{ "$schema_version": "5.3", "review_mode": "fresh", "claim_restatement": { "index_wording": "Liquid–Liquid Phase Separation in Nuclear Bodies", "entry_form": "phenomenon", "gradeable_restatement": "Liquid–liquid phase separation assembles and organizes nuclear bodies in living cells, and the liquid state itself confers their compositional and functional properties.", "restatement_required": true, "split_into": [], "parent_claim": null, "scope_qualifiers": [ { "qualifier": "Body class, constituent, timescale, species/cell state, expression level, scaffold/interaction architecture and endogenous versus synthetic intervention", "determinable_before_outcome": true, "determined_from": "Enrollment and experimental design, before results; no responder-defined scope.", "action": "retained" } ] }, "hypothesis": { "name": "Liquid–Liquid Phase Separation in Nuclear Bodies", "central_claim": "Liquid–liquid phase separation assembles and organizes nuclear bodies in living cells, and the liquid state itself confers their compositional and functional properties.", "proposed_mechanism": "Liquid–liquid phase separation assembles and organizes nuclear bodies in living cells, and the liquid state itself confers their compositional and functional properties.", "claimed_scope": "Endogenous nuclear-body assembly and state-specific composition/function, with nucleolar phases, speckles, paraspeckles, Cajal and PML bodies kept distinct.", "claimed_level": [ "assembly", "organization", "function" ], "is_conjunctive": true, "conjunctive_note": "Use the dedicated nuclear-body index entry, distinct from transcriptional condensates and pathological RBP solidification. Register weakest-link across the broad claim while reporting body-class-specific causal results; generalized failure does not downgrade a separately scoped success." }, "rubric_routing": { "primary_rubric": "03-epigenetics-gene-regulation.md", "secondary_rubrics": [], "index_notes_applied": [ "Use the dedicated nuclear-body index entry, distinct from transcriptional condensates and pathological RBP solidification. Register weakest-link across the broad claim while reporting body-class-specific causal results; generalized failure does not downgrade a separately scoped success." ], "rubric_fit_note": "Exact archived v5.3 framework. Any stale index empirical framing is rechecked against primary results." }, "subclaim_matrix": { "subclaims": [ { "id": "SC1", "statement": "Macroscopic liquid–liquid demixing occurs in nuclear bodies at endogenous concentrations.", "subclaim_type": "existence", "scope": "nucleoli, speckles, paraspeckles and other named body classes", "claimed_scope": "nucleoli, speckles, paraspeckles and other named body classes", "governing_rubric": "03-epigenetics-gene-regulation.md", "key_evidence_anchor": "Endogenous saturation/partitioning and physical-state controls", "hsef_level": "Ε", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Ε: endogenous nucleolar demixing and composition-dependent physical organization have context-specific causal support, with native concentration/phase controls. This scoped existence success does not extend identically to all classes or constituents." }, { "id": "SC2", "statement": "The liquid state, beyond multivalent assembly, organizes nuclear-body composition and function.", "subclaim_type": "mechanism", "scope": "state-specific endogenous body perturbations", "claimed_scope": "state-specific endogenous body perturbations", "governing_rubric": "03-epigenetics-gene-regulation.md", "key_evidence_anchor": "Interaction/function-matched material-state change and rescue", "hsef_level": "Δ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Δ: endogenous NPM1 opto-gelation alters specific pre-rRNA processing relative to light controls; emerging charge/domain tests add support. Liquidity-only matched functional rescue and broader body classes remain unresolved, preventing a general necessity inference." }, { "id": "SC3", "statement": "LLPS is the common organizing physics across nuclear-body classes.", "subclaim_type": "generalization", "scope": "body classes and conditions specified before outcomes", "claimed_scope": "body classes and conditions specified before outcomes", "governing_rubric": "03-epigenetics-gene-regulation.md", "key_evidence_anchor": "Orthogonal demixing versus polymer/stoichiometric/scaffold tests", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Γ: class-general LLPS remains a mechanistic model, constrained by endogenous paraspeckle micelle tests, RNA-gel/partly solid nucleolar measurements and scaffold/binding alternatives. Restricted successes cannot establish common physics." } ], "aggregation_rule": "weakest-link", "aggregation_preregistered": true, "aggregation_rationale": "Use the dedicated nuclear-body index entry, distinct from transcriptional condensates and pathological RBP solidification. Register weakest-link across the broad claim while reporting body-class-specific causal results; generalized failure does not downgrade a separately scoped success.", "primary_subclaim_id": "SC2", "aggregation_derivation": "Preregistered weakest-link aggregation returns Γ from SC3 common organizing physics, despite scoped SC1 Ε and SC2 Δ. Primary SC2 and its scope-matched sensitivity return Δ; broad class-general scope remains Γ. This does not downgrade genuine nucleolar demixing or functional material-property contributions.", "aggregation_alternatives": { "weakest_link_would_return": "Γ", "primary_subclaim_would_return": "Δ", "scope_matched_would_return": "Δ", "note": "Separate narrow successes do not replace the preregistered gate." }, "index_rule_deviation": "" }, "competing_models": { "models_evaluated": [ { "rank_in_tournament": 1, "model_id": "M2", "is_nominal": false, "name": "Pluralist soft-matter mechanisms", "core_claim": "Demixing, percolation, polymer scaffolding, RNA maturation and active production cooperate differently by body/constituent.", "explains_what_nominal_does_not": "Demixing, percolation, polymer scaffolding, RNA maturation and active production cooperate differently by body/constituent.", "strongest_supporting_evidence": [ "Endogenous micelle deletions, endogenous opto-gel processing, RNA transport and near-native aspiration: PMID33885174,31399547,37683610,40434645." ], "strongest_contradictory_evidence": [ "Pluralism is broad rather than one complete predictive model; independent state-only functional rescues remain sparse." ], "hsef_level_for_this_model": "Ε", "rationale": "Endogenous micelle deletions, endogenous opto-gel processing, RNA transport and near-native aspiration: PMID33885174,31399547,37683610,40434645. Pluralism is broad rather than one complete predictive model; independent state-only functional rescues remain sparse." }, { "rank_in_tournament": 2, "model_id": "M1", "is_nominal": true, "name": "Macroscopic LLPS", "core_claim": "Common demixing and liquid material state organize all named nuclear-body classes.", "explains_what_nominal_does_not": "Common demixing and liquid material state organize all named nuclear-body classes.", "strongest_supporting_evidence": [ "Native nucleolar physical data, worm phase predictions, composition/partition and speckle/PML contrasts: PMID27212236,26351690,32405004,38381607,37219517." ], "strongest_contradictory_evidence": [ "Paraspeckle micelles, functional partially solid compartments and nondiagnostic phenomenology prevent universal inference." ], "hsef_level_for_this_model": "Γ", "rationale": "Native nucleolar physical data, worm phase predictions, composition/partition and speckle/PML contrasts: PMID27212236,26351690,32405004,38381607,37219517. Paraspeckle micelles, functional partially solid compartments and nondiagnostic phenomenology prevent universal inference." }, { "rank_in_tournament": 3, "model_id": "M3", "is_nominal": false, "name": "RNA block-copolymer micelles", "core_claim": "NEAT1 architecture constrains paraspeckle geometry through microphase separation.", "explains_what_nominal_does_not": "NEAT1 architecture constrains paraspeckle geometry through microphase separation.", "strongest_supporting_evidence": [ "Expression-matched end deletions plus size/shape/transcription predictions: PMID33885174; assembly/tether framework PMID29932899." ], "strongest_contradictory_evidence": [ "Shared HAP1/investigator platform; restricted paraspeckle geometry does not explain other bodies or all functions." ], "hsef_level_for_this_model": "Ε", "rationale": "Expression-matched end deletions plus size/shape/transcription predictions: PMID33885174; assembly/tether framework PMID29932899. Shared HAP1/investigator platform; restricted paraspeckle geometry does not explain other bodies or all functions." }, { "rank_in_tournament": 4, "model_id": "M5", "is_nominal": false, "name": "Dynamic gel/polymer scaffolds", "core_claim": "RNA/protein networks can support rapid small-protein diffusion while constraining large substrates.", "explains_what_nominal_does_not": "RNA/protein networks can support rapid small-protein diffusion while constraining large substrates.", "strongest_supporting_evidence": [ "Native RNA dynamics, RNase/aspiration and opto-gel mesh contrast: PMID37683610,40434645,31399547." ], "strongest_contradictory_evidence": [ "Timescale/probe-dependent and mixed with liquid phases; static scaffold is not a universal body explanation." ], "hsef_level_for_this_model": "Ε", "rationale": "Native RNA dynamics, RNase/aspiration and opto-gel mesh contrast: PMID37683610,40434645,31399547. Timescale/probe-dependent and mixed with liquid phases; static scaffold is not a universal body explanation." }, { "rank_in_tournament": 5, "model_id": "M4", "is_nominal": false, "name": "Polymer bridging or clustered binding", "core_claim": "DNA/RNA scaffolds can concentrate proteins without autonomous bulk demixing.", "explains_what_nominal_does_not": "DNA/RNA scaffolds can concentrate proteins without autonomous bulk demixing.", "strongest_supporting_evidence": [ "Cohesin DNA-length dependence, HSV PolII binding and half-FRAP benchmarks: PMID33568486,31038454,36526633." ], "strongest_contradictory_evidence": [ "Comparator systems do not establish that every canonical body forms by BIPS; stronger direct native-body tests required." ], "hsef_level_for_this_model": "Δ", "rationale": "Cohesin DNA-length dependence, HSV PolII binding and half-FRAP benchmarks: PMID33568486,31038454,36526633. Comparator systems do not establish that every canonical body forms by BIPS; stronger direct native-body tests required." } ], "tournament_summary": "Descriptive comparison; does not modify the nominal score. Compare locked, body-specific predictions with a reversible endogenous material-state edit that preserves client binding, enzyme abundance and RNA output, paired with direct rheology/interfacial measures and functional rescue.", "study_separating_rank1_from_rank2": "Compare locked, body-specific predictions with a reversible endogenous material-state edit that preserves client binding, enzyme abundance and RNA output, paired with direct rheology/interfacial measures and functional rescue.", "nominal_wins_only_by_funding_artifact": false, "level_unchanged_by_tournament": true }, "evidence_inventory": [ { "n": 1, "pmid": "27212236", "title": "Coexisting Liquid Phases Underlie Nucleolar Subcompartments.", "citation": "Feric M, Vaidya N, Harmon TS et al. Coexisting Liquid Phases Underlie Nucleolar Subcompartments. Cell. 2016.", "doi": "10.1016/j.cell.2016.04.047", "pmcid": "PMC5127388", "url": "https://pubmed.ncbi.nlm.nih.gov/27212236/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27212236/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID27212236", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph2, 1:Results:paragraph3, 1:Results:paragraph11, 1:Results:paragraph13, 1:Results:paragraph15, 1:Results:paragraph17, 1:Results:paragraph18. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "frog/mammalian cells and reconstitution", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Nucleolar GC/DFC have distinct fusion dynamics, low surface tension and reconstituted immiscible phases; concentration/domain manipulations alter organization.", "what_it_does_not_show": "Injection and domain changes affect binding/valency; FIB1 deletion can localize by native co-recruitment. Assembly physics does not alone prove function requires liquid state.", "confounders_present": [ "Injection and domain changes affect binding/valency; FIB1 deletion can localize by native co-recruitment. Assembly physics does not alone prove function requires liquid state." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 2, "pmid": "36755093", "title": "Aberrant phase separation and nucleolar dysfunction in rare genetic diseases.", "citation": "Mensah MA, Niskanen H, Magalhaes AP et al. Aberrant phase separation and nucleolar dysfunction in rare genetic diseases. Nature. 2023.", "doi": "10.1038/s41586-022-05682-1", "pmcid": "PMC9931588", "url": "https://pubmed.ncbi.nlm.nih.gov/36755093/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36755093/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID36755093", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human natural variant and cell experiments", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "HMGB1 frameshifts replace an acidic tail with basic residues, cause nucleolar mispartitioning and alter rRNA biogenesis; 12/13 tested variants enhance partitioning.", "what_it_does_not_show": "Charge, interaction targets and location change together; not liquidity-only loss/rescue across body classes.", "confounders_present": [ "Charge, interaction targets and location change together; not liquidity-only loss/rescue across body classes." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 3, "pmid": "30500535", "title": "Liquid Nuclear Condensates Mechanically Sense and Restructure the Genome.", "citation": "Shin Y, Chang YC, Lee DSW et al. Liquid Nuclear Condensates Mechanically Sense and Restructure the Genome. Cell. 2018.", "doi": "10.1016/j.cell.2018.10.057", "pmcid": "PMC6724728", "url": "https://pubmed.ncbi.nlm.nih.gov/30500535/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30500535/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID30849377" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID30500535", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "synthetic locus-targeted cell condensates", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "CasDrop optogenetic condensates exclude/pull chromatin and prefer softer genomic regions.", "what_it_does_not_show": "Engineered IDR/optogenetic assembly, not unmodified endogenous nuclear bodies; linked erratum PMID30849377 details unexamined.", "confounders_present": [ "Engineered IDR/optogenetic assembly, not unmodified endogenous nuclear bodies; linked erratum PMID30849377 details unexamined." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 4, "pmid": "32405004", "title": "Composition-dependent thermodynamics of intracellular phase separation.", "citation": "Riback JA, Zhu L, Ferrolino MC et al. Composition-dependent thermodynamics of intracellular phase separation. Nature. 2020.", "doi": "10.1038/s41586-020-2256-2", "pmcid": "PMC7733533", "url": "https://pubmed.ncbi.nlm.nih.gov/32405004/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32405004/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID32405004", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Main text:paragraph0, 2:Main text:paragraph3, 2:Main text:paragraph4, 2:Main text:paragraph5, 2:Main text:paragraph6, 2:Main text:paragraph7. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "living human cells and biomimetic controls", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Dense/dilute concentration and transfer-energy measurements show heterotypic composition-dependent partitioning; fixed single-component saturation is absent, with RNA/transcription and valency contrasts.", "what_it_does_not_show": "Increased expression and ActD influence substrate supply; multicomponent nonfixed saturation is not disproof of LLPS, while partitioning is not liquid-state functional rescue.", "confounders_present": [ "Increased expression and ActD influence substrate supply; multicomponent nonfixed saturation is not disproof of LLPS, while partitioning is not liquid-state functional rescue." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 5, "pmid": "38503281", "title": "Macromolecular condensation organizes nucleolar sub-phases to set up a pH gradient.", "citation": "King MR, Ruff KM, Lin AZ et al. Macromolecular condensation organizes nucleolar sub-phases to set up a pH gradient. Cell. 2024.", "doi": "10.1016/j.cell.2024.02.029", "pmcid": "PMC11938373", "url": "https://pubmed.ncbi.nlm.nih.gov/38503281/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38503281/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID38503281", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "cell and reconstitution chemistry", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Charge patterns and RNA binding organize subphases and nucleolar pH gradients.", "what_it_does_not_show": "Binding/coacervation/composition vary together; a pH difference does not uniquely identify liquidity-dependent biological output.", "confounders_present": [ "Binding/coacervation/composition vary together; a pH difference does not uniquely identify liquidity-dependent biological output." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 6, "pmid": "38745030", "title": "Phase separation-competent FBL promotes early pre-rRNA processing and translation in acute myeloid leukaemia.", "citation": "Yang L, Zhang Z, Jiang P et al. Phase separation-competent FBL promotes early pre-rRNA processing and translation in acute myeloid leukaemia. Nature cell biology. 2024.", "doi": "10.1038/s41556-024-01420-z", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/38745030/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38745030/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID38745030", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Publisher HTML paragraphs:paragraph202, 0:Publisher HTML paragraphs:paragraph204, 0:Publisher HTML paragraphs:paragraph206, 0:Publisher HTML paragraphs:paragraph208, 0:Publisher HTML paragraphs:paragraph212. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "AML depletion/rescue and mouse screen", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "FBL domain rescues link condensation-competent architecture to growth and rRNA processing; public extended-data captions report failed hnRNPA1-PLD substitution and retained FRAP for catalytic mutants.", "what_it_does_not_show": "Main body/supplements not accessible; only original extended-data captions examined. Phase competence alone is insufficient in the failed PLD rescue, and drug/charge/binding specificity remains.", "confounders_present": [ "Main body/supplements not accessible; only original extended-data captions examined. Phase competence alone is insufficient in the failed PLD rescue, and drug/charge/binding specificity remains." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 7, "pmid": "33522570", "title": "Phase transition of fibrillarin LC domain regulates localization and protein interaction of fibrillarin.", "citation": "Kim E, Kwon I et al. Phase transition of fibrillarin LC domain regulates localization and protein interaction of fibrillarin. The Biochemical journal. 2021.", "doi": "10.1042/BCJ20200847", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/33522570/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33522570/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID33522570", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "reconstitution and expressed cellular mutants", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "FBL phenylalanine substitutions impair liquid/hydrogel assembly, DFC location and partner interactions.", "what_it_does_not_show": "Both hydrogel and liquid states fail alongside binding; expressed mutant is not endogenous liquidity-only rescue.", "confounders_present": [ "Both hydrogel and liquid states fail alongside binding; expressed mutant is not endogenous liquidity-only rescue." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 8, "pmid": "31296649", "title": "The nucleolus functions as a phase-separated protein quality control compartment.", "citation": "Frottin F, Schueder F, Tiwary S et al. The nucleolus functions as a phase-separated protein quality control compartment. Science (New York, N.Y.). 2019.", "doi": "10.1126/science.aaw9157", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/31296649/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31296649/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID31296649", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "stressed mammalian culture", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Misfolded proteins enter nucleolar GC, with Hsp70-dependent recovery and prolonged-stress solidification/quality-control failure.", "what_it_does_not_show": "Stress, chaperone function and damage vary together; no isolated material-state requirement at normal homeostasis.", "confounders_present": [ "Stress, chaperone function and damage vary together; no isolated material-state requirement at normal homeostasis." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 9, "pmid": "31540874", "title": "Nascent Pre-rRNA Sorting via Phase Separation Drives the Assembly of Dense Fibrillar Components in the Human Nucleolus.", "citation": "Yao RW, Xu G, Wang Y et al. Nascent Pre-rRNA Sorting via Phase Separation Drives the Assembly of Dense Fibrillar Components in the Human Nucleolus. Molecular cell. 2019.", "doi": "10.1016/j.molcel.2019.08.014", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/31540874/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31540874/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID31540874", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human cell RNA sorting", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "FBL RNA binding/GAR self-association organizes nascent pre-rRNA traffic and DFC clusters.", "what_it_does_not_show": "RNA binding, self-association and localization are coupled; functional condensate contribution does not show simple-liquid exclusivity.", "confounders_present": [ "RNA binding, self-association and localization are coupled; functional condensate contribution does not show simple-liquid exclusivity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 10, "pmid": "34315935", "title": "Size conservation emerges spontaneously in biomolecular condensates formed by scaffolds and surfactant clients.", "citation": "Sanchez-Burgos I, Joseph JA, Collepardo-Guevara R et al. Size conservation emerges spontaneously in biomolecular condensates formed by scaffolds and surfactant clients. Scientific reports. 2021.", "doi": "10.1038/s41598-021-94309-y", "pmcid": "PMC8316449", "url": "https://pubmed.ncbi.nlm.nih.gov/34315935/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34315935/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID34315935", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "original molecular simulation comparator", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Scaffold/surfactant-client simulations yield size-conserved multiple droplets or coarsening depending on ratio.", "what_it_does_not_show": "Computational existence of size arrest is not endogenous body demonstration; lack of coalescence alone cannot rule out liquids.", "confounders_present": [ "Computational existence of size arrest is not endogenous body demonstration; lack of coalescence alone cannot rule out liquids." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 11, "pmid": "21368180", "title": "Active liquid-like behavior of nucleoli determines their size and shape in Xenopus laevis oocytes.", "citation": "Brangwynne CP, Mitchison TJ, Hyman AA et al. Active liquid-like behavior of nucleoli determines their size and shape in Xenopus laevis oocytes. Proceedings of the National Academy of Sciences of the United States of America. 2011.", "doi": "10.1073/pnas.1017150108", "pmcid": "PMC3060270", "url": "https://pubmed.ncbi.nlm.nih.gov/21368180/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21368180/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID21368180", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "frog oocyte physical measurement", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Native nucleoli undergo fusion, deformation and ATP-sensitive viscous relaxation with coalescence-linked size distributions.", "what_it_does_not_show": "Large amphibian oocytes are a restricted physical context; dynamic fluidity is not alone functional-state necessity.", "confounders_present": [ "Large amphibian oocytes are a restricted physical context; dynamic fluidity is not alone functional-state necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 12, "pmid": "34819511", "title": "Chromatin network retards nucleoli coalescence.", "citation": "Qi Y, Zhang B et al. Chromatin network retards nucleoli coalescence. Nature communications. 2021.", "doi": "10.1038/s41467-021-27123-9", "pmcid": "PMC8613291", "url": "https://pubmed.ncbi.nlm.nih.gov/34819511/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34819511/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID34819511", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "original human-genome simulation comparator", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Hi-C-parameterized genome simulations predict nucleolar nucleation/arrest and a metastable two-droplet state.", "what_it_does_not_show": "Model agreement with physical measures does not prove all nuclear bodies demix; chromatin arrest can mimic non-coarsening phenotypes.", "confounders_present": [ "Model agreement with physical measures does not prove all nuclear bodies demix; chromatin arrest can mimic non-coarsening phenotypes." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 13, "pmid": "33885174", "title": "Paraspeckles are constructed as block copolymer micelles.", "citation": "Yamazaki T, Yamamoto T, Yoshino H et al. Paraspeckles are constructed as block copolymer micelles. The EMBO journal. 2021.", "doi": "10.15252/embj.2020107270", "pmcid": "PMC8204865", "url": "https://pubmed.ncbi.nlm.nih.gov/33885174/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33885174/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID33885174", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Publisher HTML paragraphs:paragraph24, 0:Publisher HTML paragraphs:paragraph28, 0:Publisher HTML paragraphs:paragraph29, 0:Publisher HTML paragraphs:paragraph30, 0:Publisher HTML paragraphs:paragraph31, 0:Publisher HTML paragraphs:paragraph33. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "endogenous human RNA domain deletion", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "NEAT1 end deletions at comparable expression remove core-shell order, enlarge and round paraspeckles; WT versus mutant transcription responses fit micelle predictions.", "what_it_does_not_show": "Restricted HAP1/mutant model; micellization is microphase separation, not absence of all phase behavior. RNA-domain changes can alter interactions, and global function not tested.", "confounders_present": [ "Restricted HAP1/mutant model; micellization is microphase separation, not absence of all phase behavior. RNA-domain changes can alter interactions, and global function not tested." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 14, "pmid": "29932899", "title": "Functional Domains of NEAT1 Architectural lncRNA Induce Paraspeckle Assembly through Phase Separation.", "citation": "Yamazaki T, Souquere S, Chujo T et al. Functional Domains of NEAT1 Architectural lncRNA Induce Paraspeckle Assembly through Phase Separation. Molecular cell. 2018.", "doi": "10.1016/j.molcel.2018.05.019", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/29932899/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29932899/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID29932899", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "endogenous RNA deletion and tether rescue", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "CRISPR NEAT1-domain deletion and NONO dimer-domain-dependent tether rescue establish multivalent assembly; selected fragments form in vitro aggregates.", "what_it_does_not_show": "RNA-protein enrichment/assembly rescue, with hexanediol sensitivity, does not distinguish a liquid state from micelle/polymer-scaffold organization.", "confounders_present": [ "RNA-protein enrichment/assembly rescue, with hexanediol sensitivity, does not distinguish a liquid state from micelle/polymer-scaffold organization." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 15, "pmid": "27646274", "title": "Structural, super-resolution microscopy analysis of paraspeckle nuclear body organization.", "citation": "West JA, Mito M, Kurosaka S et al. Structural, super-resolution microscopy analysis of paraspeckle nuclear body organization. The Journal of cell biology. 2016.", "doi": "10.1083/jcb.201601071", "pmcid": "PMC5037409", "url": "https://pubmed.ncbi.nlm.nih.gov/27646274/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27646274/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID27646274", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "cell super-resolution and FUS loss", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Paraspeckles have ordered radial core-shell NEAT1/protein organization; FUS loss fragments them.", "what_it_does_not_show": "Radial morphology and loss of scaffold cohesion do not alone distinguish all physical models or establish material-state function.", "confounders_present": [ "Radial morphology and loss of scaffold cohesion do not alone distinguish all physical models or establish material-state function." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 16, "pmid": "28404604", "title": "Unusual semi-extractability as a hallmark of nuclear body-associated architectural noncoding RNAs.", "citation": "Chujo T, Yamazaki T, Kawaguchi T et al. Unusual semi-extractability as a hallmark of nuclear body-associated architectural noncoding RNAs. The EMBO journal. 2017.", "doi": "10.15252/embj.201695848", "pmcid": "PMC5430218", "url": "https://pubmed.ncbi.nlm.nih.gov/28404604/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28404604/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID28404604", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "RNA extraction perturbation", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Needle shearing/heating improves NEAT1 recovery about 20-fold; FUS prion-like interactions affect semi-extractability.", "what_it_does_not_show": "Extraction tenacity and estimated transcript numbers do not measure liquid versus gel state in living cells.", "confounders_present": [ "Extraction tenacity and estimated transcript numbers do not measure liquid versus gel state in living cells." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 17, "pmid": "30180948", "title": "CRISPRa-mediated NEAT1 lncRNA upregulation induces formation of intact paraspeckles.", "citation": "Yamazaki T, Fujikawa C, Kubota A et al. CRISPRa-mediated NEAT1 lncRNA upregulation induces formation of intact paraspeckles. Biochemical and biophysical research communications. 2018.", "doi": "10.1016/j.bbrc.2018.08.158", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/30180948/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30180948/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID30180948", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "endogenous promoter CRISPR activation", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "NEAT1 promoter activation in two lines increases intact core-shell paraspeckles.", "what_it_does_not_show": "Endogenous locus activation changes abundance; it does not isolate liquid-state functional necessity.", "confounders_present": [ "Endogenous locus activation changes abundance; it does not isolate liquid-state functional necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 18, "pmid": "32923585", "title": "Integrator restrains paraspeckles assembly by promoting isoform switching of the lncRNA NEAT1.", "citation": "Barra J, Gaidosh GS, Blumenthal E et al. Integrator restrains paraspeckles assembly by promoting isoform switching of the lncRNA NEAT1. Science advances. 2020.", "doi": "10.1126/sciadv.aaz9072", "pmcid": "PMC7455494", "url": "https://pubmed.ncbi.nlm.nih.gov/32923585/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32923585/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID32923585", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "cell isoform-processing perturbation", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Integrator cleavage changes NEAT1 isoforms and restrains paraspeckle assembly.", "what_it_does_not_show": "Broad RNA-processing mediator; no liquid-state-specific intervention or complete functional rescue.", "confounders_present": [ "Broad RNA-processing mediator; no liquid-state-specific intervention or complete functional rescue." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 19, "pmid": "38381607", "title": "SRRM2 phase separation drives assembly of nuclear speckle subcompartments.", "citation": "Zhang M, Gu Z, Guo S et al. SRRM2 phase separation drives assembly of nuclear speckle subcompartments. Cell reports. 2024.", "doi": "10.1016/j.celrep.2024.113827", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/38381607/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38381607/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID38381607", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "human speckle component replacement", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "SRRM2/SON form immiscible subcompartments; oligomerizable synthetic modules replace RS assembly roles while serines tune liquidity and target splicing.", "what_it_does_not_show": "Original abstract only in this packet. Synthetic oligomer rescue of assembly is not automatically matched liquid-state functional rescue; distinct splicing factors have nonredundant direct functions.", "confounders_present": [ "Original abstract only in this packet. Synthetic oligomer rescue of assembly is not automatically matched liquid-state functional rescue; distinct splicing factors have nonredundant direct functions." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 20, "pmid": "39181135", "title": "Disruption of nuclear speckle integrity dysregulates RNA splicing in C9ORF72-FTD/ALS.", "citation": "Wu R, Ye Y, Dong D et al. Disruption of nuclear speckle integrity dysregulates RNA splicing in C9ORF72-FTD/ALS. Neuron. 2024.", "doi": "10.1016/j.neuron.2024.07.025", "pmcid": "PMC11502262", "url": "https://pubmed.ncbi.nlm.nih.gov/39181135/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39181135/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID39181135", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human neurons/mouse and patient disease tissue", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "C9 repeat RNA/DPRs alter speckle dynamics and sequester SRRM2; integrity loss changes splicing and neuronal viability.", "what_it_does_not_show": "Disease toxicity and factor sequestration alter binding/abundance globally; cannot isolate liquid-state-only causation.", "confounders_present": [ "Disease toxicity and factor sequestration alter binding/abundance globally; cannot isolate liquid-state-only causation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 21, "pmid": "33095160", "title": "SON and SRRM2 are essential for nuclear speckle formation.", "citation": "Ilik İA, Malszycki M, Lübke AK et al. SON and SRRM2 are essential for nuclear speckle formation. eLife. 2020.", "doi": "10.7554/eLife.60579", "pmcid": "PMC7671692", "url": "https://pubmed.ncbi.nlm.nih.gov/33095160/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33095160/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID33095160", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph9, 1:Results:paragraph15, 1:Results:paragraph17, 1:Results:paragraph31, 1:Results:paragraph32, 1:Results:paragraph48. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "endogenous human truncation and co-depletion", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "SON/SRRM2 co-loss disperses multiple speckle markers without comparable Cajal loss; original shows SC35 chiefly recognizes SRRM2 and truncation alone can remove SC35 staining without dissolving speckles.", "what_it_does_not_show": "Protein loss and antibody epitope loss must be separated from body loss; scaffold requirement is not proof that liquidity itself is essential.", "confounders_present": [ "Protein loss and antibody epitope loss must be separated from body loss; scaffold requirement is not proof that liquidity itself is essential." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 22, "pmid": "40233760", "title": "Phosphorylation-dependent charge blocks regulate the relaxation of nuclear speckle networks.", "citation": "Zhang M, Gu Z, Sun Y et al. Phosphorylation-dependent charge blocks regulate the relaxation of nuclear speckle networks. Molecular cell. 2025.", "doi": "10.1016/j.molcel.2025.03.016", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/40233760/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40233760/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID40233760", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human charge/phosphorylation perturbation", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "SRRM2 charge blocks alter network relaxation without markedly shifting condensation threshold; CK2 phosphorylation is linked to splicing after DNA damage.", "what_it_does_not_show": "Abstract-only quantitative/rescue details; CK2 has many substrates and charge edits alter interactions. Supports a stronger state-function test but not broad common-liquid generality.", "confounders_present": [ "Abstract-only quantitative/rescue details; CK2 has many substrates and charge edits alter interactions. Supports a stronger state-function test but not broad common-liquid generality." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 23, "pmid": "30692529", "title": "Cycles of protein condensation and discharge in nuclear organelles studied by fluorescence lifetime imaging.", "citation": "Pliss A, Levchenko SM, Liu L et al. Cycles of protein condensation and discharge in nuclear organelles studied by fluorescence lifetime imaging. Nature communications. 2019.", "doi": "10.1038/s41467-019-08354-3", "pmcid": "PMC6349932", "url": "https://pubmed.ncbi.nlm.nih.gov/30692529/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30692529/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID30692529", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Weak", "system": "living-cell fluorescence lifetime imaging", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Nuclear-body component concentrations fluctuate synchronously across cells' organelles.", "what_it_does_not_show": "Concentration cycles and fluorescence environment are not direct demixing or causal material-state tests.", "confounders_present": [ "Concentration cycles and fluorescence environment are not direct demixing or causal material-state tests." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 24, "pmid": "39747580", "title": "Nuclear speckles regulate functional programs in cancer.", "citation": "Alexander KA, Yu R, Skuli N et al. Nuclear speckles regulate functional programs in cancer. Nature cell biology. 2025.", "doi": "10.1038/s41556-024-01570-0", "pmcid": "PMC12039181", "url": "https://pubmed.ncbi.nlm.nih.gov/39747580/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39747580/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID39747580", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human cancer association and targeting perturbation", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "HIF2alpha speckle-targeting motifs influence selected ccRCC transcriptional programs; speckle states correlate with outcomes.", "what_it_does_not_show": "Motif-mediated spatial targeting and tissue state do not isolate liquidity, and prognostic association is not therapeutic primacy.", "confounders_present": [ "Motif-mediated spatial targeting and tissue state do not isolate liquidity, and prognostic association is not therapeutic primacy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 25, "pmid": "22718948", "title": "Malat1 is not an essential component of nuclear speckles in mice.", "citation": "Nakagawa S, Ip JY, Shioi G et al. Malat1 is not an essential component of nuclear speckles in mice. RNA (New York, N.Y.). 2012.", "doi": "10.1261/rna.033217.112", "pmcid": "PMC3404370", "url": "https://pubmed.ncbi.nlm.nih.gov/22718948/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22718948/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID22718948", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "endogenous mouse RNA deletion", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Malat1 knockout mice retain speckle markers and normal baseline viability/fertility, with context-specific NEAT1 changes.", "what_it_does_not_show": "Baseline absence phenotype does not exclude stress-specific function or all alternative RNA contributions; scaffold redundancy matters.", "confounders_present": [ "Baseline absence phenotype does not exclude stress-specific function or all alternative RNA contributions; scaffold redundancy matters." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 26, "pmid": "36526633", "title": "Detecting and quantifying liquid-liquid phase separation in living cells by model-free calibrated half-bleaching.", "citation": "Muzzopappa F, Hummert J, Anfossi M et al. Detecting and quantifying liquid-liquid phase separation in living cells by model-free calibrated half-bleaching. Nature communications. 2022.", "doi": "10.1038/s41467-022-35430-y", "pmcid": "PMC9758202", "url": "https://pubmed.ncbi.nlm.nih.gov/36526633/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36526633/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID36526633", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "benchmarked live-cell/reconstituted methods", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Controlled LLPS and clustered-binding systems show classic FRAP/hexanediol are nondiagnostic; calibrated half-FRAP probes preferential internal mixing.", "what_it_does_not_show": "Interfacial barriers vary by body and probe; benchmark specificity is not itself full-body functional proof.", "confounders_present": [ "Interfacial barriers vary by body and probe; benchmark specificity is not itself full-body functional proof." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 27, "pmid": "35963432", "title": "Phase-separation antagonists potently inhibit transcription and broadly increase nucleosome density.", "citation": "Meduri R, Rubio LS, Mohajan S et al. Phase-separation antagonists potently inhibit transcription and broadly increase nucleosome density. The Journal of biological chemistry. 2022.", "doi": "10.1016/j.jbc.2022.102365", "pmcid": "PMC9486037", "url": "https://pubmed.ncbi.nlm.nih.gov/35963432/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35963432/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID35963432", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "yeast solvent perturbation comparator", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Both 1,6-HD and nominal-control 2,5-HD suppress coalescing/noncoalescing gene transcription and increase nucleosome density.", "what_it_does_not_show": "Dose/temperature/organism-specific off-target effect; does not invalidate all orthogonal LLPS studies.", "confounders_present": [ "Dose/temperature/organism-specific off-target effect; does not invalidate all orthogonal LLPS studies." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 28, "pmid": "33536240", "title": "1,6-hexanediol rapidly immobilizes and condenses chromatin in living human cells.", "citation": "Itoh Y, Iida S, Tamura S et al. 1,6-hexanediol rapidly immobilizes and condenses chromatin in living human cells. Life science alliance. 2021.", "doi": "10.26508/lsa.202001005", "pmcid": "PMC7898662", "url": "https://pubmed.ncbi.nlm.nih.gov/33536240/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33536240/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID33536240", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "human live-cell solvent/chromatin comparator", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Hexanediol dose-dependently immobilizes/hypercondenses chromatin; 5 percent or more freezes tested chromatin motion.", "what_it_does_not_show": "A distinct chromatin effect, not universal evidence against condensates; lower concentrations still require assay-specific validation.", "confounders_present": [ "A distinct chromatin effect, not universal evidence against condensates; lower concentrations still require assay-specific validation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 29, "pmid": "33608942", "title": "RNA polymerase II condensate formation and association with Cajal and histone locus bodies in living human cells.", "citation": "Imada T, Shimi T, Kaiho A et al. RNA polymerase II condensate formation and association with Cajal and histone locus bodies in living human cells. Genes to cells : devoted to molecular & cellular mechanisms. 2021.", "doi": "10.1111/gtc.12840", "pmcid": "PMC8252594", "url": "https://pubmed.ncbi.nlm.nih.gov/33608942/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33608942/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID33608942", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human endogenous knockout/imaging", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "PolII clusters form near CB/HLB; coilin knockout changes associations without PC number/timing changes, and PC removal leaves CB/HLB.", "what_it_does_not_show": "Hexanediol-based liquidity ranking is not definitive; demonstrates separable assembly dependencies, not proof that CBs never phase separate.", "confounders_present": [ "Hexanediol-based liquidity ranking is not definitive; demonstrates separable assembly dependencies, not proof that CBs never phase separate." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 30, "pmid": "34404453", "title": "Time-dependent effect of 1,6-hexanediol on biomolecular condensates and 3D chromatin organization.", "citation": "Liu X, Jiang S, Ma L et al. Time-dependent effect of 1,6-hexanediol on biomolecular condensates and 3D chromatin organization. Genome biology. 2021.", "doi": "10.1186/s13059-021-02455-3", "pmcid": "PMC8369800", "url": "https://pubmed.ncbi.nlm.nih.gov/34404453/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34404453/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID34404453", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human timed solvent/chromatin perturbation", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "1.5 percent short treatment dissolves bodies with different chromatin-contact effects than longer exposure/aggregation.", "what_it_does_not_show": "Retained viability does not rule out kinase/transcription off-targets; neither dose nor 2,5-HD is universally specific.", "confounders_present": [ "Retained viability does not rule out kinase/transcription off-targets; neither dose nor 2,5-HD is universally specific." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 31, "pmid": "33814344", "title": "1,6-Hexanediol, commonly used to dissolve liquid-liquid phase separated condensates, directly impairs kinase and phosphatase activities.", "citation": "Düster R, Kaltheuner IH, Schmitz M et al. 1,6-Hexanediol, commonly used to dissolve liquid-liquid phase separated condensates, directly impairs kinase and phosphatase activities. The Journal of biological chemistry. 2021.", "doi": "10.1016/j.jbc.2021.100260", "pmcid": "PMC7948595", "url": "https://pubmed.ncbi.nlm.nih.gov/33814344/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33814344/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID33814344", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Results:paragraph2, 0:Results:paragraph3, 0:Results:paragraph5, 0:Results:paragraph6, 0:Results:paragraph13, 0:Results:paragraph16. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "biochemical enzyme/solvent comparator", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Structured low-concentration kinases and IDR-deleted P-TEFb are inhibited by hexanediol; dilution restores activity and kinase inhibition can preserve CTD droplets.", "what_it_does_not_show": "Tested enzymes/protocol, not direct cellular degree estimate. Reversibility does not make solvent effects LLPS-specific.", "confounders_present": [ "Tested enzymes/protocol, not direct cellular degree estimate. Reversibility does not make solvent effects LLPS-specific." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 32, "pmid": "34326237", "title": "lncRNA SLERT controls phase separation of FC/DFCs to facilitate Pol I transcription.", "citation": "Wu M, Xu G, Han C et al. lncRNA SLERT controls phase separation of FC/DFCs to facilitate Pol I transcription. Science (New York, N.Y.). 2021.", "doi": "10.1126/science.abf6582", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/34326237/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34326237/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID34326237", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human lncRNA/helicase interaction tests", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "SLERT favors closed DDX21 conformation and loose clusters linked to FC/DFC fluidity and PolI processivity.", "what_it_does_not_show": "Helicase conformation, multimerization and RNA binding are inseparable in these selected abstract claims; no body-general liquid-state inference.", "confounders_present": [ "Helicase conformation, multimerization and RNA binding are inseparable in these selected abstract claims; no body-general liquid-state inference." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 33, "pmid": "37683610", "title": "Viscoelasticity and advective flow of RNA underlies nucleolar form and function.", "citation": "Riback JA, Eeftens JM, Lee DSW et al. Viscoelasticity and advective flow of RNA underlies nucleolar form and function. Molecular cell. 2023.", "doi": "10.1016/j.molcel.2023.08.006", "pmcid": "PMC11089468", "url": "https://pubmed.ncbi.nlm.nih.gov/37683610/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37683610/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID37683610", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph3, 1:RESULTS:paragraph4, 1:RESULTS:paragraph6, 1:RESULTS:paragraph7, 1:RESULTS:paragraph10, 1:RESULTS:paragraph11, 1:RESULTS:paragraph12. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "human RNA pulse-chase/rheology modeling", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Slow directional RNA motion and approximately 5000-fold RNA/NPM1 diffusivity differences support entangled RNA with rapid protein movement through its mesh.", "what_it_does_not_show": "RNA labeling, washout, noise floor and maturation mixtures limit inferred transport parameters. Maxwell-fit/gel interpretation is model-supported, not proof every constituent is solid.", "confounders_present": [ "RNA labeling, washout, noise floor and maturation mixtures limit inferred transport parameters. Maxwell-fit/gel interpretation is model-supported, not proof every constituent is solid." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 34, "pmid": "39738032", "title": "DDX18 coordinates nucleolus phase separation and nuclear organization to control the pluripotency of human embryonic stem cells.", "citation": "Shi X, Li Y, Zhou H et al. DDX18 coordinates nucleolus phase separation and nuclear organization to control the pluripotency of human embryonic stem cells. Nature communications. 2024.", "doi": "10.1038/s41467-024-55054-8", "pmcid": "PMC11685540", "url": "https://pubmed.ncbi.nlm.nih.gov/39738032/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39738032/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID39738032", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human stem-cell depletion and synthetic rescue", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "DDX18 loss disrupts nucleolar/chromatin organization; NoCasDrop targeted condensation restores selected centromere/heterochromatin readouts.", "what_it_does_not_show": "Synthetic rescue of structure, not necessarily pluripotency or material-state-only rescue; helicase/RNA binding and transcription confounds.", "confounders_present": [ "Synthetic rescue of structure, not necessarily pluripotency or material-state-only rescue; helicase/RNA binding and transcription confounds." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 35, "pmid": "41861784", "title": "LncRNA-splicing factor condensates regulate hypoxia-responsive pre-mRNA processing near nuclear speckles.", "citation": "Song YJ, Shinn MK, Bangru S et al. LncRNA-splicing factor condensates regulate hypoxia-responsive pre-mRNA processing near nuclear speckles. Molecular cell. 2026.", "doi": "10.1016/j.molcel.2026.02.014", "pmcid": "PMC13007718", "url": "https://pubmed.ncbi.nlm.nih.gov/41861784/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41861784/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "UpdateOf: PMID39554052" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID41861784", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human hypoxia and splicing perturbation", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "MALAT1 modulates SRSF1/pre-mRNA interactions and condensation near speckles with hypoxia-responsive splicing.", "what_it_does_not_show": "PubMed journal issue is dated 19 March 2026, before the cutoff; earlier preprint is the same work. Interaction/recruitment specificity versus liquid state remains, original body not examined.", "confounders_present": [ "PubMed journal issue is dated 19 March 2026, before the cutoff; earlier preprint is the same work. Interaction/recruitment specificity versus liquid state remains, original body not examined." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 36, "pmid": "33333019", "title": "RNA-Mediated Feedback Control of Transcriptional Condensates.", "citation": "Henninger JE, Oksuz O, Shrinivas K et al. RNA-Mediated Feedback Control of Transcriptional Condensates. Cell. 2021.", "doi": "10.1016/j.cell.2020.11.030", "pmcid": "PMC8128340", "url": "https://pubmed.ncbi.nlm.nih.gov/33333019/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33333019/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID33333019", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "cell/reconstitution RNA feedback", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "RNA amount promotes then dissolves transcriptional condensates, consistent with nonequilibrium feedback.", "what_it_does_not_show": "Transcriptional cluster comparator, not the canonical body classes' universal assembly or liquidity function.", "confounders_present": [ "Transcriptional cluster comparator, not the canonical body classes' universal assembly or liquidity function." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 37, "pmid": "29930090", "title": "Imaging dynamic and selective low-complexity domain interactions that control gene transcription.", "citation": "Chong S, Dugast-Darzacq C, Liu Z et al. Imaging dynamic and selective low-complexity domain interactions that control gene transcription. Science (New York, N.Y.). 2018.", "doi": "10.1126/science.aar2555", "pmcid": "PMC6961784", "url": "https://pubmed.ncbi.nlm.nih.gov/29930090/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29930090/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID29930090", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "single-molecule human transcription comparator", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Physiological dynamic LCD hubs stabilize binding and recruit PolII without detectable macroscopic phase separation.", "what_it_does_not_show": "Local hubs at tested loci do not rule out other bodies or nanoscopic condensation; a distinct comparator rather than nucleolar null.", "confounders_present": [ "Local hubs at tested loci do not rule out other bodies or nanoscopic condensation; a distinct comparator rather than nucleolar null." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 38, "pmid": "31391587", "title": "Pol II phosphorylation regulates a switch between transcriptional and splicing condensates.", "citation": "Guo YE, Manteiga JC, Henninger JE et al. Pol II phosphorylation regulates a switch between transcriptional and splicing condensates. Nature. 2019.", "doi": "10.1038/s41586-019-1464-0", "pmcid": "PMC6706314", "url": "https://pubmed.ncbi.nlm.nih.gov/31391587/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31391587/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID31391587", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "PolII phosphorylation partition tests", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "CTD phosphorylation shifts partition preference from mediator to splicing-factor condensates.", "what_it_does_not_show": "Phosphorylation also regulates conventional binding/enzymatic activity; not unique evidence of an endogenous required liquid phase.", "confounders_present": [ "Phosphorylation also regulates conventional binding/enzymatic activity; not unique evidence of an endogenous required liquid phase." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 39, "pmid": "26776729", "title": "Nucleation by rRNA Dictates the Precision of Nucleolus Assembly.", "citation": "Falahati H, Pelham-Webb B, Blythe S et al. Nucleation by rRNA Dictates the Precision of Nucleolus Assembly. Current biology : CB. 2016.", "doi": "10.1016/j.cub.2015.11.065", "pmcid": "PMC5866055", "url": "https://pubmed.ncbi.nlm.nih.gov/26776729/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26776729/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID26776729", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "endogenous fly embryo rDNA contrast", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "rRNA transcription seeds precisely timed nucleoli; without rDNA, variable high-concentration assemblies still arise.", "what_it_does_not_show": "Seeding and phase behavior can cooperate; activity-defined formation does not alone isolate physical state required for function.", "confounders_present": [ "Seeding and phase behavior can cooperate; activity-defined formation does not alone isolate physical state required for function." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 40, "pmid": "26464461", "title": "Alu element-containing RNAs maintain nucleolar structure and function.", "citation": "Caudron-Herger M, Pankert T, Seiler J et al. Alu element-containing RNAs maintain nucleolar structure and function. The EMBO journal. 2015.", "doi": "10.15252/embj.201591458", "pmcid": "PMC4682651", "url": "https://pubmed.ncbi.nlm.nih.gov/26464461/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26464461/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID26464461", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human RNA antisense/overexpression", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Alu RNA depletion disrupts nucleolar structure/rRNA transcription, while added RNA increases size and pre-rRNA.", "what_it_does_not_show": "RNA scaffold and PolII/PolI cross-talk are changed together; not liquid-state-selective necessity.", "confounders_present": [ "RNA scaffold and PolII/PolI cross-talk are changed together; not liquid-state-selective necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 41, "pmid": "36423630", "title": "Chromatin localization of nucleophosmin organizes ribosome biogenesis.", "citation": "Ugolini I, Bilokapic S, Ferrolino M et al. Chromatin localization of nucleophosmin organizes ribosome biogenesis. Molecular cell. 2022.", "doi": "10.1016/j.molcel.2022.10.033", "pmcid": "PMC9949351", "url": "https://pubmed.ncbi.nlm.nih.gov/36423630/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36423630/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID36423630", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "fission yeast endogenous sorting tests", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Fkbp39 chromatin localization/binding directs nascent 60S partition and improves ribosomal assembly.", "what_it_does_not_show": "Native sorting and binding are causal in yeast, but liquidity-only separation and broad body generality are untested here.", "confounders_present": [ "Native sorting and binding are causal in yeast, but liquidity-only separation and broad body generality are untested here." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 42, "pmid": "40604277", "title": "Mapping and engineering RNA-driven architecture of the multiphase nucleolus.", "citation": "Quinodoz SA, Jiang L, Abu-Alfa AA et al. Mapping and engineering RNA-driven architecture of the multiphase nucleolus. Nature. 2025.", "doi": "10.1038/s41586-025-09207-4", "pmcid": "PMC12350172", "url": "https://pubmed.ncbi.nlm.nih.gov/40604277/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40604277/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "UpdateOf: PMID39386460" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID40604277", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "RNA sequencing/imaging and engineered nucleoli", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Sequential processing maps spatial maturation; engineered SSU defects invert layers and prevent outflux, while LSU precursors build the outer layer.", "what_it_does_not_show": "Synthetic rDNA plus processing perturbation changes substrate architecture itself; supports RNA-programmed structure rather than universal simple-liquid necessity.", "confounders_present": [ "Synthetic rDNA plus processing perturbation changes substrate architecture itself; supports RNA-programmed structure rather than universal simple-liquid necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 43, "pmid": "34739832", "title": "RNA promotes the formation of spatial compartments in the nucleus.", "citation": "Quinodoz SA, Jachowicz JW, Bhat P et al. RNA promotes the formation of spatial compartments in the nucleus. Cell. 2021.", "doi": "10.1016/j.cell.2021.10.014", "pmcid": "PMC9115877", "url": "https://pubmed.ncbi.nlm.nih.gov/34739832/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34739832/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID34739832", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human spatial RNA/DNA maps and recruitment perturbation", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "RD-SPRITE identifies RNA territories; selected RNAs recruit regulators and alter contacts/function.", "what_it_does_not_show": "Spatial enrichment and binding-guided assembly do not uniquely identify demixing versus scaffold-driven territories.", "confounders_present": [ "Spatial enrichment and binding-guided assembly do not uniquely identify demixing versus scaffold-driven territories." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 44, "pmid": "20357773", "title": "Coilin-dependent snRNP assembly is essential for zebrafish embryogenesis.", "citation": "Strzelecka M, Trowitzsch S, Weber G et al. Coilin-dependent snRNP assembly is essential for zebrafish embryogenesis. Nature structural & molecular biology. 2010.", "doi": "10.1038/nsmb.1783", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/20357773/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/20357773/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID20357773", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "zebrafish coilin depletion and product bypass", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Coilin loss disperses CB, impairs snRNP production and arrests development; mature human snRNPs restore mRNA/viability while RNA alone does not.", "what_it_does_not_show": "Product bypass shows CB-associated assembly is useful yet not an irreplaceable liquid prerequisite; depletion is not a material-state edit.", "confounders_present": [ "Product bypass shows CB-associated assembly is useful yet not an irreplaceable liquid prerequisite; depletion is not a material-state edit." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 45, "pmid": "26997247", "title": "Cajal bodies are linked to genome conformation.", "citation": "Wang Q, Sawyer IA, Sung MH et al. Cajal bodies are linked to genome conformation. Nature communications. 2016.", "doi": "10.1038/ncomms10966", "pmcid": "PMC4802181", "url": "https://pubmed.ncbi.nlm.nih.gov/26997247/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26997247/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID26997247", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human CB disassembly and genomic contacts", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "CB RNAi disassembly changes gene clustering/expression and increases splicing noise.", "what_it_does_not_show": "Coilin/assembly loss and snRNP supply explain effects without requiring phase-state-specific causation.", "confounders_present": [ "Coilin/assembly loss and snRNP supply explain effects without requiring phase-state-specific causation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 46, "pmid": "17081985", "title": "The mechanisms of PML-nuclear body formation.", "citation": "Shen TH, Lin HK, Scaglioni PP et al. The mechanisms of PML-nuclear body formation. Molecular cell. 2006.", "doi": "10.1016/j.molcel.2006.09.013", "pmcid": "PMC1978182", "url": "https://pubmed.ncbi.nlm.nih.gov/17081985/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/17081985/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID29654784" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID17081985", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "PML-null addback and motif perturbation", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "PML addback restores bodies, and SUMO-binding/RING mutants alter nucleation/recruitment.", "what_it_does_not_show": "SUMO architecture versus liquid state not separated; linked erratum PMID29654784 metadata checked but details unavailable.", "confounders_present": [ "SUMO architecture versus liquid state not separated; linked erratum PMID29654784 metadata checked but details unavailable." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 47, "pmid": "37219517", "title": "Phase separation is required for PML nuclear body biogenesis and function.", "citation": "Wu W, Tan Y, Yin H et al. Phase separation is required for PML nuclear body biogenesis and function. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2023.", "doi": "10.1096/fj.202300216R", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/37219517/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37219517/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID37219517", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "patient-variant PML cellular comparison", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "A216V/L268P compare dynamics, packing, recruitment/PTMs and stress/senescence outputs with retained overall RBCC oligomerization.", "what_it_does_not_show": "Important positive variant comparison, but FRAP is not alone LLPS proof and altered binding/packing may change output; original body unavailable.", "confounders_present": [ "Important positive variant comparison, but FRAP is not alone LLPS proof and altered binding/packing may change output; original body unavailable." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 48, "pmid": "29483575", "title": "Self-interaction of NPM1 modulates multiple mechanisms of liquid-liquid phase separation.", "citation": "Mitrea DM, Cika JA, Stanley CB et al. Self-interaction of NPM1 modulates multiple mechanisms of liquid-liquid phase separation. Nature communications. 2018.", "doi": "10.1038/s41467-018-03255-3", "pmcid": "PMC5827731", "url": "https://pubmed.ncbi.nlm.nih.gov/29483575/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29483575/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID29483575", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "NPM1 reconstitution biophysics", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "NPM1 conformation changes valency and switches competing homo/heterotypic LLPS mechanisms.", "what_it_does_not_show": "Biophysical reconstitution is not endogenous liquid-state-selective function or cross-class necessity.", "confounders_present": [ "Biophysical reconstitution is not endogenous liquid-state-selective function or cross-class necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 49, "pmid": "26836305", "title": "Nucleophosmin integrates within the nucleolus via multi-modal interactions with proteins displaying R-rich linear motifs and rRNA.", "citation": "Mitrea DM, Cika JA, Guy CS et al. Nucleophosmin integrates within the nucleolus via multi-modal interactions with proteins displaying R-rich linear motifs and rRNA. eLife. 2016.", "doi": "10.7554/eLife.13571", "pmcid": "PMC4786410", "url": "https://pubmed.ncbi.nlm.nih.gov/26836305/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26836305/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID26836305", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "NPM1 reconstitution and cell localization", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Multivalent acidic motifs, oligomerization and RNA-binding domains drive NPM1 coassembly and nucleolar localization.", "what_it_does_not_show": "Loss of interaction/localization is not selective loss of liquidity while retaining same clients/function.", "confounders_present": [ "Loss of interaction/localization is not selective loss of liquidity while retaining same clients/function." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 50, "pmid": "30498217", "title": "Compositional adaptability in NPM1-SURF6 scaffolding networks enabled by dynamic switching of phase separation mechanisms.", "citation": "Ferrolino MC, Mitrea DM, Michael JR et al. Compositional adaptability in NPM1-SURF6 scaffolding networks enabled by dynamic switching of phase separation mechanisms. Nature communications. 2018.", "doi": "10.1038/s41467-018-07530-1", "pmcid": "PMC6265330", "url": "https://pubmed.ncbi.nlm.nih.gov/30498217/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30498217/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID30498217", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "NPM1-SURF6 reconstitution", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Crowding/concentration modulates interconversion of homo/heterotypic scaffolding networks.", "what_it_does_not_show": "Proposed vectorial output is not directly established by this in vitro network alone.", "confounders_present": [ "Proposed vectorial output is not directly established by this in vitro network alone." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 51, "pmid": "30981631", "title": "C9orf72 Poly(PR) Dipeptide Repeats Disturb Biomolecular Phase Separation and Disrupt Nucleolar Function.", "citation": "White MR, Mitrea DM, Zhang P et al. C9orf72 Poly(PR) Dipeptide Repeats Disturb Biomolecular Phase Separation and Disrupt Nucleolar Function. Molecular cell. 2019.", "doi": "10.1016/j.molcel.2019.03.019", "pmcid": "PMC6525025", "url": "https://pubmed.ncbi.nlm.nih.gov/30981631/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30981631/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID30981631", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "DPR reconstitution/cellular exposure", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "PolyPR binds NPM1 acidic regions, dissolves in vitro droplets and disperses cell NPM1 while trapping RNA statically.", "what_it_does_not_show": "Broad pathogenic interactions, not an isolated physiological liquid-state perturbation/rescue.", "confounders_present": [ "Broad pathogenic interactions, not an isolated physiological liquid-state perturbation/rescue." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 52, "pmid": "33568486", "title": "Bridging-induced phase separation induced by cohesin SMC protein complexes.", "citation": "Ryu JK, Bouchoux C, Liu HW et al. Bridging-induced phase separation induced by cohesin SMC protein complexes. Science advances. 2021.", "doi": "10.1126/sciadv.abe5905", "pmcid": "PMC7875533", "url": "https://pubmed.ncbi.nlm.nih.gov/33568486/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33568486/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID33568486", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "cohesin DNA reconstitution/cell comparator", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Liquid-like cohesin-DNA clusters depend on DNA length above 3 kb, supporting bridging-induced condensation.", "what_it_does_not_show": "DNA polymer comparator, not direct paraspeckle/Cajal mechanism; fusion/FRAP do not uniquely identify protein LLPS.", "confounders_present": [ "DNA polymer comparator, not direct paraspeckle/Cajal mechanism; fusion/FRAP do not uniquely identify protein LLPS." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 53, "pmid": "31038454", "title": "Evidence for DNA-mediated nuclear compartmentalization distinct from phase separation.", "citation": "McSwiggen DT, Hansen AS, Teves SS et al. Evidence for DNA-mediated nuclear compartmentalization distinct from phase separation. eLife. 2019.", "doi": "10.7554/eLife.47098", "pmcid": "PMC6522219", "url": "https://pubmed.ncbi.nlm.nih.gov/31038454/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31038454/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID31038454", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "infected human nuclear binding comparator", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "HSV replication compartments concentrate PolII through accessible DNA/rebinding despite unrestricted interfacial diffusion.", "what_it_does_not_show": "Viral compartment context, not native nucleolar null; provides a mechanism that reproduces misleading puncta phenomenology.", "confounders_present": [ "Viral compartment context, not native nucleolar null; provides a mechanism that reproduces misleading puncta phenomenology." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 54, "pmid": "38720076", "title": "Genome organization around nuclear speckles drives mRNA splicing efficiency.", "citation": "Bhat P, Chow A, Emert B et al. Genome organization around nuclear speckles drives mRNA splicing efficiency. Nature. 2024.", "doi": "10.1038/s41586-024-07429-6", "pmcid": "PMC11164319", "url": "https://pubmed.ncbi.nlm.nih.gov/38720076/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38720076/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "UpdateOf: PMID36711853" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID38720076", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "human spatial splicing recruitment", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Speckle proximity predicts more spliceosome binding, and directed pre-mRNA recruitment increases splicing.", "what_it_does_not_show": "Spatial concentration is functionally sufficient in the tested assay, but does not identify liquidity as the causal feature; preprint is not separate replication.", "confounders_present": [ "Spatial concentration is functionally sufficient in the tested assay, but does not identify liquidity as the causal feature; preprint is not separate replication." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 55, "pmid": "35929045", "title": "SRRM2 organizes splicing condensates to regulate alternative splicing.", "citation": "Xu S, Lai SK, Sim DY et al. SRRM2 organizes splicing condensates to regulate alternative splicing. Nucleic acids research. 2022.", "doi": "10.1093/nar/gkac669", "pmcid": "PMC9410892", "url": "https://pubmed.ncbi.nlm.nih.gov/35929045/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35929045/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID35929045", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "endogenous SRRM2 knock-in/depletion", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "EGFP-SRRM2 knock-in dynamics and depletion link scaffold to selected exon splicing, viability and differentiation.", "what_it_does_not_show": "SRRM2 is itself a spliceosome protein; generic factor loss is not liquid-state-only necessity, and sphere/FRAP criteria are incomplete.", "confounders_present": [ "SRRM2 is itself a spliceosome protein; generic factor loss is not liquid-state-only necessity, and sphere/FRAP criteria are incomplete." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 56, "pmid": "31315647", "title": "Disruption of nuclear speckles reduces chromatin interactions in active compartments.", "citation": "Hu S, Lv P, Yan Z et al. Disruption of nuclear speckles reduces chromatin interactions in active compartments. Epigenetics & chromatin. 2019.", "doi": "10.1186/s13072-019-0289-2", "pmcid": "PMC6636040", "url": "https://pubmed.ncbi.nlm.nih.gov/31315647/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31315647/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID31315647", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "mouse hepatocyte scaffold knockdown", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "SRRM2 depletion disperses speckles and changes active-compartment interactions and 1282 genes; contact changes do not track expression changes.", "what_it_does_not_show": "Broad scaffold/splicing loss and uncoupled contacts constrain unique material-state interpretation.", "confounders_present": [ "Broad scaffold/splicing loss and uncoupled contacts constrain unique material-state interpretation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 57, "pmid": "18948503", "title": "De novo formation of a subnuclear body.", "citation": "Kaiser TE, Intine RV, Dundr M et al. De novo formation of a subnuclear body. Science (New York, N.Y.). 2008.", "doi": "10.1126/science.1165216", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/18948503/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/18948503/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID18948503", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "synthetic chromatin-tethered CB assembly", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Multiple structural or functional CB components nucleate apparently functional bodies when immobilized on chromatin.", "what_it_does_not_show": "Nonhierarchical self-organization does not prove LLPS; tethered high local concentration is engineered.", "confounders_present": [ "Nonhierarchical self-organization does not prove LLPS; tethered high local concentration is engineered." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 58, "pmid": "21170033", "title": "Direct visualization of the co-transcriptional assembly of a nuclear body by noncoding RNAs.", "citation": "Mao YS, Sunwoo H, Zhang B et al. Direct visualization of the co-transcriptional assembly of a nuclear body by noncoding RNAs. Nature cell biology. 2011.", "doi": "10.1038/ncb2140", "pmcid": "PMC3007124", "url": "https://pubmed.ncbi.nlm.nih.gov/21170033/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21170033/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID21170033", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "inducible RNA and live paraspeckle assembly", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Nascent NEAT1 transcription recruits functional paraspeckle proteins and retains mRNAs; continued transcription supports maintenance.", "what_it_does_not_show": "RNA platform and activity-dependence do not specify a bulk liquid or forbid microphase separation.", "confounders_present": [ "RNA platform and activity-dependence do not specify a bulk liquid or forbid microphase separation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 59, "pmid": "31399547", "title": "Controlling the material properties and rRNA processing function of the nucleolus using light.", "citation": "Zhu L, Richardson TM, Wacheul L et al. Controlling the material properties and rRNA processing function of the nucleolus using light. Proceedings of the National Academy of Sciences of the United States of America. 2019.", "doi": "10.1073/pnas.1903870116", "pmcid": "PMC6717270", "url": "https://pubmed.ncbi.nlm.nih.gov/31399547/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31399547/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID31399547", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Publisher HTML paragraphs:paragraph19, 0:Publisher HTML paragraphs:paragraph21, 0:Publisher HTML paragraphs:paragraph24, 0:Publisher HTML paragraphs:paragraph26, 0:Publisher HTML paragraphs:paragraph28, 0:Publisher HTML paragraphs:paragraph30, 0:Publisher HTML paragraphs:paragraph32, 0:Publisher HTML paragraphs:paragraph34, 0:Publisher HTML paragraphs:paragraph31, 0:Publisher HTML paragraphs:paragraph33, 0:Publisher HTML paragraphs:paragraph35, 0:Publisher HTML paragraphs:paragraph37, 0:Publisher HTML paragraphs:paragraph40. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "endogenous NPM1 optogenetic state perturbation", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Endogenous-locus NPM1-Cry2olig cells accumulate 46S/45S and lose downstream precursors relative to light controls; activated mesh hinders large complexes while small-protein mobility persists.", "what_it_does_not_show": "Processing assay uses 24–72 h light with general toxicity normalized; concentration/percolation and new interactions vary. Selected body shows no matched light-off functional rescue, and processing is selectively impaired rather than globally absent.", "confounders_present": [ "Processing assay uses 24–72 h light with general toxicity normalized; concentration/percolation and new interactions vary. Selected body shows no matched light-off functional rescue, and processing is selectively impaired rather than globally absent." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 60, "pmid": "40434645", "title": "Micropipette aspiration reveals differential RNA-dependent viscoelasticity of nucleolar subcompartments.", "citation": "Cheng HH, Roggeveen JV, Wang H et al. Micropipette aspiration reveals differential RNA-dependent viscoelasticity of nucleolar subcompartments. Proceedings of the National Academy of Sciences of the United States of America. 2025.", "doi": "10.1073/pnas.2407423122", "pmcid": "PMC12146704", "url": "https://pubmed.ncbi.nlm.nih.gov/40434645/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40434645/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID40434645", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "near-native frog aspiration and RNase", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Micropipette aspiration shows liquid-like GC but partly solid-like DFC/FC; RNase fluidizes internal phases and changes tension.", "what_it_does_not_show": "Restricted oocyte/aspiration context; RNA destruction changes substrate and interactions along with rheology, not selective functional rescue.", "confounders_present": [ "Restricted oocyte/aspiration context; RNA destruction changes substrate and interactions along with rheology, not selective functional rescue." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 61, "pmid": "38192101", "title": "Anomalous coarsening of coalescing nucleoli in human cells.", "citation": "Arsenadze G, Caragine CM, Coakley T et al. Anomalous coarsening of coalescing nucleoli in human cells. Biophysical journal. 2024.", "doi": "10.1016/j.bpj.2024.01.005", "pmcid": "PMC11163295", "url": "https://pubmed.ncbi.nlm.nih.gov/38192101/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38192101/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID38192101", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human live-cell physical imaging/simulation", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Chromatin depletion/flow accompanies coalescing nucleoli; short-range attraction models anomalous volume distribution.", "what_it_does_not_show": "Model-supported attraction and coarsening, not biological-function necessity or universally equilibrated liquid droplets.", "confounders_present": [ "Model-supported attraction and coarsening, not biological-function necessity or universally equilibrated liquid droplets." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 62, "pmid": "26351690", "title": "RNA transcription modulates phase transition-driven nuclear body assembly.", "citation": "Berry J, Weber SC, Vaidya N et al. RNA transcription modulates phase transition-driven nuclear body assembly. Proceedings of the National Academy of Sciences of the United States of America. 2015.", "doi": "10.1073/pnas.1509317112", "pmcid": "PMC4586886", "url": "https://pubmed.ncbi.nlm.nih.gov/26351690/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26351690/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID26351690", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "endogenous worm size/transcription perturbation", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Cell-size/concentration perturbation and nucleolar/extranucleolar kinetics agree with phase-transition predictions modulated by rRNA transcription.", "what_it_does_not_show": "Embryonic worm regime and active seeding; doesn't show every nuclear body shares the same physics.", "confounders_present": [ "Embryonic worm regime and active seeding; doesn't show every nuclear body shares the same physics." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 63, "pmid": "27374333", "title": "Compositional Control of Phase-Separated Cellular Bodies.", "citation": "Banani SF, Rice AM, Peeples WB et al. Compositional Control of Phase-Separated Cellular Bodies. Cell. 2016.", "doi": "10.1016/j.cell.2016.06.010", "pmcid": "PMC4967043", "url": "https://pubmed.ncbi.nlm.nih.gov/27374333/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27374333/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID27374333", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "engineered scaffold/client and natural-body comparison", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Changing scaffold ratio/valency switches client composition in reconstitutions/cells, with analogous PML/P-body partitioning.", "what_it_does_not_show": "Analogous natural partitioning is not identical physical proof, and synthetic-liquid compositional control is not body-general liquid necessity.", "confounders_present": [ "Analogous natural partitioning is not identical physical proof, and synthetic-liquid compositional control is not body-general liquid necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] } ], "verification_summary": { "load_bearing_claims_checked": 67, "verified": 67, "unverified": 0, "contradicted": 0, "note": "Verified attribution is distinct from mechanism truth or complete body access." }, "factual_issues_found": [], "cap_rules_applied": [ { "subclaim_id": "SC3", "cap": "Γ", "cap_source": "rubric", "triggered": true, "trigger_text_quoted": "Mechanistic plausibility plus in vitro reconstitution or simplified cellular support caps at Γ.", "specific_trigger": "Γ: class-general LLPS remains a mechanistic model, constrained by endogenous paraspeckle micelle tests, RNA-gel/partly solid nucleolar measurements and scaffold/binding alternatives. Restricted successes cannot establish common physics.", "resulting_ceiling": "Γ" } ], "cap_precedence_resolutions": [ { "collision": "Perturbation in a defined setting versus broader inference", "subclaim_scope_cap_binds_on": "Liquid–liquid phase separation assembles and organizes nuclear bodies in living cells, and the liquid state itself confers their compositional and functional properties.", "subclaim_scope_threshold_binds_on": "The precise experimentally tested subclaim scope", "resolution": "Nucleolar physical demixing earns context-scoped Ε; endogenous NPM1 tagging with light controls and size-selective mesh/processing readouts crosses Δ contribution. It is not withheld merely because no RCT exists. Lack of full reversible functional rescue and classes with alternative physics constrain broader claims; Γ applies to common-physics generalization, not re-capping the assembled native nucleolar evidence.", "note": "Convergent lines are assessed as a set; one weak leg is not re-capped over the assembled case." } ], "boundary_check_BGD": [ { "subclaim_id": "SC1", "field_valid_perturbation_quote": "\n- Endogenous degron of a condensate component with matched rescue, AND evidence that the specific condensate state (not generic protein loss) drives the phenotype\n- Locus-specific disruption of looping with locus-specific effect\n- Combinatorial histone-mark perturbation showing direct output dependence\n- Critically: specificity against cell-cycle collapse, global transcriptional collapse, and replication stress must be demonstrated", "qualifying_evidence_present": "yes", "qualifying_evidence_citation": "PMID27212236, PMID36755093, PMID30500535, PMID32405004, PMID38503281, PMID38745030, PMID33522570, PMID31296649, PMID31540874, PMID34315935, PMID21368180, PMID34819511, PMID33885174, PMID29932899, PMID27646274, PMID28404604, PMID30180948, PMID32923585, PMID38381607, PMID39181135, PMID33095160, PMID40233760, PMID22718948, PMID36526633, PMID33608942, PMID34326237, PMID37683610, PMID39738032, PMID41861784, PMID33333019, PMID29930090, PMID31391587, PMID26776729, PMID26464461, PMID36423630, PMID40604277, PMID34739832, PMID17081985, PMID37219517, PMID29483575, PMID26836305, PMID30498217, PMID30981631, PMID33568486, PMID31038454, PMID35929045, PMID18948503, PMID21170033, PMID31399547, PMID40434645, PMID38192101, PMID26351690, PMID27374333", "gamma_hard_rules_triggered": [ "FRAP exchange, rounded puncta and solvent sensitivity alone cannot establish LLPS or liquid-state-specific function.", "Protein/RNA depletion, localization and binding changes must be distinguished from a state-only intervention; synthetic assembly does not by itself generalize to endogenous bodies." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Ε: endogenous nucleolar demixing and composition-dependent physical organization have context-specific causal support, with native concentration/phase controls. This scoped existence success does not extend identically to all classes or constituents.", "ceiling_from_boundary_check": "Δ or higher" }, { "subclaim_id": "SC2", "field_valid_perturbation_quote": "\n- Endogenous degron of a condensate component with matched rescue, AND evidence that the specific condensate state (not generic protein loss) drives the phenotype\n- Locus-specific disruption of looping with locus-specific effect\n- Combinatorial histone-mark perturbation showing direct output dependence\n- Critically: specificity against cell-cycle collapse, global transcriptional collapse, and replication stress must be demonstrated", "qualifying_evidence_present": "yes", "qualifying_evidence_citation": "PMID27212236, PMID36755093, PMID32405004, PMID38503281, PMID38745030, PMID33522570, PMID31296649, PMID31540874, PMID33885174, PMID29932899, PMID32923585, PMID38381607, PMID39181135, PMID33095160, PMID40233760, PMID39747580, PMID35963432, PMID33536240, PMID34404453, PMID33814344, PMID34326237, PMID37683610, PMID39738032, PMID41861784, PMID31391587, PMID26464461, PMID36423630, PMID40604277, PMID34739832, PMID20357773, PMID26997247, PMID17081985, PMID37219517, PMID29483575, PMID26836305, PMID30498217, PMID30981631, PMID38720076, PMID35929045, PMID31315647, PMID21170033, PMID31399547, PMID40434645, PMID27374333", "gamma_hard_rules_triggered": [ "FRAP exchange, rounded puncta and solvent sensitivity alone cannot establish LLPS or liquid-state-specific function.", "Protein/RNA depletion, localization and binding changes must be distinguished from a state-only intervention; synthetic assembly does not by itself generalize to endogenous bodies." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Δ: endogenous NPM1 opto-gelation alters specific pre-rRNA processing relative to light controls; emerging charge/domain tests add support. Liquidity-only matched functional rescue and broader body classes remain unresolved, preventing a general necessity inference.", "ceiling_from_boundary_check": "Δ or higher" }, { "subclaim_id": "SC3", "field_valid_perturbation_quote": "\n- Endogenous degron of a condensate component with matched rescue, AND evidence that the specific condensate state (not generic protein loss) drives the phenotype\n- Locus-specific disruption of looping with locus-specific effect\n- Combinatorial histone-mark perturbation showing direct output dependence\n- Critically: specificity against cell-cycle collapse, global transcriptional collapse, and replication stress must be demonstrated", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "PMID27212236, PMID30500535, PMID32405004, PMID34315935, PMID21368180, PMID34819511, PMID33885174, PMID29932899, PMID27646274, PMID28404604, PMID30180948, PMID38381607, PMID33095160, PMID22718948, PMID36526633, PMID35963432, PMID33536240, PMID33608942, PMID34404453, PMID33814344, PMID37683610, PMID33333019, PMID29930090, PMID26776729, PMID40604277, PMID34739832, PMID20357773, PMID26997247, PMID33568486, PMID31038454, PMID18948503, PMID21170033, PMID40434645, PMID38192101, PMID26351690, PMID27374333", "gamma_hard_rules_triggered": [ "FRAP exchange, rounded puncta and solvent sensitivity alone cannot establish LLPS or liquid-state-specific function.", "Protein/RNA depletion, localization and binding changes must be distinguished from a state-only intervention; synthetic assembly does not by itself generalize to endogenous bodies." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Γ: class-general LLPS remains a mechanistic model, constrained by endogenous paraspeckle micelle tests, RNA-gel/partly solid nucleolar measurements and scaffold/binding alternatives. Restricted successes cannot establish common physics.", "ceiling_from_boundary_check": "Γ" } ], "thresholds_tested": [ { "subclaim_id": "SC1", "threshold": "Δ", "requirement_quoted": "Requires at least one endogenous perturbation showing the proposed feature contributes causally to the claimed output.", "satisfied": "yes", "supporting_evidence": [ "[1] Nucleolar GC/DFC have distinct fusion dynamics, low surface tension and reconstituted immiscible phases; concentration/domain manipulations alter organization.", "[2] HMGB1 frameshifts replace an acidic tail with basic residues, cause nucleolar mispartitioning and alter rRNA biogenesis; 12/13 tested variants enhance partitioning.", "[3] CasDrop optogenetic condensates exclude/pull chromatin and prefer softer genomic regions.", "[4] Dense/dilute concentration and transfer-energy measurements show heterotypic composition-dependent partitioning; fixed single-component saturation is absent, with RNA/transcription and valency contrasts.", "[5] Charge patterns and RNA binding organize subphases and nucleolar pH gradients.", "[6] FBL domain rescues link condensation-competent architecture to growth and rRNA processing; public extended-data captions report failed hnRNPA1-PLD substitution and retained FRAP for catalytic mutants.", "[7] FBL phenylalanine substitutions impair liquid/hydrogel assembly, DFC location and partner interactions.", "[8] Misfolded proteins enter nucleolar GC, with Hsp70-dependent recovery and prolonged-stress solidification/quality-control failure.", "[9] FBL RNA binding/GAR self-association organizes nascent pre-rRNA traffic and DFC clusters.", "[10] Scaffold/surfactant-client simulations yield size-conserved multiple droplets or coarsening depending on ratio.", "[11] Native nucleoli undergo fusion, deformation and ATP-sensitive viscous relaxation with coalescence-linked size distributions.", "[12] Hi-C-parameterized genome simulations predict nucleolar nucleation/arrest and a metastable two-droplet state.", "[13] NEAT1 end deletions at comparable expression remove core-shell order, enlarge and round paraspeckles; WT versus mutant transcription responses fit micelle predictions.", "[14] CRISPR NEAT1-domain deletion and NONO dimer-domain-dependent tether rescue establish multivalent assembly; selected fragments form in vitro aggregates.", "[15] Paraspeckles have ordered radial core-shell NEAT1/protein organization; FUS loss fragments them.", "[16] Needle shearing/heating improves NEAT1 recovery about 20-fold; FUS prion-like interactions affect semi-extractability.", "[17] NEAT1 promoter activation in two lines increases intact core-shell paraspeckles.", "[18] Integrator cleavage changes NEAT1 isoforms and restrains paraspeckle assembly.", "[19] SRRM2/SON form immiscible subcompartments; oligomerizable synthetic modules replace RS assembly roles while serines tune liquidity and target splicing.", "[20] C9 repeat RNA/DPRs alter speckle dynamics and sequester SRRM2; integrity loss changes splicing and neuronal viability.", "[21] SON/SRRM2 co-loss disperses multiple speckle markers without comparable Cajal loss; original shows SC35 chiefly recognizes SRRM2 and truncation alone can remove SC35 staining without dissolving speckles.", "[22] SRRM2 charge blocks alter network relaxation without markedly shifting condensation threshold; CK2 phosphorylation is linked to splicing after DNA damage.", "[25] Malat1 knockout mice retain speckle markers and normal baseline viability/fertility, with context-specific NEAT1 changes.", "[26] Controlled LLPS and clustered-binding systems show classic FRAP/hexanediol are nondiagnostic; calibrated half-FRAP probes preferential internal mixing.", "[29] PolII clusters form near CB/HLB; coilin knockout changes associations without PC number/timing changes, and PC removal leaves CB/HLB.", "[32] SLERT favors closed DDX21 conformation and loose clusters linked to FC/DFC fluidity and PolI processivity.", "[33] Slow directional RNA motion and approximately 5000-fold RNA/NPM1 diffusivity differences support entangled RNA with rapid protein movement through its mesh.", "[34] DDX18 loss disrupts nucleolar/chromatin organization; NoCasDrop targeted condensation restores selected centromere/heterochromatin readouts.", "[35] MALAT1 modulates SRSF1/pre-mRNA interactions and condensation near speckles with hypoxia-responsive splicing.", "[36] RNA amount promotes then dissolves transcriptional condensates, consistent with nonequilibrium feedback.", "[37] Physiological dynamic LCD hubs stabilize binding and recruit PolII without detectable macroscopic phase separation.", "[38] CTD phosphorylation shifts partition preference from mediator to splicing-factor condensates.", "[39] rRNA transcription seeds precisely timed nucleoli; without rDNA, variable high-concentration assemblies still arise.", "[40] Alu RNA depletion disrupts nucleolar structure/rRNA transcription, while added RNA increases size and pre-rRNA.", "[41] Fkbp39 chromatin localization/binding directs nascent 60S partition and improves ribosomal assembly.", "[42] Sequential processing maps spatial maturation; engineered SSU defects invert layers and prevent outflux, while LSU precursors build the outer layer.", "[43] RD-SPRITE identifies RNA territories; selected RNAs recruit regulators and alter contacts/function.", "[46] PML addback restores bodies, and SUMO-binding/RING mutants alter nucleation/recruitment.", "[47] A216V/L268P compare dynamics, packing, recruitment/PTMs and stress/senescence outputs with retained overall RBCC oligomerization.", "[48] NPM1 conformation changes valency and switches competing homo/heterotypic LLPS mechanisms.", "[49] Multivalent acidic motifs, oligomerization and RNA-binding domains drive NPM1 coassembly and nucleolar localization.", "[50] Crowding/concentration modulates interconversion of homo/heterotypic scaffolding networks.", "[51] PolyPR binds NPM1 acidic regions, dissolves in vitro droplets and disperses cell NPM1 while trapping RNA statically.", "[52] Liquid-like cohesin-DNA clusters depend on DNA length above 3 kb, supporting bridging-induced condensation.", "[53] HSV replication compartments concentrate PolII through accessible DNA/rebinding despite unrestricted interfacial diffusion.", "[55] EGFP-SRRM2 knock-in dynamics and depletion link scaffold to selected exon splicing, viability and differentiation.", "[57] Multiple structural or functional CB components nucleate apparently functional bodies when immobilized on chromatin.", "[58] Nascent NEAT1 transcription recruits functional paraspeckle proteins and retains mRNAs; continued transcription supports maintenance.", "[59] Endogenous-locus NPM1-Cry2olig cells accumulate 46S/45S and lose downstream precursors relative to light controls; activated mesh hinders large complexes while small-protein mobility persists.", "[60] Micropipette aspiration shows liquid-like GC but partly solid-like DFC/FC; RNase fluidizes internal phases and changes tension.", "[61] Chromatin depletion/flow accompanies coalescing nucleoli; short-range attraction models anomalous volume distribution.", "[62] Cell-size/concentration perturbation and nucleolar/extranucleolar kinetics agree with phase-transition predictions modulated by rRNA transcription.", "[63] Changing scaffold ratio/valency switches client composition in reconstitutions/cells, with analogous PML/P-body partitioning." ], "what_would_cross_it": "" }, { "subclaim_id": "SC1", "threshold": "Ε", "requirement_quoted": "Requires context-specific causality with clear scope restriction. Many enhancer, condensate, or accessibility claims belong here.", "satisfied": "yes", "supporting_evidence": [ "[1] Nucleolar GC/DFC have distinct fusion dynamics, low surface tension and reconstituted immiscible phases; concentration/domain manipulations alter organization.", "[2] HMGB1 frameshifts replace an acidic tail with basic residues, cause nucleolar mispartitioning and alter rRNA biogenesis; 12/13 tested variants enhance partitioning.", "[3] CasDrop optogenetic condensates exclude/pull chromatin and prefer softer genomic regions.", "[4] Dense/dilute concentration and transfer-energy measurements show heterotypic composition-dependent partitioning; fixed single-component saturation is absent, with RNA/transcription and valency contrasts.", "[5] Charge patterns and RNA binding organize subphases and nucleolar pH gradients.", "[6] FBL domain rescues link condensation-competent architecture to growth and rRNA processing; public extended-data captions report failed hnRNPA1-PLD substitution and retained FRAP for catalytic mutants.", "[7] FBL phenylalanine substitutions impair liquid/hydrogel assembly, DFC location and partner interactions.", "[8] Misfolded proteins enter nucleolar GC, with Hsp70-dependent recovery and prolonged-stress solidification/quality-control failure.", "[9] FBL RNA binding/GAR self-association organizes nascent pre-rRNA traffic and DFC clusters.", "[10] Scaffold/surfactant-client simulations yield size-conserved multiple droplets or coarsening depending on ratio.", "[11] Native nucleoli undergo fusion, deformation and ATP-sensitive viscous relaxation with coalescence-linked size distributions.", "[12] Hi-C-parameterized genome simulations predict nucleolar nucleation/arrest and a metastable two-droplet state.", "[13] NEAT1 end deletions at comparable expression remove core-shell order, enlarge and round paraspeckles; WT versus mutant transcription responses fit micelle predictions.", "[14] CRISPR NEAT1-domain deletion and NONO dimer-domain-dependent tether rescue establish multivalent assembly; selected fragments form in vitro aggregates.", "[15] Paraspeckles have ordered radial core-shell NEAT1/protein organization; FUS loss fragments them.", "[16] Needle shearing/heating improves NEAT1 recovery about 20-fold; FUS prion-like interactions affect semi-extractability.", "[17] NEAT1 promoter activation in two lines increases intact core-shell paraspeckles.", "[18] Integrator cleavage changes NEAT1 isoforms and restrains paraspeckle assembly.", "[19] SRRM2/SON form immiscible subcompartments; oligomerizable synthetic modules replace RS assembly roles while serines tune liquidity and target splicing.", "[20] C9 repeat RNA/DPRs alter speckle dynamics and sequester SRRM2; integrity loss changes splicing and neuronal viability.", "[21] SON/SRRM2 co-loss disperses multiple speckle markers without comparable Cajal loss; original shows SC35 chiefly recognizes SRRM2 and truncation alone can remove SC35 staining without dissolving speckles.", "[22] SRRM2 charge blocks alter network relaxation without markedly shifting condensation threshold; CK2 phosphorylation is linked to splicing after DNA damage.", "[25] Malat1 knockout mice retain speckle markers and normal baseline viability/fertility, with context-specific NEAT1 changes.", "[26] Controlled LLPS and clustered-binding systems show classic FRAP/hexanediol are nondiagnostic; calibrated half-FRAP probes preferential internal mixing.", "[29] PolII clusters form near CB/HLB; coilin knockout changes associations without PC number/timing changes, and PC removal leaves CB/HLB.", "[32] SLERT favors closed DDX21 conformation and loose clusters linked to FC/DFC fluidity and PolI processivity.", "[33] Slow directional RNA motion and approximately 5000-fold RNA/NPM1 diffusivity differences support entangled RNA with rapid protein movement through its mesh.", "[34] DDX18 loss disrupts nucleolar/chromatin organization; NoCasDrop targeted condensation restores selected centromere/heterochromatin readouts.", "[35] MALAT1 modulates SRSF1/pre-mRNA interactions and condensation near speckles with hypoxia-responsive splicing.", "[36] RNA amount promotes then dissolves transcriptional condensates, consistent with nonequilibrium feedback.", "[37] Physiological dynamic LCD hubs stabilize binding and recruit PolII without detectable macroscopic phase separation.", "[38] CTD phosphorylation shifts partition preference from mediator to splicing-factor condensates.", "[39] rRNA transcription seeds precisely timed nucleoli; without rDNA, variable high-concentration assemblies still arise.", "[40] Alu RNA depletion disrupts nucleolar structure/rRNA transcription, while added RNA increases size and pre-rRNA.", "[41] Fkbp39 chromatin localization/binding directs nascent 60S partition and improves ribosomal assembly.", "[42] Sequential processing maps spatial maturation; engineered SSU defects invert layers and prevent outflux, while LSU precursors build the outer layer.", "[43] RD-SPRITE identifies RNA territories; selected RNAs recruit regulators and alter contacts/function.", "[46] PML addback restores bodies, and SUMO-binding/RING mutants alter nucleation/recruitment.", "[47] A216V/L268P compare dynamics, packing, recruitment/PTMs and stress/senescence outputs with retained overall RBCC oligomerization.", "[48] NPM1 conformation changes valency and switches competing homo/heterotypic LLPS mechanisms.", "[49] Multivalent acidic motifs, oligomerization and RNA-binding domains drive NPM1 coassembly and nucleolar localization.", "[50] Crowding/concentration modulates interconversion of homo/heterotypic scaffolding networks.", "[51] PolyPR binds NPM1 acidic regions, dissolves in vitro droplets and disperses cell NPM1 while trapping RNA statically.", "[52] Liquid-like cohesin-DNA clusters depend on DNA length above 3 kb, supporting bridging-induced condensation.", "[53] HSV replication compartments concentrate PolII through accessible DNA/rebinding despite unrestricted interfacial diffusion.", "[55] EGFP-SRRM2 knock-in dynamics and depletion link scaffold to selected exon splicing, viability and differentiation.", "[57] Multiple structural or functional CB components nucleate apparently functional bodies when immobilized on chromatin.", "[58] Nascent NEAT1 transcription recruits functional paraspeckle proteins and retains mRNAs; continued transcription supports maintenance.", "[59] Endogenous-locus NPM1-Cry2olig cells accumulate 46S/45S and lose downstream precursors relative to light controls; activated mesh hinders large complexes while small-protein mobility persists.", "[60] Micropipette aspiration shows liquid-like GC but partly solid-like DFC/FC; RNase fluidizes internal phases and changes tension.", "[61] Chromatin depletion/flow accompanies coalescing nucleoli; short-range attraction models anomalous volume distribution.", "[62] Cell-size/concentration perturbation and nucleolar/extranucleolar kinetics agree with phase-transition predictions modulated by rRNA transcription.", "[63] Changing scaffold ratio/valency switches client composition in reconstitutions/cells, with analogous PML/P-body partitioning." ], "what_would_cross_it": "" }, { "subclaim_id": "SC1", "threshold": "Ζ", "requirement_quoted": "Requires:\n- Independent causal tests across loci or systems\n- Specificity beyond global transcriptional collapse\n- Narrowing of key alternatives", "satisfied": "no", "supporting_evidence": [ "[1] Nucleolar GC/DFC have distinct fusion dynamics, low surface tension and reconstituted immiscible phases; concentration/domain manipulations alter organization.", "[2] HMGB1 frameshifts replace an acidic tail with basic residues, cause nucleolar mispartitioning and alter rRNA biogenesis; 12/13 tested variants enhance partitioning.", "[3] CasDrop optogenetic condensates exclude/pull chromatin and prefer softer genomic regions.", "[4] Dense/dilute concentration and transfer-energy measurements show heterotypic composition-dependent partitioning; fixed single-component saturation is absent, with RNA/transcription and valency contrasts.", "[5] Charge patterns and RNA binding organize subphases and nucleolar pH gradients.", "[6] FBL domain rescues link condensation-competent architecture to growth and rRNA processing; public extended-data captions report failed hnRNPA1-PLD substitution and retained FRAP for catalytic mutants.", "[7] FBL phenylalanine substitutions impair liquid/hydrogel assembly, DFC location and partner interactions.", "[8] Misfolded proteins enter nucleolar GC, with Hsp70-dependent recovery and prolonged-stress solidification/quality-control failure.", "[9] FBL RNA binding/GAR self-association organizes nascent pre-rRNA traffic and DFC clusters.", "[10] Scaffold/surfactant-client simulations yield size-conserved multiple droplets or coarsening depending on ratio.", "[11] Native nucleoli undergo fusion, deformation and ATP-sensitive viscous relaxation with coalescence-linked size distributions.", "[12] Hi-C-parameterized genome simulations predict nucleolar nucleation/arrest and a metastable two-droplet state.", "[13] NEAT1 end deletions at comparable expression remove core-shell order, enlarge and round paraspeckles; WT versus mutant transcription responses fit micelle predictions.", "[14] CRISPR NEAT1-domain deletion and NONO dimer-domain-dependent tether rescue establish multivalent assembly; selected fragments form in vitro aggregates.", "[15] Paraspeckles have ordered radial core-shell NEAT1/protein organization; FUS loss fragments them.", "[16] Needle shearing/heating improves NEAT1 recovery about 20-fold; FUS prion-like interactions affect semi-extractability.", "[17] NEAT1 promoter activation in two lines increases intact core-shell paraspeckles.", "[18] Integrator cleavage changes NEAT1 isoforms and restrains paraspeckle assembly.", "[19] SRRM2/SON form immiscible subcompartments; oligomerizable synthetic modules replace RS assembly roles while serines tune liquidity and target splicing.", "[20] C9 repeat RNA/DPRs alter speckle dynamics and sequester SRRM2; integrity loss changes splicing and neuronal viability.", "[21] SON/SRRM2 co-loss disperses multiple speckle markers without comparable Cajal loss; original shows SC35 chiefly recognizes SRRM2 and truncation alone can remove SC35 staining without dissolving speckles.", "[22] SRRM2 charge blocks alter network relaxation without markedly shifting condensation threshold; CK2 phosphorylation is linked to splicing after DNA damage.", "[25] Malat1 knockout mice retain speckle markers and normal baseline viability/fertility, with context-specific NEAT1 changes.", "[26] Controlled LLPS and clustered-binding systems show classic FRAP/hexanediol are nondiagnostic; calibrated half-FRAP probes preferential internal mixing.", "[29] PolII clusters form near CB/HLB; coilin knockout changes associations without PC number/timing changes, and PC removal leaves CB/HLB.", "[32] SLERT favors closed DDX21 conformation and loose clusters linked to FC/DFC fluidity and PolI processivity.", "[33] Slow directional RNA motion and approximately 5000-fold RNA/NPM1 diffusivity differences support entangled RNA with rapid protein movement through its mesh.", "[34] DDX18 loss disrupts nucleolar/chromatin organization; NoCasDrop targeted condensation restores selected centromere/heterochromatin readouts.", "[35] MALAT1 modulates SRSF1/pre-mRNA interactions and condensation near speckles with hypoxia-responsive splicing.", "[36] RNA amount promotes then dissolves transcriptional condensates, consistent with nonequilibrium feedback.", "[37] Physiological dynamic LCD hubs stabilize binding and recruit PolII without detectable macroscopic phase separation.", "[38] CTD phosphorylation shifts partition preference from mediator to splicing-factor condensates.", "[39] rRNA transcription seeds precisely timed nucleoli; without rDNA, variable high-concentration assemblies still arise.", "[40] Alu RNA depletion disrupts nucleolar structure/rRNA transcription, while added RNA increases size and pre-rRNA.", "[41] Fkbp39 chromatin localization/binding directs nascent 60S partition and improves ribosomal assembly.", "[42] Sequential processing maps spatial maturation; engineered SSU defects invert layers and prevent outflux, while LSU precursors build the outer layer.", "[43] RD-SPRITE identifies RNA territories; selected RNAs recruit regulators and alter contacts/function.", "[46] PML addback restores bodies, and SUMO-binding/RING mutants alter nucleation/recruitment.", "[47] A216V/L268P compare dynamics, packing, recruitment/PTMs and stress/senescence outputs with retained overall RBCC oligomerization.", "[48] NPM1 conformation changes valency and switches competing homo/heterotypic LLPS mechanisms.", "[49] Multivalent acidic motifs, oligomerization and RNA-binding domains drive NPM1 coassembly and nucleolar localization.", "[50] Crowding/concentration modulates interconversion of homo/heterotypic scaffolding networks.", "[51] PolyPR binds NPM1 acidic regions, dissolves in vitro droplets and disperses cell NPM1 while trapping RNA statically.", "[52] Liquid-like cohesin-DNA clusters depend on DNA length above 3 kb, supporting bridging-induced condensation.", "[53] HSV replication compartments concentrate PolII through accessible DNA/rebinding despite unrestricted interfacial diffusion.", "[55] EGFP-SRRM2 knock-in dynamics and depletion link scaffold to selected exon splicing, viability and differentiation.", "[57] Multiple structural or functional CB components nucleate apparently functional bodies when immobilized on chromatin.", "[58] Nascent NEAT1 transcription recruits functional paraspeckle proteins and retains mRNAs; continued transcription supports maintenance.", "[59] Endogenous-locus NPM1-Cry2olig cells accumulate 46S/45S and lose downstream precursors relative to light controls; activated mesh hinders large complexes while small-protein mobility persists.", "[60] Micropipette aspiration shows liquid-like GC but partly solid-like DFC/FC; RNase fluidizes internal phases and changes tension.", "[61] Chromatin depletion/flow accompanies coalescing nucleoli; short-range attraction models anomalous volume distribution.", "[62] Cell-size/concentration perturbation and nucleolar/extranucleolar kinetics agree with phase-transition predictions modulated by rRNA transcription.", "[63] Changing scaffold ratio/valency switches client composition in reconstitutions/cells, with analogous PML/P-body partitioning." ], "what_would_cross_it": "A prespecified causal test matching this subclaim, with mechanistic engagement, meaningful phenotype change and an appropriate negative control." }, { "subclaim_id": "SC2", "threshold": "Δ", "requirement_quoted": "Requires at least one endogenous perturbation showing the proposed feature contributes causally to the claimed output.", "satisfied": "yes", "supporting_evidence": [ "[1] Nucleolar GC/DFC have distinct fusion dynamics, low surface tension and reconstituted immiscible phases; concentration/domain manipulations alter organization.", "[2] HMGB1 frameshifts replace an acidic tail with basic residues, cause nucleolar mispartitioning and alter rRNA biogenesis; 12/13 tested variants enhance partitioning.", "[4] Dense/dilute concentration and transfer-energy measurements show heterotypic composition-dependent partitioning; fixed single-component saturation is absent, with RNA/transcription and valency contrasts.", "[5] Charge patterns and RNA binding organize subphases and nucleolar pH gradients.", "[6] FBL domain rescues link condensation-competent architecture to growth and rRNA processing; public extended-data captions report failed hnRNPA1-PLD substitution and retained FRAP for catalytic mutants.", "[7] FBL phenylalanine substitutions impair liquid/hydrogel assembly, DFC location and partner interactions.", "[8] Misfolded proteins enter nucleolar GC, with Hsp70-dependent recovery and prolonged-stress solidification/quality-control failure.", "[9] FBL RNA binding/GAR self-association organizes nascent pre-rRNA traffic and DFC clusters.", "[13] NEAT1 end deletions at comparable expression remove core-shell order, enlarge and round paraspeckles; WT versus mutant transcription responses fit micelle predictions.", "[14] CRISPR NEAT1-domain deletion and NONO dimer-domain-dependent tether rescue establish multivalent assembly; selected fragments form in vitro aggregates.", "[18] Integrator cleavage changes NEAT1 isoforms and restrains paraspeckle assembly.", "[19] SRRM2/SON form immiscible subcompartments; oligomerizable synthetic modules replace RS assembly roles while serines tune liquidity and target splicing.", "[20] C9 repeat RNA/DPRs alter speckle dynamics and sequester SRRM2; integrity loss changes splicing and neuronal viability.", "[21] SON/SRRM2 co-loss disperses multiple speckle markers without comparable Cajal loss; original shows SC35 chiefly recognizes SRRM2 and truncation alone can remove SC35 staining without dissolving speckles.", "[22] SRRM2 charge blocks alter network relaxation without markedly shifting condensation threshold; CK2 phosphorylation is linked to splicing after DNA damage.", "[24] HIF2alpha speckle-targeting motifs influence selected ccRCC transcriptional programs; speckle states correlate with outcomes.", "[27] Both 1,6-HD and nominal-control 2,5-HD suppress coalescing/noncoalescing gene transcription and increase nucleosome density.", "[28] Hexanediol dose-dependently immobilizes/hypercondenses chromatin; 5 percent or more freezes tested chromatin motion.", "[30] 1.5 percent short treatment dissolves bodies with different chromatin-contact effects than longer exposure/aggregation.", "[31] Structured low-concentration kinases and IDR-deleted P-TEFb are inhibited by hexanediol; dilution restores activity and kinase inhibition can preserve CTD droplets.", "[32] SLERT favors closed DDX21 conformation and loose clusters linked to FC/DFC fluidity and PolI processivity.", "[33] Slow directional RNA motion and approximately 5000-fold RNA/NPM1 diffusivity differences support entangled RNA with rapid protein movement through its mesh.", "[34] DDX18 loss disrupts nucleolar/chromatin organization; NoCasDrop targeted condensation restores selected centromere/heterochromatin readouts.", "[35] MALAT1 modulates SRSF1/pre-mRNA interactions and condensation near speckles with hypoxia-responsive splicing.", "[38] CTD phosphorylation shifts partition preference from mediator to splicing-factor condensates.", "[40] Alu RNA depletion disrupts nucleolar structure/rRNA transcription, while added RNA increases size and pre-rRNA.", "[41] Fkbp39 chromatin localization/binding directs nascent 60S partition and improves ribosomal assembly.", "[42] Sequential processing maps spatial maturation; engineered SSU defects invert layers and prevent outflux, while LSU precursors build the outer layer.", "[43] RD-SPRITE identifies RNA territories; selected RNAs recruit regulators and alter contacts/function.", "[44] Coilin loss disperses CB, impairs snRNP production and arrests development; mature human snRNPs restore mRNA/viability while RNA alone does not.", "[45] CB RNAi disassembly changes gene clustering/expression and increases splicing noise.", "[46] PML addback restores bodies, and SUMO-binding/RING mutants alter nucleation/recruitment.", "[47] A216V/L268P compare dynamics, packing, recruitment/PTMs and stress/senescence outputs with retained overall RBCC oligomerization.", "[48] NPM1 conformation changes valency and switches competing homo/heterotypic LLPS mechanisms.", "[49] Multivalent acidic motifs, oligomerization and RNA-binding domains drive NPM1 coassembly and nucleolar localization.", "[50] Crowding/concentration modulates interconversion of homo/heterotypic scaffolding networks.", "[51] PolyPR binds NPM1 acidic regions, dissolves in vitro droplets and disperses cell NPM1 while trapping RNA statically.", "[54] Speckle proximity predicts more spliceosome binding, and directed pre-mRNA recruitment increases splicing.", "[55] EGFP-SRRM2 knock-in dynamics and depletion link scaffold to selected exon splicing, viability and differentiation.", "[56] SRRM2 depletion disperses speckles and changes active-compartment interactions and 1282 genes; contact changes do not track expression changes.", "[58] Nascent NEAT1 transcription recruits functional paraspeckle proteins and retains mRNAs; continued transcription supports maintenance.", "[59] Endogenous-locus NPM1-Cry2olig cells accumulate 46S/45S and lose downstream precursors relative to light controls; activated mesh hinders large complexes while small-protein mobility persists.", "[60] Micropipette aspiration shows liquid-like GC but partly solid-like DFC/FC; RNase fluidizes internal phases and changes tension.", "[63] Changing scaffold ratio/valency switches client composition in reconstitutions/cells, with analogous PML/P-body partitioning." ], "what_would_cross_it": "" }, { "subclaim_id": "SC2", "threshold": "Ε", "requirement_quoted": "Requires context-specific causality with clear scope restriction. Many enhancer, condensate, or accessibility claims belong here.", "satisfied": "no", "supporting_evidence": [ "[1] Nucleolar GC/DFC have distinct fusion dynamics, low surface tension and reconstituted immiscible phases; concentration/domain manipulations alter organization.", "[2] HMGB1 frameshifts replace an acidic tail with basic residues, cause nucleolar mispartitioning and alter rRNA biogenesis; 12/13 tested variants enhance partitioning.", "[4] Dense/dilute concentration and transfer-energy measurements show heterotypic composition-dependent partitioning; fixed single-component saturation is absent, with RNA/transcription and valency contrasts.", "[5] Charge patterns and RNA binding organize subphases and nucleolar pH gradients.", "[6] FBL domain rescues link condensation-competent architecture to growth and rRNA processing; public extended-data captions report failed hnRNPA1-PLD substitution and retained FRAP for catalytic mutants.", "[7] FBL phenylalanine substitutions impair liquid/hydrogel assembly, DFC location and partner interactions.", "[8] Misfolded proteins enter nucleolar GC, with Hsp70-dependent recovery and prolonged-stress solidification/quality-control failure.", "[9] FBL RNA binding/GAR self-association organizes nascent pre-rRNA traffic and DFC clusters.", "[13] NEAT1 end deletions at comparable expression remove core-shell order, enlarge and round paraspeckles; WT versus mutant transcription responses fit micelle predictions.", "[14] CRISPR NEAT1-domain deletion and NONO dimer-domain-dependent tether rescue establish multivalent assembly; selected fragments form in vitro aggregates.", "[18] Integrator cleavage changes NEAT1 isoforms and restrains paraspeckle assembly.", "[19] SRRM2/SON form immiscible subcompartments; oligomerizable synthetic modules replace RS assembly roles while serines tune liquidity and target splicing.", "[20] C9 repeat RNA/DPRs alter speckle dynamics and sequester SRRM2; integrity loss changes splicing and neuronal viability.", "[21] SON/SRRM2 co-loss disperses multiple speckle markers without comparable Cajal loss; original shows SC35 chiefly recognizes SRRM2 and truncation alone can remove SC35 staining without dissolving speckles.", "[22] SRRM2 charge blocks alter network relaxation without markedly shifting condensation threshold; CK2 phosphorylation is linked to splicing after DNA damage.", "[24] HIF2alpha speckle-targeting motifs influence selected ccRCC transcriptional programs; speckle states correlate with outcomes.", "[27] Both 1,6-HD and nominal-control 2,5-HD suppress coalescing/noncoalescing gene transcription and increase nucleosome density.", "[28] Hexanediol dose-dependently immobilizes/hypercondenses chromatin; 5 percent or more freezes tested chromatin motion.", "[30] 1.5 percent short treatment dissolves bodies with different chromatin-contact effects than longer exposure/aggregation.", "[31] Structured low-concentration kinases and IDR-deleted P-TEFb are inhibited by hexanediol; dilution restores activity and kinase inhibition can preserve CTD droplets.", "[32] SLERT favors closed DDX21 conformation and loose clusters linked to FC/DFC fluidity and PolI processivity.", "[33] Slow directional RNA motion and approximately 5000-fold RNA/NPM1 diffusivity differences support entangled RNA with rapid protein movement through its mesh.", "[34] DDX18 loss disrupts nucleolar/chromatin organization; NoCasDrop targeted condensation restores selected centromere/heterochromatin readouts.", "[35] MALAT1 modulates SRSF1/pre-mRNA interactions and condensation near speckles with hypoxia-responsive splicing.", "[38] CTD phosphorylation shifts partition preference from mediator to splicing-factor condensates.", "[40] Alu RNA depletion disrupts nucleolar structure/rRNA transcription, while added RNA increases size and pre-rRNA.", "[41] Fkbp39 chromatin localization/binding directs nascent 60S partition and improves ribosomal assembly.", "[42] Sequential processing maps spatial maturation; engineered SSU defects invert layers and prevent outflux, while LSU precursors build the outer layer.", "[43] RD-SPRITE identifies RNA territories; selected RNAs recruit regulators and alter contacts/function.", "[44] Coilin loss disperses CB, impairs snRNP production and arrests development; mature human snRNPs restore mRNA/viability while RNA alone does not.", "[45] CB RNAi disassembly changes gene clustering/expression and increases splicing noise.", "[46] PML addback restores bodies, and SUMO-binding/RING mutants alter nucleation/recruitment.", "[47] A216V/L268P compare dynamics, packing, recruitment/PTMs and stress/senescence outputs with retained overall RBCC oligomerization.", "[48] NPM1 conformation changes valency and switches competing homo/heterotypic LLPS mechanisms.", "[49] Multivalent acidic motifs, oligomerization and RNA-binding domains drive NPM1 coassembly and nucleolar localization.", "[50] Crowding/concentration modulates interconversion of homo/heterotypic scaffolding networks.", "[51] PolyPR binds NPM1 acidic regions, dissolves in vitro droplets and disperses cell NPM1 while trapping RNA statically.", "[54] Speckle proximity predicts more spliceosome binding, and directed pre-mRNA recruitment increases splicing.", "[55] EGFP-SRRM2 knock-in dynamics and depletion link scaffold to selected exon splicing, viability and differentiation.", "[56] SRRM2 depletion disperses speckles and changes active-compartment interactions and 1282 genes; contact changes do not track expression changes.", "[58] Nascent NEAT1 transcription recruits functional paraspeckle proteins and retains mRNAs; continued transcription supports maintenance.", "[59] Endogenous-locus NPM1-Cry2olig cells accumulate 46S/45S and lose downstream precursors relative to light controls; activated mesh hinders large complexes while small-protein mobility persists.", "[60] Micropipette aspiration shows liquid-like GC but partly solid-like DFC/FC; RNase fluidizes internal phases and changes tension.", "[63] Changing scaffold ratio/valency switches client composition in reconstitutions/cells, with analogous PML/P-body partitioning." ], "what_would_cross_it": "A prespecified causal test matching this subclaim, with mechanistic engagement, meaningful phenotype change and an appropriate negative control." }, { "subclaim_id": "SC3", "threshold": "Δ", "requirement_quoted": "Requires at least one endogenous perturbation showing the proposed feature contributes causally to the claimed output.", "satisfied": "no", "supporting_evidence": [ "[1] Nucleolar GC/DFC have distinct fusion dynamics, low surface tension and reconstituted immiscible phases; concentration/domain manipulations alter organization.", "[3] CasDrop optogenetic condensates exclude/pull chromatin and prefer softer genomic regions.", "[4] Dense/dilute concentration and transfer-energy measurements show heterotypic composition-dependent partitioning; fixed single-component saturation is absent, with RNA/transcription and valency contrasts.", "[10] Scaffold/surfactant-client simulations yield size-conserved multiple droplets or coarsening depending on ratio.", "[11] Native nucleoli undergo fusion, deformation and ATP-sensitive viscous relaxation with coalescence-linked size distributions.", "[12] Hi-C-parameterized genome simulations predict nucleolar nucleation/arrest and a metastable two-droplet state.", "[13] NEAT1 end deletions at comparable expression remove core-shell order, enlarge and round paraspeckles; WT versus mutant transcription responses fit micelle predictions.", "[14] CRISPR NEAT1-domain deletion and NONO dimer-domain-dependent tether rescue establish multivalent assembly; selected fragments form in vitro aggregates.", "[15] Paraspeckles have ordered radial core-shell NEAT1/protein organization; FUS loss fragments them.", "[16] Needle shearing/heating improves NEAT1 recovery about 20-fold; FUS prion-like interactions affect semi-extractability.", "[17] NEAT1 promoter activation in two lines increases intact core-shell paraspeckles.", "[19] SRRM2/SON form immiscible subcompartments; oligomerizable synthetic modules replace RS assembly roles while serines tune liquidity and target splicing.", "[21] SON/SRRM2 co-loss disperses multiple speckle markers without comparable Cajal loss; original shows SC35 chiefly recognizes SRRM2 and truncation alone can remove SC35 staining without dissolving speckles.", "[25] Malat1 knockout mice retain speckle markers and normal baseline viability/fertility, with context-specific NEAT1 changes.", "[26] Controlled LLPS and clustered-binding systems show classic FRAP/hexanediol are nondiagnostic; calibrated half-FRAP probes preferential internal mixing.", "[27] Both 1,6-HD and nominal-control 2,5-HD suppress coalescing/noncoalescing gene transcription and increase nucleosome density.", "[28] Hexanediol dose-dependently immobilizes/hypercondenses chromatin; 5 percent or more freezes tested chromatin motion.", "[29] PolII clusters form near CB/HLB; coilin knockout changes associations without PC number/timing changes, and PC removal leaves CB/HLB.", "[30] 1.5 percent short treatment dissolves bodies with different chromatin-contact effects than longer exposure/aggregation.", "[31] Structured low-concentration kinases and IDR-deleted P-TEFb are inhibited by hexanediol; dilution restores activity and kinase inhibition can preserve CTD droplets.", "[33] Slow directional RNA motion and approximately 5000-fold RNA/NPM1 diffusivity differences support entangled RNA with rapid protein movement through its mesh.", "[36] RNA amount promotes then dissolves transcriptional condensates, consistent with nonequilibrium feedback.", "[37] Physiological dynamic LCD hubs stabilize binding and recruit PolII without detectable macroscopic phase separation.", "[39] rRNA transcription seeds precisely timed nucleoli; without rDNA, variable high-concentration assemblies still arise.", "[42] Sequential processing maps spatial maturation; engineered SSU defects invert layers and prevent outflux, while LSU precursors build the outer layer.", "[43] RD-SPRITE identifies RNA territories; selected RNAs recruit regulators and alter contacts/function.", "[44] Coilin loss disperses CB, impairs snRNP production and arrests development; mature human snRNPs restore mRNA/viability while RNA alone does not.", "[45] CB RNAi disassembly changes gene clustering/expression and increases splicing noise.", "[52] Liquid-like cohesin-DNA clusters depend on DNA length above 3 kb, supporting bridging-induced condensation.", "[53] HSV replication compartments concentrate PolII through accessible DNA/rebinding despite unrestricted interfacial diffusion.", "[57] Multiple structural or functional CB components nucleate apparently functional bodies when immobilized on chromatin.", "[58] Nascent NEAT1 transcription recruits functional paraspeckle proteins and retains mRNAs; continued transcription supports maintenance.", "[60] Micropipette aspiration shows liquid-like GC but partly solid-like DFC/FC; RNase fluidizes internal phases and changes tension.", "[61] Chromatin depletion/flow accompanies coalescing nucleoli; short-range attraction models anomalous volume distribution.", "[62] Cell-size/concentration perturbation and nucleolar/extranucleolar kinetics agree with phase-transition predictions modulated by rRNA transcription.", "[63] Changing scaffold ratio/valency switches client composition in reconstitutions/cells, with analogous PML/P-body partitioning." ], "what_would_cross_it": "A prespecified causal test matching this subclaim, with mechanistic engagement, meaningful phenotype change and an appropriate negative control." } ], "generalization_check": { "generalization_tested": "yes", "context_boundary_mapped": "yes", "internal_negative_controls": [ "2019 endogenous NPM1-Cry2olig RNA processing versus identically light-exposed untagged cells; small versus large clients and activation threshold.", "2021 NEAT1 end deletions with comparable RNA expression and WT/mutant transcription responses.", "2020 SRRM2 truncation: lost SC35 epitope with retained alternative markers; co-depletion preserves Cajal number.", "2021 low-concentration structured kinases, IDR-deleted P-TEFb and dilution recovery show solvent off-targets.", "2022 benchmark separates clustered binding from LLPS through preferential internal mixing rather than classical FRAP." ], "note": "Body classes, subphases, RNA versus protein probes, developmental/stressed cells, endogenous versus expressed/tethered constructs and timescales are explicitly distinguished. A gel-like RNA mesh can coexist with liquid-like protein-rich material; microphase separation is not no phase separation." }, "falsification_patterns_met": [ { "pattern": "Alternative physical model predicts endogenous architecture after targeted edit", "evidence": "NEAT1 expression-matched end deletion changes ordered shells/size as micelle model predicts, PMID33885174.", "downgrade_applied": false }, { "pattern": "Fast protein FRAP coexists with a slow RNA network", "evidence": "RNA/NPM1 diffusivity contrast and aspiration, PMID37683610,40434645.", "downgrade_applied": false } ], "pitfalls_flagged": [ { "pitfall": "FRAP or hexanediol equated with LLPS proof", "where": "Half-FRAP binding benchmark and direct enzyme inhibition." }, { "pitfall": "Antibody epitope loss equated with body dissolution", "where": "SC35 staining is lost in deep SRRM2 truncation while other markers remain." }, { "pitfall": "Liquid and gel treated as mutually exclusive at every timescale", "where": "RNA entanglement and small-protein diffusion coexist in nucleoli." }, { "pitfall": "Condensation rescue equated with liquid-specific functional rescue", "where": "NONO tether, synthetic oligomers and FBL PLD substitution distinguish these burdens." }, { "pitfall": "Provider review citation presented as original test", "where": "Consensus broad gel-rescue statement replaced by original Zhu passage." } ], "causal_tally_audit": { "tally_claimed_by_document": 62, "tally_after_audit": 62, "items_rejected": [ "Null and negative contrasts are discriminators, not positive threshold crossings. Reports and replications are not independent causal lines.", "Shared cohorts, experimental platforms, transgenic lineages and repeated outcomes do not constitute fully independent causal lines." ] }, "steelman": { "case_one_rung_higher": "Steelman Δ for the broad claim: nucleolar material perturbation, expression-matched paraspeckle architecture and speckle charge-state/function tests together show physical organization is causal. This supports the pluralist mechanism, but does not distinguish common macroscopic LLPS as the organizing physics across all registered classes.", "case_one_rung_lower": "Steelman Β: routine evidence is imaging/partition association with binding confounding. Γ remains justified by physical reconstitution, native phase measurements and causal perturbations; reducing everything to association would discard original endogenous tests.", "which_rejected": "Retain Γ for the weakest-link broad statement and explicitly preserve Ε existence and Δ selected functional contribution. Do not claim phase separation refuted or merely a metaphor.", "blocking_cap_threshold_or_missing_experiment": "Missing experiment: In preregistered nucleolar, speckle and paraspeckle systems, use endogenous reversible sequence/charge edits that change relaxation or demixing while preserving abundance, RNA/client affinity and catalytic activity; rescue the material state with matched constructs and test physical and processing outputs separately." }, "final_score": { "hsef_level": "Γ", "hsef_descriptor": "Mechanistically plausible, partial system support", "confidence": "Moderate", "confidence_rationale": "Multiple independent studies across nucleoli, speckles, paraspeckles, Cajal and PML bodies, with partial replication, but substantive evidence-quality reservations remain and are documented in the review itself: probe- and timescale-dependent material measurements, physical assays resting on expressed optogenetic constructs, a shared haploid-cell and investigator platform for the paraspeckle line, mixed liquid and partly solid phases within one body, and the demonstrated non-specificity of hexanediol and classical FRAP. Evidence density and reproducibility set the Moderate band, not the reviewer's access depth and not correctness.", "rests_on_non_peer_reviewed_work": false, "rationale": "Preregistered weakest-link aggregation returns Γ from SC3 common organizing physics, despite scoped SC1 Ε and SC2 Δ. Primary SC2 and its scope-matched sensitivity return Δ; broad class-general scope remains Γ. This does not downgrade genuine nucleolar demixing or functional material-property contributions." }, "role_of_mechanism": { "classification": "reinforcing / stabilizing factor", "derivation_step_matched": 5, "derivation": "Canonical step 5 fits the broad registered mechanism: condensation/material organization changes assembly and throughput in selected contexts, without unique necessity across all body classes. This role does not claim primary initiation or deny a restricted scaffold requirement.", "tournament_used_as_tiebreaker": false, "note": "Derived from causal direction, not tournament rank." }, "extended_scoring_MSD": { "momentum": { "value": "Mechanistic only", "artifact": "The named work is active and genuinely mechanistic (2024 FBL domain and speckle subphase studies, 2025 charge-network, micropipette-aspiration and engineered RNA-architecture studies, 2026 hypoxia splicing), but every one is a completed publication and none attempts the boundary check identified as decisive: a liquidity-only matched functional rescue across the preregistered body classes. No currently recruiting study asserted.", "justification": "The named work is active and genuinely mechanistic (2024 FBL domain and speckle subphase studies, 2025 charge-network, micropipette-aspiration and engineered RNA-architecture studies, 2026 hypoxia splicing), but every one is a completed publication and none attempts the boundary check identified as decisive: a liquidity-only matched functional rescue across the preregistered body classes. No currently recruiting study asserted." }, "stability": { "value": "Stable", "trigger": "No named pending result is asserted to be likely to move the registered score imminently.", "justification": "No named pending result is asserted to be likely to move the registered score imminently." }, "divergence": { "implied_level": null, "implied_level_basis": "No single field-implied level is defensible from conflicting framings.", "assessed_level": "Γ", "gap_in_rungs": null, "value": "Contested", "justification": "No manufactured field consensus or arithmetic gap. Artifact for the split: review and grant framing of phase separation as the established organizing principle of nuclear bodies implies a high rung, while the methodological literature in the same field argues that the standard diagnostics cannot distinguish controlled demixing from clustered binding, implying a much lower one (PMID36526633,33814344,33885174)." }, "calibration_note": "M/S/D never modify HSEF level or confidence." }, "change_record": { "applies": false, "prior_level": "Ranking categorical verdict visible; no prior letter used as a target", "prior_confidence": null, "prior_source": null, "derived_before_consulting_prior": false, "new_level": "Γ", "direction": "newly assigned", "what_moved_it": "Fresh primary evidence appraisal; not blinded.", "divergence_from_other_reviewers": null }, "proposed_decisive_experiments": [ { "name": "Registered boundary experiment", "experiment": "In preregistered nucleolar, speckle and paraspeckle systems, use endogenous reversible sequence/charge edits that change relaxation or demixing while preserving abundance, RNA/client affinity and catalytic activity; rescue the material state with matched constructs and test physical and processing outputs separately.", "readout": "Calibrated interfacial mixing/rheology, client composition, nascent-rRNA maturation or endogenous splicing and cell-state measures", "critical_control": "Expression/valency/client-affinity matched rescue, light/solvent controls, orthogonal probes of RNA/protein mobility, cell-cycle and global transcription stress", "supporting_result": "Output changes track state across orthogonal edits and recover on state restoration with binding/function conserved", "falsifying_result": "Output remains intact after verified state change, or only loss of binding/scaffold explains impairment" } ], "knowledge_gaps": [ { "name": "Gap 1", "statement": "Measure physical state at endogenous concentrations with multiple constituents and timescales, rather than assigning a whole body from one protein FRAP curve.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 2", "statement": "Preserve RNA/client affinity, valency, protein abundance and catalysis while selectively changing state; use matched functional restoration.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 3", "statement": "Add light-off processing rescue and shorter perturbation windows to separate mesh effects from 24–72 h light toxicity.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 4", "statement": "Test predicted paraspeckle micelle geometry against alternative arrested-liquid/BIPS models without redefining all microphase separation as bulk LLPS.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 5", "statement": "Separate phosphorylation effects on spliceosome binding and global CK2 activity from network relaxation.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 6", "statement": "Quantify PML variant effects on partner binding, SUMO and arsenic response independently of FRAP-inferred liquidity.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 7", "statement": "Extend state/function tests to Cajal and other classes while preserving their macromolecular-product supply.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 8", "statement": "Map active RNA maturation, entanglement and interfacial transport with calibrated identifiable models and independent replication.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 9", "statement": "Complete unavailable original bodies, supplements and linked correction details before reproducing decisive figures publicly.", "relevance": "Limits mechanism identification or scope." } ], "review_metadata": { "review_date": "2026-10-08", "reviewer": "Codex", "evidence_base_note": "63 primary reports; literature cutoff 2026-10-08; source examination UTC date 2026-10-08; bounded critical review, not exhaustive systematic review.", "literature_tools_available": true, "literature_tools_note": "Life Sciences Literature PubMed/Entrez; attempted Europe PMC XML and successful public NCBI PMC direct HTTPS access are separately logged. Signed-in Consensus browser discovery and targeted indexed full-text checks are reconciled with original sections; failed matches and source substitutions remain explicit. Zero Consensus API calls. SciSpace discovery was also used; matched primary leads were resolved to original records before counting. See scispace-leads.json.", "skill_version": "5.3", "validator_run": "exact archived v5.3 validator 2.3; see validator.txt", "validator_warnings_addressed": "Phenomenon entry was restated as the preregistered causal claim. No real phenomenon is labelled refuted; warning is explicitly justified.", "consensus_consistency_audit": "2026-10-09; supplementary provenance/source reconciliation; original grading retained; prior grades visible." }, "is_calibration_entry": { "value": false, "entry_role": "not_calibration", "blind_graded": null, "completed_blinded_calibration": false, "expected_band_sealed_at": "", "target_sha256": "", "target_authorship": "not applicable", "target_author_saw_review": null, "future_run_status": "not prepared", "unblinded_reason": "Ranking categorical verdict and index guidance were visible. No completed blinded calibration claimed." }, "upper_ladder_check": { "final_level_below_zeta": true, "equivalents_considered": [ { "kind": "mendelian_randomization", "available": false, "why_not_sufficient": "Endogenous locus edits/degrons with interaction-matched rescue, allele natural experiments and graded function/rheology tests are live high-level routes. They can reach upper levels without an RCT. Current convergent evidence supports scoped demixing and contribution, but not common liquid-only organization across all classes." }, { "kind": "natural_experiment", "available": false, "why_not_sufficient": "Endogenous locus edits/degrons with interaction-matched rescue, allele natural experiments and graded function/rheology tests are live high-level routes. They can reach upper levels without an RCT. Current convergent evidence supports scoped demixing and contribution, but not common liquid-only organization across all classes." }, { "kind": "dose_response_across_populations", "available": false, "why_not_sufficient": "Endogenous locus edits/degrons with interaction-matched rescue, allele natural experiments and graded function/rheology tests are live high-level routes. They can reach upper levels without an RCT. Current convergent evidence supports scoped demixing and contribution, but not common liquid-only organization across all classes." }, { "kind": "withdrawal_rechallenge", "available": false, "why_not_sufficient": "Endogenous locus edits/degrons with interaction-matched rescue, allele natural experiments and graded function/rheology tests are live high-level routes. They can reach upper levels without an RCT. Current convergent evidence supports scoped demixing and contribution, but not common liquid-only organization across all classes." }, { "kind": "therapeutic_perturbation_hard_endpoint", "available": false, "why_not_sufficient": "Endogenous locus edits/degrons with interaction-matched rescue, allele natural experiments and graded function/rheology tests are live high-level routes. They can reach upper levels without an RCT. Current convergent evidence supports scoped demixing and contribution, but not common liquid-only organization across all classes." } ], "convergence_present": true, "cap_reapplied_to_convergent_set": false }, "provenance_header": { "sources_total": 63, "claims_total": 67, "claims_verified": 67, "claims_unverified": 0, "claims_contradicted": 0, "tier_a_sources": 63, "generated_by": "Codex; HSEF v5.3", "gate_passed": true }, "claims": [ { "id": "C1", "text": "Nucleolar GC/DFC have distinct fusion dynamics, low surface tension and reconstituted immiscible phases; concentration/domain manipulations alter organization. Injection and domain changes affect binding/valency; FIB1 deletion can localize by native co-recruitment. Assembly physics does not alone prove function requires liquid state.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 1 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph2, 1:Results:paragraph3, 1:Results:paragraph11, 1:Results:paragraph13, 1:Results:paragraph15, 1:Results:paragraph17, 1:Results:paragraph18. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C2", "text": "HMGB1 frameshifts replace an acidic tail with basic residues, cause nucleolar mispartitioning and alter rRNA biogenesis; 12/13 tested variants enhance partitioning. Charge, interaction targets and location change together; not liquidity-only loss/rescue across body classes.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 2 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C3", "text": "CasDrop optogenetic condensates exclude/pull chromatin and prefer softer genomic regions. Engineered IDR/optogenetic assembly, not unmodified endogenous nuclear bodies; linked erratum PMID30849377 details unexamined.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 3 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C4", "text": "Dense/dilute concentration and transfer-energy measurements show heterotypic composition-dependent partitioning; fixed single-component saturation is absent, with RNA/transcription and valency contrasts. Increased expression and ActD influence substrate supply; multicomponent nonfixed saturation is not disproof of LLPS, while partitioning is not liquid-state functional rescue.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 4 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Main text:paragraph0, 2:Main text:paragraph3, 2:Main text:paragraph4, 2:Main text:paragraph5, 2:Main text:paragraph6, 2:Main text:paragraph7. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C5", "text": "Charge patterns and RNA binding organize subphases and nucleolar pH gradients. Binding/coacervation/composition vary together; a pH difference does not uniquely identify liquidity-dependent biological output.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 5 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C6", "text": "FBL domain rescues link condensation-competent architecture to growth and rRNA processing; public extended-data captions report failed hnRNPA1-PLD substitution and retained FRAP for catalytic mutants. Main body/supplements not accessible; only original extended-data captions examined. Phase competence alone is insufficient in the failed PLD rescue, and drug/charge/binding specificity remains.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 6 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Publisher HTML paragraphs:paragraph202, 0:Publisher HTML paragraphs:paragraph204, 0:Publisher HTML paragraphs:paragraph206, 0:Publisher HTML paragraphs:paragraph208, 0:Publisher HTML paragraphs:paragraph212. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C7", "text": "FBL phenylalanine substitutions impair liquid/hydrogel assembly, DFC location and partner interactions. Both hydrogel and liquid states fail alongside binding; expressed mutant is not endogenous liquidity-only rescue.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 7 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C8", "text": "Misfolded proteins enter nucleolar GC, with Hsp70-dependent recovery and prolonged-stress solidification/quality-control failure. Stress, chaperone function and damage vary together; no isolated material-state requirement at normal homeostasis.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 8 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C9", "text": "FBL RNA binding/GAR self-association organizes nascent pre-rRNA traffic and DFC clusters. RNA binding, self-association and localization are coupled; functional condensate contribution does not show simple-liquid exclusivity.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 9 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C10", "text": "Scaffold/surfactant-client simulations yield size-conserved multiple droplets or coarsening depending on ratio. Computational existence of size arrest is not endogenous body demonstration; lack of coalescence alone cannot rule out liquids.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 10 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C11", "text": "Native nucleoli undergo fusion, deformation and ATP-sensitive viscous relaxation with coalescence-linked size distributions. Large amphibian oocytes are a restricted physical context; dynamic fluidity is not alone functional-state necessity.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 11 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C12", "text": "Hi-C-parameterized genome simulations predict nucleolar nucleation/arrest and a metastable two-droplet state. Model agreement with physical measures does not prove all nuclear bodies demix; chromatin arrest can mimic non-coarsening phenotypes.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 12 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C13", "text": "NEAT1 end deletions at comparable expression remove core-shell order, enlarge and round paraspeckles; WT versus mutant transcription responses fit micelle predictions. Restricted HAP1/mutant model; micellization is microphase separation, not absence of all phase behavior. RNA-domain changes can alter interactions, and global function not tested.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 13 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Publisher HTML paragraphs:paragraph24, 0:Publisher HTML paragraphs:paragraph28, 0:Publisher HTML paragraphs:paragraph29, 0:Publisher HTML paragraphs:paragraph30, 0:Publisher HTML paragraphs:paragraph31, 0:Publisher HTML paragraphs:paragraph33. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C14", "text": "CRISPR NEAT1-domain deletion and NONO dimer-domain-dependent tether rescue establish multivalent assembly; selected fragments form in vitro aggregates. RNA-protein enrichment/assembly rescue, with hexanediol sensitivity, does not distinguish a liquid state from micelle/polymer-scaffold organization.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 14 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C15", "text": "Paraspeckles have ordered radial core-shell NEAT1/protein organization; FUS loss fragments them. Radial morphology and loss of scaffold cohesion do not alone distinguish all physical models or establish material-state function.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 15 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C16", "text": "Needle shearing/heating improves NEAT1 recovery about 20-fold; FUS prion-like interactions affect semi-extractability. Extraction tenacity and estimated transcript numbers do not measure liquid versus gel state in living cells.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 16 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C17", "text": "NEAT1 promoter activation in two lines increases intact core-shell paraspeckles. Endogenous locus activation changes abundance; it does not isolate liquid-state functional necessity.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 17 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C18", "text": "Integrator cleavage changes NEAT1 isoforms and restrains paraspeckle assembly. Broad RNA-processing mediator; no liquid-state-specific intervention or complete functional rescue.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 18 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C19", "text": "SRRM2/SON form immiscible subcompartments; oligomerizable synthetic modules replace RS assembly roles while serines tune liquidity and target splicing. Original abstract only in this packet. Synthetic oligomer rescue of assembly is not automatically matched liquid-state functional rescue; distinct splicing factors have nonredundant direct functions.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 19 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C20", "text": "C9 repeat RNA/DPRs alter speckle dynamics and sequester SRRM2; integrity loss changes splicing and neuronal viability. Disease toxicity and factor sequestration alter binding/abundance globally; cannot isolate liquid-state-only causation.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 20 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C21", "text": "SON/SRRM2 co-loss disperses multiple speckle markers without comparable Cajal loss; original shows SC35 chiefly recognizes SRRM2 and truncation alone can remove SC35 staining without dissolving speckles. Protein loss and antibody epitope loss must be separated from body loss; scaffold requirement is not proof that liquidity itself is essential.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 21 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph9, 1:Results:paragraph15, 1:Results:paragraph17, 1:Results:paragraph31, 1:Results:paragraph32, 1:Results:paragraph48. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C22", "text": "SRRM2 charge blocks alter network relaxation without markedly shifting condensation threshold; CK2 phosphorylation is linked to splicing after DNA damage. Abstract-only quantitative/rescue details; CK2 has many substrates and charge edits alter interactions. Supports a stronger state-function test but not broad common-liquid generality.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 22 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C23", "text": "Nuclear-body component concentrations fluctuate synchronously across cells' organelles. Concentration cycles and fluorescence environment are not direct demixing or causal material-state tests.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 23 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C24", "text": "HIF2alpha speckle-targeting motifs influence selected ccRCC transcriptional programs; speckle states correlate with outcomes. Motif-mediated spatial targeting and tissue state do not isolate liquidity, and prognostic association is not therapeutic primacy.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 24 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C25", "text": "Malat1 knockout mice retain speckle markers and normal baseline viability/fertility, with context-specific NEAT1 changes. Baseline absence phenotype does not exclude stress-specific function or all alternative RNA contributions; scaffold redundancy matters.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 25 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C26", "text": "Controlled LLPS and clustered-binding systems show classic FRAP/hexanediol are nondiagnostic; calibrated half-FRAP probes preferential internal mixing. Interfacial barriers vary by body and probe; benchmark specificity is not itself full-body functional proof.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 26 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C27", "text": "Both 1,6-HD and nominal-control 2,5-HD suppress coalescing/noncoalescing gene transcription and increase nucleosome density. Dose/temperature/organism-specific off-target effect; does not invalidate all orthogonal LLPS studies.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 27 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C28", "text": "Hexanediol dose-dependently immobilizes/hypercondenses chromatin; 5 percent or more freezes tested chromatin motion. A distinct chromatin effect, not universal evidence against condensates; lower concentrations still require assay-specific validation.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 28 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C29", "text": "PolII clusters form near CB/HLB; coilin knockout changes associations without PC number/timing changes, and PC removal leaves CB/HLB. Hexanediol-based liquidity ranking is not definitive; demonstrates separable assembly dependencies, not proof that CBs never phase separate.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 29 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C30", "text": "1.5 percent short treatment dissolves bodies with different chromatin-contact effects than longer exposure/aggregation. Retained viability does not rule out kinase/transcription off-targets; neither dose nor 2,5-HD is universally specific.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 30 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C31", "text": "Structured low-concentration kinases and IDR-deleted P-TEFb are inhibited by hexanediol; dilution restores activity and kinase inhibition can preserve CTD droplets. Tested enzymes/protocol, not direct cellular degree estimate. Reversibility does not make solvent effects LLPS-specific.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 31 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Results:paragraph2, 0:Results:paragraph3, 0:Results:paragraph5, 0:Results:paragraph6, 0:Results:paragraph13, 0:Results:paragraph16. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C32", "text": "SLERT favors closed DDX21 conformation and loose clusters linked to FC/DFC fluidity and PolI processivity. Helicase conformation, multimerization and RNA binding are inseparable in these selected abstract claims; no body-general liquid-state inference.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 32 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C33", "text": "Slow directional RNA motion and approximately 5000-fold RNA/NPM1 diffusivity differences support entangled RNA with rapid protein movement through its mesh. RNA labeling, washout, noise floor and maturation mixtures limit inferred transport parameters. Maxwell-fit/gel interpretation is model-supported, not proof every constituent is solid.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 33 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph3, 1:RESULTS:paragraph4, 1:RESULTS:paragraph6, 1:RESULTS:paragraph7, 1:RESULTS:paragraph10, 1:RESULTS:paragraph11, 1:RESULTS:paragraph12. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C34", "text": "DDX18 loss disrupts nucleolar/chromatin organization; NoCasDrop targeted condensation restores selected centromere/heterochromatin readouts. Synthetic rescue of structure, not necessarily pluripotency or material-state-only rescue; helicase/RNA binding and transcription confounds.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 34 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C35", "text": "MALAT1 modulates SRSF1/pre-mRNA interactions and condensation near speckles with hypoxia-responsive splicing. PubMed journal issue is dated 19 March 2026, before the cutoff; earlier preprint is the same work. Interaction/recruitment specificity versus liquid state remains, original body not examined.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 35 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C36", "text": "RNA amount promotes then dissolves transcriptional condensates, consistent with nonequilibrium feedback. Transcriptional cluster comparator, not the canonical body classes' universal assembly or liquidity function.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 36 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C37", "text": "Physiological dynamic LCD hubs stabilize binding and recruit PolII without detectable macroscopic phase separation. Local hubs at tested loci do not rule out other bodies or nanoscopic condensation; a distinct comparator rather than nucleolar null.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 37 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C38", "text": "CTD phosphorylation shifts partition preference from mediator to splicing-factor condensates. Phosphorylation also regulates conventional binding/enzymatic activity; not unique evidence of an endogenous required liquid phase.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 38 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C39", "text": "rRNA transcription seeds precisely timed nucleoli; without rDNA, variable high-concentration assemblies still arise. Seeding and phase behavior can cooperate; activity-defined formation does not alone isolate physical state required for function.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 39 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C40", "text": "Alu RNA depletion disrupts nucleolar structure/rRNA transcription, while added RNA increases size and pre-rRNA. RNA scaffold and PolII/PolI cross-talk are changed together; not liquid-state-selective necessity.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 40 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C41", "text": "Fkbp39 chromatin localization/binding directs nascent 60S partition and improves ribosomal assembly. Native sorting and binding are causal in yeast, but liquidity-only separation and broad body generality are untested here.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 41 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C42", "text": "Sequential processing maps spatial maturation; engineered SSU defects invert layers and prevent outflux, while LSU precursors build the outer layer. Synthetic rDNA plus processing perturbation changes substrate architecture itself; supports RNA-programmed structure rather than universal simple-liquid necessity.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 42 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C43", "text": "RD-SPRITE identifies RNA territories; selected RNAs recruit regulators and alter contacts/function. Spatial enrichment and binding-guided assembly do not uniquely identify demixing versus scaffold-driven territories.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 43 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C44", "text": "Coilin loss disperses CB, impairs snRNP production and arrests development; mature human snRNPs restore mRNA/viability while RNA alone does not. Product bypass shows CB-associated assembly is useful yet not an irreplaceable liquid prerequisite; depletion is not a material-state edit.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 44 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C45", "text": "CB RNAi disassembly changes gene clustering/expression and increases splicing noise. Coilin/assembly loss and snRNP supply explain effects without requiring phase-state-specific causation.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 45 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C46", "text": "PML addback restores bodies, and SUMO-binding/RING mutants alter nucleation/recruitment. SUMO architecture versus liquid state not separated; linked erratum PMID29654784 metadata checked but details unavailable.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 46 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C47", "text": "A216V/L268P compare dynamics, packing, recruitment/PTMs and stress/senescence outputs with retained overall RBCC oligomerization. Important positive variant comparison, but FRAP is not alone LLPS proof and altered binding/packing may change output; original body unavailable.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 47 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C48", "text": "NPM1 conformation changes valency and switches competing homo/heterotypic LLPS mechanisms. Biophysical reconstitution is not endogenous liquid-state-selective function or cross-class necessity.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 48 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C49", "text": "Multivalent acidic motifs, oligomerization and RNA-binding domains drive NPM1 coassembly and nucleolar localization. Loss of interaction/localization is not selective loss of liquidity while retaining same clients/function.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 49 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C50", "text": "Crowding/concentration modulates interconversion of homo/heterotypic scaffolding networks. Proposed vectorial output is not directly established by this in vitro network alone.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 50 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C51", "text": "PolyPR binds NPM1 acidic regions, dissolves in vitro droplets and disperses cell NPM1 while trapping RNA statically. Broad pathogenic interactions, not an isolated physiological liquid-state perturbation/rescue.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 51 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C52", "text": "Liquid-like cohesin-DNA clusters depend on DNA length above 3 kb, supporting bridging-induced condensation. DNA polymer comparator, not direct paraspeckle/Cajal mechanism; fusion/FRAP do not uniquely identify protein LLPS.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 52 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C53", "text": "HSV replication compartments concentrate PolII through accessible DNA/rebinding despite unrestricted interfacial diffusion. Viral compartment context, not native nucleolar null; provides a mechanism that reproduces misleading puncta phenomenology.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 53 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C54", "text": "Speckle proximity predicts more spliceosome binding, and directed pre-mRNA recruitment increases splicing. Spatial concentration is functionally sufficient in the tested assay, but does not identify liquidity as the causal feature; preprint is not separate replication.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 54 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C55", "text": "EGFP-SRRM2 knock-in dynamics and depletion link scaffold to selected exon splicing, viability and differentiation. SRRM2 is itself a spliceosome protein; generic factor loss is not liquid-state-only necessity, and sphere/FRAP criteria are incomplete.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 55 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C56", "text": "SRRM2 depletion disperses speckles and changes active-compartment interactions and 1282 genes; contact changes do not track expression changes. Broad scaffold/splicing loss and uncoupled contacts constrain unique material-state interpretation.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 56 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C57", "text": "Multiple structural or functional CB components nucleate apparently functional bodies when immobilized on chromatin. Nonhierarchical self-organization does not prove LLPS; tethered high local concentration is engineered.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 57 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C58", "text": "Nascent NEAT1 transcription recruits functional paraspeckle proteins and retains mRNAs; continued transcription supports maintenance. RNA platform and activity-dependence do not specify a bulk liquid or forbid microphase separation.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 58 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C59", "text": "Endogenous-locus NPM1-Cry2olig cells accumulate 46S/45S and lose downstream precursors relative to light controls; activated mesh hinders large complexes while small-protein mobility persists. Processing assay uses 24–72 h light with general toxicity normalized; concentration/percolation and new interactions vary. Selected body shows no matched light-off functional rescue, and processing is selectively impaired rather than globally absent.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 59 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Publisher HTML paragraphs:paragraph19, 0:Publisher HTML paragraphs:paragraph21, 0:Publisher HTML paragraphs:paragraph24, 0:Publisher HTML paragraphs:paragraph26, 0:Publisher HTML paragraphs:paragraph28, 0:Publisher HTML paragraphs:paragraph30, 0:Publisher HTML paragraphs:paragraph32, 0:Publisher HTML paragraphs:paragraph34, 0:Publisher HTML paragraphs:paragraph31, 0:Publisher HTML paragraphs:paragraph33, 0:Publisher HTML paragraphs:paragraph35, 0:Publisher HTML paragraphs:paragraph37, 0:Publisher HTML paragraphs:paragraph40. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C60", "text": "Micropipette aspiration shows liquid-like GC but partly solid-like DFC/FC; RNase fluidizes internal phases and changes tension. Restricted oocyte/aspiration context; RNA destruction changes substrate and interactions along with rheology, not selective functional rescue.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 60 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C61", "text": "Chromatin depletion/flow accompanies coalescing nucleoli; short-range attraction models anomalous volume distribution. Model-supported attraction and coarsening, not biological-function necessity or universally equilibrated liquid droplets.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 61 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C62", "text": "Cell-size/concentration perturbation and nucleolar/extranucleolar kinetics agree with phase-transition predictions modulated by rRNA transcription. Embryonic worm regime and active seeding; doesn't show every nuclear body shares the same physics.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 62 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "C63", "text": "Changing scaffold ratio/valency switches client composition in reconstitutions/cells, with analogous PML/P-body partitioning. Analogous natural partitioning is not identical physical proof, and synthetic-liquid compositional control is not body-general liquid necessity.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 63 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-08", "note": "" }, { "id": "CSC1", "text": "Ε: endogenous nucleolar demixing and composition-dependent physical organization have context-specific causal support, with native concentration/phase controls. This scoped existence success does not extend identically to all classes or constituents.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 25, 26, 29, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 46, 47, 48, 49, 50, 51, 52, 53, 55, 57, 58, 59, 60, 61, 62, 63 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-08", "note": "" }, { "id": "CSC2", "text": "Δ: endogenous NPM1 opto-gelation alters specific pre-rRNA processing relative to light controls; emerging charge/domain tests add support. Liquidity-only matched functional rescue and broader body classes remain unresolved, preventing a general necessity inference.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 1, 2, 4, 5, 6, 7, 8, 9, 13, 14, 18, 19, 20, 21, 22, 24, 27, 28, 30, 31, 32, 33, 34, 35, 38, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 54, 55, 56, 58, 59, 60, 63 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-08", "note": "" }, { "id": "CSC3", "text": "Γ: class-general LLPS remains a mechanistic model, constrained by endogenous paraspeckle micelle tests, RNA-gel/partly solid nucleolar measurements and scaffold/binding alternatives. Restricted successes cannot establish common physics.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 1, 3, 4, 10, 11, 12, 13, 14, 15, 16, 17, 19, 21, 23, 25, 26, 27, 28, 29, 30, 31, 33, 36, 37, 39, 42, 43, 44, 45, 52, 53, 57, 58, 60, 61, 62, 63 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-08", "note": "" }, { "id": "CH", "text": "Endogenous nuclear condensation and selected material-state effects are supported, but common macroscopic LLPS and simple-liquid necessity across nuclear bodies are not established.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 1, 4, 59, 13, 33, 60 ], "verification": "verified", "verified_against": "Bounded synthesis of examined sources; score is adjudication.", "verified_on": "2026-10-08", "note": "" } ], "citation_ledger": [ { "n": 1, "citation": "Feric M, Vaidya N, Harmon TS et al. 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The EMBO journal. 2021.", "tier": "A", "kind": "primary", "pmid": "33885174", "doi": "10.15252/embj.2020107270", "url": "https://pubmed.ncbi.nlm.nih.gov/33885174/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID33885174", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Publisher HTML paragraphs:paragraph24, 0:Publisher HTML paragraphs:paragraph28, 0:Publisher HTML paragraphs:paragraph29, 0:Publisher HTML paragraphs:paragraph30, 0:Publisher HTML paragraphs:paragraph31, 0:Publisher HTML paragraphs:paragraph33. No complete-paper or supplement audit claimed.", "carries_claims": [ "C13", "CSC1", "CSC2", "CSC3", "CH" ] }, { "n": 14, "citation": "Yamazaki T, Souquere S, Chujo T et al. Functional Domains of NEAT1 Architectural lncRNA Induce Paraspeckle Assembly through Phase Separation. Molecular cell. 2018.", "tier": "A", "kind": "primary", "pmid": "29932899", "doi": "10.1016/j.molcel.2018.05.019", "url": "https://pubmed.ncbi.nlm.nih.gov/29932899/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID29932899", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C14", "CSC1", "CSC2", "CSC3" ] }, { "n": 15, "citation": "West JA, Mito M, Kurosaka S et al. Structural, super-resolution microscopy analysis of paraspeckle nuclear body organization. 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Science advances. 2020.", "tier": "A", "kind": "primary", "pmid": "32923585", "doi": "10.1126/sciadv.aaz9072", "url": "https://pubmed.ncbi.nlm.nih.gov/32923585/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID32923585", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C18", "CSC1", "CSC2" ] }, { "n": 19, "citation": "Zhang M, Gu Z, Guo S et al. SRRM2 phase separation drives assembly of nuclear speckle subcompartments. Cell reports. 2024.", "tier": "A", "kind": "primary", "pmid": "38381607", "doi": "10.1016/j.celrep.2024.113827", "url": "https://pubmed.ncbi.nlm.nih.gov/38381607/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID38381607", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C19", "CSC1", "CSC2", "CSC3" ] }, { "n": 20, "citation": "Wu R, Ye Y, Dong D et al. Disruption of nuclear speckle integrity dysregulates RNA splicing in C9ORF72-FTD/ALS. Neuron. 2024.", "tier": "A", "kind": "primary", "pmid": "39181135", "doi": "10.1016/j.neuron.2024.07.025", "url": "https://pubmed.ncbi.nlm.nih.gov/39181135/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID39181135", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C20", "CSC1", "CSC2" ] }, { "n": 21, "citation": "Ilik İA, Malszycki M, Lübke AK et al. SON and SRRM2 are essential for nuclear speckle formation. eLife. 2020.", "tier": "A", "kind": "primary", "pmid": "33095160", "doi": "10.7554/eLife.60579", "url": "https://pubmed.ncbi.nlm.nih.gov/33095160/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-08", "status_checked_on": "2026-10-08", "study_id": "PMID33095160", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph9, 1:Results:paragraph15, 1:Results:paragraph17, 1:Results:paragraph31, 1:Results:paragraph32, 1:Results:paragraph48. No complete-paper or supplement audit claimed.", "carries_claims": [ "C21", "CSC1", "CSC2", "CSC3" ] }, { "n": 22, "citation": "Zhang M, Gu Z, Sun Y et al. Phosphorylation-dependent charge blocks regulate the relaxation of nuclear speckle networks. 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