Q92626 (PXDN_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Peroxidasin homolog
EC=1.11.1.7

Alternative name(s):
Melanoma-associated antigen MG50
Vascular peroxidase 1
p53-responsive gene 2 protein

Gene names

Name:	PXDN
Synonyms:	KIAA0230, MG50, PRG2, VPO, VPO1

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	1479 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Displays low peroxidase activity and is likely to participate in H2O2 metabolism and peroxidative reactions in the cardiovascular system. Plays a role in extracellular matrix formation. Ref.3 Ref.9
Catalytic activity	2 phenolic donor + H2O2 = 2 phenoxyl radical of the donor + 2 H2O. Ref.3 Ref.9
Cofactor	Binds 1 calcium ion per subunit By similarity. Ref.3 Binds 1 heme B (iron-protoporphyrin IX) group covalently per subunit. Ref.3
Subcellular location	Secreted › extracellular space › extracellular matrix. Note: Enriched in the peritubular space of fibrotic kidneys. Ref.8 Ref.9
Tissue specificity	Expressed at higher levels in heart, lung, ovary, spleen, intestine and placenta, and at lower levels in liver, colon, pancreas, kidney, thymus, skeletal muscle and prostate. Expressed in tumors such as melanoma, breast cancer, ovarian cancer and glioblastoma. A shorter form probably lacking the signal sequence is found in testis and in EB1 cells undergoing p53/TP53-dependent apoptosis. Ref.1 Ref.2 Ref.3 Ref.9
Developmental stage	Expressed in fetal liver and spleen. Ref.2
Induction	By TGFB1 in fibroblasts and up-regulated in apoptotic cells. Ref.1 Ref.9
Sequence similarities	Belongs to the peroxidase family. XPO subfamily. Contains 4 Ig-like C2-type (immunoglobulin-like) domains. Contains 4 LRR (leucine-rich) repeats. Contains 1 LRRCT domain. Contains 1 LRRNT domain. Contains 1 VWFC domain.
Biophysicochemical properties	Kinetic parameters: KM=0.15 mM for H2O2 Ref.3
Sequence caution	The sequence AAF06354.1 differs from that shown. Reason: Erroneous initiation. The sequence BAA13219.1 differs from that shown. Reason: Erroneous initiation.

Ontologies

Keywords
Biological process	Hydrogen peroxide
Cellular component	Extracellular matrix Secreted
Coding sequence diversity	Alternative splicing Polymorphism
Domain	Immunoglobulin domain Leucine-rich repeat Repeat Signal
Ligand	Calcium Heme Iron Metal-binding
Molecular function	Oxidoreductase Peroxidase
PTM	Disulfide bond Glycoprotein Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	extracellular matrix organization Inferred from direct assay Ref.9. Source: UniProtKB hydrogen peroxide catabolic process Inferred from direct assay Ref.3. Source: UniProtKB immune response Non-traceable author statement Ref.2. Source: UniProtKB
Cellular_component	endoplasmic reticulum Inferred from direct assay Ref.9. Source: UniProtKB extracellular matrix Inferred from direct assay Ref.9. Source: UniProtKB extracellular space Inferred from direct assay Ref.3. Source: UniProtKB proteinaceous extracellular matrix Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	extracellular matrix structural constituent Inferred from direct assay Ref.9. Source: UniProtKB heme binding Inferred from direct assay Ref.3. Source: UniProtKB interleukin-1 receptor antagonist activity Non-traceable author statement Ref.2. Source: UniProtKB metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW peroxidase activity Inferred from direct assay Ref.3Ref.9. Source: UniProtKB
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Note: Additional isoforms seem to exist.

Isoform 1 (identifier: Q92626-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: Q92626-2)

The sequence of this isoform differs from the canonical sequence as follows:
     703-727: YHYNDLVSPQYLNLIANLSGCTAHR → QCQSLFFLLHGLSNGVEHASVKSHS
     728-1479: Missing.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 26	26	Potential
	Chain	27 – 1479	1453	Peroxidasin homolog		PRO_0000319619
Regions
	Domain	27 – 63	37	LRRNT
	Repeat	87 – 108	22	LRR 1
	Repeat	111 – 132	22	LRR 2
	Repeat	135 – 156	22	LRR 3
	Repeat	159 – 180	22	LRR 4
	Domain	192 – 245	54	LRRCT
	Domain	246 – 332	87	Ig-like C2-type 1
	Domain	342 – 428	87	Ig-like C2-type 2
	Domain	433 – 520	88	Ig-like C2-type 3
	Domain	521 – 610	90	Ig-like C2-type 4
	Domain	1413 – 1471	59	VWFC
Sites
	Active site	827	1	Proton acceptor By similarity
	Metal binding	828	1	Calcium By similarity
	Metal binding	907	1	Calcium By similarity
	Metal binding	909	1	Calcium; via carbonyl oxygen By similarity
	Metal binding	911	1	Calcium By similarity
	Metal binding	913	1	Calcium By similarity
	Metal binding	1074	1	Iron (heme axial ligand) By similarity
	Binding site	826	1	Heme (covalent; via 2 links) By similarity
	Binding site	980	1	Heme (covalent; via 2 links) By similarity
	Site	977	1	Transition state stabilizer By similarity
Amino acid modifications
	Modified residue	1176	1	Phosphotyrosine Ref.7
	Modified residue	1180	1	Phosphoserine Ref.7
	Glycosylation	640	1	N-linked (GlcNAc...) Potential
	Glycosylation	699	1	N-linked (GlcNAc...) Potential
	Glycosylation	719	1	N-linked (GlcNAc...) Potential
	Glycosylation	731	1	N-linked (GlcNAc...) Potential
	Glycosylation	865	1	N-linked (GlcNAc...) Potential
	Glycosylation	1178	1	N-linked (GlcNAc...) Ref.10
	Glycosylation	1280	1	N-linked (GlcNAc...) Potential
	Glycosylation	1368	1	N-linked (GlcNAc...) Potential
	Glycosylation	1425	1	N-linked (GlcNAc...) Potential
	Disulfide bond	267 ↔ 317		By similarity
	Disulfide bond	363 ↔ 412		By similarity
	Disulfide bond	454 ↔ 502		By similarity
	Disulfide bond	546 ↔ 594		By similarity
	Disulfide bond	732 ↔ 748		By similarity
	Disulfide bond	847 ↔ 857		By similarity
	Disulfide bond	851 ↔ 875		By similarity
	Disulfide bond	959 ↔ 970		By similarity
	Disulfide bond	1177 ↔ 1234		By similarity
	Disulfide bond	1275 ↔ 1301		By similarity
Natural variations
	Alternative sequence	703 – 727	25	YHYND…CTAHR → QCQSLFFLLHGLSNGVEHAS VKSHS in isoform 2.		VSP_031516
	Alternative sequence	728 – 1479	752	Missing in isoform 2.		VSP_031517
	Natural variant	1198	1	R → Q. Corresponds to variant rs6723697 [ dbSNP | Ensembl ].		VAR_050487
	Natural variant	1261	1	Q → R. Corresponds to variant rs6723697 [ dbSNP | Ensembl ].		VAR_039048

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified February 26, 2008. Version 2. Checksum: 7A75F533D89C6AAD	FASTA	1,479	165,275
	10 20 30 40 50 60 MAKRSRGPGR RCLLALVLFC AWGTLAVVAQ KPGAGCPSRC LCFRTTVRCM HLLLEAVPAV 70 80 90 100 110 120 APQTSILDLR FNRIREIQPG AFRRLRNLNT LLLNNNQIKR IPSGAFEDLE NLKYLYLYKN 130 140 150 160 170 180 EIQSIDRQAF KGLASLEQLY LHFNQIETLD PDSFQHLPKL ERLFLHNNRI THLVPGTFNH 190 200 210 220 230 240 LESMKRLRLD SNTLHCDCEI LWLADLLKTY AESGNAQAAA ICEYPRRIQG RSVATITPEE 250 260 270 280 290 300 LNCERPRITS EPQDADVTSG NTVYFTCRAE GNPKPEIIWL RNNNELSMKT DSRLNLLDDG 310 320 330 340 350 360 TLMIQNTQET DQGIYQCMAK NVAGEVKTQE VTLRYFGSPA RPTFVIQPQN TEVLVGESVT 370 380 390 400 410 420 LECSATGHPP PRISWTRGDR TPLPVDPRVN ITPSGGLYIQ NVVQGDSGEY ACSATNNIDS 430 440 450 460 470 480 VHATAFIIVQ ALPQFTVTPQ DRVVIEGQTV DFQCEAKGNP PPVIAWTKGG SQLSVDRRHL 490 500 510 520 530 540 VLSSGTLRIS GVALHDQGQY ECQAVNIIGS QKVVAHLTVQ PRVTPVFASI PSDTTVEVGA 550 560 570 580 590 600 NVQLPCSSQG EPEPAITWNK DGVQVTESGK FHISPEGFLT INDVGPADAG RYECVARNTI 610 620 630 640 650 660 GSASVSMVLS VNVPDVSRNG DPFVATSIVE AIATVDRAIN STRTHLFDSR PRSPNDLLAL 670 680 690 700 710 720 FRYPRDPYTV EQARAGEIFE RTLQLIQEHV QHGLMVDLNG TSYHYNDLVS PQYLNLIANL 730 740 750 760 770 780 SGCTAHRRVN NCSDMCFHQK YRTHDGTCNN LQHPMWGASL TAFERLLKSV YENGFNTPRG 790 800 810 820 830 840 INPHRLYNGH ALPMPRLVST TLIGTETVTP DEQFTHMLMQ WGQFLDHDLD STVVALSQAR 850 860 870 880 890 900 FSDGQHCSNV CSNDPPCFSV MIPPNDSRAR SGARCMFFVR SSPVCGSGMT SLLMNSVYPR 910 920 930 940 950 960 EQINQLTSYI DASNVYGSTE HEARSIRDLA SHRGLLRQGI VQRSGKPLLP FATGPPTECM 970 980 990 1000 1010 1020 RDENESPIPC FLAGDHRANE QLGLTSMHTL WFREHNRIAT ELLKLNPHWD GDTIYYETRK 1030 1040 1050 1060 1070 1080 IVGAEIQHIT YQHWLPKILG EVGMRTLGEY HGYDPGINAG IFNAFATAAF RFGHTLVNPL 1090 1100 1110 1120 1130 1140 LYRLDENFQP IAQDHLPLHK AFFSPFRIVN EGGIDPLLRG LFGVAGKMRV PSQLLNTELT 1150 1160 1170 1180 1190 1200 ERLFSMAHTV ALDLAAINIQ RGRDHGIPPY HDYRVYCNLS AAHTFEDLKN EIKNPEIREK 1210 1220 1230 1240 1250 1260 LKRLYGSTLN IDLFPALVVE DLVPGSRLGP TLMCLLSTQF KRLRDGDRLW YENPGVFSPA 1270 1280 1290 1300 1310 1320 QLTQIKQTSL ARILCDNADN ITRVQSDVFR VAEFPHGYGS CDEIPRVDLR VWQDCCEDCR 1330 1340 1350 1360 1370 1380 TRGQFNAFSY HFRGRRSLEF SYQEDKPTKK TRPRKIPSVG RQGEHLSNST SAFSTRSDAS 1390 1400 1410 1420 1430 1440 GTNDFREFVL EMQKTITDLR TQIKKLESRL STTECVDAGG ESHANNTKWK KDACTICECK 1450 1460 1470 DGQVTCFVEA CPPATCAVPV NIPGACCPVC LQKRAEEKP
	Isoform 2 [UniParc]. Checksum: 16391EA8B7F61878	FASTA	727	80,329
	10 20 30 40 50 60 MAKRSRGPGR RCLLALVLFC AWGTLAVVAQ KPGAGCPSRC LCFRTTVRCM HLLLEAVPAV 70 80 90 100 110 120 APQTSILDLR FNRIREIQPG AFRRLRNLNT LLLNNNQIKR IPSGAFEDLE NLKYLYLYKN 130 140 150 160 170 180 EIQSIDRQAF KGLASLEQLY LHFNQIETLD PDSFQHLPKL ERLFLHNNRI THLVPGTFNH 190 200 210 220 230 240 LESMKRLRLD SNTLHCDCEI LWLADLLKTY AESGNAQAAA ICEYPRRIQG RSVATITPEE 250 260 270 280 290 300 LNCERPRITS EPQDADVTSG NTVYFTCRAE GNPKPEIIWL RNNNELSMKT DSRLNLLDDG 310 320 330 340 350 360 TLMIQNTQET DQGIYQCMAK NVAGEVKTQE VTLRYFGSPA RPTFVIQPQN TEVLVGESVT 370 380 390 400 410 420 LECSATGHPP PRISWTRGDR TPLPVDPRVN ITPSGGLYIQ NVVQGDSGEY ACSATNNIDS 430 440 450 460 470 480 VHATAFIIVQ ALPQFTVTPQ DRVVIEGQTV DFQCEAKGNP PPVIAWTKGG SQLSVDRRHL 490 500 510 520 530 540 VLSSGTLRIS GVALHDQGQY ECQAVNIIGS QKVVAHLTVQ PRVTPVFASI PSDTTVEVGA 550 560 570 580 590 600 NVQLPCSSQG EPEPAITWNK DGVQVTESGK FHISPEGFLT INDVGPADAG RYECVARNTI 610 620 630 640 650 660 GSASVSMVLS VNVPDVSRNG DPFVATSIVE AIATVDRAIN STRTHLFDSR PRSPNDLLAL 670 680 690 700 710 720 FRYPRDPYTV EQARAGEIFE RTLQLIQEHV QHGLMVDLNG TSQCQSLFFL LHGLSNGVEH ASVKSHS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Isolation of differentially expressed cDNAs from p53-dependent apoptotic cells: activation of the human homologue of the Drosophila peroxidasin gene." Horikoshi N., Cong J., Kley N., Shenk T. Biochem. Biophys. Res. Commun. 261:864-869(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), INDUCTION, TISSUE SPECIFICITY.
[2]	"A novel melanoma gene (MG50) encoding the interleukin 1 receptor antagonist and six epitopes recognized by human cytolytic T lymphocytes." Mitchell M.S., Kan-Mitchell J., Minev B., Edman C., Deans R.J. Cancer Res. 60:6448-6456(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, DEVELOPMENTAL STAGE.
[3]	"Identification and characterization of VPO1, a new animal heme-containing peroxidase." Cheng G., Salerno J.C., Cao Z., Pagano P.J., Lambeth J.D. Free Radic. Biol. Med. 45:1682-1694(2008) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), 3D-STRUCTURE MODELING, FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, HEME COFACTOR, TISSUE SPECIFICITY.
[4]	"Prediction of the coding sequences of unidentified human genes. VI. The coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of cDNA clones from cell line KG-1 and brain." Nagase T., Seki N., Ishikawa K., Ohira M., Kawarabayasi Y., Ohara O., Tanaka A., Kotani H., Miyajima N., Nomura N. DNA Res. 3:321-329(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Tissue: Bone marrow.
[5]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 6-1479 (ISOFORM 2). Tissue: Chondrosarcoma.
[7]	"Large-scale phosphoproteome analysis of human liver tissue by enrichment and fractionation of phosphopeptides with strong anion exchange chromatography." Han G., Ye M., Zhou H., Jiang X., Feng S., Jiang X., Tian R., Wan D., Zou H., Gu J. Proteomics 8:1346-1361(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-1176 AND SER-1180, MASS SPECTROMETRY. Tissue: Liver.
[8]	Cheng G. Unpublished observations (FEB-2008) Cited for: SUBCELLULAR LOCATION.
[9]	"Peroxidasin is secreted and incorporated into the extracellular matrix of myofibroblasts and fibrotic kidney." Peterfi Z., Donko A., Orient A., Sum A., Prokai A., Molnar B., Vereb Z., Rajnavolgyi E., Kovacs K.J., Muller V., Szabo A.J., Geiszt M. Am. J. Pathol. 175:725-735(2009) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, INDUCTION BY TGFB1.
[10]	"Glycoproteomics analysis of human liver tissue by combination of multiple enzyme digestion and hydrazide chemistry." Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H. J. Proteome Res. 8:651-661(2009) [PubMed] [Europe PMC] [Abstract] Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-1178, MASS SPECTROMETRY. Tissue: Liver.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AF200348 mRNA. Translation: AAF06354.1. Different initiation. EF090903 mRNA. Translation: ABO25865.1. D86983 mRNA. Translation: BAA13219.1. Different initiation. CH471053 Genomic DNA. Translation: EAX01084.1. CH471053 Genomic DNA. Translation: EAX01085.1. BC098579 mRNA. Translation: AAH98579.1.
IPI	IPI00016112. IPI00791587.
RefSeq	NP_036425.1. NM_012293.1.
UniGene	Hs.332197.
3D structure databases
HSSP	HSSP built from PDB template 1D5L based on UniProtKB P05164.
ProteinModelPortal	Q92626.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q92626. 1 interaction.
STRING	9606.ENSP00000252804.
Protein family/group databases
PeroxiBase	3355. HsPxd01.
PTM databases
PhosphoSite	Q92626.
Polymorphism databases
DMDM	172045828.
Proteomic databases
PaxDb	Q92626.
PRIDE	Q92626.
Protocols and materials databases
DNASU	7837.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000252804; ENSP00000252804; ENSG00000130508.
GeneID	7837.
KEGG	hsa:7837.
UCSC	uc002qxa.3. human. uc002qxb.1. human.
Organism-specific databases
CTD	7837.
GeneCards	GC02M001635.
HGNC	HGNC:14966. PXDN.
HPA	HPA012375.
MIM	605158. gene.
neXtProt	NX_Q92626.
Orphanet	289499. Congenital cataract microcornea with corneal opacity.
PharmGKB	PA128394535.
HUGE	Search...
GenAtlas	Search...
Phylogenomic databases
eggNOG	NOG262194.
HOGENOM	HOG000016084.
HOVERGEN	HBG108312.
InParanoid	Q92626.
OMA	EPVITWN.
OrthoDB	EOG4J1179.
Gene expression databases
ArrayExpress	Q92626.
Bgee	Q92626.
CleanEx	HS_PRG2. HS_PXDN.
Genevestigator	Q92626.
Family and domain databases
Gene3D	1.10.640.10. 2 hits. 2.60.40.10. 4 hits.
InterPro	IPR000483. Cys-rich_flank_reg_C. IPR010255. Haem_peroxidase. IPR002007. Haem_peroxidase_animal. IPR019791. Haem_peroxidase_animal_subgr. IPR007110. Ig-like_dom. IPR013783. Ig-like_fold. IPR013098. Ig_I-set. IPR003598. Ig_sub2. IPR001611. Leu-rich_rpt. IPR003591. Leu-rich_rpt_typical-subtyp. IPR000372. LRR-contain_N. IPR001007. VWF_C. [Graphical view]
Pfam	PF03098. An_peroxidase. 1 hit. PF07679. I-set. 4 hits. PF00093. VWC. 1 hit. [Graphical view]
PRINTS	PR00457. ANPEROXIDASE.
SMART	SM00408. IGc2. 4 hits. SM00369. LRR_TYP. 4 hits. SM00082. LRRCT. 1 hit. SM00013. LRRNT. 1 hit. SM00214. VWC. 1 hit. [Graphical view]
SUPFAM	SSF48113. Peroxidase_super. 1 hit.
PROSITE	PS50835. IG_LIKE. 4 hits. PS51450. LRR. 5 hits. PS00435. PEROXIDASE_1. False negative. PS00436. PEROXIDASE_2. False negative. PS50292. PEROXIDASE_3. 1 hit. PS01208. VWFC_1. 1 hit. PS50184. VWFC_2. 1 hit. [Graphical view]
ProtoNet	Search...
Other
ChiTaRS	PXDN. human.
GenomeRNAi	7837.
NextBio	30238.
SOURCE	Search...

Entry information

Entry name

PXDN_HUMAN

Accession

Primary (citable) accession number: Q92626
Secondary accession number(s): A8QM65, D6W4Y0, Q4KMG2

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 26, 2008
Last sequence update:	February 26, 2008
Last modified:	May 1, 2013
This is version 120 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.