PLPP5

Summary

PLPP5 (phospholipid phosphatase 5, HGNC:25026) is a protein-coding gene on chromosome 8p11.23, encoding Phospholipid phosphatase 5 (Q8NEB5). Magnesium-independent phospholipid phosphatase with broad substrate specificity.

Enables diacylglycerol diphosphate phosphatase activity and phosphatidate phosphatase activity. Involved in phospholipid dephosphorylation. Predicted to be located in cytoplasm and plasma membrane. Predicted to be active in membrane.

Source: NCBI Gene 84513 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 1 total
• MANE Select transcript: NM_001102559

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25026
Approved symbol	PLPP5
Name	phospholipid phosphatase 5
Location	8p11.23
Locus type	gene with protein product
Status	Approved
Aliases	HTPAP, DPPL1
Ensembl gene	ENSG00000147535
Ensembl biotype	protein_coding
OMIM	610626
Entrez	84513

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 8 protein_coding, 4 protein_coding_CDS_not_defined, 3 retained_intron, 1 nonsense_mediated_decay

ENST00000419686, ENST00000422581, ENST00000424479, ENST00000524409, ENST00000524616, ENST00000527758, ENST00000527793, ENST00000528814, ENST00000529359, ENST00000530193, ENST00000530432, ENST00000531109, ENST00000531483, ENST00000531823, ENST00000534339, ENST00000935602

RefSeq mRNA: 10 — MANE Select: NM_001102559 NM_001102559, NM_001102560, NM_001354452, NM_001354454, NM_001354456, NM_001354457, NM_001354458, NM_001354459, NM_001410920, NM_032483

CCDS: CCDS47841, CCDS47842, CCDS47843, CCDS87598, CCDS94281

Canonical transcript exons

ENST00000424479 — 7 exons

Exon	Start	End
ENSE00001639664	38268882	38268990
ENSE00001648622	38263130	38264604
ENSE00002304873	38269126	38269224
ENSE00003470591	38266141	38266311
ENSE00003486456	38268371	38268461
ENSE00003620558	38267267	38267391
ENSE00003627486	38267897	38267960

Expression profiles

Bgee: expression breadth ubiquitous, 232 present calls, max score 98.95.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.0682 / max 254.9153, expressed in 1753 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
92737	15.9756	1753
92736	2.0925	1067

Top tissues by expression

250 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
body of pancreas	UBERON:0001150	98.95	gold quality
right uterine tube	UBERON:0001302	98.39	gold quality
adenohypophysis	UBERON:0002196	98.33	gold quality
pituitary gland	UBERON:0000007	97.73	gold quality
pancreas	UBERON:0001264	97.59	gold quality
islet of Langerhans	UBERON:0000006	96.64	gold quality
rectum	UBERON:0001052	96.43	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	95.99	gold quality
body of stomach	UBERON:0001161	95.93	gold quality
prostate gland	UBERON:0002367	95.87	gold quality
gall bladder	UBERON:0002110	95.70	gold quality
endocervix	UBERON:0000458	95.62	gold quality
bone marrow cell	CL:0002092	95.60	gold quality
right coronary artery	UBERON:0001625	95.59	gold quality
stromal cell of endometrium	CL:0002255	95.36	gold quality
cortical plate	UBERON:0005343	95.27	gold quality
ganglionic eminence	UBERON:0004023	95.15	gold quality
minor salivary gland	UBERON:0001830	95.03	gold quality
stomach	UBERON:0000945	95.00	gold quality
vermiform appendix	UBERON:0001154	95.00	gold quality
right lobe of thyroid gland	UBERON:0001119	94.90	gold quality
left lobe of thyroid gland	UBERON:0001120	94.88	gold quality
saliva-secreting gland	UBERON:0001044	94.76	gold quality
small intestine Peyer’s patch	UBERON:0003454	94.64	gold quality
metanephros cortex	UBERON:0010533	94.36	gold quality
epithelial cell of pancreas	CL:0000083	94.27	gold quality
ascending aorta	UBERON:0001496	94.22	gold quality
spleen	UBERON:0002106	94.18	gold quality
left coronary artery	UBERON:0001626	94.16	gold quality
mucosa of transverse colon	UBERON:0004991	94.10	gold quality

Single-cell (SCXA)

Detected in 11 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-HCAD-4	yes	106.77
E-CURD-88	yes	99.81
E-CURD-122	yes	67.35
E-MTAB-9467	yes	53.02
E-CURD-46	yes	46.93
E-MTAB-8410	yes	40.40
E-HCAD-1	yes	36.97
E-ANND-3	yes	32.35
E-HCAD-11	yes	25.30
E-MTAB-10553	yes	13.14
E-GEOD-124858	no	130.83

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

7 targeting PLPP5, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-5197-3P	98.71	67.05	1905
HSA-MIR-16-1-3P	98.70	69.23	1538
HSA-MIR-6750-3P	96.79	67.50	740
HSA-MIR-759	96.16	66.77	873

Literature-anchored findings (GeneRIF, showing 7)

• HTPAP is a novel metastatic suppressor gene for hepatocellular carcinoma (PMID:16261160)
• DPPL1 and DPPL2 represent a novel type of mammalian phosphatidate phosphatase. (PMID:17590538)
• microarray experiments on PPAPDC1B knockdown indicated this gene interfered with cell signaling pathways, including Janus-activated kinase-signal transducer and activator of transcription, mitogen-activated protein kinase, and protein kinase C pathways (PMID:18757432)
• HTPAP-1 may be the transcript of HTPAP to exhibit a suppressive role on hepatocellular cancer(HCC) metastasis, and can be a prognostic marker for HCC. (PMID:21219541)
• Findings identify an HTPAP genotype and associated gene expression pattern that favors metastasis progression and that could be used to predict tumor metastasis and prognosis in HCC patients. (PMID:21531764)
• PPAPDC1B and WHSC1L1 played a major role in regulating the survival of breast cancer, pancreatic adenocarcinoma and small-cell lung cancer-derived cell lines. (PMID:24051013)
• genetic variants at loci -1053 and +64 of the HTPAP promoter affect the expression of HTPAP, which might be a novel determinant and target for HCC prognosis (PMID:24603412)

Cross-species orthologs

11 orthologs

Organism	Symbol	Gene ID
danio_rerio	plpp5	ENSDARG00000057672
mus_musculus	Plpp5	ENSMUSG00000031570
rattus_norvegicus	Plpp5	ENSRNOG00000069017
drosophila_melanogaster	wun	FBGN0016078
drosophila_melanogaster	laza	FBGN0037163
drosophila_melanogaster	CG11438	FBGN0037164
drosophila_melanogaster	CG11437	FBGN0037165
drosophila_melanogaster	CG11426	FBGN0037166
drosophila_melanogaster	CG11425	FBGN0037167
drosophila_melanogaster	CG12746	FBGN0037341
drosophila_melanogaster	wun2	FBGN0041087

Paralogs (9): PLPP1 (ENSG00000067113), PLPPR2 (ENSG00000105520), PLPPR5 (ENSG00000117598), PLPPR4 (ENSG00000117600), PLPPR3 (ENSG00000129951), PLPP2 (ENSG00000141934), PLPPR1 (ENSG00000148123), PLPP3 (ENSG00000162407), PLPP4 (ENSG00000203805)

Protein

Protein identifiers

Phospholipid phosphatase 5 — Q8NEB5 (reviewed: Q8NEB5)

Alternative names: Phosphatidic acid phosphatase type 2 domain-containing protein 1B

All UniProt accessions (6): Q8NEB5, A0A140VK38, E9PNB1, H0YCK0, H0YCQ3, H0YDY2

UniProt curated annotations — full annotation on UniProt →

Function. Magnesium-independent phospholipid phosphatase with broad substrate specificity. Preferentially catalyzes the conversion of diacylglycerol pyrophosphate into phosphatidate but can also act on phosphatidate and lysophosphatidate. Phospholipid phosphatases are involved in both the synthesis of lipids and the generation or degradation of lipid-signaling molecules.

Subcellular location. Cell membrane.

Tissue specificity. Ubiquitous.

Activity regulation. Magnesium-independent phospholipid phosphatase. Inhibited by N-ethylmaleimide.

Pathway. Lipid metabolism; phospholipid metabolism.

Miscellaneous. May be a metastatic suppressor for hepatocellular carcinoma.

Similarity. Belongs to the PA-phosphatase related phosphoesterase family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q8NEB5-1	1	yes
Q8NEB5-2	2
Q8NEB5-3	3
Q8NEB5-4	4

RefSeq proteins (10): NP_001096029, NP_001096030, NP_001341381, NP_001341383, NP_001341385, NP_001341386, NP_001341387, NP_001341388, NP_001397849, NP_115872 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000326	PAP2/HPO	Domain
IPR036938	PAP2/HPO_sf	Homologous_superfamily
IPR043216	PAP-like	Family

Pfam: PF01569

Enzyme classification (BRENDA):

• EC 3.1.3.4 — phosphatidate phosphatase (BRENDA: 31 organisms, 190 substrates, 196 inhibitors, 44 Km, 3 kcat entries)
• EC 3.1.3.81 — diacylglycerol diphosphate phosphatase (BRENDA: 0 organisms, 0 substrates, 0 inhibitors, 0 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

10 substrates with measured Km, best-characterized 10. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
PHOSPHATIDIC ACID	0.0054–1.2	17
LYSOPHOSPHATIDATE	0.046–0.179	3
PHOSPHATIDATE	0.284–0.369	3
SPHINGOSINE-1-PHOSPHATE	0.028–0.26	3
CERAMIDE-1-PHOSPHATE	0.022–0.052	2
DIACYLGLYCEROL DIPHOSPHATE	0.041–0.104	2
LYSOPHOSPHATIDIC ACID	0.295–0.58	2
1,2-DIACYL-SN-GLYCEROL-3-PHOSPHATE	0.5954	1
2-(4,4-DIFLUORO-5,7-DIMETHYL-4-BORA-3A,4A-DIAZA-	0.024	1
DIOCTANOYL PHOSPHATIDIC ACID	1.4	1

Catalyzed reactions (Rhea), 5 shown:

• a 1,2-diacyl-sn-glycero-3-phosphate + H2O = a 1,2-diacyl-sn-glycerol + phosphate (RHEA:27429)
• a 1,2-diacyl-sn-glycerol 3-diphosphate + H2O = a 1,2-diacyl-sn-glycero-3-phosphate + phosphate + H(+) (RHEA:27449)
• 1-(9Z-octadecenoyl)-sn-glycero-3-phosphate + H2O = 1-(9Z-octadecenoyl)-sn-glycerol + phosphate (RHEA:39835)
• 1,2-dioctanoyl-sn-glycero-3-diphosphate + H2O = 1,2-dioctanoyl-sn-glycero-3-phosphate + phosphate + H(+) (RHEA:42856)
• 1,2-dioctanoyl-sn-glycero-3-phosphate + H2O = 1,2-dioctanoyl-sn-glycerol + phosphate (RHEA:42860)

UniProt features (28 total): topological domain 7, transmembrane region 6, splice variant 5, region of interest 3, mutagenesis site 3, active site 2, chain 1, site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NEB5-F1	91.84	0.83

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (3): 152 (proton donors); 208 (nucleophile); 212 (stabilizes the active site histidine for nucleophilic attack)

Mutagenesis-validated functional residues (3):

Position	Phenotype
115	loss of phosphatase activity; when associated with a-152 and with a-208.
152	loss of phosphatase activity; when associated with a-115 and with a-208.
208	loss of phosphatase activity; when associated with a-115 and with a-152.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2029485	Role of phospholipids in phagocytosis

MSigDB gene sets: 142 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, GOBP_LIPID_MODIFICATION, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, REACTOME_INNATE_IMMUNE_SYSTEM, ZHAN_MULTIPLE_MYELOMA_PR_DN, GOBP_PHOSPHOLIPID_DEPHOSPHORYLATION, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, CEBPB_01, CEBP_Q2, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_5, GOBP_LIPID_METABOLIC_PROCESS, GOBP_DEPHOSPHORYLATION, CCCNNGGGAR_OLF1_01, WGGAATGY_TEF1_Q6, MASSARWEH_TAMOXIFEN_RESISTANCE_UP

GO Biological Process (3): phospholipid metabolic process (GO:0006644), phospholipid dephosphorylation (GO:0046839), lipid metabolic process (GO:0006629)

GO Molecular Function (4): diacylglycerol diphosphate phosphatase activity (GO:0000810), phosphatidate phosphatase activity (GO:0008195), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (3): cytoplasm (GO:0005737), plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Fcgamma receptor (FCGR) dependent phagocytosis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
lipid metabolic process	1
organophosphate metabolic process	1
dephosphorylation	1
lipid modification	1
primary metabolic process	1
pyrophosphatase activity	1
lipid phosphatase activity	1
binding	1
catalytic activity	1
intracellular anatomical structure	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

850 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PLPP5	DDHD2	O94830	621
PLPP5	LSM1	O15116	590
PLPP5	NSD3	Q9BZ95	583
PLPP5	ZNF703	Q9H7S9	573
PLPP5	BAG4	O95429	571
PLPP5	TM2D2	Q9BX73	570
PLPP5	ERLIN2	O94905	544
PLPP5	PLPP6	Q8IY26	538
PLPP5	PLPP7	Q8NBV4	515
PLPP5	PLPBP	O94903	514
PLPP5	RAB11FIP1	Q6WKZ4	480
PLPP5	LETM2	Q2VYF4	478
PLPP5	PLPP1	O14494	447
PLPP5	ADAM32	Q8TC27	447
PLPP5	LPIN1	Q14693	442

IntAct

8 interactions, top by confidence:

A	B	Type	Score
CTXN3	PLPP5	psi-mi:“MI:0915”(physical association)	0.560
PLPP5		psi-mi:“MI:0915”(physical association)	0.560
	PLPP5	psi-mi:“MI:0915”(physical association)	0.000
glpA	PLPP5	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (4): PPAPDC1B (Synthetic Lethality), SLC29A2 (Two-hybrid), CTXN3 (Two-hybrid), PPAPDC1B (Affinity Capture-RNA)

ESM2 similar proteins: A4IFN5, A6NDV4, B1AWJ5, B1AZA5, B2LYG4, P59266, Q05B45, Q0VCJ8, Q3KRC4, Q3UMZ3, Q5EA70, Q5H8A4, Q5QJU3, Q5RBJ7, Q5U3C3, Q5VTY9, Q5ZMH6, Q6PHN7, Q6TCH4, Q6W5G4, Q6ZVK1, Q7Z7J7, Q865K8, Q86WK9, Q8BHH9, Q8BMT9, Q8BWB6, Q8C1E7, Q8K3J9, Q8N6M3, Q8NBT3, Q8NEB5, Q8NFT2, Q8VCW4, Q8VCY8, Q8VD53, Q8VDI9, Q96GM1, Q9BSA9, Q9BXJ8

Diamond homologs: O08564, O14494, O14495, O43688, O88956, P60588, P97544, Q04396, Q0VBU9, Q0WNG6, Q10022, Q2HJ61, Q3SZE3, Q3UMZ3, Q5VZY2, Q61469, Q6GQ62, Q6IQH6, Q86AF0, Q8K593, Q8LFD1, Q8NEB5, Q99JY8, Q9DAX2, Q9V576, Q9XI60, B0CM95, B0KWE9, B1MTH4, Q86YN1, Q9ZU49, Q29RT8, Q54PR7, Q6GM05, Q6WAY2, Q7Z2D5, Q8BFZ2, Q8TBJ4, B2KI79, Q32ZL2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

1 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	1
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1643 predictions. Top by Δscore:

Variant	Effect	Δscore
8:38267265:A:AC	donor_gain	1.0000
8:38267266:C:CC	donor_gain	1.0000
8:38267314:T:TA	donor_gain	1.0000
8:38268439:A:T	acceptor_gain	1.0000
8:38268880:A:AC	donor_gain	1.0000
8:38268881:C:CC	donor_gain	1.0000
8:38268881:CAAA:C	donor_gain	1.0000
8:38268908:C:CA	donor_gain	1.0000
8:38269124:A:AC	donor_gain	1.0000
8:38269125:C:CC	donor_gain	1.0000
8:38266307:TGCAA:T	acceptor_gain	0.9900
8:38266309:CAA:C	acceptor_gain	0.9900
8:38266312:C:CC	acceptor_gain	0.9900
8:38267319:ATCC:A	donor_gain	0.9900
8:38267891:ACTT:A	donor_loss	0.9900
8:38267892:CTTA:C	donor_loss	0.9900
8:38267893:TTACC:T	donor_loss	0.9900
8:38267894:T:TG	donor_loss	0.9900
8:38268440:G:C	acceptor_gain	0.9900
8:38268440:G:GC	acceptor_gain	0.9900
8:38268871:T:A	donor_gain	0.9900
8:38268905:A:AC	donor_gain	0.9900
8:38268906:C:CC	donor_gain	0.9900
8:38268989:CC:C	acceptor_gain	0.9900
8:38268990:CC:C	acceptor_gain	0.9900
8:38269123:TACAG:T	donor_loss	0.9900
8:38269124:ACAG:A	donor_loss	0.9900
8:38269125:CA:C	donor_gain	0.9900
8:38267199:CTAG:C	donor_gain	0.9800
8:38267392:C:CC	acceptor_gain	0.9800

AlphaMissense

1720 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:38267953:G:C	S94R	0.999
8:38267953:G:T	S94R	0.999
8:38267955:T:G	S94R	0.999
8:38266141:C:G	D212H	0.997
8:38267289:G:C	S147R	0.996
8:38267289:G:T	S147R	0.996
8:38267291:T:G	S147R	0.996
8:38264604:T:A	D212V	0.995
8:38267286:G:C	F148L	0.995
8:38267286:G:T	F148L	0.995
8:38267288:A:G	F148L	0.995
8:38267329:C:G	C134S	0.995
8:38267330:A:T	C134S	0.995
8:38267901:C:A	G112W	0.995
8:38264580:C:T	G220E	0.994
8:38267280:A:C	S150R	0.994
8:38267280:A:T	S150R	0.994
8:38267282:T:G	S150R	0.994
8:38267292:C:A	K146N	0.994
8:38267292:C:G	K146N	0.994
8:38267296:C:G	R145P	0.994
8:38267361:G:C	F123L	0.994
8:38267361:G:T	F123L	0.994
8:38267363:A:G	F123L	0.994
8:38267365:C:G	C122S	0.994
8:38267366:A:T	C122S	0.994
8:38267368:C:G	R121P	0.994
8:38264604:T:G	D212A	0.993
8:38267900:C:T	G112E	0.993
8:38267911:T:A	K108N	0.993

dbSNP variants (sampled 300 via entrez): RS1000058844 (8:38270782 A>G), RS1000366334 (8:38270423 A>C), RS1000431558 (8:38270684 A>C,T), RS1000864322 (8:38264224 T>A,C,G), RS1000895238 (8:38264430 G>A,C,T), RS1001466543 (8:38269314 A>C,G,T), RS1001535321 (8:38267464 A>G), RS1001702332 (8:38265171 C>T), RS1001867440 (8:38265616 C>T), RS1001900268 (8:38265876 T>A,G), RS1002520255 (8:38268915 C>T), RS1003377775 (8:38266834 A>G), RS1004443495 (8:38269042 T>C), RS1004647101 (8:38266765 CAAAA>C,CA,CAAAAA), RS1004884739 (8:38270205 C>G)

Disease associations

OMIM: gene MIM:610626 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST004521_242	Autism spectrum disorder or schizophrenia	4.000000e-09
GCST006803_65	Schizophrenia	6.000000e-10

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

47 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression	7
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	4
Cyclosporine	increases expression	4
trichostatin A	affects cotreatment, decreases expression	3
Estradiol	decreases expression, increases expression	2
Tunicamycin	increases expression	2
Thapsigargin	increases expression	2
triphenyl phosphate	affects expression	1
bisphenol A	affects expression	1
deoxynivalenol	decreases expression	1
decabromobiphenyl ether	affects expression	1
arsenite	increases methylation	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
cupric chloride	increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
entinostat	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
belinostat	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	increases expression	1
jinfukang	affects cotreatment, increases expression	1
NSC 689534	affects binding, increases expression	1
NSC668394	increases expression	1
Sunitinib	increases expression	1
Vorinostat	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Arsenic	increases expression, affects cotreatment, increases abundance	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.