies suggested by the eight prediction methods, for all predicted membrane proteins, is available on the public Human Protein Atlas portal (www.proteinatlas.org).
|
|
| 43. |
- Garcia-Vaz, Eliana, et al.
(författare)
-
Inhibition of NFAT signaling restores microvascular endothelial function in diabetic mice
- 2020
-
Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 69:3, s. 424-435
-
Tidskriftsartikel (refereegranskat)abstract
- Central to the development of diabetic macro- and microvascular disease is endothelial dysfunction, which appears well before any clinical sign but, importantly, is potentially reversible. We previously demonstrated that hyperglycemia activates nuclear factor of activated T cells (NFAT) in conduit and medium-sized resistance arteries and that NFAT blockade abolishes diabetes-driven aggravation of atherosclerosis. In this study, we test whether NFAT plays a role in the development of endothelial dysfunction in diabetes. NFAT-dependent transcriptional activity was elevated in skin microvessels of diabetic Akita (Ins21/2) mice when compared with nondiabetic littermates. Treatment of diabetic mice with the NFAT blocker A-285222 reduced NFATc3 nuclear accumulation and NFAT-luciferase transcriptional activity in skin microvessels, resulting in improved microvascular function, as assessed by laser Doppler imaging and iontophoresis of acetylcholine and localized heating. This improvement was abolished by pretreatment with the nitric oxide (NO) synthase inhibitor L-NGnitro-L-arginine methyl ester, while iontophoresis of the NO donor sodium nitroprusside eliminated the observed differences. A-285222 treatment enhanced dermis endothelial NO synthase expression and plasma NO levels of diabetic mice. It also prevented induction of inflammatory cytokines interleukin-6 and osteopontin, lowered plasma endothelin-1 and blood pressure, and improved mouse survival without affecting blood glucose. In vivo inhibition of NFAT may represent a novel therapeutic modality to preserve endothelial function in diabetes.
|
|
| 44. |
|
|
| 45. |
|
|
| 46. |
- Janson, Staffan, 1945-, et al.
(författare)
-
Äldre i Värmland : Om hälsa, levnadsvanor och livssituation 2006
- 2007
-
Bok (övrigt vetenskapligt/konstnärligt)abstract
- Landstinget har i samarbete med Karlstads universitet gjort flera befolkningsundersökningar i Värmland och publicerat rapporter om både den vuxna befolkningens och barns hälsa, senast med rapporten Värmlänningarnas Liv och Hälsa 2004. Någon befolkningsstudie av de äldres hälsa och livsvillkor har dock inte gjorts tidigare.Efter tre års förarbeten och samråd mellan landstinget, Värmlands kommuner och flera institutioner vid Karlstads universitet genomfördes den föreliggande studien av de äldres hälsa under senhösten 2006, i form av en omfattande postenkät. Urvalet utgjordes av 2500 slumpmässigt uttagna kvinnor och män som var 80 år eller äldre. Svarsfrekvensen var 60 procent, vilket får betraktas som mycket bra med tanke på att cirka 15 procent i denna åldersgrupp lever i särskilda boenden.Studien avspeglar således hälsan och livsvillkoren för de äldre. Överlag visar det sig att de äldre mår bra och har stor kapacitet att fungera som aktiva samhällsmedborgare. Samtidigt är det många som har kroniska besvär, med värk, syn- och hörselnedsättning, inkontinensbesvär etc. Det föreligger också en klar social gradient, där särskilt äldre kvinnor med arbetarbakgrund har både mer sjukdom och större ekonomiska problem än de övriga.
|
|
| 47. |
- Jonasson, Kalle, et al.
(författare)
-
The 6th HUPO Antibody Initiative (HAI) workshop : Sharing data about affinity reagents and other recent developments
- 2010
-
Ingår i: Proteomics. - : Wiley. - 1615-9853 .- 1615-9861. ; 10:11, s. 2066-2068
-
Tidskriftsartikel (refereegranskat)abstract
- The Human Antibody Initiative (HAI) aims to promote and facilitate the use of antibodies for proteomics research. The 6th workshop for the HUPO Antibody Initiative (HAI) held in September 2009 was co-chaired by Michael Snyder and Mathias Uhlen and discussed several aspects of antibody production, their validation, and attempts to standardise this process, in particular, when subsequently described in the literature. An update on the progress of the Human Protein Atlas was also presented to the attendees.
|
|
| 48. |
- Jujić, Amra, et al.
(författare)
-
Glucose-dependent insulinotropic peptide and risk of cardiovascular events and mortality : a prospective study
- 2020
-
Ingår i: Diabetologia. - : Springer. - 0012-186X .- 1432-0428. ; 63:5, s. 1043-1054
-
Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis: Evidence that glucose-dependent insulinotropic peptide (GIP) and/or the GIP receptor (GIPR) are involved in cardiovascular biology is emerging. We hypothesised that GIP has untoward effects on cardiovascular biology, in contrast to glucagon-like peptide 1 (GLP-1), and therefore investigated the effects of GIP and GLP-1 concentrations on cardiovascular disease (CVD) and mortality risk.Methods: GIP concentrations were successfully measured during OGTTs in two independent populations (Malmo Diet Cancer-Cardiovascular Cohort [MDC-CC] and Prevalence, Prediction and Prevention of Diabetes in Botnia [PPP-Botnia]) in a total of 8044 subjects. GLP-1 (n = 3625) was measured in MDC-CC. The incidence of CVD and mortality was assessed via national/regional registers or questionnaires. Further, a two-sample Mendelian randomisation (2SMR) analysis between the GIP pathway and outcomes (coronary artery disease [CAD] and myocardial infarction) was carried out using a GIP-associated genetic variant, rs1800437, as instrumental variable. An additional reverse 2SMR was performed with CAD as exposure variable and GIP as outcome variable, with the instrumental variables constructed from 114 known genetic risk variants for CAD.Results: In meta-analyses, higher fasting levels of GIP were associated with risk of higher total mortality (HR[95% CI] = 1.22 [1.11, 1.35]; p = 4.5 x 10(-5)) and death from CVD (HR[95% CI] 1.30 [1.11, 1.52]; p = 0.001). In accordance, 2SMR analysis revealed that increasing GIP concentrations were associated with CAD and myocardial infarction, and an additional reverse 2SMR revealed no significant effect of CAD on GIP levels, thus confirming a possible effect solely of GIP on CAD.Conclusions/interpretation: In two prospective, community-based studies, elevated levels of GIP were associated with greater risk of all-cause and cardiovascular mortality within 5-9 years of follow-up, whereas GLP-1 levels were not associated with excess risk. Further studies are warranted to determine the cardiovascular effects of GIP per se.
|
|
| 49. |
- Keogan, Katharine, et al.
(författare)
-
Global phenological insensitivity to shifting ocean temperatures among seabirds
- 2018
-
Ingår i: Nature Climate Change. - : Springer Science and Business Media LLC. - 1758-678X .- 1758-6798. ; 8:4, s. 313-318
-
Tidskriftsartikel (refereegranskat)abstract
- Reproductive timing in many taxa plays a key role in determining breeding productivity(1), and is often sensitive to climatic conditions(2). Current climate change may alter the timing of breeding at different rates across trophic levels, potentially resulting in temporal mismatch between the resource requirements of predators and their prey(3). This is of particular concern for higher-trophic-level organisms, whose longer generation times confer a lower rate of evolutionary rescue than primary producers or consumers(4). However, the disconnection between studies of ecological change in marine systems makes it difficult to detect general changes in the timing of reproduction(5). Here, we use a comprehensive meta-analysis of 209 phenological time series from 145 breeding populations to show that, on average, seabird populations worldwide have not adjusted their breeding seasons over time (-0.020 days yr(-1)) or in response to sea surface temperature (SST) (-0.272 days degrees C-1) between 1952 and 2015. However, marked between-year variation in timing observed in resident species and some Pelecaniformes and Suliformes (cormorants, gannets and boobies) may imply that timing, in some cases, is affected by unmeasured environmental conditions. This limited temperature-mediated plasticity of reproductive timing in seabirds potentially makes these top predators highly vulnerable to future mismatch with lower-trophic-level resources(2).
|
|
| 50. |
- Keuenhof, Katharina, 1994, et al.
(författare)
-
Large organellar changes occur during mild heat shock in yeast
- 2021
-
Ingår i: Journal of cell science. - : The Company of Biologists. - 1477-9137 .- 0021-9533. ; 135:5
-
Tidskriftsartikel (refereegranskat)abstract
- When the temperature is increased, the heat shock response is activated to protect the cellular environment. The transcriptomics and proteomics of this process are intensively studied, while information about how the cell responds structurally to heat stress is mostly lacking. Here, Saccharomyces cerevisiae were subjected to a mild continuous heat shock (38°C) and intermittently cryo-immobilized for electron microscopy. Through measuring changes in all distinguishable organelle numbers, sizes, and morphologies in over 2100 electron micrographs a major restructuring of the cell's internal architecture during the progressive heat shock was revealed. The cell grew larger but most organelles within it expanded even more, shrinking the volume of the cytoplasm. Organelles responded to heat shock at different times, both in terms of size and number, and adaptations of certain organelles' morphology (such as the vacuole), were observed. Multivesicular bodies grew to almost 170% in size, indicating a previously unknown involvement in the heat shock response. A previously undescribed electron translucent structure accumulated close to the plasma membrane. This all-encompassing approach provides a detailed chronological progression of organelle adaptation throughout the cellular heat-stress response.
|
|
