De novo GTP Biosynthesis Is Critical for Virulence of the Fungal Pathogen Cryptococcus neoformans
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{"title"=>"De novo GTP Biosynthesis Is Critical for Virulence of the Fungal Pathogen Cryptococcus neoformans", "type"=>"journal", "authors"=>[{"first_name"=>"Carl A.", "last_name"=>"Morrow", "scopus_author_id"=>"36951739100"}, {"first_name"=>"Eugene", "last_name"=>"Valkov", "scopus_author_id"=>"26021569300"}, {"first_name"=>"Anna", "last_name"=>"Stamp", "scopus_author_id"=>"14059028600"}, {"first_name"=>"Eve W.L.", "last_name"=>"Chow", "scopus_author_id"=>"54386636600"}, {"first_name"=>"I. Russel", "last_name"=>"Lee", "scopus_author_id"=>"55150008100"}, {"first_name"=>"Ania", "last_name"=>"Wronski", "scopus_author_id"=>"24342212800"}, {"first_name"=>"Simon J.", "last_name"=>"Williams", "scopus_author_id"=>"57195445459"}, {"first_name"=>"Justine M.", "last_name"=>"Hill", "scopus_author_id"=>"7404771438"}, {"first_name"=>"Julianne T.", "last_name"=>"Djordjevic", "scopus_author_id"=>"7003424997"}, {"first_name"=>"Ulrike", "last_name"=>"Kappler", "scopus_author_id"=>"6603150947"}, {"first_name"=>"Bostjan", "last_name"=>"Kobe", "scopus_author_id"=>"7006478950"}, {"first_name"=>"James A.", "last_name"=>"Fraser", "scopus_author_id"=>"7202394250"}], "year"=>2012, "source"=>"PLoS Pathogens", "identifiers"=>{"pui"=>"365953687", "issn"=>"15537366", "isbn"=>"1553-7366", "doi"=>"10.1371/journal.ppat.1002957", "scopus"=>"2-s2.0-84868150577", "pmid"=>"23071437", "sgr"=>"84868150577"}, "id"=>"9cefe54c-8560-3c8e-b924-ac5e67394b2e", "abstract"=>"We have investigated the potential of the GTP synthesis pathways as chemotherapeutic targets in the human pathogen Cryptococcus neoformans, a common cause of fatal fungal meningoencephalitis. We find that de novo GTP biosynthesis, but not the alternate salvage pathway, is critical to cryptococcal dissemination and survival in vivo. Loss of inosine monophosphate dehydrogenase (IMPDH) in the de novo pathway results in slow growth and virulence factor defects, while loss of the cognate phosphoribosyltransferase in the salvage pathway yielded no phenotypes. Further, the Cryptococcus species complex displays variable sensitivity to the IMPDH inhibitor mycophenolic acid, and we uncover a rare drug-resistant subtype of C. gattii that suggests an adaptive response to microbial IMPDH inhibitors in its environmental niche. We report the structural and functional characterization of IMPDH from Cryptococcus, revealing insights into the basis for drug resistance and suggesting strategies for the development of fungal-specific inhibitors. The crystal structure reveals the position of the IMPDH moveable flap and catalytic arginine in the open conformation for the first time, plus unique, exploitable differences in the highly conserved active site. Treatment with mycophenolic acid led to significantly increased survival times in a nematode model, validating de novo GTP biosynthesis as an antifungal target in Cryptococcus.", "link"=>"http://www.mendeley.com/research/novo-gtp-biosynthesis-critical-virulence-fungal-pathogen-cryptococcus-neoformans", "reader_count"=>25, "reader_count_by_academic_status"=>{"Researcher"=>13, "Student > Doctoral Student"=>4, "Student > Ph. D. Student"=>3, "Student > Master"=>3, "Other"=>1, "Professor"=>1}, "reader_count_by_user_role"=>{"Researcher"=>13, "Student > Doctoral Student"=>4, "Student > Ph. D. Student"=>3, "Student > Master"=>3, "Other"=>1, "Professor"=>1}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>1, "Agricultural and Biological Sciences"=>19, "Medicine and Dentistry"=>4, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>4}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>19}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>1}}, "reader_count_by_country"=>{"Chile"=>1}, "group_count"=>1}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/560796"], "description"=>"<p>Serial dilution spotting assays of selected IMPDH mutants on YNB plus 5 µg/mL MPA. Robust growth on MPA is observed in the deletion mutant <i>imd1</i>Δ transformed with either the <i>CgIMD1</i> allele or any <i>IMD1</i> allele uniting the residues K336 and E446. Two copies of the MPA-sensitive <i>CnIMD1</i> allele (in H99 <i>CnIMD1</i>) result in only a very modest increase in resistance to MPA and IMPDH heterotetramerization (in H99 <i>CgIMD1</i>) does not appear to produce novel phenotypes. The juxtaposed image depicts which portions of the IMPDH allele are present, with yellow representing <i>CnIMD1</i> and blue representing <i>CgIMD1</i>, split into three thirds with the vertical bars depicting the six unique residues. Two proteins are depicted for the H99 background where the wild-type allele is also present.</p>", "links"=>[], "tags"=>["impdh", "confers", "mediated", "amino"], "article_id"=>231273, "categories"=>["Biochemistry", "Microbiology"], "users"=>["Carl A. Morrow", "Eugene Valkov", "Anna Stamp", "Eve W. L. Chow", "I. Russel Lee", "Ania Wronski", "Simon J. Williams", "Justine M. Hill", "Julianne T. Djordjevic", "Ulrike Kappler", "Bostjan Kobe", "James A. Fraser"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002957.g006", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_C_gattii_IMPDH_confers_resistance_to_MPA_mediated_by_two_amino_acids_/231273", "title"=>"<i>C. gattii</i> IMPDH confers resistance to MPA, mediated by two amino acids.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-10-11 00:21:13"}
  • {"files"=>["https://ndownloader.figshare.com/files/560406"], "description"=>"<p>(A) Strains were grown for five days in RPMI 1640 media supplemented with 10% serum and monitored spectrophotometrically at 600 nm. (B) <i>C. neoformans</i> capsule biosynthesis was examined by growth in RPMI 1640 media plus 10% serum for 16 hours at 30°C and visualized using India ink; the halo of clearance denotes the capsule. Scale bar is 10 µm. Capsular diameter was measured relative to cellular diameter using CellProfiler image analysis software. Bars denote the average relative diameter from three biological replicates. Standard error bars are shown; <i>p</i><0.05 *; <i>p</i><0.01 **; <i>p</i><0.001 ***; <i>p</i><0.0001 ****. (C) Melanin production was determined on <i>Cryptococcus </i>l-DOPA melanization plates incubated for two days. (D) Mating proficiency was assayed by co-culturing strains on Murashige-Skoog or V8 medium in the dark for two weeks at 25°C. Magnification is 40×. All assays involving the <i>imd1</i>Δ strain were supplemented with 1 mM guanine.</p>", "links"=>[], "tags"=>["purine", "biosynthesis", "genes", "virulence"], "article_id"=>230888, "categories"=>["Biochemistry", "Microbiology"], "users"=>["Carl A. Morrow", "Eugene Valkov", "Anna Stamp", "Eve W. L. Chow", "I. Russel Lee", "Ania Wronski", "Simon J. Williams", "Justine M. Hill", "Julianne T. Djordjevic", "Ulrike Kappler", "Bostjan Kobe", "James A. Fraser"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002957.g002", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Contribution_of_purine_biosynthesis_genes_to_the_virulence_component_of_Cryptococcus_/230888", "title"=>"Contribution of purine biosynthesis genes to the virulence component of <i>Cryptococcus</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-10-11 00:14:48"}
  • {"files"=>["https://ndownloader.figshare.com/files/560997"], "description"=>"<p>(A) The <i>Cryptococcus neoformans</i> IMPDH structure indicates that the flap adopts an open conformation in the ligand-bound state, with the catalytic R458 folded above the active site. The flap is rainbow colored and the catalytic arginine and IMP in the active site are depicted in stick representation. (B) The <i>Tritrichomonas foetus</i> IMPDH structure in complex with mizoribine phosphate (MZP) is in the closed conformation, with the flap extending out over the active site pocket and the catalytic arginine positioned underneath. (C) The <i>Bacillus anthracis</i> structure shows the unbound apoenzyme also adopts the closed conformation, with the flap closed over the active site.</p>", "links"=>[], "tags"=>["conformations", "impdh"], "article_id"=>231477, "categories"=>["Biochemistry", "Microbiology"], "users"=>["Carl A. Morrow", "Eugene Valkov", "Anna Stamp", "Eve W. L. Chow", "I. Russel Lee", "Ania Wronski", "Simon J. Williams", "Justine M. Hill", "Julianne T. Djordjevic", "Ulrike Kappler", "Bostjan Kobe", "James A. Fraser"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002957.g008", "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_open_and_closed_conformations_of_the_IMPDH_mobile_flap_/231477", "title"=>"The open and closed conformations of the IMPDH mobile flap.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-10-11 00:24:37"}
  • {"files"=>["https://ndownloader.figshare.com/files/560721"], "description"=>"<p>(A) Resistance to the IMPDH inhibitor MPA was assessed in all haploid molecular types of the pathogenic <i>C. neoformans/C. gattii</i> species complex using a serial dilution spotting assay on YNB plus 5 µg/mL MPA. (B) Precise sensitivity to MPA was determined <i>via</i> MIC broth microdilution assay. MIC<sub>50</sub> and MIC<sub>90</sub> are the concentrations at which growth was inhibited by 50% or 90%, respectively. Standard error bars are displayed for all strains.</p>", "links"=>[], "tags"=>["vgiv", "molecular", "resistant"], "article_id"=>231203, "categories"=>["Biochemistry", "Microbiology"], "users"=>["Carl A. Morrow", "Eugene Valkov", "Anna Stamp", "Eve W. L. Chow", "I. Russel Lee", "Ania Wronski", "Simon J. Williams", "Justine M. Hill", "Julianne T. Djordjevic", "Ulrike Kappler", "Bostjan Kobe", "James A. Fraser"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002957.g005", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_C_gattii_VGIV_molecular_type_is_resistant_to_MPA_/231203", "title"=>"The <i>C. gattii</i> VGIV molecular type is resistant to MPA.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-10-11 00:20:03"}
  • {"files"=>["https://ndownloader.figshare.com/files/560283"], "description"=>"<p>(A) BLASTp analysis using <i>S. cerevisiae</i> orthologs reveals that the majority of the components of the canonical purine biosynthetic pathway are present in the genome of <i>C. neoformans</i> var. <i>grubii</i>. Enzymes or activities missing are greyed. (B) 10-fold serial dilutions of indicated strains were spotted onto YNB medium supplemented with specified purines (1 mM) and/or MPA (5 µg/mL) and incubated for two days at 30°C. The <i>imd1</i>Δ deletion strain is an auxotroph; MPA mimics the effect of an <i>imd1</i>Δ deletion, while <i>E. coli</i> guaB is highly resistant to MPA. A phenotype for the <i>hpt1</i>Δ strain is only observed in the presence of MPA.</p>", "links"=>[], "tags"=>["purine", "metabolic", "pathway"], "article_id"=>230767, "categories"=>["Biochemistry", "Microbiology"], "users"=>["Carl A. Morrow", "Eugene Valkov", "Anna Stamp", "Eve W. L. Chow", "I. Russel Lee", "Ania Wronski", "Simon J. Williams", "Justine M. Hill", "Julianne T. Djordjevic", "Ulrike Kappler", "Bostjan Kobe", "James A. Fraser"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002957.g001", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Components_of_the_purine_metabolic_pathway_in_Cryptococcus_/230767", "title"=>"Components of the purine metabolic pathway in <i>Cryptococcus</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-10-11 00:12:47"}
  • {"files"=>["https://ndownloader.figshare.com/files/297811", "https://ndownloader.figshare.com/files/297848", "https://ndownloader.figshare.com/files/297879", "https://ndownloader.figshare.com/files/297909", "https://ndownloader.figshare.com/files/297937", "https://ndownloader.figshare.com/files/297980", "https://ndownloader.figshare.com/files/298066", "https://ndownloader.figshare.com/files/298112", "https://ndownloader.figshare.com/files/298149", "https://ndownloader.figshare.com/files/298235", "https://ndownloader.figshare.com/files/298295", "https://ndownloader.figshare.com/files/298362"], "description"=>"<div><p>We have investigated the potential of the GTP synthesis pathways as chemotherapeutic targets in the human pathogen <em>Cryptococcus neoformans</em>, a common cause of fatal fungal meningoencephalitis. We find that <em>de novo</em> GTP biosynthesis, but not the alternate salvage pathway, is critical to cryptococcal dissemination and survival <em>in vivo</em>. Loss of inosine monophosphate dehydrogenase (IMPDH) in the <em>de novo</em> pathway results in slow growth and virulence factor defects, while loss of the cognate phosphoribosyltransferase in the salvage pathway yielded no phenotypes. Further, the <em>Cryptococcus</em> species complex displays variable sensitivity to the IMPDH inhibitor mycophenolic acid, and we uncover a rare drug-resistant subtype of <em>C. gattii</em> that suggests an adaptive response to microbial IMPDH inhibitors in its environmental niche. We report the structural and functional characterization of IMPDH from <em>Cryptococcus</em>, revealing insights into the basis for drug resistance and suggesting strategies for the development of fungal-specific inhibitors. The crystal structure reveals the position of the IMPDH moveable flap and catalytic arginine in the open conformation for the first time, plus unique, exploitable differences in the highly conserved active site. Treatment with mycophenolic acid led to significantly increased survival times in a nematode model, validating <em>de novo</em> GTP biosynthesis as an antifungal target in <em>Cryptococcus</em>.</p> </div>", "links"=>[], "tags"=>["gtp", "biosynthesis", "virulence", "fungal", "pathogen"], "article_id"=>118704, "categories"=>["Biochemistry", "Microbiology"], "users"=>["Carl A. Morrow", "Eugene Valkov", "Anna Stamp", "Eve W. L. Chow", "I. Russel Lee", "Ania Wronski", "Simon J. Williams", "Justine M. Hill", "Julianne T. Djordjevic", "Ulrike Kappler", "Bostjan Kobe", "James A. Fraser"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1002957.s001", "https://dx.doi.org/10.1371/journal.ppat.1002957.s002", "https://dx.doi.org/10.1371/journal.ppat.1002957.s003", "https://dx.doi.org/10.1371/journal.ppat.1002957.s004", "https://dx.doi.org/10.1371/journal.ppat.1002957.s005", "https://dx.doi.org/10.1371/journal.ppat.1002957.s006", "https://dx.doi.org/10.1371/journal.ppat.1002957.s007", "https://dx.doi.org/10.1371/journal.ppat.1002957.s008", "https://dx.doi.org/10.1371/journal.ppat.1002957.s009", "https://dx.doi.org/10.1371/journal.ppat.1002957.s010", "https://dx.doi.org/10.1371/journal.ppat.1002957.s011", "https://dx.doi.org/10.1371/journal.ppat.1002957.s012"], "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_De_novo_GTP_Biosynthesis_Is_Critical_for_Virulence_of_the_Fungal_Pathogen_Cryptococcus_neoformans_/118704", "title"=>"<em>De novo</em> GTP Biosynthesis Is Critical for Virulence of the Fungal Pathogen <em>Cryptococcus neoformans</em>", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2012-10-11 02:25:04"}
  • {"files"=>["https://ndownloader.figshare.com/files/560619"], "description"=>"<p>(A) Fungal burden of <i>imd1</i>Δ cells recovered from the lungs and brain of BALB/c mice infected with 5×10<sup>5</sup> cells <i>via</i> nasal inhalation. Bars represent mean colony-forming units (CFU)/g ± standard error. (B) N2 Bristol young adult nematodes were co-cultured with <i>C. neoformans</i> wild-type strain H99 on minimal medium supplemented with 5, 10 or 20 µg/mL MPA or 5 µg/mL fluconazole. MPA significantly enhanced nematode survival over eight days, as did fluconazole treatment; <i>p</i><0.05 *; <i>p</i><0.01 **.</p>", "links"=>[], "tags"=>["pathogenicity", "murine", "nematode"], "article_id"=>231101, "categories"=>["Biochemistry", "Microbiology"], "users"=>["Carl A. Morrow", "Eugene Valkov", "Anna Stamp", "Eve W. L. Chow", "I. Russel Lee", "Ania Wronski", "Simon J. Williams", "Justine M. Hill", "Julianne T. Djordjevic", "Ulrike Kappler", "Bostjan Kobe", "James A. Fraser"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002957.g004", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_IMPDH_is_essential_for_pathogenicity_in_murine_and_nematode_hosts_/231101", "title"=>"IMPDH is essential for pathogenicity in murine and nematode hosts.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-10-11 00:18:21"}
  • {"files"=>["https://ndownloader.figshare.com/files/560889"], "description"=>"<p>(A) Active site residues of <i>C. neoformans</i> IMPDH with IMP and MPA ligands in ball-and-stick representation, with hydrogen-bonding interactions indicated by dashed lines. Figure displays residues within 4 Å of the active site except for T347, which adopts a strikingly different conformation in the <i>Cryptococcus</i> enzyme. (B) Residues 339–356 of <i>Cryptococcus</i> IMPDH (green) form the active site loop and are highly conserved. Comparison of the <i>C. neoformans E</i>•IMP•MPA complex active site loop conformation with the hamster <i>E</i>-XMP*•MPA complex and the human type I IMPDH in complex with the substrate analogue 6-chloropurine ribotide (CPR) are shown. IMP, CPR and the catalytic cysteine are shown in stick representation, while MPA is omitted. (C) Surface representation of the active site pocket of <i>C. neoformans</i> and Chinese hamster IMPDH. The white arrow indicates the region around T347, which forms a unique, potentially exploitable cavity in the fungal enzyme. MPA is omitted for clarity.</p>", "links"=>[], "tags"=>["microbiology", "Biochemistry"], "article_id"=>231374, "categories"=>["Biochemistry", "Microbiology"], "users"=>["Carl A. Morrow", "Eugene Valkov", "Anna Stamp", "Eve W. L. Chow", "I. Russel Lee", "Ania Wronski", "Simon J. Williams", "Justine M. Hill", "Julianne T. Djordjevic", "Ulrike Kappler", "Bostjan Kobe", "James A. Fraser"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002957.g007", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Structure_of_C_neoformans_IMPDH_/231374", "title"=>"Structure of <i>C. neoformans</i> IMPDH.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-10-11 00:22:54"}
  • {"files"=>["https://ndownloader.figshare.com/files/561093"], "description"=>"<p>Steady-state and inhibition constants for species with well-characterized IMPDHs. UC, uncompetitive; NC, noncompetitive; ND, no data; NA, not applicable. Values are from <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1002957#ppat.1002957-Umejiego1\" target=\"_blank\">[19]</a>, <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1002957#ppat.1002957-Kohler1\" target=\"_blank\">[21]</a>, <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1002957#ppat.1002957-Digits1\" target=\"_blank\">[28]</a>, <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1002957#ppat.1002957-Hansen1\" target=\"_blank\">[58]</a>.</p>", "links"=>[], "tags"=>["parameters", "impdh", "characterized"], "article_id"=>231575, "categories"=>["Biochemistry", "Microbiology"], "users"=>["Carl A. Morrow", "Eugene Valkov", "Anna Stamp", "Eve W. L. Chow", "I. Russel Lee", "Ania Wronski", "Simon J. Williams", "Justine M. Hill", "Julianne T. Djordjevic", "Ulrike Kappler", "Bostjan Kobe", "James A. Fraser"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002957.t001", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Kinetic_parameters_for_IMPDH_from_characterized_species_/231575", "title"=>"Kinetic parameters for IMPDH from characterized species.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-10-11 00:26:15"}
  • {"files"=>["https://ndownloader.figshare.com/files/560511"], "description"=>"<p>(A) Survival of Bristol N2 strain nematodes co-cultured with indicated <i>Cryptococcus</i> strains cultured on rich Brain Heart Infusion medium or minimal YNB medium at 25°C. (B) Survival of female BALB/c mice infected with 5×10<sup>5</sup> cells <i>via</i> nasal inhalation. (C) Virulence of indicated <i>Cryptococcus</i> strains co-cultured with nematodes on rich and minimal medium at 25°C. (D) Virulence of the <i>imd1</i>Δ mutant in BALB/c mice infected with 5×10<sup>5</sup> cells <i>via</i> nasal inhalation. Virulence was determined using Kaplan-Meier survival analysis with statistical significance determined using a log-rank test. Survival times were not significantly different for the <i>hpt1</i>Δ strain in either model. <i>imd1</i>Δ was significantly attenuated in the nematode model on minimal medium (<i>p</i><0.0001) and in the murine model (<i>p</i><0.0001).</p>", "links"=>[], "tags"=>["invertebrate", "mammalian"], "article_id"=>231000, "categories"=>["Biochemistry", "Microbiology"], "users"=>["Carl A. Morrow", "Eugene Valkov", "Anna Stamp", "Eve W. L. Chow", "I. Russel Lee", "Ania Wronski", "Simon J. Williams", "Justine M. Hill", "Julianne T. Djordjevic", "Ulrike Kappler", "Bostjan Kobe", "James A. Fraser"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002957.g003", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Virulence_of_imd1_and_hpt1_in_invertebrate_and_mammalian_host_systems_/231000", "title"=>"Virulence of <i>imd1</i>Δ and <i>hpt1</i>Δ in invertebrate and mammalian host systems.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-10-11 00:16:40"}

PMC Usage Stats | Further Information

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Relative Metric

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