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{"title"=>"Tick-borne encephalitis virus replication, intracellular trafficking, and pathogenicity in human intestinal Caco-2 cell monolayers", "type"=>"journal", "authors"=>[{"first_name"=>"Chao", "last_name"=>"Yu", "scopus_author_id"=>"55918825600"}, {"first_name"=>"Katharina", "last_name"=>"Achazi", "scopus_author_id"=>"23007344700"}, {"first_name"=>"Lars", "last_name"=>"Möller", "scopus_author_id"=>"24473568200"}, {"first_name"=>"Joerg D.", "last_name"=>"Schulzke", "scopus_author_id"=>"35502556700"}, {"first_name"=>"Matthias", "last_name"=>"Niedrig", "scopus_author_id"=>"7003827932"}, {"first_name"=>"Roland", "last_name"=>"Bücker", "scopus_author_id"=>"10043068400"}], "year"=>2014, "source"=>"PLoS ONE", "identifiers"=>{"pmid"=>"24820351", "sgr"=>"84901248531", "doi"=>"10.1371/journal.pone.0096957", "scopus"=>"2-s2.0-84901248531", "pui"=>"373143876", "issn"=>"19326203"}, "id"=>"29b4b44b-121c-3e9a-bfa7-8a52a4584262", "abstract"=>"Tick-borne encephalitis virus (TBEV) is one of the most important vector-borne viruses in Europe and Asia. Its transmission mainly occurs by the bite of an infected tick. However, consuming milk products from infected livestock animals caused TBEV cases. To better understand TBEV transmission via the alimentary route, we studied viral infection of human intestinal epithelial cells. Caco-2 cells were used to investigate pathological effects of TBEV infection. TBEV-infected Caco-2 monolayers showed morphological changes including cytoskeleton rearrangements and cytoplasmic vacuolization. Ultrastructural analysis revealed dilatation of the rough endoplasmic reticulum and further enlargement to TBEV containing caverns. Caco-2 monolayers maintained an intact epithelial barrier with stable transepithelial electrical resistance (TER) during early stage of infection. Concomitantly, viruses were detected in the basolateral medium, implying a transcytosis pathway. When Caco-2 cells were pre-treated with inhibitors of cellular pathways of endocytosis TBEV cell entry was efficiently blocked, suggesting that actin filaments (Cytochalasin) and microtubules (Nocodazole) are important for PI3K-dependent (LY294002) virus endocytosis. Moreover, experimental fluid uptake assay showed increased intracellular accumulation of FITC-dextran containing vesicles. Immunofluorescence microscopy revealed co-localization of TBEV with early endosome antigen-1 (EEA1) as well as with sorting nexin-5 (SNX5), pointing to macropinocytosis as trafficking mechanism. In the late phase of infection, further evidence was found for translocation of virus via the paracellular pathway. Five days after infection TER was slightly decreased. Epithelial barrier integrity was impaired due to increased epithelial apoptosis, leading to passive viral translocation. These findings illuminate pathomechanisms in TBEV infection of human intestinal epithelial cells and viral transmission via the alimentary route.", "link"=>"http://www.mendeley.com/research/tickborne-encephalitis-virus-replication-intracellular-trafficking-pathogenicity-human-intestinal-ca-2", "reader_count"=>15, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>1, "Researcher"=>2, "Student > Ph. D. Student"=>4, "Student > Postgraduate"=>1, "Student > Master"=>2, "Other"=>1, "Student > Bachelor"=>2, "Professor"=>2}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>1, "Researcher"=>2, "Student > Ph. D. Student"=>4, "Student > Postgraduate"=>1, "Student > Master"=>2, "Other"=>1, "Student > Bachelor"=>2, "Professor"=>2}, "reader_count_by_subject_area"=>{"Unspecified"=>1, "Biochemistry, Genetics and Molecular Biology"=>4, "Agricultural and Biological Sciences"=>4, "Medicine and Dentistry"=>2, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Veterinary Science and Veterinary Medicine"=>1, "Immunology and Microbiology"=>2}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>2}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>4}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>4}, "Unspecified"=>{"Unspecified"=>1}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}, "Veterinary Science and Veterinary Medicine"=>{"Veterinary Science and Veterinary Medicine"=>1}}, "reader_count_by_country"=>{"United States"=>1}, "group_count"=>0}

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• http://doi.org/10.1186/s12985-019-1200-2
• http://doi.org/10.1021/acsami.6b15151
• http://doi.org/10.1128/JVI.01926-20
• http://doi.org/10.3390/v10070350
• http://doi.org/10.1186/s12920-019-0503-x
• http://doi.org/10.1016/j.cois.2016.04.015
• http://doi.org/10.1186/s13071-015-1099-4
• http://doi.org/10.1146/annurev-immunol-042718-041417
• http://doi.org/10.1128/JVI.00292-19

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• {"files"=>["https://ndownloader.figshare.com/files/1494064"], "description"=>"<p>(<b>A</b>) Impaired TBEV entry by EIPA. Dose-dependence of EIPA-induced inhibition of TBEV entry. Caco-2 cells were pre-treated with EIPA for 30 min, followed by incubation with TBEV in the presence of the inhibitor. After 1 h, virus entry was monitored by RT-qPCR. n = 4; *<i>P</i><0.05, **<i>P</i><0.01 to DMSO control in Student's t test. (<b>B</b>) Fluid uptake. Accumulation of intracellular FITC-dextran (green) induced by TBEV infection. Caco-2 cells were treated with TBEV strain K23 for 1 h and then washed with PBS. Subsequently, cells were incubated with FITC-labeled dextran (1 mg/ml). After 4 h, cells were washed, fixed and observed by confocal microscopy. One representative image of a triplicate is depicted. (<b>C</b>) Accumulation of dextran in cells was analyzed by counting the total number of intracellular FITC-dextran-containing vesicles in a low power field using ImageJ. **<i>P</i><0.01 (n = 3). (<b>D</b>) Immunofluorescence microscopy. TBEV co-localization (as merge in yellow, indicated by arrows) with early endosomal antigen-1 (EEA1) or (<b>E</b>) Sorting nexin-5 (SNX5) after virus entry. Cells were fixed and stained for TBEV anti-E protein and EEA1 or SNX5 with primary antibodies, followed by secondary antibodies as indicated in the image. A representative image (63× objective) is shown. Yellow dots as merge indicate TBEV particles in co-localization with EEA1 or SNX5.</p>", "links"=>[], "tags"=>["anatomy", "Digestive system", "gastrointestinal tract", "Small intestine", "cell biology", "Cell processes", "Cell death", "Signal transduction", "cell signaling", "Cell physiology", "Molecular cell biology", "Computational biology", "Population modeling", "Infectious disease modeling", "microbiology", "Virology", "Viral transmission and infection", "Host cells", "Viral entry", "Viral replication", "organisms", "animals", "invertebrates", "arthropoda", "arachnida", "ixodes", "ticks", "physiology", "electrophysiology", "Veterinary science", "Veterinary diseases", "Zoonoses", "Veterinary medicine", "Livestock care", "epidemiology", "disease vectors", "Gastroenterology and hepatology", "Gastrointestinal infections", "Infectious diseases", "Viral diseases", "macropinocytosis", "tbev", "infected", "caco-2"], "article_id"=>1023776, "categories"=>["Biological Sciences"], "users"=>["Chao Yu", "Katharina Achazi", "Lars Möller", "Joerg D. Schulzke", "Matthias Niedrig", "Roland Bücker"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0096957.g005", "stats"=>{"downloads"=>0, "page_views"=>22, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Characteristics_of_macropinocytosis_in_TBEV_infected_Caco_2_cells_/1023776", "title"=>"Characteristics of macropinocytosis in TBEV infected Caco-2 cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-05-12 03:18:22"}
• {"files"=>["https://ndownloader.figshare.com/files/1494059"], "description"=>"<p>All photographs were taken at 12(rER) containing TBEV are indicated by asterisks and ribosomes of the rER are indicated by small vertical arrows. (A) bar  = 1 µm, (B) bar  = 500 nm, (C) bar  = 500 nm, (D) bar  = 200 nm.</p>", "links"=>[], "tags"=>["anatomy", "Digestive system", "gastrointestinal tract", "Small intestine", "cell biology", "Cell processes", "Cell death", "Signal transduction", "cell signaling", "Cell physiology", "Molecular cell biology", "Computational biology", "Population modeling", "Infectious disease modeling", "microbiology", "Virology", "Viral transmission and infection", "Host cells", "Viral entry", "Viral replication", "organisms", "animals", "invertebrates", "arthropoda", "arachnida", "ixodes", "ticks", "physiology", "electrophysiology", "Veterinary science", "Veterinary diseases", "Zoonoses", "Veterinary medicine", "Livestock care", "epidemiology", "disease vectors", "Gastroenterology and hepatology", "Gastrointestinal infections", "Infectious diseases", "Viral diseases", "tbev-infected", "caco-2", "cells", "ultrathin", "electron"], "article_id"=>1023771, "categories"=>["Biological Sciences"], "users"=>["Chao Yu", "Katharina Achazi", "Lars Möller", "Joerg D. Schulzke", "Matthias Niedrig", "Roland Bücker"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0096957.g003", "stats"=>{"downloads"=>3, "page_views"=>133, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Ultrastructural_analysis_of_TBEV_infected_Caco_2_cells_by_ultrathin_section_transmission_electron_microscopy_/1023771", "title"=>"Ultrastructural analysis of TBEV-infected Caco-2 cells by ultrathin section transmission electron microscopy.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-05-12 03:18:22"}
• {"files"=>["https://ndownloader.figshare.com/files/1494042"], "description"=>"<p>Human cells infected with TBEV strains K23, Sofjin, and Ania at an MOI of 0.1. Viral supernatant and intracellular viral RNA were harvested at 24(<b>A</b>) Intracellular TBEV RNA copy numbers, measured by RT-qPCR. (<b>B</b>) Viral titers in the supernatant determined by plaque assay, n = 3; *<i>P</i><0.05, **<i>P</i><0.01 to initial virus titer in Student's <i>t</i> test. (<b>C</b>) Immunofluorescence assay of TBEV-infected Caco-2 cell monolayers. Caco-2 cells infected with TBEV K23 strain were fixed at different time points and subjected to immunofluorescence assay. TBEV E (green), nuclei (blue, DAPI = 4′-6-diamidino-2-phenylindole dihydrochloride). One representative image of a triplicate is shown.</p>", "links"=>[], "tags"=>["anatomy", "Digestive system", "gastrointestinal tract", "Small intestine", "cell biology", "Cell processes", "Cell death", "Signal transduction", "cell signaling", "Cell physiology", "Molecular cell biology", "Computational biology", "Population modeling", "Infectious disease modeling", "microbiology", "Virology", "Viral transmission and infection", "Host cells", "Viral entry", "Viral replication", "organisms", "animals", "invertebrates", "arthropoda", "arachnida", "ixodes", "ticks", "physiology", "electrophysiology", "Veterinary science", "Veterinary diseases", "Zoonoses", "Veterinary medicine", "Livestock care", "epidemiology", "disease vectors", "Gastroenterology and hepatology", "Gastrointestinal infections", "Infectious diseases", "Viral diseases", "cells", "susceptible", "tbev"], "article_id"=>1023765, "categories"=>["Biological Sciences"], "users"=>["Chao Yu", "Katharina Achazi", "Lars Möller", "Joerg D. Schulzke", "Matthias Niedrig", "Roland Bücker"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0096957.g001", "stats"=>{"downloads"=>2, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Caco_2_cells_are_susceptible_to_TBEV_infection_/1023765", "title"=>"Caco-2 cells are susceptible to TBEV infection.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-05-12 03:18:22"}
• {"files"=>["https://ndownloader.figshare.com/files/1494123", "https://ndownloader.figshare.com/files/1494124", "https://ndownloader.figshare.com/files/1494125", "https://ndownloader.figshare.com/files/1494126", "https://ndownloader.figshare.com/files/1494127", "https://ndownloader.figshare.com/files/1494128", "https://ndownloader.figshare.com/files/1494129"], "description"=>"<div><p>Tick-borne encephalitis virus (TBEV) is one of the most important vector-borne viruses in Europe and Asia. Its transmission mainly occurs by the bite of an infected tick. However, consuming milk products from infected livestock animals caused TBEV cases. To better understand TBEV transmission via the alimentary route, we studied viral infection of human intestinal epithelial cells. Caco-2 cells were used to investigate pathological effects of TBEV infection. TBEV-infected Caco-2 monolayers showed morphological changes including cytoskeleton rearrangements and cytoplasmic vacuolization. Ultrastructural analysis revealed dilatation of the rough endoplasmic reticulum and further enlargement to TBEV containing caverns. Caco-2 monolayers maintained an intact epithelial barrier with stable transepithelial electrical resistance (TER) during early stage of infection. Concomitantly, viruses were detected in the basolateral medium, implying a transcytosis pathway. When Caco-2 cells were pre-treated with inhibitors of cellular pathways of endocytosis TBEV cell entry was efficiently blocked, suggesting that actin filaments (Cytochalasin) and microtubules (Nocodazole) are important for PI3K-dependent (LY294002) virus endocytosis. Moreover, experimental fluid uptake assay showed increased intracellular accumulation of FITC-dextran containing vesicles. Immunofluorescence microscopy revealed co-localization of TBEV with early endosome antigen-1 (EEA1) as well as with sorting nexin-5 (SNX5), pointing to macropinocytosis as trafficking mechanism. In the late phase of infection, further evidence was found for translocation of virus via the paracellular pathway. Five days after infection TER was slightly decreased. Epithelial barrier integrity was impaired due to increased epithelial apoptosis, leading to passive viral translocation. These findings illuminate pathomechanisms in TBEV infection of human intestinal epithelial cells and viral transmission via the alimentary route.</p></div>", "links"=>[], "tags"=>["anatomy", "Digestive system", "gastrointestinal tract", "Small intestine", "cell biology", "Cell processes", "Cell death", "Signal transduction", "cell signaling", "Cell physiology", "Molecular cell biology", "Computational biology", "Population modeling", "Infectious disease modeling", "microbiology", "Virology", "Viral transmission and infection", "Host cells", "Viral entry", "Viral replication", "organisms", "animals", "invertebrates", "arthropoda", "arachnida", "ixodes", "ticks", "physiology", "electrophysiology", "Veterinary science", "Veterinary diseases", "Zoonoses", "Veterinary medicine", "Livestock care", "epidemiology", "disease vectors", "Gastroenterology and hepatology", "Gastrointestinal infections", "Infectious diseases", "Viral diseases", "encephalitis", "intracellular", "pathogenicity", "intestinal", "caco-2"], "article_id"=>1023822, "categories"=>["Biological Sciences"], "users"=>["Chao Yu", "Katharina Achazi", "Lars Möller", "Joerg D. Schulzke", "Matthias Niedrig", "Roland Bücker"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0096957.s001", "https://dx.doi.org/10.1371/journal.pone.0096957.s002", "https://dx.doi.org/10.1371/journal.pone.0096957.s003", "https://dx.doi.org/10.1371/journal.pone.0096957.s004", "https://dx.doi.org/10.1371/journal.pone.0096957.s005", "https://dx.doi.org/10.1371/journal.pone.0096957.s006", "https://dx.doi.org/10.1371/journal.pone.0096957.s007"], "stats"=>{"downloads"=>6, "page_views"=>16, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Tick_Borne_Encephalitis_Virus_Replication_Intracellular_Trafficking_and_Pathogenicity_in_Human_Intestinal_Caco_2_Cell_Monolayers_/1023822", "title"=>"Tick-Borne Encephalitis Virus Replication, Intracellular Trafficking, and Pathogenicity in Human Intestinal Caco-2 Cell Monolayers", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2014-05-12 03:18:22"}
• {"files"=>["https://ndownloader.figshare.com/files/1494060"], "description"=>"<p>(<b>A</b>) Actin re-arrangements following TBEV infection. Cells infected with TBEV strain K23 were fixed at 24 h. Samples were stained for actin microfilament and the apical cell-domain (perijunctional cytoskeleton) was visualized by fluorescence microscopy with Acti-stain 488 phalloidin. Non-infected cells were used as controls. White arrows indicate representative areas of more condensed actin filaments in the right image. (<b>B</b>) Inhibition of TBEV cell entry by blocking microfilaments. Caco-2 cells were treated with cytochalasin D (Cyt D), nocodazole (Noc) or LY294002 (LY) for 30 min. DMSO treated Caco-2 cells were used as control. After treatment with inhibitors, cells were incubated with TBEV strain K23 for 1 h. Virus entry was monitored by RT-qPCR, n = 3; **<i>P</i><0.01 to control in Student's t test.</p>", "links"=>[], "tags"=>["anatomy", "Digestive system", "gastrointestinal tract", "Small intestine", "cell biology", "Cell processes", "Cell death", "Signal transduction", "cell signaling", "Cell physiology", "Molecular cell biology", "Computational biology", "Population modeling", "Infectious disease modeling", "microbiology", "Virology", "Viral transmission and infection", "Host cells", "Viral entry", "Viral replication", "organisms", "animals", "invertebrates", "arthropoda", "arachnida", "ixodes", "ticks", "physiology", "electrophysiology", "Veterinary science", "Veterinary diseases", "Zoonoses", "Veterinary medicine", "Livestock care", "epidemiology", "disease vectors", "Gastroenterology and hepatology", "Gastrointestinal infections", "Infectious diseases", "Viral diseases", "tbev", "caco-2"], "article_id"=>1023772, "categories"=>["Biological Sciences"], "users"=>["Chao Yu", "Katharina Achazi", "Lars Möller", "Joerg D. Schulzke", "Matthias Niedrig", "Roland Bücker"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0096957.g004", "stats"=>{"downloads"=>0, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cytoskeletal_integrity_is_important_for_TBEV_infection_in_Caco_2_cells_/1023772", "title"=>"Cytoskeletal integrity is important for TBEV infection in Caco-2 cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-05-12 03:18:22"}
• {"files"=>["https://ndownloader.figshare.com/files/1494044"], "description"=>"<p>Caco-2 cells were infected with TBEV K23 virus. Cellular morphological changes and vacuolization were monitored by light microscopy. Caco-2 cells were infected with TBEV strain K23 and fixed at 24 h, 48 h and 72 h. Cells were observed with the 40× objective (400× total magnification). Details of cytoplasmic vacuolization are visualized by immunofluorescence (IF) microscopy. 3 representative vacuoles are indicated by white asterisks in each sub-image. Samples were incubated with anti-TBEV E antibody and then stained with secondary anti-mouse antibody conjugated to FITC (green). Nuclei were stained with DAPI (blue).</p>", "links"=>[], "tags"=>["anatomy", "Digestive system", "gastrointestinal tract", "Small intestine", "cell biology", "Cell processes", "Cell death", "Signal transduction", "cell signaling", "Cell physiology", "Molecular cell biology", "Computational biology", "Population modeling", "Infectious disease modeling", "microbiology", "Virology", "Viral transmission and infection", "Host cells", "Viral entry", "Viral replication", "organisms", "animals", "invertebrates", "arthropoda", "arachnida", "ixodes", "ticks", "physiology", "electrophysiology", "Veterinary science", "Veterinary diseases", "Zoonoses", "Veterinary medicine", "Livestock care", "epidemiology", "disease vectors", "Gastroenterology and hepatology", "Gastrointestinal infections", "Infectious diseases", "Viral diseases", "induced", "tbev"], "article_id"=>1023767, "categories"=>["Biological Sciences"], "users"=>["Chao Yu", "Katharina Achazi", "Lars Möller", "Joerg D. Schulzke", "Matthias Niedrig", "Roland Bücker"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0096957.g002", "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Vacuolization_induced_by_TBEV_infection_/1023767", "title"=>"Vacuolization induced by TBEV infection.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-05-12 03:18:22"}
• {"files"=>["https://ndownloader.figshare.com/files/1494065"], "description"=>"<p>(<b>A</b>) Virus amount in basal medium. Polarized Caco-2 monolayers grown on permeable supports were infected with TBEV strain K23 from the apical surface. Basal medium was harvest at different time points and viral RNA in each sample was detected by RT-qPCR. The data were displayed as mean with standard deviation. (<b>B</b>) Transepithelial electric resistance (TER) measurements during TBEV infection. Polarized Caco-2 monolayers, grown on permeable supports, infected with TBEV K23 (circles) from the apical surface. Non-infected cells served as controls (triangles). TER values were measured from 0 h to 120 h post infection. n = 5, *<i>P</i><0.05, **<i>P</i><0.01 to control in Student's t test. (<b>C</b>) Cell viability during TBEV infection. Caco-2 cells were infected with TBEV strain K23 at an MOI of 1 and cell viability was analyzed by MTT assay. Cell viability was measured and calculated as a percentage of non-infected control cells. Data were expressed as mean ± standard error of the mean. (<b>D</b>) Analysis of TUNEL-positive cells. Confluent Caco-2 cells were infected with TBEV strain K23 and apoptosis was detected by a terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) at 48 h and 120 h post infection. The ratios of TUNEL-positive cells to all cells were analyzed in 4 low-power fields from 3 independent samples of each group. **<i>P</i><0.01.</p>", "links"=>[], "tags"=>["anatomy", "Digestive system", "gastrointestinal tract", "Small intestine", "cell biology", "Cell processes", "Cell death", "Signal transduction", "cell signaling", "Cell physiology", "Molecular cell biology", "Computational biology", "Population modeling", "Infectious disease modeling", "microbiology", "Virology", "Viral transmission and infection", "Host cells", "Viral entry", "Viral replication", "organisms", "animals", "invertebrates", "arthropoda", "arachnida", "ixodes", "ticks", "physiology", "electrophysiology", "Veterinary science", "Veterinary diseases", "Zoonoses", "Veterinary medicine", "Livestock care", "epidemiology", "disease vectors", "Gastroenterology and hepatology", "Gastrointestinal infections", "Infectious diseases", "Viral diseases", "tbev", "caco-2", "monolayers", "affecting", "transepithelial"], "article_id"=>1023777, "categories"=>["Biological Sciences"], "users"=>["Chao Yu", "Katharina Achazi", "Lars Möller", "Joerg D. Schulzke", "Matthias Niedrig", "Roland Bücker"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0096957.g006", "stats"=>{"downloads"=>0, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Translocation_of_TBEV_through_Caco_2_monolayers_without_affecting_transepithelial_electrical_resistance_TER_/1023777", "title"=>"Translocation of TBEV through Caco-2 monolayers without affecting transepithelial electrical resistance (TER).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-05-12 03:18:22"}

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Relative Metric

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F1000Prime