| 1. |
- Gomes, CPC, et al.
(författare)
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Catalyzing Transcriptomics Research in Cardiovascular Disease: The CardioRNA COST Action CA17129
- 2019
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Ingår i: Non-coding RNA. - : MDPI AG. - 2311-553X. ; 5:2
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Tidskriftsartikel (refereegranskat)abstract
- Cardiovascular disease (CVD) remains the leading cause of death worldwide and, despite continuous advances, better diagnostic and prognostic tools, as well as therapy, are needed. The human transcriptome, which is the set of all RNA produced in a cell, is much more complex than previously thought and the lack of dialogue between researchers and industrials and consensus on guidelines to generate data make it harder to compare and reproduce results. This European Cooperation in Science and Technology (COST) Action aims to accelerate the understanding of transcriptomics in CVD and further the translation of experimental data into usable applications to improve personalized medicine in this field by creating an interdisciplinary network. It aims to provide opportunities for collaboration between stakeholders from complementary backgrounds, allowing the functions of different RNAs and their interactions to be more rapidly deciphered in the cardiovascular context for translation into the clinic, thus fostering personalized medicine and meeting a current public health challenge. Thus, this Action will advance studies on cardiovascular transcriptomics, generate innovative projects, and consolidate the leadership of European research groups in the field.COST (European Cooperation in Science and Technology) is a funding organization for research and innovation networks (www.cost.eu).
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| 2. |
- Wernly, B, et al.
(författare)
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Anti-CD3 Antibody Treatment Reduces Scar Formation in a Rat Model of Myocardial Infarction
- 2020
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Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 9:2
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Antibody treatment with anti-thymocyte globulin (ATG) has been shown to be cardioprotective. We aimed to evaluate which single anti-T-cell epitope antibody alters chemokine expression at a level similar to ATG and identified CD3, which is a T-cell co-receptor mediating T-cell activation. Based on these results, the effects of anti-CD3 antibody treatment on angiogenesis and cardioprotection were tested in vitro and in vivo. Methods: Concentrations of IL-8 and MCP-1 in supernatants of human peripheral blood mononuclear cell (PBMC) cultures following distinct antibody treatments were evaluated by Enzyme-linked Immunosorbent Assay (ELISA). In vivo, anti-CD3 antibodies or vehicle were injected intravenously in rats subjected to acute myocardial infarction (AMI). Chemotaxis and angiogenesis were evaluated using tube and migration assays. Intracellular pathways were assessed using Western blot. Extracellular vesicles (EVs) were quantitatively evaluated using fluorescence-activated cell scanning, exoELISA, and nanoparticle tracking analysis. Also, microRNA profiles were determined by next-generation sequencing. Results: Only PBMC stimulation with anti-CD3 antibody led to IL-8 and MCP-1 changes in secretion, similar to ATG. In a rat model of AMI, systemic treatment with an anti-CD3 antibody markedly reduced infarct scar size (27.8% (Inter-quartile range; IQR 16.2–34.9) vs. 12.6% (IQR 8.3–27.2); p < 0.01). The secretomes of anti-CD3 treated PBMC neither induced cardioprotective pathways in cardiomyocytes nor pro-angiogenic mechanisms in human umbilical vein endothelial cell (HUVECs) in vitro. While EVs quantities remained unchanged, PBMC incubation with an anti-CD3 antibody led to alterations in EVs miRNA expression. Conclusion: Treatment with an anti-CD3 antibody led to decreased scar size in a rat model of AMI. Whereas cardioprotective and pro-angiogenetic pathways were unaltered by anti-CD3 treatment, qualitative changes in the EVs miRNA expression could be observed, which might be causal for the observed cardioprotective phenotype. We provide evidence that EVs are a potential cardioprotective treatment target. Our findings will also provide the basis for a more detailed analysis of putatively relevant miRNA candidates.
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| 3. |
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| 4. |
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| 5. |
- Jakic, B, et al.
(författare)
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The Effects of Endurance Exercise and Diet on Atherosclerosis in Young and Aged ApoE-/- and Wild-Type Mice
- 2019
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Ingår i: Gerontology. - : S. Karger AG. - 1423-0003 .- 0304-324X. ; 65:1, s. 45-56
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Tidskriftsartikel (refereegranskat)abstract
- <b><i>Background:</i></b> Atherosclerosis is the leading cause of death worldwide. The disease development is by and large driven by old age and lifestyle factors, such as diet, physical activity, and smoking. In the present study, we have investigated the effect of exercise and diet on the development of atherosclerosis in young and aged mice. <b><i>Objective:</i></b> This study aimed at comparing multiple age-dependent factors that may influence atherosclerosis in a transgenic mouse model. <b><i>Methods:</i></b> Young (14 weeks) and aged (49–52 weeks) C57BL/6 wild-type (WT) and atherosclerosis-prone ApoE<sup>–/–</sup> mice were subjected to physical endurance exercise on a treadmill, with or without a high-fat diet. Five weeks later, the frequencies of regulatory T cells (T<sub>REGs</sub>) in lymph nodes were assessed by flow cytometry, plasmatic cytokines (interleukin [IL]-1β, IL-6, IL-10, IL-17, interferon-γ, tumor necrosis factor-α, and transforming growth factor [TGF]-β<sub>1</sub>) levels were determined by Luminex assay. Lipids (cholesterol and triglycerides) and anti-heat shock protein 60 (HSP60) autoantibodies were measured by ELISA. Aortic lesion sizes were assessed by <i>en face</i> imaging. Microarray analysis and qPCR of skeletal muscle gene expression were also performed. <b><i>Results:</i></b> Exercise leads to a reduction of aortic lesions in young ApoE<sup>–/–</sup> and aged WT mice independent of diet. In most groups, this reduction was followed by an increased proportion of T<sub>REGs</sub> and TGF-β<sub>1</sub> levels. Moreover, gene expression analysis showed that exercise seems to affect the AMPK signaling pathway. In particular, PGC-1α<sub>1</sub> mRNA was induced in aged WT mice, whereas it was reduced in young ApoE<sup>–/–</sup> mice. In addition, GSEA analysis showed a marked reduction in the insulin signaling pathway in aged ApoE<sup>–/–</sup> mice. <b><i>Conclusion:</i></b> Practicing endurance exercise seems to be enough for reducing early aortic lesion formation, independent of diet. However, this was only true in mice with smaller aortic lesions, since mice with large, advanced, complicated atherosclerotic plaques did not show any reduction in lesion size with exercise training.
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| 6. |
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| 7. |
- Duchon, Tomas, et al.
(författare)
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Establishing structure-sensitivity of ceria reducibility : real-time observations of surface hydrogen interactions
- 2020
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Ingår i: Journal of Materials Chemistry A. - : ROYAL SOC CHEMISTRY. - 2050-7488 .- 2050-7496. ; 8:11, s. 5501-5507
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Tidskriftsartikel (refereegranskat)abstract
- The first Layer of atoms on an oxide cataLyst provides the first sites for adsorption of reactants and the Last sites before products or oxygen are desorbed. We employ a unique combination of morphological, structural, and chemical analyses of a model ceria cataLyst with different surface terminations under an H2 environment to unequivocally establish the effect of the Last Layer of atoms on surface reduction. (111) and (100) terminated epitaxiaL isLands of ceria are simultaneously studied in situ allowing for a direct investigation of the structure reducibility relationship under identical conditions. Kinetic rate constants of Ce4+ to Ce3+ transformation and equilibrium concentrations are extracted for both surface terminations. Unlike the kinetic rate constants, which are practically the same for both types of isLands, more pronounced oxygen release, and overall higher reducibility were observed for (100) isLands compared to (111) ones. The findings are in agreement with coordination -Limited oxygen vacancy formation energies calculated by density functional theory. The results point out the important aspect of surface terminations in redox processes, with particular impact on the catalytic reactions of a variety of catalysts.
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| 8. |
- Haschka, J, et al.
(författare)
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Identification of circulating microRNA patterns in patients in psoriasis and psoriatic arthritis
- 2023
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Ingår i: Rheumatology (Oxford, England). - : Oxford University Press (OUP). - 1462-0332 .- 1462-0324. ; 62:10, s. 3448-3458
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Tidskriftsartikel (refereegranskat)abstract
- ObjectivemiRNAs are small non-coding RNAs that control gene expression. Specific intra- and extracellular miRNA signatures have been identified in various diseases. Whether certain miRNA signatures are associated with psoriasis (PsO) and PsA is currently unknown. We aimed to search for circulating miRNA signatures associated with PsO and PsA patients.MethodsExpression of miRNAs was analysed by reverse transcription quantitative real-time PCR (RT-qPCR) in the serum of PsA, PsO patients and healthy controls. Demographic and disease-specific characteristics and imaging data from hand MRI were recorded. In the discovery phase, 192 miRNA assays were analysed in 48 samples (PsA, PsO, controls: each N = 16). For validation, 17 selected miRNAs were measured in the total population.ResultsA total of 141 patients and controls were analysed (51 PsA, 40 PsO, 50 controls). In the discovery phase 51 miRNAs in PsO and 64 miRNAs in PsA were down- or upregulated compared with controls, with 33 miRNAs being changed in both (adj. P < 0.05). The 17 top candidates from discovery were assessed in the validation phase, 9 of them discriminated PsA and PsO from controls [area under the curve (AUC) ≥0.70, all P < 0.05]. Four miRNAs (miR-19b-3p, miR-21-5p, miR-92a-3p and let-7b-5p) were significantly differently regulated between PsO and PsA. A combination of these miRNAs increased the AUC to 0.92 in multivariate regression model to discriminate PsO and PsA.ConclusionmiRNA signatures in PsA and PsO patients differ from controls. Nine miRNAs were differentially regulated in PsA and PsO patients, five of them previously reported to be involved in bone and cartilage metabolism, indicating an intimate association of psoriatic inflammation and bone/cartilage changes.
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| 11. |
- Messner, M, et al.
(författare)
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Small molecule inhibitors of the mitochondrial ClpXP protease possess cytostatic potential and re-sensitize chemo-resistant cancers
- 2021
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1, s. 11185-
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Tidskriftsartikel (refereegranskat)abstract
- The human mitochondrial ClpXP protease complex (HsClpXP) has recently attracted major attention as a target for novel anti-cancer therapies. Despite its important role in disease progression, the cellular role of HsClpXP is poorly characterized and only few small molecule inhibitors have been reported. Herein, we screened previously established S. aureus ClpXP inhibitors against the related human protease complex and identified potent small molecules against human ClpXP. The hit compounds showed anti-cancer activity in a panoply of leukemia, liver and breast cancer cell lines. We found that the bacterial ClpXP inhibitor 334 impairs the electron transport chain (ETC), enhances the production of mitochondrial reactive oxygen species (mtROS) and thereby promotes protein carbonylation, aberrant proteostasis and apoptosis. In addition, 334 induces cell death in re-isolated patient-derived xenograft (PDX) leukemia cells, potentiates the effect of DNA-damaging cytostatics and re-sensitizes resistant cancers to chemotherapy in non-apoptotic doses.
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| 12. |
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| 13. |
- Butt, Linus, et al.
(författare)
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A molecular mechanism explaining albuminuria in kidney disease
- 2020
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Ingår i: Nature Metabolism. - : Springer Nature. - 2522-5812. ; 2:5, s. 461-474
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Tidskriftsartikel (refereegranskat)abstract
- Mammalian kidneys constantly filter large amounts of liquid, with almost complete retention of albumin and other macromolecules in the plasma. Breakdown of the three-layered renal filtration barrier results in loss of albumin into urine (albuminuria) across the wall of small renal capillaries, and is a leading cause of chronic kidney disease. However, exactly how the renal filter works and why its permeability is altered in kidney diseases is poorly understood. Here we show that the permeability of the renal filter is modulated through compression of the capillary wall. We collect morphometric data prior to and after onset of albuminuria in a mouse model equivalent to a human genetic disease affecting the renal filtration barrier. Combining quantitative analyses with mathematical modelling, we demonstrate that morphological alterations of the glomerular filtration barrier lead to reduced compressive forces that counteract filtration pressure, thereby resulting in capillary dilatation, and ultimately albuminuria. Our results reveal distinct functions of the different layers of the filtration barrier and expand the molecular understanding of defective renal filtration in chronic kidney disease.
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| 14. |
- Cassel, Claes M., et al.
(författare)
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On measurement of intangible assets: A study of robustness of partial least squares
- 2000
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Ingår i: Total quality management. - : Taylor & Francis Group. - 1360-0613 .- 0954-4127. ; 11:7, s. 897-907
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Tidskriftsartikel (refereegranskat)abstract
- The customer asset is an important intangible. Its value depends, for example, on the customer satisfaction level. Thus, it is important to monitor that level, and to identify cost-efficient actions to improve it. The European Customer Satisfaction Index (ECSI) system is based on a structural model for such monitoring, a model that is estimated by partial least squares (PLS). The robustness of PLS applied on an ESCI-like measurement model is studied in the present paper. Monte Carlo simulations show that PLS is reasonably robust against multicollinearity, skew response distributions and various types of model misspecifications. This is true, in particular, when estimating the customer satisfaction index.
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| 15. |
- Hackl, Peter, et al.
(författare)
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Structural analysis and measurement of customer perceptions, assuming measurement and specifications errors
- 2001
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Ingår i: Total quality management. - : Taylor & Francis Ltd. - 1360-0613 .- 0954-4127. ; 12:7-8, s. 873-881
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Tidskriftsartikel (refereegranskat)abstract
- In previous research (e.g. Cassel et al., 1999,Journal of Applied Statistics26, pp. 435-446; Cassel et al., 2000, Total Quality Management, 11, pp. 897-907) the bias and precision effects, for various specification problems, on the structural analysis and measurement of customer perceptions have been studied. In this paper the combined effects of some of the most significant problems, misspecifications and skew response distributions, and certain types of measurement errors, are studied. The measurement errors considered reflect the bias due to the inertia of respondents in adapting to changes. In the situation of repeated measurements, the later response tends to be biased towards the former response. This effect can be modelled by implementing certain change filtering assumptions. A simulation study using the European Performance Satisfaction Index (EPSI) structure demonstrates that the EPSI measurement methodology using partial least squares is very robust with respect to the problems introduced in the simulations. This is true, in particular, when estimating the inner structure of the model and when estimating the outer measurement relations of the model. The estimated values of the latent variables (such as the customer satisfaction index) are affected in an expected way.
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| 16. |
- Hoffmann, Mikael, et al.
(författare)
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Guiding principles for the use of knowledge bases and real-world data in clinical decision support systems : report by an international expert workshop at Karolinska Institutet
- 2020
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Ingår i: Expert Review of Clinical Pharmacology. - : Taylor & Francis. - 1751-2433 .- 1751-2441. ; 13:9, s. 925-934
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Technical and logical breakthroughs have provided new opportunities in medicine to use knowledge bases and large-scale clinical data (real-world) at point-of-care as part of a learning healthcare system to diminish the knowledge-practice gap. Areas covered The article is based on presentations, discussions and recommendations from an international scientific workshop. Value, research needs and funding avenues of knowledge bases and access to real-world data as well as transparency and incorporation of patient perspectives are discussed. Expert opinion Evidence-based, publicly funded, well-structured and curated knowledge bases are of global importance. They ought to be considered as a public responsibility requiring transparency and handling of conflicts of interest. Information has to be made accessible for clinical decision support systems (CDSS) for healthcare staff and patients. Access to rich and real-world data is essential for a learning health care ecosystem and can be augmented by data on patient-reported outcomes and preferences. This field can progress by the establishment of an international policy group for developing a best practice guideline on the development, maintenance, governance, evaluation principles and financing of open-source knowledge bases and handling of real-world data.
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| 17. |
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| 18. |
- Marazioti, Antonia, et al.
(författare)
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KRAS signaling in malignant pleural mesothelioma
- 2022
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Ingår i: EMBO Molecular Medicine. - : EMBO. - 1757-4684 .- 1757-4676. ; 14:2
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Tidskriftsartikel (refereegranskat)abstract
- Malignant pleural mesothelioma (MPM) arises from mesothelial cells lining the pleural cavity of asbestos-exposed individuals and rapidly leads to death. MPM harbors loss-of-function mutations in BAP1, NF2, CDKN2A, and TP53, but isolated deletion of these genes alone in mice does not cause MPM and mouse models of the disease are sparse. Here, we show that a proportion of human MPM harbor point mutations, copy number alterations, and overexpression of KRAS with or without TP53 changes. These are likely pathogenic, since ectopic expression of mutant KRASG12D in the pleural mesothelium of conditional mice causes epithelioid MPM and cooperates with TP53 deletion to drive a more aggressive disease form with biphasic features and pleural effusions. Murine MPM cell lines derived from these tumors carry the initiating KRASG12D lesions, secondary Bap1 alterations, and human MPM-like gene expression profiles. Moreover, they are transplantable and actionable by KRAS inhibition. Our results indicate that KRAS alterations alone or in accomplice with TP53 alterations likely play an important and underestimated role in a proportion of patients with MPM, which warrants further exploration.
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| 19. |
- Martin, Michael, et al.
(författare)
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Assessing the aggregated environmental benefits from by-product and utility synergies in the Swedish biofuel industry
- 2020
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Ingår i: Biofuels. - : Taylor & Francis. - 1759-7269 .- 1759-7277. ; 11:6, s. 683-698
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Tidskriftsartikel (refereegranskat)abstract
- The production of biofuels in Sweden has increased significantly in the past years in order to reduce fossil fuel dependence and mitigate climate impacts. Nonetheless, current methodological guidelines for assessing the GHG savings from the use of biofuels do not fully account for benefits from by-products and other utilities (e.g. waste heat and electricity) from biofuel production. This study therefore reviews the aggregated environmental performance of these multi-functional biofuel systems by assessing impacts and benefits from relevant production processes in Sweden in order to improve the decision base for biofuel producers and policymakers in the transition to a bio-based and circular economy. This was done by (1) conducting a mapping of the Swedish biofuel production portfolio, (2) developing future production scenarios, and (3) application of life cycle assessment methodology to assess the environmental performance of the production processes. Special focus was provided to review the potential benefits from replacing conventional products and services with by-products and utilities. The results provide evidence that failure to account for non-fuel-related benefits from biofuel production leads to an underestimation of the contribution of biofuels to reduce greenhouse gas emissions and other environmental impacts when replacing fossil fuels, showing the importance of their multi-functionality.
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| 20. |
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| 21. |
- Suarez, Carolina, et al.
(författare)
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Novel and unusual genes for nitrogen and metal cycling in Planctomycetota- and KSB1-affiliated metagenome-assembled genomes reconstructed from a marine subsea tunnel
- 2023
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Ingår i: FEMS microbiology letters. - 0378-1097 .- 1574-6968. ; 370
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Tidskriftsartikel (refereegranskat)abstract
- The Oslofjord subsea road tunnel is a unique environment in which the typically anoxic marine deep subsurface is exposed to oxygen. Concrete biodeterioration and steel corrosion in the tunnel have been linked to the growth of iron- and manganese-oxidizing biofilms in areas of saline water seepage. Surprisingly, previous 16S rRNA gene surveys of biofilm samples revealed microbial communities dominated by sequences affiliated with nitrogen-cycling microorganisms. This study aimed to identify microbial genomes with metabolic potential for novel nitrogen- and metal-cycling reactions, representing biofilm microorganisms that could link these cycles and play a role in concrete biodeterioration. We reconstructed 33 abundant, novel metagenome-assembled genomes (MAGs) affiliated with the phylum Planctomycetota and the candidate phylum KSB1. We identified novel and unusual genes and gene clusters in these MAGs related to anaerobic ammonium oxidation, nitrite oxidation, and other nitrogen-cycling reactions. Additionally, 26 of 33 MAGs also had the potential for iron, manganese, and arsenite cycling, suggesting that bacteria represented by these genomes might couple these reactions. Our results expand the diversity of microorganisms putatively involved in nitrogen and metal cycling, and contribute to our understanding of potential biofilm impacts on built infrastructure.
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