Cone snails, or cones, are highly venomous sea snails of the family Conidae.[1]

A group of shells belonging to various species of cone snails

Fossils of cone snails have been found from the Eocene to the Holocene epochs.[2] Cone snail species have shells that are roughly conical in shape. Many species have colorful patterning on the shell surface.[3] Cone snails are almost exclusively tropical in distribution.

All cone snails are venomous and capable of stinging. Cone snails use a modified radula tooth and a venom gland to attack and paralyze their prey before engulfing it. The tooth, which is likened to a dart or a harpoon, is barbed and can be extended some distance out from the head of the snail at the end of the proboscis.

Cone snail venoms are mainly peptide-based, and contain many different toxins that vary in their effects. The sting of several larger species of cone snails can be serious, and even fatal to humans. Cone snail venom also shows promise for medical use.[4][5]

Distribution and habitat

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There are over 900 different species of cone snails.[6] Cone snails are typically found in warm tropical seas and oceans worldwide. Cone snails reach their greatest diversity in the Western Indo-Pacific region. While the majority of cone snails are found in warm tropical waters, some species have adapted to temperate/semi-tropical environments and are endemic to areas such as the Cape coast of South Africa,[7][8] the Mediterranean,[9] or the cool subtropical waters of southern California (Californiconus californicus).[10]

Cone snails are found in all tropical and subtropical seas. They live on a variety of substrates, from the intertidal zone and deeper areas, to sand, rocks or coral reefs.

Shell

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Cone snails have a large variety of shell colors and patterns, with local varieties and color forms of the same species often occurring. This variety in color and pattern has led to the creation of a large number of known synonyms and probable synonyms, making it difficult to give an exact taxonomic assignment for many snails in this genus. As of 2009, more than 3,200 different species names have been assigned, with an average of 16 new species names introduced each year.[11]

The shells of cone snails vary in size and are conical in shape. The shell is whorled in the form of an inverted cone, with the anterior end being narrower. The protruding parts of the top of the whorls, that form the spire, are in the shape of another more flattened cone. The aperture is elongated and narrow with the sharp operculum being very small. The outer lip is simple, thin, and sharp, without a callus, and has a notched tip at the upper part. The columella is straight.

The larger species of cone snails can grow up to 23 cm (9.1 in) in length. The shells of cone snails are often brightly colored with a variety of patterns. Some species color patterns may be partially or completely hidden under an opaque layer of periostracum. In other species, the topmost shell layer is a thin periostracum, a transparent yellowish or brownish membrane.

Physiology and behavior

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Cone snails are carnivorous. Their prey consists of marine worms, small fish, molluscs, and other cone snails. Cone snails are slow-moving, and use a venomous harpoon to disable faster-moving prey.

The osphradium in cone snails is more specialized than in other groups of gastropods. It is through this sensory modality that cone snails are able to sense their prey. The cone snails immobilize their prey using a modified, dartlike, barbed radular tooth, made of chitin, along with a venom gland containing neurotoxins.

Molecular phylogeny research has shown that preying on fish has evolved at least twice independently in cone snails. Some species appear to have also evolved prey mimicry, where they release chemicals that resemble the sex pheromones certain ragworms release during their short breeding season. The researchers hypothesize that these chemicals cause the prey to be more easily harpooned, but are still uncertain as to exactly how this occurs in the wild.[12]

Harpoon

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An individual (Conus pennaceus) attacking one of a cluster of three snails of the species Cymatium nicobaricum, in Hawaii

Cone snails use a harpoon-like structure called a radula tooth for predation. Radula teeth are modified teeth, primarily made of chitin and formed inside the mouth of the snail, in a structure known as the toxoglossan radula. Each specialized cone snail tooth is stored in the radula sac, except for the tooth that is in current use.[13]

The radula tooth is hollow and barbed, and is attached to the tip of the radula in the radular sac, inside the snail's throat. When the snail detects a prey animal nearby, it extends a long flexible tube called a proboscis towards the prey. The radula tooth is loaded with venom from the venom bulb and, still attached to the radula, is fired from the proboscis into the prey by a powerful muscular contraction. The venom can paralyze smaller fish almost instantly. The snail then retracts the radula, drawing the subdued prey into the mouth. After the prey has been digested, the cone snail will regurgitate any indigestible material, such as spines and scales, along with the harpoon. There is always a radular tooth in the radular sac. A tooth may also be used in self-defense when the snail feels threatened.[14][15]

The venom of cone snails contains hundreds of different compounds, and its exact composition varies widely from one species to another. The toxins in cone snail venom are referred to as conotoxins, and are composed of various peptides, each targeting a specific nerve channel or receptor. Some cone snail venoms also contain a pain-reducing toxin.

Relevance to humans

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Dangers

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A live textile cone (Conus textile), one of several species whose venom can cause serious harm to a human

Cone snails are prized for their brightly colored and patterned shells,[16] which may tempt people to pick them up. This is risky, as the snail often fires its harpoon in self defense when disturbed. The harpoons of some of the larger species of cone snail can penetrate gloves or wetsuits.

The sting of many of the smallest cone species may be no worse than a bee or hornet sting,[17] but the sting of a few of the larger tropical fish-eating species, such as Conus geographus, Conus tulipa and Conus striatus, can be fatal. Other dangerous species are Conus pennaceus, Conus textile, Conus aulicus, Conus magus and Conus marmoreus.[18] According to Goldfrank's Toxicologic Emergencies, about 27 human deaths can be confidently attributed to cone snail envenomation, though the actual number is almost certainly much higher; some three dozen people are estimated to have died from geography cone envenomation alone.[19]

Most of the cone snails that hunt worms are not a risk to humans, with the exception of larger species. One of the fish-eating species, the geography cone, Conus geographus, is also known colloquially as the "cigarette snail", a gallows humor exaggeration implying that, when stung by this creature, the victim will have only enough time to smoke a cigarette before dying.[14][20]

Symptoms of a more serious cone snail sting include severe, localized pain, swelling, numbness and tingling, and vomiting. Symptoms can start immediately or can be delayed for days. Severe cases involve muscle paralysis, changes in vision and respiratory failure that can lead to death. If stung, one should seek medical attention as soon as possible.[21]

Medical use

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The appeal of conotoxins for creating pharmaceutical drugs is the precision and speed with which the chemicals act; many of the compounds target only a particular class of receptor. This means that they can reliably and quickly produce a particular effect on the body's systems without side effects; for example, almost instantly reducing heart rate or turning off the signaling of a single class of nerve, such as pain receptors.

Ziconotide, a pain reliever 1,000 times as powerful as morphine, was initially isolated from the venom of the magician cone snail, Conus magus.[22] It was approved by the U.S. Food and Drug Administration in December 2004 under the name Prialt. Other drugs based on cone snail venom targeting Alzheimer's disease, Parkinson's disease, depression, and epilepsy are in clinical or preclinical trials.[23][24]

Many peptides produced by the cone snails show prospects for being potent pharmaceuticals, such as AVC1, isolated from the Australian species, the Queen Victoria cone, Conus victoriae, and have been highly effective in treating postsurgical and neuropathic pain, even accelerating recovery from nerve injury.

Geography and tulip cone snails are known to secrete a type of insulin that paralyzes nearby fish by causing hypoglycaemic shock. They are the only two non-human animal species known to use insulin as a weapon.[25] Cone snail insulin is capable of binding to human insulin receptors and researchers are studying its use as a potent fast-acting therapeutic insulin.[26]

Shell collecting

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The intricate color patterns of cone snails have made them one of the most popular species for shell collectors.[27][28]

Conus gloriamaris, also known as "Glory of the Seas", one of the most famous and sought-after seashells in past centuries, with only a few specimens in private collections. The rarity of this species' shells led to high market prices for the objects, until the habitat of this cone snail was discovered, which decreased prices dramatically.[29]

As jewelry

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Naturally occurring, beach-worn cone shell tops can function as beads without any further modification. In Hawaii, these natural beads were traditionally collected from the beach drift to make puka shell jewelry. Since it is difficult to obtain enough naturally occurring cone snail tops, almost all modern puka shell jewelry uses cheaper imitations, cut from thin shells of other species of mollusk, or made of plastic.

Species

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Until 2009 all species within the family Conidae were placed in one genus, Conus. Testing of the molecular phylogeny of the Conidae was first conducted by Christopher Meyer and Alan Kohn,[30] and has continued, particularly with the advent of nuclear DNA testing.

In 2009, J.K. Tucker and M.J. Tenorio proposed a classification system consisting of three distinct families and 82 genera for living species of cone snails. This classification is based on shell morphology, radular differences, anatomy, physiology, and cladistics, with comparisons to molecular (DNA) studies.[31] Published accounts of Conidae that use these new genera include J.K. Tucker & M.J. Tenorio (2009), and Bouchet et al. (2011).[32] Tucker and Tenorio's proposed classification system for the cone shells and other clades of Conoidean gastropods is shown in Tucker & Tenorio cone snail taxonomy 2009.

Some experts, however, still prefer to use the traditional classification. For example, in the November 2011 version of the World Register of Marine Species, all species within the family Conidae were placed in the genus Conus. The binomial names of species in the 82 genera of living cone snails listed in Tucker & Tenorio 2009 were recognized by the World Register of Marine Species as "alternative representations".[33] Debate within the scientific community regarding this issue has continued, and additional molecular phylogeny studies are being carried out in an attempt to clarify the issue.[31][34][35][36][37][38][39][40][41][42]

In 2015, in the Journal of Molluscan Studies, Puillandre, Duda, Meyer, Olivera & Bouchet presented a new classification for the old genus Conus. Using 329 species, the authors carried out molecular phylogenetic analyses. The results suggested that the authors should place all cone snails in a single family, Conidae, containing four genera: Conus, Conasprella, Profundiconus and Californiconus. The authors group 85% of all known cone snail species under Conus. They recognize 57 subgenera within Conus, and 11 subgenera within the genus Conasprella.[1]

Taxonomy

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  • Afonsoconus Tucker & Tenorio, 2013
  • Africonus Petuch, 1975
  • Afroconus Petuch, 1975
  • Ammirales Schepman, 1913
  • Asperi Schepman, 1913
  • Asprella Schaufuss, 1869
  • Atlanticonus Petuch & Sargent, 2012
  • Attenuiconus Petuch, 2013
  • Austroconus Tucker & Tenorio, 2009
  • Bermudaconus Petuch, 2013
  • Brasiliconus Petuch, 2013
  • Calibanus da Motta, 1991
  • Cariboconus Petuch, 2003
  • Chelyconus Mörch, 1842
  • Cleobula 1930
  • Conasprelloides Tucker & Tenorio, 2009
  • Coronaxis Swainson, 1840
  • Cucullus Röding, 1798
  • Cylinder Montfort, 1810
  • Cylindrus Deshayes, 1824
  • Darioconus Iredale, 1930
  • Dauciconus Cotton, 1945
  • Dendroconus Swainson, 1840
  • Ductoconus da Motta, 1991
  • Embrikena Iredale, 1937
  • Endemoconus Iredale, 1931
  • Erythroconus da Motta, 1991
  • Eugeniconus da Motta, 1991
  • Floraconus Iredale, 1930
  • Gastridium Mödeer, 1793
  • Gladioconus Tucker & Tenorio, 2009
  • Gradiconus da Motta, 1991
  • Hermes Montfort, 1810
  • Heroconus da Motta, 1991
  • Isoconus Tucker & Tenorio, 2013
  • Kermasprella Powell, 1958
  • Ketyconus da Motta, 1991
  • Kioconus da Motta, 1991
  • Lautoconus Monterosato, 1923
  • Leporiconus Iredale, 1930
  • Leptoconus Swainson, 1840
  • Lilliconus Raybaudi Massilia, 1994
  • Lithoconus Mörch, 1852
  • Magelliconus da Motta, 1991
  • Mamiconus Cotton & Godfrey, 1932
  • Nitidoconus Tucker & Tenorio, 2013
  • Ongoconus da Motta, 1991
  • Phasmoconus Mörch, 1852
  • Pionoconus Mörch, 1852
  • Poremskiconus Petuch, 2013
  • Profundiconus Kuroda, 1956
  • Stephanoconus Mörch, 1852
  • Textilia Swainson, 1840
  • Tuliparia Swainson, 1840
  • Turriconus Shikama & Habe, 1968
  • Virgiconus Cotton, 1945
  • Virroconus Iredale, 1930

See also

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  • ConoServer, a database of cone snail toxins, known as conopeptides.[43] These toxins are of importance to medical research.
  • Conotoxin

References

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  1. ^ a b Puillandre N, Duda TF, Meyer C, Olivera BM, Bouchet P (February 2015). "One, four or 100 genera? A new classification of the cone snails". The Journal of Molluscan Studies. 81 (1): 1–23. doi:10.1093/mollus/eyu055. PMC 4541476. PMID 26300576.
  2. ^ Pek I, Vašíček Z, Roček Z, Hajn V, Mikuláš R (1996). Základy Zoopaleontologie [Basics of Zoopaleontology] (in Czech). Olomouc. p. 264. ISBN 80-7067-599-3.
  3. ^ Hendricks JR (2015). "Glowing seashells: diversity of fossilized coloration patterns on coral reef-associated cone snail (Gastropoda: Conidae) shells from the Neogene of the Dominican Republic". PLOS ONE. 10 (4): e0120924. Bibcode:2015PLoSO..1020924H. doi:10.1371/journal.pone.0120924. PMC 4382297. PMID 25830769.
  4. ^ Olivera BM, Teichert RW (October 2007). "Diversity of the neurotoxic Conus peptides: a model for concerted pharmacological discovery". Molecular Interventions. 7 (5): 251–60. doi:10.1124/mi.7.5.7. PMID 17932414.
  5. ^ Van Oosten R (September 2008). "Nature's brew". Quest online. p. 2. Archived from the original on November 23, 2010.
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  7. ^ Tenorio, M. J. & Monteiro, A. J. (2008). The Family Conidae. The South African species of Conus. In: Poppe, G. T. & Groh, K. (eds): A Conchological Iconography. Hackenheim: ConchBooks. 47 pp., 60 pls.
  8. ^ Branch GM, Griffiths CL, Branch ML, Beckley LE (2010). Two oceans : a guide to the marine life of Southern Africa. Cape Town: Struik Nature. ISBN 978-1-77007-772-0.
  9. ^ Monteiro AJ, Tenorio MJ, Poppe GT (2004). "The Family Conidae. The West African and Mediterranean species of Conus". In Poppe GT, Groh K (eds.). A Conchological Iconography. Hackenheim: ConchBooks. p. 102.
  10. ^ Tenorio MJ, Tucker JK, Chaney HW (2012). "The Families Conilithidae and Conidae. The Cones of the Eastern Pacific". In Poppe GT, Groh K (eds.). A Conchological Iconography. Hackenheim: ConchBooks. p. 112.
  11. ^ "The Conus biodiversity website".
  12. ^ Cone Snails Use Sexual Enticements to Lure Prey Out of Hiding | University of Utah Health
  13. ^ Franklin JB, Fernando SA, Chalke BA, Krishnan KS (2007). "Radular morphology of Conus (Gastropoda: Caenogastropoda: Conidae) from India". Molluscan Research. 27 (3): 1. doi:10.11646/mr.27.3.1.
  14. ^ a b "Cone Snail Profile". National Geographic. Archived from the original on 10 June 2008.
  15. ^ Kohn AJ (March 1956). "Piscivorous Gastropods of the Genus Conus". Proceedings of the National Academy of Sciences of the United States of America. 42 (3): 168–71. Bibcode:1956PNAS...42..168K. doi:10.1073/pnas.42.3.168. PMC 528241. PMID 16589843.
  16. ^ Dipper F (2016-04-29). The Marine World: A Natural History of Ocean Life. Princeton University Press. ISBN 978-0-9573946-2-9.
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  18. ^ "Killer Cones". Archived from the original on 2008-12-26. Retrieved 2010-02-24.
  19. ^ "Conus Geographus: The Geography Cone". penelope.uchicago.edu. Retrieved 2020-07-30.
  20. ^ Machalek AZ (September 2002). "Secrets of the Killer Snails". Bethesda, MD: National Institute of General Medical Sciences, National Institutes of Health. Archived from the original on 18 October 2011.
  21. ^ Kapil, Sasha; Hendriksen, Stephen; Cooper, Jeffrey S. (2022), "Cone Snail Toxicity", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 29262115, retrieved 2023-01-29
  22. ^ ANI (2007). "Sea snail venom paves way for potent new painkiller". Compassionate health care network. Archived from the original on 2016-10-18. Retrieved 2008-11-19.
  23. ^ Louise Yeoman (2006-03-28). "Venomous snails aid medical science". BBC. Retrieved 2008-11-19.
  24. ^ Yuhas, Daisy (2012). "Healing the Brain with Snail Venom". Scientific American Mind. 23 (6): 12. doi:10.1038/scientificamericanmind0113-12.
  25. ^ Safavi-Hemami H, Gajewiak J, Karanth S, Robinson SD, Ueberheide B, Douglass AD, et al. (February 2015). "Specialized insulin is used for chemical warfare by fish-hunting cone snails". Proceedings of the National Academy of Sciences of the United States of America. 112 (6): 1743–8. Bibcode:2015PNAS..112.1743S. doi:10.1073/pnas.1423857112. PMC 4330763. PMID 25605914.
  26. ^ Gorai B, Vashisth H (18 October 2021). "Structures and interactions of insulin-like peptides from cone snail venom". Proteins: Structure, Function, and Bioinformatics. 90 (3): 680–690. doi:10.1002/prot.26265. PMC 8816879. PMID 34661928.
  27. ^ "Conidae - worldwideconchology". Archived from the original on 2009-06-18. Retrieved 2010-02-24.
  28. ^ "Conus gloriamaris". ConeShells. Archived from the original on 23 July 2011.{{cite web}}: CS1 maint: unfit URL (link)
  29. ^ "Conus gloriamaris, Glory of the Seas Cone photos". www.oceanlight.com.
  30. ^ Kohn A (2009). "Interview of Professor Alan Kohn, Professor Emeritus, Zoology". Seashell Collector (Interview). Archived from the original on February 27, 2012.
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  33. ^ Bouchet P (14 August 2011). "Conidae J. Fleming, 1822". World Register of Marine Species (WoRMS). ' Traditionally, all cone shells were included in the Linnaean genus Conus. Tucker & Tenorio (2009) proposed an alternative shell- and radula-based classification that recognized 4 families and 80 genera of cones. In 2011, WoRMS, still recognized a single family Conidae (following Puillandre et al. 2011), but Tucker & Tenorio's 80 genera classification was presented as "alternative representation"
  34. ^ C.M.L. Afonso & M.J. Tenorio (August 2011), A new, distinct endemic Africonus species (Gastropoda, Conidae) from Sao Vicente Island, Cape Verde Archipelago, West Africa, Gloria Maris 50(5): 124–135
  35. ^ P. Bouchet, Yu I. Kantor, A. Sysoev, and N. Puillandre (March 2011), A New Operational Classification of the Conoidea, Journal of Molluscan Studies 77:273–308, at p. 275.
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  38. ^ Williams ST, Duda TF (July 2008). "Did tectonic activity stimulate oligo-miocene speciation in the Indo-West Pacific?". Evolution; International Journal of Organic Evolution. 62 (7): 1618–34. doi:10.1111/j.1558-5646.2008.00399.x. hdl:2027.42/73573. PMID 18410535. S2CID 11714846.
  39. ^ R.L. Cunha, R. Castilho, L. Ruber, & R. Zardoya (2005), Patterns of cladogenesis in the venomous marine gastropod genus Conus from the Cape Verde Islands Systematic Biology 54(4):634-650.
  40. ^ Duda TF, Kohn AJ (February 2005). "Species-level phylogeography and evolutionary history of the hyperdiverse marine gastropod genus Conus". Molecular Phylogenetics and Evolution. 34 (2): 257–72. Bibcode:2005MolPE..34..257D. doi:10.1016/j.ympev.2004.09.012. PMID 15619440.
  41. ^ Duda TF, Rolán E (January 2005). "Explosive radiation of Cape Verde Conus, a marine species flock". Molecular Ecology. 14 (1): 267–72. Bibcode:2005MolEc..14..267D. doi:10.1111/j.1365-294x.2004.02397.x. PMID 15643969. S2CID 27304985.
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  43. ^ Kaas Q, Yu R, Jin AH, Dutertre S, Craik DJ (January 2012). "ConoServer: updated content, knowledge, and discovery tools in the conopeptide database". Nucleic Acids Research. 40 (Database issue): D325-30. doi:10.1093/nar/gkr886. PMC 3245185. PMID 22058133.

Further reading

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  • Flomenbaum NE, Goldfrank LR, Hoffman RS, Howland MA, Lewin NA, Nelson LS, eds. (28 March 2006). Goldfrank's Toxicologic Emergencies (8th ed.). New York: McGraw-Hill. ISBN 978-0-07-143763-9.
  • Gmelin, J. F. 1791. Systema naturae per regna tria naturae. Editio decima tertia. Systema Naturae, 13th ed., vol. 1(6): 3021–3910. Lipsiae.
  • Bruguière JG (1792). "Histoire Naturelle des Vers". Encyclopédie Méthodique. Vol. 1. Paris: Panckoucke. pp. 345–757.
  • Sowerby, G. B., II. 1833. Conus. Conchological Illustrations pls. 36–37
  • (in French) Bernardi AC (1858). Monographie du genre Conus (in French).
  • Reeve L (1844). "Conchologia Iconica". Monograph of the genus Conus. Vol. 1. pp. 40–47.
  • Kiener LC (1845). "Genre Cone. (Conus, Lin.).". Spécies Général et Iconographie des Coquilles Vivantes. Vol. 2. pp. 1–111.
  • Clench WJ (1942). "The Genus Conus in the Western Atlantic". Johnsonia. 1 (6): 1–40.
  • Van Mol JJ, Tursch B, Kempf M (1967). "Mollusques prosobranches: Les Conidae du Brésil. Étude basée en partie sur les spécimens recueillis par la Calypso". Annales de l'Institut Océanographique. 45: 233–254.
  • Vink DL, von Cosel R (1985). "The Conus cedonulli complex: Historical review, taxonomy and biological observations". Revue suisse de Zoologie. 92: 525–603. doi:10.5962/bhl.part.81894.
  • Petuch EJ (1986). "New South American gastropods in the genera Conus (Conidae) and Latirus (Fasciolariidae)". Proceedings of the Biological Society of Washington. 99: 8–14.
  • Petuch, E. J. 1987. New Caribbean molluscan faunas. [v] + 154 + A1-A4, 29 pls. Coastal Education & Research Foundation: Charlottesville, Virginia
  • Petuch, E. J. 1988. Neogene history of tropical American mollusks. [vi] + 217, 39 pls. Coastal Education & Research Foundation: Charlottesville, Virginia
  • Petuch EJ (1990). "A new molluscan faunule from the Caribbean coast of Panama". Nautilus. 104: 57–70.
  • Petuch EJ (1992). "Molluscan discoveries from the tropical Western Atlantic region. Part II. New species of Conus from the Bahamas Platform, Central American and northern South American coasts, and the Lesser Antilles". La Conchiglia. 24 (265): 10–15.
  • Petuch EJ (2000). "A review of the conid subgenus Purpuriconus da Motta, 1991, with the descriptions of two new Bahamian species". Ruthenica: Russian Malacological Journal. 10: 81–87.
  • Petuch EJ (2004). Cenozoic Seas. Boca Raton: CRC Press.
  • Tenorio MJ, Tucker JK, Chaney HW (2012). "The Families Conilithidae and Conidae. The Cones of the Eastern Pacific". In Poppe GT, Groh K (eds.). A Conchological Iconography. Hackenheim: ConchBooks. p. 112.
  • Coltro Jr J (2004). "New species of Conidae from northeastern Brazil (Mollusca: Gastropoda)". Strombus. 11: 1–16.
  • García EF (2006). "Conus sauros, a new Conus species (Gastropoda: Conidae) from the Gulf of Mexico". Novapex. 7: 71–76.
  • Franklin JB, Subramanian KA, Fernando SA, Krishnan KS (2009). "Diversity and Distribution of Conidae from the Tamil Nadu Coast of India (Mollusca: Caenogastropoda: Conidae)". Zootaxa. 2250: 1–63. doi:10.11646/zootaxa.2250.1.1.
  • Franklin JB, Fernando SA, Chalke BA, Krishnan KS (2007). "Radular morphology of Conus (Gastropoda: Caenogastropoda: Conidae) from India" (PDF). Molluscan Research. 27 (3): 111–122. doi:10.11646/mr.27.3.1.
  • Peters H, O'Leary BC, Hawkins JP, Carpenter KE, Roberts CM (2013). "Conus: first comprehensive conservation red list assessment of a marine gastropod mollusc genus". PLOS ONE. 8 (12): e83353. Bibcode:2013PLoSO...883353P. doi:10.1371/journal.pone.0083353. PMC 3871662. PMID 24376693.
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