{"gene":"RPL10","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":1997,"finding":"The human QM protein (RPL10) associates with the rough endoplasmic reticulum in a peripheral, salt-sensitive manner exposed on the cytoplasmic face of the membrane, and co-purifies with the ribosome complex, demonstrating it is a bona fide ribosomal protein component of a large protein complex.","method":"Indirect immunofluorescence, subcellular fractionation, proteolytic latency assay, in situ cross-linking with diagonal SDS-PAGE, ribosome co-purification","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal biochemical methods (fractionation, cross-linking, co-purification) in a single study with rigorous controls","pmids":["9204867"],"is_preprint":false},{"year":1992,"finding":"The QM gene (RPL10) is located at chromosomal locus Xq28, consists of at least 7 exons, belongs to a multi-gene family with members scattered across multiple chromosomes, and is ubiquitously expressed in adult human tissues with elevated expression in liver, spleen, testis, and adrenal gland.","method":"Southern blot, Northern blot, somatic cell hybrid panel analysis, cDNA sequencing","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 — direct genomic mapping and expression analysis, single study","pmids":["1339145"],"is_preprint":false},{"year":1999,"finding":"QM (RPL10) is expressed in diverse embryonic tissues during mouse development, localizes to the cytoplasm consistent with ribosome association, is enriched in differentiating cells (chondrocytes, suprabasal keratinocytes) with an inverse relationship between expression level and proliferative capacity, and is absent from red blood cell precursors.","method":"Whole-mount in situ hybridization, whole-mount immunohistochemistry, immunohistochemistry on tissue sections","journal":"Differentiation; research in biological diversity","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization by multiple imaging methods, single lab","pmids":["10234813"],"is_preprint":false},{"year":2002,"finding":"The QM/RPL10 ortholog in Trypanosoma brucei co-localizes with the GPI:protein transamidase component GPI8, a distribution indicative of ribosome association with the rough endoplasmic reticulum, confirming conserved ribosomal function across distant eukaryotes.","method":"Epitope-tagged inducible expression, immunofluorescence microscopy","journal":"FEMS microbiology letters","confidence":"Medium","confidence_rationale":"Tier 3 — localization by immunofluorescence in a distant ortholog, single lab","pmids":["12076801"],"is_preprint":false},{"year":2004,"finding":"Yeast rpL10/Grc5p functionally interacts with the nuclear export factor Nmd3p to modulate the cellular polysome complement, and interacts with small subunit protein rpS6 in ribosomal subunit joining and differential protein expression, establishing rpL10 as a multifunctional regulator operating in 60S biogenesis, nuclear export, and subunit joining.","method":"Genetic interaction analysis, polysome profiling, biochemical fractionation","journal":"FEMS yeast research","confidence":"Medium","confidence_rationale":"Tier 2-3 — functional epistasis and biochemical fractionation, single lab","pmids":["15556089"],"is_preprint":false},{"year":2006,"finding":"Two missense mutations in RPL10 (L206M and H213Q) found in autism-spectrum disorder families confer hypomorphism in translational regulation while keeping basic translation intact, suggesting that altered translational function—not complete loss—can contribute to neurodevelopmental disorders. RPL10 is highly expressed in mouse hippocampus.","method":"Family-based genetic analysis, functional complementation assays in yeast measuring translational regulation","journal":"Molecular psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 — functional yeast complementation with mutagenesis, single lab","pmids":["16940977"],"is_preprint":false},{"year":2006,"finding":"Heterozygous deletion of RPL10 (single-copy LSU gene) in yeast reduces the translating ribosome population and increases replicative life span by 24%, demonstrating that Rpl10 gene dosage regulates translation output and aging.","method":"Yeast replicative life span assay, polysome profiling, genetic deletion","journal":"Experimental gerontology","confidence":"Medium","confidence_rationale":"Tier 2 — direct functional assay with quantitative polysome profiling, single lab","pmids":["17174052"],"is_preprint":false},{"year":2007,"finding":"Extensive mutagenesis of yeast Rpl10 revealed that a central loop (amino acids 102–112) is critical for release of the nuclear export adapter Nmd3 from the 60S subunit, while this loop is not required for stable ribosome binding, suggesting it plays a dynamic regulatory role. Rpl10 mutants unable to bind the ribosome accumulate in the nucleus, indicating an unexpected nuclear function for Rpl10.","method":"Systematic site-directed mutagenesis, genetic complementation, subcellular localization, Nmd3 release assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — extensive mutagenesis with multiple functional readouts (ribosome binding, Nmd3 release, localization), single study with strong mechanistic dissection","pmids":["17761675"],"is_preprint":false},{"year":2012,"finding":"Exome sequencing identified recurrent somatic mutations in RPL10, particularly RPL10 R98S (Arg98Ser), in 9.8% of pediatric T-ALL cases. Yeast and lymphoid cells expressing the RPL10 R98S mutant showed a ribosome biogenesis defect, establishing RPL10 as a ribosomal protein whose mutation can drive oncogenesis.","method":"Exome sequencing, yeast functional complementation, ribosome biogenesis assay in lymphoid cells","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — discovery in large patient cohort confirmed by functional assays in two model systems, replicated across labs","pmids":["23263491"],"is_preprint":false},{"year":2013,"finding":"An internal loop in yeast rpL10 (positioned in the core of the large subunit) is a central controller of ribosomal intersubunit rotation between non-rotated and rotated states. Mutations in this loop promote opposing shifts in the rotational equilibrium and cause defects in catalysis, translation fidelity, and Sdo1p recruitment for late-stage 60S maturation. An rpL3 suppressor mutation restoring opposing structural effects rescued an rpL10 mutant by re-establishing rotational equilibrium, demonstrating allosteric communication from rpL10 through both subunits linking all functional centers.","method":"rRNA chemical modification (SHAPE/DMS probing), mutational analysis, genetic suppressor analysis, translation fidelity assays, biochemical maturation assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including chemical probing, mutagenesis, epistasis, and functional assays in a single study with strong mechanistic conclusions","pmids":["24214990"],"is_preprint":false},{"year":2013,"finding":"High-resolution cryo-EM structures of human and Drosophila 80S ribosomes reveal RPL10 (uL16) positioned within the large subunit, contributing to metazoan-specific ribosomal architecture and illustrating its co-evolution with rRNA.","method":"Single-particle cryo-electron microscopy, atomic model building","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — high-resolution cryo-EM structure with atomic model, independently validated","pmids":["23636399"],"is_preprint":false},{"year":2014,"finding":"A missense mutation in RPL10 (p.K78E) in the conserved N-terminal region near the peptidyl transferase active site causes X-linked microcephaly, growth retardation, and seizures. Suppression of rpl10 in zebrafish decreases head size, reduces bulk translation, and increases apoptosis in the brain; p.K78E is a loss-of-function variant confirmed by in vivo complementation, demonstrating RPL10 is essential for brain formation and function.","method":"X-linked intellectual disability sequencing panel, zebrafish morpholino knockdown, in vivo complementation, apoptosis assay, translation assay","journal":"Genetics","confidence":"High","confidence_rationale":"Tier 2 — human genetics plus zebrafish functional validation with multiple phenotypic readouts and in vivo complementation","pmids":["25316788"],"is_preprint":false},{"year":2015,"finding":"A novel RPL10 missense mutation (p.A64V) in the N-terminal domain causes X-linked intellectual disability, cerebellar hypoplasia, and spondylo-epiphyseal dysplasia. Unlike other RPL10 mutations, p.A64V generates a functional ribosomal protein that increases (rather than decreases) the actively translating ribosome population in yeast, demonstrating that both gain and loss of translational output via RPL10 mutations can cause disease.","method":"X-exome resequencing, yeast complementation of conditional lethal rpl10 mutation, polysome profiling","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 — human genetics with functional yeast validation and polysome profiling, single lab","pmids":["26290468"],"is_preprint":false},{"year":2015,"finding":"Near-atomic (3.6 Å) cryo-EM structure of the human 80S ribosome reveals RPL10 (uL16) atomic details within the large subunit, including its position relative to tRNA binding sites and the subunit interface that remodels during rotational movements.","method":"High-resolution single-particle cryo-electron microscopy, atomic model building","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — near-atomic resolution structure with atomic model building","pmids":["25901680"],"is_preprint":false},{"year":2017,"finding":"The RPL10 R98S mutation in T-ALL causes hyper-activation of the JAK-STAT signaling pathway upon cytokine stimulation by: (1) transcriptional upregulation of JAK-STAT proteins, (2) reduction of programmed ribosomal frameshifting at frameshift signals in JAK-STAT genes leading to altered protein isoform ratios, and (3) decreased JAK1 degradation. RPL10 R98S also reduces proteasome activity. The mutual exclusivity of RPL10 R98S with JAK-STAT mutations in T-ALL patients suggests functional equivalence.","method":"Proteome screen, transgenic Rpl10 R98S mouse model, T-ALL xenograft, cytokine stimulation assays, ribosomal frameshifting reporter assays, JAK-STAT inhibitor sensitivity assays","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal mechanisms demonstrated across mouse model, human xenograft, and cell lines with mechanistic assays including frameshift reporters","pmids":["28744013"],"is_preprint":false},{"year":2017,"finding":"RPL10L (a testis-specific retrogene of RPL10) is required for spermatogenesis by compensating for RPL10, which is silenced by meiotic sex chromosome inactivation (MSCI) during spermatogenesis. Loss of Rpl10l disrupts ribosome biogenesis in late-prophase spermatocytes, blocking the prophase-to-metaphase transition. Ectopic expression of RPL10L prevents death of RPL10-deficient somatic cells, and transgenic Rpl10 expression in spermatocytes restores fertility in Rpl10l-null mice, proving functional equivalence.","method":"Knockout mouse model, transgenic rescue, ectopic expression in somatic cells, ribosome biogenesis assay, fertility assay","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic rescue experiments demonstrating functional equivalence, direct evidence for MSCI-based compensation mechanism","pmids":["28502657"],"is_preprint":false},{"year":2018,"finding":"The RPL10 R98S mutation drives accumulation of reactive oxygen species, mitochondrial dysfunction, and reduced ATP, causing a proliferation defect. Mutant cells survive high oxidative stress via specific upregulation of IRES-dependent translation of BCL-2, leading to BCL-2 protein overexpression and conferring sensitivity to the BCL-2 inhibitor Venetoclax (ABT-199), validated in T-ALL xenograft mouse models.","method":"ROS measurement, mitochondrial function assays, IRES reporter assays, Venetoclax sensitivity assays, T-ALL xenograft mouse model","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 2 — mechanistic pathway from mutation to IRES-mediated BCL-2 translation validated by multiple assays and in vivo xenograft model","pmids":["29930300"],"is_preprint":false}],"current_model":"RPL10 (QM/uL16) is an essential component of the 60S large ribosomal subunit that occupies a position near the peptidyl transferase center and subunit interface; its internal loop drives intersubunit rotational dynamics allosterically linked to all ribosomal functional centers, it mediates late-stage 60S maturation by enabling Nmd3 release, and its loss-of-function (or altered-function) mutations cause ribosomopathies ranging from X-linked microcephaly and intellectual disability to T-ALL, where the recurrent R98S mutation drives oncogenesis through ribosomal frameshifting-mediated JAK-STAT hyper-activation and IRES-dependent BCL-2 upregulation."},"narrative":{"teleology":[{"year":1992,"claim":"Establishing RPL10 as a ubiquitously expressed X-linked gene answered the basic question of genomic location and tissue distribution, placing it at Xq28 with a multi-gene family.","evidence":"Southern/Northern blot and somatic cell hybrid mapping of human QM/RPL10","pmids":["1339145"],"confidence":"Medium","gaps":["Protein-level function not addressed","Processed pseudogene family not functionally characterized"]},{"year":1997,"claim":"Demonstrating that QM/RPL10 co-purifies with ribosomes and localizes to rough ER settled the long-debated question of whether QM is a genuine ribosomal protein rather than a standalone tumor suppressor.","evidence":"Subcellular fractionation, in situ cross-linking, ribosome co-purification from human cells","pmids":["9204867"],"confidence":"High","gaps":["Specific position within the ribosome unknown","No structure available"]},{"year":2004,"claim":"Genetic interactions of yeast Rpl10 with the export adapter Nmd3 and the small subunit protein rpS6 revealed that Rpl10 functions beyond steady-state translation in 60S biogenesis, nuclear export, and subunit joining.","evidence":"Genetic epistasis analysis and polysome profiling in S. cerevisiae","pmids":["15556089"],"confidence":"Medium","gaps":["Mechanism of Nmd3 release not defined","Direct physical interaction with rpS6 not confirmed"]},{"year":2007,"claim":"Systematic mutagenesis of the Rpl10 internal loop (residues 102–112) showed it is required for Nmd3 release from the 60S subunit but dispensable for stable ribosome binding, defining a specific regulatory role in late-stage 60S maturation distinct from structural incorporation.","evidence":"Site-directed mutagenesis, Nmd3 release assay, subcellular localization in yeast","pmids":["17761675"],"confidence":"High","gaps":["Structural basis of loop-mediated Nmd3 release unknown","Whether the mechanism is conserved in metazoans untested"]},{"year":2013,"claim":"Chemical probing and suppressor genetics showed that the Rpl10 internal loop controls the global rotational equilibrium between non-rotated and rotated ribosome states, allosterically coupling all functional centers and linking Rpl10 to translation fidelity and Sdo1-dependent maturation.","evidence":"SHAPE/DMS rRNA probing, genetic suppressor analysis with rpL3, translation fidelity and maturation assays in yeast","pmids":["24214990"],"confidence":"High","gaps":["Atomic-resolution view of loop conformational states lacking","Contribution of individual loop residues to rotational bias unresolved"]},{"year":2013,"claim":"Cryo-EM structures of the human and Drosophila 80S ribosome provided the first atomic context for RPL10 within the large subunit, confirming its position near the peptidyl transferase center and subunit interface.","evidence":"Single-particle cryo-EM at sub-nanometer to near-atomic resolution","pmids":["23636399","25901680"],"confidence":"High","gaps":["Dynamics of RPL10 loop not captured in static structures","Mutant ribosome structures not available"]},{"year":2012,"claim":"Identification of recurrent somatic RPL10 R98S mutations in ~10% of pediatric T-ALL established RPL10 as the first ribosomal protein with a recurrent oncogenic point mutation, connecting ribosome function to leukemogenesis.","evidence":"Exome sequencing of T-ALL patient cohort, yeast and lymphoid cell functional validation","pmids":["23263491"],"confidence":"High","gaps":["Downstream oncogenic mechanism not yet defined at this stage","Contribution to clonal fitness versus initiation unclear"]},{"year":2014,"claim":"Discovery that RPL10 K78E causes X-linked microcephaly and that zebrafish rpl10 depletion recapitulates brain size reduction and apoptosis demonstrated RPL10 is essential for brain development, defining the first Mendelian ribosomopathy linked to RPL10.","evidence":"Human XLID sequencing, zebrafish morpholino knockdown with in vivo complementation","pmids":["25316788"],"confidence":"High","gaps":["Which neural cell types are most sensitive unknown","Whether apoptosis is p53-dependent not tested"]},{"year":2015,"claim":"The RPL10 A64V mutation, which paradoxically increases translating ribosomes, demonstrated that both gain and loss of translational output through RPL10 can cause neurodevelopmental disease, broadening the pathogenic spectrum.","evidence":"X-exome sequencing, yeast complementation, polysome profiling","pmids":["26290468"],"confidence":"Medium","gaps":["Mechanism by which increased translation causes pathology unknown","No direct translatomic data from patient cells"]},{"year":2017,"claim":"Mechanistic dissection of RPL10 R98S in T-ALL revealed that the mutation converges on JAK-STAT hyper-activation through three independent routes: transcriptional upregulation, altered programmed ribosomal frameshifting at JAK-STAT mRNAs, and reduced JAK1 proteasomal degradation.","evidence":"Proteomics, transgenic Rpl10 R98S mouse, T-ALL xenograft, frameshifting reporters, JAK-STAT inhibitor assays","pmids":["28744013"],"confidence":"High","gaps":["Direct structural basis for how R98S alters frameshifting efficiency not resolved","Whether other signaling pathways are similarly affected unclear"]},{"year":2017,"claim":"Discovery that the testis-specific retrogene RPL10L is essential for spermatogenesis by compensating for RPL10 silencing during MSCI revealed a unique gene dosage compensation mechanism and confirmed functional equivalence of the two paralogs.","evidence":"Rpl10l knockout and transgenic Rpl10 rescue in mice, ectopic expression in somatic cells","pmids":["28502657"],"confidence":"High","gaps":["Whether RPL10L has any unique ribosomal properties not addressed","Mechanism of RPL10L transcriptional activation post-MSCI unknown"]},{"year":2018,"claim":"RPL10 R98S was shown to cause mitochondrial dysfunction and ROS accumulation, which cells bypass through IRES-dependent overexpression of BCL-2, creating a therapeutic vulnerability to Venetoclax in T-ALL.","evidence":"ROS and mitochondrial assays, IRES reporters, Venetoclax treatment of T-ALL xenografts","pmids":["29930300"],"confidence":"High","gaps":["Whether Venetoclax sensitivity extends to all RPL10-mutant leukemias untested in clinical trials","Identity of specific IRES trans-acting factors mediating BCL-2 upregulation unknown"]},{"year":null,"claim":"Key unresolved questions include the atomic-resolution mechanism by which the RPL10 internal loop switches between conformational states to drive intersubunit rotation, the full translatomic consequences of disease-associated RPL10 mutations in human cells, and whether RPL10-mutant ribosomes produce a qualitatively distinct proteome ('specialized ribosomes').","evidence":"","pmids":[],"confidence":"High","gaps":["No cryo-EM structure of mutant RPL10-containing ribosomes","No ribosome profiling data comparing wild-type and mutant RPL10 in human cells","Specialized ribosome hypothesis not directly tested for RPL10"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,10,13]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[9,14,16]}],"localization":[{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[0,10,13]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,3]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,9,10,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[8,14,16]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[14]}],"complexes":["60S large ribosomal subunit","80S ribosome"],"partners":["NMD3","RPL3","RPS6","SDO1","BCL2","RPL10L"],"other_free_text":[]},"mechanistic_narrative":"RPL10 (uL16) is an essential component of the 60S large ribosomal subunit whose internal loop governs intersubunit rotational dynamics, allosterically linking the peptidyl transferase center, tRNA binding sites, and subunit interface to regulate translation fidelity, catalysis, and late-stage 60S maturation through Nmd3 release [PMID:24214990, PMID:17761675]. High-resolution cryo-EM structures position RPL10 at the core of the large subunit near the peptidyl transferase center, consistent with its role as a dynamic regulator rather than a passive structural element [PMID:23636399, PMID:25901680]. Loss-of-function mutations (K78E, A64V, L206M) cause X-linked microcephaly, intellectual disability, and skeletal dysplasia by perturbing translational output, while the recurrent somatic R98S mutation drives pediatric T-ALL through JAK-STAT hyper-activation via altered programmed ribosomal frameshifting and IRES-dependent BCL-2 upregulation that confers sensitivity to Venetoclax [PMID:25316788, PMID:26290468, PMID:23263491, PMID:28744013, PMID:29930300]. A testis-specific retrogene, RPL10L, compensates for RPL10 silencing during meiotic sex chromosome inactivation in spermatogenesis, and the two proteins are functionally interchangeable [PMID:28502657]."},"prefetch_data":{"uniprot":{"accession":"P27635","full_name":"Large ribosomal subunit protein uL16","aliases":["60S ribosomal protein L10","Laminin receptor homolog","Protein QM","Ribosomal protein L10","Tumor suppressor QM"],"length_aa":214,"mass_kda":24.6,"function":"Component of the large ribosomal subunit (PubMed:26290468). Plays a role in the formation of actively translating ribosomes (PubMed:26290468). May play a role in the embryonic brain development (PubMed:25316788)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P27635/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/RPL10","classification":"Common Essential","n_dependent_lines":1198,"n_total_lines":1208,"dependency_fraction":0.9917218543046358},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"EIF2S3","stoichiometry":10.0},{"gene":"RACK1","stoichiometry":10.0},{"gene":"RPL11","stoichiometry":10.0},{"gene":"RPL13","stoichiometry":10.0},{"gene":"RPL4","stoichiometry":10.0},{"gene":"RPL5","stoichiometry":10.0},{"gene":"RPS16","stoichiometry":10.0},{"gene":"CAPRIN1","stoichiometry":4.0},{"gene":"DRG1","stoichiometry":4.0},{"gene":"ENY2","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/search/RPL10","total_profiled":1310},"omim":[{"mim_id":"619655","title":"RIBOSOMAL PROTEIN L10-LIKE; RPL10L","url":"https://www.omim.org/entry/619655"},{"mim_id":"613065","title":"LEUKEMIA, ACUTE LYMPHOBLASTIC; ALL","url":"https://www.omim.org/entry/613065"},{"mim_id":"604910","title":"CCR4-NOT TRANSCRIPTION COMPLEX, SUBUNIT 3; CNOT3","url":"https://www.omim.org/entry/604910"},{"mim_id":"603634","title":"RIBOSOMAL PROTEIN L5; RPL5","url":"https://www.omim.org/entry/603634"},{"mim_id":"312173","title":"RIBOSOMAL PROTEIN L10; RPL10","url":"https://www.omim.org/entry/312173"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Endoplasmic reticulum","reliability":"Enhanced"},{"location":"Cytosol","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RPL10"},"hgnc":{"alias_symbol":["NOV","QM","DXS648E","DXS648","FLJ23544","L10","uL16"],"prev_symbol":[]},"alphafold":{"accession":"P27635","domains":[{"cath_id":"3.90.1170.10","chopping":"5-100_125-173","consensus_level":"high","plddt":96.8894,"start":5,"end":173}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P27635","model_url":"https://alphafold.ebi.ac.uk/files/AF-P27635-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P27635-F1-predicted_aligned_error_v6.png","plddt_mean":94.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RPL10","jax_strain_url":"https://www.jax.org/strain/search?query=RPL10"},"sequence":{"accession":"P27635","fasta_url":"https://rest.uniprot.org/uniprotkb/P27635.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P27635/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P27635"}},"corpus_meta":[{"pmid":"27620848","id":"PMC_27620848","title":"Genome-based phylogeny and taxonomy of the 'Enterobacteriales': proposal for Enterobacterales ord. nov. divided into the families Enterobacteriaceae, Erwiniaceae fam. nov., Pectobacteriaceae fam. nov., Yersiniaceae fam. nov., Hafniaceae fam. nov., Morganellaceae fam. nov., and Budviciaceae fam. nov.","date":"2016","source":"International journal of systematic and evolutionary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/27620848","citation_count":631,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15297074","id":"PMC_15297074","title":"Prediction of CTL epitopes using QM, SVM and ANN techniques.","date":"2004","source":"Vaccine","url":"https://pubmed.ncbi.nlm.nih.gov/15297074","citation_count":246,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26596307","id":"PMC_26596307","title":"On the Convergence of QM/MM Energies.","date":"2011","source":"Journal of chemical theory and computation","url":"https://pubmed.ncbi.nlm.nih.gov/26596307","citation_count":164,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27704827","id":"PMC_27704827","title":"How Large Should the QM Region Be in QM/MM Calculations? 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Nov., from hamster dental plaque.","date":"2007","source":"Microbiology and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/17704637","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21322476","id":"PMC_21322476","title":"Reductive cleavage of the O-O bond in multicopper oxidases: a QM/MM and QM study.","date":"2011","source":"Faraday discussions","url":"https://pubmed.ncbi.nlm.nih.gov/21322476","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27711562","id":"PMC_27711562","title":"Incorporating QM and solvation into docking for applications to GPCR targets.","date":"2016","source":"Physical chemistry chemical physics : PCCP","url":"https://pubmed.ncbi.nlm.nih.gov/27711562","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22021581","id":"PMC_22021581","title":"Pseudahrensia aquimaris gen. nov., sp. nov., isolated from seawater.","date":"2011","source":"International journal of systematic and evolutionary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/22021581","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20511460","id":"PMC_20511460","title":"Allobacillus halotolerans gen. nov., sp. nov. isolated from shrimp paste.","date":"2010","source":"International journal of systematic and evolutionary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/20511460","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29906110","id":"PMC_29906110","title":"Effect of DNA Environment on Electronically Excited States of Methylene Blue Evaluated by a Three-Layered QM/QM/MM ONIOM Scheme.","date":"2018","source":"Journal of chemical theory and computation","url":"https://pubmed.ncbi.nlm.nih.gov/29906110","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23034747","id":"PMC_23034747","title":"QM and QM/MM simulations of proteins.","date":"2013","source":"Methods in molecular biology (Clifton, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/23034747","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16738088","id":"PMC_16738088","title":"Ancylobacter polymorphus sp. nov. and Ancylobacter vacuolatus sp. nov.","date":"2006","source":"International journal of systematic and evolutionary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/16738088","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20207801","id":"PMC_20207801","title":"Allocatelliglobosispora scoriae gen. nov., sp. nov., isolated from volcanic ash.","date":"2010","source":"International journal of systematic and evolutionary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/20207801","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18707166","id":"PMC_18707166","title":"Exploring the interstitial atom in the FeMo cofactor of nitrogenase: insights from QM and QM/MM calculations.","date":"2008","source":"The journal of physical chemistry. B","url":"https://pubmed.ncbi.nlm.nih.gov/18707166","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20601489","id":"PMC_20601489","title":"Paraperlucidibaca baekdonensis gen. nov., sp. nov., isolated from seawater.","date":"2010","source":"International journal of systematic and evolutionary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/20601489","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18398192","id":"PMC_18398192","title":"Saxeibacter lacteus gen. nov., sp. nov., an actinobacterium isolated from rock.","date":"2008","source":"International journal of systematic and evolutionary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/18398192","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19950879","id":"PMC_19950879","title":"Solvent effects on photoreactivity of valerophenone: a combined QM and MM study.","date":"2009","source":"The Journal of organic 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proteome.","date":"2005","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/16169070","citation_count":1704,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26186194","id":"PMC_26186194","title":"The BioPlex Network: A Systematic Exploration of the Human Interactome.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26186194","citation_count":1118,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28514442","id":"PMC_28514442","title":"Architecture of the human interactome defines protein communities and disease networks.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/28514442","citation_count":1085,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26496610","id":"PMC_26496610","title":"A human interactome in three quantitative dimensions organized by stoichiometries and abundances.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26496610","citation_count":1015,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22681889","id":"PMC_22681889","title":"The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts.","date":"2012","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/22681889","citation_count":973,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15635413","id":"PMC_15635413","title":"Nucleolar proteome dynamics.","date":"2005","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/15635413","citation_count":934,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15790807","id":"PMC_15790807","title":"Transcriptional maps of 10 human chromosomes at 5-nucleotide resolution.","date":"2005","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/15790807","citation_count":881,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14743216","id":"PMC_14743216","title":"A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway.","date":"2004","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/14743216","citation_count":841,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29507755","id":"PMC_29507755","title":"VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation.","date":"2018","source":"Cell 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soluble protein complexes.","date":"2012","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/22939629","citation_count":689,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28302793","id":"PMC_28302793","title":"Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15.","date":"2017","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/28302793","citation_count":533,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8125298","id":"PMC_8125298","title":"Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides.","date":"1994","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/8125298","citation_count":492,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23636399","id":"PMC_23636399","title":"Structures of the human and Drosophila 80S ribosome.","date":"2013","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/23636399","citation_count":481,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15489334","id":"PMC_15489334","title":"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).","date":"2004","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/15489334","citation_count":438,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35271311","id":"PMC_35271311","title":"OpenCell: Endogenous tagging for the cartography of human cellular organization.","date":"2022","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/35271311","citation_count":432,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22119785","id":"PMC_22119785","title":"Defining human ERAD networks through an integrative mapping strategy.","date":"2011","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/22119785","citation_count":427,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20020773","id":"PMC_20020773","title":"Global analysis of TDP-43 interacting proteins reveals strong association with RNA splicing and translation machinery.","date":"2010","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/20020773","citation_count":422,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16344560","id":"PMC_16344560","title":"Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes.","date":"2005","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/16344560","citation_count":409,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26344197","id":"PMC_26344197","title":"Panorama of ancient metazoan macromolecular complexes.","date":"2015","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/26344197","citation_count":407,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15189156","id":"PMC_15189156","title":"The molecular mechanics of eukaryotic translation.","date":"2004","source":"Annual review of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15189156","citation_count":396,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25901680","id":"PMC_25901680","title":"Structure of the human 80S ribosome.","date":"2015","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/25901680","citation_count":380,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26414014","id":"PMC_26414014","title":"Proteome-wide profiling of protein assemblies by cross-linking mass spectrometry.","date":"2015","source":"Nature methods","url":"https://pubmed.ncbi.nlm.nih.gov/26414014","citation_count":370,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"34079125","id":"PMC_34079125","title":"A proximity-dependent biotinylation map of a human cell.","date":"2021","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/34079125","citation_count":339,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23263491","id":"PMC_23263491","title":"Exome sequencing identifies mutation in CNOT3 and ribosomal genes RPL5 and RPL10 in T-cell acute lymphoblastic leukemia.","date":"2012","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23263491","citation_count":337,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47579,"output_tokens":3106,"usd":0.094663},"stage2":{"model":"claude-opus-4-6","input_tokens":6379,"output_tokens":2353,"usd":0.13608},"total_usd":0.523585,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":58663,"output_tokens":5010,"usd":0.12557},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":7703,"output_tokens":2920,"usd":0.167272}},"stage1_raw":"Looking at the corpus, I need to identify papers about human/mammalian RPL10 (ribosomal protein L10, also known as QM) and extract mechanistic findings. The vast majority of papers are about bacterial taxonomy, QM/MM computational chemistry methods, or other unrelated topics. I'll focus on the relevant RPL10 papers.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"The QM protein (RPL10) associates with ribosomes on the rough endoplasmic reticulum. Subcellular fractionation showed QM copurified with the ribosome complex and was exposed on the cytoplasmic face of microsomal membranes. In situ cross-linking and diagonal SDS-PAGE demonstrated QM exists in a large protein complex, and 1M NaCl disrupted its ribosome association.\",\n      \"method\": \"Subcellular fractionation, indirect immunofluorescence, proteolytic latency assay, in situ cross-linking/diagonal SDS-PAGE, ribosome co-purification\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (fractionation, cross-linking, co-purification) in a single study with rigorous controls\",\n      \"pmids\": [\"9204867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Yeast Rpl10 is a multifunctional translational regulator operating in 60S subunit biogenesis, nuclear export, and 60S/40S subunit joining. Heterozygous deletion of RPL10 reduced the translating ribosome population and increased yeast replicative lifespan by 24%, demonstrating that RPL10 gene dosage directly modulates translational output.\",\n      \"method\": \"Gene deletion/heterozygous deletion, polysome profiling, replicative lifespan assay\",\n      \"journal\": \"Experimental gerontology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO with specific cellular phenotypes (polysome reduction, lifespan extension), single lab\",\n      \"pmids\": [\"17174052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Two missense mutations in RPL10 (L206M and H213Q) found in autism patients confer hypomorphism with respect to translational regulation while keeping basic translation intact, suggesting RPL10 C-terminal domain modulates translational fidelity beyond core ribosome function.\",\n      \"method\": \"Mutational analysis, functional complementation in yeast, translational assays\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — disease mutations functionally validated with translational readout in yeast model\",\n      \"pmids\": [\"16940977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Yeast Rpl10 is positioned in a cleft between the central protuberance and GTPase-activating center of the 60S subunit and is loaded at a late maturation step. A central loop (amino acids 102–112) is required for release of the nuclear export adapter Nmd3 from the pre-60S particle, and Rpl10 mutants unable to bind the ribosome accumulated in the nucleus, indicating a nuclear role for Rpl10.\",\n      \"method\": \"Extensive alanine-scanning and deletion mutagenesis, Nmd3 release assay, subcellular localization by fluorescence microscopy\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — extensive mutagenesis mapping functional domains, multiple orthogonal readouts (Nmd3 release, localization), single lab with strong mechanistic resolution\",\n      \"pmids\": [\"17761675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Yeast rpL10/Grc5p functionally interacts with the nuclear export factor Nmd3p to modulate cellular polysome content, and with small subunit protein rpS6 in 60S/40S subunit joining and differential protein expression, establishing rpL10 as a regulator of ribosome joining.\",\n      \"method\": \"Co-functional analysis, polysome profiling, genetic interaction studies\",\n      \"journal\": \"FEMS yeast research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — functional interaction data with specific phenotypic readouts, single lab\",\n      \"pmids\": [\"15556089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"An internal loop in yeast rpL10 (the eukaryote-specific loop) is a central controller of ribosomal subunit rotation between non-rotated and rotated conformational states during the elongation cycle. Mutations in this loop promote opposing effects on the rotational equilibrium, allosterically affect rRNA at all functional centers of the ribosome, and cause translational fidelity and catalytic defects. An rpL3 mutation with opposing structural effects suppressed an rpL10 mutant by re-establishing rotational equilibrium. The loop is also involved in Sdo1p recruitment for late-stage 60S maturation.\",\n      \"method\": \"Site-directed mutagenesis, rRNA chemical modification analysis (SHAPE/DMS), translation fidelity assays, genetic suppressor analysis, biochemical sedimentation assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (mutagenesis, chemical probing, genetic epistasis, biochemical assays), strong mechanistic resolution in single study\",\n      \"pmids\": [\"24214990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RPL10 is expressed in anterior neural structures in zebrafish; morpholino-mediated suppression of rpl10 decreases head size, reduces bulk translation, and increases apoptosis in the brain. The autism/intellectual disability mutation p.K78E (near the peptidyl transferase active site of the 60S subunit) is a loss-of-function variant by in vivo complementation, causing microcephaly.\",\n      \"method\": \"Morpholino knockdown in zebrafish, in vivo complementation assay, bulk translation measurement, apoptosis assay (TUNEL), whole-mount in situ hybridization\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in vivo (KD phenotype, translation measurement, complementation), independently confirms functional importance of N-terminal domain near peptidyl transferase center\",\n      \"pmids\": [\"25316788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A novel RPL10 missense mutation p.A64V (N-terminal domain) generates a functional ribosomal protein that complements translational defects of a conditional lethal yeast rpl10 mutation but, unlike previously reported mutations, increases rather than decreases the actively translating ribosome population, expanding the mechanistic spectrum of RPL10 mutations.\",\n      \"method\": \"Yeast complementation assay, polysome profiling\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional complementation plus polysome profiling, single lab\",\n      \"pmids\": [\"26290468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The recurrent T-ALL somatic mutation RPL10 R98S causes JAK-STAT pathway hyper-activation through: (1) proteome-level overexpression of JAK-STAT proteins, (2) reduction of programmed ribosomal frameshifting at frameshift signals within Jak-Stat mRNAs leading to altered protein output, and (3) decreased JAK1 degradation. RPL10 R98S cells also show reduced proteasome activity. The mutation is mutually exclusive with JAK-STAT pathway mutations in patients, suggesting functional equivalence.\",\n      \"method\": \"Quantitative proteomics, transgenic mouse model, T-ALL xenograft, ribosomal frameshifting reporter assay, cytokine stimulation/JAK-STAT signaling assay, drug sensitivity assay\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (proteomics, transgenic model, frameshifting assay, xenograft), replicated across engineered cells and patient samples\",\n      \"pmids\": [\"28744013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The murine autosomal retrogene Rpl10l (testis-specific) compensates for MSCI-mediated transcriptional silencing of X-linked Rpl10 in late-prophase spermatocytes. Loss of Rpl10l disrupts ribosome biogenesis in spermatocytes, blocking the prophase-to-metaphase transition of meiosis I and causing male infertility. Ectopic expression of RPL10L rescues RPL10-deficient somatic cells, and transgenic Rpl10 expression in spermatocytes restores fertility in Rpl10l-null mice.\",\n      \"method\": \"Knockout mouse model, transgenic rescue, ectopic expression in cultured cells, spermatocyte analysis, ribosome biogenesis assay\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with defined meiotic phenotype, multiple genetic rescue experiments confirming functional equivalence of RPL10 and RPL10L\",\n      \"pmids\": [\"28502657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RPL10 R98S mutant leukemia cells accumulate reactive oxygen species causing mitochondrial dysfunction and reduced ATP, impairing proliferation. Cells survive via specific upregulation of IRES-mediated translation of BCL-2 mRNA, leading to BCL-2 protein overexpression and resistance to apoptosis. RPL10 R98S cells show selective sensitivity to BCL-2 inhibitor Venetoclax.\",\n      \"method\": \"ROS measurement, mitochondrial function assays, IRES reporter assay, BCL-2 protein quantification, xenograft mouse model, drug sensitivity assay\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (metabolic assays, IRES reporter, xenograft), mechanistic link from ribosomal mutation to specific translational output demonstrated\",\n      \"pmids\": [\"29930300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"QM (RPL10) protein shows cytoplasmic localization consistent with ribosome association during mouse embryonic development, and is differentially expressed in developing tissues with an inverse relationship between QM expression and cell proliferative capacity in cartilage and skin, suggesting roles in differentiation-linked translational control.\",\n      \"method\": \"Whole-mount in situ hybridization, whole-mount immunohistochemistry, tissue section immunohistochemistry\",\n      \"journal\": \"Differentiation; research in biological diversity\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — localization without direct functional manipulation; correlative only\",\n      \"pmids\": [\"10234813\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RPL10 (QM) is an essential component of the 60S ribosomal large subunit whose eukaryote-specific internal loop controls intersubunit rotational dynamics during translational elongation, mediates late-stage 60S maturation by enabling Nmd3 release and Sdo1p recruitment, and whose oncogenic mutations (e.g., R98S) alter ribosomal frameshifting and IRES-dependent translation to dysregulate JAK-STAT signaling and BCL-2 expression in T-cell leukemia.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper before extracting discoveries.\n\n**Classification:**\n\nFrom the main corpus of 100 papers:\n- Papers 1, 2, 3, 4, 5, 6, 7, 10, 12, 14, 15, 16, 17, 18, 19, 22, 24, 25, 28, 29, 30, 31, 32, 33, 34, 35, 36, 40, 41, 42, 43, 44, 46, 47, 48, 49, 50, 52, 54, 55, 56, 59, 60, 61, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 → EXCLUDE (QM/MM methods, bacterial taxonomy, or off-target genes like NOV/CCN3)\n- Paper 8: KEEP (yeast Rpl10, ortholog, ribosomal life span)\n- Paper 9: KEEP (RPL10L compensating for RPL10 in meiosis — describes canonical RPL10 function)\n- Paper 11: KEEP (human RPL10, neurodevelopment/microcephaly)\n- Paper 13: KEEP (human RPL10, autism mutations)\n- Paper 20: KEEP (RPL10 R98S, JAK-STAT, T-ALL)\n- Paper 21: EXCLUDE (NOV/CCN3, not RPL10)\n- Paper 23: KEEP (yeast rpL10, ribosomal rotation)\n- Paper 26: EXCLUDE (NOV gene regulation by WT1)\n- Paper 27: KEEP (RPL10 R98S, BCL-2 IRES translation, T-ALL)\n- Paper 37: EXCLUDE (CCN3/NOV, calcium signaling)\n- Paper 38: KEEP (plant mitochondrial rpl10 — but plant/organelle context is fundamentally different from mammalian RPL10; EXCLUDE as symbol collision in plant organelles)\n- Paper 39: KEEP (QM protein = RPL10 human homolog, ribosome association)\n- Paper 45: KEEP (yeast Rpl10 mutational analysis)\n- Paper 51: KEEP (human RPL10 mutation, intellectual disability)\n- Paper 53: EXCLUDE (plant NbRPL10 — plant pathogen defense, incompatible context; symbol collision)\n- Paper 57: EXCLUDE (CCN3/NOV)\n- Paper 58: KEEP (yeast rpL10/Grc5p, ribosome biogenesis)\n- Paper 62: KEEP (QM/RPL10 in Trypanosoma — ortholog, ribosome)\n- Paper 72: KEEP (QM/RPL10 mouse development expression pattern)\n- Paper 75: KEEP (QM gene genomic organization, Xq28)\n\nFrom gene2pubmed papers:\n- Paper 30: KEEP (RPL10 R98S mutations in T-ALL, ribosome biogenesis defect)\n- Paper 19: KEEP (human/Drosophila 80S ribosome structure — includes RPL10 position)\n- Paper 27: KEEP (human ribosome structure)\n- Papers 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,20,21,22,23,24,25,26,28,29: These are large proteomics/interactome screens — RPL10 appears as one of thousands of proteins; these don't provide specific mechanistic findings about RPL10. EXCLUDE from discoveries (no specific RPL10 mechanism).\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"The human QM protein (RPL10) associates with the rough endoplasmic reticulum in a peripheral, salt-sensitive manner exposed on the cytoplasmic face of the membrane, and co-purifies with the ribosome complex, demonstrating it is a bona fide ribosomal protein component of a large protein complex.\",\n      \"method\": \"Indirect immunofluorescence, subcellular fractionation, proteolytic latency assay, in situ cross-linking with diagonal SDS-PAGE, ribosome co-purification\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal biochemical methods (fractionation, cross-linking, co-purification) in a single study with rigorous controls\",\n      \"pmids\": [\"9204867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"The QM gene (RPL10) is located at chromosomal locus Xq28, consists of at least 7 exons, belongs to a multi-gene family with members scattered across multiple chromosomes, and is ubiquitously expressed in adult human tissues with elevated expression in liver, spleen, testis, and adrenal gland.\",\n      \"method\": \"Southern blot, Northern blot, somatic cell hybrid panel analysis, cDNA sequencing\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct genomic mapping and expression analysis, single study\",\n      \"pmids\": [\"1339145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"QM (RPL10) is expressed in diverse embryonic tissues during mouse development, localizes to the cytoplasm consistent with ribosome association, is enriched in differentiating cells (chondrocytes, suprabasal keratinocytes) with an inverse relationship between expression level and proliferative capacity, and is absent from red blood cell precursors.\",\n      \"method\": \"Whole-mount in situ hybridization, whole-mount immunohistochemistry, immunohistochemistry on tissue sections\",\n      \"journal\": \"Differentiation; research in biological diversity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization by multiple imaging methods, single lab\",\n      \"pmids\": [\"10234813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The QM/RPL10 ortholog in Trypanosoma brucei co-localizes with the GPI:protein transamidase component GPI8, a distribution indicative of ribosome association with the rough endoplasmic reticulum, confirming conserved ribosomal function across distant eukaryotes.\",\n      \"method\": \"Epitope-tagged inducible expression, immunofluorescence microscopy\",\n      \"journal\": \"FEMS microbiology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — localization by immunofluorescence in a distant ortholog, single lab\",\n      \"pmids\": [\"12076801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Yeast rpL10/Grc5p functionally interacts with the nuclear export factor Nmd3p to modulate the cellular polysome complement, and interacts with small subunit protein rpS6 in ribosomal subunit joining and differential protein expression, establishing rpL10 as a multifunctional regulator operating in 60S biogenesis, nuclear export, and subunit joining.\",\n      \"method\": \"Genetic interaction analysis, polysome profiling, biochemical fractionation\",\n      \"journal\": \"FEMS yeast research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional epistasis and biochemical fractionation, single lab\",\n      \"pmids\": [\"15556089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Two missense mutations in RPL10 (L206M and H213Q) found in autism-spectrum disorder families confer hypomorphism in translational regulation while keeping basic translation intact, suggesting that altered translational function—not complete loss—can contribute to neurodevelopmental disorders. RPL10 is highly expressed in mouse hippocampus.\",\n      \"method\": \"Family-based genetic analysis, functional complementation assays in yeast measuring translational regulation\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional yeast complementation with mutagenesis, single lab\",\n      \"pmids\": [\"16940977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Heterozygous deletion of RPL10 (single-copy LSU gene) in yeast reduces the translating ribosome population and increases replicative life span by 24%, demonstrating that Rpl10 gene dosage regulates translation output and aging.\",\n      \"method\": \"Yeast replicative life span assay, polysome profiling, genetic deletion\",\n      \"journal\": \"Experimental gerontology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct functional assay with quantitative polysome profiling, single lab\",\n      \"pmids\": [\"17174052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Extensive mutagenesis of yeast Rpl10 revealed that a central loop (amino acids 102–112) is critical for release of the nuclear export adapter Nmd3 from the 60S subunit, while this loop is not required for stable ribosome binding, suggesting it plays a dynamic regulatory role. Rpl10 mutants unable to bind the ribosome accumulate in the nucleus, indicating an unexpected nuclear function for Rpl10.\",\n      \"method\": \"Systematic site-directed mutagenesis, genetic complementation, subcellular localization, Nmd3 release assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — extensive mutagenesis with multiple functional readouts (ribosome binding, Nmd3 release, localization), single study with strong mechanistic dissection\",\n      \"pmids\": [\"17761675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Exome sequencing identified recurrent somatic mutations in RPL10, particularly RPL10 R98S (Arg98Ser), in 9.8% of pediatric T-ALL cases. Yeast and lymphoid cells expressing the RPL10 R98S mutant showed a ribosome biogenesis defect, establishing RPL10 as a ribosomal protein whose mutation can drive oncogenesis.\",\n      \"method\": \"Exome sequencing, yeast functional complementation, ribosome biogenesis assay in lymphoid cells\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — discovery in large patient cohort confirmed by functional assays in two model systems, replicated across labs\",\n      \"pmids\": [\"23263491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"An internal loop in yeast rpL10 (positioned in the core of the large subunit) is a central controller of ribosomal intersubunit rotation between non-rotated and rotated states. Mutations in this loop promote opposing shifts in the rotational equilibrium and cause defects in catalysis, translation fidelity, and Sdo1p recruitment for late-stage 60S maturation. An rpL3 suppressor mutation restoring opposing structural effects rescued an rpL10 mutant by re-establishing rotational equilibrium, demonstrating allosteric communication from rpL10 through both subunits linking all functional centers.\",\n      \"method\": \"rRNA chemical modification (SHAPE/DMS probing), mutational analysis, genetic suppressor analysis, translation fidelity assays, biochemical maturation assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including chemical probing, mutagenesis, epistasis, and functional assays in a single study with strong mechanistic conclusions\",\n      \"pmids\": [\"24214990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"High-resolution cryo-EM structures of human and Drosophila 80S ribosomes reveal RPL10 (uL16) positioned within the large subunit, contributing to metazoan-specific ribosomal architecture and illustrating its co-evolution with rRNA.\",\n      \"method\": \"Single-particle cryo-electron microscopy, atomic model building\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution cryo-EM structure with atomic model, independently validated\",\n      \"pmids\": [\"23636399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A missense mutation in RPL10 (p.K78E) in the conserved N-terminal region near the peptidyl transferase active site causes X-linked microcephaly, growth retardation, and seizures. Suppression of rpl10 in zebrafish decreases head size, reduces bulk translation, and increases apoptosis in the brain; p.K78E is a loss-of-function variant confirmed by in vivo complementation, demonstrating RPL10 is essential for brain formation and function.\",\n      \"method\": \"X-linked intellectual disability sequencing panel, zebrafish morpholino knockdown, in vivo complementation, apoptosis assay, translation assay\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — human genetics plus zebrafish functional validation with multiple phenotypic readouts and in vivo complementation\",\n      \"pmids\": [\"25316788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A novel RPL10 missense mutation (p.A64V) in the N-terminal domain causes X-linked intellectual disability, cerebellar hypoplasia, and spondylo-epiphyseal dysplasia. Unlike other RPL10 mutations, p.A64V generates a functional ribosomal protein that increases (rather than decreases) the actively translating ribosome population in yeast, demonstrating that both gain and loss of translational output via RPL10 mutations can cause disease.\",\n      \"method\": \"X-exome resequencing, yeast complementation of conditional lethal rpl10 mutation, polysome profiling\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — human genetics with functional yeast validation and polysome profiling, single lab\",\n      \"pmids\": [\"26290468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Near-atomic (3.6 Å) cryo-EM structure of the human 80S ribosome reveals RPL10 (uL16) atomic details within the large subunit, including its position relative to tRNA binding sites and the subunit interface that remodels during rotational movements.\",\n      \"method\": \"High-resolution single-particle cryo-electron microscopy, atomic model building\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — near-atomic resolution structure with atomic model building\",\n      \"pmids\": [\"25901680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The RPL10 R98S mutation in T-ALL causes hyper-activation of the JAK-STAT signaling pathway upon cytokine stimulation by: (1) transcriptional upregulation of JAK-STAT proteins, (2) reduction of programmed ribosomal frameshifting at frameshift signals in JAK-STAT genes leading to altered protein isoform ratios, and (3) decreased JAK1 degradation. RPL10 R98S also reduces proteasome activity. The mutual exclusivity of RPL10 R98S with JAK-STAT mutations in T-ALL patients suggests functional equivalence.\",\n      \"method\": \"Proteome screen, transgenic Rpl10 R98S mouse model, T-ALL xenograft, cytokine stimulation assays, ribosomal frameshifting reporter assays, JAK-STAT inhibitor sensitivity assays\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal mechanisms demonstrated across mouse model, human xenograft, and cell lines with mechanistic assays including frameshift reporters\",\n      \"pmids\": [\"28744013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RPL10L (a testis-specific retrogene of RPL10) is required for spermatogenesis by compensating for RPL10, which is silenced by meiotic sex chromosome inactivation (MSCI) during spermatogenesis. Loss of Rpl10l disrupts ribosome biogenesis in late-prophase spermatocytes, blocking the prophase-to-metaphase transition. Ectopic expression of RPL10L prevents death of RPL10-deficient somatic cells, and transgenic Rpl10 expression in spermatocytes restores fertility in Rpl10l-null mice, proving functional equivalence.\",\n      \"method\": \"Knockout mouse model, transgenic rescue, ectopic expression in somatic cells, ribosome biogenesis assay, fertility assay\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic rescue experiments demonstrating functional equivalence, direct evidence for MSCI-based compensation mechanism\",\n      \"pmids\": [\"28502657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The RPL10 R98S mutation drives accumulation of reactive oxygen species, mitochondrial dysfunction, and reduced ATP, causing a proliferation defect. Mutant cells survive high oxidative stress via specific upregulation of IRES-dependent translation of BCL-2, leading to BCL-2 protein overexpression and conferring sensitivity to the BCL-2 inhibitor Venetoclax (ABT-199), validated in T-ALL xenograft mouse models.\",\n      \"method\": \"ROS measurement, mitochondrial function assays, IRES reporter assays, Venetoclax sensitivity assays, T-ALL xenograft mouse model\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway from mutation to IRES-mediated BCL-2 translation validated by multiple assays and in vivo xenograft model\",\n      \"pmids\": [\"29930300\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RPL10 (QM/uL16) is an essential component of the 60S large ribosomal subunit that occupies a position near the peptidyl transferase center and subunit interface; its internal loop drives intersubunit rotational dynamics allosterically linked to all ribosomal functional centers, it mediates late-stage 60S maturation by enabling Nmd3 release, and its loss-of-function (or altered-function) mutations cause ribosomopathies ranging from X-linked microcephaly and intellectual disability to T-ALL, where the recurrent R98S mutation drives oncogenesis through ribosomal frameshifting-mediated JAK-STAT hyper-activation and IRES-dependent BCL-2 upregulation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"RPL10 is an essential component of the 60S ribosomal large subunit that controls intersubunit rotational dynamics during translational elongation and mediates late-stage 60S maturation. Its eukaryote-specific internal loop governs the equilibrium between rotated and non-rotated ribosomal conformational states, allosterically affects rRNA structure at all functional centers, and is required for release of the nuclear export adapter Nmd3 and recruitment of the maturation factor Sdo1p [PMID:24214990, PMID:17761675]. The recurrent somatic mutation R98S, found in T-cell acute lymphoblastic leukemia, alters programmed ribosomal frameshifting to hyperactivate JAK-STAT signaling and upregulates IRES-dependent translation of BCL-2, conferring apoptosis resistance and selective sensitivity to the BCL-2 inhibitor venetoclax [PMID:28744013, PMID:29930300]. Missense mutations in RPL10 have also been identified as causative variants in X-linked intellectual disability, with functional validation showing loss-of-function effects on translational fidelity and brain development in zebrafish [PMID:25316788, PMID:16940977].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Establishing that RPL10 (QM) is a bona fide ribosomal protein resolved its identity as a structural component of the translational machinery rather than an independent tumor suppressor.\",\n      \"evidence\": \"Subcellular fractionation, in situ cross-linking, and ribosome co-purification from microsomal membranes\",\n      \"pmids\": [\"9204867\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise binding site on the ribosome unknown\", \"No structural data at atomic resolution\", \"Function beyond structural association not addressed\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstration that RPL10 functionally interacts with Nmd3p and rpS6 established it as a regulator of 60S nuclear export and 60S–40S subunit joining, moving beyond a purely structural role.\",\n      \"evidence\": \"Genetic interaction studies and polysome profiling in yeast\",\n      \"pmids\": [\"15556089\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physical interaction mechanism not determined\", \"No direct binding assays performed\", \"Pathway from RPL10 to differential protein expression unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Heterozygous RPL10 deletion reduced translating ribosomes and extended yeast lifespan, while disease-associated C-terminal mutations (L206M, H213Q) impaired translational fidelity without abolishing core translation, revealing that RPL10 dosage and specific domains modulate translational quality beyond basic ribosome function.\",\n      \"evidence\": \"Gene deletion, polysome profiling, replicative lifespan assay, and yeast complementation with translational readouts\",\n      \"pmids\": [\"17174052\", \"16940977\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking reduced RPL10 to longevity not defined\", \"Specific translational targets affected by C-terminal mutations unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Mapping RPL10 to the cleft between the central protuberance and GTPase-activating center, and identifying its central loop (aa 102–112) as required for Nmd3 release, defined the structural basis for RPL10's role in late 60S maturation.\",\n      \"evidence\": \"Extensive alanine-scanning and deletion mutagenesis with Nmd3 release assays and fluorescence microscopy in yeast\",\n      \"pmids\": [\"17761675\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct structural visualization of RPL10–Nmd3 interface lacking\", \"Whether RPL10 loading is the rate-limiting maturation step unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identifying the eukaryote-specific internal loop of RPL10 as a central controller of intersubunit rotation during elongation — with mutations allosterically reshaping rRNA across all functional centers — established RPL10 as a dynamic regulator of translational mechanics, not merely a passive structural element.\",\n      \"evidence\": \"Site-directed mutagenesis, SHAPE/DMS chemical probing of rRNA, translation fidelity assays, genetic suppressor analysis with rpL3 in yeast\",\n      \"pmids\": [\"24214990\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No single-molecule or cryo-EM visualization of rotational states caused by RPL10 mutations\", \"Quantitative contribution of RPL10 loop versus other factors to rotational equilibrium not measured\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"In vivo zebrafish studies confirmed that RPL10 is required for vertebrate brain development and bulk translation, and classified the intellectual-disability-associated K78E mutation as loss-of-function near the peptidyl transferase center.\",\n      \"evidence\": \"Morpholino knockdown, in vivo complementation, TUNEL apoptosis assay, and translation measurement in zebrafish\",\n      \"pmids\": [\"25316788\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which specific mRNAs are translationally affected in the developing brain remains unknown\", \"Whether microcephaly is solely due to reduced bulk translation or also translational fidelity defects not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Discovery that the T-ALL somatic mutation R98S hyperactivates JAK-STAT signaling by reducing programmed ribosomal frameshifting and decreasing JAK1 degradation revealed a direct oncogenic mechanism through altered translational regulation, while RPL10L was shown to compensate for X-linked RPL10 silencing during meiosis.\",\n      \"evidence\": \"Quantitative proteomics, transgenic mouse models, frameshifting reporters, xenograft studies (R98S); knockout and transgenic rescue mice (RPL10L)\",\n      \"pmids\": [\"28744013\", \"28502657\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether R98S alters ribosomal rotation states analogously to yeast internal-loop mutations not tested\", \"Structural basis for R98S-mediated frameshifting change unknown\", \"Whether RPL10L has any functional differences from RPL10 beyond expression pattern not determined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linking RPL10 R98S to mitochondrial dysfunction, ROS accumulation, and compensatory IRES-dependent BCL-2 upregulation explained the anti-apoptotic advantage of mutant leukemia cells and identified venetoclax sensitivity as a therapeutic vulnerability.\",\n      \"evidence\": \"ROS measurement, mitochondrial function assays, IRES reporter assays, BCL-2 quantification, xenograft drug sensitivity studies\",\n      \"pmids\": [\"29930300\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which RPL10 R98S ribosomes selectively enhance BCL-2 IRES activity not defined\", \"Whether other IRES-dependent mRNAs are similarly affected unknown\", \"In vivo clinical validation of venetoclax sensitivity in RPL10-mutant T-ALL pending\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the RPL10 internal loop structurally communicates with the peptidyl transferase center and decoding center to simultaneously control rotational dynamics, frameshifting fidelity, and IRES-dependent initiation remains unresolved at atomic resolution.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution cryo-EM structure of RPL10-mutant ribosomes in defined rotational states\", \"Comprehensive ribosome profiling of RPL10-mutant cells to identify the full spectrum of translationally affected mRNAs not performed\", \"Whether RPL10 mutations differentially affect cap-dependent versus IRES-dependent translation through the same or distinct mechanisms remains unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 3, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [0, 3, 5]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 11]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 3, 5, 6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8, 10]}\n    ],\n    \"complexes\": [\n      \"60S ribosomal large subunit\"\n    ],\n    \"partners\": [\n      \"NMD3\",\n      \"SDO1\",\n      \"RPL3\",\n      \"RPS6\",\n      \"BCL2\",\n      \"JAK1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"RPL10 (uL16) is an essential component of the 60S large ribosomal subunit whose internal loop governs intersubunit rotational dynamics, allosterically linking the peptidyl transferase center, tRNA binding sites, and subunit interface to regulate translation fidelity, catalysis, and late-stage 60S maturation through Nmd3 release [PMID:24214990, PMID:17761675]. High-resolution cryo-EM structures position RPL10 at the core of the large subunit near the peptidyl transferase center, consistent with its role as a dynamic regulator rather than a passive structural element [PMID:23636399, PMID:25901680]. Loss-of-function mutations (K78E, A64V, L206M) cause X-linked microcephaly, intellectual disability, and skeletal dysplasia by perturbing translational output, while the recurrent somatic R98S mutation drives pediatric T-ALL through JAK-STAT hyper-activation via altered programmed ribosomal frameshifting and IRES-dependent BCL-2 upregulation that confers sensitivity to Venetoclax [PMID:25316788, PMID:26290468, PMID:23263491, PMID:28744013, PMID:29930300]. A testis-specific retrogene, RPL10L, compensates for RPL10 silencing during meiotic sex chromosome inactivation in spermatogenesis, and the two proteins are functionally interchangeable [PMID:28502657].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Establishing RPL10 as a ubiquitously expressed X-linked gene answered the basic question of genomic location and tissue distribution, placing it at Xq28 with a multi-gene family.\",\n      \"evidence\": \"Southern/Northern blot and somatic cell hybrid mapping of human QM/RPL10\",\n      \"pmids\": [\"1339145\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Protein-level function not addressed\", \"Processed pseudogene family not functionally characterized\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Demonstrating that QM/RPL10 co-purifies with ribosomes and localizes to rough ER settled the long-debated question of whether QM is a genuine ribosomal protein rather than a standalone tumor suppressor.\",\n      \"evidence\": \"Subcellular fractionation, in situ cross-linking, ribosome co-purification from human cells\",\n      \"pmids\": [\"9204867\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific position within the ribosome unknown\", \"No structure available\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Genetic interactions of yeast Rpl10 with the export adapter Nmd3 and the small subunit protein rpS6 revealed that Rpl10 functions beyond steady-state translation in 60S biogenesis, nuclear export, and subunit joining.\",\n      \"evidence\": \"Genetic epistasis analysis and polysome profiling in S. cerevisiae\",\n      \"pmids\": [\"15556089\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of Nmd3 release not defined\", \"Direct physical interaction with rpS6 not confirmed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Systematic mutagenesis of the Rpl10 internal loop (residues 102–112) showed it is required for Nmd3 release from the 60S subunit but dispensable for stable ribosome binding, defining a specific regulatory role in late-stage 60S maturation distinct from structural incorporation.\",\n      \"evidence\": \"Site-directed mutagenesis, Nmd3 release assay, subcellular localization in yeast\",\n      \"pmids\": [\"17761675\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of loop-mediated Nmd3 release unknown\", \"Whether the mechanism is conserved in metazoans untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Chemical probing and suppressor genetics showed that the Rpl10 internal loop controls the global rotational equilibrium between non-rotated and rotated ribosome states, allosterically coupling all functional centers and linking Rpl10 to translation fidelity and Sdo1-dependent maturation.\",\n      \"evidence\": \"SHAPE/DMS rRNA probing, genetic suppressor analysis with rpL3, translation fidelity and maturation assays in yeast\",\n      \"pmids\": [\"24214990\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution view of loop conformational states lacking\", \"Contribution of individual loop residues to rotational bias unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Cryo-EM structures of the human and Drosophila 80S ribosome provided the first atomic context for RPL10 within the large subunit, confirming its position near the peptidyl transferase center and subunit interface.\",\n      \"evidence\": \"Single-particle cryo-EM at sub-nanometer to near-atomic resolution\",\n      \"pmids\": [\"23636399\", \"25901680\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dynamics of RPL10 loop not captured in static structures\", \"Mutant ribosome structures not available\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of recurrent somatic RPL10 R98S mutations in ~10% of pediatric T-ALL established RPL10 as the first ribosomal protein with a recurrent oncogenic point mutation, connecting ribosome function to leukemogenesis.\",\n      \"evidence\": \"Exome sequencing of T-ALL patient cohort, yeast and lymphoid cell functional validation\",\n      \"pmids\": [\"23263491\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream oncogenic mechanism not yet defined at this stage\", \"Contribution to clonal fitness versus initiation unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Discovery that RPL10 K78E causes X-linked microcephaly and that zebrafish rpl10 depletion recapitulates brain size reduction and apoptosis demonstrated RPL10 is essential for brain development, defining the first Mendelian ribosomopathy linked to RPL10.\",\n      \"evidence\": \"Human XLID sequencing, zebrafish morpholino knockdown with in vivo complementation\",\n      \"pmids\": [\"25316788\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which neural cell types are most sensitive unknown\", \"Whether apoptosis is p53-dependent not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The RPL10 A64V mutation, which paradoxically increases translating ribosomes, demonstrated that both gain and loss of translational output through RPL10 can cause neurodevelopmental disease, broadening the pathogenic spectrum.\",\n      \"evidence\": \"X-exome sequencing, yeast complementation, polysome profiling\",\n      \"pmids\": [\"26290468\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which increased translation causes pathology unknown\", \"No direct translatomic data from patient cells\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Mechanistic dissection of RPL10 R98S in T-ALL revealed that the mutation converges on JAK-STAT hyper-activation through three independent routes: transcriptional upregulation, altered programmed ribosomal frameshifting at JAK-STAT mRNAs, and reduced JAK1 proteasomal degradation.\",\n      \"evidence\": \"Proteomics, transgenic Rpl10 R98S mouse, T-ALL xenograft, frameshifting reporters, JAK-STAT inhibitor assays\",\n      \"pmids\": [\"28744013\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct structural basis for how R98S alters frameshifting efficiency not resolved\", \"Whether other signaling pathways are similarly affected unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Discovery that the testis-specific retrogene RPL10L is essential for spermatogenesis by compensating for RPL10 silencing during MSCI revealed a unique gene dosage compensation mechanism and confirmed functional equivalence of the two paralogs.\",\n      \"evidence\": \"Rpl10l knockout and transgenic Rpl10 rescue in mice, ectopic expression in somatic cells\",\n      \"pmids\": [\"28502657\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether RPL10L has any unique ribosomal properties not addressed\", \"Mechanism of RPL10L transcriptional activation post-MSCI unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"RPL10 R98S was shown to cause mitochondrial dysfunction and ROS accumulation, which cells bypass through IRES-dependent overexpression of BCL-2, creating a therapeutic vulnerability to Venetoclax in T-ALL.\",\n      \"evidence\": \"ROS and mitochondrial assays, IRES reporters, Venetoclax treatment of T-ALL xenografts\",\n      \"pmids\": [\"29930300\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Venetoclax sensitivity extends to all RPL10-mutant leukemias untested in clinical trials\", \"Identity of specific IRES trans-acting factors mediating BCL-2 upregulation unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the atomic-resolution mechanism by which the RPL10 internal loop switches between conformational states to drive intersubunit rotation, the full translatomic consequences of disease-associated RPL10 mutations in human cells, and whether RPL10-mutant ribosomes produce a qualitatively distinct proteome ('specialized ribosomes').\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No cryo-EM structure of mutant RPL10-containing ribosomes\", \"No ribosome profiling data comparing wild-type and mutant RPL10 in human cells\", \"Specialized ribosome hypothesis not directly tested for RPL10\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 10, 13]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [9, 14, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [0, 10, 13]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 9, 10, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8, 14, 16]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"complexes\": [\n      \"60S large ribosomal subunit\",\n      \"80S ribosome\"\n    ],\n    \"partners\": [\n      \"NMD3\",\n      \"RPL3\",\n      \"RPS6\",\n      \"SDO1\",\n      \"BCL2\",\n      \"RPL10L\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}