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Article ; Online: Re-defining synthetic lethality by phenotypic profiling for precision oncology.

Akimov, Yevhen / Aittokallio, Tero

Cell chemical biology

2021 Volume 28, Issue 3, Page(s) 246–256

Abstract: High-throughput functional and genomic screening techniques provide systematic means for phenotypic discovery. Using synthetic lethality (SL) as a paradigm for anticancer drug and target discovery, we describe how these screening technologies may offer ... ...

Abstract	High-throughput functional and genomic screening techniques provide systematic means for phenotypic discovery. Using synthetic lethality (SL) as a paradigm for anticancer drug and target discovery, we describe how these screening technologies may offer new possibilities to identify therapeutically relevant and selective SL interactions by addressing some of the challenges that have made robust discovery of SL candidates difficult. We further introduce an extended concept of SL interaction, in which a simultaneous perturbation of two or more cellular components reduces cell viability more than expected by their individual effects, which we feel is highly befitting for anticancer applications. We also highlight the potential benefits and challenges related to computational quantification of synergistic interactions and cancer selectivity. Finally, we explore how tumoral heterogeneity can be exploited to find phenotype-specific SL interactions for precision oncology using high-throughput functional screening and the exciting opportunities these methods provide for the identification of subclonal SL interactions.
MeSH term(s)	Drug Discovery ; High-Throughput Screening Assays ; Humans ; Neoplasms/drug therapy ; Neoplasms/genetics ; Neoplasms/pathology ; Phenotype ; Precision Medicine
Language	English
Publishing date	2021-02-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ISSN	2451-9448
ISSN (online)	2451-9448
DOI	10.1016/j.chembiol.2021.01.026
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Article ; Online: Improved detection of differentially represented DNA barcodes for high-throughput clonal phenomics.

Akimov, Yevhen / Bulanova, Daria / Timonen, Sanna / Wennerberg, Krister / Aittokallio, Tero

Molecular systems biology

2020 Volume 16, Issue 3, Page(s) e9195

Abstract: Cellular DNA barcoding has become a popular approach to study heterogeneity of cell populations and to identify clones with differential response to cellular stimuli. However, there is a lack of reliable methods for statistical inference of ... ...

Abstract	Cellular DNA barcoding has become a popular approach to study heterogeneity of cell populations and to identify clones with differential response to cellular stimuli. However, there is a lack of reliable methods for statistical inference of differentially responding clones. Here, we used mixtures of DNA-barcoded cell pools to generate a realistic benchmark read count dataset for modelling a range of outcomes of clone-tracing experiments. By accounting for the statistical properties intrinsic to the DNA barcode read count data, we implemented an improved algorithm that results in a significantly lower false-positive rate, compared to current RNA-seq data analysis algorithms, especially when detecting differentially responding clones in experiments with strong selection pressure. Building on the reliable statistical methodology, we illustrate how multidimensional phenotypic profiling enables one to deconvolute phenotypically distinct clonal subpopulations within a cancer cell line. The mixture control dataset and our analysis results provide a foundation for benchmarking and improving algorithms for clone-tracing experiments.
MeSH term(s)	Algorithms ; Cell Line, Tumor ; Clone Cells ; DNA Barcoding, Taxonomic/methods ; HEK293 Cells ; High-Throughput Nucleotide Sequencing ; Humans ; Neoplasms/genetics ; Phenomics/methods ; Selection, Genetic ; Sequence Analysis, DNA
Language	English
Publishing date	2020-03-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2193510-5
ISSN	1744-4292 ; 1744-4292
ISSN (online)	1744-4292
ISSN	1744-4292
DOI	10.15252/msb.20199195
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Article ; Online: CRISPRi screening reveals regulators of tau pathology shared between exosomal and vesicle-free tau.

Polanco, Juan Carlos / Akimov, Yevhen / Fernandes, Avinash / Briner, Adam / Hand, Gabriel Rhys / van Roijen, Marloes / Balistreri, Giuseppe / Götz, Jürgen

Life science alliance

2022 Volume 6, Issue 1

Abstract: The aggregation of the microtubule-associated protein tau is a defining feature of Alzheimer's disease and other tauopathies. Tau pathology is believed to be driven by free tau aggregates and tau carried within exosome-like extracellular vesicles, both ... ...

Abstract	The aggregation of the microtubule-associated protein tau is a defining feature of Alzheimer's disease and other tauopathies. Tau pathology is believed to be driven by free tau aggregates and tau carried within exosome-like extracellular vesicles, both of which propagate trans-synaptically and induce tau pathology in recipient neurons by a corrupting process of seeding. Here, we performed a genome-wide CRISPRi screen in tau biosensor cells and identified cellular regulators shared by both mechanisms of tau seeding. We identified ANKLE2, BANF1, NUSAP1, EIF1AD, and VPS18 as the top validated regulators that restrict tau aggregation initiated by both exosomal and vesicle-free tau seeds. None of our validated hits affected the uptake of either form of tau seeds, supporting the notion that they operate through a cell-autonomous mechanism downstream of the seed uptake. Lastly, validation studies with human brain tissue also revealed that several of the identified protein hits are down-regulated in the brains of Alzheimer's patients, suggesting that their decreased activity may be required for the emergence or progression of tau pathology in the human brain.
MeSH term(s)	Humans ; tau Proteins/genetics ; tau Proteins/metabolism ; Tauopathies/genetics ; Tauopathies/metabolism ; Tauopathies/pathology ; Alzheimer Disease/metabolism ; Brain/metabolism ; Neurons/metabolism ; Exosomes/genetics
Chemical Substances	tau Proteins
Language	English
Publishing date	2022-10-31
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2575-1077
ISSN (online)	2575-1077
DOI	10.26508/lsa.202201689
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Article ; Online: Multi-modal meta-analysis of cancer cell line omics profiles identifies ECHDC1 as a novel breast tumor suppressor.

Jaiswal, Alok / Gautam, Prson / Pietilä, Elina A / Timonen, Sanna / Nordström, Nora / Akimov, Yevhen / Sipari, Nina / Tanoli, Ziaurrehman / Fleischer, Thomas / Lehti, Kaisa / Wennerberg, Krister / Aittokallio, Tero

Molecular systems biology

2021 Volume 17, Issue 3, Page(s) e9526

Abstract: Molecular and functional profiling of cancer cell lines is subject to laboratory-specific experimental practices and data analysis protocols. The current challenge therefore is how to make an integrated use of the omics profiles of cancer cell lines for ... ...

Abstract	Molecular and functional profiling of cancer cell lines is subject to laboratory-specific experimental practices and data analysis protocols. The current challenge therefore is how to make an integrated use of the omics profiles of cancer cell lines for reliable biological discoveries. Here, we carried out a systematic analysis of nine types of data modalities using meta-analysis of 53 omics studies across 12 research laboratories for 2,018 cell lines. To account for a relatively low consistency observed for certain data modalities, we developed a robust data integration approach that identifies reproducible signals shared among multiple data modalities and studies. We demonstrated the power of the integrative analyses by identifying a novel driver gene, ECHDC1, with tumor suppressive role validated both in breast cancer cells and patient tumors. The multi-modal meta-analysis approach also identified synthetic lethal partners of cancer drivers, including a co-dependency of PTEN deficient endometrial cancer cells on RNA helicases.
MeSH term(s)	Algorithms ; Breast Neoplasms/genetics ; Cell Line, Tumor ; Databases, Genetic ; Epistasis, Genetic ; Female ; Genes, Tumor Suppressor ; Genomics ; Humans ; Mass Spectrometry ; Reproducibility of Results ; Synthetic Lethal Mutations
Language	English
Publishing date	2021-03-12
Publishing country	England
Document type	Journal Article ; Meta-Analysis ; Research Support, Non-U.S. Gov't
ZDB-ID	2193510-5
ISSN	1744-4292 ; 1744-4292
ISSN (online)	1744-4292
ISSN	1744-4292
DOI	10.15252/msb.20209526
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Article ; Online: Genetic and functional implications of an exonic TRIM55 variant in heart failure.

Heliste, Juho / Chheda, Himanshu / Paatero, Ilkka / Salminen, Tiina A / Akimov, Yevhen / Paavola, Jere / Elenius, Klaus / Aittokallio, Tero

Journal of molecular and cellular cardiology

2019 Volume 138, Page(s) 222–233

Abstract: Background: To tackle the missing heritability of sporadic heart failure, we screened for novel heart failure-associated genetic variants in the Finnish population and functionally characterized a novel variant in vitro and in vivo.: Methods and ... ...

Abstract	Background: To tackle the missing heritability of sporadic heart failure, we screened for novel heart failure-associated genetic variants in the Finnish population and functionally characterized a novel variant in vitro and in vivo. Methods and results: Heart failure-associated variants were screened in genotyping array data of the FINRISK study, consisting of 994 cases and 20,118 controls. Based on logistic regression analysis, a potentially damaging variant in TRIM55 (rs138811034), encoding an E140K variant, was selected for validations. In HL-1 cardiomyocytes, we used CRISPR/Cas9 technology to introduce the variant in the endogenous locus, and additionally TRIM55 wildtype or E140K was overexpressed from plasmid. Functional responses were profiled using whole-genome RNA sequencing, RT-PCR and Western analyses, cell viability and cell cycle assays and cell surface area measurements. In zebrafish embryos, cardiac contractility was measured using videomicroscopy after CRISPR-mediated knockout of trim55a or plasmid overexpression of TRIM55 WT or E140K. Genes related to muscle contraction and cardiac stress were highly regulated in Trim55 E140K/- cardiomyocytes. When compared to the WT/WT cells, the variant cells demonstrated reduced viability, significant hypertrophic response to isoproterenol, p21 protein overexpression and impaired cell cycle progression. In zebrafish embryos, the deletion of trim55a or overexpression of TRIM55 E140K reduced cardiac contractility as compared to embryos with wildtype genotype or overexpression of WT TRIM55, respectively. Conclusions: A previously uncharacterized TRIM55 E140K variant demonstrated a number of functional implications for cardiomyocyte functions in vitro and in vivo. These findings suggest a novel role for TRIM55 polymorphism in predisposing to heart failure.
MeSH term(s)	Actinin/metabolism ; Animals ; Base Sequence ; Calcium/metabolism ; Cardiomegaly/complications ; Cardiomegaly/genetics ; Cardiomegaly/pathology ; Cell Cycle ; Cell Line ; Cell Survival ; Chromosomes, Human, Pair 8/genetics ; Cohort Studies ; Embryo, Nonmammalian/metabolism ; Exons/genetics ; Finland ; Gene Expression Regulation ; Genetic Variation ; Heart Failure/genetics ; Heart Failure/physiopathology ; Humans ; Myocardial Contraction/genetics ; Myocytes, Cardiac/metabolism ; Myocytes, Cardiac/pathology ; Sequestosome-1 Protein/metabolism ; Serum Response Factor/metabolism ; Stress, Physiological/genetics ; Tripartite Motif Proteins/genetics ; Zebrafish/embryology
Chemical Substances	SQSTM1 protein, human ; Sequestosome-1 Protein ; Serum Response Factor ; TRIM55 protein, human ; Tripartite Motif Proteins ; Actinin (11003-00-2) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2019-12-19
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80157-4
ISSN	1095-8584 ; 0022-2828
ISSN (online)	1095-8584
ISSN	0022-2828
DOI	10.1016/j.yjmcc.2019.12.008
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Article ; Online: Seed-effect modeling improves the consistency of genome-wide loss-of-function screens and identifies synthetic lethal vulnerabilities in cancer cells.

Jaiswal, Alok / Peddinti, Gopal / Akimov, Yevhen / Wennerberg, Krister / Kuznetsov, Sergey / Tang, Jing / Aittokallio, Tero

Genome medicine

2017 Volume 9, Issue 1, Page(s) 51

Abstract: Background: Genome-wide loss-of-function profiling is widely used for systematic identification of genetic dependencies in cancer cells; however, the poor reproducibility of RNA interference (RNAi) screens has been a major concern due to frequent off- ... ...

Abstract	Background: Genome-wide loss-of-function profiling is widely used for systematic identification of genetic dependencies in cancer cells; however, the poor reproducibility of RNA interference (RNAi) screens has been a major concern due to frequent off-target effects. Currently, a detailed understanding of the key factors contributing to the sub-optimal consistency is still a lacking, especially on how to improve the reliability of future RNAi screens by controlling for factors that determine their off-target propensity. Methods: We performed a systematic, quantitative analysis of the consistency between two genome-wide shRNA screens conducted on a compendium of cancer cell lines, and also compared several gene summarization methods for inferring gene essentiality from shRNA level data. We then devised novel concepts of seed essentiality and shRNA family, based on seed region sequences of shRNAs, to study in-depth the contribution of seed-mediated off-target effects to the consistency of the two screens. We further investigated two seed-sequence properties, seed pairing stability, and target abundance in terms of their capability to minimize the off-target effects in post-screening data analysis. Finally, we applied this novel methodology to identify genetic interactions and synthetic lethal partners of cancer drivers, and confirmed differential essentiality phenotypes by detailed CRISPR/Cas9 experiments. Results: Using the novel concepts of seed essentiality and shRNA family, we demonstrate how genome-wide loss-of-function profiling of a common set of cancer cell lines can be actually made fairly reproducible when considering seed-mediated off-target effects. Importantly, by excluding shRNAs having higher propensity for off-target effects, based on their seed-sequence properties, one can remove noise from the genome-wide shRNA datasets. As a translational application case, we demonstrate enhanced reproducibility of genetic interaction partners of common cancer drivers, as well as identify novel synthetic lethal partners of a major oncogenic driver, PIK3CA, supported by a complementary CRISPR/Cas9 experiment. Conclusions: We provide practical guidelines for improved design and analysis of genome-wide loss-of-function profiling and demonstrate how this novel strategy can be applied towards improved mapping of genetic dependencies of cancer cells to aid development of targeted anticancer treatments.
MeSH term(s)	Class I Phosphatidylinositol 3-Kinases ; Genomics ; Guidelines as Topic ; Humans ; Models, Genetic ; Neoplasms/genetics ; Phosphatidylinositol 3-Kinases ; RNA Interference ; Reproducibility of Results
Chemical Substances	Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Class I Phosphatidylinositol 3-Kinases (EC 2.7.1.137) ; PIK3CA protein, human (EC 2.7.1.137)
Language	English
Publishing date	2017-06-01
Publishing country	England
Document type	Journal Article
ZDB-ID	2484394-5
ISSN	1756-994X ; 1756-994X
ISSN (online)	1756-994X
ISSN	1756-994X
DOI	10.1186/s13073-017-0440-2
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Article ; Online: Orphan G protein-coupled receptor GPRC5A modulates integrin β1-mediated epithelial cell adhesion.

Bulanova, Daria R / Akimov, Yevhen A / Rokka, Anne / Laajala, Teemu D / Aittokallio, Tero / Kouvonen, Petri / Pellinen, Teijo / Kuznetsov, Sergey G

Cell adhesion & migration

2017 Volume 11, Issue 5-6, Page(s) 434–446

Abstract: G-Protein Coupled Receptor (GPCR), Class C, Group 5, Member A (GPRC5A) has been implicated in several malignancies. The underlying mechanisms, however, remain poorly understood. Using a panel of human cell lines, we demonstrate that CRISPR/Cas9-mediated ... ...

Abstract	G-Protein Coupled Receptor (GPCR), Class C, Group 5, Member A (GPRC5A) has been implicated in several malignancies. The underlying mechanisms, however, remain poorly understood. Using a panel of human cell lines, we demonstrate that CRISPR/Cas9-mediated knockout and RNAi-mediated depletion of GPRC5A impairs cell adhesion to integrin substrates: collagens I and IV, fibronectin, as well as to extracellular matrix proteins derived from the Engelbreth-Holm-Swarm (EHS) mouse sarcoma (Matrigel). Consistent with the phenotype, knock-out of GPRC5A correlated with a reduced integrin β1 (ITGB1) protein expression, impaired phosphorylation of the focal adhesion kinase (FAK), and lower activity of small GTPases RhoA and Rac1. Furthermore, we provide the first evidence for a direct interaction between GPRC5A and a receptor tyrosine kinase EphA2, an upstream regulator of FAK, although its contribution to the observed adhesion phenotype is unclear. Our findings reveal an unprecedented role for GPRC5A in regulation of the ITGB1-mediated cell adhesion and it's downstream signaling, thus indicating a potential novel role for GPRC5A in human epithelial cancers.
MeSH term(s)	CRISPR-Cas Systems/genetics ; CRISPR-Cas Systems/physiology ; Cell Adhesion/genetics ; Cell Adhesion/physiology ; Cell Line, Tumor ; Cell Movement/genetics ; Cell Movement/physiology ; Epithelial Cells/cytology ; Epithelial Cells/metabolism ; HeLa Cells ; Humans ; Immunoblotting ; Immunoprecipitation ; Integrin beta1/genetics ; Integrin beta1/metabolism ; MCF-7 Cells ; RNA Interference ; Receptors, G-Protein-Coupled/genetics ; Receptors, G-Protein-Coupled/metabolism ; Signal Transduction/genetics ; Signal Transduction/physiology ; Tandem Mass Spectrometry
Chemical Substances	GPRC5A protein, human ; Integrin beta1 ; Receptors, G-Protein-Coupled
Language	English
Publishing date	2017-02-06
Publishing country	United States
Document type	Journal Article
ISSN	1933-6926
ISSN (online)	1933-6926
DOI	10.1080/19336918.2016.1245264
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Article ; Online: Network pharmacology modeling identifies synergistic Aurora B and ZAK interaction in triple-negative breast cancer.

Tang, Jing / Gautam, Prson / Gupta, Abhishekh / He, Liye / Timonen, Sanna / Akimov, Yevhen / Wang, Wenyu / Szwajda, Agnieszka / Jaiswal, Alok / Turei, Denes / Yadav, Bhagwan / Kankainen, Matti / Saarela, Jani / Saez-Rodriguez, Julio / Wennerberg, Krister / Aittokallio, Tero

NPJ systems biology and applications

2019 Volume 5, Page(s) 20

Abstract: Cancer cells with heterogeneous mutation landscapes and extensive functional redundancy easily develop resistance to monotherapies by emerging activation of compensating or bypassing pathways. To achieve more effective and sustained clinical responses, ... ...

Abstract	Cancer cells with heterogeneous mutation landscapes and extensive functional redundancy easily develop resistance to monotherapies by emerging activation of compensating or bypassing pathways. To achieve more effective and sustained clinical responses, synergistic interactions of multiple druggable targets that inhibit redundant cancer survival pathways are often required. Here, we report a systematic polypharmacology strategy to predict, test, and understand the selective drug combinations for MDA-MB-231 triple-negative breast cancer cells. We started by applying our network pharmacology model to predict synergistic drug combinations. Next, by utilizing kinome-wide drug-target profiles and gene expression data, we pinpointed a synergistic target interaction between Aurora B and ZAK kinase inhibition that led to enhanced growth inhibition and cytotoxicity, as validated by combinatorial siRNA, CRISPR/Cas9, and drug combination experiments. The mechanism of such a context-specific target interaction was elucidated using a dynamic simulation of MDA-MB-231 signaling network, suggesting a cross-talk between p53 and p38 pathways. Our results demonstrate the potential of polypharmacological modeling to systematically interrogate target interactions that may lead to clinically actionable and personalized treatment options.
MeSH term(s)	Antineoplastic Combined Chemotherapy Protocols/metabolism ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Apoptosis/drug effects ; Aurora Kinase B/metabolism ; Aurora Kinase B/physiology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Computer Simulation ; Drug Interactions/genetics ; Drug Synergism ; Female ; Humans ; MAP Kinase Kinase Kinases/metabolism ; MAP Kinase Kinase Kinases/physiology ; Models, Biological ; Protein Kinase Inhibitors/pharmacology ; Protein Kinases/metabolism ; Signal Transduction/drug effects ; Triple Negative Breast Neoplasms/drug therapy ; Triple Negative Breast Neoplasms/genetics ; Triple Negative Breast Neoplasms/metabolism
Chemical Substances	Protein Kinase Inhibitors ; Protein Kinases (EC 2.7.-) ; AURKB protein, human (EC 2.7.11.1) ; Aurora Kinase B (EC 2.7.11.1) ; MAP Kinase Kinase Kinases (EC 2.7.11.25) ; MAP3K20 protein, human (EC 2.7.11.25)
Language	English
Publishing date	2019-07-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2056-7189
ISSN (online)	2056-7189
DOI	10.1038/s41540-019-0098-z
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Article: Chemical, Physical and Biological Triggers of Evolutionary Conserved Bcl-xL-Mediated Apoptosis.

Ianevski, Aleksandr / Kulesskiy, Evgeny / Krpina, Klara / Lou, Guofeng / Aman, Yahyah / Bugai, Andrii / Aasumets, Koit / Akimov, Yevhen / Bulanova, Daria / Gildemann, Kiira / Arutyunyan, Albert F / Susova, Olga Yu / Zhuze, Alexei L / Ji, Ping / Wang, Wei / Holien, Toril / Bugge, Marit / Zusinaite, Eva / Oksenych, Valentyn /

Lysvand, Hilde / Gerhold, Joachim M / Bjørås, Magnar / Johansen, Pål / Waage, Anders / Heckman, Caroline A / Fang, Evandro F / Kainov, Denis E

Cancers

2020 Volume 12, Issue 6

Abstract: Background: The evidence that pan-Bcl-2 or Bcl-xL-specific inhibitors prematurely kill virus-infected or RNA/DNA-transfected cells provides rationale for investigating these apoptotic inducers further. We hypothesized that not only invasive RNA or DNA ( ... ...

Abstract	Background: The evidence that pan-Bcl-2 or Bcl-xL-specific inhibitors prematurely kill virus-infected or RNA/DNA-transfected cells provides rationale for investigating these apoptotic inducers further. We hypothesized that not only invasive RNA or DNA (biological factors) but also DNA/RNA-damaging chemical or physical factors could trigger apoptosis that have been sensitized with pan-Bcl-2 or Bcl-xL-specific agents; Methods: We tested chemical and physical factors plus Bcl-xL-specific inhibitor A-1155463 in cells of various origins and the small roundworms (
Language	English
Publishing date	2020-06-25
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers12061694
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Article ; Online: Antiviral Properties of Chemical Inhibitors of Cellular Anti-Apoptotic Bcl-2 Proteins.

Bulanova, Daria / Ianevski, Aleksandr / Bugai, Andrii / Akimov, Yevhen / Kuivanen, Suvi / Paavilainen, Henrik / Kakkola, Laura / Nandania, Jatin / Turunen, Laura / Ohman, Tiina / Ala-Hongisto, Hanna / Pesonen, Hanna M / Kuisma, Marika S / Honkimaa, Anni / Walton, Emma L / Oksenych, Valentyn / Lorey, Martina B / Guschin, Dmitry / Shim, Jungmin /

Viruses

2017 Volume 9, Issue 10

Abstract: Viral diseases remain serious threats to public health because of the shortage of effective means of control. To combat the surge of viral diseases, new treatments are urgently needed. Here we show that small-molecules, which inhibit cellular anti- ... ...

Abstract	Viral diseases remain serious threats to public health because of the shortage of effective means of control. To combat the surge of viral diseases, new treatments are urgently needed. Here we show that small-molecules, which inhibit cellular anti-apoptotic Bcl-2 proteins (Bcl-2i), induced the premature death of cells infected with different RNA or DNA viruses, whereas, at the same concentrations, no toxicity was observed in mock-infected cells. Moreover, these compounds limited viral replication and spread. Surprisingly, Bcl-2i also induced the premature apoptosis of cells transfected with viral RNA or plasmid DNA but not of mock-transfected cells. These results suggest that Bcl-2i sensitizes cells containing foreign RNA or DNA to apoptosis. A comparison of the toxicity, antiviral activity, and side effects of six Bcl-2i allowed us to select A-1155463 as an antiviral lead candidate. Thus, our results pave the way for the further development of Bcl-2i for the prevention and treatment of viral diseases.
Keywords	covid19
Language	English
Publishing date	2017-09-25
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v9100271
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