User:Oxyjenn/sandbox

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Luciferase-like monooxygenase
Structure of the non-fluorescent flavoprotein from Photobacterium leiognathi.[1]
Identifiers
SymbolBac_luciferase
PfamPF00296
InterProIPR016048
PROSITEPDOC00397
SCOP21nfp / SCOPe / SUPFAM
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
PDB1brl​, 1bsl​, 1ezw​, 1fvp​, 1luc​, 1m41​, 1nfp​, 1nqk​, 1rhc​, 1xkj​
Firefly luciferase
Structure of Photinus pyralis firefly luciferase.
Identifiers
OrganismPhotinus pyralis
SymbolFirefly luciferase
PDB1LCI More structures
UniProtP08659
Other data
EC number1.13.12.7
Search for
StructuresSwiss-model
DomainsInterPro
Luciferase catalytic domain
crystal structure of a luciferase domain from the dinoflagellate lingulodinium polyedrum
Identifiers
SymbolLuciferase_cat
PfamPF10285
InterProIPR018804
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
Luciferase/LBP N-terminal domain
Identifiers
SymbolLuciferase_N
PfamPF05295
InterProIPR007959
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
Luciferase helical bundle domain
crystal structure of a luciferase domain from the dinoflagellate lingulodinium polyedrum
Identifiers
SymbolLuciferase_3H
PfamPF10284
InterProIPR018475
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

Luciferase is a generic term for the class of oxidative enzymes used in bioluminescence and is distinct from a photoprotein. One famous example is the firefly luciferase (EC 1.13.12.7) from the firefly Photinus pyralis.[2] "Firefly luciferase" as a laboratory reagent usually refers to P. pyralis luciferase although recombinant luciferases from several other species of fireflies are also commercially available. The name is derived from Lucifer, the root of which means 'light-bearer' (lucem ferre).

Chemical reaction[edit]

The chemical reaction catalyzed by firefly luciferase takes place in two steps:

  • luciferyl adenylate + O2 → oxyluciferin + AMP + light

Light is emitted because the reaction forms a product, oxyluciferin, in an electronically excited state. The reaction releases a photon of light as oxyluciferin returns to the ground state.

Luciferyl adenylate can additionally participate in a side reaction with O2 to form hydrogen peroxide and dehydroluciferyl-AMP. About 20% of the luciferyl adenylate intermediate is oxidized in this pathway. [3]

The reaction catalyzed by bacterial luciferase is also an oxidative process:

  • FMNH2 + O2 + RCHO → FMN + RCOOH + H2O + light

In the reaction, a reduced flavin mononucleotide oxidizes a long-chain aliphatic aldehyde to an aliphatic carboxylic acid. The reaction forms an excited hydroxyflavin intermediate, which is dehydrated to the product FMN to emit blue-green light. [4]

Nearly all of the energy input into the reaction is transformed into light. The reaction is 80%[5] to 90%[6] efficient. As a comparison, the incandescent light bulb only converts about 10% of its energy into light.[7] and a 150 lumen per Watt (lm/W) LED converts 20% of input energy to visible light.[6]

Mechanism[edit]

Firefly luciferase generates light from luciferin in a multistep process. First, D-luciferin is adenylated by MgATP to form luciferyl adenylate and pyrophosphate. After activation by ATP, luciferyl adenylate is oxidized by molecular oxygen to form a dioxetanone ring. A decarboxylation reaction forms an excited state of oxyluciferin, which tautomerizes between the keto-enol form. The reaction finally emits light as oxyluciferin returns to the ground state. [8]

Luciferase Structure[edit]

The protein structure of firefly luciferase consists of two compact domains: the N-terminal domain and the C-terminal domain. The N-terminal domain is composed of two β-sheets in an αβαβα structure and a β barrel. The two β-sheets stack on top of each other, with the β-barrel covering the end of the sheets. [8]

The C-terminal domain is connected to the N-terminal domain by a flexible hinge, which can separate the two domains. The amino-acid sequence on the surface of the two domains facing each other are conserved between bacterial and firefly luciferase, thereby strongly suggesting that the active site is located in the cleft between the domains. [9]

During a reaction, luciferase has a conformational change and goes into a “closed” form with the two domains coming together to enclose the substrate. This ensures that water is excluded from the reaction and does not hydrolyze ATP or the electronically excited product.[9]

Spectral Differences in Bioluminescence[edit]

Luciferase bioluminescence color can vary between yellow-green (λmax = 550 nm) to red (λmax = 620). [10] There are currently several different mechanisms describing how the structure of luciferase affects the emission spectrum of the photon and effectively the color of light emitted.

One mechanism proposes that the color of the emitted light depends on whether the product is in the keto or enol form. The mechanism suggests that red light is emitted from the keto form of oxyluciferin, while green light is emitted from the enol form of oxyluciferin. [11] [12] However, 5,5-dimethyloxyluciferin emits green light even though it is constricted to the keto form because it cannot tautomerize. [13]

Another mechanism proposes that twisting the angle between benzothiazole and thiazole rings in oxyluciferin determines the color of bioluminescence. This explanation proposes that a planar keto form with an angle of 0° between the two rings corresponds to a higher energy state and emits a higher-energy green light, whereas an angle of 90° puts the structure in a lower energy state and emits a lower-energy red light. [14]

The most recent explanation for the bioluminescence color examines the microenvironment of the excited oxyluciferin. Studies suggest that the interactions between the excited state product and nearby residues can force the oxyluciferin into an even higher energy form, which results in the emission of green light. For example, Arg 218 and His 245 can affect the microenvironment to emit green light. [15] Similarly, other results have indicated that the microenvironment of luciferase can force oxyluciferin into a more rigid, high-energy structure, forcing it to emit a high-energy green light. [16]

Bifunctionality of Luciferase[edit]

Luciferase can function in two different pathways: a bioluminescence pathway and a CoA-ligase pathway. [17] In both pathways, luciferase initially catalyzes an adenylation reaction with MgATP. However, in the CoA-ligase pathway, CoA can displace AMP to form luciferyl CoA.

Fatty acyl-CoA synthetase similarly activates fatty acids with ATP, followed by substitution of AMP with CoA. Because of their similar activities, luciferase is able to replace fatty acyl-CoA synthetase and convert long-chain fatty acids into fatty-acyl CoA for beta oxidation. [17]

Luciferase has two modes of enzyme activity: bioluminescence activity and CoA synthetase activity [18]

Regulation[edit]

D-luciferin is the substrate for luciferase’s bioluminescence reaction, while L-luciferin is the substrate for luciferyl-CoA synthetase activity. Both reactions are inhibited by the substrate’s enantiomer: L-luciferin and D-luciferin inhibit the bioluminescence pathway and the CoA-ligase pathway, respectively.[18] This shows that luciferase can differentiate between the isomers of the luciferin structure.

L-luciferin is able to emit a weak light even though it is a competitive inhibitor of D-luciferin and the bioluminescence pathway.[19] Light is emitted because the CoA synthesis pathway can be converted to the bioluminescence reaction by hydrolyzing the final product via an esterase back to D-luciferin. [20]

Luciferase activity is additionally inhibited by oxyluciferin [21] and allosterically activated by ATP. When ATP binds to the enzyme’s two allosteric sites, luciferase’s affinity to bind ATP in its active site increases. [10]

Examples[edit]

A variety of organisms regulate their light production using different luciferases in a variety of light-emitting reactions. The most famous are the fireflies,[8] although the enzyme exists in organisms as different as the Jack-O-Lantern mushroom (Omphalotus olearius) and many marine creatures. In fireflies, the oxygen required is supplied through a tube in the abdomen called the abdominal trachea. The luciferases of fireflies - of which there are over 2000 species - and of the Elateroidea (fireflies, click beetles and relatives) in general - are diverse enough to be useful in molecular phylogeny. The most thoroughly studied luciferase is that of the Photinini firefly Photinus pyralis, which has an optimum pH of 7.8.[22]

Also well studied is the luciferase from Renilla reniformis. In this organism, the luciferase (Renilla-luciferin 2-monooxygenase)is closely associated with a luciferin-binding protein as well as a green fluorescent protein (GFP). Calcium triggers release of the luciferin (coelenterazine) from the luciferin binding protein. The substrate is then available for oxidation by the luciferase, where it is degraded to coelenteramide with a resultant release of energy. In the absence of GFP, this energy would be released as a photon of blue light (peak emission wavelength 482 nm). However, due to the closely associated GFP, the energy released by the luciferase is instead coupled through resonance energy transfer to the fluorophore of the GFP, and is subsequently released as a photon of green light (peak emission wavelength 510 nm). The catalyzed reaction is:[23]

Newer luciferases have recently been identified that, unlike Renilla or Firefly luciferase, are naturally secreted molecules. One such example is the Metridia luciferase (MetLuc)that is derived from the marine copepod Metridia longa. The Metridia longa secreted luciferase gene encodes a 24 kDa protein containing an N-terminal secretory signal peptide of 17 amino acid residues. The sensitivity and high signal intensity of this luciferase molecule proves advantageous in many reporter studies. Some of the benefits of using a secreted reporter molecule like MetLuc is its no-lysis protocol that allows one to be able to conduct live cell assays and multiple assays on the same cell.[24]

Applications[edit]

Luciferase can be produced in the lab through genetic engineering for a number of purposes. Luciferase genes can be synthesized and inserted into organisms or transfected into cells. Mice, silkworms, and potatoes are just a few organisms that have already been engineered to produce the protein.[25]

In the luciferase reaction, light is emitted when luciferase acts on the appropriate luciferin substrate. Photon emission can be detected by light sensitive apparatus such as a luminometer or modified optical microscopes. This allows observation of biological processes.[26]

In biological research, luciferase commonly is used as a reporter to assess the transcriptional activity in cells that are transfected with a genetic construct containing the luciferase gene under the control of a promoter of interest.[27] Additionally proluminescent molecules that are converted to luciferin upon activity of a particular enzyme can be used to detect enzyme activity in coupled or two-step luciferase assays. Such substrates have been used to detect caspase activity and cytochrome P450 activity, among others.[26][27]

Luciferase can also be used to detect the level of cellular ATP in cell viability assays or for kinase activity assays.[27][28] Luciferase can act as an ATP sensor protein through biotinylation. Biotinylation will immobilize luciferase on the cell-surface by binding to a streptavidin-biotin complex. This allows luciferase to detect the efflux of ATP from the cell and will effectively display the real-time detection of ATP release through bioluminescence. [29] Luciferase can additionally be made more sensitive for ATP detection by increasing the luminescence intensity through genetic modification.[30]

Whole animal imaging (referred to as in vivo or, occasionally, ex vivo imaging) is a powerful technique for studying cell populations in live animals, such as mice.[31] Different types of cells (e.g. bone marrow stem cells, T-cells) can be engineered to express a luciferase allowing their non-invasive visualization inside a live animal using a sensitive charge-couple device camera (CCD camera).This technique has been used to follow tumorigenesis and response of tumors to treatment in animal models.[32][33] However, environmental factors and therapeutic interferences may cause some discrepancies between tumor burden and bioluminescence intensity in relation to changes in proliferative activity. The intensity of the signal measured by in vivo imaging may depend on various factors, such as D-luciferin absorption through the peritoneum, blood flow, cell membrane permeability, availability of co-factors, intracellular pH and transparency of overlying tissue, in addition to the amount of luciferase.[34]

Luciferase can be used in blood banks to determine if red blood cells are starting to break down. Forensic investigators can use a dilute solution containing the enzyme to uncover traces of blood remaining on surfaces at a crime scene. Luciferase is a heat sensitive protein that is used in studies on protein denaturation, testing the protective capacities of heat shock proteins. The opportunities for using luciferase continue to expand.[35]

Dinoflagellate luciferase[edit]

Dinoflagellate luciferase is a multi-domain protein, consisting of an N-terminal domain, and three catalytic domains, each of which preceeded by a helical bundle domain. The structure of the dinoflagellate luciferase catalytic domain has been solved.[36] The core part of the domain is a 10 stranded beta barrel that is structurally similar to lipocalins and FABP.[36] The N-terminal domain is conserved between dinoflagellate luciferase and luciferin binding proteins (LBPs). It has been suggested that this region may mediate an interaction between LBP and luciferase or their association with the vacuolar membrane.[37] The helical bundle domain has a three helix bundle structure that holds four important histidines that are thought to play a role in the pH regulation of the enzyme.[36]

See also[edit]


References[edit]

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  2. ^ Gould SJ, Subramani S (November 1988). "Firefly luciferase as a tool in molecular and cell biology". Anal. Biochem. 175 (1): 5–13. doi:10.1016/0003-2697(88)90353-3. PMID 3072883.{{cite journal}}: CS1 maint: date and year (link)
  3. ^ Fraga H, Fernandes D, Novotny J, Fontes R, Esteves da Silva JC (June 2006). "Firefly luciferase produces hydrogen peroxide as a coproduct in dehydroluciferyl adenylate formation". ChemBioChem. 7 (6): 929–35. doi:10.1002/cbic.200500443. PMID 16642538.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  4. ^ Fisher AJ, Thompson TB, Thoden JB, Baldwin TO, Rayment I (September 1996). "The 1.5-A resolution crystal structure of bacterial luciferase in low salt conditions". J. Biol. Chem. 271 (36): 21956–68. doi:10.1074/jbc.271.36.21956. PMID 8703001.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  5. ^ Elizabeth Wilson (Jan 18, 1999). "What's That Stuff?". Chemical and Engineering News. 77 (3): 65. doi:10.1021/cen-v077n003.p065.
  6. ^ a b Vanessa Knivett (2009). "Lighting the way". EE Times.
  7. ^ General Electric TP-110, page 23, table.
  8. ^ a b c Baldwin TO (March 1996). "Firefly luciferase: the structure is known, but the mystery remains". Structure. 4 (3): 223–8. doi:10.1016/S0969-2126(96)00026-3. PMID 8805542.{{cite journal}}: CS1 maint: date and year (link)
  9. ^ a b Conti E, Franks NP, Brick P (March 1996). "Crystal structure of firefly luciferase throws light on a superfamily of adenylate-forming enzymes". Structure. 4 (3): 287–98. doi:10.1016/s0969-2126(96)00033-0. PMID 8805533.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  10. ^ a b Ugarova NN (July 1989). "Luciferase of Luciola mingrelica fireflies. Kinetics and regulation mechanism". J. Biolumin. Chemilumin. 4 (1): 406–18. doi:10.1002/bio.1170040155. PMID 2801227.{{cite journal}}: CS1 maint: date and year (link)
  11. ^ White EH, Rapaport E, Hopkins TA, Seliger HH (April 1969). "Chemi- and bioluminescence of firefly luciferin". J. Am. Chem. Soc. 91 (8): 2178–80. doi:10.1021/ja01036a093. PMID 5784183.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  12. ^ Fraga H (February 2008). "Firefly luminescence: a historical perspective and recent developments". Photochem. Photobiol. Sci. 7 (2): 146–58. doi:10.1039/b719181b. PMID 18264582.{{cite journal}}: CS1 maint: date and year (link)
  13. ^ Branchini BR, Southworth TL, Murtiashaw MH; et al. (June 2004). "An alternative mechanism of bioluminescence color determination in firefly luciferase". Biochemistry. 43 (23): 7255–62. doi:10.1021/bi036175d. PMID 15182171. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  14. ^ McCapra F,Gilfoyle DJ, Young DW; et al. (of publication: 1994). Bioluminescence and Chemiluminescence: Fundamentals and Applied. {{cite book}}: Check date values in: |date= (help); Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  15. ^ Nakatani N, Hasegawa JY, Nakatsuji H (July 2007). "Red light in chemiluminescence and yellow-green light in bioluminescence: color-tuning mechanism of firefly, Photinus pyralis, studied by the symmetry-adapted cluster-configuration interaction method". J. Am. Chem. Soc. 129 (28): 8756–65. doi:10.1021/ja0611691. PMID 17585760.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  16. ^ Nakamura M, Niwa K, Maki S; et al. (December 2006). "Construction of a new firefly bioluminescence system using L-luciferin as substrate". Anal. Biochem. 47 (1): 1197–1200. doi:10.1016/j.tetlet.2005.12.033. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  17. ^ a b Oba Y, Ojika M, Inouye S (April 2003). "Firefly luciferase is a bifunctional enzyme: ATP-dependent monooxygenase and a long chain fatty acyl-CoA synthetase". FEBS Lett. 540 (1–3): 251–4. doi:10.1016/s0014-5793(03)00272-2. PMID 12681517.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  18. ^ a b Nakamura M, Maki S, Amano Y; et al. (June 2005). "Firefly luciferase exhibits bimodal action depending on the luciferin chirality". Biochem. Biophys. Res. Commun. 331 (2): 471–5. doi:10.1016/j.bbrc.2005.03.202. PMID 15850783. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  19. ^ Lembert N (July 1996). "Firefly luciferase can use L-luciferin to produce light". Biochem. J. 317 ( Pt 1) (Pt 1): 273–7. doi:10.1042/bj3170273. PMC 1217473. PMID 8694774.{{cite journal}}: CS1 maint: date and year (link)
  20. ^ Nakamura M, Maki S, Amano Y; et al. (June 2005). "Firefly luciferase exhibits bimodal action depending on the luciferin chirality". Biochem. Biophys. Res. Commun. 331 (2): 471–5. doi:10.1016/j.bbrc.2005.03.202. PMID 15850783. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  21. ^ Ribeiro C, Esteves da Silva JC (September 2008). "Kinetics of inhibition of firefly luciferase by oxyluciferin and dehydroluciferyl-adenylate". Photochem. Photobiol. Sci. 7 (9): 1085–90. doi:10.1039/b809935a. PMID 18754056.{{cite journal}}: CS1 maint: date and year (link)
  22. ^ Steghens JP, Min KL, Bernengo JC (November 1998). "Firefly luciferase has two nucleotide binding sites: effect of nucleoside monophosphate and CoA on the light-emission spectra". Biochem. J. 336 (1): 109–13. doi:10.1042/bj3360109. PMC 1219848. PMID 9806891.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  23. ^ Shimomura O (1985). "Bioluminescence in the sea: photoprotein systems". Symp. Soc. Exp. Biol. 39: 351–72. PMID 2871634.
  24. ^ Baldwin TO; Lee, Jongsung; Jung, Eunsun; Kim, Sang-Cheol; Kang, Jung-Il; Lee, Jienny; Kim, Yong-Woo; Sung, Young Kwan; Kang, Hee-Kyoung (June 2009). "A cell-based system for screening hair growth-promoting agents". Archives of Dermatological Research. 301 (3): 381–385. doi:10.1007/s00403-009-0931-0. PMID 19277688.{{cite journal}}: CS1 maint: date and year (link)
  25. ^ Contag CH, Bachmann MH (2002). "Advances in in vivo bioluminescence imaging of gene expression". Annu Rev Biomed Eng. 4: 235–60. doi:10.1146/annurev.bioeng.4.111901.093336. PMID 12117758.
  26. ^ a b "Introduction to Bioluminescence Assays". Promega Corporation. Retrieved 2009-03-07.
  27. ^ a b c Fan F, Wood KV (February 2007). "Bioluminescent assays for high-throughput screening". Assay Drug Dev Technol. 5 (1): 127–36. doi:10.1089/adt.2006.053. PMID 17355205.{{cite journal}}: CS1 maint: date and year (link)
  28. ^ Meisenheimer PL, O’Brien MA, Cali JJ (September 2008). "Luminogenic enzyme substrates: The basis for a new paradigm in assay design" (PDF). Promega Notes. 100: 22–26.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  29. ^ Nakamura M, Mie M, Funabashi H, Yamamoto K, Ando J, Kobatake E (May 2006). "Cell-surface-localized ATP detection with immobilized firefly luciferase". Anal. Biochem. 352 (1): 61–7. doi:10.1016/j.ab.2006.02.019. PMID 16564487.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  30. ^ Fujii H, Noda K, Asami Y, Kuroda A, Sakata M, Tokida A (July 2007). "Increase in bioluminescence intensity of firefly luciferase using genetic modification". Anal. Biochem. 366 (2): 131–6. doi:10.1016/j.ab.2007.04.018. PMID 17540326.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  31. ^ Greer LF, Szalay AA (2002). "Imaging of light emission from the expression of luciferases in living cells and organisms: a review". Luminescence. 17 (1): 43–74. doi:10.1002/bio.676. PMID 11816060.
  32. ^ Lyons SK, Meuwissen R, Krimpenfort P, Berns A (November 2003). "The generation of a conditional reporter that enables bioluminescence imaging of Cre/loxP-dependent tumorigenesis in mice". Cancer Res. 63 (21): 7042–6. PMID 14612492.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  33. ^ Becher OJ, Holland EC (April 2006). "Genetically engineered models have advantages over xenografts for preclinical studies". Cancer Res. 66 (7): 3355–8, discussion 3358–9. doi:10.1158/0008-5472.CAN-05-3827. PMID 16585152.{{cite journal}}: CS1 maint: date and year (link)
  34. ^ Inoue Y., Tojo A., Sekine R., Soda Y., Kobayashi S., Nomura A., Izawa K., Kitamura T., Okubo T.; et al. (2006). "In vitro validation of bioluminescent monitoring of disease progression and therapeutic response in leukaemia model animals". European Journal of Nuclear Medicine & Molecular Imaging. 33 (5): 557–565. doi:10.1007/s00259-005-0048-4. PMID 16501974. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  35. ^ Massoud TF, Paulmurugan R, De A, Ray P, Gambhir SS (February 2007). "Reporter gene imaging of protein-protein interactions in living subjects". Curr. Opin. Biotechnol. 18 (1): 31–7. doi:10.1016/j.copbio.2007.01.007. PMC 4141564. PMID 17254764.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  36. ^ a b c Schultz LW, Liu L, Cegielski M, Hastings JW (February 2005). "Crystal structure of a pH-regulated luciferase catalyzing the bioluminescent oxidation of an open tetrapyrrole". Proc. Natl. Acad. Sci. U.S.A. 102 (5): 1378–83. doi:10.1073/pnas.0409335102. PMC 547824. PMID 15665092.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  37. ^ Okamoto OK, Liu L, Robertson DL, Hastings JW (December 2001). "Members of a dinoflagellate luciferase gene family differ in synonymous substitution rates". Biochemistry. 40 (51): 15862–8. doi:10.1021/bi011651q. PMID 11747464.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)

External links[edit]


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