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Hallström, Björn M.
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Publications (10 of 12) Show all publications
Wang, D., Eraslan, B., Wieland, T., Hallström, B. M., Hopf, T., Zolg, D. P., . . . Kuster, B. (2019). A deep proteome and transcriptome abundance atlas of 29 healthy human tissues. Molecular Systems Biology, 15(2), Article ID e8503.
Open this publication in new window or tab >>A deep proteome and transcriptome abundance atlas of 29 healthy human tissues
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2019 (English)In: Molecular Systems Biology, ISSN 1744-4292, E-ISSN 1744-4292, Vol. 15, no 2, article id e8503Article in journal (Refereed) Published
Abstract [en]

Genome-, transcriptome- and proteome-wide measurements provide insights into how biological systems are regulated. However, fundamental aspects relating to which human proteins exist, where they are expressed and in which quantities are not fully understood. Therefore, we generated a quantitative proteome and transcriptome abundance atlas of 29 paired healthy human tissues from the Human Protein Atlas project representing human genes by 18,072 transcripts and 13,640 proteins including 37 without prior protein-level evidence. The analysis revealed that hundreds of proteins, particularly in testis, could not be detected even for highly expressed mRNAs, that few proteins show tissue-specific expression, that strong differences between mRNA and protein quantities within and across tissues exist and that protein expression is often more stable across tissues than that of transcripts. Only 238 of 9,848 amino acid variants found by exome sequencing could be confidently detected at the protein level showing that proteogenomics remains challenging, needs better computational methods and requires rigorous validation. Many uses of this resource can be envisaged including the study of gene/protein expression regulation and biomarker specificity evaluation.

Place, publisher, year, edition, pages
WILEY, 2019
Keywords
human proteome, human transcriptome, proteogenomics, quantitative mass spectrometry, RNA-Seq
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-246279 (URN)10.15252/msb.20188503 (DOI)000459628300002 ()30777892 (PubMedID)2-s2.0-85061866375 (Scopus ID)
Note

QC 20190325

Available from: 2019-03-25 Created: 2019-03-25 Last updated: 2019-04-04Bibliographically approved
Eraslan, B., Wang, D., Gusic, M., Prokisch, H., Hallström, B. M., Uhlén, M., . . . Gagneur, J. (2019). Quantification and discovery of sequence determinants of protein-per-mRNA amount in 29 human tissues. Molecular Systems Biology, 15(2), Article ID e8513.
Open this publication in new window or tab >>Quantification and discovery of sequence determinants of protein-per-mRNA amount in 29 human tissues
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2019 (English)In: Molecular Systems Biology, ISSN 1744-4292, E-ISSN 1744-4292, Vol. 15, no 2, article id e8513Article in journal (Refereed) Published
Abstract [en]

Despite their importance in determining protein abundance, a comprehensive catalogue of sequence features controlling protein-to-mRNA (PTR) ratios and a quantification of their effects are still lacking. Here, we quantified PTR ratios for 11,575 proteins across 29 human tissues using matched transcriptomes and proteomes. We estimated by regression the contribution of known sequence determinants of protein synthesis and degradation in addition to 45 mRNA and 3 protein sequence motifs that we found by association testing. While PTR ratios span more than 2 orders of magnitude, our integrative model predicts PTR ratios at a median precision of 3.2-fold. A reporter assay provided functional support for two novel UTR motifs, and an immobilized mRNA affinity competition-binding assay identified motif-specific bound proteins for one motif. Moreover, our integrative model led to a new metric of codon optimality that captures the effects of codon frequency on protein synthesis and degradation. Altogether, this study shows that a large fraction of PTR ratio variation in human tissues can be predicted from sequence, and it identifies many new candidate post-transcriptional regulatory elements.

Place, publisher, year, edition, pages
WILEY, 2019
Keywords
codon usage, mRNA sequence motifs, proteomics, transcriptomics, translational control
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-246280 (URN)10.15252/msb.20188513 (DOI)000459628300004 ()30777893 (PubMedID)2-s2.0-85061855104 (Scopus ID)
Note

QC 20190325

Available from: 2019-03-25 Created: 2019-03-25 Last updated: 2019-04-04Bibliographically approved
Carreras-Puigvert, J., Zitnik, M., Jemth, A.-S. -., Carter, M., Unterlass, J. E., Hallström, B. M., . . . Helleday, T. (2017). A comprehensive structural, biochemical and biological profiling of the human NUDIX hydrolase family. Nature Communications, 8(1), Article ID 1541.
Open this publication in new window or tab >>A comprehensive structural, biochemical and biological profiling of the human NUDIX hydrolase family
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2017 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, no 1, article id 1541Article in journal (Refereed) Published
Abstract [en]

The NUDIX enzymes are involved in cellular metabolism and homeostasis, as well as mRNA processing. Although highly conserved throughout all organisms, their biological roles and biochemical redundancies remain largely unclear. To address this, we globally resolve their individual properties and inter-relationships. We purify 18 of the human NUDIX proteins and screen 52 substrates, providing a substrate redundancy map. Using crystal structures, we generate sequence alignment analyses revealing four major structural classes. To a certain extent, their substrate preference redundancies correlate with structural classes, thus linking structure and activity relationships. To elucidate interdependence among the NUDIX hydrolases, we pairwise deplete them generating an epistatic interaction map, evaluate cell cycle perturbations upon knockdown in normal and cancer cells, and analyse their protein and mRNA expression in normal and cancer tissues. Using a novel FUSION algorithm, we integrate all data creating a comprehensive NUDIX enzyme profile map, which will prove fundamental to understanding their biological functionality.

Place, publisher, year, edition, pages
Nature Publishing Group, 2017
Keywords
Nudix hydrolase, NUDT1 protein, NUDT10 protein, NUDT11 protein, NUDT12 protein, NUDT13 protein, NUDT14 protein, NUDT16 protein, NUDT17 protein, NUDT19 protein, NUDT20 protein, NUDT21 protein, NUDT22 protein, NUDT4 protein, NUDT5 protein, NUDT6 protein, NUDT7 protein, NUDT8 protein, unclassified drug, algorithm, biochemical composition, cancer, enzyme, enzyme activity, gene expression, homeostasis, metabolism, protein, A-549 cell line, Article, breast cancer, cancer cell line, cancer tissue, cell cycle, cell cycle regulation, cell survival, colorectal cancer, controlled study, DNA content, enzyme structure, functional genomics, gene interaction, gene silencing, human, human cell, human tissue, immunohistochemistry, melanoma, phylogenetic tree, protein expression, sequence alignment, tissue microarray, upregulation
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:kth:diva-227131 (URN)10.1038/s41467-017-01642-w (DOI)2-s2.0-85034433549 (Scopus ID)
Note

QC 20180503

Available from: 2018-05-03 Created: 2018-05-03 Last updated: 2018-05-03Bibliographically approved
Palmgren, M., Engstrom, K., Hallström, B. M., Wahlberg, K., Sondergaard, D. A., Sall, T., . . . Broberg, K. (2017). AS3MT-mediated tolerance to arsenic evolved by multiple independent horizontal gene transfers from bacteria to eukaryotes. PLoS ONE, 12(4), Article ID e0175422.
Open this publication in new window or tab >>AS3MT-mediated tolerance to arsenic evolved by multiple independent horizontal gene transfers from bacteria to eukaryotes
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2017 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 4, article id e0175422Article in journal (Refereed) Published
Abstract [en]

Organisms have evolved the ability to tolerate toxic substances in their environments, often by producing metabolic enzymes that efficiently detoxify the toxicant. Inorganic arsenic is one of the most toxic and carcinogenic substances in the environment, but many organisms, including humans, metabolise inorganic arsenic to less toxic metabolites. This multistep process produces mono-, di-, and trimethylated arsenic metabolites, which the organism excretes. In humans, arsenite methyltransferase (AS3MT) appears to be the main metabolic enzyme that methylates arsenic. In this study, we examined the evolutionary origin of AS3MT and assessed the ability of different genotypes to produce methylated arsenic metabolites. Phylogenetic analysis suggests that multiple, independent horizontal gene transfers between different bacteria, and from bacteria to eukaryotes, increased tolerance to environmental arsenic during evolution. These findings are supported by the observation that genetic variation in AS3MT correlates with the capacity to methylate arsenic. Adaptation to arsenic thus serves as a model for how organisms evolve to survive under toxic conditions.

Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE, 2017
National Category
Biological Sciences
Identifiers
urn:nbn:se:kth:diva-207680 (URN)10.1371/journal.pone.0175422 (DOI)000399875900029 ()28426741 (PubMedID)2-s2.0-85018461279 (Scopus ID)
Note

QC 20170601

Available from: 2017-06-01 Created: 2017-06-01 Last updated: 2017-11-29Bibliographically approved
Huang, M., Bao, J., Hallström, B. M., Petranovic, D. & Nielsen, J. (2017). Efficient protein production by yeast requires global tuning of metabolism. Nature Communications, 8(1), Article ID 1131.
Open this publication in new window or tab >>Efficient protein production by yeast requires global tuning of metabolism
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2017 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, no 1, article id 1131Article in journal (Refereed) Published
Abstract [en]

The biotech industry relies on cell factories for production of pharmaceutical proteins, of which several are among the top-selling medicines. There is, therefore, considerable interest in improving the efficiency of protein production by cell factories. Protein secretion involves numerous intracellular processes with many underlying mechanisms still remaining unclear. Here, we use RNA-seq to study the genome-wide transcriptional response to protein secretion in mutant yeast strains. We find that many cellular processes have to be attuned to support efficient protein secretion. In particular, altered energy metabolism resulting in reduced respiration and increased fermentation, as well as balancing of amino-acid biosynthesis and reduced thiamine biosynthesis seem to be particularly important. We confirm our findings by inverse engineering and physiological characterization and show that by tuning metabolism cells are able to efficiently secrete recombinant proteins. Our findings provide increased understanding of which cellular regulations and pathways are associated with efficient protein secretion.

Place, publisher, year, edition, pages
Nature Publishing Group, 2017
Keywords
amylase, carbohydrate, protein, thiamine, biological production, biotechnology, efficiency measurement, genetic engineering, metabolism, yeast, AAC3 gene, amino acid synthesis, amylase release, ANB1 gene, Article, bacterium culture, carbohydrate metabolism, CYC7 gene, DAN1 gene, endoplasmic reticulum stress, energy metabolism, fermentation, fungal gene, FUR1 gene, genome-wide association study, MSS11 gene, nonhuman, PHO12 gene, PHO84 gene, PHO89 gene, protein metabolism, protein secretion, reporter gene, RNA sequence, SNF2 gene, SPL2 gene, SUT1 gene, SWI4 gene, TEC1 gene, TIR3 gene
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-227126 (URN)10.1038/s41467-017-00999-2 (DOI)2-s2.0-85032290095 (Scopus ID)
Note

QC 20180508

Available from: 2018-05-08 Created: 2018-05-08 Last updated: 2018-05-08Bibliographically approved
Fletcher, E., Feizi, A., Bisschops, M. M., Hallström, B. M., Khoomrung, S., Siewers, V. & Nielsen, J. (2017). Evolutionary engineering reveals divergent paths when yeast is adapted to different acidic environments. Metabolic engineering, 39, 19-28
Open this publication in new window or tab >>Evolutionary engineering reveals divergent paths when yeast is adapted to different acidic environments
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2017 (English)In: Metabolic engineering, ISSN 1096-7176, E-ISSN 1096-7184, Vol. 39, p. 19-28Article in journal (Refereed) Published
Abstract [en]

Tolerance of yeast to acid stress is important for many industrial processes including organic acid production. Therefore, elucidating the molecular basis of long term adaptation to acidic environments will be beneficial for engineering production strains to thrive under such harsh conditions. Previous studies using gene expression analysis have suggested that both organic and inorganic acids display similar responses during short term exposure to acidic conditions. However, biological mechanisms that will lead to long term adaptation of yeast to acidic conditions remains unknown and whether these mechanisms will be similar for tolerance to both organic and inorganic acids is yet to be explored. We therefore evolved Saccharomyces cerevisiae to acquire tolerance to HCl (inorganic acid) and to 0.3 M L-lactic acid (organic acid) at pH 2.8 and then isolated several low pH tolerant strains. Whole genome sequencing and RNA-seq analysis of the evolved strains revealed different sets of genome alterations suggesting a divergence in adaptation to these two acids. An altered sterol composition and impaired iron uptake contributed to HCl tolerance whereas the formation of a multicellular morphology and rapid lactate degradation was crucial for tolerance to high concentrations of lactic acid. Our findings highlight the contribution of both the selection pressure and nature of the acid as a driver for directing the evolutionary path towards tolerance to low pH. The choice of carbon source was also an important factor in the evolutionary process since cells evolved on two different carbon sources (raffinose and glucose) generated a different set of mutations in response to the presence of lactic acid. Therefore, different strategies are required for a rational design of low pH tolerant strains depending on the acid of interest.

Place, publisher, year, edition, pages
Academic Press, 2017
Keywords
Adaptive laboratory evolution, Lactic acid, Low pH, Yeast, Biology, Gene expression, Genes, Inorganic acids, Organic acids, Plants (botany), Biological mechanisms, Different carbon sources, Evolutionary engineering, Evolutionary process, Gene expression analysis, Organic acid productions, Whole genome sequencing
National Category
Biological Sciences
Identifiers
urn:nbn:se:kth:diva-202835 (URN)10.1016/j.ymben.2016.10.010 (DOI)000392565200003 ()2-s2.0-85008240309 (Scopus ID)
Funder
Novo NordiskKnut and Alice Wallenberg Foundation
Note

QC 20170320

Available from: 2017-03-20 Created: 2017-03-20 Last updated: 2017-11-29Bibliographically approved
Haglund, F., Hallström, B. M., Nilsson, I.-L., Hoog, A., Juhlin, C. C. & Larsson, C. (2017). Inflammatory infiltrates in parathyroid tumors. European Journal of Endocrinology, 177(6), 445-453
Open this publication in new window or tab >>Inflammatory infiltrates in parathyroid tumors
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2017 (English)In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 177, no 6, p. 445-453Article in journal (Refereed) Published
Abstract [en]

Context: Inflammatory infiltrates are sometimes present in solid tumors and may be coupled to clinical behavior or etiology. Infectious viruses contribute to tumorigenesis in a significant fraction of human neoplasias. Objective: Characterize inflammatory infiltrates and possible viral transcription in primary hyperparathyroidism. Design: From the period 2007 to 2016, a total of 55 parathyroid tumors (51 adenomas and 4 hyperplasias) with prominent inflammatory infiltrates were identified from more than 2000 parathyroid tumors in the pathology archives, and investigated by immunohistochemistry for CD4, CD8, CD20 and CD45 and scored as +0, +1 or +2. Clinicopathological data were compared to 142 parathyroid adenomas without histological evidence of inflammation. Transcriptome sequencing was performed for 13 parathyroid tumors (four inflammatory, 9 non-inflammatory) to identify potential viral transcripts. Results: Tumors had prominent germinal center-like nodular (+2) lymphocytic infiltrates consisting of T and B lymphocytes (31%) and/or diffuse (+1-2) infiltrates of predominantly CD8+T lymphocytes (84%). In the majority of cases with adjacent normal parathyroid tissue, the normal rim was unaffected by the inflammatory infiltrates (96%). Presence of inflammatory infiltrates was associated with higher levels of serum-PTH (P = 0.007) and oxyphilic differentiation (P = 0.002). Co-existent autoimmune disease was observed in 27% of patients with inflammatory infiltrates, which in turn was associated with oxyphilic differentiation (P = 0.041). Additionally, prescription of anti-inflammatory drugs was associated with lower serum ionized calcium (P = 0.037). Conclusions: No evidence of virus-like sequences in the parathyroid tumors could be found by transcriptome sequencing, suggesting that other factors may contribute to attract the immune system to the parathyroid tumor tissue.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:kth:diva-220264 (URN)10.1530/EJE-17-0277 (DOI)000416665100006 ()28855268 (PubMedID)2-s2.0-85031801940 (Scopus ID)
Note

QC 20180112

Available from: 2018-01-12 Created: 2018-01-12 Last updated: 2018-01-12Bibliographically approved
Pateraki, I., Andersen-Ranberg, J., Jensen, N. B., Wubshet, S. G., Heskes, A. M., Forman, V., . . . Hamberger, B. (2017). Total biosynthesis of the cyclic AMP booster for skolin from Coleus forskohlii. eLIFE, 6, Article ID e23001.
Open this publication in new window or tab >>Total biosynthesis of the cyclic AMP booster for skolin from Coleus forskohlii
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2017 (English)In: eLIFE, E-ISSN 2050-084X, Vol. 6, article id e23001Article in journal (Refereed) Published
Abstract [en]

Forskolin is a unique structurally complex labdane-type diterpenoid used in the treatment of glaucoma and heart failure based on its activity as a cyclic AMP booster. Commercial production of forskolin relies exclusively on extraction from its only known natural source, the plant Coleus forskohlii, in which forskolin accumulates in the root cork. Here, we report the discovery of five cytochrome P450s and two acetyltransferases which catalyze a cascade of reactions converting the forskolin precursor 13R-manoyl oxide into forskolin and a diverse array of additional labdane-type diterpenoids. A minimal set of three P450s in combination with a single acetyl transferase was identified that catalyzes the conversion of 13R-manoyl oxide into forskolin as demonstrated by transient expression in Nicotiana benthamiana. The entire pathway for forskolin production from glucose encompassing expression of nine genes was stably integrated into Saccharomyces cerevisiae and afforded forskolin titers of 40 mg/L.

Place, publisher, year, edition, pages
ELIFE SCIENCES PUBLICATIONS LTD, 2017
National Category
Biomedical Laboratory Science/Technology
Identifiers
urn:nbn:se:kth:diva-206294 (URN)10.7554/eLife.23001 (DOI)000398905500001 ()
Note

QC 20170508

Available from: 2017-05-08 Created: 2017-05-08 Last updated: 2017-11-29Bibliographically approved
van Wijk, X. M., Dohrmann, S., Hallström, B. M., Li, S., Voldborg, B. G., Meng, B. X., . . . Esko, J. D. (2017). Whole-Genome Sequencing of Invasion-Resistant Cells Identifies Laminin α2 as a Host Factor for Bacterial Invasion. mBio, 8(1), Article ID e02128-16.
Open this publication in new window or tab >>Whole-Genome Sequencing of Invasion-Resistant Cells Identifies Laminin α2 as a Host Factor for Bacterial Invasion
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2017 (English)In: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 8, no 1, article id e02128-16Article in journal (Refereed) Published
Abstract [en]

To understand the role of glycosaminoglycans in bacterial cellular invasion, xylosyltransferase-deficient mutants of Chinese hamster ovary (CHO) cells were created using clustered regularly interspaced short palindromic repeat (CRISPR) and CRISPR-associated gene 9 (CRISPR-cas9) gene targeting. When these mutants were compared to the pgsA745 cell line, a CHO xylosyltransferase mutant generated previously using chemical mutagenesis, an unexpected result was obtained. Bacterial invasion of pgsA745 cells by group B Streptococcus (GBS), group A Streptococcus, and Staphylococcus aureus was markedly reduced compared to the invasion of wild-type cells, but newly generated CRISPR-cas9 mutants were only resistant to GBS. Invasion of pgsA745 cells was not restored by transfection with xylosyltransferase, suggesting that an additional mutation conferring panresistance to multiple bacteria was present in pgsA745 cells. Whole-genome sequencing and transcriptome sequencing (RNA-Seq) uncovered a deletion in the gene encoding the laminin subunit alpha 2 (Lama2) that eliminated much of domain L4a. Silencing of the long Lama2 isoform in wild-type cells strongly reduced bacterial invasion, whereas transfection with human LAMA2 cDNA significantly enhanced invasion in pgsA745 cells. The addition of exogenous laminin-alpha 2 beta 1 gamma 1/laminin-alpha 2 beta 2 gamma 1 strongly increased bacterial invasion in CHO cells, as well as in human alveolar basal epithelial and human brain microvascular endothelial cells. Thus, the L4a domain in laminin alpha 2 is important for cellular invasion by a number of bacterial pathogens. IMPORTANCE Pathogenic bacteria penetrate host cellular barriers by attachment to extracellular matrix molecules, such as proteoglycans, laminins, and collagens, leading to invasion of epithelial and endothelial cells. Here, we show that cellular invasion by the human pathogens group B Streptococcus, group A Streptococcus, and Staphylococcus aureus depends on a specific domain of the laminin alpha 2 subunit. This finding may provide new leads for the molecular pathogenesis of these bacteria and the development of novel antimicrobial drugs.

Place, publisher, year, edition, pages
American Society for Microbiology, 2017
National Category
Biological Sciences
Identifiers
urn:nbn:se:kth:diva-204747 (URN)10.1128/mBio.02128-16 (DOI)000395835000077 ()2-s2.0-85014850706 (Scopus ID)
Note

QC 20170601

Available from: 2017-06-01 Created: 2017-06-01 Last updated: 2017-06-01Bibliographically approved
Butler, L. M., Hallström, B. M., Fagerberg, L., Pontén, F., Uhlén, M., Renné, T. & Odeberg, J. (2016). Analysis of Body-wide Unfractionated Tissue Data to Identify a Core Human Endothelial Transcriptome. Cell Systems, 3(3), 287-301.e3
Open this publication in new window or tab >>Analysis of Body-wide Unfractionated Tissue Data to Identify a Core Human Endothelial Transcriptome
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2016 (English)In: Cell Systems, ISSN 2405-4712, Vol. 3, no 3, p. 287-301.e3Article in journal (Refereed) Published
Abstract [en]

Endothelial cells line blood vessels and regulate hemostasis, inflammation, and blood pressure. Proteins critical for these specialized functions tend to be predominantly expressed in endothelial cells across vascular beds. Here, we present a systems approach to identify a panel of human endothelial-enriched genes using global, body-wide transcriptomics data from 124 tissue samples from 32 organs. We identified known and unknown endothelial-enriched gene transcripts and used antibody-based profiling to confirm expression across vascular beds. The majority of identified transcripts could be detected in cultured endothelial cells from various vascular beds, and we observed maintenance of relative expression in early passage cells. In summary, we describe a widely applicable method to determine cell-type-specific transcriptome profiles in a whole-organism context, based on differential abundance across tissues. We identify potential vascular drug targets or endothelial biomarkers and highlight candidates for functional studies to increase understanding of the endothelium in health and disease.

Place, publisher, year, edition, pages
Cell Press, 2016
National Category
Biological Sciences
Identifiers
urn:nbn:se:kth:diva-202878 (URN)10.1016/j.cels.2016.08.001 (DOI)000395775300011 ()2-s2.0-84991734935 (Scopus ID)
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

QC 20170310

Available from: 2017-03-10 Created: 2017-03-10 Last updated: 2017-03-31Bibliographically approved
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