| 1. |
- Fagerberg, Linn, et al.
(författare)
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Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics
- 2014
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Ingår i: Molecular & Cellular Proteomics. - 1535-9476 .- 1535-9484. ; 13:2, s. 397-406
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Tidskriftsartikel (refereegranskat)abstract
- Global classification of the human proteins with regards to spatial expression patterns across organs and tissues is important for studies of human biology and disease. Here, we used a quantitative transcriptomics analysis (RNA-Seq) to classify the tissue-specific expression of genes across a representative set of all major human organs and tissues and combined this analysis with antibody- based profiling of the same tissues. To present the data, we launch a new version of the Human Protein Atlas that integrates RNA and protein expression data corresponding to 80% of the human protein-coding genes with access to the primary data for both the RNA and the protein analysis on an individual gene level. We present a classification of all human protein-coding genes with regards to tissue-specificity and spatial expression pattern. The integrative human expression map can be used as a starting point to explore the molecular constituents of the human body.
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| 2. |
- Fagerberg, Linn, et al.
(författare)
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Contribution of antibody-based protein profiling to the human chromosome-centric proteome project (C-HPP)
- 2013
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Ingår i: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 12:6, s. 2439-2448
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Tidskriftsartikel (refereegranskat)abstract
- A gene-centric Human Proteome Project has been proposed to characterize the human protein-coding genes in a chromosome-centered manner to understand human biology and disease. Here, we report on the protein evidence for all genes predicted from the genome sequence based on manual annotation from literature (UniProt), antibody-based profiling in cells, tissues and organs and analysis of the transcript profiles using next generation sequencing in human cell lines of different origins. We estimate that there is good evidence for protein existence for 69% (n = 13985) of the human protein-coding genes, while 23% have only evidence on the RNA level and 7% still lack experimental evidence. Analysis of the expression patterns shows few tissue-specific proteins and approximately half of the genes expressed in all the analyzed cells. The status for each gene with regards to protein evidence is visualized in a chromosome-centric manner as part of a new version of the Human Protein Atlas (www.proteinatlas.org).
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| 3. |
- Forsberg, Kalle, et al.
(författare)
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A Systematic Review Of Erythropoietin In Experimental Stroke
- 2009
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Ingår i: Stroke. - 0039-2499. ; 40:4
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Konferensbidrag (refereegranskat)abstract
- Introduction: Erythropoietin (EPO), a hematopoietic growth factor, has promise as a neuroprotectant in animal models of ischemic stroke. EPO is thought not only to protect neurons from cell death, but also is hypothesized to promote regeneration post stroke. Here we report a systematic review and meta-analysis of the published animal data characterizing the efficacy of EPO. Methods We conducted a systematic review and random effects weighted mean difference meta-analysis only including studies describing the efficacy of EPO in models of focal cerebral ischemia. Primary outcomes were infarct size and neurobehavioral score. A stratified analysis to identify the impact of elements of study quality and design was also conducted. Results Only 11 of 943 studies met our inclusion criteria. Infarct size was reported in 15 experiments using 191 animals. Neurobehavioral score was reported in 16 experiments using 287 animals. EPO improved infarct size by 30.5% (95%Cl 19.3%-41.7%) and neurobehavioral score by 37.4% (31.2– 43.7%). For infarct size, EPO was least effective in thrombotic models of ischemia, (16% versus to 44.8% and 24% in permanent and transient models of ischemia respectively, X2 =1.47 x 10–04). Using a scoring system derived from the STAIR criteria,study quality was modest with a median score of 4 out of 11 for both outcomes. Studies that randomized to treatment group reported smaller infarct sizes compared to those that did not (18.0% versus 44.8%, n=113 versus 78 animals, X2 = 3.4 x 10–05). Studies that blinded assessment of outcome also showed a smaller improvement in neurobehavioral score (31.1% versus 41.6%, n=107 versus 167, X2 = 8.9 x 10–4). Only 11.7% of the animals in the total dataset had a co-morbidity common to human stroke (hypertension) and this co-morbidity was only reported for neurobehavioral comparisons, not for infarct size. Blinded induction of ischemia was reported in 2 experiments (21.5% of animals) measuring infarct volume. Conclusions: Aggregation of the animal data for EPO in ischemic stroke indicates mean effect sizes of 30.5% and 37.4% for infarct volume and neurobehavioral score respectively. However, when the impact of common sources of bias are considered these effect sizes fall suggesting we are overestimating its potential benefit. As common human co-morbidities may reduce therapeutic efficacy, broader testing to delineate the range of circumstances in which EPO works would be beneficial before clinical trialing.
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| 4. |
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| 5. |
- Grapotte, M, et al.
(författare)
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Discovery of widespread transcription initiation at microsatellites predictable by sequence-based deep neural network
- 2021
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1, s. 3297-
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Tidskriftsartikel (refereegranskat)abstract
- Using the Cap Analysis of Gene Expression (CAGE) technology, the FANTOM5 consortium provided one of the most comprehensive maps of transcription start sites (TSSs) in several species. Strikingly, ~72% of them could not be assigned to a specific gene and initiate at unconventional regions, outside promoters or enhancers. Here, we probe these unassigned TSSs and show that, in all species studied, a significant fraction of CAGE peaks initiate at microsatellites, also called short tandem repeats (STRs). To confirm this transcription, we develop Cap Trap RNA-seq, a technology which combines cap trapping and long read MinION sequencing. We train sequence-based deep learning models able to predict CAGE signal at STRs with high accuracy. These models unveil the importance of STR surrounding sequences not only to distinguish STR classes, but also to predict the level of transcription initiation. Importantly, genetic variants linked to human diseases are preferentially found at STRs with high transcription initiation level, supporting the biological and clinical relevance of transcription initiation at STRs. Together, our results extend the repertoire of non-coding transcription associated with DNA tandem repeats and complexify STR polymorphism.
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| 6. |
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| 7. |
- Jerndal, Mikael, et al.
(författare)
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A systematic review and meta-analysis of erythropoietin in experimental stroke.
- 2010
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Ingår i: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 1559-7016. ; 30:5, s. 961-8
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Forskningsöversikt (refereegranskat)abstract
- Erythropoietin (EPO) has shown promise as a neuroprotectant in animal models of ischemic stroke. EPO is thought not only to protect neurons from cell death, but also to promote regeneration after stroke. Here, we report a systematic review and meta-analysis of the efficacy of EPO in animal models of focal cerebral ischemia. Primary outcomes were infarct size and neurobehavioral outcome. Nineteen studies involving 346 animals for infarct size and 425 animals for neurobehavioral outcome met our inclusion criteria. Erythropoietin improved infarct size by 30.0% (95% CI: 21.3 to 38.8) and neurobehavioral outcome by 39.8% (33.7 to 45.9). Studies that randomized to treatment group or that blinded assessment of outcome showed lower efficacy. Erythropoietin was tested in animals with hypertension in no studies reporting infarct size and in 7.5% of the animals reporting neurobehavioral outcome. These findings show efficacy for EPO in experimental stroke, but when the impact of common sources of bias are considered, this efficacy falls, suggesting we may be overestimating its potential benefit. As common human co-morbidities may reduce therapeutic efficacy, broader testing to delineate the range of circumstances in which EPO works best would be beneficial.
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| 8. |
- Jerndal, Mikael, et al.
(författare)
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Systematic review and meta-analysis of the efficacy of basic fibroblast growth factor in experimental stroke
- 2009
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Ingår i: European Stroke conference, Stockholm, Sweden May.
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Konferensbidrag (refereegranskat)abstract
- Background Basic fibroblast growth factor (bFGF) has been shown to have a potent trophic effect on brain neurons, glia and endothelial cells in both in vitro and in vivo studies and is a candidate drug for treatment of ischemic stroke. Any decision to proceed to clinical trials should be based on an unbiased assessment of all available animal data. This assessment should evaluate the efficacy of the drug as well as the characteristics and limits to that efficacy. We use a systematic approach to assess the evidence for protective effects of bFGF in animal models of focal cerebral ischemia. Methods We have performed a systematic review and meta-analysis of studies describing the efficacy of bFGF in animal models of focal cerebral ischemia where outcome was measured as infarct size or neurological score. Study quality was scored against a quality checklist and certain study characteristics were looked at individually. A random effects model was used and the significance level was set to p<0.001 to allow for multiple comparisons. Results Systematic review identified 21 publications of which 20 report infarct size from 520 animals and 10 report neurological score from 223 animals. bFGF reduced infarct size by 25.7% (95% confidence interval 21.7-29.8%) and improved neurological score by 28.1% (23.0-33.2%). Efficacy was higher with intra-arterial administration which showed a reduction of infarct size by 57.6% (33.8-81.3%, p=9.8E-07). Overall study quality was moderate with a median quality score of 6/11, interquartile range 5-7. Studies that performed blinded assessment of outcome showed lesser efficacy on infarct size reduction than those who did not blind, 20.2% (12.2-28.1) compared to 29.4% (26.7-32.1%, p=0.00073). The use of animals with associated comorbidities was rare, with only 4.4% aged animals and no animals with diabetes or hypertension. Aged animals showed lower effect size with only 4.7% reduction of infarct size (-9.0-18.3%, p=1.0E-05). Conclusion Our study shows that bFGF-1 has efficacy in experimental ischemic stroke. The effect of study quality and bias limits the strength of this conclusion. Further research is needed to test the efficacy in animals with associated co morbidities.
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| 9. |
- Karlsson, Max, et al.
(författare)
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Genome-wide single cell annotation of the human protein-coding genes
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- An important quest for the life science community is to deliver a complete annotation of the human building-blocks of life, the genes and the proteins. Here, we report on a genome-wide effort to annotate all protein-coding genes based on single cell transcriptomics data representing all major tissues and organs in the human body, integrated with data from bulk transcriptomics and antibody-based tissue profiling. Altogether, 25 tissues have been analyzed with single cell transcriptomics resulting in genome-wide expression in 444 single cell types using a strategy involving pooling data from individual cells to obtain genome-wide expression profiles of individual cell type. We introduce a new genome-wide classification tool based on clustering of similar expression profiles across single cell types, which can be visualized using dimensional reduction maps (UMAP). The clustering classification is integrated with a new “tau” score classification for all protein-coding genes, resulting in a measure of single cell specificity across all cell types for all individual genes. The analysis has allowed us to annotate all human protein-coding genes with regards to function and spatial distribution across individual cell types across all major tissues and organs in the human body. A new version of the open access Human Protein Atlas (www.proteinatlas.org) has been launched to enable researchers to explore the new genome-wide annotation on an individual gene level.
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| 10. |
- Uhlén, Mathias, et al.
(författare)
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Tissue-based map of the human proteome
- 2015
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 347:6220, s. 1260419-
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Tidskriftsartikel (refereegranskat)abstract
- Resolving the molecular details of proteome variation in the different tissues and organs of the human body will greatly increase our knowledge of human biology and disease. Here, we present a map of the human tissue proteome based on an integrated omics approach that involves quantitative transcriptomics at the tissue and organ level, combined with tissue microarray-based immunohistochemistry, to achieve spatial localization of proteins down to the single-cell level. Our tissue-based analysis detected more than 90% of the putative protein-coding genes. We used this approach to explore the human secretome, the membrane proteome, the druggable proteome, the cancer proteome, and the metabolic functions in 32 different tissues and organs. All the data are integrated in an interactive Web-based database that allows exploration of individual proteins, as well as navigation of global expression patterns, in all major tissues and organs in the human body.
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