Reducing AD-Like Pathology in 3xTg-AD Mouse Model by DNA Epitope Vaccine — A Novel Immunotherapeutic Strategy
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{"title"=>"Reducing AD-like pathology in 3xTg-AD mouse model by DNA epitope vaccine - A novel immunotherapeutic strategy", "type"=>"journal", "authors"=>[{"first_name"=>"Nina", "last_name"=>"Movsesyan", "scopus_author_id"=>"8763150800"}, {"first_name"=>"Anahit", "last_name"=>"Ghochikyan", "scopus_author_id"=>"6602513968"}, {"first_name"=>"Mikayel", "last_name"=>"Mkrtichyan", "scopus_author_id"=>"8763150900"}, {"first_name"=>"Irina", "last_name"=>"Petrushina", "scopus_author_id"=>"6603828337"}, {"first_name"=>"Hayk", "last_name"=>"Davtyan", "scopus_author_id"=>"23004031500"}, {"first_name"=>"Purevdorj B.", "last_name"=>"Olkhanud", "scopus_author_id"=>"14013995800"}, {"first_name"=>"Elizabeth", "last_name"=>"Head", "scopus_author_id"=>"7005966043"}, {"first_name"=>"Arya", "last_name"=>"Biragyn", "scopus_author_id"=>"6604062381"}, {"first_name"=>"David H.", "last_name"=>"Cribbs", "scopus_author_id"=>"56759700600"}, {"first_name"=>"Michael G.", "last_name"=>"Agadjanyan", "scopus_author_id"=>"35592929300"}], "year"=>2008, "source"=>"PLoS ONE", "identifiers"=>{"scopus"=>"2-s2.0-47749107621", "sgr"=>"47749107621", "issn"=>"19326203", "doi"=>"10.1371/journal.pone.0002124", "pmid"=>"18461171", "isbn"=>"1932-6203", "pui"=>"352025129"}, "id"=>"2609a113-97b7-3e03-8059-3b25ca996d09", "abstract"=>"BACKGROUND: The development of a safe and effective AD vaccine requires a delicate balance between providing an adequate anti-Abeta antibody response sufficient to provide therapeutic benefit, while eliminating an adverse T cell-mediated proinflammatory autoimmune response. To achieve this goal we have designed a prototype chemokine-based DNA epitope vaccine expressing a fusion protein that consists of 3 copies of the self-B cell epitope of Abeta(42) (Abeta(1-11)) , a non-self T helper cell epitope (PADRE), and macrophage-derived chemokine (MDC/CCL22) as a molecular adjuvant to promote a strong anti-inflammatory Th2 phenotype.\\n\\nMETHODS AND FINDINGS: We generated pMDC-3Abeta(1-11)-PADRE construct and immunized 3xTg-AD mouse model starting at age of 3-4 months old. We demonstrated that prophylactic immunizations with the DNA epitope vaccine generated a robust Th2 immune response that induced high titers of anti-Abeta antibody, which in turn inhibited accumulation of Abeta pathology in the brains of older mice. Importantly, vaccination reduced glial activation and prevented the development of behavioral deficits in aged animals without increasing the incidence of microhemorrhages.\\n\\nCONCLUSIONS: Data from this transitional pre-clinical study suggest that our DNA epitope vaccine could be used as a safe and effective strategy for AD therapy. Future safety and immunology studies in large animals with the goal to achieve effective humoral immunity without adverse effects should help to translate this study to human clinical trials.", "link"=>"http://www.mendeley.com/research/reducing-adlike-pathology-3xtgad-mouse-model-dna-epitope-vaccine-novel-immunotherapeutic-strategy", "reader_count"=>40, "reader_count_by_academic_status"=>{"Unspecified"=>3, "Professor > Associate Professor"=>3, "Researcher"=>9, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>7, "Student > Postgraduate"=>2, "Student > Master"=>4, "Other"=>3, "Student > Bachelor"=>4, "Professor"=>3}, "reader_count_by_user_role"=>{"Unspecified"=>3, "Professor > Associate Professor"=>3, "Researcher"=>9, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>7, "Student > Postgraduate"=>2, "Student > Master"=>4, "Other"=>3, "Student > Bachelor"=>4, "Professor"=>3}, "reader_count_by_subject_area"=>{"Unspecified"=>4, "Nursing and Health Professions"=>1, "Biochemistry, Genetics and Molecular Biology"=>2, "Medicine and Dentistry"=>10, "Agricultural and Biological Sciences"=>15, "Neuroscience"=>1, "Arts and Humanities"=>1, "Psychology"=>3, "Chemistry"=>1, "Social Sciences"=>1, "Economics, Econometrics and Finance"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>10}, "Neuroscience"=>{"Neuroscience"=>1}, "Chemistry"=>{"Chemistry"=>1}, "Social Sciences"=>{"Social Sciences"=>1}, "Psychology"=>{"Psychology"=>3}, "Economics, Econometrics and Finance"=>{"Economics, Econometrics and Finance"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>15}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>2}, "Unspecified"=>{"Unspecified"=>4}, "Arts and Humanities"=>{"Arts and Humanities"=>1}}, "reader_count_by_country"=>{"United States"=>1, "China"=>1, "France"=>1, "Spain"=>2}, "group_count"=>2}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/931741"], "description"=>"<p>A) Fusion gene encoding epitope vaccine, 3Aβ<sub>1–11</sub> and PADRE (aKXVAAWTLKAAaZC, x = L-cyclohexylalanine, Z = aminocaproic acid) was introduced into pCMVE-AB/hMDC in frame to the 3′-end of mature <i>MDC</i> exactly as shown. <i>MDC</i> gene is fused to the IP10 signal sequence in its 5′-end and to the <i>3Aβ<sub>1–11</sub>-PADRE</i> minigene in its 3′-end through small spacer. Transcription of <i>MDC-3Aβ<sub>1–11</sub>-PADRE</i> gene is controlled by CMV promoter/enhancer. B) To analyze the intracellular expression of pMDC-3Aβ<sub>1–11</sub>-PADRE, transiently transfected CHO cells were permeabilized/fixed and stained with anti-Aβ 6E10 antibody followed by FITC-conjugated anti mouse IgG. Cells were analyzed by FACScan. Approximately ∼65% of CHO cells transfected with pMDC-3Aβ<sub>1–11</sub>-PADRE showed 6E10-positive staining. Cells transfected with control vector showed only background staining. C) The secretion of MDC-3Aβ<sub>1–11</sub>-PADRE by transfected CHO cells was demonstrated by IP/WB. MDC-3Aβ<sub>1–11</sub>-PADRE protein was immunoprecipitated from the growth medium of transfected CHO cells with anti-Aβ antibody (6E10), separated by 15% Tris-SDS PAGE and transferred onto nitrocellulose membrane. Proteins were visualized by staining with 6E10 followed by HRP-conjugated anti-mouse IgG. Lane 1 represent vector (pCMVE-AB/MDC); Lane 2 represent Epitope Vaccine (pMDC-3Aβ<sub>1–11</sub>-PADRE). D) 3–4 mo old C57/Bl6 (n = 6) or 3xTg-AD (n = 4) mice were immunized 5 times biweekly. Blood was collected after 3<sup>rd</sup>, 4<sup>th</sup> and 5<sup>th</sup> immunizations and humoral immune response was analyzed in sera. Seven days after the last immunization mice were sacrificed and cellular immune response was analyzed in splenocytes. Experiment with C57/Bl6 mice was repeated (total n = 12). Next, 3–4 mo old 3xTg-AD (n = 9) mice were immunized 11 times as indicated. Blood was collected and humoral immune response was analyzed in sera. After 11<sup>th</sup> immunization behavioral studies were conducted and upon its completion, mice were sacrificed and neuropathological changes were analyzed in the brains of experimental and control mice.</p>", "links"=>[], "tags"=>["dna", "immunizations"], "article_id"=>602176, "categories"=>["Neuroscience", "Immunology"], "users"=>["Nina Movsesyan", "Anahit Ghochikyan", "Mikayel Mkrtichyan", "Irina Petrushina", "Hayk Davtyan", "Purevdorj B. Olkhanud", "Elizabeth Head", "Arya Biragyn", "David H. Cribbs", "Michael G. Agadjanyan"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0002124.g001", "stats"=>{"downloads"=>0, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Schematic_representation_of_DNA_vaccine_construct_its_expression_and_immunizations_schedules_/602176", "title"=>"Schematic representation of DNA vaccine construct, its expression, and immunizations schedules.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 10:29:31"}
  • {"files"=>["https://ndownloader.figshare.com/files/932031"], "description"=>"<p>A) Concentrations of anti-Aβ antibody were detected in the sera of individual animals (n = 9 vaccinated mice, n = 5 MDC-irrelevant control, n = 5 non-vaccinated mice) after each immunization. B–C) Proliferation of CD4<sup>+</sup>T cells (B) and production of cytokines by this T cell subset (C) were detected by flow cytometry in pooled splenocyte cultures (n = 4) after 5<sup>th</sup> immunization. Data are presented after subtraction of the percent of proliferating or cytokine-producing CD4<sup>+</sup> T cells in non-re-stimulated immune splenocyte cultures from the percent of proliferating or cytokine-producing cells detected in the cultures of splenocytes re-stimulated with PADRE. D) Th2-polarization was confirmed by antibody isotypes analysis: vaccine induced primarily IgG1 type antibody.</p>", "links"=>[], "tags"=>["epitope", "concentrations", "antibody", "3xtg-ad", "mice", "activates", "proliferation", "th2-polarized", "padre-specific"], "article_id"=>602465, "categories"=>["Neuroscience", "Immunology"], "users"=>["Nina Movsesyan", "Anahit Ghochikyan", "Mikayel Mkrtichyan", "Irina Petrushina", "Hayk Davtyan", "Purevdorj B. Olkhanud", "Elizabeth Head", "Arya Biragyn", "David H. Cribbs", "Michael G. Agadjanyan"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0002124.g003", "stats"=>{"downloads"=>0, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_DNA_epitope_vaccine_induces_production_of_high_concentrations_of_anti_A_antibody_in_3xTg_AD_mice_and_activates_proliferation_of_Th2_polarized_PADRE_specific_CD4_T_cells_/602465", "title"=>"DNA epitope vaccine induces production of high concentrations of anti-Aβ antibody in 3xTg-AD mice and activates proliferation of Th2-polarized PADRE-specific CD4<sup>+</sup>T cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 10:31:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/932423"], "description"=>"<p>Densitometric quantification of bands (relative optical density) revealed significant reduction in the level of Aβ oligomers (3-mers and 6-mers) in brain extracts from immune mice in comparison to control animals (*P<0.05 and ***P<0.001, respectively). Of note, in these experiments we did not detect clear bands of higher molecular weight oligomers in the soluble extracts of proteins from brains of vaccinated or non-vaccinated 3xTg-AD mice. Representative picture of WB is presented (Lanes 1-3 non-vaccinated, lanes 4-6 vaccinated).</p>", "links"=>[], "tags"=>["oligomeric", "forms", "hemibrain", "homogenates", "ip", "wb", "biotinylated", "monoclonal"], "article_id"=>602853, "categories"=>["Neuroscience", "Immunology"], "users"=>["Nina Movsesyan", "Anahit Ghochikyan", "Mikayel Mkrtichyan", "Irina Petrushina", "Hayk Davtyan", "Purevdorj B. Olkhanud", "Elizabeth Head", "Arya Biragyn", "David H. Cribbs", "Michael G. Agadjanyan"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0002124.g006", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_level_of_oligomeric_forms_of_A_946_detected_in_hemibrain_homogenates_by_combination_of_IP_with_WB_using_biotinylated_anti_A_946_20_1_monoclonal_antibody_/602853", "title"=>"The level of oligomeric forms of Aβ detected in hemibrain homogenates by combination of IP with WB using biotinylated anti-Aβ 20.1 monoclonal antibody.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 10:33:27"}
  • {"files"=>["https://ndownloader.figshare.com/files/932640"], "description"=>"<p>A) Image analysis of immunohistochemical staining demonstrates no differences in the levels of early-stage phosphorylated tau (AT100) in the hemibrains of vaccinated and control mice. Representative images of hippocampal regions (Hp) from vaccinated and non-vaccinated mice are presented (scale bar 100 µm). B) Image analysis of immunohistochemical staining demonstrates no differences in the levels of mid-stage phosphorylated tau (AT8) in the hemibrains of vaccinated and control mice Representative images of hippocampal regions (Hp) from vaccinated and non-vaccinated mice are presented (scale bar 100 µm). C) Image analysis of immunohistochemical staining demonstrates no differences in the levels of late-stage phosphorylated tau (PHF) in the hemibrains of vaccinated and control mice Representative images of hippocampal regions (Hp) from vaccinated and non-vaccinated mice are presented (scale bar 100 µm).</p>", "links"=>[], "tags"=>["phosphorylated", "tau", "brains", "vaccinated", "mice"], "article_id"=>603073, "categories"=>["Neuroscience", "Immunology"], "users"=>["Nina Movsesyan", "Anahit Ghochikyan", "Mikayel Mkrtichyan", "Irina Petrushina", "Hayk Davtyan", "Purevdorj B. Olkhanud", "Elizabeth Head", "Arya Biragyn", "David H. Cribbs", "Michael G. Agadjanyan"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0002124.g008", "stats"=>{"downloads"=>0, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Decrease_in_the_levels_of_phosphorylated_tau_detected_in_the_brains_of_vaccinated_mice_was_not_statistically_significant_/603073", "title"=>"Decrease in the levels of phosphorylated tau detected in the brains of vaccinated mice was not statistically significant.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 10:34:47"}
  • {"files"=>["https://ndownloader.figshare.com/files/932520"], "description"=>"<p>A) Image analysis of immunohistochemical staining showing no differences in the levels of total tau (HT-7) in the hemibrains of vaccinated and control mice (scale bar 50 µm), Hp-hippocampus. B–C) Quantitative analysis (ELISA) of SDS-extracted (soluble) tau level revealed no differences between vaccinated and control mice (B). Decrease in the levels of FA-extracted (insoluble) tau was not statistically significant (C).</p>", "links"=>[], "tags"=>["epitope", "soluble", "insoluble", "tau", "brains"], "article_id"=>602954, "categories"=>["Neuroscience", "Immunology"], "users"=>["Nina Movsesyan", "Anahit Ghochikyan", "Mikayel Mkrtichyan", "Irina Petrushina", "Hayk Davtyan", "Purevdorj B. Olkhanud", "Elizabeth Head", "Arya Biragyn", "David H. Cribbs", "Michael G. Agadjanyan"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0002124.g007", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_DNA_epitope_vaccine_does_not_affect_the_level_of_soluble_and_insoluble_tau_in_the_brains_of_immune_mice_/602954", "title"=>"DNA epitope vaccine does not affect the level of soluble and insoluble tau in the brains of immune mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 10:34:06"}
  • {"files"=>["https://ndownloader.figshare.com/files/932169"], "description"=>"<p>A) The escape latency to reach the platform was significantly decreased in the groups of non-transgenic (n = 6) and 3xTg-AD immune mice (n = 9) versus age-matched groups of MDC-irrelevant control (n = 5) and non-vaccinated control 3xTg-AD mice (n = 5). Four trials per training day for each mouse were used until the criterion was reached in average ≤20 sec; maximal time allowed to find the platform = 60 sec. B) The number of correct quadrant crosses was significantly higher in a group of immune 3xTg-AD mice versus age-matched control groups for both 1.5- and 24-hr (short and long memory, respectively) probe trials. Of note, we did not find significant differences for the time spent in the quadrant opposite to the quadrant containing the platform during the training (data not shown) C) In both 1.5- and 24-hr probe trials the initial latency to cross the platform location was significantly lower in a group of immune mice versus both groups of age-matched controls. *P<0.05; **P<0.01; ***P<0.001 denote significant differences with respect to both MDC-irrelevant control and non-vaccinated 3xTg-AD mice of the same age. Error bars indicate SD.</p>", "links"=>[], "tags"=>["epitope", "improves", "retention", "spatial"], "article_id"=>602604, "categories"=>["Neuroscience", "Immunology"], "users"=>["Nina Movsesyan", "Anahit Ghochikyan", "Mikayel Mkrtichyan", "Irina Petrushina", "Hayk Davtyan", "Purevdorj B. Olkhanud", "Elizabeth Head", "Arya Biragyn", "David H. Cribbs", "Michael G. Agadjanyan"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0002124.g004", "stats"=>{"downloads"=>1, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_DNA_epitope_vaccine_improves_acquisition_and_retention_of_spatial_memory_in_immune_mice_/602604", "title"=>"DNA epitope vaccine improves acquisition and retention of spatial memory in immune mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 10:32:00"}
  • {"files"=>["https://ndownloader.figshare.com/files/932752"], "description"=>"<p>A) Image analysis of hemibrains stained with anti-GFAP antibody showed significantly less astrocytosis (P<0.05) in mice vaccinated with DNA epitope vaccine in comparison with control mice (scale bar 50 µm). Representative images of cortical regions (Ctx) from vaccinated and non-vaccinated mice are presented. B) Image analysis of hemibrains from immunized or control mice, stained with anti-CD45 antibody, showed significantly less microglia activation (P<0.001) in mice immunized with DNA epitope vaccine. Representative images of hippocampal regions (Hp) are presented (scale bar 50 µm). C) Level of microhemorrhages in the hemibrains of vaccinated mice did not differ from that in control animals. Image analysis of hemibrains from vaccinated or control mice were performed after Prussian blue staining. Of note, characteristic blue hemosiderin-positive profiles were observed in the neocortical, leptomeningeal, hippocampal and thalamic areas of hemibrain. Representative images of cortical (Ctx) and hippocampal (Hp) regions are presented (scale bar 200 µm).</p>", "links"=>[], "tags"=>["dna", "epitope", "leads", "astrocytosis", "microglia", "activation", "inducing", "cerebral"], "article_id"=>603182, "categories"=>["Neuroscience", "Immunology"], "users"=>["Nina Movsesyan", "Anahit Ghochikyan", "Mikayel Mkrtichyan", "Irina Petrushina", "Hayk Davtyan", "Purevdorj B. Olkhanud", "Elizabeth Head", "Arya Biragyn", "David H. Cribbs", "Michael G. Agadjanyan"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0002124.g009", "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Vaccination_with_DNA_epitope_vaccine_leads_to_less_astrocytosis_and_microglia_activation_without_inducing_cerebral_hemorrhages_/603182", "title"=>"Vaccination with DNA epitope vaccine leads to less astrocytosis and microglia activation without inducing cerebral hemorrhages.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 10:35:25"}
  • {"files"=>["https://ndownloader.figshare.com/files/932306"], "description"=>"<p>A) A significant reduction in Aβ load (6E10-immunoreactive core and diffuse plaques) was detected in the hemibrains of vaccinated mice compared to the control animals (**P<0.01). Representative images of immunized and control mice hemibrains stained with 6E10 (scale bar 50 µm), Ctx-cortex, S-subiculum, WM-white matter. B) A significant reduction of ThS-positive core Aβ plaques was observed in the hemibrains of vaccinated mice (*P<0.05) compared to the control animals. Shown are representative images of ThS-stained hemibrains of vaccinated or control mice were (scale bar 300 µm), S-subiculum. C) As a result of DNA epitope vaccination, significant reduction (***P<0.001) of insoluble Aβ<sub>42</sub> level in brain homogenates was observed, although, decrease in level of insoluble Aβ<sub>40</sub> was not statistically significant. D) Both soluble Aβ<sub>40</sub> and Aβ<sub>42</sub> levels in brain homogenates of immunized mice were significantly reduced (***P<0.001) following epitope vaccine immunization. Bars represent average±SD for n = 5 in the group of control mice, and n = 9 in the group of vaccinated 3xTg-AD mice.</p>", "links"=>[], "tags"=>["epitope", "depositions", "brains", "3xtg-ad", "mice"], "article_id"=>602735, "categories"=>["Neuroscience", "Immunology"], "users"=>["Nina Movsesyan", "Anahit Ghochikyan", "Mikayel Mkrtichyan", "Irina Petrushina", "Hayk Davtyan", "Purevdorj B. Olkhanud", "Elizabeth Head", "Arya Biragyn", "David H. Cribbs", "Michael G. Agadjanyan"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0002124.g005", "stats"=>{"downloads"=>1, "page_views"=>27, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_DNA_epitope_vaccine_reduces_A_946_depositions_in_the_brains_of_immune_3xTg_AD_mice_at_age_18_177_0_5_mo_/602735", "title"=>"DNA epitope vaccine reduces Aβ depositions in the brains of immune 3xTg-AD mice at age 18±0.5 mo.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 10:32:46"}
  • {"files"=>["https://ndownloader.figshare.com/files/931927"], "description"=>"<p>A) DNA epitope vaccine induces very strong humoral immune response in 3–4 mo old C57/Bl6 mice (n = 6). Group of non-vaccinated (n = 6) as well as group of mice (n = 6) injected with plasmid encoding MDC fused with irrelevant antigen did not generate anti-Aβ antibody. B) Anti-Aβ antibody generated in mice immunized with DNA epitope vaccine recognizes human Aβ deposits when used in immunohistochemical experiments in an AD case, and this binding is blocked by pre-absorption of sera with both Aβ<sub>42</sub> or Aβ<sub>1–11</sub> peptide. C) DNA epitope vaccine induces the production of anti-Aβ antibody of predominantly IgG1 isotype in wild-type (C57/Bl6) animals. D) IgG1/IgG2a<sup>b</sup> ratio in wild-type (C57/Bl6) and 3xTg-AD mice was equal to 32.4±3.2 and 16.7±2, respectively, which is an indirect measurement of Th2-type immune response induced by DNA epitope vaccine. Of note, all experiments with C57Bl/6 mice were repeated (n = 6) with the similar results.</p>", "links"=>[], "tags"=>["epitope", "th2", "polarized", "humoral", "responses"], "article_id"=>602359, "categories"=>["Neuroscience", "Immunology"], "users"=>["Nina Movsesyan", "Anahit Ghochikyan", "Mikayel Mkrtichyan", "Irina Petrushina", "Hayk Davtyan", "Purevdorj B. Olkhanud", "Elizabeth Head", "Arya Biragyn", "David H. Cribbs", "Michael G. Agadjanyan"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0002124.g002", "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_DNA_epitope_vaccine_induces_strong_Th2_polarized_humoral_immune_responses_specific_to_human_A_946_/602359", "title"=>"DNA epitope vaccine induces strong Th2 polarized humoral immune responses specific to human Aβ.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 10:30:36"}

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Relative Metric

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