Generation of Human Antigen-Specific Monoclonal IgM Antibodies Using Vaccinated “Human Immune System” Mice
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{"title"=>"Generation of human antigen-specific monoclonal IgM antibodies using vaccinated \"human immune system\" mice", "type"=>"journal", "authors"=>[{"first_name"=>"Pablo D.", "last_name"=>"Becker", "scopus_author_id"=>"8516289200"}, {"first_name"=>"Nicolas", "last_name"=>"Legrand", "scopus_author_id"=>"55608918700"}, {"first_name"=>"Caroline M M", "last_name"=>"van Geelen", "scopus_author_id"=>"6508188450"}, {"first_name"=>"Miriam", "last_name"=>"Noerder", "scopus_author_id"=>"24481587900"}, {"first_name"=>"Nicholas D.", "last_name"=>"Huntington", "scopus_author_id"=>"55922608600"}, {"first_name"=>"Annick", "last_name"=>"Lim", "scopus_author_id"=>"7202659122"}, {"first_name"=>"Etsuko", "last_name"=>"Yasuda", "scopus_author_id"=>"24336929300"}, {"first_name"=>"Sean A.", "last_name"=>"Diehl", "scopus_author_id"=>"7101684541"}, {"first_name"=>"Ferenc A.", "last_name"=>"Scheeren", "scopus_author_id"=>"8264235200"}, {"first_name"=>"Michael", "last_name"=>"Ott", "scopus_author_id"=>"7202375420"}, {"first_name"=>"Kees", "last_name"=>"Weijer", "scopus_author_id"=>"7003450829"}, {"first_name"=>"Heiner", "last_name"=>"Wedemeyer", "scopus_author_id"=>"7003486117"}, {"first_name"=>"Jamesdi P.", "last_name"=>"di Santo", "scopus_author_id"=>"7005126254"}, {"first_name"=>"Tim", "last_name"=>"Beaumont", "scopus_author_id"=>"6701662506"}, {"first_name"=>"Carlos A.", "last_name"=>"Guzman", "scopus_author_id"=>"7103258580"}, {"first_name"=>"Hergen", "last_name"=>"Spits", "scopus_author_id"=>"7006756535"}], "year"=>2010, "source"=>"PLoS ONE", "identifiers"=>{"pmid"=>"20957227", "sgr"=>"78049251370", "doi"=>"10.1371/journal.pone.0013137", "scopus"=>"2-s2.0-78049251370", "pui"=>"359856591", "isbn"=>"1932-6203 (Electronic) 1932-6203 (Linking)", "issn"=>"19326203"}, "id"=>"a6f5832e-cfcc-33e8-b8fc-c94f17667e5c", "abstract"=>"BACKGROUND: Passive transfer of antibodies not only provides immediate short-term protection against disease, but also can be exploited as a therapeutic tool. However, the 'humanization' of murine monoclonal antibodies (mAbs) is a time-consuming and expensive process that has the inherent drawback of potentially altering antigenic specificity and/or affinity. The immortalization of human B cells represents an alternative for obtaining human mAbs, but relies on the availability of biological samples from vaccinated individuals or convalescent patients. In this work we describe a novel approach to generate fully human mAbs by combining a humanized mouse model with a new B cell immortalization technique. METHODOLOGY/PRINCIPAL FINDINGS: After transplantation with CD34+CD38 human hematopoietic progenitor cells, BALB/c Rag2/IL-2Rgammac/ mice acquire a human immune system and harbor B cells with a diverse IgM repertoire. \"Human Immune System\" mice were then immunized with two commercial vaccine antigens, tetanus toxoid and hepatitis B surface antigen. Sorted human CD19+CD27+ B cells were retrovirally transduced with the human B cell lymphoma (BCL)-6 and BCL-XL genes, and subsequently cultured in the presence of CD40-ligand and IL-21. This procedure allows generating stable B cell receptor-positive B cells that secrete immunoglobulins. We recovered stable B cell clones that produced IgM specific for tetanus toxoid and the hepatitis B surface antigen, respectively. CONCLUSION/SIGNIFICANCE: This work provides the proof-of-concept for the usefulness of this novel method based on the immunization of humanized mice for the rapid generation of human mAbs against a wide range of antigens.", "link"=>"http://www.mendeley.com/research/generation-human-antigenspecific-monoclonal-igm-antibodies-using-vaccinated-human-immune-system-mice", "reader_count"=>83, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>4, "Researcher"=>33, "Student > Doctoral Student"=>6, "Student > Ph. D. Student"=>16, "Other"=>14, "Student > Master"=>2, "Student > Bachelor"=>4, "Lecturer"=>1, "Professor"=>2}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>4, "Researcher"=>33, "Student > Doctoral Student"=>6, "Student > Ph. D. Student"=>16, "Other"=>14, "Student > Master"=>2, "Student > Bachelor"=>4, "Lecturer"=>1, "Professor"=>2}, "reader_count_by_subject_area"=>{"Engineering"=>2, "Unspecified"=>3, "Biochemistry, Genetics and Molecular Biology"=>4, "Agricultural and Biological Sciences"=>54, "Medicine and Dentistry"=>8, "Pharmacology, Toxicology and Pharmaceutical Science"=>2, "Business, Management and Accounting"=>1, "Computer Science"=>1, "Immunology and Microbiology"=>8}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>2}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>8}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>8}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>54}, "Computer Science"=>{"Computer Science"=>1}, "Business, Management and Accounting"=>{"Business, Management and Accounting"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>4}, "Unspecified"=>{"Unspecified"=>3}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>2}}, "reader_count_by_country"=>{"Netherlands"=>3, "Sweden"=>1, "Brazil"=>1, "Mexico"=>1, "Australia"=>1, "France"=>1, "Germany"=>2}, "group_count"=>2}

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  • {"files"=>["https://ndownloader.figshare.com/files/411704", "https://ndownloader.figshare.com/files/411727", "https://ndownloader.figshare.com/files/411739", "https://ndownloader.figshare.com/files/411752", "https://ndownloader.figshare.com/files/411758"], "description"=>"<div><h3>Background</h3><p>Passive transfer of antibodies not only provides immediate short-term protection against disease, but also can be exploited as a therapeutic tool. However, the ‘humanization’ of murine monoclonal antibodies (mAbs) is a time-consuming and expensive process that has the inherent drawback of potentially altering antigenic specificity and/or affinity. The immortalization of human B cells represents an alternative for obtaining human mAbs, but relies on the availability of biological samples from vaccinated individuals or convalescent patients. In this work we describe a novel approach to generate fully human mAbs by combining a humanized mouse model with a new B cell immortalization technique.</p><h3>Methodology/Principal Findings</h3><p>After transplantation with CD34<sup>+</sup>CD38<sup>−</sup> human hematopoietic progenitor cells, BALB/c Rag2<sup>−/−</sup>IL-2Rγc<sup>−/−</sup> mice acquire a human immune system and harbor B cells with a diverse IgM repertoire. “Human Immune System” mice were then immunized with two commercial vaccine antigens, tetanus toxoid and hepatitis B surface antigen. Sorted human CD19<sup>+</sup>CD27<sup>+</sup> B cells were retrovirally transduced with the human B cell lymphoma <em>(BCL)-6</em> and <em>BCL-XL</em> genes, and subsequently cultured in the presence of CD40-ligand and IL-21. This procedure allows generating stable B cell receptor-positive B cells that secrete immunoglobulins. We recovered stable B cell clones that produced IgM specific for tetanus toxoid and the hepatitis B surface antigen, respectively.</p><h3>Conclusion/Significance</h3><p>This work provides the proof-of-concept for the usefulness of this novel method based on the immunization of humanized mice for the rapid generation of human mAbs against a wide range of antigens.</p></div>", "links"=>[], "tags"=>["antigen-specific", "monoclonal", "igm", "antibodies", "vaccinated", "mice"], "article_id"=>141320, "categories"=>["Biotechnology", "Immunology"], "users"=>["Pablo D. Becker", "Nicolas Legrand", "Caroline M. M. van Geelen", "Miriam Noerder", "Nicholas D. Huntington", "Annick Lim", "Etsuko Yasuda", "Sean A. Diehl", "Ferenc A. Scheeren", "Michael Ott", "Kees Weijer", "Heiner Wedemeyer", "James P. Di Santo", "Tim Beaumont", "Carlos A. Guzmán", "Hergen Spits"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0013137.s001", "https://dx.doi.org/10.1371/journal.pone.0013137.s002", "https://dx.doi.org/10.1371/journal.pone.0013137.s003", "https://dx.doi.org/10.1371/journal.pone.0013137.s004", "https://dx.doi.org/10.1371/journal.pone.0013137.s005"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Generation_of_Human_Antigen_Specific_Monoclonal_IgM_Antibodies_Using_Vaccinated_Human_Immune_System_Mice/141320", "title"=>"Generation of Human Antigen-Specific Monoclonal IgM Antibodies Using Vaccinated “Human Immune System” Mice", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2010-10-04 00:22:00"}
  • {"files"=>["https://ndownloader.figshare.com/files/826807"], "description"=>"<p>(A) HIS mice are generated by transplanting sorted human CD34<sup>+</sup>CD38<sup>−</sup> HSC-enriched cell fraction into conditioned (3.5 Gy irradiation) newborn Rag2<sup>−/−</sup> IL-2Rγc<sup>−/−</sup> mice. After 6 to 8 weeks post-transplantation, human lymphoid and myeloid cell subsets are found in the blood and lymphoid organs of the reconstituted animals. (B) The top panel shows the flow cytometry analysis of human T (CD3<sup>+</sup>) and B (CD19<sup>+</sup>) cells found in the spleen of 8-week old HIS mice. The expression of IgM and IgD on the surface of B cells is depicted on the low panel. (C) The relative proportion of B cells expressing an IgM, IgG or IgA BCR was determined by quantitative PCR for both control PBMC and HIS splenocytes. Percentages represent the frequency of IgM, IgG and IgA (C<sub>H</sub>μ, C<sub>H</sub>γ and C<sub>H</sub>α) containing V<sub>H</sub> PCR products out of the total V<sub>H</sub> PCR products from each spleen. The horizontal bars indicate the mean value. (D) The graph shows the concentration of total IgM and IgG (mean values: horizontal bars) in the plasma of 10- to 14-week old naive HIS mice. (E) The naive IgM B cell repertoire of HIS mice was evaluated on splenocytes by performing a BCR immunoscope for each V<sub>H</sub> family. The profiles obtained with control human PBMC are also shown.</p>", "links"=>[], "tags"=>["cells"], "article_id"=>497160, "categories"=>["Biotechnology", "Immunology"], "users"=>["Pablo D. Becker", "Nicolas Legrand", "Caroline M. M. van Geelen", "Miriam Noerder", "Nicholas D. Huntington", "Annick Lim", "Etsuko Yasuda", "Sean A. Diehl", "Ferenc A. Scheeren", "Michael Ott", "Kees Weijer", "Heiner Wedemeyer", "James P. Di Santo", "Tim Beaumont", "Carlos A. Guzmán", "Hergen Spits"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0013137.g001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Characterization_of_B_cells_in_na_239_ve_HIS_mice_/497160", "title"=>"Characterization of B cells in naïve HIS mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-10-04 01:59:20"}
  • {"files"=>["https://ndownloader.figshare.com/files/826992"], "description"=>"<p>(A) The graph shows the titers of HBsAg-specific IgM measured by ELISA in PBS-injected and HBsAg-vaccinated HIS mice, 10 days after the third i.m. injection. Vaccinated mice are designated as responder animals when antigen-specific antibody titers are above the cut-off value (doted horizontal line). Responder animals with a detectable antigen-specific IgG response are indicated by the horizontal arrows. (B) The graphs show the concentration of total IgM (top graph) and IgG (bottom graph) in the plasma of PBS-injected (open squares) or vaccinated HIS mice (pool of HBsAg- and TT-vaccinated) at the end of the vaccination protocol (mean values: horizontal bars). The vaccinated are separated between non-responder (- columns; open circles) and responder (+ columns; closed squares) mice. (C) The graph shows the number of human cells (hCD45<sup>+</sup>) harvested in mLN of PBS-injected vs. vaccinated (TT and HBsAg) HIS mice. The mLN were not detected in 43% of mock-injected mice, as compared to 16% of vaccinated animals (symbols placed under the doted line). The animals without detectable mLN were excluded to calculate the average number of human cells per group (horizontal bar). * p<0.05; ** p<0.01.</p>", "links"=>[], "tags"=>["immunology", "biotechnology/bioengineering", "immunology/immune response"], "article_id"=>497339, "categories"=>["Biotechnology", "Immunology"], "users"=>["Pablo D. Becker", "Nicolas Legrand", "Caroline M. M. van Geelen", "Miriam Noerder", "Nicholas D. Huntington", "Annick Lim", "Etsuko Yasuda", "Sean A. Diehl", "Ferenc A. Scheeren", "Michael Ott", "Kees Weijer", "Heiner Wedemeyer", "James P. Di Santo", "Tim Beaumont", "Carlos A. Guzmán", "Hergen Spits"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0013137.g002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Vaccination_of_HIS_mice_/497339", "title"=>"Vaccination of HIS mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-10-04 02:02:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/827111"], "description"=>"<p>Subsets of human B cells (CD45<sup>+</sup>CD19<sup>+</sup>) were sorted from BM and spleens of vaccinated HIS mice. The strategy 1 (upper part) was used on 3 responder HBsAg-vaccinated animals and gave rise to the following B cell subsets: (i) CD27<sup>hi</sup>CD38<sup>hi</sup>, (ii) CD27<sup>+</sup>CD38<sup>lo/int</sup>IgD<sup>+</sup>, and (iii) CD27<sup>+</sup>CD38<sup>lo/int</sup>IgD<sup>−</sup>. The strategy 2 (lower part) was used on 3 responder TT-vaccinated animals and gave rise to the following B cell subsets: (iv) CD27<sup>+</sup>IgM<sup>+</sup>IgG<sup>−</sup>, and (v) CD27<sup>+</sup>IgM<sup>−</sup>IgG<sup>+</sup>. The respective frequency and name (from i to v) of each sorted B cell subsets is indicated in the corresponding flow cytometry dot plot.</p>", "links"=>[], "tags"=>["sorting"], "article_id"=>497463, "categories"=>["Biotechnology", "Immunology"], "users"=>["Pablo D. Becker", "Nicolas Legrand", "Caroline M. M. van Geelen", "Miriam Noerder", "Nicholas D. Huntington", "Annick Lim", "Etsuko Yasuda", "Sean A. Diehl", "Ferenc A. Scheeren", "Michael Ott", "Kees Weijer", "Heiner Wedemeyer", "James P. Di Santo", "Tim Beaumont", "Carlos A. Guzmán", "Hergen Spits"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0013137.g003"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Memory_B_cell_sorting_strategies_/497463", "title"=>"Memory B cell sorting strategies.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-10-04 02:04:23"}
  • {"files"=>["https://ndownloader.figshare.com/files/827270"], "description"=>"<p>(A) After obtaining monoclonal TT-specific B cell lines, B cell clones were tested for cross-reactivity against unrelated antigens from HBV or RSV in an ELISA test. (B) The direct binding of phycoerythrin-labeled TT on TT ELISA positive B cell clones was determined by flow cytometry, and 3 sub-types of clones are observed: high, intermediate and low binding clones. Values in the histograms show the percentage of cells within the indicated gate.</p>", "links"=>[], "tags"=>["generated", "tt-specific"], "article_id"=>497614, "categories"=>["Biotechnology", "Immunology"], "users"=>["Pablo D. Becker", "Nicolas Legrand", "Caroline M. M. van Geelen", "Miriam Noerder", "Nicholas D. Huntington", "Annick Lim", "Etsuko Yasuda", "Sean A. Diehl", "Ferenc A. Scheeren", "Michael Ott", "Kees Weijer", "Heiner Wedemeyer", "James P. Di Santo", "Tim Beaumont", "Carlos A. Guzmán", "Hergen Spits"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0013137.g004"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Characterization_of_the_generated_TT_specific_human_B_cell_clones_/497614", "title"=>"Characterization of the generated TT-specific human B cell clones.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-10-04 02:06:54"}
  • {"files"=>["https://ndownloader.figshare.com/files/827470"], "description"=>"<p>The data from HIS mice were generated with B cells isolated from the spleen of naïve animals. The values are expressed as the relative frequency (%) of each IgM-V<sub>H</sub> family.</p>", "links"=>[], "tags"=>["usage", "igm", "mice"], "article_id"=>497817, "categories"=>["Biotechnology", "Immunology"], "users"=>["Pablo D. Becker", "Nicolas Legrand", "Caroline M. M. van Geelen", "Miriam Noerder", "Nicholas D. Huntington", "Annick Lim", "Etsuko Yasuda", "Sean A. Diehl", "Ferenc A. Scheeren", "Michael Ott", "Kees Weijer", "Heiner Wedemeyer", "James P. Di Santo", "Tim Beaumont", "Carlos A. Guzmán", "Hergen Spits"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0013137.t001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Average_V_H_family_usage_for_IgM_in_HIS_BALB_Rag_947_mice_and_control_human_PBMC_/497817", "title"=>"Average V<sub>H</sub> family usage for IgM in HIS (BALB-Rag/γ) mice and control human PBMC.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2010-10-04 02:10:17"}
  • {"files"=>["https://ndownloader.figshare.com/files/827526"], "description"=>"<p>The data from the TT and HBsAg vaccination experiments are pooled. Values are expressed as a mean (± S.E.M.) number of human cells, human B cells and human T cells found in control (PBS-injected) or vaccinated animals. The vaccinated animals were further distributed between responder and non-responder animals, as determined by antigen-specific ELISA. Statistical analysis was performed on the cell numbers harvested from vaccinated animals, as compared to the control group (* p<0.05; ** p<0.01).</p>", "links"=>[], "tags"=>["numbers", "spleen", "vaccinated"], "article_id"=>497876, "categories"=>["Biotechnology", "Immunology"], "users"=>["Pablo D. Becker", "Nicolas Legrand", "Caroline M. M. van Geelen", "Miriam Noerder", "Nicholas D. Huntington", "Annick Lim", "Etsuko Yasuda", "Sean A. Diehl", "Ferenc A. Scheeren", "Michael Ott", "Kees Weijer", "Heiner Wedemeyer", "James P. Di Santo", "Tim Beaumont", "Carlos A. Guzmán", "Hergen Spits"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0013137.t002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Human_cell_numbers_measured_in_the_spleen_of_vaccinated_HIS_mice_/497876", "title"=>"Human cell numbers measured in the spleen of vaccinated HIS mice.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2010-10-04 02:11:16"}

PMC Usage Stats | Further Information

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  • {"month"=>"4", "scanned-page-browse"=>"0", "cited-by"=>"0", "abstract"=>"4", "full-text"=>"53", "year"=>"2011", "pdf"=>"37", "unique-ip"=>"48", "figure"=>"13", "scanned-summary"=>"0", "supp-data"=>"2"}
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  • {"month"=>"6", "scanned-page-browse"=>"0", "cited-by"=>"0", "abstract"=>"2", "full-text"=>"20", "year"=>"2011", "pdf"=>"21", "unique-ip"=>"29", "figure"=>"16", "scanned-summary"=>"0", "supp-data"=>"1"}
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  • {"unique-ip"=>"14", "full-text"=>"18", "pdf"=>"4", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2013", "month"=>"4"}
  • {"unique-ip"=>"25", "full-text"=>"23", "pdf"=>"18", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"3", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2012", "month"=>"11"}
  • {"unique-ip"=>"20", "full-text"=>"18", "pdf"=>"9", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"3", "cited-by"=>"0", "year"=>"2013", "month"=>"5"}
  • {"unique-ip"=>"17", "full-text"=>"12", "pdf"=>"7", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"5", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2013", "month"=>"6"}
  • {"unique-ip"=>"18", "full-text"=>"21", "pdf"=>"3", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2013", "month"=>"7"}
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  • {"unique-ip"=>"18", "full-text"=>"21", "pdf"=>"6", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2013", "month"=>"9"}
  • {"unique-ip"=>"9", "full-text"=>"9", "pdf"=>"6", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2013", "month"=>"10"}
  • {"unique-ip"=>"16", "full-text"=>"18", "pdf"=>"3", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"3", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2013", "month"=>"11"}
  • {"unique-ip"=>"13", "full-text"=>"14", "pdf"=>"6", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"2", "cited-by"=>"0", "year"=>"2013", "month"=>"12"}
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  • {"unique-ip"=>"11", "full-text"=>"11", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"5", "supp-data"=>"0", "cited-by"=>"1", "year"=>"2016", "month"=>"9"}
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  • {"unique-ip"=>"10", "full-text"=>"7", "pdf"=>"3", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"11"}
  • {"unique-ip"=>"5", "full-text"=>"5", "pdf"=>"2", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2016", "month"=>"12"}
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  • {"unique-ip"=>"7", "full-text"=>"8", "pdf"=>"0", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"8"}
  • {"unique-ip"=>"5", "full-text"=>"7", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"9"}
  • {"unique-ip"=>"9", "full-text"=>"10", "pdf"=>"3", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"10"}
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  • {"unique-ip"=>"8", "full-text"=>"6", "pdf"=>"3", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"5", "cited-by"=>"0", "year"=>"2017", "month"=>"12"}
  • {"unique-ip"=>"6", "full-text"=>"6", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"1"}
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  • {"unique-ip"=>"18", "full-text"=>"18", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"5"}
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  • {"unique-ip"=>"9", "full-text"=>"10", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"2", "cited-by"=>"0", "year"=>"2018", "month"=>"7"}
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  • {"unique-ip"=>"8", "full-text"=>"10", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"9"}
  • {"unique-ip"=>"8", "full-text"=>"10", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"10"}
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  • {"unique-ip"=>"8", "full-text"=>"9", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"2"}
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  • {"unique-ip"=>"9", "full-text"=>"9", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"8"}
  • {"unique-ip"=>"5", "full-text"=>"5", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"9"}
  • {"unique-ip"=>"18", "full-text"=>"22", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"5", "cited-by"=>"0", "year"=>"2019", "month"=>"10"}
  • {"unique-ip"=>"6", "full-text"=>"2", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"3", "supp-data"=>"9", "cited-by"=>"0", "year"=>"2019", "month"=>"12"}
  • {"unique-ip"=>"17", "full-text"=>"14", "pdf"=>"7", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"18", "cited-by"=>"0", "year"=>"2020", "month"=>"2"}
  • {"unique-ip"=>"23", "full-text"=>"26", "pdf"=>"8", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"3"}
  • {"unique-ip"=>"20", "full-text"=>"19", "pdf"=>"4", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"3", "year"=>"2020", "month"=>"4"}
  • {"unique-ip"=>"17", "full-text"=>"20", "pdf"=>"4", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"5"}
  • {"unique-ip"=>"18", "full-text"=>"15", "pdf"=>"5", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"6"}
  • {"unique-ip"=>"14", "full-text"=>"33", "pdf"=>"5", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"16", "supp-data"=>"5", "cited-by"=>"2", "year"=>"2020", "month"=>"7"}
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Relative Metric

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