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  • 1
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    Phenotypic Modulation of Smooth Muscle Cells in Atherosclerosis Is Associated With Downregulation of LMOD1, SYNPO2, PDLIM7, PLN , and SYNM
    Ovid Technologies (Wolters Kluwer Health) ; 2016
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 36, No. 9 ( 2016-09), p. 1947-1961
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 36, No. 9 ( 2016-09), p. 1947-1961
    Abstract: Key augmented processes in atherosclerosis have been identified, whereas less is known about downregulated pathways. Here, we applied a systems biology approach to examine suppressed molecular signatures, with the hypothesis that they may provide insight into mechanisms contributing to plaque stability. Approach and Results— Muscle contraction, muscle development, and actin cytoskeleton were the most downregulated pathways (false discovery rate=6.99e-21, 1.66e-6, 2.54e-10, respectively) in microarrays from human carotid plaques (n=177) versus healthy arteries (n=15). In addition to typical smooth muscle cell (SMC) markers, these pathways also encompassed cytoskeleton-related genes previously not associated with atherosclerosis. SYNPO2, SYNM, LMOD1, PDLIM7 , and PLN expression positively correlated to typical SMC markers in plaques (Pearson r 〉 0.6, P 〈 0.0001) and in rat intimal hyperplasia ( r 〉 0.8, P 〈 0.0001). By immunohistochemistry, the proteins were expressed in SMCs in normal vessels, but largely absent in human plaques and intimal hyperplasia. Subcellularly, most proteins localized to the cytoskeleton in cultured SMCs and were regulated by active enhancer histone modification H3K27ac by chromatin immunoprecipitation-sequencing. Functionally, the genes were downregulated by PDGFB (platelet-derived growth factor beta) and IFNg (interferron gamma), exposure to shear flow stress, and oxLDL (oxidized low-density lipoprotein) loading. Genetic variants in PDLIM7, PLN , and SYNPO2 loci associated with progression of carotid intima-media thickness in high-risk subjects without symptoms of cardiovascular disease (n=3378). By eQTL (expression quantitative trait locus), rs11746443 also associated with PDLIM7 expression in plaques. Mechanistically, silencing of PDLIM7 in vitro led to downregulation of SMC markers and disruption of the actin cytoskeleton, decreased cell spreading, and increased proliferation. Conclusions— We identified a panel of genes that reflect the altered phenotype of SMCs in vascular disease and could be early sensitive markers of SMC dedifferentiation.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/ATVBAHA.116.307893
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2016
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  • 2
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    Abstract 443: Absence of Pro-Protein Convertase Subtilisin/Kexin 6 Increases Flow-Mediated Outward Remodeling in the Mouse Common Carotid Artery
    Ovid Technologies (Wolters Kluwer Health) ; 2017
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 37, No. suppl_1 ( 2017-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 37, No. suppl_1 ( 2017-05)
    Abstract: Objective: Proprotein convertases (PCSKs) process matrix metalloproteases and cytokines but their function in vasculature is largely unknown. Previously, we demonstrated upregulation of PCSK6 in atherosclerotic plaques, localization to smooth muscle cells in the fibrous cap and positive correlation to inflammation, extracellular matrix remodeling and cytokines. Here, our aim was to evaluate the effects of PCSK6 on flow-mediated vascular remodeling in mice using high-frequency ultrasound and myography. Materials and Methods: PCSK6 -/- and C57Bl/6J mice were compared in this study divided in baseline control and increased flow groups. Increased flow was created in the right common carotid artery (CCA) by ligation of the left CCA. All animals were subjected to high-frequency ultrasound examination prior to surgery, at 3 and 5 weeks after surgery. Upon euthanization 6 weeks post-surgery the right CCA was harvested for myography evaluation, subsequently fixed at optimal stretch and prepared for histological evaluation. Results: The vascular circumference at optimal stretch in myography was strongly correlated (Pearson r=0.74, p 〈 0.001) and in agreement with the diastolic circumference measured by high-frequency ultrasound in examined animals. A significant increase in diastolic circumference was seen at 3 and 5 weeks after surgery in PCSK6 -/- mice with increased flow compared to PCSK6 -/- control group (1.6±0.15 mm vs 1.4±0.08 mm, p 〈 0.05 and 1.7±0.09 mm vs 1.4±0.12 mm, p 〈 0.01). Myography revealed a significant increase in circumference at optimal stretch (1.7±0.21 mm vs 1.4±0.08 mm, p 〈 0.05) in PCSK6 -/- mice subjected to increased flow compared to PCSK6 -/- control group. A significant flow-mediated increase in medial contractility was identified (0.68±0.14 mN/mm vs 0.45±0.11 mN/mm, p 〈 0.05) in C57Bl/6J mice compared to C57Bl/6J control where as an absence of flow-mediated increase in medial contractility was seen in PCSK6 -/- mice. Conclusion: Absence of PCSK6 increases outward remodeling and reduces medial contractility in response to increased blood flow.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.37.suppl_1.443
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2017
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  • 3
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    Abstract 26: Who is Going to Stroke? Biomarkers for the Unstable Carotid Atheroma
    Ovid Technologies (Wolters Kluwer Health) ; 2015
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 35, No. suppl_1 ( 2015-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 35, No. suppl_1 ( 2015-05)
    Abstract: Unstable carotid stenosis is an important source of extracranial atheroembolism and stroke. Current interventional therapy is based on surrogate markers for stroke risk and no precise diagnostic tool is available for identification of either individuals or lesions at risk. Thus, biomarkers for the unstable carotid atheroma may improve selection of patient for intervention. Here, a high-throughput pipeline for identification of circulating biomarkers for unstable carotid atherosclerosis was developed. Carotid plaques were part of the Biobank for Karolinska Endarterectomies (BiKE) and obtained from patients treated for symptomatic (S) and asymptomatic (AS) carotid stenosis together with peripheral plasma and ‘local’ plasma (n = 47) sampled after clamping prior to arteriotomy. Screening of proteins was processed through Luminex based, suspension-bead assays using over 10,000 antibodies from the Human Protein Resource (HPR) and compared to peripheral plasma (n = 200 total). Plasma analysis identified 150 significantly dysregulated candidates based on three comparisons: proteins enriched in local plasma compared to peripheral plasma; in local plasma from S compared with AS patients; in peripheral plasma from S compared with AS patients. Pathway analysis revealed that detected proteins were related to ossification, lysosomes, magnesium transport, prenylation, collagens, lipid metabolism, and transcription factors. Identified candidate proteins were further filtered using public database mining, comparisons with transcriptomic data from BiKE, and qPCR/IHC in matched endarterectomies. Among the identified candidates, THEMIS2 and BLVRB were examples of proteins successfully validated as upregulated in both plaques and plasma from S patients and localized to CD68+ macrophages. Extensive analysis of plasma and tissue samples from patients undergoing carotid surgery permitted identification of several potential biomarkers for unstable carotid atherosclerosis. Further validation in larger cohorts of unstable atherosclerosis is necessary in order to determine predictive power for the identification of individuals at risk as well as for the development of targeted bioimaging for lesion detection.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.35.suppl_1.26
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2015
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  • 4
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    Expression of Interleukin 6 signaling receptors in carotid atherosclerosis
    SAGE Publications ; 2021
    In:  Vascular Medicine Vol. 26, No. 1 ( 2021-02), p. 3-10
    Details
    In: Vascular Medicine, SAGE Publications, Vol. 26, No. 1 ( 2021-02), p. 3-10
    Abstract: Interleukin (IL) 6 contributes to atherosclerotic plaque development through IL6 membrane-bound (IL6R and gp130) and soluble (sIL6R and sgp130) receptors. We investigated IL6 receptor expression in carotid plaques and its correlation with circulating IL6 and soluble receptor levels. Plasma samples and carotid plaques were obtained from 78 patients in the Biobank of Karolinska Endarterectomies study. IL6, sIL6R, and sgp130 were measured in plasma and IL6, IL6R, sIL6R, GP130, and s GP130-RAPS (s GP130) gene expression assessed in carotid plaques. Correlations between plaque IL6 signaling gene expression and plasma levels were determined by Spearman’s correlation. Differences in plasma and gene expression levels between patients with ( n = 53) and without ( n = 25) a history of a cerebral event and statin-treated ( n = 65) and non-treated ( n = 11), were estimated by Kruskal–Wallis. IL6 and its receptors were all expressed in carotid plaques. There was a positive, borderline significant, moderate correlation between plasma IL6 and sIL6R and the respective gene expression levels (rho 0.23 and 0.22, both p = 0.05). IL6R expression was higher in patients with a history of a cerebrovascular event compared to those without ( p = 0.007). Statin-treated had higher IL6R, sIL6R, and s GP130 expression levels and plasma sIL6R compared to non-treated patients (all p 〈 0.05). In conclusion, all components of the IL6 signaling pathways are expressed in carotid artery plaques and IL6 and sIL6R plasma levels correlate moderately with IL6 and sIL6R. Our data suggest that IL6 signaling in the circulation might mirror the system activity in the plaque, thus adding novel perspectives to the role of IL6 signaling in atherosclerosis.
    Type of Medium: Online Resource
    ISSN: 1358-863X , 1477-0377
    URL: Article
    DOI: 10.1177/1358863X20977662
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2021
    detail.hit.zdb_id: 2027562-6
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  • 5
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    Abstract 420: Proprotein Convertase Subtilisin/Kexin 6 Is Involved In Lipid Metabolism In Liver
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 42, No. Suppl_1 ( 2022-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 42, No. Suppl_1 ( 2022-05)
    Abstract: Introduction: PCSK6 is a protease that activates cytokines and growth factors and strongly enriched in healthy human liver, however its function in this context has not been explored. We have previously shown that PCSK6 is induced in atherosclerotic plaques from patients with symptoms of stroke and important for regulating several cell types in this context. Here, we aimed to investigate the role of PCSK6 in lipid metabolism in liver, particularly in the context of atherosclerosis and non-alcoholic fatty liver disease (NAFLD). Methods: We used publically available datasets and several atherosclerosis biobanks to investigate the expression of PCSK6 in healthy and diseased human tissues. In addition, we used full Pcsk6 -/- mice as well as liver specific conditional Pcsk6 -/- knockout mice compared to littermate controls, to investigate the effects of PCSK6 ablation on lipid metabolism. Results: Genetic analyses of the PCSK6 locus identified a variant, rs7181043, that was significantly associated with PCSK6 mRNA expression in healthy human adipose tissue, liver and in atherosclerotic plaques. The same variant was associated specifically with plaque fat content and atherosclerotic patient’s plasma LDL levels. In addition, PCSK6 mRNA expression in plaques was positively correlated with total plasma cholesterol and LDL levels in atherosclerotic patients as well as lipid metabolism associated pathways within the carotid plaque. Microarray comparison of the livers from Pcsk6 -/- mice and controls showed that VLDL particle assembly was one of the upregulated processes. I n vivo studies showed that Pcsk6 -/- mice have higher plasma cholesterol and LPL levels at baseline compared to controls, and lower levels of LDLR in their liver. These findings were further confirmed in liver specific conditional knockouts. Preliminary results show that liver specific knockout mice develop increased liver steatosis and fibrosis on a modified western diet. Conclusions: Our data suggests that PCSK6 is involved in cholesterol and metabolic control in liver. Breeding of liver specific Pcsk6 knockout mice on an ApoE -/- background is currently ongoing and will provide insight into the role of liver PCSK6 in atherosclerosis and NAFLD development.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.42.suppl_1.420
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
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  • 6
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    Abstract 105: Proprotein Convertase Subtilisin/kexin Type 6 (Pcsk6) Plays A Role In Angiogenesis Regulation
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 42, No. Suppl_1 ( 2022-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 42, No. Suppl_1 ( 2022-05)
    Abstract: Background: PCSK6 cleaves and activates growth factors involved in cell differentiation and Pcsk6-/- mice exhibit 25% embryonic lethality, while surviving offspring have blindness and cyclopia. We have shown that PCSK6 localizes to vascular smooth muscle cells of intra-plaque neovessels. We therefore hypothesize that the processes of angiogenesis, atherosclerosis and plaque neovascularisation share common molecular regulators and that PCSK6 plays a role in these processes. Methods: Association between SNPs near the PCSK6 gene and levels of 90 plasma proteins was tested using data from 30,931 individuals in the SCALLOP consortium. Associations of angiogenic factors with PCSK6 (transcriptomic and proteomic) and patient symptomatology were explored in a biobank of plaque endarterectomies (BiKE). Morpholino technology was used for Pcsk6 knockdown in zebrafish, coupled with vascular phenotype studies. Pcsk6-/- mice were used to study the expression of vasculogenesis related genes and vascular morphology at baseline (12 weeks). Results: Rs7178801 and rs11639051 in the PCSK6 gene were found to relate to plasma PDGFB and VEGFD levels. TGFB2, VEGFA, VEGFC, PDGFA and PLAUR associated with patients symptomatology in BiKE and correlated with PCSK6 levels. Gross phenotypic and histological examination of zebrafish embryos with ablated PCSK6 showed improper peripheral vascular patterning of intersegmental vessels along with cerebral and myocardial haemorrhage hemorrhage. Expression of angiogenic factors; Vegfa, Vegfb, Angpt1 and Tgfb2 were altered in the heart, liver and adipose tissue in Pcsk6-/- mice. Vessel density, length and branch numbers were reduced in the Pcsk6 -/- compared to the controls in the superficial but more significantly in the deep peripheral vessels. The smooth muscle cell coverage of the retinal vasculature was also reduced in the Pcsk6 -/- mice vs controls and Pdgfa was significantly downregulated compared to controls in mouse retinas. Conclusions: PCSK6 associates with levels of angiogenic factors on the genetic, transcriptomic and proteomic level. Lack of Pcsk6 in mice and zebrafish led to vascular patterning defects. Further planned studies will examine PCSK6 in pathological neovascularization.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.42.suppl_1.105
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
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  • 7
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    Abstract 217: PCSK6 Is A Key Regulator Of Immune Status In Mice And Its Ablation Increases Atherosclerotic Plaque Burden In A Bone Marrow Transplant Model
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 42, No. Suppl_1 ( 2022-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 42, No. Suppl_1 ( 2022-05)
    Abstract: Introduction: Proprotein convertase subtilisins/kexins (PCSKs) activate cytokines and growth factors and have been implicated in various cancers. We have previously shown that PCSK6 is a key protease modulating smooth muscle cell response in atherosclerosis, but its expression also correlated positively with typical markers of T lymphocytes and macrophages in plaques and it was localised in the proximity of these cells. Here, we hypothesized that PCSK6 may be involved in modulating inflammatory responses and aimed to elucidate its role in a hyperlipidemic mice model. Methods: Detailed immunophenotyping using histology, FACS-, OLINK- and ELISA-based analyses and primary cell cultures was used to compare Pcsk6 -/- and littermate controls. Atherosclerosis was evaluated in Ldlr -/- mice upon bone marrow transplant with Pcsk6 -/- or wild-type bone-marrow. Results: At baseline Pcks6 -/- mice showed an enrichment of pro-inflammatory cytokines Ccl2, Ccl3, Ccl20, Cxcl1 and in particular Il17a and Il17f in plasma compared controls. Spleens of Pcsk6 -/- mice had an increased number of germinal centres and FACS analysis showed that they contained significantly more CD8+ T cells. Microarray analysis of spleens from Pcsk6 -/- vs. controls confirmed that T cell markers CD4, CD3E and CD3G were upregulated. In vitro , splenocytes isolated from Pcsk6 -/- mice secreted more IFN-γ, IL-2 and IL-10 than controls upon stimulation with α-CD3 and α-CD28 antibodies. Moreover, peritoneal macrophages from Pcsk6 -/- mice secreted more TNF-α, MCP-1, IL-6 and IL-10 compared to control mice upon LPS stimulation. Interestingly, bone marrow derived macrophages from Pcsk6 -/- mice were also more prone to lipid uptake. Finally, in vivo transplantation of Pcsk6 -/- bone marrow to Ldlr -/- mice led to increased atherosclerotic plaque burden compared to controls, as quantified in the aortic root. Conclusions: PCSK6 ablation led to increased number of CD8+ T cells, as well as macrophage and cytokine activation. Transplantation of Pcsk6 -/- bone marrow resulted in an increase in atherosclerotic plaque burden compared to controls. Taken together, these results indicate that PCSK6 is a key regulator of the immune system, though the exact mechanisms involved require further investigation.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.42.suppl_1.217
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
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  • 8
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    Virtual Transcriptomics : Noninvasive Phenotyping of Atherosclerosis by Decoding Plaque Biology From Computed Tomography Angiography Imaging
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 41, No. 5 ( 2021-05-05), p. 1738-1750
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 41, No. 5 ( 2021-05-05), p. 1738-1750
    Abstract: Therapeutic advancements in atherosclerotic cardiovascular disease have improved prevention of ischemic stroke and myocardial infarction, but diagnostic methods for atherosclerotic plaque phenotyping to aid individualized therapy are lacking. In this feasibility study, we aimed to elucidate plaque biology by decoding the molecular phenotype of plaques through analysis of computed-tomography angiography images, making a predictive model for plaque biology referred to as virtual transcriptomics. Approach and Results: We employed machine intelligence using paired computed-tomography angiography and transcriptomics from carotid endarterectomies of 40 patients undergoing stroke-preventive surgery for carotid stenosis. Computed tomography angiographies were analyzed with novel software for accurate characterization of plaque morphology and plaque transcriptomes obtained from microarrays, followed by mathematical modeling for prediction of molecular signatures. Four hundred fourteen coding and noncoding RNAs were robustly predicted using supervised models to estimate gene expression based on plaque morphology. Examples of predicted transcripts included ion transporters, cytokine receptors, and a number of microRNAs whereas pathway analyses demonstrated enrichment of several biological processes relevant for the pathophysiology of atherosclerosis and plaque instability. Finally, the ability of the models to predict plaque gene expression was demonstrated using computed tomography angiographies from 4 sequestered patients and comparisons with transcriptomes of corresponding lesions. Conclusions: The results of this pilot study show that atherosclerotic plaque phenotyping by image analysis of conventional computed-tomography angiography can elucidate the molecular signature of atherosclerotic lesions in a multiscale setting. The study holds promise for optimized personalized therapy in the prevention of myocardial infarction and ischemic stroke, which warrants further investigations in larger cohorts.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/ATVBAHA.121.315969
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
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  • 9
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    Deficiency of the T cell regulator Casitas B-cell lymphoma-B aggravates atherosclerosis by inducing CD8+ T cell-mediated macrophage death
    Oxford University Press (OUP) ; 2019
    In:  European Heart Journal Vol. 40, No. 4 ( 2019-01-21), p. 372-382
    Details
    In: European Heart Journal, Oxford University Press (OUP), Vol. 40, No. 4 ( 2019-01-21), p. 372-382
    Type of Medium: Online Resource
    ISSN: 0195-668X , 1522-9645
    URL: Article
    DOI: 10.1093/eurheartj/ehy714
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
    detail.hit.zdb_id: 2001908-7
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  • 10
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    Adenosine-to-inosine RNA editing controls cathepsin S expression in atherosclerosis by enabling HuR-mediated post-transcriptional regulation
    Springer Science and Business Media LLC ; 2016
    In:  Nature Medicine Vol. 22, No. 10 ( 2016-10), p. 1140-1150
    Details
    In: Nature Medicine, Springer Science and Business Media LLC, Vol. 22, No. 10 ( 2016-10), p. 1140-1150
    Type of Medium: Online Resource
    ISSN: 1078-8956 , 1546-170X
    URL: Article
    DOI: 10.1038/nm.4172
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2016
    detail.hit.zdb_id: 1484517-9
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