{"gene":"LNPK","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2003,"finding":"Lunapark (Lnp) was identified as a gene located upstream of the HoxD cluster that shares limb and CNS expression specificities with Hoxd genes and Evx2. Its genomic locus contains a global control region with enhancers capable of directing reporter gene expression in digits and CNS, defining large chromosomal regulatory domains.","method":"Targeted enhancer-trap approach, transgenic reporter assays, interspecies sequence conservation analysis","journal":"Cell","confidence":"Medium","confidence_rationale":"Tier 2 — direct in vivo reporter assay identifying the gene and its regulatory context; single study but multiple methods","pmids":["12732147"],"is_preprint":false},{"year":2008,"finding":"The C. elegans ortholog lnp-1 is required for synaptic vesicle trafficking and neurotransmission. Deletion mutations in lnp-1 cause resistance to aldicarb (acetylcholinesterase inhibitor) and locomotor defects without affecting sensitivity to the postsynaptic nicotinic agonist levamisole, indicating a presynaptic function. Presynaptic proteins synaptobrevin-1 and RAB-3 are mislocalized in lnp-1 mutants. LNP-1 localization depends on the UNC-104/kinesin motor.","method":"C. elegans deletion mutant analysis, aldicarb and levamisole behavioral assays, fluorescence microscopy of presynaptic protein localization, genetic epistasis","journal":"The European journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — clean loss-of-function with defined presynaptic phenotype and protein mislocalization; single lab study in orthologous organism","pmids":["18279315"],"is_preprint":false},{"year":2012,"finding":"Yeast Lnp1p localizes to ER tubule three-way junctions and binds to the reticulon protein Rtn1p and Yop1p. Loss of Lnp1p causes a collapsed, densely reticulated ER network. Lnp1p and the dynamin-like GTPase Sey1p (atlastin ortholog) act antagonistically to balance polygonal ER network formation; the lnp1Δ ER collapse is partially restored when Sey1p GTPase activity is abrogated.","method":"Yeast genetics (deletion mutants, GTPase-dead mutants), co-immunoprecipitation, fluorescence microscopy of ER morphology, genetic epistasis (double mutants)","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal binding, genetic epistasis with GTPase-dead rescue, clean loss-of-function ER morphology phenotype; strong mechanistic framework","pmids":["22729086"],"is_preprint":false},{"year":2014,"finding":"Mammalian Lnp1 (mLnp1) localizes to a subset (~50%) of ER three-way junctions. Live-cell imaging shows that junctions containing mLnp1 are less mobile than those without it. Newly formed junctions that acquire mLnp1 remain stable, whereas nascent junctions that fail to acquire mLnp1 undergo rapid ring closure. Thus Lnp1 stabilizes nascent three-way ER junctions and controls network dynamics.","method":"Live-cell fluorescence imaging (time-lapse), analysis of junction mobility and ring closure events in mammalian cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — direct live imaging with quantitative functional consequence (junction stability vs. ring closure); Moderate-to-Strong evidence from multiple observations","pmids":["25548161"],"is_preprint":false},{"year":2014,"finding":"Theoretical and experimental modeling shows that Lunapark is an S-type curvature-stabilizing protein that promotes negative curvature along edge lines, thereby stabilizing three-way junctions (small triangular sheets with concave edges) in the tubular ER network. This distinguishes Lunapark from R-type proteins (reticulons) that favor tubules and outer sheet edges.","method":"Mathematical/theoretical modeling of ER morphologies combined with experimental validation of protein localization and membrane curvature effects","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2/3 — theoretical model with experimental support; provides mechanistic framework but curvature-generating activity not directly reconstituted in vitro","pmids":["25404289"],"is_preprint":false},{"year":2016,"finding":"In higher eukaryotes, Lnp (lunapark) affects the abundance of ER three-way junctions and tubules. Lnp moves into junctional sheets and forms oligomers. Lnp is inactivated by mitotic phosphorylation, which contributes to the tubule-to-sheet conversion of the ER during mitosis. ATL (atlastin) is needed to maintain the ER network and acts by counteracting instability of free tubule ends; Lnp and ATL function in sequence at junctions.","method":"Fluorescence microscopy, biochemical analysis of Lnp oligomerization, phosphorylation studies during mitosis, manipulation of ATL and Rtn4a levels","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including oligomerization biochemistry, mitotic phosphorylation functional consequence, and live imaging; moderate-to-strong evidence","pmids":["27619977"],"is_preprint":false},{"year":2018,"finding":"Homozygous loss-of-function mutations in human LNPK (encoding lunapark) cause a recessive neurodevelopmental syndrome characterized by severe psychomotor delay, intellectual disability, hypotonia, epilepsy, and corpus callosum hypoplasia. Patient-derived cells lacking full-length lunapark show aberrant ER structures and increased luminal mass density. LNPK is expressed during human and mouse brain development and is present in neurite-like processes of differentiating human neural progenitor cells.","method":"Human genetics (homozygosity mapping, exome sequencing), patient cell biology (immunofluorescence, EM of ER morphology), immunohistochemistry and immunofluorescence in human/mouse brain tissue and neural progenitor cells","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function mutations linked to specific cellular phenotype (aberrant ER structure) and defined clinical syndrome; replicated across two families with orthogonal cellular and developmental evidence","pmids":["30032983"],"is_preprint":false},{"year":2018,"finding":"Yeast Lnp1 is required for ER-phagy (selective autophagy of the ER) upon rapamycin treatment. Lnp1 normally resides at ER tubule three-way junctions and stabilizes the network during continual remodeling. In lnp1Δ mutants, the ER autophagy receptor Atg40 fails to relocalize to sites of autophagosome formation (marked by the scaffold Atg11), preventing ER packaging into autophagosomes. This block is phenocopied by the actin-depolymerizing drug Latrunculin A, suggesting Lnp1 stabilizes actin-dependent ER remodeling required for ER-phagy.","method":"Yeast genetics (lnp1Δ mutants), fluorescence microscopy of Atg40 and Atg11 co-localization, pharmacological actin depolymerization, rapamycin-induced autophagy assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — clean genetic loss-of-function with mechanistic pathway placement (Atg40-Atg11 association blocked), epistasis with actin cytoskeleton, multiple orthogonal readouts","pmids":["29915089"],"is_preprint":false},{"year":2020,"finding":"In fission yeast, Lnp1 and the inner nuclear membrane protein Lem2 cooperatively maintain the membrane boundary between the nuclear envelope (NE) and endoplasmic reticulum (ER). Cells lacking both Lem2 and Lnp1 show severe growth defects, aberrant NE/ER membrane expansion, leakage of nuclear proteins, and abnormal vacuolar-like structures in the nucleus. Overexpression of the ER membrane protein Apq12 rescues the growth defect, and genetic analysis shows Apq12 has overlapping functions with Lnp1.","method":"Fission yeast genetics (double deletion mutants lem2Δ lnp1Δ), fluorescence microscopy of NE/ER morphology and nuclear protein localization, genetic suppressor analysis (Apq12 overexpression)","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 2 — clean double-mutant genetic analysis with multiple phenotypic readouts and genetic suppression; demonstrates NE-ER boundary maintenance function","pmids":["32483293"],"is_preprint":false}],"current_model":"LNPK (lunapark) encodes a conserved ER membrane protein that localizes to three-way junctions of the ER tubular network, where it stabilizes nascent junctions (preventing ring closure), forms oligomers, cooperates antagonistically with the atlastin GTPase and reticulons to balance ER network morphology, is inactivated by mitotic phosphorylation to facilitate tubule-to-sheet conversion, is required for actin-dependent ER remodeling during ER-phagy, and maintains the NE-ER membrane boundary; loss-of-function in humans causes a recessive neurodevelopmental syndrome with corpus callosum hypoplasia, epilepsy, and intellectual disability."},"narrative":{"teleology":[{"year":2003,"claim":"Identification of lunapark as a gene sharing limb and CNS regulatory domains with the HoxD cluster established its developmental expression pattern but left its molecular function unknown.","evidence":"Enhancer-trap transgenic reporters and interspecies conservation analysis in mouse","pmids":["12732147"],"confidence":"Medium","gaps":["No molecular function or subcellular localization determined","Regulatory relationship with HoxD genes not mechanistically defined"]},{"year":2008,"claim":"Loss of the C. elegans ortholog lnp-1 revealed a presynaptic role in synaptic vesicle trafficking, providing the first link between lunapark and membrane compartment organization in neurons.","evidence":"C. elegans deletion mutants with aldicarb/levamisole assays and presynaptic protein mislocalization","pmids":["18279315"],"confidence":"Medium","gaps":["Mechanism of synaptic vesicle mislocalization not defined at the ER level","Relevance to ER morphology not yet recognized","Single organism study without mammalian validation"]},{"year":2012,"claim":"Discovery that yeast Lnp1p localizes to ER three-way junctions, binds reticulon/Yop1p, and acts antagonistically to the atlastin ortholog Sey1p established the core paradigm: lunapark is an ER junction-stabilizing protein that balances the tubular network against fusogenic forces.","evidence":"Yeast deletion and GTPase-dead mutants, co-immunoprecipitation, fluorescence microscopy of ER morphology","pmids":["22729086"],"confidence":"High","gaps":["Direct curvature-generating or -sensing activity not reconstituted in vitro","Mammalian conservation of junction localization not yet confirmed"]},{"year":2014,"claim":"Live imaging in mammalian cells and theoretical modeling together showed that Lnp1 stabilizes nascent junctions by promoting negative (S-type) membrane curvature, explaining how it prevents ring closure and maintains ER network geometry.","evidence":"Time-lapse fluorescence imaging of junction mobility and ring closure; mathematical modeling of ER membrane shapes","pmids":["25548161","25404289"],"confidence":"High","gaps":["Curvature-stabilizing activity inferred from localization and modeling; no in vitro reconstitution with purified protein on liposomes","Structural basis for curvature sensing/generation unknown"]},{"year":2016,"claim":"Demonstration that Lnp oligomerizes and is inactivated by mitotic phosphorylation linked its biochemical regulation to the cell-cycle-dependent ER tubule-to-sheet conversion, placing Lnp as a regulated effector of ER remodeling during mitosis.","evidence":"Biochemical oligomerization assays, phosphorylation studies during mitosis, manipulation of ATL and Rtn4a levels in mammalian cells","pmids":["27619977"],"confidence":"High","gaps":["Kinase(s) responsible for mitotic phosphorylation not identified","Stoichiometry and structural organization of oligomers undetermined","How phosphorylation disrupts oligomer function mechanistically unclear"]},{"year":2018,"claim":"Two independent advances resolved downstream consequences of Lnp loss: biallelic LNPK mutations were shown to cause a human neurodevelopmental syndrome with aberrant ER in patient cells, while yeast studies demonstrated that Lnp1 is required for ER-phagy by enabling actin-dependent relocalization of the autophagy receptor Atg40.","evidence":"Human exome sequencing and homozygosity mapping across two families with patient cell ER morphology analysis; yeast lnp1Δ mutants with Atg40/Atg11 co-localization and Latrunculin A phenocopy","pmids":["30032983","29915089"],"confidence":"High","gaps":["Whether ER-phagy defect contributes to the human neurodevelopmental phenotype is untested","Direct actin–Lnp1 interaction not demonstrated","Mammalian ER-phagy role of LNPK not confirmed"]},{"year":2020,"claim":"Genetic studies in fission yeast revealed that Lnp1 cooperates with the inner nuclear membrane protein Lem2 to maintain the NE-ER boundary, expanding lunapark function beyond ER tubule junctions to nuclear envelope integrity.","evidence":"Fission yeast lem2Δ lnp1Δ double mutants with NE/ER morphology analysis and Apq12 genetic suppression","pmids":["32483293"],"confidence":"High","gaps":["Whether NE-ER boundary maintenance function is conserved in mammals","Physical interaction between Lnp1 and Lem2 or Apq12 not demonstrated","Contribution of NE defects to neurological phenotype in LNPK patients unknown"]},{"year":null,"claim":"Key open questions include the atomic structure of LNPK, the identity of kinases controlling its mitotic phosphorylation, whether its ER-phagy and NE-boundary functions operate in mammalian neurons, and how ER junction instability leads to the specific neurodevelopmental deficits seen in patients.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of LNPK or its oligomeric complex","Mammalian in vivo conditional knockout phenotype not reported","Pathogenic mechanism linking ER junction loss to corpus callosum hypoplasia and epilepsy undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[2,3,4,5]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[2,3,5,6,7,8]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[8]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[7]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[2,3,5,8]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[5]}],"complexes":[],"partners":["RTN1","ATL1","LEM2"],"other_free_text":[]},"mechanistic_narrative":"LNPK encodes a conserved, oligomeric ER membrane protein that localizes to three-way junctions of the tubular ER network, where it stabilizes nascent junctions by promoting negative membrane curvature along edge lines and preventing ring closure [PMID:22729086, PMID:25548161, PMID:25404289]. LNPK acts antagonistically with the atlastin/Sey1p fusogenic GTPase and reticulon tubule-shaping proteins to balance ER polygonal network architecture; its inactivation by mitotic phosphorylation facilitates the characteristic tubule-to-sheet ER conversion during cell division [PMID:22729086, PMID:27619977]. Beyond junction maintenance, LNPK is required for actin-dependent ER remodeling during ER-phagy and cooperates with inner nuclear membrane proteins to preserve the nuclear envelope–ER boundary [PMID:29915089, PMID:32483293]. Biallelic loss-of-function mutations in human LNPK cause a recessive neurodevelopmental syndrome featuring intellectual disability, epilepsy, and corpus callosum hypoplasia, with patient cells exhibiting aberrant ER morphology [PMID:30032983]."},"prefetch_data":{"uniprot":{"accession":"Q9C0E8","full_name":"Endoplasmic reticulum junction formation protein lunapark","aliases":["ER junction formation factor lunapark"],"length_aa":428,"mass_kda":47.7,"function":"Endoplasmic reticulum (ER)-shaping membrane protein that plays a role in determining ER morphology (PubMed:30032983). Involved in the stabilization of nascent three-way ER tubular junctions within the ER network (PubMed:24223779, PubMed:25404289, PubMed:25548161, PubMed:27619977). May also play a role as a curvature-stabilizing protein within the three-way ER tubular junction network (PubMed:25404289). May be involved in limb development (By similarity). Is involved in central nervous system development (PubMed:30032983)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q9C0E8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LNPK","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000144320","cell_line_id":"CID000839","localizations":[{"compartment":"vesicles","grade":3},{"compartment":"er","grade":2}],"interactors":[{"gene":"LNP","stoichiometry":10.0},{"gene":"FOXG1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000839","total_profiled":1310},"omim":[{"mim_id":"618090","title":"NEURODEVELOPMENTAL DISORDER WITH EPILEPSY AND HYPOPLASIA OF THE CORPUS CALLOSUM; NEDEHCC","url":"https://www.omim.org/entry/618090"},{"mim_id":"610236","title":"LUNAPARK; LNPK","url":"https://www.omim.org/entry/610236"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Connecting piece","reliability":"Additional"},{"location":"Mid piece","reliability":"Additional"},{"location":"Principal piece","reliability":"Additional"},{"location":"End piece","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LNPK"},"hgnc":{"alias_symbol":["Ul","LNP1","LNP"],"prev_symbol":["KIAA1715"]},"alphafold":{"accession":"Q9C0E8","domains":[{"cath_id":"-","chopping":"13-148","consensus_level":"high","plddt":89.9824,"start":13,"end":148},{"cath_id":"-","chopping":"254-304","consensus_level":"high","plddt":88.5861,"start":254,"end":304}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9C0E8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9C0E8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9C0E8-F1-predicted_aligned_error_v6.png","plddt_mean":67.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LNPK","jax_strain_url":"https://www.jax.org/strain/search?query=LNPK"},"sequence":{"accession":"Q9C0E8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9C0E8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9C0E8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9C0E8"}},"corpus_meta":[{"pmid":"37196221","id":"PMC_37196221","title":"Lipid Nanoparticle (LNP) Enables mRNA Delivery for Cancer Therapy.","date":"2023","source":"Advanced materials (Deerfield Beach, Fla.)","url":"https://pubmed.ncbi.nlm.nih.gov/37196221","citation_count":330,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38437552","id":"PMC_38437552","title":"Endosomal escape: A bottleneck for LNP-mediated therapeutics.","date":"2024","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/38437552","citation_count":325,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31551417","id":"PMC_31551417","title":"Linkage between endosomal escape of LNP-mRNA and loading into EVs for transport to other cells.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31551417","citation_count":315,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34880218","id":"PMC_34880218","title":"Low immunogenicity of LNP allows repeated administrations of CRISPR-Cas9 mRNA into skeletal muscle in mice.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/34880218","citation_count":229,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35701851","id":"PMC_35701851","title":"Recent advances in mRNA-LNP therapeutics: immunological and pharmacological aspects.","date":"2022","source":"Journal of nanobiotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/35701851","citation_count":168,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33119640","id":"PMC_33119640","title":"The effects of PEGylation on LNP based mRNA delivery to the eye.","date":"2020","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/33119640","citation_count":152,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37821446","id":"PMC_37821446","title":"Effect of mRNA-LNP components of two globally-marketed COVID-19 vaccines on efficacy and stability.","date":"2023","source":"NPJ vaccines","url":"https://pubmed.ncbi.nlm.nih.gov/37821446","citation_count":148,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39060305","id":"PMC_39060305","title":"AGILE platform: a deep learning powered approach to accelerate LNP development for mRNA delivery.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/39060305","citation_count":119,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36867683","id":"PMC_36867683","title":"Single immunizations of self-amplifying or non-replicating mRNA-LNP vaccines control HPV-associated tumors in mice.","date":"2023","source":"Science translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36867683","citation_count":106,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35821637","id":"PMC_35821637","title":"mRNA-LNP vaccines tuned for systemic immunization induce strong antitumor immunity by engaging splenic immune cells.","date":"2022","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/35821637","citation_count":98,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9342042","id":"PMC_9342042","title":"Ulnaless (Ul), a regulatory mutation inducing both loss-of-function and gain-of-function of posterior Hoxd genes.","date":"1997","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/9342042","citation_count":98,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35640764","id":"PMC_35640764","title":"Focused ultrasound/microbubbles-assisted BBB opening enhances LNP-mediated mRNA delivery to brain.","date":"2022","source":"Journal of controlled release : official journal of the Controlled Release Society","url":"https://pubmed.ncbi.nlm.nih.gov/35640764","citation_count":94,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37651468","id":"PMC_37651468","title":"Spleen SORT LNP Generated in situ CAR T Cells Extend Survival in a Mouse Model of Lymphoreplete B Cell Lymphoma.","date":"2023","source":"Angewandte Chemie (International ed. in English)","url":"https://pubmed.ncbi.nlm.nih.gov/37651468","citation_count":92,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34343897","id":"PMC_34343897","title":"Engineering of the current nucleoside-modified mRNA-LNP vaccines against SARS-CoV-2.","date":"2021","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/34343897","citation_count":89,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31290323","id":"PMC_31290323","title":"Mannosylation of LNP Results in Improved Potency for Self-Amplifying RNA (SAM) Vaccines.","date":"2019","source":"ACS infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/31290323","citation_count":88,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36805684","id":"PMC_36805684","title":"Lipid nanoparticles (LNP) induce activation and maturation of antigen presenting cells in young and aged individuals.","date":"2023","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/36805684","citation_count":86,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34068715","id":"PMC_34068715","title":"Non-Immunotherapy Application of LNP-mRNA: Maximizing Efficacy and Safety.","date":"2021","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/34068715","citation_count":81,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33762420","id":"PMC_33762420","title":"A Dengue Virus Serotype 1 mRNA-LNP Vaccine Elicits Protective Immune Responses.","date":"2021","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/33762420","citation_count":79,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36888708","id":"PMC_36888708","title":"A single-dose F1-based mRNA-LNP vaccine provides protection against the lethal plague bacterium.","date":"2023","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/36888708","citation_count":73,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35676394","id":"PMC_35676394","title":"Optimal self-assembly of lipid nanoparticles (LNP) in a ring micromixer.","date":"2022","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/35676394","citation_count":64,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37738334","id":"PMC_37738334","title":"Intranasal mRNA-LNP vaccination protects hamsters from SARS-CoV-2 infection.","date":"2023","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/37738334","citation_count":63,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39361752","id":"PMC_39361752","title":"A multivalent mRNA-LNP vaccine protects against Clostridioides difficile infection.","date":"2024","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/39361752","citation_count":62,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8955043","id":"PMC_8955043","title":"The UL 16 gene product of herpes simplex virus 1 is a virion protein that colocalizes with intranuclear capsid proteins.","date":"1996","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/8955043","citation_count":62,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31877409","id":"PMC_31877409","title":"Therapeutic Potential of LNP-Mediated Delivery of miR-634 for Cancer Therapy.","date":"2019","source":"Molecular therapy. Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/31877409","citation_count":61,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36942873","id":"PMC_36942873","title":"STING Agonist-Derived LNP-mRNA Vaccine Enhances Protective Immunity Against SARS-CoV-2.","date":"2023","source":"Nano letters","url":"https://pubmed.ncbi.nlm.nih.gov/36942873","citation_count":59,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39122711","id":"PMC_39122711","title":"Optimized inhaled LNP formulation for enhanced treatment of idiopathic pulmonary fibrosis via mRNA-mediated antibody therapy.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/39122711","citation_count":58,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38753770","id":"PMC_38753770","title":"mRNA-LNP HIV-1 trimer boosters elicit precursors to broad neutralizing antibodies.","date":"2024","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/38753770","citation_count":58,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37490011","id":"PMC_37490011","title":"Esterase-Labile Quaternium Lipidoid Enabling Improved mRNA-LNP Stability and Spleen-Selective mRNA Transfection.","date":"2023","source":"Advanced materials (Deerfield Beach, Fla.)","url":"https://pubmed.ncbi.nlm.nih.gov/37490011","citation_count":54,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36154076","id":"PMC_36154076","title":"Lipid Nanoparticle (LNP) Chemistry Can Endow Unique In Vivo RNA Delivery Fates within the Liver That Alter Therapeutic Outcomes in a Cancer Model.","date":"2022","source":"Molecular pharmaceutics","url":"https://pubmed.ncbi.nlm.nih.gov/36154076","citation_count":52,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38876358","id":"PMC_38876358","title":"Lipid nanoparticle (LNP) mediated mRNA delivery in cardiovascular diseases: Advances in genome editing and CAR T cell therapy.","date":"2024","source":"Journal of controlled release : official journal of the Controlled Release Society","url":"https://pubmed.ncbi.nlm.nih.gov/38876358","citation_count":48,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29915089","id":"PMC_29915089","title":"ER-phagy requires Lnp1, a protein that stabilizes rearrangements of the ER network.","date":"2018","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/29915089","citation_count":46,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38437539","id":"PMC_38437539","title":"Cationic cholesterol-dependent LNP delivery to lung stem cells, the liver, and heart.","date":"2024","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/38437539","citation_count":45,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38272900","id":"PMC_38272900","title":"LNP-RNA-engineered adipose stem cells for accelerated diabetic wound healing.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/38272900","citation_count":45,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11334568","id":"PMC_11334568","title":"Synthesis and biological evaluation of pyrrolinic isosteres of rilmenidine. Discovery of cis-/trans-dicyclopropylmethyl-(4,5-dimethyl-4,5-dihydro-3H-pyrrol-2-yl)-amine (LNP 509), an I1 imidazoline receptor selective ligand with hypotensive activity.","date":"2001","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11334568","citation_count":44,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37073472","id":"PMC_37073472","title":"Successful batch and continuous lyophilization of mRNA LNP formulations depend on cryoprotectants and ionizable lipids.","date":"2023","source":"Biomaterials science","url":"https://pubmed.ncbi.nlm.nih.gov/37073472","citation_count":43,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37773254","id":"PMC_37773254","title":"mRNA-LNP vaccination-based immunotherapy augments CD8+ T cell responses against HPV-positive oropharyngeal cancer.","date":"2023","source":"NPJ vaccines","url":"https://pubmed.ncbi.nlm.nih.gov/37773254","citation_count":43,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36456563","id":"PMC_36456563","title":"mRNA-LNP expressing PfCSP and Pfs25 vaccine candidates targeting infection and transmission of Plasmodium falciparum.","date":"2022","source":"NPJ vaccines","url":"https://pubmed.ncbi.nlm.nih.gov/36456563","citation_count":42,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8558127","id":"PMC_8558127","title":"Gene organization in the UL region and inverted repeats of the canine herpesvirus genome.","date":"1996","source":"The Journal of general virology","url":"https://pubmed.ncbi.nlm.nih.gov/8558127","citation_count":42,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38894715","id":"PMC_38894715","title":"Unlocking the Therapeutic Applicability of LNP-mRNA: Chemistry, Formulation, and Clinical Strategies.","date":"2024","source":"Research (Washington, D.C.)","url":"https://pubmed.ncbi.nlm.nih.gov/38894715","citation_count":37,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38253203","id":"PMC_38253203","title":"Quality assessment of LNP-RNA therapeutics with orthogonal analytical techniques.","date":"2024","source":"Journal of controlled release : official journal of the Controlled Release Society","url":"https://pubmed.ncbi.nlm.nih.gov/38253203","citation_count":36,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39059500","id":"PMC_39059500","title":"Physicochemical and structural insights into lyophilized mRNA-LNP from lyoprotectant and buffer screenings.","date":"2024","source":"Journal of controlled release : official journal of the Controlled Release Society","url":"https://pubmed.ncbi.nlm.nih.gov/39059500","citation_count":35,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40023226","id":"PMC_40023226","title":"Investigating the stability of RNA-lipid nanoparticles in biological fluids: Unveiling its crucial role for understanding LNP performance.","date":"2025","source":"Journal of controlled release : official journal of the Controlled Release Society","url":"https://pubmed.ncbi.nlm.nih.gov/40023226","citation_count":35,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38029740","id":"PMC_38029740","title":"VEGFA mRNA-LNP promotes biliary epithelial cell-to-hepatocyte conversion in acute and chronic liver diseases and reverses steatosis and fibrosis.","date":"2023","source":"Cell stem cell","url":"https://pubmed.ncbi.nlm.nih.gov/38029740","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1473563","id":"PMC_1473563","title":"Blockade of the pacemaker current by intracellular application of UL-FS 49 and UL-AH 99 in sheep cardiac Purkinje fibers.","date":"1992","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/1473563","citation_count":30,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38697317","id":"PMC_38697317","title":"Alpha-galactosylceramide improves the potency of mRNA LNP vaccines against cancer and intracellular bacteria.","date":"2024","source":"Journal of controlled release : official journal of the Controlled Release Society","url":"https://pubmed.ncbi.nlm.nih.gov/38697317","citation_count":29,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32483293","id":"PMC_32483293","title":"Lem2 and Lnp1 maintain the membrane boundary between the nuclear envelope and endoplasmic reticulum.","date":"2020","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/32483293","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30032983","id":"PMC_30032983","title":"Mutations in LNPK, Encoding the Endoplasmic Reticulum Junction Stabilizer Lunapark, Cause a Recessive Neurodevelopmental Syndrome.","date":"2018","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30032983","citation_count":27,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8806172","id":"PMC_8806172","title":"The BamHI fragment 9 of pseudorabies virus contains genes homologous to the UL24, UL25, UL26, and UL 26.5 genes of herpes simplex virus type 1.","date":"1996","source":"Virus research","url":"https://pubmed.ncbi.nlm.nih.gov/8806172","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37515040","id":"PMC_37515040","title":"Development and Characterization of an In Vitro Cell-Based Assay to Predict Potency of mRNA-LNP-Based Vaccines.","date":"2023","source":"Vaccines","url":"https://pubmed.ncbi.nlm.nih.gov/37515040","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38612407","id":"PMC_38612407","title":"mRNA-LNP COVID-19 Vaccine Lipids Induce Complement Activation and Production of Proinflammatory Cytokines: Mechanisms, Effects of Complement Inhibitors, and Relevance to Adverse Reactions.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38612407","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40478935","id":"PMC_40478935","title":"An Il12 mRNA-LNP adjuvant enhances mRNA vaccine-induced CD8 T cell responses.","date":"2025","source":"Science immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40478935","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38753808","id":"PMC_38753808","title":"mRNA-LNP prime boost evolves precursors toward VRC01-like broadly neutralizing antibodies in preclinical humanized mouse models.","date":"2024","source":"Science immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38753808","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35073387","id":"PMC_35073387","title":"Langerhans cells and cDC1s play redundant roles in mRNA-LNP induced protective anti-influenza and anti-SARS-CoV-2 immune responses.","date":"2022","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/35073387","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35631687","id":"PMC_35631687","title":"Development of an LNP-Encapsulated mRNA-RBD Vaccine against SARS-CoV-2 and Its Variants.","date":"2022","source":"Pharmaceutics","url":"https://pubmed.ncbi.nlm.nih.gov/35631687","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37345198","id":"PMC_37345198","title":"mRNA-Lipid Nanoparticle (LNP) Delivery of Humanized EpCAM-CD3 Bispecific Antibody Significantly Blocks Colorectal Cancer Tumor Growth.","date":"2023","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/37345198","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37515169","id":"PMC_37515169","title":"A Trivalent HSV-2 gC2, gD2, gE2 Nucleoside-Modified mRNA-LNP Vaccine Provides Outstanding Protection in Mice against Genital and Non-Genital HSV-1 Infection, Comparable to the Same Antigens Derived from HSV-1.","date":"2023","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/37515169","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38233833","id":"PMC_38233833","title":"Engineered EVs with pathogen proteins: promising vaccine alternatives to LNP-mRNA vaccines.","date":"2024","source":"Journal of biomedical science","url":"https://pubmed.ncbi.nlm.nih.gov/38233833","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37579889","id":"PMC_37579889","title":"Evaluating how cationic lipid affects mRNA-LNP physical properties and biodistribution.","date":"2023","source":"European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V","url":"https://pubmed.ncbi.nlm.nih.gov/37579889","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38028196","id":"PMC_38028196","title":"Astrocyte-targeted siRNA delivery by adenosine-functionalized LNP in mouse TBI model.","date":"2023","source":"Molecular therapy. Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/38028196","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38081560","id":"PMC_38081560","title":"Effects of PEG antibodies on in vivo performance of LNP-mRNA vaccines.","date":"2023","source":"International journal of pharmaceutics","url":"https://pubmed.ncbi.nlm.nih.gov/38081560","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9740784","id":"PMC_9740784","title":"Analysis of human herpesvirus 6 U3 gene, which is a positional homolog of human cytomegalovirus UL 24 gene.","date":"1998","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/9740784","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39844298","id":"PMC_39844298","title":"Delivery of FGF18 using mRNA-LNP protects the cartilage against degeneration via alleviating chondrocyte senescence.","date":"2025","source":"Journal of nanobiotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/39844298","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35935984","id":"PMC_35935984","title":"Comparative immunogenicity of an mRNA/LNP and a DNA vaccine targeting HIV gag conserved elements in macaques.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35935984","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35835315","id":"PMC_35835315","title":"A multiple-target mRNA-LNP vaccine induces protective immunity against experimental multi-serotype DENV in mice.","date":"2022","source":"Virologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/35835315","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36198358","id":"PMC_36198358","title":"An efficient approach for SARS-CoV-2 monoclonal antibody production via modified mRNA-LNP immunization.","date":"2022","source":"International journal of pharmaceutics","url":"https://pubmed.ncbi.nlm.nih.gov/36198358","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39179645","id":"PMC_39179645","title":"Impact of mixing and shaking on mRNA-LNP drug product quality characteristics.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/39179645","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35921835","id":"PMC_35921835","title":"Multiplexed LNP-mRNA vaccination against pathogenic coronavirus species.","date":"2022","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/35921835","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38738752","id":"PMC_38738752","title":"Preformed Vesicle Approach to LNP Manufacturing Enhances Retinal mRNA Delivery.","date":"2024","source":"Small (Weinheim an der Bergstrasse, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/38738752","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38987276","id":"PMC_38987276","title":"Enhancing cross-protection against influenza by heterologous sequential immunization with mRNA LNP and protein nanoparticle vaccines.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/38987276","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24899204","id":"PMC_24899204","title":"Limited dissemination and shedding of the UL128 complex-intact, UL/b'-defective rhesus cytomegalovirus strain 180.92.","date":"2014","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/24899204","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36617516","id":"PMC_36617516","title":"Targeting Ligand Independent Tropism of siRNA-LNP by Small Molecules for Directed Therapy of Liver or Myeloid Immune Cells.","date":"2023","source":"Advanced healthcare materials","url":"https://pubmed.ncbi.nlm.nih.gov/36617516","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35791320","id":"PMC_35791320","title":"Safety and immunogenicity of mRNA-LNP COVID-19 vaccine CVnCoV in Latin American adults: A phase 2 randomized study.","date":"2022","source":"Vaccine: X","url":"https://pubmed.ncbi.nlm.nih.gov/35791320","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35746593","id":"PMC_35746593","title":"Protective Immune Responses Induced by an mRNA-LNP Vaccine Encoding prM-E Proteins against Japanese Encephalitis Virus Infection.","date":"2022","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/35746593","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39295145","id":"PMC_39295145","title":"Synergistic integration of mRNA-LNP with CAR-engineered immune cells: Pioneering progress in immunotherapy.","date":"2024","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/39295145","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40038251","id":"PMC_40038251","title":"LNP-RNA-mediated antigen presentation leverages SARS-CoV-2-specific immunity for cancer treatment.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/40038251","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39522562","id":"PMC_39522562","title":"Characterization of mRNA-LNP structural features and mechanisms for enhanced mRNA vaccine immunogenicity.","date":"2024","source":"Journal of controlled release : official journal of the Controlled Release Society","url":"https://pubmed.ncbi.nlm.nih.gov/39522562","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38829038","id":"PMC_38829038","title":"Imidazolyl Lipids Enhanced LNP Endosomal Escape for Ferroptosis RNAi Treatment of Cancer.","date":"2024","source":"Small (Weinheim an der Bergstrasse, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/38829038","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25138242","id":"PMC_25138242","title":"The regulatory effect of UL-16 binding protein-3 expression on the cytotoxicity of NK cells in cancer patients.","date":"2014","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/25138242","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39900125","id":"PMC_39900125","title":"Overview on LNP-mRNA encapsulation unit operation: Mixing technologies, scalability, and influence of formulation & process parameters on physico-chemical characteristics.","date":"2025","source":"International journal of pharmaceutics","url":"https://pubmed.ncbi.nlm.nih.gov/39900125","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18346081","id":"PMC_18346081","title":"Non-photochemical loss in PSII in high- and low-light-grown leaves of Vicia faba quantified by several fluorescence parameters including L(NP), F0/F'm, a novel parameter.","date":"2008","source":"Physiologia plantarum","url":"https://pubmed.ncbi.nlm.nih.gov/18346081","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38576454","id":"PMC_38576454","title":"Physiologically based modeling of LNP-mediated delivery of mRNA in the vascular system.","date":"2024","source":"Molecular therapy. Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/38576454","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38400152","id":"PMC_38400152","title":"Correlating Stability-Indicating Biochemical and Biophysical Characteristics with In Vitro Cell Potency in mRNA LNP Vaccine.","date":"2024","source":"Vaccines","url":"https://pubmed.ncbi.nlm.nih.gov/38400152","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28711653","id":"PMC_28711653","title":"Highly conserved intragenic HSV-2 sequences: Results from next-generation sequencing of HSV-2 UL and US regions from genital swabs collected from 3 continents.","date":"2017","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/28711653","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37025641","id":"PMC_37025641","title":"A novel Toxoplasma gondii TGGT1_316290 mRNA-LNP vaccine elicits protective immune response against toxoplasmosis in mice.","date":"2023","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/37025641","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37122740","id":"PMC_37122740","title":"Immunization with a novel mRNA vaccine, TGGT1_216200 mRNA-LNP, prolongs survival time in BALB/c mice against acute toxoplasmosis.","date":"2023","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37122740","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39278354","id":"PMC_39278354","title":"LNP-mRNA vaccine prevents type 1 diabetes in non-obese diabetes mice.","date":"2024","source":"Journal of controlled release : official journal of the Controlled Release Society","url":"https://pubmed.ncbi.nlm.nih.gov/39278354","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39385468","id":"PMC_39385468","title":"Efficient and safe in vivo treatment of primary hyperoxaluria type 1 via LNP-CRISPR-Cas9-mediated glycolate oxidase disruption.","date":"2024","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/39385468","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38575581","id":"PMC_38575581","title":"Potent and long-lasting humoral and cellular immunity against varicella zoster virus induced by mRNA-LNP vaccine.","date":"2024","source":"NPJ vaccines","url":"https://pubmed.ncbi.nlm.nih.gov/38575581","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18279315","id":"PMC_18279315","title":"The evolutionarily conserved gene LNP-1 is required for synaptic vesicle trafficking and synaptic transmission.","date":"2008","source":"The European journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/18279315","citation_count":11,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33959636","id":"PMC_33959636","title":"Impact of Ribosome Activity on SARS-CoV-2 LNP - Based mRNA Vaccines.","date":"2021","source":"Frontiers in molecular biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/33959636","citation_count":11,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40120689","id":"PMC_40120689","title":"Lipid nanoparticle (LNP) mediated mRNA delivery in neurodegenerative diseases.","date":"2025","source":"Journal of controlled release : official journal of the Controlled Release Society","url":"https://pubmed.ncbi.nlm.nih.gov/40120689","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38891903","id":"PMC_38891903","title":"Analytical Ultracentrifugation to Assess the Quality of LNP-mRNA Therapeutics.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38891903","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40494942","id":"PMC_40494942","title":"The design, manufacture and LNP formulation of mRNA for research use.","date":"2025","source":"Nature protocols","url":"https://pubmed.ncbi.nlm.nih.gov/40494942","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38538969","id":"PMC_38538969","title":"In vivo LNP-CRISPR Approaches for the Treatment of Hemophilia.","date":"2024","source":"Molecular diagnosis & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/38538969","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31560700","id":"PMC_31560700","title":"A prospective randomized trial on abacavir/lamivudine plus darunavir/ritonavir or raltegravir in HIV-positive drug-naïve patients with CD4<200 cells/uL (the PRADAR study).","date":"2019","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/31560700","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39955975","id":"PMC_39955975","title":"An LNP-mRNA vaccine modulates innate cell trafficking and promotes polyfunctional Th1 CD4+ T cell responses to enhance BCG-induced protective immunity against Mycobacterium tuberculosis.","date":"2025","source":"EBioMedicine","url":"https://pubmed.ncbi.nlm.nih.gov/39955975","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36014345","id":"PMC_36014345","title":"Z-Guggulsterone Is a Potential Lead Molecule of Dawa-ul-Kurkum against Hepatocellular Carcinoma.","date":"2022","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/36014345","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40286880","id":"PMC_40286880","title":"From in vitro to in vivo: The Dominant role of PEG-Lipids in LNP performance.","date":"2025","source":"European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V","url":"https://pubmed.ncbi.nlm.nih.gov/40286880","citation_count":9,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38399987","id":"PMC_38399987","title":"Safety, Immunogenicity, and Mechanism of a Rotavirus mRNA-LNP Vaccine in Mice.","date":"2024","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/38399987","citation_count":9,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35620070","id":"PMC_35620070","title":"Single-cell suspension preparation from murine organs following in vivo mRNA-LNP exposure.","date":"2022","source":"STAR protocols","url":"https://pubmed.ncbi.nlm.nih.gov/35620070","citation_count":8,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17081983","id":"PMC_17081983","title":"Global, in vivo, and site-specific phosphorylation dynamics in signaling networks.","date":"2006","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/17081983","citation_count":2861,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26186194","id":"PMC_26186194","title":"The BioPlex Network: A Systematic Exploration of the Human Interactome.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26186194","citation_count":1118,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28514442","id":"PMC_28514442","title":"Architecture of the human interactome defines protein communities and disease networks.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/28514442","citation_count":1085,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26496610","id":"PMC_26496610","title":"A human interactome in three quantitative dimensions organized by stoichiometries and abundances.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26496610","citation_count":1015,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32296183","id":"PMC_32296183","title":"A reference map of the human binary protein interactome.","date":"2020","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/32296183","citation_count":849,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14702039","id":"PMC_14702039","title":"Complete sequencing and characterization of 21,243 full-length human cDNAs.","date":"2003","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/14702039","citation_count":754,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17353931","id":"PMC_17353931","title":"Large-scale mapping of human protein-protein interactions by mass spectrometry.","date":"2007","source":"Molecular systems biology","url":"https://pubmed.ncbi.nlm.nih.gov/17353931","citation_count":733,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33961781","id":"PMC_33961781","title":"Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33961781","citation_count":705,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29395067","id":"PMC_29395067","title":"High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies.","date":"2018","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/29395067","citation_count":580,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15489334","id":"PMC_15489334","title":"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).","date":"2004","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/15489334","citation_count":438,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26638075","id":"PMC_26638075","title":"A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26638075","citation_count":433,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16344560","id":"PMC_16344560","title":"Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes.","date":"2005","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/16344560","citation_count":409,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12732147","id":"PMC_12732147","title":"A global control region defines a chromosomal regulatory landscape containing the HoxD cluster.","date":"2003","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/12732147","citation_count":375,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"34079125","id":"PMC_34079125","title":"A proximity-dependent biotinylation map of a human cell.","date":"2021","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/34079125","citation_count":339,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22810586","id":"PMC_22810586","title":"Interpreting cancer genomes using systematic host network perturbations by tumour virus proteins.","date":"2012","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/22810586","citation_count":319,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23251661","id":"PMC_23251661","title":"Novel genetic loci identified for the pathophysiology of childhood obesity in the Hispanic population.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23251661","citation_count":312,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"27173435","id":"PMC_27173435","title":"An organelle-specific protein landscape identifies novel diseases and molecular mechanisms.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/27173435","citation_count":211,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"30833792","id":"PMC_30833792","title":"A protein-interaction network of interferon-stimulated genes extends the innate immune system landscape.","date":"2019","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30833792","citation_count":159,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"27619977","id":"PMC_27619977","title":"Cooperation of the ER-shaping proteins atlastin, lunapark, and reticulons to generate a tubular membrane network.","date":"2016","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/27619977","citation_count":150,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32877691","id":"PMC_32877691","title":"A High-Density Human Mitochondrial Proximity Interaction Network.","date":"2020","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/32877691","citation_count":148,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19322201","id":"PMC_19322201","title":"Ubiquitin-mediated proteolysis of HuR by heat shock.","date":"2009","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/19322201","citation_count":142,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22729086","id":"PMC_22729086","title":"ER network formation requires a balance of the dynamin-like GTPase Sey1p and the Lunapark family member Lnp1p.","date":"2012","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/22729086","citation_count":126,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22699663","id":"PMC_22699663","title":"Genome-wide association study of periodontal pathogen colonization.","date":"2012","source":"Journal of dental research","url":"https://pubmed.ncbi.nlm.nih.gov/22699663","citation_count":110,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25548161","id":"PMC_25548161","title":"Lunapark stabilizes nascent three-way junctions in the endoplasmic reticulum.","date":"2014","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/25548161","citation_count":105,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"27716508","id":"PMC_27716508","title":"Regulation of the CUL3 Ubiquitin Ligase by a Calcium-Dependent Co-adaptor.","date":"2016","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/27716508","citation_count":105,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25404289","id":"PMC_25404289","title":"A model for the generation and interconversion of ER morphologies.","date":"2014","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/25404289","citation_count":101,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28692057","id":"PMC_28692057","title":"The interactome of metabolic enzyme carbonic anhydrase IX reveals novel roles in tumor cell migration and invadopodia/MMP14-mediated invasion.","date":"2017","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/28692057","citation_count":96,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28561026","id":"PMC_28561026","title":"R2TP/Prefoldin-like component RUVBL1/RUVBL2 directly interacts with ZNHIT2 to regulate assembly of U5 small nuclear ribonucleoprotein.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/28561026","citation_count":94,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":45597,"output_tokens":1419,"usd":0.079038},"stage2":{"model":"claude-opus-4-6","input_tokens":4625,"output_tokens":1562,"usd":0.093262},"total_usd":0.412742,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":57835,"output_tokens":3317,"usd":0.11163},"round2_rules_fired":"R2,R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":6250,"output_tokens":2185,"usd":0.128812}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"Loss-of-function mutations in LNPK (encoding lunapark) cause aberrant ER structures and increased luminal mass density in patient-derived cells, and LNPK localizes to neurite-like processes in differentiating human neural progenitor cells, implicating it as a curvature-stabilizing protein at tubular three-way junctions of the ER required for normal neurodevelopment.\",\n      \"method\": \"Human genetics (homozygous loss-of-function mutations), patient cell morphological analysis (aberrant ER structures, increased luminal mass density), immunofluorescence/localization in human neural progenitor cells\",\n      \"journal\": \"American Journal of Human Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO (patient cells) with defined cellular phenotype (aberrant ER, luminal mass density), localization in neural progenitor cells; single study\",\n      \"pmids\": [\"30032983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Yeast Lnp1 (ortholog of LNPK) normally resides at three-way junctions of the ER network and is required for ER-phagy; in lnp1Δ mutants, rapamycin-induced localization of the ER-phagy receptor Atg40 to autophagosome formation sites is blocked, preventing association of Atg40 with the scaffold Atg11 and packaging of ER into autophagosomes; this block is phenocopied by actin depolymerization with Latrunculin A, placing Lnp1 in an actin-dependent ER remodeling pathway required for ER-phagy.\",\n      \"method\": \"Genetic deletion (lnp1Δ), fluorescence microscopy of ER-phagy markers (Atg40, Atg11), epistasis with actin depolymerization drug, rapamycin treatment\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype, epistasis with actin cytoskeleton, multiple orthogonal readouts in a single study\",\n      \"pmids\": [\"29915089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Fission yeast Lnp1 (ortholog of LNPK) cooperates with the inner nuclear membrane protein Lem2 to maintain the boundary between the nuclear envelope (NE) and the endoplasmic reticulum (ER); cells lacking both Lem2 and Lnp1 show severe growth defects, aberrant NE/ER membrane expansion, abnormal leakage of nuclear proteins, and vacuolar-like structures in the nucleus; overexpression of the ER membrane protein Apq12 rescues the growth defect and has overlapping function with Lnp1, as shown by genetic epistasis.\",\n      \"method\": \"Double deletion mutants (lem2Δ lnp1Δ), fluorescence microscopy of NE/ER markers and nuclear protein localization, genetic epistasis (Apq12 overexpression rescue)\",\n      \"journal\": \"Communications Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean double-KO with defined cellular phenotypes and genetic epistasis/rescue in multiple orthogonal readouts\",\n      \"pmids\": [\"32483293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"C. elegans lnp-1 (ortholog of LNPK) is required for synaptic vesicle trafficking and neurotransmission; lnp-1 deletion mutants show increased resistance to aldicarb (acetylcholinesterase inhibitor) but normal sensitivity to levamisole (postsynaptic nicotinic agonist), indicating a presynaptic function; lnp-1 mutants also display mislocalization of presynaptic proteins synaptobrevin-1 and RAB-3, and lnp-1 localization in neurons depends on the UNC-104/kinesin motor protein.\",\n      \"method\": \"Deletion genetics in C. elegans, pharmacological assays (aldicarb/levamisole resistance), fluorescence imaging of presynaptic protein localization (synaptobrevin-1, RAB-3), epistasis with unc-104 kinesin\",\n      \"journal\": \"The European Journal of Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with multiple orthogonal readouts (pharmacological + localization + epistasis) but in a single study in a model organism\",\n      \"pmids\": [\"18279315\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LNPK (lunapark) is an ER membrane protein that localizes to and stabilizes three-way junctions of the ER tubular network; it cooperates with other membrane proteins (e.g., Lem2) to maintain the boundary between the ER and nuclear envelope, facilitates actin-dependent ER remodeling required for selective ER autophagy (ER-phagy) by enabling the ER-phagy receptor to reach autophagosome assembly sites, and its C. elegans ortholog additionally regulates presynaptic vesicle trafficking via kinesin-dependent transport; loss-of-function mutations in humans cause a recessive neurodevelopmental syndrome with aberrant ER morphology.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper carefully, then extract discoveries only from KEEP papers.\n\n**Classification:**\n\nFrom the main corpus (100 papers): Nearly all are about LNP (lipid nanoparticle) drug delivery technology — these are ALIAS COLLISION (case A). The \"LNP\" in these papers stands for \"lipid nanoparticle,\" not the LNPK gene (lunapark/KIAA1715).\n\nPapers to KEEP from main corpus:\n- [31] PMID:29915089 — ER-phagy requires Lnp1 (yeast ortholog, consistent with LNPK function) ✓ KEEP\n- [46] PMID:32483293 — Lem2 and Lnp1 maintain NE-ER boundary (fission yeast ortholog) ✓ KEEP\n- [47] PMID:30032983 — Mutations in LNPK cause neurodevelopmental syndrome ✓ KEEP\n- [89] PMID:18279315 — C. elegans lnp-1 in synaptic vesicle trafficking ✓ KEEP\n\nPapers [34] (LNP 509, imidazoline receptor ligand) — EXCLUDE (chemical compound name collision)\nPaper [80] (L(NP) fluorescence parameter in plants) — EXCLUDE (symbol collision, plant physiology)\n\nAll other main corpus papers = EXCLUDE (LNP = lipid nanoparticle, alias collision)\n\nFrom gene2pubmed-curated papers:\n- [15] PMID:12732147 — Identifies Lunapark (Lnp) gene near HoxD, describes its expression pattern ✓ KEEP (foundational paper identifying the gene)\n- [21] PMID:27619977 — Cooperation of atlastin, lunapark, reticulons ✓ KEEP\n- [24] PMID:22729086 — Lnp1p in ER network formation (yeast) ✓ KEEP\n- [26] PMID:25548161 — Lunapark stabilizes nascent three-way junctions ✓ KEEP\n- [28] PMID:25404289 — Model for ER morphologies, Lunapark as S-type protein ✓ KEEP\n- All other gene2pubmed papers = large-scale proteomics/interactome studies, cDNA sequencing, GWAS — EXCLUDE (no direct mechanistic findings about LNPK specifically, or pure expression/association data)\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"Lunapark (Lnp) was identified as a gene located upstream of the HoxD cluster that shares limb and CNS expression specificities with Hoxd genes and Evx2. Its genomic locus contains a global control region with enhancers capable of directing reporter gene expression in digits and CNS, defining large chromosomal regulatory domains.\",\n      \"method\": \"Targeted enhancer-trap approach, transgenic reporter assays, interspecies sequence conservation analysis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct in vivo reporter assay identifying the gene and its regulatory context; single study but multiple methods\",\n      \"pmids\": [\"12732147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The C. elegans ortholog lnp-1 is required for synaptic vesicle trafficking and neurotransmission. Deletion mutations in lnp-1 cause resistance to aldicarb (acetylcholinesterase inhibitor) and locomotor defects without affecting sensitivity to the postsynaptic nicotinic agonist levamisole, indicating a presynaptic function. Presynaptic proteins synaptobrevin-1 and RAB-3 are mislocalized in lnp-1 mutants. LNP-1 localization depends on the UNC-104/kinesin motor.\",\n      \"method\": \"C. elegans deletion mutant analysis, aldicarb and levamisole behavioral assays, fluorescence microscopy of presynaptic protein localization, genetic epistasis\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean loss-of-function with defined presynaptic phenotype and protein mislocalization; single lab study in orthologous organism\",\n      \"pmids\": [\"18279315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Yeast Lnp1p localizes to ER tubule three-way junctions and binds to the reticulon protein Rtn1p and Yop1p. Loss of Lnp1p causes a collapsed, densely reticulated ER network. Lnp1p and the dynamin-like GTPase Sey1p (atlastin ortholog) act antagonistically to balance polygonal ER network formation; the lnp1Δ ER collapse is partially restored when Sey1p GTPase activity is abrogated.\",\n      \"method\": \"Yeast genetics (deletion mutants, GTPase-dead mutants), co-immunoprecipitation, fluorescence microscopy of ER morphology, genetic epistasis (double mutants)\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding, genetic epistasis with GTPase-dead rescue, clean loss-of-function ER morphology phenotype; strong mechanistic framework\",\n      \"pmids\": [\"22729086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Mammalian Lnp1 (mLnp1) localizes to a subset (~50%) of ER three-way junctions. Live-cell imaging shows that junctions containing mLnp1 are less mobile than those without it. Newly formed junctions that acquire mLnp1 remain stable, whereas nascent junctions that fail to acquire mLnp1 undergo rapid ring closure. Thus Lnp1 stabilizes nascent three-way ER junctions and controls network dynamics.\",\n      \"method\": \"Live-cell fluorescence imaging (time-lapse), analysis of junction mobility and ring closure events in mammalian cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct live imaging with quantitative functional consequence (junction stability vs. ring closure); Moderate-to-Strong evidence from multiple observations\",\n      \"pmids\": [\"25548161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Theoretical and experimental modeling shows that Lunapark is an S-type curvature-stabilizing protein that promotes negative curvature along edge lines, thereby stabilizing three-way junctions (small triangular sheets with concave edges) in the tubular ER network. This distinguishes Lunapark from R-type proteins (reticulons) that favor tubules and outer sheet edges.\",\n      \"method\": \"Mathematical/theoretical modeling of ER morphologies combined with experimental validation of protein localization and membrane curvature effects\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — theoretical model with experimental support; provides mechanistic framework but curvature-generating activity not directly reconstituted in vitro\",\n      \"pmids\": [\"25404289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In higher eukaryotes, Lnp (lunapark) affects the abundance of ER three-way junctions and tubules. Lnp moves into junctional sheets and forms oligomers. Lnp is inactivated by mitotic phosphorylation, which contributes to the tubule-to-sheet conversion of the ER during mitosis. ATL (atlastin) is needed to maintain the ER network and acts by counteracting instability of free tubule ends; Lnp and ATL function in sequence at junctions.\",\n      \"method\": \"Fluorescence microscopy, biochemical analysis of Lnp oligomerization, phosphorylation studies during mitosis, manipulation of ATL and Rtn4a levels\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including oligomerization biochemistry, mitotic phosphorylation functional consequence, and live imaging; moderate-to-strong evidence\",\n      \"pmids\": [\"27619977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Homozygous loss-of-function mutations in human LNPK (encoding lunapark) cause a recessive neurodevelopmental syndrome characterized by severe psychomotor delay, intellectual disability, hypotonia, epilepsy, and corpus callosum hypoplasia. Patient-derived cells lacking full-length lunapark show aberrant ER structures and increased luminal mass density. LNPK is expressed during human and mouse brain development and is present in neurite-like processes of differentiating human neural progenitor cells.\",\n      \"method\": \"Human genetics (homozygosity mapping, exome sequencing), patient cell biology (immunofluorescence, EM of ER morphology), immunohistochemistry and immunofluorescence in human/mouse brain tissue and neural progenitor cells\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function mutations linked to specific cellular phenotype (aberrant ER structure) and defined clinical syndrome; replicated across two families with orthogonal cellular and developmental evidence\",\n      \"pmids\": [\"30032983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Yeast Lnp1 is required for ER-phagy (selective autophagy of the ER) upon rapamycin treatment. Lnp1 normally resides at ER tubule three-way junctions and stabilizes the network during continual remodeling. In lnp1Δ mutants, the ER autophagy receptor Atg40 fails to relocalize to sites of autophagosome formation (marked by the scaffold Atg11), preventing ER packaging into autophagosomes. This block is phenocopied by the actin-depolymerizing drug Latrunculin A, suggesting Lnp1 stabilizes actin-dependent ER remodeling required for ER-phagy.\",\n      \"method\": \"Yeast genetics (lnp1Δ mutants), fluorescence microscopy of Atg40 and Atg11 co-localization, pharmacological actin depolymerization, rapamycin-induced autophagy assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic loss-of-function with mechanistic pathway placement (Atg40-Atg11 association blocked), epistasis with actin cytoskeleton, multiple orthogonal readouts\",\n      \"pmids\": [\"29915089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In fission yeast, Lnp1 and the inner nuclear membrane protein Lem2 cooperatively maintain the membrane boundary between the nuclear envelope (NE) and endoplasmic reticulum (ER). Cells lacking both Lem2 and Lnp1 show severe growth defects, aberrant NE/ER membrane expansion, leakage of nuclear proteins, and abnormal vacuolar-like structures in the nucleus. Overexpression of the ER membrane protein Apq12 rescues the growth defect, and genetic analysis shows Apq12 has overlapping functions with Lnp1.\",\n      \"method\": \"Fission yeast genetics (double deletion mutants lem2Δ lnp1Δ), fluorescence microscopy of NE/ER morphology and nuclear protein localization, genetic suppressor analysis (Apq12 overexpression)\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean double-mutant genetic analysis with multiple phenotypic readouts and genetic suppression; demonstrates NE-ER boundary maintenance function\",\n      \"pmids\": [\"32483293\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LNPK (lunapark) encodes a conserved ER membrane protein that localizes to three-way junctions of the ER tubular network, where it stabilizes nascent junctions (preventing ring closure), forms oligomers, cooperates antagonistically with the atlastin GTPase and reticulons to balance ER network morphology, is inactivated by mitotic phosphorylation to facilitate tubule-to-sheet conversion, is required for actin-dependent ER remodeling during ER-phagy, and maintains the NE-ER membrane boundary; loss-of-function in humans causes a recessive neurodevelopmental syndrome with corpus callosum hypoplasia, epilepsy, and intellectual disability.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"LNPK (lunapark) is an ER membrane protein that localizes to three-way junctions of the tubular ER network and stabilizes ER architecture; loss of function leads to aberrant ER structures with increased luminal mass density, and in cooperation with the inner nuclear membrane protein Lem2, LNPK maintains the boundary between the nuclear envelope and the peripheral ER [PMID:30032983, PMID:32483293]. LNPK is required for selective ER autophagy (ER-phagy) by enabling actin-dependent ER remodeling that allows the ER-phagy receptor Atg40 to reach autophagosome assembly sites [PMID:29915089]. The C. elegans ortholog lnp-1 additionally functions presynaptically in neurons, where it regulates synaptic vesicle protein localization in a kinesin UNC-104-dependent manner [PMID:18279315]. Loss-of-function mutations in human LNPK cause a recessive neurodevelopmental syndrome associated with aberrant ER morphology [PMID:30032983].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Before this work, LNPK had no assigned neuronal function; C. elegans lnp-1 deletion revealed a presynaptic role in synaptic vesicle trafficking dependent on the UNC-104 kinesin motor, establishing that the gene product operates at the intersection of membrane trafficking and axonal transport.\",\n      \"evidence\": \"C. elegans lnp-1 deletion mutants with aldicarb/levamisole pharmacological assays, fluorescence imaging of synaptobrevin-1 and RAB-3 mislocalization, and epistasis with unc-104 kinesin\",\n      \"pmids\": [\"18279315\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single study in one model organism; not independently replicated\",\n        \"Whether the presynaptic vesicle trafficking role is conserved in mammals is unknown\",\n        \"Mechanism by which lnp-1 coordinates with UNC-104/kinesin is unresolved\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Two studies converged to establish that LNPK/Lnp1 functions at tubular ER three-way junctions: human genetic studies showed loss-of-function mutations cause a neurodevelopmental syndrome with aberrant ER morphology, while yeast studies demonstrated that Lnp1 is required for actin-dependent ER remodeling enabling ER-phagy receptor Atg40 delivery to autophagosome formation sites.\",\n      \"evidence\": \"Human patient homozygous loss-of-function mutations with ER morphological analysis in patient-derived cells and neural progenitor localization (human genetics); yeast lnp1Δ deletion with fluorescence microscopy of Atg40/Atg11, epistasis with latrunculin A actin depolymerization (yeast genetics)\",\n      \"pmids\": [\"30032983\", \"29915089\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the ER-phagy function is conserved in mammalian LNPK has not been tested\",\n        \"Structural basis for LNPK stabilization of three-way junctions is unknown\",\n        \"Molecular link between ER junction stabilization and the neurodevelopmental phenotype is not established\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The role of LNPK was expanded from peripheral ER junction maintenance to nuclear envelope–ER boundary control: fission yeast Lnp1 cooperates with the inner nuclear membrane protein Lem2 to prevent aberrant NE/ER expansion and nuclear protein leakage, with genetic rescue by the ER membrane protein Apq12 defining an overlapping functional axis.\",\n      \"evidence\": \"Fission yeast lem2Δ lnp1Δ double deletion mutants with fluorescence microscopy of NE/ER markers, nuclear protein leakage assays, and Apq12 overexpression rescue\",\n      \"pmids\": [\"32483293\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether LNPK and LEM2 cooperate at the NE–ER boundary in mammalian cells is untested\",\n        \"Physical interaction between Lnp1 and Lem2 has not been demonstrated\",\n        \"Mechanism by which Lnp1 prevents nuclear protein leakage is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural mechanism by which LNPK stabilizes three-way ER junctions, whether its ER-phagy and NE boundary functions are conserved in mammalian neurons, and how ER junction destabilization leads to the neurodevelopmental phenotype in patients.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of LNPK at ER junctions exists\",\n        \"Mammalian ER-phagy role for LNPK has not been directly demonstrated\",\n        \"Pathogenic mechanism linking ER morphology defects to neuronal dysfunction is not defined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"LEM2\",\n      \"ATG40\",\n      \"ATG11\",\n      \"UNC-104\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"LNPK encodes a conserved, oligomeric ER membrane protein that localizes to three-way junctions of the tubular ER network, where it stabilizes nascent junctions by promoting negative membrane curvature along edge lines and preventing ring closure [PMID:22729086, PMID:25548161, PMID:25404289]. LNPK acts antagonistically with the atlastin/Sey1p fusogenic GTPase and reticulon tubule-shaping proteins to balance ER polygonal network architecture; its inactivation by mitotic phosphorylation facilitates the characteristic tubule-to-sheet ER conversion during cell division [PMID:22729086, PMID:27619977]. Beyond junction maintenance, LNPK is required for actin-dependent ER remodeling during ER-phagy and cooperates with inner nuclear membrane proteins to preserve the nuclear envelope–ER boundary [PMID:29915089, PMID:32483293]. Biallelic loss-of-function mutations in human LNPK cause a recessive neurodevelopmental syndrome featuring intellectual disability, epilepsy, and corpus callosum hypoplasia, with patient cells exhibiting aberrant ER morphology [PMID:30032983].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Identification of lunapark as a gene sharing limb and CNS regulatory domains with the HoxD cluster established its developmental expression pattern but left its molecular function unknown.\",\n      \"evidence\": \"Enhancer-trap transgenic reporters and interspecies conservation analysis in mouse\",\n      \"pmids\": [\"12732147\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No molecular function or subcellular localization determined\",\n        \"Regulatory relationship with HoxD genes not mechanistically defined\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Loss of the C. elegans ortholog lnp-1 revealed a presynaptic role in synaptic vesicle trafficking, providing the first link between lunapark and membrane compartment organization in neurons.\",\n      \"evidence\": \"C. elegans deletion mutants with aldicarb/levamisole assays and presynaptic protein mislocalization\",\n      \"pmids\": [\"18279315\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism of synaptic vesicle mislocalization not defined at the ER level\",\n        \"Relevance to ER morphology not yet recognized\",\n        \"Single organism study without mammalian validation\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Discovery that yeast Lnp1p localizes to ER three-way junctions, binds reticulon/Yop1p, and acts antagonistically to the atlastin ortholog Sey1p established the core paradigm: lunapark is an ER junction-stabilizing protein that balances the tubular network against fusogenic forces.\",\n      \"evidence\": \"Yeast deletion and GTPase-dead mutants, co-immunoprecipitation, fluorescence microscopy of ER morphology\",\n      \"pmids\": [\"22729086\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct curvature-generating or -sensing activity not reconstituted in vitro\",\n        \"Mammalian conservation of junction localization not yet confirmed\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Live imaging in mammalian cells and theoretical modeling together showed that Lnp1 stabilizes nascent junctions by promoting negative (S-type) membrane curvature, explaining how it prevents ring closure and maintains ER network geometry.\",\n      \"evidence\": \"Time-lapse fluorescence imaging of junction mobility and ring closure; mathematical modeling of ER membrane shapes\",\n      \"pmids\": [\"25548161\", \"25404289\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Curvature-stabilizing activity inferred from localization and modeling; no in vitro reconstitution with purified protein on liposomes\",\n        \"Structural basis for curvature sensing/generation unknown\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstration that Lnp oligomerizes and is inactivated by mitotic phosphorylation linked its biochemical regulation to the cell-cycle-dependent ER tubule-to-sheet conversion, placing Lnp as a regulated effector of ER remodeling during mitosis.\",\n      \"evidence\": \"Biochemical oligomerization assays, phosphorylation studies during mitosis, manipulation of ATL and Rtn4a levels in mammalian cells\",\n      \"pmids\": [\"27619977\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Kinase(s) responsible for mitotic phosphorylation not identified\",\n        \"Stoichiometry and structural organization of oligomers undetermined\",\n        \"How phosphorylation disrupts oligomer function mechanistically unclear\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Two independent advances resolved downstream consequences of Lnp loss: biallelic LNPK mutations were shown to cause a human neurodevelopmental syndrome with aberrant ER in patient cells, while yeast studies demonstrated that Lnp1 is required for ER-phagy by enabling actin-dependent relocalization of the autophagy receptor Atg40.\",\n      \"evidence\": \"Human exome sequencing and homozygosity mapping across two families with patient cell ER morphology analysis; yeast lnp1Δ mutants with Atg40/Atg11 co-localization and Latrunculin A phenocopy\",\n      \"pmids\": [\"30032983\", \"29915089\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether ER-phagy defect contributes to the human neurodevelopmental phenotype is untested\",\n        \"Direct actin–Lnp1 interaction not demonstrated\",\n        \"Mammalian ER-phagy role of LNPK not confirmed\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Genetic studies in fission yeast revealed that Lnp1 cooperates with the inner nuclear membrane protein Lem2 to maintain the NE-ER boundary, expanding lunapark function beyond ER tubule junctions to nuclear envelope integrity.\",\n      \"evidence\": \"Fission yeast lem2Δ lnp1Δ double mutants with NE/ER morphology analysis and Apq12 genetic suppression\",\n      \"pmids\": [\"32483293\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether NE-ER boundary maintenance function is conserved in mammals\",\n        \"Physical interaction between Lnp1 and Lem2 or Apq12 not demonstrated\",\n        \"Contribution of NE defects to neurological phenotype in LNPK patients unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include the atomic structure of LNPK, the identity of kinases controlling its mitotic phosphorylation, whether its ER-phagy and NE-boundary functions operate in mammalian neurons, and how ER junction instability leads to the specific neurodevelopmental deficits seen in patients.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structure of LNPK or its oligomeric complex\",\n        \"Mammalian in vivo conditional knockout phenotype not reported\",\n        \"Pathogenic mechanism linking ER junction loss to corpus callosum hypoplasia and epilepsy undefined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [2, 3, 4, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [2, 3, 5, 6, 7, 8]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [2, 3, 5, 8]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"RTN1\",\n      \"ATL1\",\n      \"LEM2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}