{"gene":"NPS","run_date":"2026-04-29T11:37:57","timeline":{"discoveries":[{"year":2012,"finding":"NPS is internalized into NPS receptor-expressing neurons via receptor-ligand complex internalization; in the hippocampal CA1 region, NPS modulates synaptic transmission and plasticity, and differentially modulates expression of proteins of the glutamatergic system involved in synaptic plasticity.","method":"Fluorophore-conjugated NPS tracking in brain slices and cell culture; single-neuron level internalization imaging; intranasal delivery in mice with behavioral readout","journal":"Neuropsychopharmacology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (live imaging, cell culture internalization, behavioral assay, protein expression analysis) in a single study","pmids":["22278093"],"is_preprint":false},{"year":2010,"finding":"NPSR1 (the NPS receptor) is essential for mediating NPS-induced hyperlocomotion, anxiolysis, and corticosterone release; NPSR1-deficient mice fail to show these NPS-induced effects, and male NPSR1-deficient mice show enhanced depression-like behavior.","method":"NPSR1 gene-targeted knockout mice; ICV NPS administration; behavioral tests (open-field, forced swim, Morris water maze); corticosterone measurements","journal":"Psychoneuroendocrinology","confidence":"High","confidence_rationale":"Tier 2 — clean KO with multiple defined behavioral and neuroendocrine phenotypes, replicated across multiple assays","pmids":["20171785"],"is_preprint":false},{"year":2015,"finding":"NPSR1 stimulation in hippocampal neurons induces calcium mobilization from the endoplasmic reticulum via activation of IP3 and ryanodine receptors, followed by store-operated calcium channel activation mediating extracellular calcium entry.","method":"Primary hippocampal neuron cultures expressing human NPSR1; single-cell calcium imaging with pharmacological dissection (IP3 receptor and ryanodine receptor antagonists; store-operated channel blockers)","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1-2 — direct intracellular calcium imaging with pharmacological pathway dissection in neurons","pmids":["25714705"],"is_preprint":false},{"year":2017,"finding":"Truncation of the NPS peptide produces fragments with biased agonism at NPSR, preferentially activating the calcium mobilization pathway over cAMP; a modified tetrapeptide analog retains anxiolytic and memory-consolidating activity in vivo but shows greatly attenuated hyperlocomotor stimulation, linking the cAMP pathway to locomotor stimulation.","method":"Calcium mobilization and cAMP assays in cells expressing human and mouse NPSR variants; in vivo behavioral testing in rodents","journal":"Neuropharmacology","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro second messenger assays with structure-activity relationship plus in vivo behavioral validation","pmids":["28267583"],"is_preprint":false},{"year":2012,"finding":"NPS stimulates human monocyte chemotaxis via selective NPSR activation; the effect is completely blocked by peptide ([ D-Cys(tBu)5]NPS, [tBu-D-Gly5]NPS) and nonpeptide (SHA 68) NPSR antagonists.","method":"In vitro chemotaxis assay with human monocytes; pharmacological antagonism with selective NPSR antagonists","journal":"Peptides","confidence":"Medium","confidence_rationale":"Tier 2 — direct functional assay with pharmacological validation using multiple selective antagonists; single lab","pmids":["23142110"],"is_preprint":false},{"year":2022,"finding":"NPS-expressing neurons in the brainstem are primarily located in the parabrachial nucleus (PB) region, are Atoh1-derived and Foxp2-expressing, distinct from Calca-, Lmx1b-, Cck-, and Pdyn-expressing PB neurons; novel NPS neuron populations identified in nucleus incertus, anterior hypothalamus, and lateral habenula.","method":"In situ hybridization, immunofluorescence, and Cre-reporter labeling in mice","journal":"The Journal of comparative neurology","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization by multiple orthogonal methods with molecular identity characterization; single lab","pmids":["36036349"],"is_preprint":false},{"year":2021,"finding":"The NPS/NPSR system regulates food intake with anorexigenic effects when NPS is centrally injected into different brain areas, and influences gastrointestinal tract functions.","method":"Review of central NPS injection studies in rodents (ICV and intra-brain-site administration) with food intake measurements","journal":"Pharmaceuticals (Basel, Switzerland)","confidence":"Low","confidence_rationale":"Tier 3 — review summarizing behavioral injection studies; no new primary mechanistic data","pmids":["33810221"],"is_preprint":false}],"current_model":"Neuropeptide S (NPS) is a 20-amino-acid peptide that acts as the endogenous ligand of the G protein-coupled receptor NPSR1, activating both calcium mobilization (via IP3 and ryanodine receptor-mediated ER release followed by store-operated calcium entry) and cAMP signaling pathways; biased agonism studies indicate that locomotor stimulation is linked to cAMP signaling while anxiolysis and memory consolidation are linked to calcium mobilization; NPS is internalized into NPSR-expressing neurons via receptor-ligand complex endocytosis, modulates glutamatergic synaptic plasticity in hippocampal CA1, stimulates monocyte chemotaxis, and NPS-expressing neurons are parabrachial nucleus neurons that are Atoh1-derived and Foxp2-expressing."},"narrative":{"teleology":[{"year":2010,"claim":"Establishing that all major behavioral and neuroendocrine effects of NPS — hyperlocomotion, anxiolysis, and corticosterone release — require NPSR1, confirming it as the sole functional receptor for NPS in vivo.","evidence":"NPSR1 knockout mice with ICV NPS injection and behavioral/neuroendocrine phenotyping","pmids":["20171785"],"confidence":"High","gaps":["Downstream intracellular signaling pathways mediating each behavioral effect were not dissected","Whether compensatory mechanisms exist in knockout animals was not addressed"]},{"year":2012,"claim":"Demonstrating that NPS enters neurons through receptor-mediated internalization and modulates hippocampal glutamatergic synaptic plasticity, providing a cellular mechanism for NPS effects on memory and cognition.","evidence":"Fluorophore-conjugated NPS tracking in brain slices and cell culture; single-neuron imaging; intranasal delivery with behavioral and proteomic readouts in mice","pmids":["22278093"],"confidence":"High","gaps":["The specific glutamatergic proteins regulated and the signaling cascade from receptor internalization to plasticity changes were not fully resolved","Whether internalization is required for synaptic modulation or is merely a desensitization event was not distinguished"]},{"year":2012,"claim":"Extending NPS function beyond the CNS by showing it drives monocyte chemotaxis via NPSR, establishing a peripheral immunomodulatory role.","evidence":"In vitro chemotaxis assay with human monocytes; pharmacological blockade with multiple selective NPSR antagonists","pmids":["23142110"],"confidence":"Medium","gaps":["In vivo immune relevance and physiological NPS concentrations at immune cell sites are unknown","Downstream signaling pathway in monocytes was not characterized"]},{"year":2015,"claim":"Resolving the intracellular calcium signaling cascade downstream of NPSR1, showing sequential IP3 receptor and ryanodine receptor-mediated ER calcium release followed by store-operated calcium entry.","evidence":"Single-cell calcium imaging with pharmacological dissection in primary hippocampal neurons expressing human NPSR1","pmids":["25714705"],"confidence":"High","gaps":["The G protein subtype coupling NPSR1 to IP3 generation was not identified","Whether the same calcium signaling cascade operates in non-hippocampal NPS target neurons was not tested"]},{"year":2017,"claim":"Dissecting biased agonism at NPSR1 revealed that cAMP signaling drives locomotor stimulation while calcium mobilization mediates anxiolysis and memory consolidation, separating therapeutic from side-effect pathways.","evidence":"Structure-activity relationship of truncated NPS analogs in calcium and cAMP assays; behavioral validation in rodents","pmids":["28267583"],"confidence":"High","gaps":["The molecular determinants on NPSR1 that confer pathway-selective coupling were not identified","Whether biased agonism translates to human physiology is untested"]},{"year":2022,"claim":"Mapping the developmental origin and molecular identity of NPS-producing neurons revealed they are Atoh1-derived, Foxp2-expressing parabrachial cells, distinct from other known PB populations, and identified novel NPS populations in the nucleus incertus, anterior hypothalamus, and lateral habenula.","evidence":"In situ hybridization, immunofluorescence, and Cre-reporter labeling in mice","pmids":["36036349"],"confidence":"Medium","gaps":["Functional contributions of each anatomically distinct NPS neuron population to behavior remain undefined","Circuit-level connectivity of NPS neurons to NPSR1-expressing target areas was not mapped"]},{"year":null,"claim":"The structural basis of NPS–NPSR1 interaction, the G protein subtype coupling specificity, and the circuit-level logic by which discrete NPS neuron populations drive distinct behavioral outputs remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of the NPS–NPSR1 complex exists","Selective ablation or activation of individual NPS neuron populations has not been performed","Endogenous release dynamics of NPS under physiological conditions are not characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[1,2,3]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,3,4]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2,3]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,1,3]}],"complexes":[],"partners":["NPSR1"],"other_free_text":[]},"mechanistic_narrative":"Neuropeptide S (NPS) is a 20-amino-acid neuropeptide that functions as the endogenous ligand for the G protein-coupled receptor NPSR1, coupling to both calcium mobilization (via IP3 and ryanodine receptor-mediated ER release followed by store-operated calcium entry) and cAMP signaling pathways to regulate arousal, anxiety, and memory [PMID:25714705, PMID:28267583]. Biased agonism studies demonstrate that NPS-driven locomotor stimulation depends on the cAMP pathway, whereas anxiolytic and memory-consolidating effects are mediated through the calcium mobilization pathway [PMID:28267583]. In the hippocampal CA1 region, NPS is internalized into NPSR-expressing neurons via receptor-ligand complex endocytosis and modulates glutamatergic synaptic plasticity [PMID:22278093]. NPS-producing neurons in the brainstem are Atoh1-derived, Foxp2-expressing cells concentrated in the parabrachial nucleus, with additional populations in the nucleus incertus, anterior hypothalamus, and lateral habenula [PMID:36036349]."},"prefetch_data":{"uniprot":{"accession":"P0C0P6","full_name":"Neuropeptide S","aliases":[],"length_aa":89,"mass_kda":10.1,"function":"Ligand for NPSR1 (PubMed:15312648, PubMed:15947423, PubMed:16720571, PubMed:16790440). Binds to its receptor with nanomolar affinity and initiates a G(q)/GNAQ-dependent phospholipase C-activating signaling pathway. This results in Ca(2+) mobilization from intracellular stores and increased intracellular Ca(2+) levels (PubMed:15312648, PubMed:15947423, PubMed:16720571, PubMed:16790440, PubMed:25714705, PubMed:26865629). In addition to this pathway, NPS binding to its receptor activates cAMP/PKA signal transduction (PubMed:26865629). Finally, both pathways converge to activate ERK1/ERK2 phosphorylation and signaling cascade (PubMed:26865629). Modulates arousal and anxiety. May play an important anorexigenic role (By similarity)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P0C0P6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NPS","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NPS","total_profiled":1310},"omim":[{"mim_id":"621336","title":"SHORT SLEEP, FAMILIAL NATURAL, 3; FNSS3","url":"https://www.omim.org/entry/621336"},{"mim_id":"613572","title":"G PROTEIN-COUPLED RECEPTOR, FAMILY C, GROUP 6, MEMBER A; GPRC6A","url":"https://www.omim.org/entry/613572"},{"mim_id":"613207","title":"ASTHMA-RELATED TRAITS, SUSCEPTIBILITY TO, 8; ASRT8","url":"https://www.omim.org/entry/613207"},{"mim_id":"609888","title":"LEPROSY, SUSCEPTIBILITY TO, 1; LPRS1","url":"https://www.omim.org/entry/609888"},{"mim_id":"609513","title":"NEUROPEPTIDE S; NPS","url":"https://www.omim.org/entry/609513"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Not detected","tissue_distribution":"Not detected","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NPS"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P0C0P6","domains":[{"cath_id":"-","chopping":"2-68","consensus_level":"medium","plddt":65.4782,"start":2,"end":68}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P0C0P6","model_url":"https://alphafold.ebi.ac.uk/files/AF-P0C0P6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P0C0P6-F1-predicted_aligned_error_v6.png","plddt_mean":65.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NPS","jax_strain_url":"https://www.jax.org/strain/search?query=NPS"},"sequence":{"accession":"P0C0P6","fasta_url":"https://rest.uniprot.org/uniprotkb/P0C0P6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P0C0P6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P0C0P6"}},"corpus_meta":[{"pmid":"34572797","id":"PMC_34572797","title":"Recent Advances in Zinc Oxide Nanoparticles (ZnO NPs) for Cancer Diagnosis, Target Drug Delivery, and Treatment.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/34572797","citation_count":216,"is_preprint":false},{"pmid":"31969653","id":"PMC_31969653","title":"Titanium dioxide nanoparticles (TiO2 NPs) promote growth and ameliorate salinity stress effects on essential oil profile and biochemical attributes of Dracocephalum moldavica.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31969653","citation_count":163,"is_preprint":false},{"pmid":"30154832","id":"PMC_30154832","title":"A Review on Green Synthesis, Biomedical Applications, and Toxicity Studies of ZnO NPs.","date":"2018","source":"Bioinorganic chemistry and applications","url":"https://pubmed.ncbi.nlm.nih.gov/30154832","citation_count":132,"is_preprint":false},{"pmid":"28110253","id":"PMC_28110253","title":"Synthesis of silver nanoparticles (Ag NPs) for anticancer activities (MCF 7 breast and A549 lung cell lines) of the crude extract of Syzygium aromaticum.","date":"2016","source":"Journal of photochemistry and photobiology. B, Biology","url":"https://pubmed.ncbi.nlm.nih.gov/28110253","citation_count":112,"is_preprint":false},{"pmid":"22214244","id":"PMC_22214244","title":"Monosaccharides versus PEG-functionalized NPs: influence in the cellular uptake.","date":"2012","source":"ACS nano","url":"https://pubmed.ncbi.nlm.nih.gov/22214244","citation_count":108,"is_preprint":false},{"pmid":"9461105","id":"PMC_9461105","title":"NPS R-568 halts or reverses osteitis fibrosa in uremic rats.","date":"1998","source":"Kidney international","url":"https://pubmed.ncbi.nlm.nih.gov/9461105","citation_count":108,"is_preprint":false},{"pmid":"28601703","id":"PMC_28601703","title":"Controlled and sustained delivery of siRNA/NPs from hydrogels expedites bone fracture healing.","date":"2017","source":"Biomaterials","url":"https://pubmed.ncbi.nlm.nih.gov/28601703","citation_count":100,"is_preprint":false},{"pmid":"29408664","id":"PMC_29408664","title":"Cytotoxicity and cellular mechanisms of toxicity of CuO NPs in mussel cells in vitro and comparative sensitivity with human cells.","date":"2018","source":"Toxicology in vitro : an international journal published in association with BIBRA","url":"https://pubmed.ncbi.nlm.nih.gov/29408664","citation_count":68,"is_preprint":false},{"pmid":"22278093","id":"PMC_22278093","title":"Intranasally administered neuropeptide S (NPS) exerts anxiolytic effects following internalization into NPS receptor-expressing neurons.","date":"2012","source":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/22278093","citation_count":66,"is_preprint":false},{"pmid":"20171785","id":"PMC_20171785","title":"Abnormal response to stress and impaired NPS-induced hyperlocomotion, anxiolytic effect and corticosterone increase in mice lacking NPSR1.","date":"2010","source":"Psychoneuroendocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/20171785","citation_count":61,"is_preprint":false},{"pmid":"33520589","id":"PMC_33520589","title":"Toxicological Consequences of Titanium Dioxide Nanoparticles (TiO2NPs) and Their Jeopardy to Human Population.","date":"2021","source":"BioNanoScience","url":"https://pubmed.ncbi.nlm.nih.gov/33520589","citation_count":59,"is_preprint":false},{"pmid":"29220804","id":"PMC_29220804","title":"Graphene and Au NPs co-mediated enzymatic silver deposition for the ultrasensitive electrochemical detection of cholesterol.","date":"2017","source":"Biosensors & bioelectronics","url":"https://pubmed.ncbi.nlm.nih.gov/29220804","citation_count":52,"is_preprint":false},{"pmid":"29240707","id":"PMC_29240707","title":"Molecular Mechanisms of Zinc Oxide Nanoparticle-Induced Genotoxicity Short Running Title: Genotoxicity of ZnO NPs.","date":"2017","source":"Materials (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/29240707","citation_count":52,"is_preprint":false},{"pmid":"25635909","id":"PMC_25635909","title":"Complete architecture of the archaeal RNA polymerase open complex from single-molecule FRET and NPS.","date":"2015","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/25635909","citation_count":49,"is_preprint":false},{"pmid":"11454016","id":"PMC_11454016","title":"Human parathyroid cell proliferation in response to calcium, NPS R-467, calcitriol and phosphate.","date":"2001","source":"European journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/11454016","citation_count":49,"is_preprint":false},{"pmid":"25358738","id":"PMC_25358738","title":"Antioxidant and antigenotoxic properties of CeO2 NPs and cerium sulphate: Studies with Drosophila melanogaster as a promising in vivo model.","date":"2014","source":"Nanotoxicology","url":"https://pubmed.ncbi.nlm.nih.gov/25358738","citation_count":48,"is_preprint":false},{"pmid":"30781732","id":"PMC_30781732","title":"Toxic Effects of TiO₂ NPs on Zebrafish.","date":"2019","source":"International journal of environmental research and public health","url":"https://pubmed.ncbi.nlm.nih.gov/30781732","citation_count":47,"is_preprint":false},{"pmid":"33320924","id":"PMC_33320924","title":"PVA based nanofiber containing CQDs modified with silica NPs and silk fibroin accelerates wound healing in a rat model.","date":"2021","source":"Journal of materials chemistry. B","url":"https://pubmed.ncbi.nlm.nih.gov/33320924","citation_count":45,"is_preprint":false},{"pmid":"30849403","id":"PMC_30849403","title":"Shape-engineered titanium dioxide nanoparticles (TiO2-NPs): cytotoxicity and genotoxicity in bronchial epithelial cells.","date":"2019","source":"Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association","url":"https://pubmed.ncbi.nlm.nih.gov/30849403","citation_count":45,"is_preprint":false},{"pmid":"35884757","id":"PMC_35884757","title":"PS-NPs Induced Neurotoxic Effects in SHSY-5Y Cells via Autophagy Activation and Mitochondrial Dysfunction.","date":"2022","source":"Brain sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35884757","citation_count":44,"is_preprint":false},{"pmid":"36241295","id":"PMC_36241295","title":"Iota carrageenan gold-silver NPs photothermal hydrogel for tumor postsurgical anti-recurrence and wound healing.","date":"2022","source":"Carbohydrate polymers","url":"https://pubmed.ncbi.nlm.nih.gov/36241295","citation_count":43,"is_preprint":false},{"pmid":"31695369","id":"PMC_31695369","title":"Cerium oxide NPs mitigate the amyloid formation of α-synuclein and associated cytotoxicity.","date":"2019","source":"International journal of nanomedicine","url":"https://pubmed.ncbi.nlm.nih.gov/31695369","citation_count":40,"is_preprint":false},{"pmid":"21396889","id":"PMC_21396889","title":"Identification and characterization of another 4-nitrophenol degradation gene cluster, nps, in Rhodococcus sp. strain PN1.","date":"2011","source":"Journal of bioscience and bioengineering","url":"https://pubmed.ncbi.nlm.nih.gov/21396889","citation_count":39,"is_preprint":false},{"pmid":"31632016","id":"PMC_31632016","title":"Conjugation Of EGCG And Chitosan NPs As A Novel Nano-Drug Delivery System.","date":"2019","source":"International journal of nanomedicine","url":"https://pubmed.ncbi.nlm.nih.gov/31632016","citation_count":38,"is_preprint":false},{"pmid":"34281191","id":"PMC_34281191","title":"Functionalized Nanoplastics (NPs) Increase the Toxicity of Metals in Fish Cell Lines.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34281191","citation_count":37,"is_preprint":false},{"pmid":"36218121","id":"PMC_36218121","title":"Self-Cascade Nanoenzyme of Cupric Oxide Nanoparticles (CuO NPs) Induced in Situ Catalysis Formation of Polyelectrolyte as Template for the Synthesis of Near-Infrared Fluorescent Silver Nanoclusters and the Application in Glutathione Detection and Bioimaging.","date":"2022","source":"Analytical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36218121","citation_count":37,"is_preprint":false},{"pmid":"28800474","id":"PMC_28800474","title":"NPS 2143, a selective calcium-sensing receptor antagonist inhibits lipopolysaccharide-induced pulmonary inflammation.","date":"2017","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/28800474","citation_count":36,"is_preprint":false},{"pmid":"33570729","id":"PMC_33570729","title":"Neuropathological and Cognitive Effects Induced by CuO-NPs in Rats and Trials for Prevention Using Pomegranate Juice.","date":"2021","source":"Neurochemical research","url":"https://pubmed.ncbi.nlm.nih.gov/33570729","citation_count":35,"is_preprint":false},{"pmid":"33432773","id":"PMC_33432773","title":"Arabinoxylan/graphene-oxide/nHAp-NPs/PVA bionano composite scaffolds for fractured bone healing.","date":"2021","source":"Journal of tissue engineering and regenerative medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33432773","citation_count":33,"is_preprint":false},{"pmid":"37203277","id":"PMC_37203277","title":"Remodeling Serine Synthesis and Metabolism via Nanoparticles (NPs)-Mediated CFL1 Silencing to Enhance the Sensitivity of Hepatocellular Carcinoma to Sorafenib.","date":"2023","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/37203277","citation_count":33,"is_preprint":false},{"pmid":"26417264","id":"PMC_26417264","title":"Encapsulation of catechin and epicatechin on BSA NPS improved their stability and antioxidant potential.","date":"2014","source":"EXCLI journal","url":"https://pubmed.ncbi.nlm.nih.gov/26417264","citation_count":33,"is_preprint":false},{"pmid":"31767318","id":"PMC_31767318","title":"Synergy between Cu-NPs and fungicides against Botrytis cinerea.","date":"2019","source":"The Science of the total environment","url":"https://pubmed.ncbi.nlm.nih.gov/31767318","citation_count":32,"is_preprint":false},{"pmid":"33983705","id":"PMC_33983705","title":"Multiplex Electrochemiluminescence Polarization Assay Based on the Surface Plasmon Coupling Effect of Au NPs and Ag@Au NPs.","date":"2021","source":"Analytical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/33983705","citation_count":29,"is_preprint":false},{"pmid":"29601471","id":"PMC_29601471","title":"Nanopulse Stimulation (NPS) Induces Tumor Ablation and Immunity in Orthotopic 4T1 Mouse Breast Cancer: A Review.","date":"2018","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/29601471","citation_count":28,"is_preprint":false},{"pmid":"36347425","id":"PMC_36347425","title":"Niclosamide-loaded nanoparticles (Ncl-NPs) reverse pulmonary fibrosis in vivo and in vitro.","date":"2022","source":"Journal of advanced research","url":"https://pubmed.ncbi.nlm.nih.gov/36347425","citation_count":28,"is_preprint":false},{"pmid":"30182775","id":"PMC_30182775","title":"Mechanism of long-term toxicity of CuO NPs to microalgae.","date":"2018","source":"Nanotoxicology","url":"https://pubmed.ncbi.nlm.nih.gov/30182775","citation_count":28,"is_preprint":false},{"pmid":"35974115","id":"PMC_35974115","title":"Insights into Ag-NPs-mediated pathophysiology and ultrastructural aberrations in ovarian tissues of darkling beetles.","date":"2022","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/35974115","citation_count":28,"is_preprint":false},{"pmid":"20188888","id":"PMC_20188888","title":"Aptamer-Au NPs conjugates-accumulated methylene blue for the sensitive electrochemical immunoassay of protein.","date":"2009","source":"Talanta","url":"https://pubmed.ncbi.nlm.nih.gov/20188888","citation_count":27,"is_preprint":false},{"pmid":"32939669","id":"PMC_32939669","title":"Amorphous Calcium Phosphate NPs Mediate the Macrophage Response and Modulate BMSC Osteogenesis.","date":"2020","source":"Inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/32939669","citation_count":26,"is_preprint":false},{"pmid":"25714705","id":"PMC_25714705","title":"Neuronal expression of the human neuropeptide S receptor NPSR1 identifies NPS-induced calcium signaling pathways.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25714705","citation_count":26,"is_preprint":false},{"pmid":"35012154","id":"PMC_35012154","title":"Formulation Development, Characterization and Antifungal Evaluation of Chitosan NPs for Topical Delivery of Voriconazole In Vitro and Ex Vivo.","date":"2021","source":"Polymers","url":"https://pubmed.ncbi.nlm.nih.gov/35012154","citation_count":25,"is_preprint":false},{"pmid":"27751687","id":"PMC_27751687","title":"Effects of PVP/PEI coated and uncoated silver NPs and PVP/PEI coating agent on three species of marine microalgae.","date":"2016","source":"The Science of the total environment","url":"https://pubmed.ncbi.nlm.nih.gov/27751687","citation_count":25,"is_preprint":false},{"pmid":"36191138","id":"PMC_36191138","title":"Biogenic synthesis of CuO-NPs as nanotherapeutics approaches to overcome multidrug-resistant Staphylococcus aureus (MDRSA).","date":"2022","source":"Artificial cells, nanomedicine, and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/36191138","citation_count":24,"is_preprint":false},{"pmid":"32183157","id":"PMC_32183157","title":"Biogenic Ceria Nanoparticles (CeO2 NPs) for Effective Photocatalytic and Cytotoxic Activity.","date":"2020","source":"Bioengineering (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/32183157","citation_count":23,"is_preprint":false},{"pmid":"27017887","id":"PMC_27017887","title":"Mechanisms of TiO2 NPs-induced phoxim metabolism in silkworm (Bombyx mori) fat body.","date":"2015","source":"Pesticide biochemistry and physiology","url":"https://pubmed.ncbi.nlm.nih.gov/27017887","citation_count":22,"is_preprint":false},{"pmid":"35264205","id":"PMC_35264205","title":"Cur@SF NPs alleviate Friedreich's ataxia in a mouse model through synergistic iron chelation and antioxidation.","date":"2022","source":"Journal of nanobiotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/35264205","citation_count":22,"is_preprint":false},{"pmid":"38090134","id":"PMC_38090134","title":"Evaluation of biogenically synthesized MgO NPs anticancer activity against breast cancer cells.","date":"2023","source":"Saudi journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38090134","citation_count":22,"is_preprint":false},{"pmid":"34543635","id":"PMC_34543635","title":"The role of iron-based nanoparticles (Fe-NPs) on methanogenesis in anaerobic digestion (AD) performance.","date":"2021","source":"Environmental research","url":"https://pubmed.ncbi.nlm.nih.gov/34543635","citation_count":21,"is_preprint":false},{"pmid":"37655325","id":"PMC_37655325","title":"Nanoparticles (NPs)-mediated lncBCMA silencing to promote eEF1A1 ubiquitination and suppress breast cancer growth and metastasis.","date":"2022","source":"Acta pharmaceutica Sinica. B","url":"https://pubmed.ncbi.nlm.nih.gov/37655325","citation_count":20,"is_preprint":false},{"pmid":"34068903","id":"PMC_34068903","title":"Molecular Mechanisms of Action of Novel Psychoactive Substances (NPS). A New Threat for Young Drug Users with Forensic-Toxicological Implications.","date":"2021","source":"Life (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/34068903","citation_count":20,"is_preprint":false},{"pmid":"29539589","id":"PMC_29539589","title":"Genotoxicity and physiological effects of CeO2 NPs on a freshwater bivalve (Corbicula fluminea).","date":"2018","source":"Aquatic toxicology (Amsterdam, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/29539589","citation_count":20,"is_preprint":false},{"pmid":"40059153","id":"PMC_40059153","title":"Modulating lipid metabolism by nanoparticles (NPs)-mediated ACSL3 silencing to inhibit hepatocellular carcinoma growth and metastasis.","date":"2025","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/40059153","citation_count":19,"is_preprint":false},{"pmid":"33229266","id":"PMC_33229266","title":"The cytotoxicity of endogenous CdS and Cd2+ ions during CdS NPs biosynthesis.","date":"2020","source":"Journal of hazardous materials","url":"https://pubmed.ncbi.nlm.nih.gov/33229266","citation_count":19,"is_preprint":false},{"pmid":"30901347","id":"PMC_30901347","title":"Enhanced antibacterial and anticancer properties of Se-NPs decorated TiO2 nanotube film.","date":"2019","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/30901347","citation_count":18,"is_preprint":false},{"pmid":"35739448","id":"PMC_35739448","title":"Hepatic and renal toxicity following the injection of copper oxide nanoparticles (CuO NPs) in mature male Westar rats: histochemical and caspase 3 immunohistochemical reactivities.","date":"2022","source":"Environmental science and pollution research international","url":"https://pubmed.ncbi.nlm.nih.gov/35739448","citation_count":18,"is_preprint":false},{"pmid":"37714480","id":"PMC_37714480","title":"Metabolomics reveals that PS-NPs promote lung injury by regulating prostaglandin B1 through the cGAS-STING pathway.","date":"2023","source":"Chemosphere","url":"https://pubmed.ncbi.nlm.nih.gov/37714480","citation_count":18,"is_preprint":false},{"pmid":"21302803","id":"PMC_21302803","title":"A comparative analysis of OTF, NPS, and DQE in energy integrating and photon counting digital x-ray detectors.","date":"2010","source":"Medical physics","url":"https://pubmed.ncbi.nlm.nih.gov/21302803","citation_count":18,"is_preprint":false},{"pmid":"36036349","id":"PMC_36036349","title":"Neuropeptide S (NPS) neurons: Parabrachial identity and novel distributions.","date":"2022","source":"The Journal of comparative neurology","url":"https://pubmed.ncbi.nlm.nih.gov/36036349","citation_count":17,"is_preprint":false},{"pmid":"34608745","id":"PMC_34608745","title":"LncRNA MEG3 restrained pulmonary fibrosis induced by NiO NPs via regulating hedgehog signaling pathway-mediated autophagy.","date":"2021","source":"Environmental toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/34608745","citation_count":17,"is_preprint":false},{"pmid":"28267583","id":"PMC_28267583","title":"Identification of the first biased NPS receptor agonist that retains anxiolytic and memory promoting effects with reduced levels of locomotor stimulation.","date":"2017","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/28267583","citation_count":17,"is_preprint":false},{"pmid":"38360669","id":"PMC_38360669","title":"Iron oxide nanoparticles coated with Glucose and conjugated with Safranal (Fe3O4@Glu-Safranal NPs) inducing apoptosis in liver cancer cell line (HepG2).","date":"2024","source":"BMC chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38360669","citation_count":17,"is_preprint":false},{"pmid":"31652841","id":"PMC_31652841","title":"NPs-TiO2 and Lincomycin Coexposure Induces DNA Damage in Cultured Human Amniotic Cells.","date":"2019","source":"Nanomaterials (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/31652841","citation_count":16,"is_preprint":false},{"pmid":"36144499","id":"PMC_36144499","title":"Trident Nano-Indexing the Proteomics Table: Next-Version Clustering of Iron Carbide NPs and Protein Corona.","date":"2022","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/36144499","citation_count":16,"is_preprint":false},{"pmid":"36177628","id":"PMC_36177628","title":"TiO2-NPs Toxicity and Safety: An Update of the Findings Published over the Last Six Years.","date":"2023","source":"Mini reviews in medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36177628","citation_count":16,"is_preprint":false},{"pmid":"24173966","id":"PMC_24173966","title":"NPS-1034, a novel MET inhibitor, inhibits the activated MET receptor and its constitutively active mutants.","date":"2013","source":"Investigational new drugs","url":"https://pubmed.ncbi.nlm.nih.gov/24173966","citation_count":16,"is_preprint":false},{"pmid":"33895847","id":"PMC_33895847","title":"LncRNA MEG3 Involved in NiO NPs-Induced Pulmonary Fibrosis via Regulating TGF-β1-Mediated PI3K/AKT Pathway.","date":"2021","source":"Toxicological sciences : an official journal of the Society of Toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/33895847","citation_count":16,"is_preprint":false},{"pmid":"37691077","id":"PMC_37691077","title":"Screening of Cu4 O3 NPs efficacy and its anticancer potential against cervical cancer.","date":"2023","source":"Cell biochemistry and function","url":"https://pubmed.ncbi.nlm.nih.gov/37691077","citation_count":16,"is_preprint":false},{"pmid":"27272068","id":"PMC_27272068","title":"Interactions of Cathinone NPS with Human Transporters and Receptors in Transfected Cells.","date":"2017","source":"Current topics in behavioral neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/27272068","citation_count":16,"is_preprint":false},{"pmid":"25339032","id":"PMC_25339032","title":"DOX-MTX-NPs augment p53 mRNA expression in OSCC model in rat: effects of IV and oral routes.","date":"2014","source":"Asian Pacific journal of cancer prevention : APJCP","url":"https://pubmed.ncbi.nlm.nih.gov/25339032","citation_count":15,"is_preprint":false},{"pmid":"31391530","id":"PMC_31391530","title":"Calcium-sensing receptor antagonist NPS-2143 suppresses proliferation and invasion of gastric cancer cells.","date":"2019","source":"Cancer gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/31391530","citation_count":15,"is_preprint":false},{"pmid":"37914044","id":"PMC_37914044","title":"DNA damage and molecular level effects induced by polystyrene (PS) nanoplastics (NPs) after Chironomus riparius (Diptera) larvae.","date":"2023","source":"Chemosphere","url":"https://pubmed.ncbi.nlm.nih.gov/37914044","citation_count":15,"is_preprint":false},{"pmid":"37352782","id":"PMC_37352782","title":"MXenes-Au NPs modified electrochemical biosensor for multiple exosome surface proteins analysis.","date":"2023","source":"Talanta","url":"https://pubmed.ncbi.nlm.nih.gov/37352782","citation_count":15,"is_preprint":false},{"pmid":"33816646","id":"PMC_33816646","title":"Targeted knockdown of the adenosine A2A receptor by lipid NPs rescues the chemotaxis of head and neck cancer memory T cells.","date":"2021","source":"Molecular therapy. Methods & clinical development","url":"https://pubmed.ncbi.nlm.nih.gov/33816646","citation_count":15,"is_preprint":false},{"pmid":"39164753","id":"PMC_39164753","title":"Stepwise-targeting and hypoxia-responsive liposome AMVY@NPs carrying siYAP and verteporfin for glioblastoma therapy.","date":"2024","source":"Journal of nanobiotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/39164753","citation_count":14,"is_preprint":false},{"pmid":"33310102","id":"PMC_33310102","title":"In situ decorated Au NPs on chitosan-encapsulated Fe3O4-NH2 NPs as magnetic nanocomposite: Investigation of its anti-colon carcinoma, anti-gastric cancer and anti-pancreatic cancer.","date":"2020","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/33310102","citation_count":14,"is_preprint":false},{"pmid":"38770330","id":"PMC_38770330","title":"Cytotoxicity of amine-modified polystyrene MPs and NPs on neural stem cells cultured from mouse subventricular zone.","date":"2024","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/38770330","citation_count":14,"is_preprint":false},{"pmid":"33297444","id":"PMC_33297444","title":"Lectin Protein as a Promising Component to Functionalize Micelles, Liposomes and Lipid NPs against Coronavirus.","date":"2020","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/33297444","citation_count":14,"is_preprint":false},{"pmid":"37686979","id":"PMC_37686979","title":"Silver-Gold Alloy Nanoparticles (AgAu NPs): Photochemical Synthesis of Novel Biocompatible, Bimetallic Alloy Nanoparticles and Study of Their In Vitro Peroxidase Nanozyme Activity.","date":"2023","source":"Nanomaterials (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/37686979","citation_count":14,"is_preprint":false},{"pmid":"24578727","id":"PMC_24578727","title":"Photosensitive fluorescent dye contributes to phototoxicity and inflammatory responses of dye-doped silica NPs in cells and mice.","date":"2014","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/24578727","citation_count":14,"is_preprint":false},{"pmid":"30627047","id":"PMC_30627047","title":"Extracellular directed ag NPs formation and investigation of their antimicrobial and cytotoxic properties.","date":"2018","source":"Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society","url":"https://pubmed.ncbi.nlm.nih.gov/30627047","citation_count":13,"is_preprint":false},{"pmid":"36618400","id":"PMC_36618400","title":"Advances in pathogenesis and nanoparticles (NPs)-mediated treatment of psoriasis.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36618400","citation_count":13,"is_preprint":false},{"pmid":"33810221","id":"PMC_33810221","title":"The Neural Network of Neuropeptide S (NPS): Implications in Food Intake and Gastrointestinal Functions.","date":"2021","source":"Pharmaceuticals (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/33810221","citation_count":13,"is_preprint":false},{"pmid":"37624191","id":"PMC_37624191","title":"Uptake of Breathable Nano- and Micro-Sized Polystyrene Particles: Comparison of Virgin and Oxidised nPS/mPS in Human Alveolar Cells.","date":"2023","source":"Toxics","url":"https://pubmed.ncbi.nlm.nih.gov/37624191","citation_count":13,"is_preprint":false},{"pmid":"38961442","id":"PMC_38961442","title":"ZnO NPs induce miR-342-5p mediated ferroptosis of spermatocytes through the NF-κB pathway in mice.","date":"2024","source":"Journal of nanobiotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/38961442","citation_count":13,"is_preprint":false},{"pmid":"30461332","id":"PMC_30461332","title":"Toxicity of ZnO nanoparticles (NPs) to THP-1 macrophages: interactions with saturated or unsaturated free fatty acids.","date":"2019","source":"Toxicology mechanisms and methods","url":"https://pubmed.ncbi.nlm.nih.gov/30461332","citation_count":13,"is_preprint":false},{"pmid":"37514207","id":"PMC_37514207","title":"Response of Maize Seedlings to Silicon Dioxide Nanoparticles (SiO2NPs) under Drought Stress.","date":"2023","source":"Plants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/37514207","citation_count":12,"is_preprint":false},{"pmid":"34896176","id":"PMC_34896176","title":"Toxic effects of SiO2NPs in early embryogenesis of Xenopuslaevis.","date":"2021","source":"Chemosphere","url":"https://pubmed.ncbi.nlm.nih.gov/34896176","citation_count":12,"is_preprint":false},{"pmid":"23142110","id":"PMC_23142110","title":"Neuropeptide S stimulates human monocyte chemotaxis via NPS receptor activation.","date":"2012","source":"Peptides","url":"https://pubmed.ncbi.nlm.nih.gov/23142110","citation_count":11,"is_preprint":false},{"pmid":"34689404","id":"PMC_34689404","title":"Synthesis, antibacterial evaluation, and safety assessment of CuS NPs against Pectobacterium carotovorum subsp. carotovorum.","date":"2021","source":"Pest management science","url":"https://pubmed.ncbi.nlm.nih.gov/34689404","citation_count":11,"is_preprint":false},{"pmid":"33992849","id":"PMC_33992849","title":"Effects of TiO2-NPs pretreatment on UV-B stress tolerance in Arabidopsis thaliana.","date":"2021","source":"Chemosphere","url":"https://pubmed.ncbi.nlm.nih.gov/33992849","citation_count":11,"is_preprint":false},{"pmid":"36989561","id":"PMC_36989561","title":"ZnO-NPs alleviate aflatoxin B1-induced hepatoxicity in ducklings by promoting hepatic metallothionein expression.","date":"2023","source":"Ecotoxicology and environmental safety","url":"https://pubmed.ncbi.nlm.nih.gov/36989561","citation_count":10,"is_preprint":false},{"pmid":"26680586","id":"PMC_26680586","title":"The Physio-Pharmacological Role of the NPS/NPSR System in Psychiatric Disorders: A Translational Overview.","date":"2016","source":"Current protein & peptide science","url":"https://pubmed.ncbi.nlm.nih.gov/26680586","citation_count":10,"is_preprint":false},{"pmid":"35872045","id":"PMC_35872045","title":"Interaction between iron oxide nanoparticles (Fe3O4 NPs) and human neutrophils: Evidence that Fe3O4 NPs possess some pro-inflammatory activities.","date":"2022","source":"Chemico-biological interactions","url":"https://pubmed.ncbi.nlm.nih.gov/35872045","citation_count":10,"is_preprint":false},{"pmid":"37809932","id":"PMC_37809932","title":"The antioxidant, anti-angiogenic, and anticancer impact of chitosan-coated herniarin-graphene oxide nanoparticles (CHG-NPs).","date":"2023","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/37809932","citation_count":10,"is_preprint":false},{"pmid":"35881211","id":"PMC_35881211","title":"Biosynthesis of Silver Chloride Nanoparticles (AgCl-NPs) from Extreme Halophiles and Evaluation of Their Biological Applications.","date":"2022","source":"Current microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/35881211","citation_count":10,"is_preprint":false},{"pmid":"31432795","id":"PMC_31432795","title":"Putative mechanism for anticancer properties of Ag-PP (NPs) extract.","date":"2019","source":"IET nanobiotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/31432795","citation_count":10,"is_preprint":false},{"pmid":"34879554","id":"PMC_34879554","title":"The ZrO2 NPs enhanced the risk of arsenate by promoting its accumulation and reducing its detoxification during food chain transfer from Daphnia magna to zebrafish.","date":"2021","source":"Journal of hazardous materials","url":"https://pubmed.ncbi.nlm.nih.gov/34879554","citation_count":10,"is_preprint":false},{"pmid":"38872978","id":"PMC_38872978","title":"Fortified electrospun collagen utilizing biocompatible Poly Glycerol Sebacate prepolymer (PGSp) and zink oxide nanoparticles (ZnO NPs) for diabetics wound healing: Physical, biological and animal studies.","date":"2024","source":"Regenerative therapy","url":"https://pubmed.ncbi.nlm.nih.gov/38872978","citation_count":10,"is_preprint":false},{"pmid":"38878924","id":"PMC_38878924","title":"Biogenesis of bacterial cellulose/xanthan/CeO2NPs composite films for active food packaging.","date":"2024","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/38878924","citation_count":10,"is_preprint":false},{"pmid":"37659510","id":"PMC_37659510","title":"NPs-Ca promotes Cd accumulation and enhances Cd tolerance of rapeseed shoots by affecting Cd transfer and Cd fixation in pectin.","date":"2023","source":"Chemosphere","url":"https://pubmed.ncbi.nlm.nih.gov/37659510","citation_count":9,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51269,"output_tokens":1657,"usd":0.089331},"stage2":{"model":"claude-opus-4-6","input_tokens":4908,"output_tokens":1734,"usd":0.101835},"total_usd":0.191166,"stage1_batch_id":"msgbatch_012ZiiCUBfB62NCTQd4Bk1Jo","stage2_batch_id":"msgbatch_01Xuqq9aUHoQouS7UVGZNStZ","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"NPS is internalized into NPS receptor-expressing neurons via receptor-ligand complex internalization; in the hippocampal CA1 region, NPS modulates synaptic transmission and plasticity, and differentially modulates expression of proteins of the glutamatergic system involved in synaptic plasticity.\",\n      \"method\": \"Fluorophore-conjugated NPS tracking in brain slices and cell culture; single-neuron level internalization imaging; intranasal delivery in mice with behavioral readout\",\n      \"journal\": \"Neuropsychopharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (live imaging, cell culture internalization, behavioral assay, protein expression analysis) in a single study\",\n      \"pmids\": [\"22278093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"NPSR1 (the NPS receptor) is essential for mediating NPS-induced hyperlocomotion, anxiolysis, and corticosterone release; NPSR1-deficient mice fail to show these NPS-induced effects, and male NPSR1-deficient mice show enhanced depression-like behavior.\",\n      \"method\": \"NPSR1 gene-targeted knockout mice; ICV NPS administration; behavioral tests (open-field, forced swim, Morris water maze); corticosterone measurements\",\n      \"journal\": \"Psychoneuroendocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with multiple defined behavioral and neuroendocrine phenotypes, replicated across multiple assays\",\n      \"pmids\": [\"20171785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NPSR1 stimulation in hippocampal neurons induces calcium mobilization from the endoplasmic reticulum via activation of IP3 and ryanodine receptors, followed by store-operated calcium channel activation mediating extracellular calcium entry.\",\n      \"method\": \"Primary hippocampal neuron cultures expressing human NPSR1; single-cell calcium imaging with pharmacological dissection (IP3 receptor and ryanodine receptor antagonists; store-operated channel blockers)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct intracellular calcium imaging with pharmacological pathway dissection in neurons\",\n      \"pmids\": [\"25714705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Truncation of the NPS peptide produces fragments with biased agonism at NPSR, preferentially activating the calcium mobilization pathway over cAMP; a modified tetrapeptide analog retains anxiolytic and memory-consolidating activity in vivo but shows greatly attenuated hyperlocomotor stimulation, linking the cAMP pathway to locomotor stimulation.\",\n      \"method\": \"Calcium mobilization and cAMP assays in cells expressing human and mouse NPSR variants; in vivo behavioral testing in rodents\",\n      \"journal\": \"Neuropharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro second messenger assays with structure-activity relationship plus in vivo behavioral validation\",\n      \"pmids\": [\"28267583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NPS stimulates human monocyte chemotaxis via selective NPSR activation; the effect is completely blocked by peptide ([ D-Cys(tBu)5]NPS, [tBu-D-Gly5]NPS) and nonpeptide (SHA 68) NPSR antagonists.\",\n      \"method\": \"In vitro chemotaxis assay with human monocytes; pharmacological antagonism with selective NPSR antagonists\",\n      \"journal\": \"Peptides\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct functional assay with pharmacological validation using multiple selective antagonists; single lab\",\n      \"pmids\": [\"23142110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NPS-expressing neurons in the brainstem are primarily located in the parabrachial nucleus (PB) region, are Atoh1-derived and Foxp2-expressing, distinct from Calca-, Lmx1b-, Cck-, and Pdyn-expressing PB neurons; novel NPS neuron populations identified in nucleus incertus, anterior hypothalamus, and lateral habenula.\",\n      \"method\": \"In situ hybridization, immunofluorescence, and Cre-reporter labeling in mice\",\n      \"journal\": \"The Journal of comparative neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization by multiple orthogonal methods with molecular identity characterization; single lab\",\n      \"pmids\": [\"36036349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The NPS/NPSR system regulates food intake with anorexigenic effects when NPS is centrally injected into different brain areas, and influences gastrointestinal tract functions.\",\n      \"method\": \"Review of central NPS injection studies in rodents (ICV and intra-brain-site administration) with food intake measurements\",\n      \"journal\": \"Pharmaceuticals (Basel, Switzerland)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — review summarizing behavioral injection studies; no new primary mechanistic data\",\n      \"pmids\": [\"33810221\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Neuropeptide S (NPS) is a 20-amino-acid peptide that acts as the endogenous ligand of the G protein-coupled receptor NPSR1, activating both calcium mobilization (via IP3 and ryanodine receptor-mediated ER release followed by store-operated calcium entry) and cAMP signaling pathways; biased agonism studies indicate that locomotor stimulation is linked to cAMP signaling while anxiolysis and memory consolidation are linked to calcium mobilization; NPS is internalized into NPSR-expressing neurons via receptor-ligand complex endocytosis, modulates glutamatergic synaptic plasticity in hippocampal CA1, stimulates monocyte chemotaxis, and NPS-expressing neurons are parabrachial nucleus neurons that are Atoh1-derived and Foxp2-expressing.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"Neuropeptide S (NPS) is a 20-amino-acid neuropeptide that functions as the endogenous ligand for the G protein-coupled receptor NPSR1, coupling to both calcium mobilization (via IP3 and ryanodine receptor-mediated ER release followed by store-operated calcium entry) and cAMP signaling pathways to regulate arousal, anxiety, and memory [PMID:25714705, PMID:28267583]. Biased agonism studies demonstrate that NPS-driven locomotor stimulation depends on the cAMP pathway, whereas anxiolytic and memory-consolidating effects are mediated through the calcium mobilization pathway [PMID:28267583]. In the hippocampal CA1 region, NPS is internalized into NPSR-expressing neurons via receptor-ligand complex endocytosis and modulates glutamatergic synaptic plasticity [PMID:22278093]. NPS-producing neurons in the brainstem are Atoh1-derived, Foxp2-expressing cells concentrated in the parabrachial nucleus, with additional populations in the nucleus incertus, anterior hypothalamus, and lateral habenula [PMID:36036349].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Establishing that all major behavioral and neuroendocrine effects of NPS — hyperlocomotion, anxiolysis, and corticosterone release — require NPSR1, confirming it as the sole functional receptor for NPS in vivo.\",\n      \"evidence\": \"NPSR1 knockout mice with ICV NPS injection and behavioral/neuroendocrine phenotyping\",\n      \"pmids\": [\"20171785\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Downstream intracellular signaling pathways mediating each behavioral effect were not dissected\",\n        \"Whether compensatory mechanisms exist in knockout animals was not addressed\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrating that NPS enters neurons through receptor-mediated internalization and modulates hippocampal glutamatergic synaptic plasticity, providing a cellular mechanism for NPS effects on memory and cognition.\",\n      \"evidence\": \"Fluorophore-conjugated NPS tracking in brain slices and cell culture; single-neuron imaging; intranasal delivery with behavioral and proteomic readouts in mice\",\n      \"pmids\": [\"22278093\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The specific glutamatergic proteins regulated and the signaling cascade from receptor internalization to plasticity changes were not fully resolved\",\n        \"Whether internalization is required for synaptic modulation or is merely a desensitization event was not distinguished\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extending NPS function beyond the CNS by showing it drives monocyte chemotaxis via NPSR, establishing a peripheral immunomodulatory role.\",\n      \"evidence\": \"In vitro chemotaxis assay with human monocytes; pharmacological blockade with multiple selective NPSR antagonists\",\n      \"pmids\": [\"23142110\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"In vivo immune relevance and physiological NPS concentrations at immune cell sites are unknown\",\n        \"Downstream signaling pathway in monocytes was not characterized\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolving the intracellular calcium signaling cascade downstream of NPSR1, showing sequential IP3 receptor and ryanodine receptor-mediated ER calcium release followed by store-operated calcium entry.\",\n      \"evidence\": \"Single-cell calcium imaging with pharmacological dissection in primary hippocampal neurons expressing human NPSR1\",\n      \"pmids\": [\"25714705\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The G protein subtype coupling NPSR1 to IP3 generation was not identified\",\n        \"Whether the same calcium signaling cascade operates in non-hippocampal NPS target neurons was not tested\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Dissecting biased agonism at NPSR1 revealed that cAMP signaling drives locomotor stimulation while calcium mobilization mediates anxiolysis and memory consolidation, separating therapeutic from side-effect pathways.\",\n      \"evidence\": \"Structure-activity relationship of truncated NPS analogs in calcium and cAMP assays; behavioral validation in rodents\",\n      \"pmids\": [\"28267583\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The molecular determinants on NPSR1 that confer pathway-selective coupling were not identified\",\n        \"Whether biased agonism translates to human physiology is untested\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mapping the developmental origin and molecular identity of NPS-producing neurons revealed they are Atoh1-derived, Foxp2-expressing parabrachial cells, distinct from other known PB populations, and identified novel NPS populations in the nucleus incertus, anterior hypothalamus, and lateral habenula.\",\n      \"evidence\": \"In situ hybridization, immunofluorescence, and Cre-reporter labeling in mice\",\n      \"pmids\": [\"36036349\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional contributions of each anatomically distinct NPS neuron population to behavior remain undefined\",\n        \"Circuit-level connectivity of NPS neurons to NPSR1-expressing target areas was not mapped\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of NPS–NPSR1 interaction, the G protein subtype coupling specificity, and the circuit-level logic by which discrete NPS neuron populations drive distinct behavioral outputs remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No crystal or cryo-EM structure of the NPS–NPSR1 complex exists\",\n        \"Selective ablation or activation of individual NPS neuron populations has not been performed\",\n        \"Endogenous release dynamics of NPS under physiological conditions are not characterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [1, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 3, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2, 3]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"NPSR1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}