CryoEM Visualization of an Adenovirus Capsid-Incorporated HIV Antigen
Publication Date
November 14, 2012
Journal
PLOS ONE
Authors
Justin W. Flatt, Tara L. Fox, Natalia Makarova, Jerry L. Blackwell, et al
Volume
7
Issue
11
Pages
e49607
DOI
https://dx.plos.org/10.1371/journal.pone.0049607
Publisher URL
http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0049607
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/23166728
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498208
Europe PMC
http://europepmc.org/abstract/MED/23166728
Web of Science
000311151900173
Scopus
84869134265
Mendeley
http://www.mendeley.com/research/cryoem-visualization-adenovirus-capsidincorporated-hiv-antigen
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Mendeley | Further Information

{"title"=>"CryoEM Visualization of an Adenovirus Capsid-Incorporated HIV Antigen", "type"=>"journal", "authors"=>[{"first_name"=>"Justin W.", "last_name"=>"Flatt", "scopus_author_id"=>"57201536186"}, {"first_name"=>"Tara L.", "last_name"=>"Fox", "scopus_author_id"=>"55613229095"}, {"first_name"=>"Natalia", "last_name"=>"Makarova", "scopus_author_id"=>"56684491700"}, {"first_name"=>"Jerry L.", "last_name"=>"Blackwell", "scopus_author_id"=>"7201740926"}, {"first_name"=>"Igor P.", "last_name"=>"Dmitriev", "scopus_author_id"=>"7005895851"}, {"first_name"=>"Elena A.", "last_name"=>"Kashentseva", "scopus_author_id"=>"16688803600"}, {"first_name"=>"David T.", "last_name"=>"Curiel", "scopus_author_id"=>"22134188600"}, {"first_name"=>"Phoebe L.", "last_name"=>"Stewart", "scopus_author_id"=>"7403039407"}], "year"=>2012, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "scopus"=>"2-s2.0-84869134265", "sgr"=>"84869134265", "pui"=>"366053734", "isbn"=>"1932-6203", "pmid"=>"23166728", "doi"=>"10.1371/journal.pone.0049607"}, "id"=>"7559c11e-4da3-3702-8db5-4cbb7abdcace", "abstract"=>"Adenoviral (Ad) vectors show promise as platforms for vaccine applications against infectious diseases including HIV. However, the requirements for eliciting protective neutralizing antibody and cellular immune responses against HIV remain a major challenge. In a novel approach to generate 2F5- and 4E10-like antibodies, we engineered an Ad vector with the HIV membrane proximal ectodomain region (MPER) epitope displayed on the hypervariable region 2 (HVR2) of the viral hexon capsid, instead of expressed as a transgene. The structure and flexibility of MPER epitopes, and the structural context of these epitopes within viral vectors, play important roles in the induced host immune responses. In this regard, understanding the critical factors for epitope presentation would facilitate optimization strategies for developing viral vaccine vectors. Therefore we undertook a cryoEM structural study of this Ad vector, which was previously shown to elicit MPER-specific humoral immune responses. A subnanometer resolution cryoEM structure was analyzed with guided molecular dynamics simulations. Due to the arrangement of hexons within the Ad capsid, there are twelve unique environments for the inserted peptide that lead to a variety of conformations for MPER, including individual α-helices, interacting α-helices, and partially extended forms. This finding is consistent with the known conformational flexibility of MPER. The presence of an extended form, or an induced extended form, is supported by interaction of this vector with the human HIV monoclonal antibody 2F5, which recognizes 14 extended amino acids within MPER. These results demonstrate that the Ad capsid influences epitope structure, flexibility and accessibility, all of which affect the host immune response. In summary, this cryoEM structural study provided a means to visualize an epitope presented on an engineered viral vector and suggested modifications for the next generation of Ad vectors with capsid-incorporated HIV epitopes.", "link"=>"http://www.mendeley.com/research/cryoem-visualization-adenovirus-capsidincorporated-hiv-antigen", "reader_count"=>7, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Researcher"=>2, "Student > Doctoral Student"=>1, "Student > Postgraduate"=>1, "Student > Master"=>1, "Lecturer"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Researcher"=>2, "Student > Doctoral Student"=>1, "Student > Postgraduate"=>1, "Student > Master"=>1, "Lecturer"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>1, "Biochemistry, Genetics and Molecular Biology"=>2, "Agricultural and Biological Sciences"=>2, "Business, Management and Accounting"=>1, "Economics, Econometrics and Finance"=>1}, "reader_count_by_subdiscipline"=>{"Economics, Econometrics and Finance"=>{"Economics, Econometrics and Finance"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>2}, "Business, Management and Accounting"=>{"Business, Management and Accounting"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>2}, "Unspecified"=>{"Unspecified"=>1}}, "reader_count_by_country"=>{"Portugal"=>1}, "group_count"=>0}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/544101"], "description"=>"<p>(A) Simulated density for hexon (blue) shown with a ribbon representation of an MDFF model of the MPER in an α-helical conformation or (B) extended conformation. The 14 amino acid 2F5 epitope is shown with a thicker ribbon in the extended model. The ribbons are colored as in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049607#pone-0049607-g002\" target=\"_blank\">Figure 2</a>.</p>", "links"=>[], "tags"=>["conformations", "mper", "penton"], "article_id"=>214592, "categories"=>["Biotechnology", "Virology", "Biochemistry", "Infectious Diseases", "Biophysics", "Immunology", "Biological Sciences"], "users"=>["Justin W. Flatt", "Tara L. Fox", "Natalia Makarova", "Jerry L. Blackwell", "Igor P. Dmitriev", "Elena A. Kashentseva", "David T. Curiel", "Phoebe L. Stewart"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0049607.g006", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Alternate_model_conformations_for_MPER_next_to_penton_base_/214592", "title"=>"Alternate model conformations for MPER next to penton base.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-11-14 01:16:32"}
  • {"files"=>["https://ndownloader.figshare.com/files/543507"], "description"=>"<p>(A) Coordinates from the final frame of an MDFF simulation show α-helices of both hexon and MPER docked within density rods of the cryoEM structure (gray). (B) Perpendicular view showing one of the two MPER density rods. (C) Additional view showing the second of the two MPER density rods at the icosahedral 2-fold axis with the final MDFF coordinates, which were not icosahedrally constrained. The isosurface threshold levels were chosen to highlight the well resolved density rods within each panel. Ribbon representations are shown for the hexon backbone (purple and blue), the MPER sequence (red), and the linker regions (green). The icosahedral 2-fold axis is indicated with an oval symbol.</p>", "links"=>[], "tags"=>["hexons", "mper"], "article_id"=>213997, "categories"=>["Biotechnology", "Virology", "Biochemistry", "Infectious Diseases", "Biophysics", "Immunology", "Biological Sciences"], "users"=>["Justin W. Flatt", "Tara L. Fox", "Natalia Makarova", "Jerry L. Blackwell", "Igor P. Dmitriev", "Elena A. Kashentseva", "David T. Curiel", "Phoebe L. Stewart"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0049607.g002", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_CryoEM_density_showing_945_helices_for_two_hexons_and_two_MPER_insertions_/213997", "title"=>"CryoEM density showing α-helices for two hexons and two MPER insertions.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-11-14 01:06:37"}
  • {"files"=>["https://ndownloader.figshare.com/files/290801", "https://ndownloader.figshare.com/files/290840", "https://ndownloader.figshare.com/files/290872", "https://ndownloader.figshare.com/files/290929", "https://ndownloader.figshare.com/files/290996", "https://ndownloader.figshare.com/files/291056"], "description"=>"<div><p>Adenoviral (Ad) vectors show promise as platforms for vaccine applications against infectious diseases including HIV. However, the requirements for eliciting protective neutralizing antibody and cellular immune responses against HIV remain a major challenge. In a novel approach to generate 2F5- and 4E10-like antibodies, we engineered an Ad vector with the HIV membrane proximal ectodomain region (MPER) epitope displayed on the hypervariable region 2 (HVR2) of the viral hexon capsid, instead of expressed as a transgene. The structure and flexibility of MPER epitopes, and the structural context of these epitopes within viral vectors, play important roles in the induced host immune responses. In this regard, understanding the critical factors for epitope presentation would facilitate optimization strategies for developing viral vaccine vectors. Therefore we undertook a cryoEM structural study of this Ad vector, which was previously shown to elicit MPER-specific humoral immune responses. A subnanometer resolution cryoEM structure was analyzed with guided molecular dynamics simulations. Due to the arrangement of hexons within the Ad capsid, there are twelve unique environments for the inserted peptide that lead to a variety of conformations for MPER, including individual α-helices, interacting α-helices, and partially extended forms. This finding is consistent with the known conformational flexibility of MPER. The presence of an extended form, or an induced extended form, is supported by interaction of this vector with the human HIV monoclonal antibody 2F5, which recognizes 14 extended amino acids within MPER. These results demonstrate that the Ad capsid influences epitope structure, flexibility and accessibility, all of which affect the host immune response. In summary, this cryoEM structural study provided a means to visualize an epitope presented on an engineered viral vector and suggested modifications for the next generation of Ad vectors with capsid-incorporated HIV epitopes.</p> </div>", "links"=>[], "tags"=>["cryoem", "visualization", "adenovirus", "capsid-incorporated", "hiv", "antigen"], "article_id"=>117257, "categories"=>["Biotechnology", "Cancer", "Biochemistry", "Biophysics", "Immunology", "Biological Sciences"], "users"=>["Justin W. Flatt", "Tara L. Fox", "Natalia Makarova", "Jerry L. Blackwell", "Igor P. Dmitriev", "Elena A. Kashentseva", "David T. Curiel", "Phoebe L. Stewart"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0049607.s001", "https://dx.doi.org/10.1371/journal.pone.0049607.s002", "https://dx.doi.org/10.1371/journal.pone.0049607.s003", "https://dx.doi.org/10.1371/journal.pone.0049607.s004", "https://dx.doi.org/10.1371/journal.pone.0049607.s005", "https://dx.doi.org/10.1371/journal.pone.0049607.s006"], "stats"=>{"downloads"=>11, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/CryoEM_Visualization_of_an_Adenovirus_Capsid_Incorporated_HIV_Antigen__/117257", "title"=>"CryoEM Visualization of an Adenovirus Capsid-Incorporated HIV Antigen", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2012-11-14 02:00:57"}
  • {"files"=>["https://ndownloader.figshare.com/files/544205"], "description"=>"<p>(A) Schematic representation of the MPER insertion incorporated within the Ad-HVR2-GP41-L15 vector. The hexon capsid protein (gray) is shown together with the N-terminal 3aa linker (blue), the MPER peptide (green), and the C-terminal 10aa linker (red). The protein-protein interface between hexons in the Ad capsid is represented by a hashed region. (B-E) Based on the structural analysis of the Ad-HVR2-GP41-L15 vector, four possible modifications are proposed which include (B) extending the N-terminal linker by 3aa, (C) extending the C-terminal linker by 4aa, (D) extending both the N- and C-terminal linkers by 2aa, and (E) swapping the N- and C- terminal linkers.</p>", "links"=>[], "tags"=>["vector", "modifications", "optimizing", "mper", "hexon", "hvr2"], "article_id"=>214688, "categories"=>["Biotechnology", "Virology", "Biochemistry", "Infectious Diseases", "Biophysics", "Immunology", "Biological Sciences"], "users"=>["Justin W. Flatt", "Tara L. Fox", "Natalia Makarova", "Jerry L. Blackwell", "Igor P. Dmitriev", "Elena A. Kashentseva", "David T. Curiel", "Phoebe L. Stewart"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0049607.g007", "stats"=>{"downloads"=>1, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Proposed_vector_modifications_for_optimizing_MPER_presentation_at_the_Ad_hexon_HVR2_site_/214688", "title"=>"Proposed vector modifications for optimizing MPER presentation at the Ad hexon HVR2 site.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-11-14 01:18:08"}
  • {"files"=>["https://ndownloader.figshare.com/files/543371"], "description"=>"<p>(A) Full virion viewed along an icosahedral 3-fold axis. Density assigned to the MPER insertion within the top facet is colored in red and gold, with red representing the MPER density within one asymmetric unit. This Ad vector is based on human Ad type 5, which has long and flexible fibers (>300 Å). Only short portions of the fiber (out to a radius of 463 Å) have been reconstructed (3 fibers are indicated with arrows). (B) Enlarged view with the 12 MPER density regions within one asymmetric unit numbered 1–12. Interacting MPER density regions from adjacent asymmetric units are numbered in parentheses. The four hexons are labeled H1–H4 and the penton base is labeled P. The icosahedral 2- and 3-fold axes are indicated with oval and triangle symbols respectively. Scale bars represent 100 Å.</p>", "links"=>[], "tags"=>["ad-hvr2-gp41-l15", "vector", "subnanometer"], "article_id"=>213853, "categories"=>["Biotechnology", "Virology", "Biochemistry", "Infectious Diseases", "Biophysics", "Immunology", "Biological Sciences"], "users"=>["Justin W. Flatt", "Tara L. Fox", "Natalia Makarova", "Jerry L. Blackwell", "Igor P. Dmitriev", "Elena A. Kashentseva", "David T. Curiel", "Phoebe L. Stewart"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0049607.g001", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_CryoEM_structure_of_the_Ad_HVR2_GP41_L15_vector_at_subnanometer_resolution_/213853", "title"=>"CryoEM structure of the Ad-HVR2-GP41-L15 vector at subnanometer resolution.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-11-14 01:04:13"}
  • {"files"=>["https://ndownloader.figshare.com/files/543966"], "description"=>"<p>Overlay of MDFF refined model (ribbons) and the cryoEM density (gray) at the strongest 2-mer site (between hexons H3 and H4 of a neighboring asymmetric unit). The ribbon coloring scheme is the same as in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049607#pone-0049607-g002\" target=\"_blank\">Figure 2</a>.</p>", "links"=>[], "tags"=>["interactions", "2-mer", "sites"], "article_id"=>214455, "categories"=>["Biotechnology", "Virology", "Biochemistry", "Infectious Diseases", "Biophysics", "Immunology", "Biological Sciences"], "users"=>["Justin W. Flatt", "Tara L. Fox", "Natalia Makarova", "Jerry L. Blackwell", "Igor P. Dmitriev", "Elena A. Kashentseva", "David T. Curiel", "Phoebe L. Stewart"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0049607.g005", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_MPER_interactions_at_2_mer_sites_are_weak_and_transient_/214455", "title"=>"MPER interactions at 2-mer sites are weak and transient.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-11-14 01:14:15"}
  • {"files"=>["https://ndownloader.figshare.com/files/543692"], "description"=>"<p>Density for two hexons (blue and purple) simulated from the final MDFF frame shown surrounding experimentally determined cryoEM density (gray) for one MPER insertion. A ribbon representation of the final MDFF model of the MPER insertion is overlaid, colored as in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049607#pone-0049607-g002\" target=\"_blank\">Figure 2</a>. A tilted view is shown to emphasize the confined nature of the cavity between the hexons.</p>", "links"=>[], "tags"=>["insertion", "cavity", "hexons", "icosahedral", "2-fold"], "article_id"=>214180, "categories"=>["Biotechnology", "Virology", "Biochemistry", "Infectious Diseases", "Biophysics", "Immunology", "Biological Sciences"], "users"=>["Justin W. Flatt", "Tara L. Fox", "Natalia Makarova", "Jerry L. Blackwell", "Igor P. Dmitriev", "Elena A. Kashentseva", "David T. Curiel", "Phoebe L. Stewart"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0049607.g003", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_MPER_insertion_within_a_narrow_cavity_between_hexons_at_the_icosahedral_2_fold_axis_/214180", "title"=>"MPER insertion within a narrow cavity between hexons at the icosahedral 2-fold axis.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-11-14 01:09:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/543848"], "description"=>"<p>(A) Overlay of MDFF refined model (ribbons) and the cryoEM density (gray) at the icosahedral 3-fold axis. The ribbon coloring scheme is the same as in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049607#pone-0049607-g002\" target=\"_blank\">Figure 2</a>. (B) Enlarged view of the helical packing interface viewed along the bundle axis with aromatic sidechains displayed (gold).</p>", "links"=>[], "tags"=>["forms", "helical", "bundle", "3-mer"], "article_id"=>214335, "categories"=>["Biotechnology", "Virology", "Biochemistry", "Infectious Diseases", "Biophysics", "Immunology", "Biological Sciences"], "users"=>["Justin W. Flatt", "Tara L. Fox", "Natalia Makarova", "Jerry L. Blackwell", "Igor P. Dmitriev", "Elena A. Kashentseva", "David T. Curiel", "Phoebe L. Stewart"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0049607.g004", "stats"=>{"downloads"=>4, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_MPER_forms_a_stable_helical_bundle_at_3_mer_sites_/214335", "title"=>"MPER forms a stable helical bundle at 3-mer sites.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-11-14 01:12:15"}

PMC Usage Stats | Further Information

  • {"unique-ip"=>"22", "full-text"=>"19", "pdf"=>"13", "abstract"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2012", "month"=>"12"}
  • {"unique-ip"=>"22", "full-text"=>"19", "pdf"=>"8", "abstract"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"20", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2013", "month"=>"1"}
  • {"unique-ip"=>"12", "full-text"=>"11", "pdf"=>"3", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"6", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2013", "month"=>"3"}
  • {"unique-ip"=>"10", "full-text"=>"10", "pdf"=>"3", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"3", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2013", "month"=>"2"}
  • {"unique-ip"=>"11", "full-text"=>"7", "pdf"=>"4", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"4", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2013", "month"=>"4"}
  • {"unique-ip"=>"24", "full-text"=>"22", "pdf"=>"11", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"16", "supp-data"=>"7", "cited-by"=>"0", "year"=>"2012", "month"=>"11"}
  • {"unique-ip"=>"9", "full-text"=>"7", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"3", "supp-data"=>"0", "cited-by"=>"1", "year"=>"2013", "month"=>"5"}
  • {"unique-ip"=>"12", "full-text"=>"9", "pdf"=>"4", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"12", "cited-by"=>"0", "year"=>"2013", "month"=>"6"}
  • {"unique-ip"=>"6", "full-text"=>"4", "pdf"=>"2", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"6", "cited-by"=>"0", "year"=>"2013", "month"=>"7"}
  • {"unique-ip"=>"5", "full-text"=>"2", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"6", "cited-by"=>"0", "year"=>"2013", "month"=>"8"}
  • {"unique-ip"=>"11", "full-text"=>"10", "pdf"=>"0", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"1", "year"=>"2013", "month"=>"9"}
  • {"unique-ip"=>"7", "full-text"=>"8", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"3", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2013", "month"=>"10"}
  • {"unique-ip"=>"5", "full-text"=>"7", "pdf"=>"3", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2013", "month"=>"11"}
  • {"unique-ip"=>"3", "full-text"=>"3", "pdf"=>"0", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2013", "month"=>"12"}
  • {"unique-ip"=>"2", "full-text"=>"3", "pdf"=>"0", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2014", "month"=>"1"}
  • {"unique-ip"=>"4", "full-text"=>"7", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2014", "month"=>"2"}
  • {"unique-ip"=>"7", "full-text"=>"5", "pdf"=>"2", "abstract"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"3", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2014", "month"=>"3"}
  • {"unique-ip"=>"3", "full-text"=>"0", "pdf"=>"2", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2014", "month"=>"5"}
  • {"unique-ip"=>"2", "full-text"=>"1", "pdf"=>"0", "abstract"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2014", "month"=>"6"}
  • {"unique-ip"=>"7", "full-text"=>"3", "pdf"=>"4", "abstract"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2014", "month"=>"4"}
  • {"unique-ip"=>"6", "full-text"=>"8", "pdf"=>"2", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2015", "month"=>"4"}
  • {"unique-ip"=>"8", "full-text"=>"6", "pdf"=>"2", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2015", "month"=>"5"}
  • {"unique-ip"=>"5", "full-text"=>"3", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2015", "month"=>"6"}
  • {"unique-ip"=>"7", "full-text"=>"12", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2015", "month"=>"7"}
  • {"unique-ip"=>"4", "full-text"=>"4", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2015", "month"=>"3"}
  • {"unique-ip"=>"5", "full-text"=>"4", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2015", "month"=>"2"}
  • {"unique-ip"=>"6", "full-text"=>"6", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2015", "month"=>"8"}
  • {"unique-ip"=>"6", "full-text"=>"5", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2015", "month"=>"9"}
  • {"unique-ip"=>"6", "full-text"=>"6", "pdf"=>"2", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2015", "month"=>"10"}
  • {"unique-ip"=>"10", "full-text"=>"8", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2014", "month"=>"7"}
  • {"unique-ip"=>"8", "full-text"=>"4", "pdf"=>"2", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"11", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2014", "month"=>"8"}
  • {"unique-ip"=>"10", "full-text"=>"4", "pdf"=>"7", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2014", "month"=>"9"}
  • {"unique-ip"=>"4", "full-text"=>"4", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2014", "month"=>"10"}
  • {"unique-ip"=>"3", "full-text"=>"3", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"1"}
  • {"unique-ip"=>"4", "full-text"=>"4", "pdf"=>"0", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"2"}
  • {"unique-ip"=>"8", "full-text"=>"6", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2014", "month"=>"11"}
  • {"unique-ip"=>"4", "full-text"=>"2", "pdf"=>"0", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"2", "cited-by"=>"0", "year"=>"2014", "month"=>"12"}
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Relative Metric

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