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erythrocytes (IE). It is encoded by the var multigene family (50–150 genes on multiple chromosomes). Two related PfEMP1 genes were cloned from the Malayan Camp (MC) strain; recombinant protein-specific antibodies reacted only with MC strain IE surfaces and blocked adherence to CD36 but not to thrombospondin, establishing PfEMP1 as the cytoadherence ligand for CD36.\",\n      \"method\": \"Gene cloning, recombinant protein expression, antibody generation, cytoadherence inhibition assay, surface immunoprecipitation, trypsin sensitivity, metabolic labeling, lactoperoxidase iodination\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (cloning, recombinant protein, functional adhesion blocking) replicated across two papers in the same year\",\n      \"pmids\": [\"7541722\", \"7606788\", \"6374009\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"Malayan Camp (MC)\"}]\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Expression of individual var genes correlates with surface antigenic variation and binding to specific host receptors; expression of a specific var gene correlated with ICAM-1 binding, establishing that PfEMP1 (encoded by individual var genes) mediates binding to ICAM-1.\",\n      \"method\": \"var gene expression profiling, cytoadherence assays to ICAM-1, correlation of transcription with binding phenotype\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — replicated across multiple studies, direct correlation of specific var transcript with ICAM-1 binding phenotype\",\n      \"pmids\": [\"7606775\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"PfEMP1, encoded by a specific var gene, is the parasite ligand mediating rosetting (binding of IE to uninfected erythrocytes). Complement receptor 1 (CR1) on uninfected erythrocytes serves as a host receptor for this PfEMP1-mediated rosetting interaction; erythrocytes with a common African CR1 polymorphism (S1(a-)) showed reduced adhesion to the PfEMP1 domain that binds normal erythrocytes.\",\n      \"method\": \"Antibody inhibition, var gene identification, CR1 polymorphism analysis, rosetting assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple approaches (antibody inhibition, genetic polymorphism analysis, rosetting assay) in a high-profile study, independently supported by subsequent work\",\n      \"pmids\": [\"9230440\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"KAHRP (knob-associated histidine-rich protein) directly binds the cytoplasmic (VARC) region of PfEMP1. Three fragments of KAHRP bind VARC; the high-affinity binding regions map to the 63-residue histidine-rich and 70-residue 5' repeat segments of KAHRP (Kd ~10^-7 M and ~3.3×10^-6 M). Deletion of these two regions abolished binding, establishing the molecular basis for PfEMP1 clustering at knobs.\",\n      \"method\": \"Pulldown binding assays with recombinant protein fragments, surface plasmon resonance (kinetic Kd measurements), deletion mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with mutagenesis and quantitative binding measurements in a single rigorous study\",\n      \"pmids\": [\"10446142\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"A recombinant 179-residue subfragment of PfEMP1 encompassing the CIDR1 domain (rC1-2[1-179]) competitively inhibits and reverses adhesion of parasitized erythrocytes to CD36 under physiological flow conditions in a concentration-dependent, strain-nonspecific manner (up to 99% inhibition), but has no effect on CSA-mediated adhesion, mapping the CD36-binding activity specifically to the CIDR1 subdomain of PfEMP1.\",\n      \"method\": \"Recombinant protein expression, parallel-plate flow chamber adhesion assay, competitive inhibition and reversal experiments with multiple parasite lines\",\n      \"journal\": \"Molecular microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro functional reconstitution with recombinant domain, multiple parasite strains, flow-based assay\",\n      \"pmids\": [\"9786187\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"A recombinant peptide corresponding to the minimal CD36-binding domain from CIDR1 of PfEMP1 (PpMC-179) inhibited adhesion of infected erythrocytes from clinical isolates to human dermal microvascular endothelial cells by 84–90% in vitro and detached already-adherent infected erythrocytes by ~80–83% in an in vivo human/SCID mouse chimeric model, demonstrating that PfEMP1's CIDR1 domain mediates cytoadherence in vivo.\",\n      \"method\": \"In vitro parallel-plate flow chamber assay, human/SCID mouse chimeric in vivo model with intravital microscopy, clinical isolates\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vivo functional validation with recombinant domain in a chimeric model, complementing in vitro data\",\n      \"pmids\": [\"12393525\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The CIDR1α domain of PfEMP1 mediates cytoadhesion of IE to human NK cell lines (via chondroitin sulfate A as the host receptor) but is not required for primary NK cell activation. In contrast, ICAM-1 on macrophages (acting through its own ligand LFA-1, not through PfEMP1 directly) is required for NK cell IFN-γ production, dissociating PfEMP1-dependent adhesion from PfEMP1-independent NK activation.\",\n      \"method\": \"Genetically engineered parasite mutant strains lacking PfEMP1 function, blocking antibodies, human genetic deficiency model, cytokine measurements\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — engineered mutant parasites, blocking antibodies, and genetic deficiency used; single lab study\",\n      \"pmids\": [\"17311092\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Binding of native PfEMP1 (encoded by var2csa) to CSA requires 4-O-sulfated disaccharides and glucuronic acid; minimum chain length for direct PfEMP1 binding is 8 monosaccharide units, and 10 for maximal inhibition of placental adhesion. Isolate-specific differences in preferred CSA structural motifs correlate with polymorphisms in var2csa-encoded PfEMP1, demonstrating structure-activity requirements for PfEMP1-CSA interaction.\",\n      \"method\": \"Direct binding assay of native PfEMP1 isolated from IE to immobilized CSA oligosaccharides (neoglycolipid probes), adhesion inhibition assays with defined oligosaccharides, multiple parasite isolates\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct binding of native PfEMP1 protein to defined chemical probes with structure-activity mapping; single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"17562715\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Among 16 DBLbetaC2 domains from the 3D7 PfEMP1 repertoire, only the DBL2betaC2 domain of the Group A PfEMP1 PF11_0521 bound ICAM-1 with high affinity; inhibition of binding was more efficient than reversal, indicating a strong interaction. Naturally acquired immune sera from east African adults (but not US controls) inhibited this binding.\",\n      \"method\": \"High-throughput Bioplex binding assay with 16 recombinant DBLbetaC2 domains, ICAM-1 binding inhibition with immune sera, sequence conservation analysis\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic recombinant domain screen with functional inhibition assays; single lab\",\n      \"pmids\": [\"19381252\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}]\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PfEMP1 is trafficked from the parasite through an exomembrane system involving Maurer's clefts. PfEMP1-GFP chimera first accumulates near the parasite surface in membranous structures, then is transferred to pre-formed mobile Maurer's clefts. Endogenous PfEMP1 and PfEMP1-GFP associate with electron-dense vesicles (EDVs) that appear responsible for trafficking PfEMP1 from Maurer's clefts to the RBC membrane. Maurer's clefts dock onto the RBC membrane at ~20 h post invasion.\",\n      \"method\": \"Live imaging of GFP-chimeric PfEMP1 in transfected parasites, immunoelectron microscopy, fractionation, cytochalasin D treatment, spatial and temporal mapping\",\n      \"journal\": \"Cellular microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging of tagged PfEMP1 combined with ultrastructural analysis and pharmacological perturbation; multiple orthogonal methods in single study\",\n      \"pmids\": [\"23421990\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The PHIST-domain protein PFE1605w binds directly to the PfEMP1 intracellular segment (ATS/VARC) with Kd = 5 ± 0.6 μM, comigrates with PfEMP1 during export, and co-localizes at knobs. A crystallographic structure of the PHIST domain was resolved and a partial model of the PHIST-PfEMP1 interaction derived by NMR. Control PHIST variants that do not localize to knobs (MAL8P1.4) or bind PfEMP1 30-fold more weakly (PFI1780w) did not show this pattern.\",\n      \"method\": \"Recombinant protein pulldown, quantitative binding (Kd), live-cell co-migration imaging, X-ray crystallography, NMR, control PHIST variant comparisons\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure + NMR + quantitative binding assay + live-cell imaging; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"24983468\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The cytosolic domain of PfEMP1 (VARC) interacts broadly with erythrocyte spectrin, with weak residue-specific preference for α-spectrin domain 17 (proximal to the erythrocyte cytoskeletal junction). KAHRP's repeat region preferentially associates with β-spectrin domains 10–14 (proximal to the spectrin-ankyrin complex). Structural models suggest a knob architecture in which PfEMP1 and KAHRP anchor to distinct spectrin sites.\",\n      \"method\": \"Biophysical binding assays, structural modeling, computational analysis, combined with prior microscopy and protein interaction data\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biophysical binding assays with structural modeling; single lab study without in-cell validation of the proposed model\",\n      \"pmids\": [\"28806784\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Structural biology of a group of PfEMP1 proteins revealed how their DBLβ domain interacts with ICAM-1, enabling prediction of ICAM-1 binders from a specific sequence motif. These ICAM-1-binding PfEMP1s were also found to interact with EPCR (via CIDRα1 domains), allowing dual-receptor binding; expression of these PfEMP1 variants is associated with increased risk of cerebral malaria.\",\n      \"method\": \"Structural biology (crystal structures), sequence motif analysis, ICAM-1 and EPCR binding assays, genomic analysis across multiple P. falciparum genomes, clinical association\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure-guided identification with functional binding assays and genomic validation across multiple strains\",\n      \"pmids\": [\"28279348\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"K13 (Kelch13) colocalizes and copurifies with PfEMP1 at PI3P-enriched tubules/vesicles of the ER in infected red cells. Elevation of PI3P (which induces artemisinin resistance) alters PfEMP1 export to the red cell and cytoadherence of infected cells to a host endothelial receptor, implicating PI3P-vesicle amplification in PfEMP1 trafficking and cytoadherence capacity.\",\n      \"method\": \"Cryo-immunoelectron microscopy, co-purification, colocalization, fluorescence microscopy, chemical inhibitors, K13 mutant parasites\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cryo-immunoEM and copurification establish colocalization; functional link to PfEMP1 export inferred from K13 mutant phenotypes; single lab\",\n      \"pmids\": [\"29363540\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The P. falciparum translation-enhancing factor (PTEF) relieves upstream ORF (uORF)-mediated translational repression of the var2csa-encoded PfEMP1 (VAR2CSA). PTEF must be proteolytically processed by PfCalpain, generating a C-terminal domain with a sterile-alpha-motif-like domain that interacts with ribosomes to facilitate translational derepression of the var2csa coding sequence. VAR2CSA protein levels in var2csa-transcribing parasites depend on PTEF expression level.\",\n      \"method\": \"Translational reporter assays, protein-protein interaction (ribosome association), protease cleavage assays, heterologous translation system, parasite genetic manipulation\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mechanistic dissection with multiple biochemical assays, protease dependence, and heterologous system validation; single lab with orthogonal methods\",\n      \"pmids\": [\"28481333\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PfEMP1 present on infected erythrocyte surfaces dampens monocyte/macrophage NF-κB activation and reduces cytokine (TNF, IL-10) and chemokine (IL-1β, IL-6, MCP-1, MIP-1α, MIP-1β) release. Parasites expressing surface PfEMP1 induced significantly lower NF-κB activation than PfEMP1-null transgenic parasites, identifying PfEMP1 as an immunosuppressive molecule that modulates macrophage transcription factor activation.\",\n      \"method\": \"PfEMP1-null transgenic parasites vs. wild-type, transcription factor activation assays (NF-κB, CREB), cytokine/chemokine ELISA, primary human monocytes\",\n      \"journal\": \"Infection and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic loss-of-function with defined molecular readout; single lab; two cell types (RAW macrophages and primary human monocytes)\",\n      \"pmids\": [\"29038124\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7; CS2\"}]\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PfEMP1 is present in extracellular vesicles (EVs) released from early-stage (up to 12 h post-invasion) P. falciparum-infected RBCs. Using PfEMP1 transport-knockout parasites, EVs were shown to originate from inside the iRBC rather than from the iRBC surface. EVs containing PfEMP1 suppressed gene expression changes in human monocytes relative to PfEMP1-knockout EVs, suggesting PfEMP1 modulates monocyte responses when present in EVs.\",\n      \"method\": \"EV isolation, PfEMP1 transport-knockout parasites, proteomics, transcriptomics of primary human monocytes\",\n      \"journal\": \"Cellular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout parasites used as controls with transcriptomic readout; origin of EVs established by genetic approach; single lab\",\n      \"pmids\": [\"29349926\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"α2-Macroglobulin (α2M) is a serum factor both required and sufficient for rosetting mediated by the PfEMP1 protein HB3VAR06. The α2M binding site maps to the C-terminal end of HB3VAR06, and α2M can bind at least four HB3VAR06 molecules, augmenting avidity for host erythrocyte carbohydrate receptors. IgM acts synergistically with α2M to lower the α2M concentration required for rosetting, but cannot induce rosetting alone.\",\n      \"method\": \"Rosetting assays, serum fractionation, recombinant domain binding, electron microscopy of α2M complexes, domain mapping\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional rosetting assay with recombinant domain mapping; serum factor identification and synergy characterization; single lab\",\n      \"pmids\": [\"26134405\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"HB3\"}]\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The co-chaperone PFA0660w binds cholesterol and directly interacts with PfHsp70-x; PfHsp70-x in turn directly interacts with the cytoplasmic tail (ATS) of PfEMP1. In vitro, cholesterol-bound PFA0660w and PfEMP1 can be simultaneously bound by PfHsp70-x to form a ternary complex, suggesting a chaperone complex for PfEMP1 transport through cholesterol-containing J-dots.\",\n      \"method\": \"Recombinant protein interaction assays, in vitro complex reconstitution, biochemical domain-mapping, cholesterol-binding assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vitro reconstitution with recombinant proteins; ternary complex demonstrated biochemically; authors note in vivo validation remains to be performed; single lab\",\n      \"pmids\": [\"30804381\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Exported chaperone Hsp70-x supports PfEMP1 export: Δhsp70-x parasites showed delayed export of PfEMP1 cytoadherence proteins and reduced adhesion of infected erythrocytes, as well as increased rigidity of infected RBCs, establishing a role for Hsp70-x in efficient PfEMP1 trafficking to the erythrocyte surface.\",\n      \"method\": \"Knockout parasites (Δhsp70-x), adhesion assays, rigidity measurements, transcriptional and translational analysis, immunofluorescence\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined cellular phenotype (delayed PfEMP1 export, reduced adhesion); single lab with multiple readouts\",\n      \"pmids\": [\"28732045\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The CIDR1α domain of PfEMP1 increases TLR7 and TLR10 mRNA expression in human B cells and sensitizes them to TLR9 signaling via MyD88. PfEMP1-CIDR1α activates B cells via phosphorylation of ERK1/2, p38 and IκBα but does not signal through the BCR (Lyn/phospho-tyrosine pathway), acting as a non-BCR polyclonal B-cell activator.\",\n      \"method\": \"Recombinant CIDR1α domain stimulation of primary human B cells, RT-PCR for TLR transcripts, kinase phosphorylation assays, pathway inhibitor studies\",\n      \"journal\": \"Acta tropica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — recombinant domain used with defined signaling readouts; multiple pathways examined; single lab\",\n      \"pmids\": [\"21620790\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"FCR3S1.2\"}]\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"var2csa switches to become highly transcribed in both rosetting and adhesive parasite populations but is sparsely translated into PfEMP1 protein and not expressed at the erythrocyte surface, indicating post-transcriptional (translational repression) mechanisms control var2csa-encoded PfEMP1 protein levels independently of transcript abundance.\",\n      \"method\": \"var gene transcription profiling, quantitative PCR, intracellular PfEMP1 protein detection, surface expression (FACS), peri-nuclear repositioning analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative transcript and protein measurements dissociating transcription from translation; single lab\",\n      \"pmids\": [\"18431472\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DC8-PfEMP1 (expressing EPCR-binding CIDRα1 domains) mediates binding to brain endothelial cells in a 3D microvessel model, with binding dependent on EPCR and ICAM-1. TNF-α activation of endothelium downregulates EPCR and decreases binding of DC8-PfEMP1-expressing IE, whereas Group B PfEMP1-expressing IE show increased binding to TNF-α-activated endothelium via ICAM-1, demonstrating heterogeneous receptor-dependent binding in a physiological 3D model.\",\n      \"method\": \"Engineered 3D human brain endothelial microvessel model, perfusion binding assays with clonal parasite lines, EPCR/ICAM-1 receptor blocking\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — 3D vessel model with receptor blocking and clonal parasite lines; single lab with physiologically relevant model\",\n      \"pmids\": [\"31138740\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Two broadly reactive human monoclonal antibodies isolated from different individuals inhibit EPCR binding of diverse CIDRα1 domains (five of six subclasses) and block parasite sequestration in bioengineered 3D human brain microvessels under flow. Structural analysis of antibody-CIDRα1 complexes reveals a shared binding mechanism dependent on three highly conserved amino acid residues within the EPCR-binding site of CIDRα1.\",\n      \"method\": \"Human monoclonal antibody isolation, cryo-EM/crystal structures of antibody-CIDRα1 complexes, EPCR binding inhibition assays, 3D brain microvessel sequestration assay under flow\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal/cryo-EM structures, functional inhibition assays, 3D vessel model; two independent antibodies from different individuals confirming shared mechanism\",\n      \"pmids\": [\"39567685\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Using selection-linked integration (SLI), parasites all expressing the same PfEMP1 variant can be generated for functional studies. PfEMP1 trafficking studies with this system identified new proteins required for PfEMP1-mediated sequestration and allowed generation of cell lines binding to common endothelial receptors (EPCR, ICAM-1), establishing PfEMP1 as sufficient to confer receptor-specific adhesion when uniformly expressed.\",\n      \"method\": \"Selection-linked integration (SLI) genome editing, parasite cell lines with defined PfEMP1 expression, receptor binding assays, proteomics of the PfEMP1 protein environment\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic system enabling uniform PfEMP1 expression with functional receptor binding assays and proteomics; single lab\",\n      \"pmids\": [\"41460168\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7; IT4\"}]\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Febrile temperature (mimicking fever) increases transcript levels of several exported parasite genes involved in PfEMP1 trafficking and accelerates PfEMP1 surface display on ring-stage IE, leading to a 2-fold increase in ring-stage IE binding in a 3D human brain microvessel model.\",\n      \"method\": \"Febrile temperature exposure of ring-stage parasites, quantitative RT-PCR for trafficking gene transcripts, flow-based adhesion assay in 3D brain microvessel model\",\n      \"journal\": \"The Journal of infectious diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct experimental manipulation (febrile exposure) with quantified transcript and functional adhesion readout in 3D model; single lab\",\n      \"pmids\": [\"40929367\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"PfEMP1 is a 200–350 kDa antigenically variant parasite protein exported to knob structures on the P. falciparum-infected erythrocyte surface, where it functions as the principal cytoadherence ligand binding host endothelial receptors (CD36, ICAM-1, EPCR, CSA, CR1, PECAM1) and mediating rosetting; it is trafficked from the parasite ER through Maurer's clefts to the erythrocyte surface via electron-dense vesicles with assistance from chaperones (Hsp70-x, PFA0660w) and anchored at knobs through direct interaction of its cytoplasmic ATS domain with KAHRP (histidine-rich and 5' repeat regions) and erythrocyte spectrin, with PfEMP1 surface levels subject to post-transcriptional/translational regulation (e.g., uORF-mediated repression of var2csa relieved by PTEF), and with PfEMP1 surface display modulated by host erythrocyte hemoglobin variants and febrile temperature; its CIDRα1 domains are the structural target of broadly inhibitory human antibodies that block EPCR binding at conserved residues and prevent parasite sequestration.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PfEMP1 (PF3D7_0100100) is the principal antigenically variant cytoadherence ligand displayed on the surface of Plasmodium falciparum-infected erythrocytes, encoded by the var multigene family whose individual members are expressed in a mutually exclusive manner to determine receptor-binding phenotype [#0, #1]. Its ectodomain, built from tandem DBL and CIDR modules, engages a spectrum of host receptors through distinct subdomains: the CIDR1\\u03b1 domain mediates strain-nonspecific adhesion to CD36 and to EPCR [#4, #5, #12], DBL\\u03b2 domains bind ICAM-1 [#8, #12], and var2csa-encoded PfEMP1 binds chondroitin sulfate A with defined oligosaccharide structure-activity requirements [#7]; PfEMP1 also mediates rosetting with uninfected erythrocytes via CR1 and, in some variants, requires serum \\u03b12-macroglobulin as a binding cofactor [#2, #17]. Dual EPCR/ICAM-1-binding variants are associated with cerebral malaria, and broadly reactive human antibodies neutralize sequestration by targeting three conserved residues in the EPCR-binding site of CIDR\\u03b11 [#12, #23]. The cytoplasmic ATS/VARC domain anchors PfEMP1 beneath knobs through direct binding to KAHRP and to erythrocyte spectrin, clustering the ligand at the cell surface [#3, #11]. PfEMP1 is exported from the parasite through Maurer's clefts and electron-dense vesicles with the assistance of chaperones and PHIST-domain proteins that engage its ATS tail [#9, #10, #19], while surface levels are controlled post-transcriptionally, including PTEF-dependent relief of uORF-mediated translational repression of var2csa [#14, #21]. Beyond adhesion, surface- and vesicle-borne PfEMP1 modulates host immune cells by dampening monocyte/macrophage NF-\\u03baB activation and cytokine release [#15, #16].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established the molecular identity of the infected-erythrocyte surface variant antigen and proved it is the parasite ligand for host cytoadherence, resolving what mediates sequestration.\",\n      \"evidence\": \"Cloning of two var-encoded PfEMP1 genes from the Malayan Camp strain, recombinant protein, antibody-based adhesion blocking to CD36, and correlation of specific var transcription with ICAM-1 binding\",\n      \"pmids\": [\"7541722\", \"7606788\", \"6374009\", \"7606775\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Domain-level mapping of receptor specificity not yet resolved\", \"Structural basis of antigenic variation across the var family not established\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"Malayan Camp (MC)\"}, {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Extended PfEMP1's receptor repertoire to rosetting, showing a single var-encoded PfEMP1 binds CR1 on uninfected erythrocytes and that a host CR1 polymorphism modulates the interaction.\",\n      \"evidence\": \"Antibody inhibition, var gene identification, CR1 polymorphism analysis and rosetting assays\",\n      \"pmids\": [\"9230440\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Domain of PfEMP1 responsible for CR1 binding not mapped here\", \"Contribution of other serum/erythrocyte factors to rosetting not addressed\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Localized the CD36-binding activity to a discrete CIDR1 subdomain, converting the whole-protein ligand into a defined receptor-binding module.\",\n      \"evidence\": \"Recombinant 179-residue CIDR1 subfragment competitively inhibited and reversed CD36 adhesion under flow across multiple parasite lines\",\n      \"pmids\": [\"9786187\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance not yet demonstrated at this stage\", \"Structural details of the CIDR1-CD36 contact unresolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Defined the molecular basis for anchoring PfEMP1 at knobs by mapping direct binding of KAHRP to the cytoplasmic VARC region.\",\n      \"evidence\": \"Recombinant fragment pulldowns, surface plasmon resonance Kd measurements, and deletion mutagenesis identifying histidine-rich and 5' repeat segments of KAHRP\",\n      \"pmids\": [\"10446142\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In-cell requirement of these KAHRP regions for knob assembly not tested here\", \"Stoichiometry of PfEMP1 clustering unresolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Validated the CIDR1 domain as the cytoadherence mediator in vivo, moving beyond in vitro flow assays to a whole-organism model.\",\n      \"evidence\": \"Minimal CIDR1 CD36-binding peptide inhibited and detached infected-erythrocyte adhesion in a human/SCID mouse chimeric model with intravital microscopy using clinical isolates\",\n      \"pmids\": [\"12393525\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Effect limited to CD36-mediated adhesion; other receptors not addressed\", \"Behavior of full-length PfEMP1 in vivo not measured\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Characterized the structural requirements and immune consequences of two additional PfEMP1 adhesion phenotypes: var2csa-CSA binding and CIDR1\\u03b1-dependent NK-cell adhesion.\",\n      \"evidence\": \"Direct binding of native var2csa-PfEMP1 to defined CSA oligosaccharides, plus engineered PfEMP1-mutant parasites and blocking antibodies dissociating PfEMP1-dependent adhesion from PfEMP1-independent NK activation\",\n      \"pmids\": [\"17562715\", \"17311092\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Isolate-specific CSA motif preferences not tied to specific residues\", \"PfEMP1's role, if any, in NK activation beyond adhesion unresolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Revealed that var2csa-encoded PfEMP1 abundance is set post-transcriptionally, dissociating high transcript levels from low protein and surface display.\",\n      \"evidence\": \"var transcription profiling and quantitative PCR compared with intracellular protein detection and surface FACS in rosetting and adhesive populations\",\n      \"pmids\": [\"18431472\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of translational repression not identified here\", \"Whether other var genes share this control unknown\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Systematically identified which PfEMP1 domain type binds ICAM-1 with high affinity and showed naturally acquired immunity targets this interaction.\",\n      \"evidence\": \"High-throughput binding screen of 16 recombinant DBLbetaC2 domains from the 3D7 repertoire, plus inhibition by east African immune sera\",\n      \"pmids\": [\"19381252\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of the DBL\\u03b2-ICAM-1 interaction not resolved here\", \"Restricted to a single high-affinity domain in one repertoire\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Uncovered a non-adhesive immunomodulatory activity for the CIDR1\\u03b1 domain as a polyclonal B-cell activator acting outside the B-cell receptor.\",\n      \"evidence\": \"Recombinant CIDR1\\u03b1 stimulation of primary human B cells with TLR transcript profiling, kinase phosphorylation assays, and pathway inhibitors\",\n      \"pmids\": [\"21620790\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor on B cells for CIDR1\\u03b1 not identified\", \"Single-lab recombinant-domain study\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"FCR3S1.2\"}]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mapped the export route of PfEMP1 from the parasite to the erythrocyte surface, identifying Maurer's clefts and electron-dense vesicles as trafficking intermediates.\",\n      \"evidence\": \"Live imaging of GFP-chimeric PfEMP1, immunoelectron microscopy, fractionation, and cytochalasin D perturbation with temporal mapping\",\n      \"pmids\": [\"23421990\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular machinery driving each transfer step not defined here\", \"How PfEMP1 inserts into the RBC membrane at knobs unknown\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified a PHIST-domain protein as a direct ATS-binding partner that accompanies PfEMP1 during export and co-localizes at knobs, adding a specific trafficking/anchoring factor.\",\n      \"evidence\": \"Recombinant pulldown with Kd measurement, live-cell co-migration imaging, X-ray crystallography and NMR, with control PHIST variants\",\n      \"pmids\": [\"24983468\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional requirement of PFE1605w for PfEMP1 export not tested by knockout here\", \"Full atomic model of the PHIST-ATS interface incomplete\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established that a specific rosetting PfEMP1 requires a serum cofactor, \\u03b12-macroglobulin, that multimerizes on the C-terminal region to boost avidity for erythrocyte receptors.\",\n      \"evidence\": \"Rosetting assays, serum fractionation, recombinant domain binding, electron microscopy of \\u03b12M complexes and domain mapping in HB3VAR06\",\n      \"pmids\": [\"26134405\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality across other rosetting PfEMP1 variants unknown\", \"Single variant characterized\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"HB3\"}]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Consolidated the mechanistic picture of PfEMP1 anchoring, trafficking chaperones, translational control, cerebral-malaria receptor usage, and immunosuppression in a burst of complementary studies.\",\n      \"evidence\": \"Spectrin-binding biophysics/modeling of VARC [#11]; \\u0394hsp70-x knockout showing delayed export and reduced adhesion [#19]; K13/PI3P-vesicle colocalization and export perturbation [#13]; PTEF-dependent, PfCalpain-processed relief of uORF repression of var2csa [#14]; crystal-structure-guided dual EPCR/ICAM-1 binding linked to cerebral malaria [#12]; and NF-\\u03baB dampening in monocytes using PfEMP1-null parasites [#15]\",\n      \"pmids\": [\"28806784\", \"28732045\", \"29363540\", \"28481333\", \"28279348\", \"29038124\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In-cell validation of the spectrin-anchoring model lacking\", \"Direct requirement of K13/PI3P for PfEMP1 export inferred rather than proven\", \"Receptor mediating monocyte immunosuppression not identified\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}, {\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7; CS2\"}]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed PfEMP1 is packaged into extracellular vesicles originating inside the infected cell and modulates monocyte gene expression from that vesicular context.\",\n      \"evidence\": \"EV isolation with PfEMP1 transport-knockout parasites as controls, proteomics, and monocyte transcriptomics\",\n      \"pmids\": [\"29349926\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which vesicular PfEMP1 alters monocyte responses unresolved\", \"Physiological role of EV-borne PfEMP1 in vivo unknown\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Reconstituted a chaperone complex handing off PfEMP1 during export and demonstrated variant- and receptor-heterogeneous binding to brain endothelium.\",\n      \"evidence\": \"In vitro ternary complex of cholesterol-bound PFA0660w, PfHsp70-x and the PfEMP1 ATS tail [#18]; and 3D brain microvessel perfusion assays with EPCR/ICAM-1 blocking of DC8- versus Group B-PfEMP1 lines under TNF-\\u03b1 activation [#22]\",\n      \"pmids\": [\"30804381\", \"31138740\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo validation of the chaperone ternary complex not performed\", \"How endothelial activation state reshapes PfEMP1 receptor usage in patients unresolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a conserved neutralization epitope on CIDR\\u03b11, showing broadly reactive human antibodies block EPCR binding and sequestration through three conserved residues.\",\n      \"evidence\": \"Human monoclonal antibody isolation, cryo-EM/crystal structures of antibody-CIDR\\u03b11 complexes, EPCR inhibition assays, and 3D brain microvessel sequestration assay under flow\",\n      \"pmids\": [\"39567685\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Coverage limited to five of six CIDR\\u03b11 subclasses\", \"In vivo protective efficacy not established\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided a genetic system to uniformly express a defined PfEMP1 variant, proving PfEMP1 is sufficient to confer receptor-specific adhesion and enabling discovery of new trafficking factors.\",\n      \"evidence\": \"Selection-linked integration genome editing, defined-variant parasite lines, receptor binding assays, and proteomics of the PfEMP1 protein environment\",\n      \"pmids\": [\"41460168\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functions of the newly identified trafficking proteins not yet characterized\", \"Single-lab system\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7; IT4\"}]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Linked host fever to accelerated PfEMP1 surface display, connecting an environmental cue to trafficking gene induction and enhanced ring-stage adhesion.\",\n      \"evidence\": \"Febrile temperature exposure of ring-stage parasites with quantitative RT-PCR of trafficking transcripts and flow-based 3D brain microvessel adhesion assay\",\n      \"pmids\": [\"40929367\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular sensor coupling temperature to trafficking gene expression unknown\", \"Consequences for disease severity in vivo not established\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the var family achieves mutually exclusive, switchable expression of a single PfEMP1 variant, and how surface PfEMP1 stoichiometry is quantitatively coordinated with knob assembly and trafficking machinery, remain open.\",\n      \"evidence\": \"No timeline discovery directly resolves the epigenetic switching mechanism or the quantitative assembly logic\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Epigenetic mechanism of mutually exclusive var expression uncharacterized in this corpus\", \"Quantitative coupling of trafficking flux to knob density unresolved\"],\n      \"attribution\": []\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0050839\", \"supporting_discovery_ids\": [0, 4, 5, 7, 8, 12, 2, 22]},\n      {\"term_id\": \"GO:0005178\", \"supporting_discovery_ids\": [1, 8, 12, 22]},\n      {\"term_id\": \"GO:0008201\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0005515\", \"supporting_discovery_ids\": [3, 10, 11, 18, 19, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0020030\", \"supporting_discovery_ids\": [0, 3, 10, 11]},\n      {\"term_id\": \"GO:0020036\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0070062\", \"supporting_discovery_ids\": [16]},\n      {\"term_id\": \"GO:0009986\", \"supporting_discovery_ids\": [0, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0007155\", \"supporting_discovery_ids\": [0, 1, 2, 4, 5, 7, 12, 22]},\n      {\"term_id\": \"GO:0046718\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"GO:0032259\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"GO:0002376\", \"supporting_discovery_ids\": [15, 16, 20]}\n    ],\n    \"complexes\": [\n      \"PfEMP1 ATS/VARC in complex with KAHRP at knobs\",\n      \"PfEMP1 ATS with erythrocyte spectrin (alpha-spectrin domain 17)\",\n      \"PfEMP1 ATS with PHIST-domain protein PFE1605w\",\n      \"Ternary chaperone complex: PfEMP1 ATS + PfHsp70-x + cholesterol-bound PFA0660w\",\n      \"PfEMP1 with K13 at PI3P-enriched ER tubules/vesicles\",\n      \"HB3VAR06 PfEMP1 with serum alpha2-macroglobulin (rosetting)\"\n    ],\n    \"partners\": [\n      \"CD36 (host receptor)\",\n      \"ICAM-1 (host receptor)\",\n      \"EPCR (host receptor)\",\n      \"Chondroitin sulfate A (host receptor, var2csa)\",\n      \"Complement receptor 1 / CR1 (rosetting receptor)\",\n      \"KAHRP\",\n      \"Erythrocyte spectrin\",\n      \"PFE1605w (PHIST-domain protein)\",\n      \"PfHsp70-x\",\n      \"PFA0660w\",\n      \"K13 (Kelch13)\",\n      \"PTEF / PfCalpain (translational control of var2csa)\",\n      \"alpha2-macroglobulin\",\n      \"IgM (synergistic rosetting cofactor)\",\n      \"Broadly neutralizing human anti-CIDR\\u03b11 monoclonal antibodies\"\n    ],\n    \"other_free_text\": [\n      \"Encoded by the var multigene family (50-150 genes); individual var expression determines receptor phenotype and antigenic variation [#0, #1].\",\n      \"CIDR1\\u03b1 is the CD36- and EPCR-binding module; DBL\\u03b2 domains bind ICAM-1; var2csa-encoded PfEMP1 binds CSA [#4, #7, #8, #12].\",\n      \"Dual EPCR/ICAM-1-binding variants are associated with cerebral malaria and are neutralized via three conserved CIDR\\u03b11 residues [#12, #23].\",\n      \"Surface levels are post-transcriptionally controlled, including PTEF-dependent relief of uORF-mediated translational repression of var2csa [#14, #21].\",\n      \"PfEMP1 surface display is enhanced by febrile temperature and modulated by trafficking-gene induction [#25].\",\n      \"Genetic systems (SLI) show PfEMP1 is sufficient to confer receptor-specific adhesion when uniformly expressed [#24].\"\n    ]\n  }\n}","audit_flag":{"gene":"PF3D7_0100100","tier":"COVERAGE","verdict":"Coverage note","subtype":"corpus_unverifiable","uniprot_band":"empty","rules_fired":"R1","issue":"R1: record has no curated symbol, so its corpus cannot name it (named in 0/100); grounding untestable — coverage note, not a collision"},"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_0100100","name":null,"product":"erythrocyte membrane protein 1, PfEMP1","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"","evaluation":null}