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Three fragments of KAHRP bind VARC, with the highest-affinity fragments (K1A and K2A) having Kd values of 1×10⁻⁷ M and 3.3×10⁻⁶ M respectively; the high-affinity binding regions were localized to the 63-residue histidine-rich and 70-residue 5′ repeats of KAHRP, and deletion of these regions abolished VARC binding.\",\n      \"method\": \"In vitro binding assays (surface plasmon resonance / kinetic binding measurements) using recombinant KAHRP fragments and recombinant VARC (cytoplasmic domain of PfEMP1); deletion mutagenesis of KAHRP fragments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with quantitative binding kinetics, deletion mutagenesis to map critical domains, replicated with multiple KAHRP fragments\",\n      \"pmids\": [\"10446142\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CIDR domains of PfEMP1 from two different parasite strains bind chondroitin sulfate A (CSA); recombinant 6xHis-tagged CIDR protein bound CHO cells expressing CSA, binding was reduced up to 94.4% by chondroitinase ABC treatment, and inhibited up to 100% by soluble CSA. In contrast, a recombinant DBL1 domain showed no binding to CHO cells.\",\n      \"method\": \"Recombinant protein expression (E. coli), binding assays on CHO cells, competitive inhibition with soluble CSA and heparan sulfate, enzymatic removal of CSA\",\n      \"journal\": \"Experimental parasitology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with recombinant protein, enzymatic and competitive inhibition controls, clear negative control (DBL1 domain)\",\n      \"pmids\": [\"10910712\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"A recombinant peptide (PpMC-179) corresponding to the minimal CD36-binding domain from CIDR1 of PfEMP1 inhibited cytoadherence of infected erythrocytes to endothelial cells and reversed (detached) already-adherent infected erythrocytes both in vitro and in vivo, demonstrating that the CIDR1 domain of PfEMP1 mediates binding to CD36.\",\n      \"method\": \"Parallel-plate flow chamber assays in vitro using human dermal microvascular endothelial cells; human/SCID mouse chimeric model for in vivo visualization; recombinant PfEMP1 CIDR1 peptide inhibition and reversal experiments\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — recombinant domain used in both in vitro and in vivo assays with inhibition and reversal of adhesion demonstrated\",\n      \"pmids\": [\"12393525\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The structural basis for PfEMP1 (var2csa-encoded) binding to chondroitin sulfate A was defined: binding required 4-O-sulfated disaccharides and glucuronic acid (not iduronic acid), the minimum chain length for direct PfEMP1 binding was 8 monosaccharide units, and 6-O-sulfation interfered with the interaction. Polymorphisms in PfEMP1 encoded by var2csa-type genes correlated with isolate-specific differences in preferred CSA structural motifs.\",\n      \"method\": \"Direct binding assay of native PfEMP1 isolated from infected erythrocytes to immobilized CSA; neoglycolipid probes of immobilized CS oligosaccharides; surface plasmon resonance; competitive inhibition assays with defined oligosaccharides; adhesion assays with defined P. falciparum isolates expressing different var2csa variants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — native protein binding reconstituted with defined structural variants, multiple orthogonal binding/inhibition methods, mutagenesis-by-natural-polymorphism approach\",\n      \"pmids\": [\"17562715\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PfEMP1 is exported via Maurer's clefts to the red blood cell surface via a defined pathway: PfEMP1-GFP accumulates near the parasite surface in membranous structures before transfer to pre-formed mobile Maurer's clefts; endogenous PfEMP1 and PfEMP1B-GFP associate with electron-dense vesicles that may traffic PfEMP1 from Maurer's clefts to the RBC membrane. Maurer's cleft docking onto the RBC membrane occurs at ~20 h post-invasion and is not affected by cytochalasin D.\",\n      \"method\": \"Live-cell imaging of GFP-chimera of PfEMP1 expressed in transfected parasites; electron microscopy; temporal analysis of Maurer's cleft development and docking; cytochalasin D treatment\",\n      \"journal\": \"Cellular microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct live imaging of PfEMP1-GFP trafficking combined with electron microscopy ultrastructure, temporal mapping, and pharmacological perturbation\",\n      \"pmids\": [\"23421990\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The PHIST protein PFE1605w binds the intracellular segment of PfEMP1 directly (Kd = 5 ± 0.6 µM), co-migrates with PfEMP1 during export, and co-localizes with PfEMP1 at knobs. The crystal structure of a PHIST domain was resolved, and a partial model of the PHIST-PfEMP1 interaction was derived by NMR. Control PHIST variants that do not locate to knobs (MAL8P1.4) or bind PfEMP1 30-fold more weakly (PFI1780w) did not display the same trafficking pattern.\",\n      \"method\": \"Recombinant protein binding assays (Kd determination), co-migration/co-localization experiments, X-ray crystallography of PHIST domain, NMR-derived partial interaction model, comparison with control PHIST variants\",\n      \"journal\": \"FASEB journal : official publication of the Federation of American Societies for Experimental Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro binding with quantitative Kd, crystal structure, NMR, and cellular localization experiments with rigorous negative controls\",\n      \"pmids\": [\"24983468\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The PHIST protein PFE1605w interacts directly with both the intracellular segment of PfEMP1 and with cytoskeletal components; conditional reduction of PFE1605w strongly reduces adhesion of infected erythrocytes to the endothelial receptor CD36 but does not affect PfEMP1 transport, indicating PFE1605w anchors PfEMP1 to the cytoskeleton at knobs to support cytoadherence.\",\n      \"method\": \"Conditional knockdown of PFE1605w, adhesion assays to CD36 and other receptors, interaction studies with PfEMP1 intracellular domain and cytoskeletal components\",\n      \"journal\": \"Cellular microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockdown with specific adhesion phenotype, direct protein interaction studies, distinction between transport and anchoring functions\",\n      \"pmids\": [\"26916885\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A crystallographic structure of a specific CIDRα1 domain of PfEMP1 in complex with ICAM-1 was determined, revealing the structural basis of ICAM-1 binding and identifying a sequence motif that predicts ICAM-1 binding. PfEMP1s containing this ICAM-1-binding motif (within domain cassettes DC8/DC13) also bind EPCR, enabling infected erythrocytes to synergistically bind both receptors simultaneously.\",\n      \"method\": \"Structural biology (X-ray crystallography of CIDRα1–ICAM-1 complex); binding assays; genome-wide sequence motif analysis across multiple P. falciparum genomes\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure of PfEMP1 domain–receptor complex, validated by binding assays and genome-scale motif analysis\",\n      \"pmids\": [\"28279348\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The folded core of the PfEMP1 cytosolic domain interacts broadly with erythrocyte spectrin, with weak but residue-specific preference for domain 17 of α-spectrin (proximal to the erythrocyte cytoskeletal junction); a protein sequence repeat region in KAHRP preferentially associates with domains 10–14 of β-spectrin (proximal to the spectrin-ankyrin complex). Combined structural models suggest a specific knob architecture for PfEMP1 and KAHRP at the erythrocyte surface.\",\n      \"method\": \"Biophysical binding assays, structural analysis (NMR/SAXS implied by the paper's biophysical approach), computational modeling, integration with previous microscopy and protein interaction data\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — biophysical and structural approaches in a single lab study; spectrin domain preference mapped but functional validation of the specific spectrin contacts is modeled rather than directly mutagenized\",\n      \"pmids\": [\"28806784\"],\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 open reading frame repression of VAR2CSA (a PfEMP1 variant) mRNA to facilitate VAR2CSA protein translation. VAR2CSA protein levels in var2csa-transcribing parasites depend on PTEF expression levels. Proteolytic processing of PTEF by PfCalpain generates a C-terminal domain that shuttles to the cytoplasm, interacts with ribosomes, and enhances translation of the var2csa coding sequence.\",\n      \"method\": \"Conditional expression manipulation of PTEF, quantification of VAR2CSA protein levels, ribosome interaction assays, heterologous translation system, characterization of PfCalpain cleavage product\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (protein level quantification, ribosome interaction, heterologous system, protease cleavage characterization) in a single rigorous study establishing translational regulation of a PfEMP1 variant\",\n      \"pmids\": [\"28481333\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"K13 colocalizes and co-purifies with PfEMP1 at PI3P tubules/vesicles of the parasite's endoplasmic reticulum in infected red cells. K13 mutation (C580Y) quantitatively increases PI3P tubules/vesicles and alters PfEMP1 export to the red cell, with chemical inhibitors and fluorescence microscopy showing that cytoadherence of infected cells to a host endothelial receptor is altered in multiple K13 mutants.\",\n      \"method\": \"Cryo-immunoelectron microscopy; co-purification; fluorescence microscopy; chemical inhibition; comparison of K13 mutant and wild-type parasites\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cryo-immunoEM localization plus co-purification plus functional adhesion assay, single study with multiple orthogonal approaches, but mechanistic link between K13/PI3P and PfEMP1 export is correlative\",\n      \"pmids\": [\"29363540\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PfEMP1 is present in extracellular vesicles (EVs) 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 infected RBC rather than from the iRBC surface. EVs from PfEMP1 knockout parasites induced more gene expression changes in human monocytes than wild-type EVs, suggesting PfEMP1 in EVs modulates host monocyte responses.\",\n      \"method\": \"EV isolation and proteomic analysis; PfEMP1 transport knockout parasite lines; monocyte stimulation with EVs; transcriptomic analysis of monocyte responses\",\n      \"journal\": \"Cellular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout comparison establishes EV origin and PfEMP1-dependent immunomodulation, multiple methods, single lab study\",\n      \"pmids\": [\"29349926\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PfHsp70-x directly interacts with the cytoplasmic tail of PfEMP1 in vitro; the co-chaperone PFA0660w (Hsp40) binds cholesterol, and PfHsp70-x forms a ternary complex with cholesterol-bound PFA0660w and PfEMP1 simultaneously in vitro. The N- and C-terminal domains of PFA0660w and PfHsp70-x respectively are critical for their chaperone activity.\",\n      \"method\": \"Recombinant protein biochemical assays; in vitro binding/complex formation experiments; domain deletion analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of ternary complex, domain mapping, but in vivo validation explicitly noted as not performed\",\n      \"pmids\": [\"30804381\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Deletion of the exported chaperone Hsp70-x in P. falciparum delayed export of PfEMP1 cytoadherence proteins and reduced adhesion of infected erythrocytes (without affecting parasite growth); Δhsp70-x IEs were also more rigid than wild-type, indicating changes in host erythrocyte modification.\",\n      \"method\": \"Gene knockout (Δhsp70-x) of exported Hsp70-x; PfEMP1 export timing assays; adhesion assays; erythrocyte rigidity measurements; transcriptional and translational profiling\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined phenotype in PfEMP1 export and adhesion, multiple readouts, single lab\",\n      \"pmids\": [\"28732045\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"α2-Macroglobulin (α2M) is a serum factor required and sufficient for rosetting mediated by the PfEMP1 protein HB3VAR06; the α2M binding site was mapped to the C-terminal end of HB3VAR06; α2M can bind at least four HB3VAR06 molecules simultaneously, plausibly augmenting avidity for host receptors. IgM works synergistically with α2M to lower the concentration required for rosetting.\",\n      \"method\": \"Rosetting assays with purified serum fractions; binding site mapping; quantification of α2M binding stoichiometry; IgM/α2M synergy assays; testing on genotypically distinct parasite isolates and patient isolates\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (serum fractionation, binding site mapping, stoichiometry measurement, field isolate validation), rigorous identification of a novel rosetting co-factor\",\n      \"pmids\": [\"26134405\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Knob density on P. falciparum-infected erythrocytes is linked to the specific PfEMP1 variant expressed: selection for IT4VAR32b expression increased knob density ~3-fold compared to unselected IEs, whereas IT4VAR60-expressing IEs were essentially knobless; switching PfEMP1 expression between variants reproducibly altered knob density. KAHRP was expressed in all sublines regardless of which PfEMP1 was expressed.\",\n      \"method\": \"Antibody panning to generate parasite sub-lines expressing specific PfEMP1 variants; atomic force microscopy (AFM) and scanning electron microscopy (SEM) to measure knob density; quantification of PfEMP1 and KAHRP expression\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — causal relationship established by switching PfEMP1 expression and observing reproducible knob density changes with two independent imaging methods and rigorous controls\",\n      \"pmids\": [\"26443460\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"One P. falciparum 3D7 sub-line simultaneously expressed two different PfEMP1 variants as surface antigens on single infected erythrocytes (confirmed by single-cell FISH and live confocal microscopy), and this dual-PfEMP1 expression enabled binding to both CD31/PECAM1 and CD54/ICAM1, with twice the adhesion efficiency to human endothelial cells compared to cells with only one PfEMP1 variant.\",\n      \"method\": \"Antibody selection of parasite sub-lines; real-time Q-PCR for var mRNA; single-cell FISH; live confocal microscopy; flow cytometry; in vitro adhesion assays\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — single-cell FISH and live confocal microscopy directly demonstrated co-expression of two PfEMP1 variants on single cells, linked to dual receptor binding phenotype with multiple orthogonal methods\",\n      \"pmids\": [\"20824088\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}]\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PfEMP1 modulates monocyte/macrophage immune responses: NF-κB activation was significantly lower in macrophages stimulated with PfEMP1-expressing parasites than with PfEMP1-null parasites; VAR2CSA PfEMP1-containing parasites specifically reduced IL-1β, IL-6, IL-10, MCP-1, MIP-1α, MIP-1β, and TNF release from human monocytes compared to PfEMP1-null parasites.\",\n      \"method\": \"Comparison of wild-type (3D7, CS2) and transgenic PfEMP1-null parasites; transcription factor activation assays (NF-κB, CREB); cytokine/chemokine measurement from RAW macrophages and human primary monocytes\",\n      \"journal\": \"Infection and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PfEMP1-null genetic controls establish specificity, multiple cytokine readouts and transcription factor measurements, single lab study\",\n      \"pmids\": [\"29038124\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}]\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The DBL1α1 domain of PfEMP1 (NTS-DBL1α1-varO from the VarO parasite line) binds heparin with micromolar affinity; binding affinity to sulfated oligosaccharides is related to the degree of sulfation and the position of sulfate groups; rosettes could be disrupted by sulfated oligosaccharides with efficacy correlating with their recombinant NTS-DBL1α1 binding affinity.\",\n      \"method\": \"Recombinant protein expression in E. coli, Pichia pastoris, and baculovirus systems; surface plasmon resonance (SPR); competitive binding assays with sulfated oligosaccharides; rosette disruption assays; antibody surface-reactivity and rosette disruption validation\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with SPR quantification, competitive inhibition, three expression systems yielding identical protein, corroborated by functional rosette disruption\",\n      \"pmids\": [\"20045435\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Two broadly reactive human monoclonal antibodies targeting CIDRα1 domains of PfEMP1 inhibit EPCR binding across five of six CIDRα1 subclasses. Structural analyses of the antibodies in complex with three different CIDRα1 antigen variants revealed that both antibodies bind three highly conserved amino acid residues of the EPCR-binding site in CIDRα1, establishing the structural basis for broad inhibition.\",\n      \"method\": \"Isolation of human monoclonal antibodies; EPCR binding inhibition assays with recombinant and native PfEMP1; parasite sequestration assays in bioengineered 3D human brain microvessels under flow; X-ray crystallography of antibody–CIDRα1 complexes\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures of multiple antibody–antigen complexes combined with functional neutralization in physiological 3D flow model and native PfEMP1, multiple CIDRα1 subclasses tested\",\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) to generate parasites all expressing the same PfEMP1 variant, survey of the protein environment of functional PfEMP1 in the host cell identified new proteins needed for PfEMP1-mediated sequestration; PfEMP1 trafficking was studied and cell lines binding the most common endothelial receptors were generated, demonstrating that the SLI system enables functional genetic editing of the expressed PfEMP1 locus.\",\n      \"method\": \"Selection-linked integration (SLI and SLI2) for genome editing of the expressed var/PfEMP1 locus; binding assays; proteomics of PfEMP1 protein environment; trafficking studies\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — novel genetic system with functional validation of receptor binding and trafficking, identification of new sequestration-required proteins, single lab study\",\n      \"pmids\": [\"41460168\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}]\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In vivo sequestration of P. falciparum-infected erythrocytes (iRBCs) was shown to depend on PfEMP1: removal of PfEMP1, preincubation of iRBCs with sera to PfEMP1, or preincubation with soluble PfEMP1-receptors prior to injection into rats significantly reduced sequestration in the microvasculature.\",\n      \"method\": \"In vivo rat sequestration model with 99mTc-labeled iRBCs; whole-body imaging and lung imaging; antibody blocking; receptor competition; histological examination\",\n      \"journal\": \"Infection and immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo model with multiple intervention approaches (antibody blocking, receptor competition, PfEMP1 removal) all reducing sequestration, direct causal role of PfEMP1 demonstrated\",\n      \"pmids\": [\"16239578\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PfEMP1-CIDR1α from the FCR3S1.2 strain increases expression of TLR7 and TLR10 mRNA in B cells and sensitizes B cells to TLR9 signaling via MyD88. CIDR1α-induced B-cell activation does not proceed through the BCR (no Lyn or phospho-tyrosine signaling), but instead induces phosphorylation of downstream kinases ERK1/2, p38, and IKBα.\",\n      \"method\": \"B-cell stimulation with recombinant PfEMP1-CIDR1α; TLR mRNA quantification; signaling pathway analysis (Lyn, phospho-tyrosine, ERK1/2, p38, IKBα); MyD88 pathway assessment\",\n      \"journal\": \"Acta tropica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — recombinant CIDR1α domain used with multiple signaling readouts; BCR pathway explicitly shown to be not involved (negative result informative); single lab study\",\n      \"pmids\": [\"21620790\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"FCR3S1.2\"}]\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Febrile temperature exposure of ring-stage P. falciparum parasites increased transcript levels of several exported parasite genes involved in PfEMP1 trafficking and accelerated PfEMP1 surface display in ring-stage infected erythrocytes, leading to a 2-fold increase in their binding in a perfusable 3D human brain microvessel model.\",\n      \"method\": \"Febrile temperature exposure of ring-stage parasites; RT-PCR quantification of PfEMP1 trafficking gene transcripts; flow adhesion assays in 3D human brain microvessel model\",\n      \"journal\": \"The Journal of infectious diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct measurement of PfEMP1 surface display and adhesion under fever conditions in a physiological flow model, multiple readouts, single lab study\",\n      \"pmids\": [\"40929367\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"PfEMP1 is a high-molecular-weight, multi-domain variant surface antigen (~350 kDa) exported from P. falciparum to knob protrusions on the infected erythrocyte surface, where it mediates cytoadherence to host endothelial receptors (including CD36, ICAM-1, EPCR, chondroitin sulfate A, and PECAM1) via its extracellular DBL and CIDR domains, while its cytoplasmic tail (VARC) is anchored to the erythrocyte cytoskeleton through direct interactions with KAHRP (via the histidine-rich and 5′ repeat regions), α-spectrin domain 17, and the PHIST protein PFE1605w; PfEMP1 is trafficked from the parasite ER through Maurer's clefts via electron-dense vesicles in a process facilitated by the exported chaperones Hsp70-x and PFA0660w (which form a ternary complex with the PfEMP1 cytoplasmic tail), the specific PfEMP1 variant expressed determines knob density on the infected erythrocyte surface, and translation of certain PfEMP1 variants (e.g., VAR2CSA) is post-transcriptionally regulated by PTEF-mediated relief of upstream ORF repression; PfEMP1 expression also modulates innate immune responses by suppressing NF-κB activation in macrophages and activating specific TLR signaling pathways in B cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PfEMP1 (PF3D7_0100300) is a multi-domain variant surface antigen exported by Plasmodium falciparum to the surface of infected erythrocytes, where it functions as the principal cytoadherence ligand that drives microvascular sequestration and rosetting of infected cells [#21]. Its extracellular DBL and CIDR domains engage a range of host receptors: the CIDR1 domain binds CD36 and mediates adhesion to endothelium [#2], CIDR domains bind chondroitin sulfate A with defined sulfation and chain-length requirements in var2csa-type variants [#1, #3], a CIDR\\u03b11 domain binds ICAM-1 and EPCR through a conserved motif that permits simultaneous dual-receptor engagement [#7, #19], and the DBL1\\u03b11 domain binds sulfated glycosaminoglycans such as heparin in a manner that governs rosette formation [#18]. Distinct PfEMP1 variants confer distinct adhesive and structural properties: co-expression of two variants on a single cell enables dual binding to PECAM1 and ICAM1 with additive adhesion [#16], the expressed variant sets knob density on the erythrocyte surface [#15], and serum \\u03b12-macroglobulin acts as a co-factor bridging certain variants into rosettes [#14]. The cytoplasmic tail (VARC) anchors PfEMP1 beneath the erythrocyte membrane through direct binding to KAHRP via its histidine-rich and 5\\u2032 repeat regions [#0], to \\u03b1-spectrin domain 17 [#8], and to the PHIST protein PFE1605w, which links PfEMP1 to the cytoskeleton to support CD36-mediated adhesion without affecting transport [#5, #6]. Export proceeds from the parasite periphery through Maurer's clefts and electron-dense vesicles to the red cell membrane [#4], a process assisted by the exported chaperones Hsp70-x and PFA0660w, which form a ternary complex with the PfEMP1 cytoplasmic tail [#12, #13], and modulated by K13-associated PI3P compartments [#10] and by febrile temperature [#23]. Translation of the VAR2CSA variant is post-transcriptionally controlled by PTEF-mediated relief of upstream ORF repression [#9]. Beyond adhesion, PfEMP1 shapes host innate immunity by suppressing NF-\\u03baB activation and cytokine release in monocytes/macrophages [#17] and by activating TLR-dependent signaling in B cells [#22].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing how the parasite surface adhesin is physically retained at the erythrocyte membrane, this work showed the PfEMP1 cytoplasmic tail is directly tethered to the knob scaffold protein KAHRP.\",\n      \"evidence\": \"SPR/kinetic binding of recombinant KAHRP fragments to recombinant VARC with deletion mapping\",\n      \"pmids\": [\"10446142\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interaction mapped in vitro; not validated at native knobs in the same study\", \"Functional consequence of disrupting the KAHRP\\u2013VARC contact not tested\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"To identify which PfEMP1 domain engages the placental-sequestration receptor, CIDR domains were shown to bind chondroitin sulfate A while DBL1 did not, assigning receptor specificity to a defined extracellular module.\",\n      \"evidence\": \"Recombinant CIDR binding to CSA-expressing CHO cells with chondroitinase and soluble-CSA competition\",\n      \"pmids\": [\"10910712\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Native full-length PfEMP1 binding not tested here\", \"In vivo relevance of CSA binding not addressed\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Extending domain-level receptor mapping to endothelial adhesion, a minimal CIDR1 peptide both blocked and reversed cytoadherence to CD36, showing CIDR1 mediates CD36 binding in vitro and in vivo.\",\n      \"evidence\": \"Flow-chamber adhesion and SCID-mouse chimeric model with recombinant CIDR1 peptide inhibition/reversal\",\n      \"pmids\": [\"12393525\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the CIDR1\\u2013CD36 contact not resolved\", \"Contribution of other domains to endothelial binding not quantified\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Moving from in vitro adhesion to whole-organism relevance, this study demonstrated that in vivo sequestration of infected erythrocytes causally depends on surface PfEMP1.\",\n      \"evidence\": \"Rat sequestration model with radiolabeled iRBCs, PfEMP1 removal, anti-PfEMP1 sera, and receptor competition\",\n      \"pmids\": [\"16239578\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific receptors driving in vivo sequestration in this model not dissected\", \"Rat vasculature is a surrogate for human microvasculature\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"To define the molecular determinants of placental adhesion, the structural requirements of var2csa-encoded PfEMP1 binding to CSA were resolved, linking natural polymorphism to preferred CSA motifs.\",\n      \"evidence\": \"Native PfEMP1 binding to defined CS neoglycolipids/oligosaccharides by SPR and competition across isolates\",\n      \"pmids\": [\"17562715\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the var2csa CIDR\\u2013CSA complex not determined\", \"Functional consequences of motif preference for placental tropism not tested\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Two studies addressed variant-level adhesion diversity: the DBL1\\u03b11 domain was shown to bind sulfated oligosaccharides in a rosette-controlling manner, and single cells were shown to co-display two PfEMP1 variants enabling dual-receptor binding.\",\n      \"evidence\": \"SPR/competition and rosette disruption with recombinant NTS-DBL1\\u03b11 [20045435]; single-cell FISH, confocal imaging and adhesion assays for dual-variant expression [20824088]\",\n      \"pmids\": [\"20045435\", \"20824088\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Regulatory mechanism permitting simultaneous two-variant expression not established\", \"Frequency of dual expression in field isolates unknown\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Beyond adhesion, PfEMP1 was shown to act as an immunomodulator on B cells, activating TLR-dependent rather than BCR-dependent signaling.\",\n      \"evidence\": \"Recombinant CIDR1\\u03b1 stimulation of B cells with TLR mRNA and kinase phosphorylation readouts, BCR pathway excluded\",\n      \"pmids\": [\"21620790\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Recombinant domain rather than native surface PfEMP1\", \"In vivo relevance to malaria B-cell responses not tested\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"FCR3S1.2\"}]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"To map the export route of PfEMP1 to the cell surface, live imaging and EM defined a Maurer's-cleft and electron-dense-vesicle pathway with timed membrane docking.\",\n      \"evidence\": \"Live-cell imaging of PfEMP1-GFP chimeras, electron microscopy, and cytochalasin D perturbation\",\n      \"pmids\": [\"23421990\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular machinery of the final vesicle-to-membrane transfer not identified\", \"GFP-chimera trafficking may differ from native PfEMP1\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identifying a cytoskeletal linker, the PHIST protein PFE1605w was shown to bind the PfEMP1 intracellular segment directly and traffic and localize with it to knobs.\",\n      \"evidence\": \"Recombinant binding (Kd), co-migration/co-localization, PHIST-domain crystal structure and NMR-derived interaction model with control PHIST variants\",\n      \"pmids\": [\"24983468\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional necessity of the interaction not tested in this study\", \"Full atomic model of the PHIST\\u2013PfEMP1 complex not resolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Two studies linked the expressed variant to surface architecture and to serum-dependent rosetting: variant identity sets knob density, and \\u03b12-macroglobulin is a required co-factor for HB3VAR06-mediated rosetting.\",\n      \"evidence\": \"Antibody-panned sublines with AFM/SEM knob quantification [26443460]; serum fractionation, binding-site mapping and stoichiometry for \\u03b12M [26134405]\",\n      \"pmids\": [\"26443460\", \"26134405\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which variant sequence dictates knob density unknown\", \"Generality of \\u03b12M dependence across other rosetting variants not established\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Separating trafficking from anchoring, conditional depletion of PFE1605w abolished CD36 adhesion without affecting PfEMP1 transport, showing PFE1605w anchors PfEMP1 to the cytoskeleton for cytoadherence.\",\n      \"evidence\": \"Conditional knockdown of PFE1605w with adhesion assays and cytoskeleton-interaction studies\",\n      \"pmids\": [\"26916885\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise cytoskeletal contacts of PFE1605w not fully defined\", \"Effect on adhesion to receptors other than CD36 not resolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Multiple 2017 studies deepened the picture of PfEMP1 receptor structure, cytoskeletal tethering, export machinery, translational control, and immune modulation.\",\n      \"evidence\": \"CIDR\\u03b11\\u2013ICAM-1 crystal structure and EPCR co-binding motif [28279348]; \\u03b1-spectrin domain-17 interaction mapping [28806784]; PTEF/uORF translational control of VAR2CSA [28481333]; \\u0394hsp70-x export/adhesion phenotype [28732045]; NF-\\u03baB and cytokine suppression in monocytes/macrophages [29038124]\",\n      \"pmids\": [\"28279348\", \"28806784\", \"28481333\", \"28732045\", \"29038124\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct functional mutagenesis of the spectrin contact not performed [28806784]\", \"In vivo validation of the Hsp70-x chaperone role beyond knockout phenotype limited\", \"Molecular basis of NF-\\u03baB suppression by PfEMP1 not defined\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}, {\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extending the immunomodulatory role, PfEMP1 was detected in extracellular vesicles originating inside the infected RBC and shown to shape monocyte transcriptional responses.\",\n      \"evidence\": \"EV proteomics with PfEMP1-transport knockout parasites and monocyte transcriptomics\",\n      \"pmids\": [\"29349926\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which PfEMP1 loads into intracellular EVs unknown\", \"In vivo immunological consequence not established\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Refining the chaperone circuit, PfHsp70-x and cholesterol-bound PFA0660w were shown to form a ternary complex with the PfEMP1 cytoplasmic tail in vitro.\",\n      \"evidence\": \"Recombinant biochemical binding, ternary-complex reconstitution, and domain-deletion analysis\",\n      \"pmids\": [\"30804381\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo validation of the ternary complex explicitly not performed\", \"Functional role of cholesterol binding in export untested\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connecting antimalarial resistance biology to adhesion, K13 was shown to co-localize with PfEMP1 at PI3P ER compartments and K13 mutation altered PfEMP1 export and cytoadherence.\",\n      \"evidence\": \"Cryo-immunoEM, co-purification, fluorescence microscopy and adhesion assays in K13-mutant vs wild-type parasites\",\n      \"pmids\": [\"29363540\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between K13/PI3P and PfEMP1 export is correlative\", \"Direct interaction versus shared compartment not distinguished\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"To define broadly neutralizable epitopes, human monoclonal antibodies were shown to block EPCR binding across most CIDR\\u03b11 subclasses by targeting three conserved residues of the EPCR-binding site.\",\n      \"evidence\": \"Human mAb isolation, EPCR-binding inhibition, sequestration assays in 3D human brain microvessels, and crystal structures of antibody\\u2013CIDR\\u03b11 complexes\",\n      \"pmids\": [\"39567685\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"One CIDR\\u03b11 subclass escaped neutralization\", \"In vivo protective efficacy not established\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Providing a genetic platform, selection-linked integration enabled editing of the expressed PfEMP1 locus, uniform variant expression, and identification of new proteins required for PfEMP1-mediated sequestration.\",\n      \"evidence\": \"SLI/SLI2 genome editing, receptor-binding cell lines, proteomics of the PfEMP1 protein environment and trafficking studies\",\n      \"pmids\": [\"41460168\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identities and mechanisms of the new sequestration-required proteins not detailed here\", \"Single-lab system requiring broader validation\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Linking host physiology to adhesion, febrile temperature accelerated PfEMP1 surface display in ring-stage cells and doubled their binding in a brain-microvessel model.\",\n      \"evidence\": \"Febrile-temperature exposure with RT-PCR of trafficking transcripts and flow adhesion in 3D human brain microvessels\",\n      \"pmids\": [\"40929367\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular sensor coupling temperature to trafficking not identified\", \"In vivo relevance to fever-associated sequestration not tested\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the enormous antigenic and adhesive diversity of PfEMP1 variants is coordinated with knob architecture, cytoskeletal anchoring, and receptor tropism in vivo, and how these determine tissue-specific sequestration and disease, remains incompletely resolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model links variant sequence to knob density and receptor choice\", \"In vivo receptor usage across tissues incompletely mapped\", \"Full-length PfEMP1 structure in the knob context not determined\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005102\", \"supporting_discovery_ids\": [1, 2, 3, 7, 18, 19]},\n      {\"term_id\": \"GO:0008201\", \"supporting_discovery_ids\": [1, 3, 18]},\n      {\"term_id\": \"GO:0050839\", \"supporting_discovery_ids\": [0, 5, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0020030\", \"supporting_discovery_ids\": [5, 15]},\n      {\"term_id\": \"GO:0009986\", \"supporting_discovery_ids\": [2, 4, 16, 21, 23]},\n      {\"term_id\": \"GO:0020036\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:1903561\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0007155\", \"supporting_discovery_ids\": [2, 7, 16, 21]},\n      {\"term_id\": \"GO:0046718\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"GO:0045069\", \"supporting_discovery_ids\": [17, 22]},\n      {\"term_id\": \"GO:0046903\", \"supporting_discovery_ids\": [4, 11, 12, 13]}\n    ],\n    \"complexes\": [\n      \"PfEMP1 cytoplasmic tail\\u2013PfHsp70-x\\u2013PFA0660w ternary chaperone complex (in vitro) [#12]\",\n      \"PfEMP1 VARC\\u2013KAHRP knob-anchoring complex [#0]\",\n      \"PfEMP1\\u2013PFE1605w (PHIST) cytoskeletal-anchoring complex [#5, #6]\"\n    ],\n    \"partners\": [\n      \"KAHRP (via histidine-rich and 5' repeat regions) [#0]\",\n      \"PFE1605w / PHIST protein [#5, #6]\",\n      \"\\u03b1-spectrin domain 17 [#8]\",\n      \"PfHsp70-x [#12, #13]\",\n      \"PFA0660w (Hsp40, cholesterol-bound) [#12]\",\n      \"K13 (shared PI3P ER compartment) [#10]\",\n      \"CD36 (host receptor) [#2]\",\n      \"ICAM-1 (host receptor) [#7]\",\n      \"EPCR (host receptor) [#7, #19]\",\n      \"Chondroitin sulfate A [#1, #3]\",\n      \"PECAM1/CD31 (host receptor) [#16]\",\n      \"Heparin / sulfated oligosaccharides [#18]\",\n      \"\\u03b12-macroglobulin (serum rosetting co-factor) [#14]\",\n      \"IgM (rosetting co-factor) [#14]\"\n    ],\n    \"other_free_text\": [\n      \"Expressed PfEMP1 variant determines knob density on the infected erythrocyte surface [#15].\",\n      \"Single infected erythrocytes can co-display two PfEMP1 variants enabling dual-receptor adhesion [#16].\",\n      \"Translation of the VAR2CSA variant is post-transcriptionally regulated by PTEF-mediated relief of upstream ORF repression [#9].\",\n      \"PfEMP1 suppresses NF-\\u03baB activation and cytokine release in monocytes/macrophages and activates TLR signaling in B cells [#17, #22].\",\n      \"CIDR\\u03b11 EPCR-binding site is broadly neutralizable by human monoclonal antibodies targeting three conserved residues [#19].\",\n      \"Febrile temperature accelerates PfEMP1 surface display and increases adhesion [#23].\",\n      \"Selection-linked integration enables genetic editing of the expressed PfEMP1 locus and uniform variant expression [#20].\",\n      \"In vivo microvascular sequestration causally requires surface PfEMP1 [#21].\"\n    ]\n  }\n}","audit_flag":{"gene":"PF3D7_0100300","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_0100300","name":null,"product":"erythrocyte membrane protein 1, PfEMP1","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"","evaluation":null}