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Castro, M., Laviña, B., Ando, K., Alvarez-Aznar, A., Abu Taha, A., Brakebusch, C., . . . Gängel, K. (2019). CDC42 deletion elicits cerebral vascular malformations via increased MEKK3-dependent KLF4 expression. Circulation Research, 124(8), 1240-1252
Open this publication in new window or tab >>CDC42 deletion elicits cerebral vascular malformations via increased MEKK3-dependent KLF4 expression
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2019 (English)In: Circulation Research, ISSN 0009-7330, E-ISSN 1524-4571, Vol. 124, no 8, p. 1240-1252Article in journal (Refereed) Published
Abstract [en]

Rationale: Aberrant formation of blood vessels precedes a broad spectrum of vascular complications; however, the cellular and molecular events governing vascular malformations are not yet fully understood. Objective: Here, we investigated the role of CDC42 (cell division cycle 42) during vascular morphogenesis and its relative importance for the development of cerebrovascular malformations. Methods and Results: To avoid secondary systemic effects often associated with embryonic gene deletion, we generated an endothelial-specific and inducible knockout approach to study postnatal vascularization of the mouse brain. Postnatal endothelial-specific deletion of Cdc42 elicits cerebrovascular malformations reminiscent of cerebral cavernous malformations (CCMs). At the cellular level, loss of CDC42 function in brain endothelial cells (ECs) impairs their sprouting, branching morphogenesis, axial polarity, and normal dispersion within the brain tissue. Disruption of CDC42 does not alter EC proliferation, but malformations occur where EC proliferation is the most pronounced during brain development-the postnatal cerebellum-indicating that a high, naturally occurring EC proliferation provides a permissive state for the appearance of these malformations. Mechanistically, CDC42 depletion in ECs elicited increased MEKK3 (mitogen-activated protein kinase kinase kinase 3)-MEK5 (mitogen-activated protein kinase kinase 5)-ERK5 (extracellular signal-regulated kinase 5) signaling and consequent detrimental overexpression of KLF (Kruppel-like factor) 2 and KLF4, recapitulating the hallmark mechanism for CCM pathogenesis. Through genetic approaches, we demonstrate that the coinactivation of Klf4 reduces the severity of vascular malformations in Cdc42 mutant mice. Moreover, we show that CDC42 interacts with CCMs and that CCM3 promotes CDC42 activity in ECs. Conclusions: We show that endothelial-specific deletion of Cdc42 elicits CCM-like cerebrovascular malformations and that CDC42 is engaged in the CCM signaling network to restrain the MEKK3-MEK5-ERK5-KLF2/4 pathway.

Keywords
Angiogenesis, vascular morphogenesis, cerebrovascular malformation, endothelial cells, CDC42, MEKK3 signaling, KLF2/4
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-347776 (URN)10.1161/CIRCRESAHA.118.314300 (DOI)000469343500021 ()30732528 (PubMedID)
Funder
Swedish Cancer Society, CAN2015/771Swedish Research Council, VR2015-00550EU, European Research Council, 2011-294556 742922Knut and Alice Wallenberg Foundation, 2012.0272EU, FP7, Seventh Framework Programme, 317250Wenner-Gren FoundationsDanish National Research Foundation
Note

List of authors in thesis manuscript: Castro, M, Laviña, B, Ando, K, Álvarez-Aznar, A, Brakebusch, C, Dejana, E, Betsholtz, C, Gängel, K

Available from: 2018-04-06 Created: 2018-04-06 Last updated: 2019-06-25Bibliographically approved
Dias, M. C., Coisne, C., Lazarevic, I., Baden, P., Hata, M., Iwamoto, N., . . . Engelhardt, B. (2019). Claudin-3-deficient C57BL/6J mice display intact brain barriers. Scientific Reports, 9, Article ID 203.
Open this publication in new window or tab >>Claudin-3-deficient C57BL/6J mice display intact brain barriers
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2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 203Article in journal (Refereed) Published
Abstract [en]

The tight junction protein claudin-3 has been identified as a transcriptional target of the Wnt/beta-catenin signaling pathway regulating blood-brain barrier (BBB) maturation. In neurological disorders loss of claudin-3 immunostaining is observed at the compromised BBB and blood-cerebrospinal fluid barrier (BCSFB). Although these observations support a central role of claudin-3 in regulating brain barriers' tight junction integrity, expression of claudin-3 at the brain barriers has remained a matter of debate. This prompted us to establish claudin-3-/-C57BL/6J mice to study the role of claudin-3 in brain barrier integrity in health and neuroinflammation. Bulk and single cell RNA sequencing and direct comparative qRT-PCR analysis of brain microvascular samples from WT and claudin-3-/- mice show beyond doubt that brain endothelial cells do not express claudin-3 mRNA. Detection of claudin-3 protein at the BBB in vivo and in vitro is rather due to junctional reactivity of anti-claudin-3 antibodies to an unknown antigen still detected in claudin-3-/- brain endothelium. We confirm expression and junctional localization of claudin-3 at the BCSFB of the choroid plexus. Our study clarifies that claudin-3 is not expressed at the BBB and shows that absence of claudin-3 does not impair brain barrier function during health and neuroinflammation in C57BL/6J mice.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-375813 (URN)10.1038/s41598-018-36731-3 (DOI)000456008900001 ()30659216 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 241861EU, FP7, Seventh Framework Programme, 607962EU, Horizon 2020, 675619 BtRAIN
Note

Correction in: SCIENTIFIC REPORTS, Volume: 9, Article Number: 10702, DOI: 10.1038/s41598-019-43511-0

Available from: 2019-02-05 Created: 2019-02-05 Last updated: 2019-08-16Bibliographically approved
Lendahl, U., Nilsson, P. & Betsholtz, C. (2019). Emerging links between cerebrovascular and neurodegenerative diseases-a special role for pericytes. EMBO Reports, 20(11), Article ID e48070.
Open this publication in new window or tab >>Emerging links between cerebrovascular and neurodegenerative diseases-a special role for pericytes
2019 (English)In: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 20, no 11, article id e48070Article, review/survey (Refereed) Published
Abstract [en]

Neurodegenerative and cerebrovascular diseases cause considerable human suffering, and therapy options for these two disease categories are limited or non-existing. It is an emerging notion that neurodegenerative and cerebrovascular diseases are linked in several ways, and in this review, we discuss the current status regarding vascular dysregulation in neurodegenerative disease, and conversely, how cerebrovascular diseases are associated with central nervous system (CNS) degeneration and dysfunction. The emerging links between neurodegenerative and cerebrovascular diseases are reviewed with a particular focus on pericytes-important cells that ensheath the endothelium in the microvasculature and which are pivotal for blood-brain barrier function and cerebral blood flow. Finally, we address how novel molecular and cellular insights into pericytes and other vascular cell types may open new avenues for diagnosis and therapy development for these important diseases.

Keywords
blood-brain barrier, cerebrovascular disease, neurodegenerative disease, neurovascular unit, pericyte
National Category
Neurosciences Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-398132 (URN)10.15252/embr.201948070 (DOI)000496229500013 ()31617312 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationSwedish Cancer Society
Available from: 2019-12-04 Created: 2019-12-04 Last updated: 2019-12-04Bibliographically approved
Hu, X., Matsumoto, K., Jung, R. S., Weston, T. A., Heizer, P. J., He, C., . . . Jian, H. (2019). GPIHBP1 expression in gliomas promotes utilization of lipoprotein-derived nutrients. eLIFE, 8, Article ID e47178.
Open this publication in new window or tab >>GPIHBP1 expression in gliomas promotes utilization of lipoprotein-derived nutrients
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2019 (English)In: eLIFE, E-ISSN 2050-084X, Vol. 8, article id e47178Article in journal (Refereed) Published
Abstract [en]

GPIHBP1, a GPI-anchored protein of capillary endothelial cells, binds lipoprotein lipase (LPL) within the subendothelial spaces and shuttles it to the capillary lumen. GPIHBP1-bound LPL is essential for the margination of triglyceride-rich lipoproteins (TRLs) along capillaries, allowing the lipolytic processing of TRLs to proceed. In peripheral tissues, the intravascular processing of TRLs by the GPIHBP1-LPL complex is crucial for the generation of lipid nutrients for adjacent parenchymal cells. GPIHBP1 is absent from the capillaries of the brain, which uses glucose for fuel; however, GPIHBP1 is expressed in the capillaries of mouse and human gliomas. Importantly, the GPIHBP1 in glioma capillaries captures locally produced LPL. We use NanoSIMS imaging to show that TRLs marginate along glioma capillaries and that there is uptake of TRL-derived lipid nutrients by surrounding glioma cells. Thus, GPIHBP1 expression in gliomas facilitates TRL processing and provides a source of lipid nutrients for glioma cells.

Place, publisher, year, edition, pages
ELIFE SCIENCES PUBLICATIONS LTD, 2019
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-390688 (URN)10.7554/eLife.47178 (DOI)000473014000001 ()31169500 (PubMedID)
Funder
Australian Research Council
Available from: 2019-08-14 Created: 2019-08-14 Last updated: 2019-08-14Bibliographically approved
van Kuijk, K., Kuppe, C., Betsholtz, C., Vanlandewijck, M., Kramann, R. & Sluimer, J. C. (2019). Heterogeneity and plasticity in healthy and atherosclerotic vasculature explored by single-cell sequencing. Cardiovascular Research, 115(12), 1705-1715
Open this publication in new window or tab >>Heterogeneity and plasticity in healthy and atherosclerotic vasculature explored by single-cell sequencing
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2019 (English)In: Cardiovascular Research, ISSN 0008-6363, E-ISSN 1755-3245, Vol. 115, no 12, p. 1705-1715Article, review/survey (Refereed) Published
Abstract [en]

Cellular characteristics and their adjustment to a state of disease have become more evident due to recent advances in imaging, fluorescent reporter mice, and whole genome RNA sequencing. The uncovered cellular heterogeneity and/or plasticity potentially complicates experimental studies and clinical applications, as markers derived from whole tissue 'bulk' sequencing is unable to yield a subtype transcriptome and specific markers. Here, we propose definitions on heterogeneity and plasticity, discuss current knowledge thereof in the vasculature and how this may be improved by single-cell sequencing (SCS). SCS is emerging as an emerging technique, enabling researchers to investigate different cell populations in more depth than ever before. Cell selection methods, e.g. flow assisted cell sorting, and the quantity of cells can influence the choice of SCS method. Smart-Seq2 offers sequencing of the complete mRNA molecule on a low quantity of cells, while Drop-seq is possible on large numbers of cells on a more superficial level. SCS has given more insight in heterogeneity in healthy vasculature, where it revealed that zonation is crucial in gene expression profiles among the anatomical axis. In diseased vasculature, this heterogeneity seems even more prominent with discovery of new immune subsets in atherosclerosis as proof. Vascular smooth muscle cells and mesenchymal cells also share these plastic characteristics with the ability to up-regulate markers linked to stem cells, such as Sca-1 or CD34. Current SCS studies show some limitations to the number of replicates, quantity of cells used, or the loss of spatial information. Bioinformatical tools could give some more insight in current datasets, making use of pseudo-time analysis or RNA velocity to investigate cell differentiation or polarization. In this review, we discuss the use of SCS in unravelling heterogeneity in the vasculature, its current limitations and promising future applications.

Place, publisher, year, edition, pages
Oxford University Press, 2019
Keywords
Heterogeneity, Single-cell sequencing, Vasculature, Atherosclerosis
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-396467 (URN)10.1093/cvr/cvz185 (DOI)000491246600011 ()31350876 (PubMedID)
Funder
Swedish Research Council, 2015-00550Swedish Cancer Society, 150735Knut and Alice Wallenberg Foundation, 2015:0030German Research Foundation (DFG), SFB TRR219
Available from: 2019-11-14 Created: 2019-11-14 Last updated: 2019-11-14Bibliographically approved
Glicksberg, B. S., Amadori, L., Akers, N. K., Sukhavasi, K., Franzen, O., Li, L., . . . Chen, R. (2019). Integrative analysis of loss-of-function variants in clinical and genomic data reveals novel genes associated with cardiovascular traits. Paper presented at 8th Varl-COSI Conference on Identification and Annotation of Genetic Variants in the Context of Structure, Function, and Disease - Medical Genomics, JUL 08, 2018, Chicago, IL, USA. BMC Medical Genomics, 12, Article ID 108.
Open this publication in new window or tab >>Integrative analysis of loss-of-function variants in clinical and genomic data reveals novel genes associated with cardiovascular traits
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2019 (English)In: BMC Medical Genomics, ISSN 1755-8794, E-ISSN 1755-8794, Vol. 12, article id 108Article in journal (Refereed) Published
Abstract [en]

Background

Genetic loss-of-function variants (LoFs) associated with disease traits are increasingly recognized as critical evidence for the selection of therapeutic targets. We integrated the analysis of genetic and clinical data from 10,511 individuals in the Mount Sinai BioMe Biobank to identify genes with loss-of-function variants (LoFs) significantly associated with cardiovascular disease (CVD) traits, and used RNA-sequence data of seven metabolic and vascular tissues isolated from 600 CVD patients in the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) study for validation. We also carried out in vitro functional studies of several candidate genes, and in vivo studies of one gene.

Results

We identified LoFs in 433 genes significantly associated with at least one of 10 major CVD traits. Next, we used RNA-sequence data from the STARNET study to validate 115 of the 433 LoF harboring-genes in that their expression levels were concordantly associated with corresponding CVD traits. Together with the documented hepatic lipid-lowering gene, APOC3, the expression levels of six additional liver LoF-genes were positively associated with levels of plasma lipids in STARNET. Candidate LoF-genes were subjected to gene silencing in HepG2 cells with marked overall effects on cellular LDLR, levels of triglycerides and on secreted APOB100 and PCSK9. In addition, we identified novel LoFs in DGAT2 associated with lower plasma cholesterol and glucose levels in BioMe that were also confirmed in STARNET, and showed a selective DGAT2-inhibitor in C57BL/6 mice not only significantly lowered fasting glucose levels but also affected body weight.

Conclusion

In sum, by integrating genetic and electronic medical record data, and leveraging one of the world's largest human RNA-sequence datasets (STARNET), we identified known and novel CVD-trait related genes that may serve as targets for CVD therapeutics and as such merit further investigation.

Place, publisher, year, edition, pages
BMC, 2019
Keywords
Loss-of-function variant, Cardiovascular traits, Genetic association, Integrative data analysis, Target identification and validation, Electronic Medical Records
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-391365 (URN)10.1186/s12920-019-0542-3 (DOI)000477599200003 ()31345219 (PubMedID)
Conference
8th Varl-COSI Conference on Identification and Annotation of Genetic Variants in the Context of Structure, Function, and Disease - Medical Genomics, JUL 08, 2018, Chicago, IL, USA
Note

Correction in: BMC MEDICAL GENOMICS, Volume: 12, Issue: 1, Article Number: 154, DOI: 10.1186/s12920-019-0573-9

Available from: 2019-09-23 Created: 2019-09-23 Last updated: 2019-12-02Bibliographically approved
Munk, A. S., Wang, W., Bechet, N. B., Eltanahy, A. M., Cheng, A. X., Sigurdsson, B., . . . Lundgaard, I. (2019). PDGF-B Is Required for Development of the Glymphatic System. Cell reports, 26(11), 2955-+
Open this publication in new window or tab >>PDGF-B Is Required for Development of the Glymphatic System
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2019 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 26, no 11, p. 2955-+Article in journal (Refereed) Published
Abstract [en]

The glymphatic system is a highly polarized cerebro-spinal fluid (CSF) transport system that facilitates the clearance of neurotoxic molecules through a brain-wide network of perivascular pathways. Herein we have mapped the development of the glymphatic system in mice. Perivascular CSF transport first emerges in hippocampus in newborn mice, and a mature glymphatic system is established in the cortex at 2 weeks of age. Formation of astrocytic endfeet and polarized expression of aquaporin 4 (AQP4) consistently co-incided with the appearance of perivascular CSF transport. Deficiency of platelet-derived growth factor B (PDGF-B) function in the PDGF retention motif knockout mouse line Pdgfb(ret/ret) suppressed the development of the glymphatic system, whose functions remained suppressed in adulthood compared with wild-type mice. These experiments map the natural development of the glymphatic system in mice and define a critical role of PDGF-B in the development of perivascular CSF transport.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-380455 (URN)10.1016/j.celrep.2019.02.050 (DOI)000460914700010 ()30865886 (PubMedID)
Funder
EU, Horizon 2020, 643417/DACAPO-ADSwedish Research Council, 2015-00550Knut and Alice Wallenberg Foundation, 2015.0030
Available from: 2019-03-28 Created: 2019-03-28 Last updated: 2019-03-28Bibliographically approved
Ando, K., Wang, W., Peng, D., Chiba, A., Lagendijk, A. K., Barske, L., . . . Betsholtz, C. (2019). Peri-arterial specification of vascular mural cells from naive mesenchyme requires Notch signaling. Development, 146(2), Article ID UNSP dev165589.
Open this publication in new window or tab >>Peri-arterial specification of vascular mural cells from naive mesenchyme requires Notch signaling
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2019 (English)In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 146, no 2, article id UNSP dev165589Article in journal (Refereed) Published
Abstract [en]

Mural cells (MCs) are essential for blood vessel stability and function; however, the mechanisms that regulate MC development remain incompletely understood, in particular those involved in MC specification. Here, we investigated the first steps of MC formation in zebrafish using transgenic reporters. Using pdgfrb and abcc9 reporters, we show that the onset of expression of abcc9, a pericyte marker in adult mice and zebrafish, occurs almost coincidentally with an increment in pdgfrb expression in peri-arterial mesenchymal cells, suggesting that these transcriptional changes mark the specification of MC lineage cells from naive pdgfrb(low) mesenchymal cells. The emergence of peri-arterial pdgfrb(high) MCs required Notch signaling. We found that pdgfrb-positive cells express notch2 in addition to notch3, and although depletion of notch2 or notch3 failed to block MC emergence, embryos depleted of both notch2 and notch3 lost mesoderm- as well as neural crest-derived pdgfrb(high) MCs. Using reporters that read out Notch signaling and Notch2 receptor cleavage, we show that Notch activation in the mesenchyme precedes specification into pdgfrb(high) MCs. Taken together, these results show that Notch signaling is necessary for peri-arterial MC specification.

Place, publisher, year, edition, pages
COMPANY BIOLOGISTS LTD, 2019
Keywords
Mural cells, Pericytes, Vascular smooth muscle cells, Zebrafish, Notch
National Category
Cell and Molecular Biology Developmental Biology
Identifiers
urn:nbn:se:uu:diva-377362 (URN)10.1242/dev.165589 (DOI)000457418100002 ()30642834 (PubMedID)
Funder
Swedish Research Council, 2015-00550Swedish Research Council, 2016-01437EU, European Research Council, AdG294556Swedish Cancer Society, 150735Knut and Alice Wallenberg Foundation, 2015.0030Knut and Alice Wallenberg Foundation, 2017.0144Ragnar Söderbergs stiftelse
Available from: 2019-02-19 Created: 2019-02-19 Last updated: 2019-02-19Bibliographically approved
Dang, T. C., Ishii, Y., Nguyen, V. D., Yamamoto, S., Hamashima, T., Okuno, N., . . . Sasahara, M. (2019). Powerful Homeostatic Control of Oligodendroglial Lineage by PDGFR alpha in Adult Brain. Cell reports, 27(4), 1073-1089
Open this publication in new window or tab >>Powerful Homeostatic Control of Oligodendroglial Lineage by PDGFR alpha in Adult Brain
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2019 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 27, no 4, p. 1073-1089Article in journal (Refereed) Published
Abstract [en]

Oligodendrocyte progenitor cells (OPCs) are widely distributed cells of ramified morphology in adult brain that express PDGFR alpha and NG2. They retain mitotic activities in adulthood and contribute to oligodendrogenesis and myelin turnover; however, the regulatory mechanisms of their cell dynamics in adult brain largely remain unknown. Here, we found that global Pdgfra inactivation in adult mice rapidly led to elimination of OPCs due to synchronous maturation toward oligodendrocytes. Surprisingly, OPC densities were robustly reconstituted by the active expansion of Nestin(+) immature cells activated in meninges and brain parenchyma, as well as a few OPCs that escaped from Pdgfra inactivation. The multipotent immature cells were induced in the meninges of Pdgfra-inactivated mice, but not of control mice. Our findings revealed powerful homeostatic control of adult OPCs, engaging dual cellular sources of adult OPC formation. These properties of the adult oligodendrocyte lineage and the alternative OPC source may be exploited in regenerative medicine.

Place, publisher, year, edition, pages
CELL PRESS, 2019
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-382826 (URN)10.1016/j.celrep.2019.03.084 (DOI)000465241300009 ()31018125 (PubMedID)
Available from: 2019-05-06 Created: 2019-05-06 Last updated: 2019-05-06Bibliographically approved
Sakamoto, K., Furuichi, Y., Yamamoto, M., Takahashi, M., Akimoto, Y., Ishikawa, T., . . . Takemoto, M. (2019). R3hdml regulates satellite cell proliferation and differentiation. EMBO Reports, 20(11), Article ID e47957.
Open this publication in new window or tab >>R3hdml regulates satellite cell proliferation and differentiation
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2019 (English)In: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 20, no 11, article id e47957Article in journal (Refereed) Published
Abstract [en]

In this study, we identified a previously uncharacterized skeletal satellite cell-secreted protein, R3h domain containing-like (R3hdml). Expression of R3hdml increases during skeletal muscle development and differentiation in mice. Body weight and skeletal muscle mass of R3hdml knockout (KO) mice are lower compared to control mice. Expression levels of cell cycle-related markers, phosphorylation of Akt, and expression of insulin-like growth factor within the skeletal muscle are reduced in R3hdml KO mice compared to control mice. Expression of R3hdml increases during muscle regeneration in response to cardiotoxin (CTX)-induced muscle injury. Recovery of handgrip strength after CTX injection was significantly impaired in R3hdml KO mice, which is rescued by R3hdml. Our results indicate that R3hdml is required for skeletal muscle development, regeneration, and, in particular, satellite cell proliferation and differentiation.

Place, publisher, year, edition, pages
WILEY, 2019
Keywords
R3hdml, sarcopenia, satellite cell, skeletal muscle
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-398030 (URN)10.15252/embr.201947957 (DOI)000496229500004 ()31524320 (PubMedID)
Available from: 2019-12-04 Created: 2019-12-04 Last updated: 2019-12-04Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-8494-971x

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