{"gene":"AQP1","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":1992,"finding":"CHIP28 (AQP1) functions as a water channel: Xenopus oocytes injected with CHIP28 RNA showed increased osmotic water permeability, reversibly inhibited by mercuric chloride, establishing CHIP28 as a functional membrane water channel.","method":"Xenopus oocyte expression system, osmotic swelling assay, mercurial inhibition","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct functional reconstitution in oocytes, replicated independently across multiple labs","pmids":["1373524"],"is_preprint":false},{"year":1992,"finding":"Purified CHIP28 (AQP1) reconstituted into proteoliposomes exhibits up to 50-fold higher osmotic water permeability than control liposomes, without increased urea or proton permeability, demonstrating that CHIP28 itself is the functional unit of the erythrocyte water channel.","method":"Protein purification from human RBCs, reconstitution into proteoliposomes, stopped-flow osmotic permeability assay, mercurial inhibition","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified protein, mercurial inhibition, low activation energy, replicated across labs","pmids":["1510932"],"is_preprint":false},{"year":1992,"finding":"CHIP28 (AQP1) is the erythrocyte water channel: stripping erythrocyte membranes of nearly all proteins except CHIP28 retained high water permeability; proteoliposomes reconstituted with solubilized CHIP28 had high Pf with low activation energy (~2.2 kcal/mol), inhibited by mercurials, and excluded urea. Single-channel water permeability ~10^-13 cm3/s.","method":"Membrane protein stripping, proteoliposome reconstitution, osmotic permeability measurement, N-terminal sequence analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods in single study, replicated by other labs","pmids":["1526967"],"is_preprint":false},{"year":1993,"finding":"Cysteine 189 is the mercury-sensitive residue in CHIP28 (AQP1): site-directed mutagenesis of each of the four cysteines (87, 102, 152, 189) to serine showed that only C189S mutant was resistant to HgCl2 inhibition. Individual CHIP28 subunits in a tetramer function independently as water pores. Residue 189 is also critical for proper protein processing.","method":"Site-directed mutagenesis, Xenopus oocyte expression, osmotic swelling assay, HgCl2 inhibition, immunoblot glycosylation analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis of all four cysteines with functional readout, clear mechanistic conclusion","pmids":["7677994"],"is_preprint":false},{"year":1993,"finding":"CHIP28 (AQP1) assembles as tetramers in membranes: freeze-fracture EM of CHIP28-reconstituted proteoliposomes, CHIP28-transfected CHO cells, and rat kidney tubules revealed intramembrane particles (~8.5 nm diameter) composed of four subunits around a central depression. Predicted single-channel Pf of 3.6×10^-14 cm3/s at 10°C was consistent with measured tissue Pf values.","method":"Freeze-fracture electron microscopy, rotary shadowing, osmotic water permeability measurement in CHO cells and kidney tubules","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural EM in multiple systems (proteoliposomes, transfected cells, native tissue) with functional correlation","pmids":["7693713"],"is_preprint":false},{"year":1993,"finding":"CHIP28 (AQP1) localizes to apical brush-border and basolateral membranes throughout proximal convoluted and straight tubules and descending thin limbs of Henle in rat kidney, comprising 3.8% of isolated proximal tubule brush border protein. CHIP28 is absent from ascending thin limbs, thick ascending limbs, distal tubules, and collecting duct, correlating precisely with constitutively high water permeability segments.","method":"Immunolocalization by light and electron microscopy, Western blotting/quantitative immunochemistry on isolated nephron segments","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — detailed subcellular fractionation and immunolocalization with functional correlation to known segment water permeabilities, replicated across labs","pmids":["7678419"],"is_preprint":false},{"year":1993,"finding":"Rat kidney CHIP28k (AQP1 ortholog with 94% identity to human CHIP28) functions as a selective water channel: expression in Xenopus oocytes increased Pf ~8-fold; not permeable to ions. Antisense cRNA blocked the cortical kidney mRNA-induced Pf increase. Apical membrane vesicles from proximal tubule had high water but low urea and proton permeabilities, enriching a 28-kDa protein 25-fold.","method":"cDNA cloning, Xenopus oocyte expression, two-electrode voltage clamp, in situ hybridization, antisense suppression, membrane vesicle reconstitution","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal functional assays, antisense suppression confirms specificity","pmids":["8421053"],"is_preprint":false},{"year":1993,"finding":"Secondary structure of purified functional CHIP28 (AQP1) consists of ~40% alpha-helix and ~43% beta-sheet/-turn by CD and FTIR spectroscopy. HgCl2 inhibition of water transport does not alter the CD spectrum, indicating mercury acts without global protein unfolding.","method":"CD spectroscopy, FTIR spectroscopy, proteoliposome reconstitution","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — structural characterization of purified protein in one study, functional correlation limited","pmids":["8218256"],"is_preprint":false},{"year":1993,"finding":"CHIP28 (AQP1) localizes to apical brush-border and basolateral membranes of proximal tubule S2/S3 segments and descending thin limbs in rat kidney; also present in subapical vesicles and vasa recta endothelium. Absent from ascending limbs, thick ascending limb, distal convoluted tubule.","method":"Immunocytochemistry on rat kidney sections, Western blotting of kidney fractions","journal":"The American journal of physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — immunolocalization replicated across multiple labs with consistent results","pmids":["1282299"],"is_preprint":false},{"year":1993,"finding":"CHIP28 (AQP1) is expressed in brush-border and basolateral membranes of nonciliated cells of the efferent duct (male reproductive tract), which shows constitutively high fluid reabsorption. Ciliated cells in the same epithelium lack CHIP28. Also found in ampulla of vas deferens, seminal vesicles, and prostate.","method":"Western blotting, indirect immunofluorescence, protein A-gold immunolabeling, freeze-fracture EM","journal":"European journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple immunolocalization methods in reproductive tract, functional implication from cell-type specificity","pmids":["8223717"],"is_preprint":false},{"year":1994,"finding":"CHIP28 (AQP1) spans the membrane four times (not six or seven as hydropathy predicts): topology mapping using chimeric reporters inserted at nine positions in the CHIP28 coding region showed only four transmembrane helices, with residues 52-68 and 143-157 residing on lumenal and cytosolic ER surfaces respectively. A second internal signal sequence (residues 155-186) re-initiates translocation of a C-terminal domain into the ER lumen.","method":"Chimeric protein topology mapping in Xenopus oocytes, protease sensitivity assay, cell-free translation of truncated cDNAs, N-linked glycosylation at engineered sites, epitope tagging","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal topology probes (protease protection, glycosylation, truncation series) in single rigorous study","pmids":["7514605"],"is_preprint":false},{"year":1994,"finding":"CHIP28 (AQP1) monomers within the tetrameric complex function independently as water channels: wild-type/non-functional heterodimers (CHIP28-C189W) showed Pf proportional to the wild-type subunit contribution; wild-type/mercurial-insensitive heterodimers (CHIP28-C189S) showed ~44% inhibition by HgCl2, consistent with exactly one sensitive subunit per dimer.","method":"Chimeric cDNA dimer construction, Xenopus oocyte expression, osmotic swelling assay, quantitative immunofluorescence for plasma membrane expression, HgCl2 inhibition","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — rigorous genetic dissection with quantitative functional readout; independent subunit activity confirmed by multiple heterodimer combinations","pmids":["7511600"],"is_preprint":false},{"year":1994,"finding":"CHIP28 (AQP1) is widely distributed in extrarenal epithelial and endothelial cells: immunostaining detected AQP1 in lung alveoli, bronchial mucosa and glands, choroid plexus, ciliary body, iris, lens surface, colonic crypt, sweat gland, pancreatic acini, gallbladder epithelium, placental syncytiotrophoblast, and vascular endothelium across multiple tissues.","method":"In situ hybridization, immunohistochemistry on rat and human tissues, Northern blot, immunoblot","journal":"The American journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — consistent immunolocalization across many tissue types in two species, implies role in epithelial/endothelial fluid transport","pmids":["7513954"],"is_preprint":false},{"year":1994,"finding":"Projection structure of CHIP28 (AQP1) at 12 Å resolution from 2D crystals in lipid bilayers: tetragonal lattice (a=b=99.2 Å), plane group p4g, with four CHIP28 dimers per unit cell. Tetrameric arrangement around 4-fold axes with central stain exclusion consistent with a pore region.","method":"2D crystallization in synthetic lipid bilayers, low-dose electron microscopy, Fourier transform image analysis","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — structural data from 2D crystals at 12 Å; single study, no mutagenesis validation","pmids":["7524655"],"is_preprint":false},{"year":1995,"finding":"AQP1 provides a pathway for small polyols including glycerol and ethylene glycol but excludes urea, meso-erythritol, and larger polyols: osmotic swelling assay in AQP1-injected oocytes and AQP1 proteoliposomes showed significant glycerol permeability inhibited by pCMBS and CuSO4. Glycerol reflection coefficient (0.74-0.80) indicates water and glycerol share the same pathway.","method":"Xenopus oocyte expression, osmotic swelling assay, tritiated glycerol uptake, stopped-flow light scattering in proteoliposomes, mercurial and copper inhibition","journal":"Pflugers Archiv : European journal of physiology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — both oocyte and proteoliposome systems used, inhibitor pharmacology consistent; finding somewhat controversial given AQP1's primary identity as a water-selective channel","pmids":["7491270"],"is_preprint":false},{"year":1995,"finding":"CHIP28 (AQP1) secondary structure contains approximately 36% alpha-helix and 42% beta-sheet by FTIR; over 80% of peptide groups undergo hydrogen-deuterium exchange within 5 min, an exceptionally high rate consistent with a large aqueous pore within the protein structure.","method":"FTIR spectroscopy in H2O and 2H2O, hydrogen-deuterium exchange kinetics","journal":"European journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — single study with spectroscopic method; H/D exchange rate mechanistically consistent with pore structure","pmids":["7588813"],"is_preprint":false},{"year":2002,"finding":"AQP1 expressed in Xenopus oocytes increases membrane CO2 permeability, suggesting AQP1 may facilitate CO2 transport in addition to water. However, data from AQP1 reconstituted into liposomes and from AQP1 knockout mice appear inconsistent with a major CO2 transport role in those preparations.","method":"Xenopus oocyte expression, CO2 permeability measurement, AQP1 knockout mouse studies, liposome reconstitution","journal":"The Journal of physiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — contradictory results between systems reported within the same paper; the CO2 transport role remains contested","pmids":["12096045"],"is_preprint":false},{"year":2003,"finding":"Hypertonicity-induced AQP1 expression in renal medullary cells requires activation of all three MAPK pathways (ERK, p38, and JNK) and a hypertonicity-response element in the AQP1 promoter: pharmacological inhibition of MEK1/2, MKK3/6, or MKK4 (upstream kinases for ERK, p38, JNK respectively) attenuated hypertonic induction of AQP1, and dominant-negative JNK1/2 significantly reduced AQP1 promoter activity.","method":"Pharmacological kinase inhibitors (U0126, SB203580, SP600125), dominant-negative kinase mutant overexpression, AQP1 promoter reporter assay, Western blot","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pathway inhibitors plus dominant-negative constructs with promoter readout in single lab study","pmids":["12600999"],"is_preprint":false},{"year":2006,"finding":"AQP1 does not play a major role in CO2 transport in red cell ghost membranes: stopped-flow measurements of CO2 transport kinetics showed no significant difference between CO(null) human variants (lacking AQP1) and controls, or between AQP1 knockout and wild-type mice. AQP1 absence did reduce NH3 transport rates by ~30%, which was attributed to an indirect effect on RhAG-mediated transport.","method":"Stopped-flow fluorimetry measuring intracellular pH changes in erythrocyte ghosts from human AQP1-null variants (CO(null)) and AQP1 knockout mice","journal":"Transfusion clinique et biologique","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — negative result for CO2 transport using human null variants and knockout mice; positive finding for indirect NH3 effect","pmids":["16574458"],"is_preprint":false},{"year":2005,"finding":"AQP1 localizes to both apical and basolateral membranes of mouse gallbladder epithelial cells, as well as subapical vesicles, whereas AQP8 is restricted to the apical membrane. This dual-membrane localization supports AQP1 as the primary basolateral pathway for transcellular water movement in gallbladder epithelium.","method":"RT-PCR, immunoblotting, immunohistochemistry on mouse gallbladder epithelium","journal":"Biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods for localization, functional implication from dual-membrane presence","pmids":["15859952"],"is_preprint":false},{"year":2010,"finding":"AQP1 expression is induced in reactive astrocytes following cortical stab wound injury in vivo and can be mimicked in vitro by scratch injury; this induction is blocked by MEK1/2 inhibitor U0126, placing AQP1 upregulation downstream of the MAPK/ERK signaling pathway in injury-reactive astrocytes.","method":"Cortical stab wound in vivo model, in vitro scratch injury assay, pharmacological MEK inhibition (U0126), immunostaining, Western blot","journal":"Glia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — both in vivo and in vitro injury models with specific pathway inhibitor, single lab","pmids":["19610096"],"is_preprint":false},{"year":2013,"finding":"AQP1 mediates fast water transport in Schwann cells and controls cell volume: lentiviral knockdown of AQP1 caused cell shrinkage while overexpression caused cell swelling. AQP1 knockdown protected against hypoxia-induced edema. Hypoxic induction of AQP1 occurs in a HIF-1α-dependent manner: HIF-1α knockdown reduced hypoxia-induced AQP1 expression at both mRNA and protein levels.","method":"Lentiviral shRNA knockdown and overexpression, cell volume measurement, hypoxia model, HIF-1α knockdown, Western blot, qPCR","journal":"Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss- and gain-of-function with functional readout plus upstream regulator identification, single lab","pmids":["23948641"],"is_preprint":false},{"year":2015,"finding":"AQP1 knockdown in osteosarcoma cells (U2OS, MG63) inhibited cell proliferation, induced G1 arrest and apoptosis, and reduced cell adhesion and invasion. AQP1 silencing suppressed TGF-β1/TGF-β2, RhoA, and LAMB2 expression, placing AQP1 upstream of TGF-β signaling and focal adhesion pathways in osteosarcoma cells.","method":"RNAi-mediated gene silencing, flow cytometry (cell cycle, apoptosis), cell adhesion and invasion assays, in vivo tumor growth in nude mice, Western blot, real-time PCR, GSEA","journal":"Cancer biology & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cellular phenotype readouts with molecular pathway analysis, in vivo validation, single lab","pmids":["26176849"],"is_preprint":false},{"year":2019,"finding":"AQP1 knockout mice show attenuation of hypoxic pulmonary hypertension: Aqp1 deficiency reduced right ventricular systolic pressure and pulmonary vascular remodeling. In vitro, Aqp1 deletion reduced hypoxia-induced proliferation, apoptosis resistance, and migration of pulmonary artery smooth muscle cells and repressed HIF-1α protein stability. AQP1 loss also protected lung endothelial cells from hypoxic apoptosis.","method":"AQP1 knockout mouse model, right ventricular pressure measurement, histomorphometry, primary cell culture, cell cycle/apoptosis/migration assays, Western blot for HIF-1α","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with in vivo and in vitro phenotypic readouts, mechanistic link to HIF-1α, single lab","pmids":["30580569"],"is_preprint":false},{"year":2019,"finding":"Both AQP1 and AQP4 contribute to cerebrospinal fluid production: AQP1 knockout, AQP4 knockout, and double knockout mice all showed significantly altered intraventricular pressure and CSF outflow compared to wild-type controls. Double knockout additionally altered ventricular compliance and CSF drainage, revealing additive roles for AQP1 in CSF homeostasis.","method":"Intraventricular pressure recording, CSF outflow measurement, MRI ventricular volume quantification in single and double AQP knockout mice","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple physiological readouts in genetic knockout models, single lab","pmids":["30813473"],"is_preprint":false},{"year":2020,"finding":"AQP1 expression declines with tendon aging; AQP1 overexpression in aged tendon stem/progenitor cells (TSPCs) attenuated senescence, restored self-renewal, migration, and tenogenic differentiation. Mechanistically, aged TSPCs showed activated JAK-STAT signaling, and AQP1 overexpression inhibited JAK-STAT pathway activation, placing AQP1 as a negative regulator of JAK-STAT-driven senescence.","method":"Lentiviral overexpression of AQP1 in aged TSPCs, senescence assays, migration and differentiation assays, Western blot for JAK-STAT pathway components","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with multiple phenotypic readouts and pathway identification, single lab","pmids":["32188840"],"is_preprint":false},{"year":2021,"finding":"The AQP1 promoter variant rs2075574 reduces AQP1 promoter activity, AQP1 protein expression, and glucose-driven osmotic water transport across the peritoneal membrane, mechanistically linking reduced AQP1 expression to impaired peritoneal ultrafiltration in dialysis patients.","method":"AQP1 promoter activity reporter assay, AQP1 expression measurement in cells and human samples, osmotic water transport assay, clinical genetic association in 1851 patients","journal":"The New England journal of medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic studies in cells plus mouse models plus large human cohort validation, multiple orthogonal methods","pmids":["34670044"],"is_preprint":false},{"year":2024,"finding":"AQP1 deficiency exacerbates phthalate (DEHP)-induced duodenal epithelial barrier disruption: DEHP directly inhibits AQP1 expression, leading to activation of the TLR4/MyD88/NF-κB inflammatory signaling pathway and disruption of intestinal integrity. AQP1 is thus mechanistically placed as a suppressor of TLR4/MyD88/NF-κB activation in intestinal epithelium.","method":"DEHP exposure in vivo and in vitro, AQP1 expression analysis, inflammatory pathway Western blot and gene expression, barrier function assays, mitochondrial morphology assessment","journal":"Journal of agricultural and food chemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mechanistic pathway identified but single lab, indirect pathway linkage without direct AQP1-TLR4 interaction evidence","pmids":["38916549"],"is_preprint":false}],"current_model":"AQP1 (CHIP28) is a homotetrameric integral membrane water channel in which each monomer functions independently as a selective aqueous pore; cysteine 189 is the mercury-sensitive residue; the protein spans the membrane four times with two NPA-containing loops folding back into the bilayer; beyond constitutive water transport in erythrocytes and renal proximal tubule/thin descending limb, AQP1 also facilitates limited glycerol transport, is regulated transcriptionally by MAPK/ERK and JNK pathways (hypertonicity) and by HIF-1α (hypoxia), and participates in cell migration, proliferation, and volume regulation via downstream effects on TGF-β, RhoA, JAK-STAT, and HIF-1α signaling."},"narrative":{"mechanistic_narrative":"AQP1 (CHIP28) is the prototypical integral-membrane water channel, establishing the molecular basis for rapid, selective osmotic water movement across erythrocyte and epithelial membranes [PMID:1373524, PMID:1526967]. Expression of CHIP28 in Xenopus oocytes and reconstitution of purified protein into proteoliposomes confer up to 50-fold increases in osmotic water permeability with low activation energy, while excluding urea and protons, demonstrating that the protein itself is the functional water pore [PMID:1510932, PMID:1526967]. AQP1 assembles as a homotetramer of ~8.5 nm intramembrane particles in which each monomer functions as an independent water-conducting unit [PMID:7693713, PMID:7511600]. Topology mapping established the unusual four-transmembrane fold with an internal signal sequence that re-initiates translocation of the C-terminal domain [PMID:7514605], and cysteine 189 is the residue responsible for mercurial inhibition and proper protein processing [PMID:7677994]. Beyond water, the channel provides a shared aqueous pathway for small polyols such as glycerol and ethylene glycol [PMID:7491270]. AQP1 is concentrated in constitutively water-permeable epithelia and endothelia—renal proximal tubule and thin descending limb, gallbladder, choroid plexus and broad extrarenal sites—where its membrane localization matches segments of high transcellular fluid flux [PMID:7678419, PMID:7513954, PMID:15859952]. Its expression is induced transcriptionally by hypertonicity through ERK/p38/JNK MAPK signaling acting on a promoter response element [PMID:12600999] and by hypoxia through HIF-1α [PMID:23948641], and AQP1 in turn participates in cell volume regulation, proliferation, migration and senescence with downstream effects on TGF-β, RhoA, JAK-STAT and HIF-1α signaling [PMID:23948641, PMID:26176849, PMID:30580569, PMID:32188840]. A promoter variant (rs2075574) that lowers AQP1 expression impairs glucose-driven osmotic water transport across the peritoneal membrane, mechanistically linking reduced channel abundance to defective peritoneal ultrafiltration in dialysis patients [PMID:34670044].","teleology":[{"year":1992,"claim":"Resolved the long-standing question of how membranes achieve high water permeability by identifying CHIP28 as a discrete, selective water channel rather than diffusion through lipid.","evidence":"CHIP28 RNA expression in Xenopus oocytes with osmotic swelling and reversible mercurial inhibition; purification and proteoliposome reconstitution with stopped-flow permeability assays","pmids":["1373524","1510932","1526967"],"confidence":"High","gaps":["Atomic pore architecture not resolved","Selectivity filter residues not yet identified"]},{"year":1993,"claim":"Defined the molecular determinant of mercurial sensitivity and showed individual subunits within the oligomer conduct water independently.","evidence":"Site-directed mutagenesis of all four cysteines to serine with oocyte osmotic swelling and HgCl2 inhibition; glycosylation/processing analysis","pmids":["7677994"],"confidence":"High","gaps":["Mechanism by which C189 modification blocks water flux not structurally defined"]},{"year":1993,"claim":"Established the quaternary structure and tissue distribution, connecting tetrameric channel particles to the kidney segments that require constitutive water permeability.","evidence":"Freeze-fracture EM of proteoliposomes, CHO cells and kidney tubules; immunolocalization across nephron segments and reproductive tract; rat ortholog cloning with antisense suppression","pmids":["7693713","7678419","1282299","8421053","8223717"],"confidence":"High","gaps":["Trafficking/sorting signals directing apical vs basolateral delivery not defined"]},{"year":1994,"claim":"Overturned the predicted six/seven-helix topology, establishing the four-transmembrane fold with an internal signal sequence, and confirmed independent monomeric pore function genetically.","evidence":"Chimeric reporter topology mapping, protease protection, glycosylation, cell-free translation; wild-type/mutant heterodimer osmotic assays with HgCl2 titration","pmids":["7514605","7511600"],"confidence":"High","gaps":["The NPA-loop pore-forming detail not resolved at this stage","Atomic-resolution channel structure not yet available"]},{"year":1994,"claim":"Provided spectroscopic and projection-structure evidence consistent with an aqueous pore embedded within the folded protein.","evidence":"CD and FTIR secondary-structure analysis, hydrogen-deuterium exchange kinetics, 12 Å 2D crystal projection structure by electron microscopy","pmids":["8218256","7524655","7588813"],"confidence":"Medium","gaps":["Low resolution; no mutagenesis validation of pore-lining residues","Single-study structural assignments"]},{"year":1995,"claim":"Extended the channel's selectivity profile, showing it conducts small polyols through the same pathway as water while excluding urea and larger solutes.","evidence":"Oocyte and proteoliposome osmotic swelling, tritiated glycerol uptake, reflection-coefficient analysis, mercurial/copper inhibition","pmids":["7491270"],"confidence":"Medium","gaps":["Physiological significance of glycerol transport unclear","Polyol permeability secondary to dominant water-channel identity"]},{"year":2006,"claim":"Tested and largely excluded a major physiological role for AQP1 in erythrocyte CO2 transport while uncovering an indirect effect on NH3 flux.","evidence":"Stopped-flow fluorimetry of pH changes in ghosts from human AQP1-null (CO-null) variants and AQP1 knockout mice; earlier oocyte CO2 permeability measurements","pmids":["16574458","12096045"],"confidence":"Medium","gaps":["Discrepancy between oocyte and reconstituted/knockout systems unresolved","Mechanism of indirect RhAG/NH3 effect not defined"]},{"year":2013,"claim":"Linked AQP1-mediated water flux to cell-volume control and identified HIF-1α as the hypoxic transcriptional regulator of AQP1.","evidence":"Lentiviral knockdown/overexpression in Schwann cells with volume measurement and hypoxic edema assays; HIF-1α knockdown with qPCR/Western readout","pmids":["23948641"],"confidence":"Medium","gaps":["Direct HIF-1α binding to AQP1 promoter not demonstrated","Single cell type"]},{"year":2015,"claim":"Placed AQP1 upstream of TGF-β, RhoA and focal-adhesion signaling in controlling proliferation, adhesion and invasion in cancer cells.","evidence":"RNAi silencing in osteosarcoma lines with cell-cycle/apoptosis/invasion assays, nude-mouse tumor growth, pathway expression analysis and GSEA","pmids":["26176849"],"confidence":"Medium","gaps":["Mechanism connecting water/solute transport to TGF-β signaling unknown","No direct molecular interaction shown"]},{"year":2019,"claim":"Established AQP1's contribution to organ-level fluid physiology and hypoxic vascular disease through knockout models.","evidence":"AQP1 knockout (and AQP1/AQP4 double knockout) mice with pulmonary hypertension hemodynamics, CSF pressure/outflow and MRI ventricular measurements, plus HIF-1α stability assays","pmids":["30580569","30813473"],"confidence":"Medium","gaps":["How AQP1 stabilizes HIF-1α protein not defined","Cell-autonomous vs systemic contributions to CSF homeostasis not separated"]},{"year":2020,"claim":"Identified AQP1 as a negative regulator of JAK-STAT-driven senescence in tissue stem/progenitor cells.","evidence":"Lentiviral AQP1 overexpression in aged tendon stem/progenitor cells with senescence, migration and differentiation assays and JAK-STAT Western blots","pmids":["32188840"],"confidence":"Medium","gaps":["Direct link between channel activity and JAK-STAT inhibition unproven","Single cell system"]},{"year":2021,"claim":"Provided human genetic and mechanistic proof that reduced AQP1 expression impairs osmotic water transport across the peritoneal membrane.","evidence":"Promoter-variant (rs2075574) reporter assays, expression and osmotic water transport measurements, and clinical genetic association in 1851 dialysis patients","pmids":["34670044"],"confidence":"High","gaps":["Whether the variant affects other AQP1-dependent tissues not addressed"]},{"year":2024,"claim":"Proposed AQP1 as a suppressor of TLR4/MyD88/NF-κB inflammatory signaling in intestinal epithelium under chemical stress.","evidence":"DEHP exposure in vivo and in vitro with AQP1 expression, inflammatory pathway Western blot/expression and barrier function assays","pmids":["38916549"],"confidence":"Low","gaps":["No direct AQP1-TLR4 interaction evidence; pathway linkage is indirect","Single lab, not independently confirmed"]},{"year":null,"claim":"How AQP1 transport activity is mechanistically coupled to the signaling pathways (TGF-β, RhoA, JAK-STAT, HIF-1α, NF-κB) it influences remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No molecular mechanism linking water/solute flux to transcriptional/signaling output","No direct physical partners identified for the signaling effects","Atomic-resolution selectivity-filter structure absent from the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,1,2,6,14]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[0,1,2,14]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[4,10,11]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4,5,8,19]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[8,19]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,1,2,5,6]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[17,21,23]}],"complexes":["AQP1 homotetramer"],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P29972","full_name":"Aquaporin-1","aliases":["Aquaporin-CHIP","Channel-like integral membrane protein of 28 kDa","Urine water channel"],"length_aa":269,"mass_kda":28.5,"function":"Forms a water channel that facilitates the transport of water across cell membranes, playing a crucial role in water homeostasis in various tissues (PubMed:1373524, PubMed:23219802). Could also be permeable to small solutes including hydrogen peroxide, glycerol and gases such as amonnia (NH3), nitric oxide (NO) and carbon dioxide (CO2) (PubMed:16682607, PubMed:17012249, PubMed:19273840, PubMed:33028705, PubMed:8584435). Recruited to the ankyrin-1 complex, a multiprotein complex of the erythrocyte membrane, it could be part of a CO2 metabolon, linking facilitated diffusion of CO2 across the membrane, anion exchange of Cl(-)/HCO3(-) and interconversion of dissolved CO2 and carbonic acid in the cytosol (PubMed:17012249, PubMed:35835865). 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co-amplified with MYCN in neuroblastoma: silent passengers or co-determinants of phenotype?","date":"2003","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/12880964","citation_count":31,"is_preprint":false},{"pmid":"20965731","id":"PMC_20965731","title":"Expression of AQP1 and AQP4 in paediatric brain tumours.","date":"2010","source":"Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia","url":"https://pubmed.ncbi.nlm.nih.gov/20965731","citation_count":30,"is_preprint":false},{"pmid":"25656365","id":"PMC_25656365","title":"Sex-dependent expression of water channel AQP1 along the rat nephron.","date":"2015","source":"American journal of physiology. Renal physiology","url":"https://pubmed.ncbi.nlm.nih.gov/25656365","citation_count":30,"is_preprint":false},{"pmid":"25859964","id":"PMC_25859964","title":"Co-immunoprecipitation from transfected cells.","date":"2015","source":"Methods in molecular biology (Clifton, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/25859964","citation_count":29,"is_preprint":false},{"pmid":"36972448","id":"PMC_36972448","title":"Biohybrid CO2 electrolysis for the direct synthesis of polyesters from CO2.","date":"2023","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/36972448","citation_count":28,"is_preprint":false},{"pmid":"7588813","id":"PMC_7588813","title":"A Fourier-transform infrared spectroscopic investigation of the hydrogen-deuterium exchange and secondary structure of the 28-kDa channel-forming integral membrane protein (CHIP28).","date":"1995","source":"European journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7588813","citation_count":27,"is_preprint":false},{"pmid":"30970608","id":"PMC_30970608","title":"AQP1-Containing Exosomes in Peritoneal Dialysis Effluent As Biomarker of Dialysis Efficiency.","date":"2019","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/30970608","citation_count":27,"is_preprint":false},{"pmid":"30178445","id":"PMC_30178445","title":"Decellularised tissues obtained by a CO2-philic detergent and supercritical CO2.","date":"2018","source":"European cells & materials","url":"https://pubmed.ncbi.nlm.nih.gov/30178445","citation_count":27,"is_preprint":false},{"pmid":"30240136","id":"PMC_30240136","title":"Something special about CO-dependent CO2 fixation.","date":"2018","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/30240136","citation_count":25,"is_preprint":false},{"pmid":"36367380","id":"PMC_36367380","title":"Role of carboxysomes in cyanobacterial CO2 assimilation: CO2 concentrating mechanisms and metabolon implications.","date":"2022","source":"Environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/36367380","citation_count":25,"is_preprint":false},{"pmid":"23948641","id":"PMC_23948641","title":"AQP1 expression alterations affect morphology and water transport in Schwann cells and hypoxia-induced up-regulation of AQP1 occurs in a HIF-1α-dependent manner.","date":"2013","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/23948641","citation_count":25,"is_preprint":false},{"pmid":"23162560","id":"PMC_23162560","title":"Co-expression and co-responses: within and beyond transcription.","date":"2012","source":"Frontiers in plant science","url":"https://pubmed.ncbi.nlm.nih.gov/23162560","citation_count":24,"is_preprint":false},{"pmid":"16525162","id":"PMC_16525162","title":"Urea and urine concentrating ability in mice lacking AQP1 and AQP3.","date":"2006","source":"American journal of physiology. Renal physiology","url":"https://pubmed.ncbi.nlm.nih.gov/16525162","citation_count":24,"is_preprint":false},{"pmid":"27419268","id":"PMC_27419268","title":"Co-stimulate or Co-inhibit Regulatory T Cells, Which Side to Go?","date":"2016","source":"Immunological investigations","url":"https://pubmed.ncbi.nlm.nih.gov/27419268","citation_count":23,"is_preprint":false},{"pmid":"22300078","id":"PMC_22300078","title":"Therapeutic potential of carbon monoxide (CO) for intestinal inflammation.","date":"2012","source":"Current medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22300078","citation_count":23,"is_preprint":false},{"pmid":"25120489","id":"PMC_25120489","title":"Analysis of co-assembly and co-localization of ameloblastin and amelogenin.","date":"2014","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/25120489","citation_count":21,"is_preprint":false},{"pmid":"36204139","id":"PMC_36204139","title":"The pathogenesis of idiopathic normal pressure hydrocephalus based on the understanding of AQP1 and AQP4.","date":"2022","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/36204139","citation_count":21,"is_preprint":false},{"pmid":"12054061","id":"PMC_12054061","title":"Aripiprazole (Otsuka Pharmaceutical Co).","date":"2002","source":"Current opinion in investigational drugs (London, England : 2000)","url":"https://pubmed.ncbi.nlm.nih.gov/12054061","citation_count":21,"is_preprint":false},{"pmid":"35451753","id":"PMC_35451753","title":"Co-immunoprecipitation Assays.","date":"2022","source":"Methods in molecular biology (Clifton, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/35451753","citation_count":20,"is_preprint":false},{"pmid":"21136710","id":"PMC_21136710","title":"Differential expression of AQP1 in microdomain-enriched membranes of renal cell carcinoma.","date":"2007","source":"Proteomics. Clinical applications","url":"https://pubmed.ncbi.nlm.nih.gov/21136710","citation_count":20,"is_preprint":false},{"pmid":"24694364","id":"PMC_24694364","title":"Plant Hsp90 and its co-chaperones.","date":"2014","source":"Current protein & peptide science","url":"https://pubmed.ncbi.nlm.nih.gov/24694364","citation_count":18,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":43974,"output_tokens":6977,"usd":0.118289,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16090,"output_tokens":4148,"usd":0.092075,"stage2_stop_reason":"end_turn"},"total_usd":0.210364,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1992,\n      \"finding\": \"CHIP28 (AQP1) functions as a water channel: Xenopus oocytes injected with CHIP28 RNA showed increased osmotic water permeability, reversibly inhibited by mercuric chloride, establishing CHIP28 as a functional membrane water channel.\",\n      \"method\": \"Xenopus oocyte expression system, osmotic swelling assay, mercurial inhibition\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct functional reconstitution in oocytes, replicated independently across multiple labs\",\n      \"pmids\": [\"1373524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"Purified CHIP28 (AQP1) reconstituted into proteoliposomes exhibits up to 50-fold higher osmotic water permeability than control liposomes, without increased urea or proton permeability, demonstrating that CHIP28 itself is the functional unit of the erythrocyte water channel.\",\n      \"method\": \"Protein purification from human RBCs, reconstitution into proteoliposomes, stopped-flow osmotic permeability assay, mercurial inhibition\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified protein, mercurial inhibition, low activation energy, replicated across labs\",\n      \"pmids\": [\"1510932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"CHIP28 (AQP1) is the erythrocyte water channel: stripping erythrocyte membranes of nearly all proteins except CHIP28 retained high water permeability; proteoliposomes reconstituted with solubilized CHIP28 had high Pf with low activation energy (~2.2 kcal/mol), inhibited by mercurials, and excluded urea. Single-channel water permeability ~10^-13 cm3/s.\",\n      \"method\": \"Membrane protein stripping, proteoliposome reconstitution, osmotic permeability measurement, N-terminal sequence analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods in single study, replicated by other labs\",\n      \"pmids\": [\"1526967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Cysteine 189 is the mercury-sensitive residue in CHIP28 (AQP1): site-directed mutagenesis of each of the four cysteines (87, 102, 152, 189) to serine showed that only C189S mutant was resistant to HgCl2 inhibition. Individual CHIP28 subunits in a tetramer function independently as water pores. Residue 189 is also critical for proper protein processing.\",\n      \"method\": \"Site-directed mutagenesis, Xenopus oocyte expression, osmotic swelling assay, HgCl2 inhibition, immunoblot glycosylation analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis of all four cysteines with functional readout, clear mechanistic conclusion\",\n      \"pmids\": [\"7677994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"CHIP28 (AQP1) assembles as tetramers in membranes: freeze-fracture EM of CHIP28-reconstituted proteoliposomes, CHIP28-transfected CHO cells, and rat kidney tubules revealed intramembrane particles (~8.5 nm diameter) composed of four subunits around a central depression. Predicted single-channel Pf of 3.6×10^-14 cm3/s at 10°C was consistent with measured tissue Pf values.\",\n      \"method\": \"Freeze-fracture electron microscopy, rotary shadowing, osmotic water permeability measurement in CHO cells and kidney tubules\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural EM in multiple systems (proteoliposomes, transfected cells, native tissue) with functional correlation\",\n      \"pmids\": [\"7693713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"CHIP28 (AQP1) localizes to apical brush-border and basolateral membranes throughout proximal convoluted and straight tubules and descending thin limbs of Henle in rat kidney, comprising 3.8% of isolated proximal tubule brush border protein. CHIP28 is absent from ascending thin limbs, thick ascending limbs, distal tubules, and collecting duct, correlating precisely with constitutively high water permeability segments.\",\n      \"method\": \"Immunolocalization by light and electron microscopy, Western blotting/quantitative immunochemistry on isolated nephron segments\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — detailed subcellular fractionation and immunolocalization with functional correlation to known segment water permeabilities, replicated across labs\",\n      \"pmids\": [\"7678419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Rat kidney CHIP28k (AQP1 ortholog with 94% identity to human CHIP28) functions as a selective water channel: expression in Xenopus oocytes increased Pf ~8-fold; not permeable to ions. Antisense cRNA blocked the cortical kidney mRNA-induced Pf increase. Apical membrane vesicles from proximal tubule had high water but low urea and proton permeabilities, enriching a 28-kDa protein 25-fold.\",\n      \"method\": \"cDNA cloning, Xenopus oocyte expression, two-electrode voltage clamp, in situ hybridization, antisense suppression, membrane vesicle reconstitution\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal functional assays, antisense suppression confirms specificity\",\n      \"pmids\": [\"8421053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Secondary structure of purified functional CHIP28 (AQP1) consists of ~40% alpha-helix and ~43% beta-sheet/-turn by CD and FTIR spectroscopy. HgCl2 inhibition of water transport does not alter the CD spectrum, indicating mercury acts without global protein unfolding.\",\n      \"method\": \"CD spectroscopy, FTIR spectroscopy, proteoliposome reconstitution\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — structural characterization of purified protein in one study, functional correlation limited\",\n      \"pmids\": [\"8218256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"CHIP28 (AQP1) localizes to apical brush-border and basolateral membranes of proximal tubule S2/S3 segments and descending thin limbs in rat kidney; also present in subapical vesicles and vasa recta endothelium. Absent from ascending limbs, thick ascending limb, distal convoluted tubule.\",\n      \"method\": \"Immunocytochemistry on rat kidney sections, Western blotting of kidney fractions\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — immunolocalization replicated across multiple labs with consistent results\",\n      \"pmids\": [\"1282299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"CHIP28 (AQP1) is expressed in brush-border and basolateral membranes of nonciliated cells of the efferent duct (male reproductive tract), which shows constitutively high fluid reabsorption. Ciliated cells in the same epithelium lack CHIP28. Also found in ampulla of vas deferens, seminal vesicles, and prostate.\",\n      \"method\": \"Western blotting, indirect immunofluorescence, protein A-gold immunolabeling, freeze-fracture EM\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple immunolocalization methods in reproductive tract, functional implication from cell-type specificity\",\n      \"pmids\": [\"8223717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"CHIP28 (AQP1) spans the membrane four times (not six or seven as hydropathy predicts): topology mapping using chimeric reporters inserted at nine positions in the CHIP28 coding region showed only four transmembrane helices, with residues 52-68 and 143-157 residing on lumenal and cytosolic ER surfaces respectively. A second internal signal sequence (residues 155-186) re-initiates translocation of a C-terminal domain into the ER lumen.\",\n      \"method\": \"Chimeric protein topology mapping in Xenopus oocytes, protease sensitivity assay, cell-free translation of truncated cDNAs, N-linked glycosylation at engineered sites, epitope tagging\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal topology probes (protease protection, glycosylation, truncation series) in single rigorous study\",\n      \"pmids\": [\"7514605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"CHIP28 (AQP1) monomers within the tetrameric complex function independently as water channels: wild-type/non-functional heterodimers (CHIP28-C189W) showed Pf proportional to the wild-type subunit contribution; wild-type/mercurial-insensitive heterodimers (CHIP28-C189S) showed ~44% inhibition by HgCl2, consistent with exactly one sensitive subunit per dimer.\",\n      \"method\": \"Chimeric cDNA dimer construction, Xenopus oocyte expression, osmotic swelling assay, quantitative immunofluorescence for plasma membrane expression, HgCl2 inhibition\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — rigorous genetic dissection with quantitative functional readout; independent subunit activity confirmed by multiple heterodimer combinations\",\n      \"pmids\": [\"7511600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"CHIP28 (AQP1) is widely distributed in extrarenal epithelial and endothelial cells: immunostaining detected AQP1 in lung alveoli, bronchial mucosa and glands, choroid plexus, ciliary body, iris, lens surface, colonic crypt, sweat gland, pancreatic acini, gallbladder epithelium, placental syncytiotrophoblast, and vascular endothelium across multiple tissues.\",\n      \"method\": \"In situ hybridization, immunohistochemistry on rat and human tissues, Northern blot, immunoblot\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — consistent immunolocalization across many tissue types in two species, implies role in epithelial/endothelial fluid transport\",\n      \"pmids\": [\"7513954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Projection structure of CHIP28 (AQP1) at 12 Å resolution from 2D crystals in lipid bilayers: tetragonal lattice (a=b=99.2 Å), plane group p4g, with four CHIP28 dimers per unit cell. Tetrameric arrangement around 4-fold axes with central stain exclusion consistent with a pore region.\",\n      \"method\": \"2D crystallization in synthetic lipid bilayers, low-dose electron microscopy, Fourier transform image analysis\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — structural data from 2D crystals at 12 Å; single study, no mutagenesis validation\",\n      \"pmids\": [\"7524655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"AQP1 provides a pathway for small polyols including glycerol and ethylene glycol but excludes urea, meso-erythritol, and larger polyols: osmotic swelling assay in AQP1-injected oocytes and AQP1 proteoliposomes showed significant glycerol permeability inhibited by pCMBS and CuSO4. Glycerol reflection coefficient (0.74-0.80) indicates water and glycerol share the same pathway.\",\n      \"method\": \"Xenopus oocyte expression, osmotic swelling assay, tritiated glycerol uptake, stopped-flow light scattering in proteoliposomes, mercurial and copper inhibition\",\n      \"journal\": \"Pflugers Archiv : European journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — both oocyte and proteoliposome systems used, inhibitor pharmacology consistent; finding somewhat controversial given AQP1's primary identity as a water-selective channel\",\n      \"pmids\": [\"7491270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"CHIP28 (AQP1) secondary structure contains approximately 36% alpha-helix and 42% beta-sheet by FTIR; over 80% of peptide groups undergo hydrogen-deuterium exchange within 5 min, an exceptionally high rate consistent with a large aqueous pore within the protein structure.\",\n      \"method\": \"FTIR spectroscopy in H2O and 2H2O, hydrogen-deuterium exchange kinetics\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — single study with spectroscopic method; H/D exchange rate mechanistically consistent with pore structure\",\n      \"pmids\": [\"7588813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"AQP1 expressed in Xenopus oocytes increases membrane CO2 permeability, suggesting AQP1 may facilitate CO2 transport in addition to water. However, data from AQP1 reconstituted into liposomes and from AQP1 knockout mice appear inconsistent with a major CO2 transport role in those preparations.\",\n      \"method\": \"Xenopus oocyte expression, CO2 permeability measurement, AQP1 knockout mouse studies, liposome reconstitution\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — contradictory results between systems reported within the same paper; the CO2 transport role remains contested\",\n      \"pmids\": [\"12096045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Hypertonicity-induced AQP1 expression in renal medullary cells requires activation of all three MAPK pathways (ERK, p38, and JNK) and a hypertonicity-response element in the AQP1 promoter: pharmacological inhibition of MEK1/2, MKK3/6, or MKK4 (upstream kinases for ERK, p38, JNK respectively) attenuated hypertonic induction of AQP1, and dominant-negative JNK1/2 significantly reduced AQP1 promoter activity.\",\n      \"method\": \"Pharmacological kinase inhibitors (U0126, SB203580, SP600125), dominant-negative kinase mutant overexpression, AQP1 promoter reporter assay, Western blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pathway inhibitors plus dominant-negative constructs with promoter readout in single lab study\",\n      \"pmids\": [\"12600999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"AQP1 does not play a major role in CO2 transport in red cell ghost membranes: stopped-flow measurements of CO2 transport kinetics showed no significant difference between CO(null) human variants (lacking AQP1) and controls, or between AQP1 knockout and wild-type mice. AQP1 absence did reduce NH3 transport rates by ~30%, which was attributed to an indirect effect on RhAG-mediated transport.\",\n      \"method\": \"Stopped-flow fluorimetry measuring intracellular pH changes in erythrocyte ghosts from human AQP1-null variants (CO(null)) and AQP1 knockout mice\",\n      \"journal\": \"Transfusion clinique et biologique\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — negative result for CO2 transport using human null variants and knockout mice; positive finding for indirect NH3 effect\",\n      \"pmids\": [\"16574458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"AQP1 localizes to both apical and basolateral membranes of mouse gallbladder epithelial cells, as well as subapical vesicles, whereas AQP8 is restricted to the apical membrane. This dual-membrane localization supports AQP1 as the primary basolateral pathway for transcellular water movement in gallbladder epithelium.\",\n      \"method\": \"RT-PCR, immunoblotting, immunohistochemistry on mouse gallbladder epithelium\",\n      \"journal\": \"Biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods for localization, functional implication from dual-membrane presence\",\n      \"pmids\": [\"15859952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"AQP1 expression is induced in reactive astrocytes following cortical stab wound injury in vivo and can be mimicked in vitro by scratch injury; this induction is blocked by MEK1/2 inhibitor U0126, placing AQP1 upregulation downstream of the MAPK/ERK signaling pathway in injury-reactive astrocytes.\",\n      \"method\": \"Cortical stab wound in vivo model, in vitro scratch injury assay, pharmacological MEK inhibition (U0126), immunostaining, Western blot\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — both in vivo and in vitro injury models with specific pathway inhibitor, single lab\",\n      \"pmids\": [\"19610096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"AQP1 mediates fast water transport in Schwann cells and controls cell volume: lentiviral knockdown of AQP1 caused cell shrinkage while overexpression caused cell swelling. AQP1 knockdown protected against hypoxia-induced edema. Hypoxic induction of AQP1 occurs in a HIF-1α-dependent manner: HIF-1α knockdown reduced hypoxia-induced AQP1 expression at both mRNA and protein levels.\",\n      \"method\": \"Lentiviral shRNA knockdown and overexpression, cell volume measurement, hypoxia model, HIF-1α knockdown, Western blot, qPCR\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss- and gain-of-function with functional readout plus upstream regulator identification, single lab\",\n      \"pmids\": [\"23948641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"AQP1 knockdown in osteosarcoma cells (U2OS, MG63) inhibited cell proliferation, induced G1 arrest and apoptosis, and reduced cell adhesion and invasion. AQP1 silencing suppressed TGF-β1/TGF-β2, RhoA, and LAMB2 expression, placing AQP1 upstream of TGF-β signaling and focal adhesion pathways in osteosarcoma cells.\",\n      \"method\": \"RNAi-mediated gene silencing, flow cytometry (cell cycle, apoptosis), cell adhesion and invasion assays, in vivo tumor growth in nude mice, Western blot, real-time PCR, GSEA\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cellular phenotype readouts with molecular pathway analysis, in vivo validation, single lab\",\n      \"pmids\": [\"26176849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"AQP1 knockout mice show attenuation of hypoxic pulmonary hypertension: Aqp1 deficiency reduced right ventricular systolic pressure and pulmonary vascular remodeling. In vitro, Aqp1 deletion reduced hypoxia-induced proliferation, apoptosis resistance, and migration of pulmonary artery smooth muscle cells and repressed HIF-1α protein stability. AQP1 loss also protected lung endothelial cells from hypoxic apoptosis.\",\n      \"method\": \"AQP1 knockout mouse model, right ventricular pressure measurement, histomorphometry, primary cell culture, cell cycle/apoptosis/migration assays, Western blot for HIF-1α\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with in vivo and in vitro phenotypic readouts, mechanistic link to HIF-1α, single lab\",\n      \"pmids\": [\"30580569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Both AQP1 and AQP4 contribute to cerebrospinal fluid production: AQP1 knockout, AQP4 knockout, and double knockout mice all showed significantly altered intraventricular pressure and CSF outflow compared to wild-type controls. Double knockout additionally altered ventricular compliance and CSF drainage, revealing additive roles for AQP1 in CSF homeostasis.\",\n      \"method\": \"Intraventricular pressure recording, CSF outflow measurement, MRI ventricular volume quantification in single and double AQP knockout mice\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple physiological readouts in genetic knockout models, single lab\",\n      \"pmids\": [\"30813473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"AQP1 expression declines with tendon aging; AQP1 overexpression in aged tendon stem/progenitor cells (TSPCs) attenuated senescence, restored self-renewal, migration, and tenogenic differentiation. Mechanistically, aged TSPCs showed activated JAK-STAT signaling, and AQP1 overexpression inhibited JAK-STAT pathway activation, placing AQP1 as a negative regulator of JAK-STAT-driven senescence.\",\n      \"method\": \"Lentiviral overexpression of AQP1 in aged TSPCs, senescence assays, migration and differentiation assays, Western blot for JAK-STAT pathway components\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with multiple phenotypic readouts and pathway identification, single lab\",\n      \"pmids\": [\"32188840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The AQP1 promoter variant rs2075574 reduces AQP1 promoter activity, AQP1 protein expression, and glucose-driven osmotic water transport across the peritoneal membrane, mechanistically linking reduced AQP1 expression to impaired peritoneal ultrafiltration in dialysis patients.\",\n      \"method\": \"AQP1 promoter activity reporter assay, AQP1 expression measurement in cells and human samples, osmotic water transport assay, clinical genetic association in 1851 patients\",\n      \"journal\": \"The New England journal of medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic studies in cells plus mouse models plus large human cohort validation, multiple orthogonal methods\",\n      \"pmids\": [\"34670044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"AQP1 deficiency exacerbates phthalate (DEHP)-induced duodenal epithelial barrier disruption: DEHP directly inhibits AQP1 expression, leading to activation of the TLR4/MyD88/NF-κB inflammatory signaling pathway and disruption of intestinal integrity. AQP1 is thus mechanistically placed as a suppressor of TLR4/MyD88/NF-κB activation in intestinal epithelium.\",\n      \"method\": \"DEHP exposure in vivo and in vitro, AQP1 expression analysis, inflammatory pathway Western blot and gene expression, barrier function assays, mitochondrial morphology assessment\",\n      \"journal\": \"Journal of agricultural and food chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mechanistic pathway identified but single lab, indirect pathway linkage without direct AQP1-TLR4 interaction evidence\",\n      \"pmids\": [\"38916549\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"AQP1 (CHIP28) is a homotetrameric integral membrane water channel in which each monomer functions independently as a selective aqueous pore; cysteine 189 is the mercury-sensitive residue; the protein spans the membrane four times with two NPA-containing loops folding back into the bilayer; beyond constitutive water transport in erythrocytes and renal proximal tubule/thin descending limb, AQP1 also facilitates limited glycerol transport, is regulated transcriptionally by MAPK/ERK and JNK pathways (hypertonicity) and by HIF-1α (hypoxia), and participates in cell migration, proliferation, and volume regulation via downstream effects on TGF-β, RhoA, JAK-STAT, and HIF-1α signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"AQP1 (CHIP28) is the prototypical integral-membrane water channel, establishing the molecular basis for rapid, selective osmotic water movement across erythrocyte and epithelial membranes [#0, #2]. Expression of CHIP28 in Xenopus oocytes and reconstitution of purified protein into proteoliposomes confer up to 50-fold increases in osmotic water permeability with low activation energy, while excluding urea and protons, demonstrating that the protein itself is the functional water pore [#1, #2]. AQP1 assembles as a homotetramer of ~8.5 nm intramembrane particles in which each monomer functions as an independent water-conducting unit [#4, #11]. Topology mapping established the unusual four-transmembrane fold with an internal signal sequence that re-initiates translocation of the C-terminal domain [#10], and cysteine 189 is the residue responsible for mercurial inhibition and proper protein processing [#3]. Beyond water, the channel provides a shared aqueous pathway for small polyols such as glycerol and ethylene glycol [#14]. AQP1 is concentrated in constitutively water-permeable epithelia and endothelia—renal proximal tubule and thin descending limb, gallbladder, choroid plexus and broad extrarenal sites—where its membrane localization matches segments of high transcellular fluid flux [#5, #12, #19]. Its expression is induced transcriptionally by hypertonicity through ERK/p38/JNK MAPK signaling acting on a promoter response element [#17] and by hypoxia through HIF-1α [#21], and AQP1 in turn participates in cell volume regulation, proliferation, migration and senescence with downstream effects on TGF-β, RhoA, JAK-STAT and HIF-1α signaling [#21, #22, #23, #25]. A promoter variant (rs2075574) that lowers AQP1 expression impairs glucose-driven osmotic water transport across the peritoneal membrane, mechanistically linking reduced channel abundance to defective peritoneal ultrafiltration in dialysis patients [#26].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Resolved the long-standing question of how membranes achieve high water permeability by identifying CHIP28 as a discrete, selective water channel rather than diffusion through lipid.\",\n      \"evidence\": \"CHIP28 RNA expression in Xenopus oocytes with osmotic swelling and reversible mercurial inhibition; purification and proteoliposome reconstitution with stopped-flow permeability assays\",\n      \"pmids\": [\"1373524\", \"1510932\", \"1526967\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic pore architecture not resolved\", \"Selectivity filter residues not yet identified\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Defined the molecular determinant of mercurial sensitivity and showed individual subunits within the oligomer conduct water independently.\",\n      \"evidence\": \"Site-directed mutagenesis of all four cysteines to serine with oocyte osmotic swelling and HgCl2 inhibition; glycosylation/processing analysis\",\n      \"pmids\": [\"7677994\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which C189 modification blocks water flux not structurally defined\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Established the quaternary structure and tissue distribution, connecting tetrameric channel particles to the kidney segments that require constitutive water permeability.\",\n      \"evidence\": \"Freeze-fracture EM of proteoliposomes, CHO cells and kidney tubules; immunolocalization across nephron segments and reproductive tract; rat ortholog cloning with antisense suppression\",\n      \"pmids\": [\"7693713\", \"7678419\", \"1282299\", \"8421053\", \"8223717\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trafficking/sorting signals directing apical vs basolateral delivery not defined\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Overturned the predicted six/seven-helix topology, establishing the four-transmembrane fold with an internal signal sequence, and confirmed independent monomeric pore function genetically.\",\n      \"evidence\": \"Chimeric reporter topology mapping, protease protection, glycosylation, cell-free translation; wild-type/mutant heterodimer osmotic assays with HgCl2 titration\",\n      \"pmids\": [\"7514605\", \"7511600\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The NPA-loop pore-forming detail not resolved at this stage\", \"Atomic-resolution channel structure not yet available\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Provided spectroscopic and projection-structure evidence consistent with an aqueous pore embedded within the folded protein.\",\n      \"evidence\": \"CD and FTIR secondary-structure analysis, hydrogen-deuterium exchange kinetics, 12 Å 2D crystal projection structure by electron microscopy\",\n      \"pmids\": [\"8218256\", \"7524655\", \"7588813\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Low resolution; no mutagenesis validation of pore-lining residues\", \"Single-study structural assignments\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Extended the channel's selectivity profile, showing it conducts small polyols through the same pathway as water while excluding urea and larger solutes.\",\n      \"evidence\": \"Oocyte and proteoliposome osmotic swelling, tritiated glycerol uptake, reflection-coefficient analysis, mercurial/copper inhibition\",\n      \"pmids\": [\"7491270\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological significance of glycerol transport unclear\", \"Polyol permeability secondary to dominant water-channel identity\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Tested and largely excluded a major physiological role for AQP1 in erythrocyte CO2 transport while uncovering an indirect effect on NH3 flux.\",\n      \"evidence\": \"Stopped-flow fluorimetry of pH changes in ghosts from human AQP1-null (CO-null) variants and AQP1 knockout mice; earlier oocyte CO2 permeability measurements\",\n      \"pmids\": [\"16574458\", \"12096045\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Discrepancy between oocyte and reconstituted/knockout systems unresolved\", \"Mechanism of indirect RhAG/NH3 effect not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linked AQP1-mediated water flux to cell-volume control and identified HIF-1α as the hypoxic transcriptional regulator of AQP1.\",\n      \"evidence\": \"Lentiviral knockdown/overexpression in Schwann cells with volume measurement and hypoxic edema assays; HIF-1α knockdown with qPCR/Western readout\",\n      \"pmids\": [\"23948641\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct HIF-1α binding to AQP1 promoter not demonstrated\", \"Single cell type\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placed AQP1 upstream of TGF-β, RhoA and focal-adhesion signaling in controlling proliferation, adhesion and invasion in cancer cells.\",\n      \"evidence\": \"RNAi silencing in osteosarcoma lines with cell-cycle/apoptosis/invasion assays, nude-mouse tumor growth, pathway expression analysis and GSEA\",\n      \"pmids\": [\"26176849\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting water/solute transport to TGF-β signaling unknown\", \"No direct molecular interaction shown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established AQP1's contribution to organ-level fluid physiology and hypoxic vascular disease through knockout models.\",\n      \"evidence\": \"AQP1 knockout (and AQP1/AQP4 double knockout) mice with pulmonary hypertension hemodynamics, CSF pressure/outflow and MRI ventricular measurements, plus HIF-1α stability assays\",\n      \"pmids\": [\"30580569\", \"30813473\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How AQP1 stabilizes HIF-1α protein not defined\", \"Cell-autonomous vs systemic contributions to CSF homeostasis not separated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified AQP1 as a negative regulator of JAK-STAT-driven senescence in tissue stem/progenitor cells.\",\n      \"evidence\": \"Lentiviral AQP1 overexpression in aged tendon stem/progenitor cells with senescence, migration and differentiation assays and JAK-STAT Western blots\",\n      \"pmids\": [\"32188840\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct link between channel activity and JAK-STAT inhibition unproven\", \"Single cell system\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided human genetic and mechanistic proof that reduced AQP1 expression impairs osmotic water transport across the peritoneal membrane.\",\n      \"evidence\": \"Promoter-variant (rs2075574) reporter assays, expression and osmotic water transport measurements, and clinical genetic association in 1851 dialysis patients\",\n      \"pmids\": [\"34670044\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the variant affects other AQP1-dependent tissues not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Proposed AQP1 as a suppressor of TLR4/MyD88/NF-κB inflammatory signaling in intestinal epithelium under chemical stress.\",\n      \"evidence\": \"DEHP exposure in vivo and in vitro with AQP1 expression, inflammatory pathway Western blot/expression and barrier function assays\",\n      \"pmids\": [\"38916549\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct AQP1-TLR4 interaction evidence; pathway linkage is indirect\", \"Single lab, not independently confirmed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How AQP1 transport activity is mechanistically coupled to the signaling pathways (TGF-β, RhoA, JAK-STAT, HIF-1α, NF-κB) it influences remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular mechanism linking water/solute flux to transcriptional/signaling output\", \"No direct physical partners identified for the signaling effects\", \"Atomic-resolution selectivity-filter structure absent from the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 1, 2, 6, 14]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [0, 1, 2, 14]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [4, 10, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 5, 8, 19]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [8, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 1, 2, 5, 6]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [17, 21, 23]}\n    ],\n    \"complexes\": [\"AQP1 homotetramer\"],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}