Free for academic non-profit institutions. Other users need a Commercial license

Aliases for VPS33B Gene

Aliases for VPS33B Gene

  • VPS33B, Late Endosome And Lysosome Associated 2 3 5
  • Vacuolar Protein Sorting-Associated Protein 33B 3
  • Vacuolar Protein Sorting 33 Homolog B (Yeast) 2
  • Vacuolar Protein Sorting 33B (Yeast Homolog) 2
  • Vacuolar Protein Sorting 33-Like Protein B 3
  • Vacuolar Protein Sorting 33 Homolog B 3
  • HVPS33B 4

External Ids for VPS33B Gene

Previous GeneCards Identifiers for VPS33B Gene

  • GC15P087731
  • GC15M084982
  • GC15M089129
  • GC15M089271
  • GC15M089342
  • GC15M091541
  • GC15M067652

Summaries for VPS33B Gene

Entrez Gene Summary for VPS33B Gene

  • Vesicle mediated protein sorting plays an important role in segregation of intracellular molecules into distinct organelles. Genetic studies in yeast have identified more than 40 vacuolar protein sorting (VPS) genes involved in vesicle transport to vacuoles. This gene is a member of the Sec-1 domain family, and encodes the human ortholog of rat Vps33b which is homologous to the yeast class C Vps33 protein. The mammalian class C vacuolar protein sorting proteins are predominantly associated with late endosomes/lysosomes, and like their yeast counterparts, may mediate vesicle trafficking steps in the endosome/lysosome pathway. Mutations in this gene are associated with arthrogryposis-renal dysfunction-cholestasis syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

GeneCards Summary for VPS33B Gene

VPS33B (VPS33B, Late Endosome And Lysosome Associated) is a Protein Coding gene. Diseases associated with VPS33B include Arthrogryposis, Renal Dysfunction, And Cholestasis 1 and Cholestasis. An important paralog of this gene is ENSG00000284946.

UniProtKB/Swiss-Prot for VPS33B Gene

  • May play a role in vesicle-mediated protein trafficking to lysosomal compartments and in membrane docking/fusion reactions of late endosomes/lysosomes. Mediates phagolysosomal fusion in macrophages (PubMed:18474358). Proposed to be involved in endosomal maturation implicating VIPAS39. In epithelial cells, the VPS33B:VIPAS39 complex may play a role in the apical recycling pathway and in the maintenance of the apical-basolateral polarity (PubMed:20190753). Seems to be involved in the sorting of specific cargos from the trans-Golgi network to alpha-granule-destined multivesicular bodies (MVBs) promoting MVBs maturation in megakaryocytes (By similarity).

Gene Wiki entry for VPS33B Gene

Additional gene information for VPS33B Gene

No data available for CIViC summary , Tocris Summary , PharmGKB "VIP" Summary , fRNAdb sequence ontologies and piRNA Summary for VPS33B Gene

Genomics for VPS33B Gene

GeneHancer (GH) Regulatory Elements for VPS33B Gene

Promoters and enhancers for VPS33B Gene
GeneHancer (GH) Identifier GH Type GH
Score
GH Sources Gene Association Score Total Score TSS distance (kb) Number of Genes Away Size (kb) Transcription Factor
Binding Sites
Gene Targets
GH15J091021 Promoter/Enhancer 2 EPDnew Ensembl ENCODE 662.1 +0.3 270 2 HDGF ARNT ARID4B SIN3A FEZF1 DMAP1 ZNF2 YY1 POLR2B ZNF766 VPS33B VPS33B-DT ENSG00000284946 ENSG00000278514 UNC45A ENSG00000259314 RCCD1 CRTC3 LOC105370970 GC15P090938
GH15J090999 Promoter 0.5 EPDnew 662.4 +23.6 23578 0.1 VPS33B PIR55905 VPS33B-DT HDDC3 UNC45A PRC1 ENSG00000284946 GC15P090938
GH15J091008 Promoter 0.5 EPDnew 650.4 +14.6 14619 0.1 VPS33B HDDC3 UNC45A LOC105370970 PIR55905 ENSG00000284946 GC15P090938
GH15J091007 Promoter 0.5 EPDnew 650.4 +15.1 15140 0.1 VPS33B HDDC3 UNC45A LOC105370970 PIR55905 ENSG00000284946 GC15P090938
GH15J090991 Promoter/Enhancer 2.3 EPDnew Ensembl ENCODE 33.2 +28.9 28947 4.3 CLOCK DMAP1 YY1 ZNF213 E2F8 ZNF143 SP3 NFYC ZNF610 GLIS1 PRC1 RCCD1 UNC45A VPS33B ENSG00000259314 VPS33B-DT ENSG00000259212 FES ENSG00000200142 GC15M090978
- Elite GeneHancer and/or Elite GeneHancer-gene association Download GeneHancer data from 2017 publication | Request up-to-date GeneHancer data (full dataset)

GeneHancers around VPS33B on UCSC Golden Path with GeneCards custom track

Top Transcription factor binding sites by QIAGEN in the VPS33B gene promoter:
  • Nkx2-5
  • Lmo2
  • HFH-3
  • FOXI1
  • AML1a
  • ER-alpha
  • E47
  • c-Ets-1
  • Olf-1
  • POU3F2 (N-Oct-5b)

Genomic Locations for VPS33B Gene

Genomic Locations for VPS33B Gene
chr15:90,998,416-91,022,621
(GRCh38/hg38)
Size:
24,206 bases
Orientation:
Minus strand
chr15:91,541,646-91,565,833
(GRCh37/hg19)
Size:
24,188 bases
Orientation:
Minus strand

Genomic View for VPS33B Gene

Genes around VPS33B on UCSC Golden Path with GeneCards custom track

Cytogenetic band:
VPS33B Gene in genomic location: bands according to Ensembl, locations according to GeneLoc (and/or Entrez Gene and/or Ensembl if different)
Genomic Location for VPS33B Gene
GeneLoc Logo Genomic Neighborhood Exon StructureGene Density

RefSeq DNA sequence for VPS33B Gene

Proteins for VPS33B Gene

  • Protein details for VPS33B Gene (UniProtKB/Swiss-Prot)

    Protein Symbol:
    Q9H267-VP33B_HUMAN
    Recommended name:
    Vacuolar protein sorting-associated protein 33B
    Protein Accession:
    Q9H267
    Secondary Accessions:
    • B3KQF6
    • Q96K14
    • Q9NRP6
    • Q9NSF3

    Protein attributes for VPS33B Gene

    Size:
    617 amino acids
    Molecular mass:
    70585 Da
    Quaternary structure:
    • Interacts with RAB11A and VIPAS39. Associates with adaptor protein complex 3 (AP-3), clathrin:AP-3 and clathrin:HGS complexes (PubMed:21411634). Interacts with M.tuberculosis PtpA.

    Alternative splice isoforms for VPS33B Gene

    UniProtKB/Swiss-Prot:

neXtProt entry for VPS33B Gene

Post-translational modifications for VPS33B Gene

  • Phosphorylated on tyrosine residues. Dephosphorylation by M.tuberculosis PtpA is necessary to induce the reduction of host phagolysosome fusion in M.tuberculosis-infected macrophages.
  • Ubiquitination at posLast=304304
  • Modification sites at PhosphoSitePlus

No data available for DME Specific Peptides for VPS33B Gene

Domains & Families for VPS33B Gene

Gene Families for VPS33B Gene

Human Protein Atlas (HPA):
  • Disease related genes
  • Predicted intracellular proteins

Protein Domains for VPS33B Gene

Graphical View of Domain Structure for InterPro Entry

Q9H267

UniProtKB/Swiss-Prot:

VP33B_HUMAN :
  • Belongs to the STXBP/unc-18/SEC1 family.
Family:
  • Belongs to the STXBP/unc-18/SEC1 family.
genes like me logo Genes that share domains with VPS33B: view

Function for VPS33B Gene

Molecular function for VPS33B Gene

UniProtKB/Swiss-Prot Function:
May play a role in vesicle-mediated protein trafficking to lysosomal compartments and in membrane docking/fusion reactions of late endosomes/lysosomes. Mediates phagolysosomal fusion in macrophages (PubMed:18474358). Proposed to be involved in endosomal maturation implicating VIPAS39. In epithelial cells, the VPS33B:VIPAS39 complex may play a role in the apical recycling pathway and in the maintenance of the apical-basolateral polarity (PubMed:20190753). Seems to be involved in the sorting of specific cargos from the trans-Golgi network to alpha-granule-destined multivesicular bodies (MVBs) promoting MVBs maturation in megakaryocytes (By similarity).

Phenotypes From GWAS Catalog for VPS33B Gene

Gene Ontology (GO) - Molecular Function for VPS33B Gene

GO ID Qualified GO term Evidence PubMed IDs
GO:0005515 protein binding IPI 16189514
genes like me logo Genes that share ontologies with VPS33B: view
genes like me logo Genes that share phenotypes with VPS33B: view

Human Phenotype Ontology for VPS33B Gene

HPO Id HPO Name Alternative Ids Definition Synonyms

Animal Models for VPS33B Gene

MGI Knock Outs for VPS33B:
  • Vps33b Vps33b<tm1a(EUCOMM)Wtsi>

Animal Model Products

miRNA for VPS33B Gene

Clone Products

No data available for Enzyme Numbers (IUBMB) , Transcription Factor Targets and HOMER Transcription for VPS33B Gene

Localization for VPS33B Gene

Subcellular locations from UniProtKB/Swiss-Prot for VPS33B Gene

Late endosome membrane; Peripheral membrane protein; Cytoplasmic side. Lysosome membrane; Peripheral membrane protein; Cytoplasmic side. Early endosome. Cytoplasmic vesicle, clathrin-coated vesicle. Recycling endosome. Note=Colocalizes in clusters with VIPAS39 at cytoplasmic organelles (PubMed:19109425). Colocalizes with RAB11A and VIPAS39 on recycling endosomes (PubMed:22753090). Colocalizes with AP-3, clathrin, Rab5 and Rab7b (PubMed:21411634). Colocalizes with M.tuberculosis PtpA in the cytosol of tuberculosis-infected macrophages and associates with phagosomes (PubMed:18474358). {ECO:0000269 PubMed:18474358, ECO:0000269 PubMed:19109425, ECO:0000269 PubMed:21411634, ECO:0000269 PubMed:22753090}.

Subcellular locations from

COMPARTMENTS
Extracellular space Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi Apparatus Nucleus Mitochondrion 0 1 2 3 4 5 Confidence
COMPARTMENTS Subcellular localization image for VPS33B gene
Compartment Confidence
lysosome 5
golgi apparatus 5
endosome 5
cytosol 3
mitochondrion 2
peroxisome 1
nucleus 1

Gene Ontology (GO) - Cellular Components for VPS33B Gene

GO ID Qualified GO term Evidence PubMed IDs
GO:0005622 intracellular IEA --
GO:0005737 cytoplasm IDA 15052268
GO:0005764 lysosome IEA,IDA 15052268
GO:0005765 lysosomal membrane IEA --
GO:0005768 endosome IEA --
genes like me logo Genes that share ontologies with VPS33B: view

No data available for Subcellular locations from the Human Protein Atlas (HPA) for VPS33B Gene

Pathways & Interactions for VPS33B Gene

SuperPathways for VPS33B Gene

No Data Available

Gene Ontology (GO) - Biological Process for VPS33B Gene

GO ID Qualified GO term Evidence PubMed IDs
GO:0006904 vesicle docking involved in exocytosis IEA --
GO:0007032 endosome organization IMP 23918659
GO:0008333 NOT endosome to lysosome transport IMP 25783203
GO:0015031 protein transport IMP 15052268
GO:0016192 vesicle-mediated transport IDA,IEA 15790593
genes like me logo Genes that share ontologies with VPS33B: view

No data available for Pathways by source and SIGNOR curated interactions for VPS33B Gene

Drugs & Compounds for VPS33B Gene

No Compound Related Data Available

Transcripts for VPS33B Gene

Unigene Clusters for VPS33B Gene

Vacuolar protein sorting 33 homolog B (yeast):
Representative Sequences:

Clone Products

Alternative Splicing Database (ASD) splice patterns (SP) for VPS33B Gene

ExUns: 1a · 1b · 1c · 1d ^ 2 ^ 3a · 3b ^ 4 ^ 5a · 5b ^ 6 ^ 7 ^ 8 ^ 9 ^ 10 ^ 11
SP1: -
SP2:
SP3: - -
SP4:
SP5: - - -

Relevant External Links for VPS33B Gene

GeneLoc Exon Structure for
VPS33B
ECgene alternative splicing isoforms for
VPS33B

Expression for VPS33B Gene

mRNA expression in normal human tissues from GTEx, Illumina, BioGPS, and CGAP SAGE for VPS33B Gene

Protein differential expression in normal tissues from HIPED for VPS33B Gene

This gene is overexpressed in Peripheral blood mononuclear cells (20.6).

Integrated Proteomics: protein expression in normal tissues and cell lines from ProteomicsDB, MaxQB, and MOPED for VPS33B Gene



Protein tissue co-expression partners for VPS33B Gene

- Elite partner

NURSA nuclear receptor signaling pathways regulating expression of VPS33B Gene:

VPS33B

SOURCE GeneReport for Unigene cluster for VPS33B Gene:

Hs.745007

mRNA Expression by UniProt/SwissProt for VPS33B Gene:

Q9H267-VP33B_HUMAN
Tissue specificity: Ubiquitous; highly expressed in testis and low expression in the lung.

Evidence on tissue expression from TISSUES for VPS33B Gene

  • Nervous system(3.4)
  • Blood(2)

Phenotype-based relationships between genes and organs from Gene ORGANizer for VPS33B Gene

Germ Layers:
  • ectoderm
  • endoderm
  • mesoderm
Systems:
  • cardiovascular
  • digestive
  • immune
  • integumentary
  • nervous
  • reproductive
  • respiratory
  • skeletal muscle
  • skeleton
  • urinary
Regions:
Head and neck:
  • brain
  • chin
  • ear
  • eye
  • face
  • forehead
  • head
  • jaw
  • mandible
  • maxilla
  • mouth
  • neck
  • outer ear
  • pituitary gland
  • skull
Thorax:
  • chest wall
  • clavicle
  • heart
  • heart valve
  • lung
  • rib
  • rib cage
  • scapula
  • sternum
Abdomen:
  • abdominal wall
  • biliary tract
  • gallbladder
  • intestine
  • kidney
  • large intestine
  • liver
  • pancreas
  • small intestine
Pelvis:
  • pelvis
  • placenta
  • ureter
  • urinary bladder
  • uterus
Limb:
  • ankle
  • arm
  • digit
  • elbow
  • femur
  • fibula
  • finger
  • foot
  • forearm
  • hand
  • hip
  • humerus
  • knee
  • lower limb
  • radius
  • shin
  • shoulder
  • thigh
  • tibia
  • toe
  • ulna
  • upper limb
  • wrist
General:
  • blood
  • blood vessel
  • coagulation system
  • skin
  • spinal column
  • vertebrae
genes like me logo Genes that share expression patterns with VPS33B: view

No data available for mRNA expression in embryonic tissues and stem cells from LifeMap Discovery and mRNA differential expression in normal tissues for VPS33B Gene

Orthologs for VPS33B Gene

This gene was present in the common ancestor of animals and fungi.

Orthologs for VPS33B Gene

Organism Taxonomy Gene Similarity Type Details
chimpanzee
(Pan troglodytes)
Mammalia VPS33B 34 33
  • 99.51 (n)
OneToOne
dog
(Canis familiaris)
Mammalia VPS33B 34 33
  • 92.49 (n)
OneToOne
oppossum
(Monodelphis domestica)
Mammalia VPS33B 34
  • 92 (a)
OneToOne
mouse
(Mus musculus)
Mammalia Vps33b 16 34 33
  • 91.25 (n)
cow
(Bos Taurus)
Mammalia VPS33B 34 33
  • 91.25 (n)
OneToOne
rat
(Rattus norvegicus)
Mammalia Vps33b 33
  • 90.71 (n)
platypus
(Ornithorhynchus anatinus)
Mammalia -- 34
  • 60 (a)
OneToMany
-- 34
  • 56 (a)
OneToMany
-- 34
  • 40 (a)
OneToMany
chicken
(Gallus gallus)
Aves VPS33B 34 33
  • 77.16 (n)
OneToOne
lizard
(Anolis carolinensis)
Reptilia VPS33B 34
  • 79 (a)
OneToOne
tropical clawed frog
(Silurana tropicalis)
Amphibia vps33b 33
  • 69.96 (n)
zebrafish
(Danio rerio)
Actinopterygii vps33b 34 33
  • 69.23 (n)
OneToOne
rainbow trout
(Oncorhynchus mykiss)
Actinopterygii Omy.8451 33
fruit fly
(Drosophila melanogaster)
Insecta CG5127 35
  • 21 (a)
Vps33B 34
  • 20 (a)
OneToOne
worm
(Caenorhabditis elegans)
Secernentea vps-33.2 34 33
  • 43.82 (n)
OneToOne
C56C10.1 35
  • 27 (a)
baker's yeast
(Saccharomyces cerevisiae)
Saccharomycetes VPS33 34
  • 19 (a)
OneToMany
sea squirt
(Ciona savignyi)
Ascidiacea -- 34
  • 46 (a)
OneToOne
Species where no ortholog for VPS33B was found in the sources mined by GeneCards:
  • A. gosspyii yeast (Ashbya gossypii)
  • Actinobacteria (Mycobacterium tuberculosis)
  • African clawed frog (Xenopus laevis)
  • African malaria mosquito (Anopheles gambiae)
  • Alicante grape (Vitis vinifera)
  • alpha proteobacteria (Wolbachia pipientis)
  • amoeba (Dictyostelium discoideum)
  • Archea (Pyrococcus horikoshii)
  • barley (Hordeum vulgare)
  • beta proteobacteria (Neisseria meningitidis)
  • bread mold (Neurospora crassa)
  • Chromalveolata (Phytophthora infestans)
  • common water flea (Daphnia pulex)
  • corn (Zea mays)
  • E. coli (Escherichia coli)
  • filamentous fungi (Aspergillus nidulans)
  • Firmicute bacteria (Streptococcus pneumoniae)
  • fission yeast (Schizosaccharomyces pombe)
  • green algae (Chlamydomonas reinhardtii)
  • honey bee (Apis mellifera)
  • K. lactis yeast (Kluyveromyces lactis)
  • loblloly pine (Pinus taeda)
  • malaria parasite (Plasmodium falciparum)
  • medicago trunc (Medicago Truncatula)
  • moss (Physcomitrella patens)
  • orangutan (Pongo pygmaeus)
  • pig (Sus scrofa)
  • rice (Oryza sativa)
  • rice blast fungus (Magnaporthe grisea)
  • schistosome parasite (Schistosoma mansoni)
  • sea anemone (Nematostella vectensis)
  • sea urchin (Strongylocentrotus purpuratus)
  • sorghum (Sorghum bicolor)
  • soybean (Glycine max)
  • stem rust fungus (Puccinia graminis)
  • sugarcane (Saccharum officinarum)
  • thale cress (Arabidopsis thaliana)
  • tomato (Lycopersicon esculentum)
  • toxoplasmosis (Toxoplasma gondii)
  • Trichoplax (Trichoplax adhaerens)
  • wheat (Triticum aestivum)

Evolution for VPS33B Gene

ENSEMBL:
Gene Tree for VPS33B (if available)
TreeFam:
Gene Tree for VPS33B (if available)
Aminode:
Evolutionary constrained regions (ECRs) for VPS33B: view image

Paralogs for VPS33B Gene

Paralogs for VPS33B Gene

(1) SIMAP similar genes for VPS33B Gene using alignment to 4 proteins:

  • VP33B_HUMAN
  • B3KQF6_HUMAN
  • F5H008_HUMAN
  • G3V3F9_HUMAN
genes like me logo Genes that share paralogs with VPS33B: view

Variants for VPS33B Gene

Sequence variations from dbSNP and Humsavar for VPS33B Gene

SNP ID Clin Chr 15 pos Variation AA Info Type
rs1013063167 uncertain-significance, Arthrogryposis, Renal Dysfunction, and Cholestasis Syndrome 90,998,713(-) A/C/G 3_prime_UTR_variant, non_coding_transcript_variant
rs1057519063 pathogenic, Arthrogryposis renal dysfunction cholestasis syndrome 91,013,842(-) G/A 5_prime_UTR_variant, coding_sequence_variant, genic_upstream_transcript_variant, non_coding_transcript_variant, stop_gained
rs11073964 benign, not specified, Arthrogryposis, Renal Dysfunction, and Cholestasis Syndrome 91,000,531(-) C/G/T coding_sequence_variant, missense_variant, non_coding_transcript_variant
rs11073967 benign, Arthrogryposis, Renal Dysfunction, and Cholestasis Syndrome 91,022,574(-) A/G 5_prime_UTR_variant, genic_upstream_transcript_variant, non_coding_transcript_variant, upstream_transcript_variant
rs111274092 benign, likely-benign, not specified, Arthrogryposis, Renal Dysfunction, and Cholestasis Syndrome 91,014,445(-) AAA/A genic_upstream_transcript_variant, intron_variant

Structural Variations from Database of Genomic Variants (DGV) for VPS33B Gene

Variant ID Type Subtype PubMed ID
dgv757e212 CNV loss 25503493
esv2672368 CNV deletion 23128226
esv3581818 CNV loss 25503493
nsv1053084 CNV gain 25217958
nsv833090 CNV loss 17160897
nsv833091 CNV loss 17160897
nsv976964 CNV duplication 23825009

Variation tolerance for VPS33B Gene

Residual Variation Intolerance Score: 5.76% of all genes are more intolerant (likely to be disease-causing)
Gene Damage Index Score: 1.81; 34.12% of all genes are more intolerant (likely to be disease-causing)

Additional Variant Information for VPS33B Gene

Human Gene Mutation Database (HGMD)
VPS33B
SNPedia medical, phenotypic, and genealogical associations of SNPs for
VPS33B

No data available for Polymorphic Variants from UniProtKB/Swiss-Prot for VPS33B Gene

Disorders for VPS33B Gene

MalaCards: The human disease database

(4) MalaCards diseases for VPS33B Gene - From: HGMD, OMIM, ClinVar, GTR, Swiss-Prot, DISEASES, and GeneCards

Disorder Aliases PubMed IDs
arthrogryposis, renal dysfunction, and cholestasis 1
  • arcs1
cholestasis
  • bile occlusion
bile duct disease
  • bile duct disorder
biliary tract disease
  • biliary tract abnormality
- elite association - COSMIC cancer census association via MalaCards

UniProtKB/Swiss-Prot

VP33B_HUMAN
  • Arthrogryposis, renal dysfunction and cholestasis syndrome 1 (ARCS1) [MIM:208085]: A multisystem disorder, characterized by neurogenic arthrogryposis multiplex congenita, renal tubular dysfunction and neonatal cholestasis with bile duct hypoplasia and low gamma glutamyl transpeptidase activity. Platelet dysfunction is common. {ECO:0000269 PubMed:15052268, ECO:0000269 PubMed:18853461, ECO:0000269 PubMed:20190753, ECO:0000269 PubMed:22753090, ECO:0000269 PubMed:23918659}. Note=The disease is caused by mutations affecting the gene represented in this entry.

Additional Disease Information for VPS33B

Genetic Association Database
(GAD)
Human Genome Epidemiology Navigator
(HuGE)
ATLAS of Genetics and Cytogenetics in Oncology and Haematology
genes like me logo Genes that share disorders with VPS33B: view

No data available for Genatlas for VPS33B Gene

Publications for VPS33B Gene

  1. Mycobacterium tuberculosis virulence is mediated by PtpA dephosphorylation of human vacuolar protein sorting 33B. (PMID: 18474358) Bach H … Av-Gay Y (Cell host & microbe 2008) 3 4 22 58
  2. Vps33B is required for delivery of endocytosed cargo to lysosomes. (PMID: 26403612) Galmes R … Klumperman J (Traffic (Copenhagen, Denmark) 2015) 2 3 58
  3. Structural basis of Vps33A recruitment to the human HOPS complex by Vps16. (PMID: 23901104) Graham SC … Owen DJ (Proceedings of the National Academy of Sciences of the United States of America 2013) 3 4 58
  4. Vps33b pathogenic mutations preferentially affect VIPAS39/SPE-39-positive endosomes. (PMID: 23918659) Tornieri K … Faundez V (Human molecular genetics 2013) 3 4 58
  5. Associations among genotype, clinical phenotype, and intracellular localization of trafficking proteins in ARC syndrome. (PMID: 22753090) Smith H … Gissen P (Human mutation 2012) 3 4 58

Products for VPS33B Gene

Sources for VPS33B Gene

Content
Loading form....