CAPN9 Gene

HGNC Family	EF-hand domain containing
Name	calpain 9
Description	Calpains are ubiquitous, well-conserved family of calcium-dependent, cysteine proteases. The calpain proteins are heterodimers consisting of an invariant small subunit and variable large subunits. The large subunit possesses a cysteine protease domain, and both subunits possess calcium-binding domains. Calpains have been implicated in neurodegenerative processes, as their activation can be triggered by calcium influx and oxidative stress. The protein encoded by this gene is expressed predominantly in stomach and small intestine and may have specialized functions in the digestive tract. This gene is thought to be associated with gastric cancer. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n CAPN9 (also known as nCL‐4) is a calcium‐dependent cysteine protease originally characterized as being predominantly expressed in the gastrointestinal tract, where it partners with calpain‐8 to form a “G‐calpain” complex essential for gastric mucosal defense against injury ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "]. Structural studies have revealed that CAPN9 contains the classical calpain domains yet exhibits unique auto‐inhibitory conformational changes that regulate its proteolytic activity ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "]."}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its gastrointestinal role, CAPN9 expression can be induced in non‐GI tissues. It contributes to cytoskeletal remodelling during transforming growth factor–β (TGFβ)–induced mesenchymal transition in breast epithelial cells and other related fibroproliferative processes ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "]. In cancer, CAPN9 appears to play context‐dependent roles. In gastric cancer, decreased CAPN9 levels are associated with diminished cell cycle arrest and apoptosis, with low expression correlating with advanced disease and poorer prognosis ["}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "8"}]}, {"type": "t", "text": "]. In contrast, in high‐grade serous ovarian cancer CAPN9 is negatively regulated by miR‐585–3p such that its overexpression can mitigate the inhibitory effects of this miRNA, thereby promoting cell proliferation and migration ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "]. In breast cancer, higher CAPN9 expression has been linked to improved clinical outcomes in patients receiving endocrine therapy ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "]."}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Additional studies have identified CAPN9 as a potential biomarker for arsenic‐associated bladder cancer ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "], and loss of CAPN9 function has been implicated in the neoplastic transformation of fibroblasts ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "]. Recent genetic analyses have further linked variants in CAPN9 with neurodevelopmental disorders such as intellectual disability ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "], and predictive models even suggest a role in modulating responses to methamphetamine exposure ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "].\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, CAPN9 performs multifaceted roles across diverse tissues, participating in cellular proteolysis, regulation of cytoskeletal dynamics, and cell differentiation. Its activity is critical not only for maintaining gastric mucosal integrity but also for modulating mesenchymal transition and influencing tumor progression. These findings highlight CAPN9’s potential as both a therapeutic target and a biomarker in a variety of pathological conditions.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Shoji Hata, Manabu Abe, Hidenori Suzuki, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Calpain 8/nCL-2 and calpain 9/nCL-4 constitute an active protease complex, G-calpain, involved in gastric mucosal defense."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Genet (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pgen.1001040"}], "href": "https://doi.org/10.1371/journal.pgen.1001040"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20686710"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20686710"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "H J Lee, S Tomioka, K Kinbara, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Characterization of a human digestive tract-specific calpain, nCL-4, expressed in the baculovirus system."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Arch Biochem Biophys (1999)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1006/abbi.1998.1021"}], "href": "https://doi.org/10.1006/abbi.1998.1021"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "9917325"}], "href": "https://pubmed.ncbi.nlm.nih.gov/9917325"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Tara L Davis, John R Walker, Patrick J Finerty, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The crystal structures of human calpains 1 and 9 imply diverse mechanisms of action and auto-inhibition."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Mol Biol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jmb.2006.11.037"}], "href": "https://doi.org/10.1016/j.jmb.2006.11.037"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17157313"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17157313"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "David H Kim, James D Beckett, Varun Nagpal, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Calpain 9 as a therapeutic target in TGFβ-induced mesenchymal transition and fibrosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Transl Med (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/scitranslmed.aau2814"}], "href": "https://doi.org/10.1126/scitranslmed.aau2814"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31316008"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31316008"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Takuro Miyazaki, Risako Akasu, Akira Miyazaki "}, {"type": "b", "children": [{"type": "t", "text": "Calpain-Associated Proteolytic Regulation of the Stromal Microenvironment in Cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Curr Pharm Des (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2174/1381612827666210311143053"}], "href": "https://doi.org/10.2174/1381612827666210311143053"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33719969"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33719969"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Peike Peng, Weicheng Wu, Junjie Zhao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Decreased expression of Calpain-9 predicts unfavorable prognosis in patients with gastric cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/srep29604"}], "href": "https://doi.org/10.1038/srep29604"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27404891"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27404891"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Y Yoshikawa, H Mukai, F Hino, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Isolation of two novel genes, down-regulated in gastric cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Jpn J Cancer Res (2000)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1349-7006.2000.tb00967.x"}], "href": "https://doi.org/10.1111/j.1349-7006.2000.tb00967.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "10835488"}], "href": "https://pubmed.ncbi.nlm.nih.gov/10835488"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "K Liu, L Li, S N Cohen "}, {"type": "b", "children": [{"type": "t", "text": "Antisense RNA-mediated deficiency of the calpain protease, nCL-4, in NIH3T3 cells is associated with neoplastic transformation and tumorigenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2000)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M005451200"}], "href": "https://doi.org/10.1074/jbc.M005451200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "10906334"}], "href": "https://pubmed.ncbi.nlm.nih.gov/10906334"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Muhammad Asaduzzaman, Stephanie Constantinou, Haoxiang Min, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tumour suppressor EP300, a modulator of paclitaxel resistance and stemness, is downregulated in metaplastic breast cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Breast Cancer Res Treat (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10549-017-4202-z"}], "href": "https://doi.org/10.1007/s10549-017-4202-z"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28341962"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28341962"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Xiaoyuan Lu, Guilin Li, Sicong Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MiR-585-3p suppresses tumor proliferation and migration by directly targeting CAPN9 in high grade serous ovarian cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Ovarian Res (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s13048-021-00841-w"}], "href": "https://doi.org/10.1186/s13048-021-00841-w"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34238324"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34238324"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Jillian Davis, Stewart G Martin, Poulam M Patel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Low calpain-9 is associated with adverse disease-specific survival following endocrine therapy in breast cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMC Cancer (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/1471-2407-14-995"}], "href": "https://doi.org/10.1186/1471-2407-14-995"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25539577"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25539577"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Lia-Beng Tan, Kow-Tong Chen, Yu-Chang Tyan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Proteomic analysis for human urinary proteins associated with arsenic intoxication."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proteomics Clin Appl (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/prca.200800021"}], "href": "https://doi.org/10.1002/prca.200800021"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21136906"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21136906"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Mohammad Haddadi, Reza Ataei "}, {"type": "b", "children": [{"type": "t", "text": "wde, calpA, if, dap160, and poe genes knock down Drosophila models exhibit neurofunctional deficit."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gene (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.gene.2022.146499"}], "href": "https://doi.org/10.1016/j.gene.2022.146499"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35447243"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35447243"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Li Zhu, Jie Zhu, Yufeng Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Chronic methamphetamine regulates the expression of MicroRNAs and putative target genes in the nucleus accumbens of mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurosci Res (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jnr.23605"}], "href": "https://doi.org/10.1002/jnr.23605"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26031216"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26031216"}]}]}]}
Synonyms	NCL-4, GC36
Proteins	CAN9_HUMAN
NCBI Gene ID	10753
API
Download Associations
Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

CAPN9 has 4,496 functional associations with biological entities spanning 9 categories (molecular profile, organism, chemical, functional term, phrase or reference, disease, phenotype or trait, structural feature, cell line, cell type or tissue, gene, protein or microRNA, sequence feature) extracted from 111 datasets.

Click the + buttons to view associations for CAPN9 from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

CAPN9 Gene

Functional Associations

Please acknowledge the Harmonizome in your publications by citing the following reference(s):

	Dataset	Summary
	Achilles Cell Line Gene Essentiality Profiles	cell lines with fitness changed by CAPN9 gene knockdown relative to other cell lines from the Achilles Cell Line Gene Essentiality Profiles dataset.
	Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles	tissues with high or low expression of CAPN9 gene relative to other tissues from the Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles	tissue samples with high or low expression of CAPN9 gene relative to other tissue samples from the Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray	tissue samples with high or low expression of CAPN9 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq	tissue samples with high or low expression of CAPN9 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq dataset.
	Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of CAPN9 gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset.
	BioGPS Cell Line Gene Expression Profiles	cell lines with high or low expression of CAPN9 gene relative to other cell lines from the BioGPS Cell Line Gene Expression Profiles dataset.
	BioGPS Human Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of CAPN9 gene relative to other cell types and tissues from the BioGPS Human Cell Type and Tissue Gene Expression Profiles dataset.
	BioGPS Mouse Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of CAPN9 gene relative to other cell types and tissues from the BioGPS Mouse Cell Type and Tissue Gene Expression Profiles dataset.
	Carcinogenome Chemical Perturbation Carcinogenicity Signatures	small molecule perturbations changing expression of CAPN9 gene from the Carcinogenome Chemical Perturbation Carcinogenicity Signatures dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of CAPN9 gene relative to other cell lines from the CCLE Cell Line Gene CNV Profiles dataset.
	CCLE Cell Line Gene Expression Profiles	cell lines with high or low expression of CAPN9 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CellMarker Gene-Cell Type Associations	cell types associated with CAPN9 gene from the CellMarker Gene-Cell Type Associations dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of CAPN9 gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of CAPN9 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets dataset.
	ChEA Transcription Factor Targets 2022	transcription factors binding the promoter of CAPN9 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	CM4AI KOLF21J CRISPRi Gene Perturbation Atlas	gene perturbations changing expression of CAPN9 gene from the CM4AI KOLF21J CRISPRi Gene Perturbation Atlas dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of CAPN9 gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing CAPN9 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with CAPN9 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025	cellular components co-occuring with CAPN9 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	COSMIC Cell Line Gene CNV Profiles	cell lines with high or low copy number of CAPN9 gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with CAPN9 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Disease Associations	diseases associated with CAPN9 gene/protein from the curated CTD Gene-Disease Associations dataset.
	dbGAP Gene-Trait Associations	traits associated with CAPN9 gene in GWAS and other genetic association datasets from the dbGAP Gene-Trait Associations dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by CAPN9 gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores	diseases associated with CAPN9 gene in GWAS datasets from the DISEASES Experimental Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores 2025	diseases associated with CAPN9 gene in GWAS datasets from the DISEASES Experimental Gene-Disease Assocation Evidence Scores 2025 dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores	diseases co-occuring with CAPN9 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores 2025	diseases co-occuring with CAPN9 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores 2025 dataset.
	DisGeNET Gene-Disease Associations	diseases associated with CAPN9 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with CAPN9 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Phenoptype Associations dataset.
	ENCODE Histone Modification Site Profiles	histone modification site profiles with high histone modification abundance at CAPN9 gene from the ENCODE Histone Modification Site Profiles dataset.
	ENCODE Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of CAPN9 gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of CAPN9 gene in ChIP-seq datasets from the ENCODE Transcription Factor Targets dataset.
	ESCAPE Omics Signatures of Genes and Proteins for Stem Cells	PubMedIDs of publications reporting gene signatures containing CAPN9 from the ESCAPE Omics Signatures of Genes and Proteins for Stem Cells dataset.
	GAD Gene-Disease Associations	diseases associated with CAPN9 gene in GWAS and other genetic association datasets from the GAD Gene-Disease Associations dataset.
	GAD High Level Gene-Disease Associations	diseases associated with CAPN9 gene in GWAS and other genetic association datasets from the GAD High Level Gene-Disease Associations dataset.
	GDSC Cell Line Gene Expression Profiles	cell lines with high or low expression of CAPN9 gene relative to other cell lines from the GDSC Cell Line Gene Expression Profiles dataset.
	GeneRIF Biological Term Annotations	biological terms co-occuring with CAPN9 gene in literature-supported statements describing functions of genes from the GeneRIF Biological Term Annotations dataset.