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56 Cards in this Set
- Front
- Back
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Name the molecular etiology of epidermolysis bullosa simplex
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blistering skin disease:
-herediatry diease, blistering of skin in response to mechanical stress -defect in basal cell keratins (type I/II intermediate filaments) |
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Laminopathies
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-group of heterogeneous genetic disorders that have been associated with mutations in genes for lamins A, B1, B2, and C
-show sthat lamins play key roles in maintaining nuclear structure, regulating transcription, controlling cell differentiation, and organizing chromatin (over 180 mutations found in LMNA gene) -laminopathies include premature aging, myopathies, neuropathies, lipodystrophies |
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: Hutchinson-Gilford Progeria Syndrome
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-extremely rare (1 in 4-8 million live births), uniformly fatal disease
-domininat mutation in LMNA which arises in paternal germ line, activating cryptic splice site (resulting in mRNA that’s missing 150 NTs) -tranlsated protein is PROGERIN, containing 50 aa internal deletion -progerin acts in dominant negative way becoming irreversibly anchored in nuclear membrane and disrupting normal lamina function -nuclei bleb at their margins, disrupted heterochromatin strucutre occurs, clustering of nuclear pores, and perturbation of downstream signaling and transcriptional events |
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Charcot-Marie-Tooth disease
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most common inherited peripheral neuropathy in humans
-weakness and atrophy of distal muscles, depressed or absent deep tendon reflexes, mild sensory loss; mutation in kinesin ATP binding pocket |
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Arp 2/3 complex
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; when activated, nucledates actin poolymeriztion by binding to F-actin and nucleating new filament at a 70° angle
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AXONEME
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Fundamental structure of cilia and flagella, which is a parallel arrangement of microtubules (9 doublets + 2 singles in the middle
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characteristics of phospholipids
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-wide range of functions in cells in addition to fundamental role in membrane structure
-major structural feature of serum lipoproteins (small vesicles) -important component of Bile -critical component of pulmonary surfactant -functions in signal transduction -serve as precursor in synthesis of other bioactive lipids -BACKBONE: GLYCEROL-3-PHOSPHATE -Fatty acid at Carbon 1 usually SATURATED and at C2 usually UNSATURATED |
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Phosphatidylethanolamine
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Pholpholipid with CH2-CH2-NH3+ on phosphate group
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Phosphatidylserine
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Phospholipid with serine on phosphate group
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Phosphatidylcholine
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lecithin has CH2-CH2-N+-(CH3)3 on phosphate group—lecithin important: older nomenclature that will appear when talking about serum deficiencies
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Phosphatidylinositol
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6-carbon sugar on phosphate group whose hydroxyl groups could be phosphorylated for differentiation
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Phosphatidylglycerol
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plays an important role in pulmonary surfactant
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Inner membrane of mitochondria houses a great deal of this lipid
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cardiolipin
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PLASMALOGENS
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: have choline head group and ether-linked alkene at C1
-heart pohspholipids are enriched in choline plasmalogens -relatively large amounts of ehanolamine plasmalogens in myelin -alkene is normally an ester in other phospholipids but here, as an ehter-linked alkene, this bond is stable under acidic/basic conditions |
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PLATELET ACTIVATING FACTOR (PAF):
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Has straight ether linkage at C1 and just acetate at C2
-major mediator of hypersensitivity, acute inflammatory reactions, anaphylactic shock -involved in platelet aggregation -acts at very low concentrations (10-10M) |
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phospholipase A1 and A2
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Lead to lysphospholipid + fatty acid
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phospholipase C
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leads to diglyceride +XP (important in cell signaling)
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phospholipase D
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leads to phosphatidic acid + X
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Sphingolipids
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-looks simlar to glycerol, but N attached to C2
-Sphingosine Ceramide (the precursor of all sphingolipids) Three types: sphingomyelin; glycoshpingolipids, gangliosides |
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Sphingomyelin
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phosphocholine head group (only sphingo lipid whose polar head is associated with P)
-palmitate residue on C2 (the one attached to N) |
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Glycosphingolipids
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(Glycolipids)
-include Cerebrosides: glucocerebroside and galactocerebrosice; galactocerebrosides most prevalent in neuronal cell membranes of brain -difference in sugar attached to C3 -found on surface of all plasma membranes of animal cells -important in interaction with surroundings (cell-cell adhesions/recognitions) -on erythrocyte plasma membrane surface define A, B and H antigens in ABO blood groups |
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Gangliosides
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-very complex
-chains of sugars on C3, but Sialic acid inclusion is the distinguishing characteristic -ganglioside GM1 is receptor for cholera toxin in the plasma membrane of intestinal epithelial cells |
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Cholesterol
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-major component of plasma membranes (1:1 ratio in relation to phospholipids)
-adds rigidity to plasma membrane and hinders lateral movement |
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2 most abundant fatty acids
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: palmatic acid (16) and stearic acid (18)
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lipid rafts
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enriched in cholesterol, shingomelyin, glycoshingolipids
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Name 4 lipid anchors that can attach integral proteins to the membrane
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isoprenyl, fatty acyl, cholesterol, glycosylphosphatidylinositol
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Glycophorin
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major glycoprotein of human erythrocyte membrane. 131 aa residues. All carbohydrate is outside the cell. N Terminus is extracellular; C is cytosolic
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INTEGRAL MEMBRANE PROTEINS of red blood cell
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-glycophorin-dimeric, part of junctional complex
-band 3 – a Cl-; HCO3- exchange protein |
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PERIPHERAL MEMBRANE PROTEINS or red blood cell
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-band 4.1- part of junctional complex
-band 4.2 – associates with band 3 -spectrin – alpha and beta chains associate to form tetramers that bridge b/t junctional complexes -actin – part of junctional complex -ankyrin-bridges b/t band 3 and spectrins |
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HEREDITARY SPHEROCYTOSIS
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-caused by mutations in spectrin alpha chain, spectrin beta cahin, ankyrin, band 4.2
-rounded shape of red cells makes it difficult for them to pass through spleed w/o rupturing -results in hemolytic anemia, jaundice, gall stones, possible premature death, Treatment: splenectomy |
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HEREDITARY ELLIPTOCYTOSIS
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results from mutations in spectin alpha chain, spectrin, beta chain, band 4.1
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Cytochrome C uses what metal to funnel electrons through the cascade.
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copper
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Organelle versus compartment
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organelle: membrane-enclosed body that contains a specific set of proteins and enzymes that carries out a specific set of metabolic tasks; compartment is a destination for protein targeting
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Characteristics of Nuclear localization signal
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nuceloplasmic proteins (histones/TFs) enter via nuclear pores
-molecules up to 9nm in diameter diffuse through pore passively, but diffusion only easy for molecules smaller than 30-30 kDa range NLS typically consist of runs or concentrations of basic residues which can be located anywhere in protein (K,R) -transport mediated by nuclear import/export receptors (importins/exportins), adaptor proteins and Ran (small, abundant GTPase |
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PEROXISOME TRANSPORT
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most proteins imported into peroxisome have C-terminal Ser-Lys-Leu (SKL)
-import requires >20 proteins (PEROXINS) and ATP hydrolysis; at least 6 different proteins form translocator -SKL bound by cytosolic receptor (Pex5) which shuttle speroxisomal proteins into peroxisomal lumen, and is transported back out |
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Zellweger syndrome
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-caused by defects in peroxisomal import
-results in peroxisomal ghosts (membranes containing few peroxisomal proteins with peroxisomal proteins in cytosol -patients with defects in membrane protein Pex2 have severe abnormalities in multiple organ systems (brain, kidney, liver) and die soon after birth -patients with defects in Pex5 have less severe disease |
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nuclear pore complex
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complexes large (125 mil Da in higher euk’s) and complex (over 30 diff porins)
-can transport up to 500 macromolecules/sec bidirectionally -4000-4000 nuclear pore complexes/cell -at the pore, inner and outer nuclear membranes continuous; pore anchored to integral membrane proteins that forma lumenal ring -disordered domains of core proteins extend toward center of pore to block diffusion of large macromolecules |
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the general features of peroxisome structure and function
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Organelle surrouned by single membrane bilayer. Major sites of oxygen utilization; contains oxidative enzymes. Contains enzymes that produce and degrade (due to catalase activity) hydrogen peroxide. Peroxisomes sequester possibly damaging reactions (ie beta-oxidation of fatty acids). Enzymes in peroxisomes present at high concentrations often in paracrystalline aggregates
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FIBRIL FORMING COLLAGEN
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-intersticial (I, II, III, V, XI)
-I-bone, tendon, dermis, cornea, dentin -II-cartilage, vitreous humor -III-reticular fibers of most tissues (lung, liver, dermis, vessel walls) -V-dermis and interstitial tissues |
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FACIT
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-fibril associateed collagens with interrupted triple helices (IX, XII, XIV)
-link fibrils to one another and other ECM macromolecules (connectging collagens) -globular N-terminus of collagen IX binds proteoglycans in ECM |
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-FORMING (SHEET FORMING)
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-collagen in basal lamina and basement membrane
-flexible strucute-interrupted triple helix -flexible sheet-like multilayered network -Associations: head to head (C to C); triple helical domains associate laterally to form sheet-like mesh work; covalent interactions-N-terminal tails to form stacked network of sheets -Clinical Application: Alport Syndrome: blood and protein in urine, kidney failure, +/- hearing loss |
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ANCHORING FILAMENTS (VII)
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-VII- binds collagen fibers to basal lamina (attaches basal lamina to underlying connective tissue)
-found in basement membranes -loss of Type VII collagen results in dystrophic epidermolysis bullosa (DEB) -Location: soft tissues, dermal-epidermal junction -Clinical Application: Epidermolysis bullosa simplex (blistering skin disease); skin blisteres in response to mechanical stress; defect in basal cell keratins (type I/II intermediate filaments) |
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COLLAGEN SYNTHESIS
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1) Pro-alpha chain synthesis (transcription)
2) hydroxylation-prolines and lysines (prolyl hydroxylation) LYSYL HYDROXYLASE (REQUIRES VIT C) 3) glycosylation-hydroxylysines 4)self-assembly-pro-α chains 5) procollagen triple helix formation 6) secretion 7) cleavage of propeptides (removal of propeptides) PROCOLLAGEN N/C-PROTEINASE 8) self-assembly into fibril 9) aggregation of collagen fibrils to form a collagen fiber LYSYL OXIDASE (REQUIRING CU) |
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Explain the difference between procollagen, tropocollagen, collagen fibrils and collagen fibers
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-Procollagen: triple-triple helix molecule with soluble globular residues attached
-Tropocollagen: triple-triple helix formed with soluble globular residues cleaved -Fibril: self-assebled fibril 10-30nm in diameter (smaller parts are tropocollagen) -Fibers: aggregation of fibrils .5-0.3μm in diameter |
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Ehlers-Danlos syndromes
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Classic Type (types I & II)- AD-Type V and rare type I collagen alterations
Vascular Type (type IV)-AD-Type III collagen alterations Dermatosparaxis Type (type VII C)-AR-Amino proteinase deficiency Kyphoscoliosis Tyhpe (type VI)-AR-Lysyl hydroxylase deficiency |
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Chondrodysplasias (Stickler syndrome)
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deficiency in Type II collagen
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Discuss the unique characteristics of collagen that are used diagnostically to detect collagen breakdown
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-Hydroxyproline: not best diagnostic test due to its regular metabolism
-Hydroxylysine glycosides: more concentrated in bone -Pyridinium cross links, telopeptides: highly specific for bone—cross links result in CTX, marker of breakdown of collagen bc CTX only found in mature collagen |
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FIBRONECTIN
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-found in most extracellular matrices as fibronectin fibrils and in plasma as soluble protein
-adhesion, migraion -dimer: 22 non-identical subunits covalently linked by disulfide bonds -single gene: 2 products (alternative splicing) (1) plasma FN-soluble; blood clotting, wound healing, phagocytosis (2) FN filaments, insoluble, cell surface assembly, deposited in ECM |
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LAMININS
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-family of large glycoproteins
-expressed early in development and a major component of basal lamina -large (85 kd), flexible, 3 polypeptide chains (alpha, beta, gamma) -asymmetric cross shape, disulfide bondeed -functional domains: binding to type IV collagen, binding to heparan sulfate, binding to entactin (nidogen), binding laminin receptor proteins (integrins) -promotes cell attachment, neurite outgrowth |
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Describe the features and relationships of glycoproteins in the basal lamina
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-basal lamina attached to underlying connective tissue in part by Type VII anchoring collagen
-basement membrane includes basal lamina and unerlying collagens -basement membrane includes basal lamina and underlying collagens |
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the major components of basal lamina and basement membrane
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perlecan, nidogen, type IV collagen laminin (integrin as well)
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the unique properties of hyaluronan
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-simple, long, thousands of nonsulfated sugars (glucoronic acid, N-acetylglucosamine)
-variable amounts in all tissues and fluids -important for cell migration -MW 4,000-8mil -larger, simpler than other GAGs also different site of production; not covalently linked to protein |
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family of enzymes that add sugar to proteins to synthesize proteoglycans
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glycosyl transferases
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AGGRECAN
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-large chondroitin sulfate PG
-majore macramolecule of cartilage -3 globular domains (G1, 2, 3) -Interglobular domain (IGD) -2 GAG attaching domains (KS, CS) -extensive hydration of CS chains—gel-like -molecules assemble into aggregates with hyaluronan as a core of the aggregate |
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Discuss the role of ECM in wound healing
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24 hr: fibrin clot
1-3 days: FN, base ment membrane components 3-5 days: collagen fibers >14 days: increased collagen |
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MATRIX METALLOPROTEINASES (MMPs)
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-Extracellular endopeptidases that selectively degrade components of the ECM (~24 members)
-proteinases -contain a zinc ion, inhibited by chelating agents -share common amino acid sequences -inhibited by tetracyclines -thought to play a role in cancer progression as ECM-degrading enzymes needed to break down structural barriers to metastasis -Regulation of MMPs -transcriptionally (growth factors, cytokines, corticosteroids) -secreted in latent form, must be activated (proenzymes/zymogen—activated by plasmin, serine proteases or activated MMPs) -inhibited by TIMPs (tissue inhibitors of MMPs -as ECM breakdown needed for tumor invasion and metastasis, TIMPs have been considered as therapeutic targets in cancer therapy |
