Xyloglucan, a plant polymer with barrier protective properties over the mucous membranes: An overview

International Journal of Molecular Sciences

Volumn 19, Issue 3, 2018, Pages

  Piqué, Núria ^a   Gómez Guillén, María del Carmen ^b   Montero, María Pilar ^b  

^a UNIVERSITY OF BARCELONA   (Spain)

^b INSTITUTE OF FOOD SCIENCE   (Spain)

Author keywords

Allergy; Barrier properties; Diarrhoea; Gastroenteritis; Medical devices; Nasal obstruction; Preventive measures; Rhinitis; Rhinosinusitis; Xyloglucan

Indexed keywords

BUDESONIDE; GALACTOSE; GELATIN; GLYCOPROTEIN; MUCIN; POLYMER; POLYSACCHARIDE; PROTEIN ZO1; RHINOSECTAN; SHORT CHAIN FATTY ACID; UNCLASSIFIED DRUG; XYLOGLUCAN; GLUCAN; PHYTOCHEMICAL; PROTECTIVE AGENT; XYLAN;

ACUTE DIARRHEA; ALLERGY; BACTERIUM ADHERENCE; BIOFILM; CORNEA LESION; DRY EYE; ELECTRIC RESISTANCE; EPITHELIUM CELL; FIBROBLAST; GASTROENTERITIS; HUMAN; HYDROGEL; IMMUNE SYSTEM; IMMUNOCOMPETENT CELL; IMMUNOFLUORESCENCE MICROSCOPY; IRRITABLE COLON; KERATINOCYTE; MACROPHAGE; MUCOSA; NONHUMAN; NOSE OBSTRUCTION; PERMEABILITY; PERMEABILITY BARRIER; PHYSICAL CHEMISTRY; PLASMA VISCOSITY; PSEUDOMONAS AERUGINOSA; RESEARCH; RESPIRATORY EPITHELIUM; REVIEW; RHINOSINUSITIS; STAPHYLOCOCCUS AUREUS; STRUCTURE ANALYSIS; TIGHT JUNCTION; UPPER RESPIRATORY TRACT INFECTION; URINARY TRACT INFECTION; WOUND HEALING; ANIMAL; CHEMISTRY; CLINICAL STUDY; CYTOLOGY; DISEASE MODEL; DISEASE PREDISPOSITION; DRUG EFFECT; HOST PATHOGEN INTERACTION; IMMUNOLOGY; METABOLISM; MICROBIOLOGY; PATHOLOGY;

ANIMALS; CLINICAL STUDIES AS TOPIC; DISEASE MODELS, ANIMAL; DISEASE SUSCEPTIBILITY; EPITHELIAL CELLS; GASTROENTERITIS; GLUCANS; HOST-PATHOGEN INTERACTIONS; HUMANS; MUCINS; MUCOUS MEMBRANE; PHYTOCHEMICALS; POLYMERS; PROTECTIVE AGENTS; URINARY TRACT INFECTIONS; XYLANS;

EID: 85042757496     PISSN: 16616596     EISSN: 14220067     Source Type: Journal    
DOI: 10.3390/ijms19030673     Document Type: Review

References (77)

1. De Servi, B.; Ranzini, F.; Piqué, N. Protective barrier properties of Rhinosectan® spray (containing xyloglucan) on an organotypic 3D airway tissue model (MucilAir): Results of an vitro study. Allergy Asthma Clin. Immunol. 2017, 13, 37. [CrossRef] [PubMed]
2. Oshima, T.; Miwa, H. Gastrointestinal mucosal barrier function and diseases. J. Gastroenterol. 2016, 51, 768–778. [CrossRef] [PubMed]
3. Andersson, M.; Greiff, L.; Ojeda, P.; Wollmer, P. Barrier-enforcing measures as treatment principle in allergic rhinitis: A systematic review. Curr. Med. Res. Opin. 2014, 30, 1131–1137. [CrossRef] [PubMed]
4. Guo, S.; Al-Sadi, R.; Said, H.M.; Ma, T.Y. Lipopolysaccharide causes an increase in intestinal tight junction permeability in vitro and in vivo by inducing enterocyte membrane expression and localization of TLR-4 and CD14. Am. J. Pathol. 2013, 182, 375–387. [CrossRef] [PubMed]
5. Mattila, P.; Joenväärä, S.; Renkonen, J.; Toppila-Salmi, S.; Renkonen, R. Allergy as an epithelial barrier disease. Clin. Transl. Allergy 2011, 1, 5. [CrossRef] [PubMed]
6. Eutamene, H.; Beaufrand, C.; Harkat, C.; Theodorou, V. The role of mucoprotectants in the management of gastrointestinal disorders. Expert Rev. Gastroenterol. Hepatol. 2018, 12, 83–90. [CrossRef] [PubMed]
7. Gao, R.; Kong, C.; Huang, L.; Li, H.; Qu, X.; Lan, P.; Wang, J.; Qin, H. Mucosa-associated microbiota signature in colorectal cancer. Eur. J. Clin. Microbiol. Infect. Dis. 2017, 36, 2073–2083. [CrossRef] [PubMed]
8. Fulbright, L.E.; Ellermann, M.; Arthur, J.C. The microbiome and the hallmarks of cancer. PLoS Pathog 2017, 13, e1006480. [CrossRef] [PubMed]
9. Gevers, D.; Kugathasan, S.; Denson, L.A.; Vázquez-Baeza, Y.; van Treuren, W; Ren, B.; Schwager, E.; Knights, D.; Song, S.J.; Yassour, M.; et al. The treatment-naive microbiome in new-onset Crohn’s disease. Cell Host Microbe 2014, 15, 382–392. [CrossRef] [PubMed]
10. Moser, G.; Fournier, C.; Peter, J. Intestinal microbiome-gut-brain axis and irritable bowel syndrome. Wien. Med. Wochenschr. 2017. [CrossRef] [PubMed]
11. Zhao, Y.; Jaber, V.; Lukiw, W.J. Secretory Products of the Human GI Tract Microbiome and Their Potential Impact on Alzheimer’s Disease (AD): Detection of Lipopolysaccharide (LPS) in AD Hippocampus. Front. Cell Infect. Microbiol. 2017, 7, 318. [CrossRef] [PubMed]
12. Pan, W.; Kang, Y. Gut microbiota and chronic kidney disease: Implications for novel mechanistic insights and therapeutic strategies. Int. Urol. Nephrol. 2017. [CrossRef] [PubMed]
13. Steelant, B.; Farré, R.; Wawrzyniak, P.; Belmans, J.; Dekimpe, E.; Vanheel, H.; van Gerven, L.; Krohn, I.K.; Bullens, D.M.A.; Ceuppens, J.L.; et al. Impaired barrier function in patients with house dust mite-induced allergic rhinitis is accompanied by decreased occludin and zonula occludens-1 expression. J. Allergy Clin. Immunol. 2016, 137, 1043–1053.e5. [CrossRef] [PubMed]
14. Steelant, B.; Seys, S.F.; Boeckxstaens, G.; Akdis, C.A.; Ceupeens, J.L.; Hellings, P.W. Restoring airway epitelial barrier dysfunction: A new therapeutic challenge in allergic airway disease. Rhinology 2016, 54, 195–205. [CrossRef] [PubMed]
15. Allegrini, A.; Pavone, D.; Carluccio, F. A randomized controlled trial comparing a xyloglucan-based nasal spray with saline in adults with symptoms of rhinosinusitis. Curr. Med. Res. Opin. 2017, 19, 1–9. [CrossRef] [PubMed]
16. De Servi, B.; Ranzini, F.; Piqué, N. Effect of Utipro(®) (containing gelatin-xyloglucan) against Escherichia coli invasion of intestinal epithelial cells: Results of an in vitro study. Future Microbiol. 2016, 11, 651–658. [CrossRef] [PubMed]
17. Fraile, B.; Alcover, J.; Royuela, M.; Rodríguez, D.; Chaves, C.; Palacios, R.; Piqué, N. Xyloglucan, hibiscus and propolis for the prevention of urinary tract infections: Results of in vitro studies. Future Microbiol. 2017, 12, 721–731. [CrossRef] [PubMed]
18. Brozek, J.L.; Bousquet, J.; Baena-Cagnani, C.E.; Bonini, S.; Canonica, G.W.; Casale, T.B.; van Wijk, R.G.; Ohta, K.; Zuberbier, T.; Schünemann, H.J. Global Allergy and Asthma European Network; Grading of Recommendations Assessment, Development and Evaluation Working Group. Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines: 2010 revision. J. Allergy Clin. Immunol. 2010, 126, 466–476. [CrossRef] [PubMed]
19. World Health Organization. Antimicrobial Resistance: Global Report on Surveillance. 2014. Available online: http://apps.who.int/iris/bitstream/10665/112642/1/9789241564748_eng.pdf (accessed on 30 December 2017).
20. World Health Organization. Global Priority List of Antibiotic-Resistant Bacteria to Guide Research, Discovery, and Development of New Antibiotics. 2017. Available online: http://www.who.int/medicines/publications/global-priority-list-antibiotic-resistant-bacteria/en/ (accessed on 30 December 2017).
21. Costelloe, C.; Metcalfe, C.; Lovering, A.; Mant, D.; Hay, A.D. Effect of antibiotic prescribing in primary care on antimicrobial resistance in individual patients: Systematic review and meta-analysis. BMJ 2010, 340, c2096. [CrossRef] [PubMed]
22. Burgalassi, S.; Raimondi, L.; Pirisino, R.; Banchelli, G.; Boldrini, E.; Saettone, M.F. Effect of xyloglucan (tamarind seed polysaccharide) on conjunctival cell adhesion to laminin and on corneal epithelium wound healing. Eur. J. Ophthalmol. 2000, 10, 71–76. [CrossRef] [PubMed]
23. Gnessi, L.; Bacarea, V.; Marusteri, M.; Piqué, N. Xyloglucan for the treatment of acute diarrhea: Results of a randomized, controlled, open-label, parallel group, multicentre, national clinical trial. BMC Gastroenterol. 2015, 15, 153. [CrossRef] [PubMed]
24. Plesea Condratovici, C.; Bacarea, V.; Piqué, N. Xyloglucan for the treatment of acute gastroenteritis in children: Results of a randomized controlled, clinical trial. Gastroenterol. Res. Pract. 2016, 2016, 6874207. [CrossRef] [PubMed]
25. Guglietta, A. Recurrent urinary tract infections in women: Risk factors, etiology, pathogenesis and prophylaxis. Future Microbiol. 2017, 12, 239–246. [CrossRef] [PubMed]
26. García-Larrosa, A.; Alexe, O. Efficacy and safety of a medical device versus placebo in the early treatment of patients with symptoms of urinary tract infection: A randomized controlled trial. Clin. Microbiol. 2016, 5, 233. [CrossRef]
27. Salvatorelli, N.; García-Larrosa, A.; Allegrini, A.; Pavone, D. A New Approach to the Treatment of Uncomplicated Cystitis: Results of a Randomized Placebo-Controlled Clinical Trial. Urol. Int. 2016, 97, 347–351. [CrossRef] [PubMed]
28. Rolando, M.; Valente, C. Establishing the tolerability and performance of tamarind seed polysaccharide (TSP) in treating dry eye syndrome: Results of a clinical study. BMC Ophthalmol. 2007, 7, 5. [CrossRef] [PubMed]
29. Authimoolam, S.P.; Dziubla, T.D. Biopolymeric mucin and synthetic polymer analogs: Their structure, function and role in biomedical applications. Polymers 2016, 8, 71. [CrossRef]
30. Rogers, D.F. Airway goblet cells: Responsive and adaptable front-line defenders. Eur. Respir. J. 1994, 7, 1690–1706. [CrossRef] [PubMed]
31. Takiishi, T.; Fenero, C.I.M.; Câmara, N.O.S. Intestinal barrier and gut microbiota: Shaping our immune responses throughout life. Tissue Barriers 2017, e1373208. [CrossRef] [PubMed]
32. Yuksel, H.; Turkeli, A. Airway epithelial barrier dysfunction in the pathogenesis and prognosis of respiratory tract diseases in childhood and adulthood. Tissue Barriers 2017, e1367458. [CrossRef] [PubMed]
33. Hooper, L.V.; Gordon, J.I. Glycans as legislators of host-microbial interactions: Spanning the spectrum from symbiosis to pathogenicity. Glycobiology 2001, 11, 1R–10R. [CrossRef] [PubMed]
34. Ruch, T.R.; Engel, J.N. Targeting the Mucosal Barrier: How Pathogens Modulate the Cellular Polarity Network. Cold Spring Harb. Perspect. Biol. 2017, 9. [CrossRef] [PubMed]
35. Fries, W.; Belvedere, A.; Vetrano, S. Sealing the broken barrier in IBD: Intestinal permeability, epithelial cells and junctions. Curr. Drug Targets 2013, 14, 1460–1470. [CrossRef] [PubMed]
36. Grover, M. Role of gut pathogens in development of irritable bowel syndrome. Indian J. Med. Res. 2014, 139, 11–18. [PubMed]
37. Kojima, T.; Go, M.; Takano, K.; Kurose, M.; Ohkuni, T.; Koizumi, J.; Kamekura, R.; Ogasawara, N.; Masaki, T.; Fuchimoto, J.; et al. Regulation of tight junctions in upper airway epithelium. Biomed. Res. Int. 2013, 2013, 947072. [CrossRef] [PubMed]
38. Soyka, M.B.; Wawrzyniak, P.; Eiwegger, T.; Holzmann, D.; Treis, A.; Wanke, K.; Jeannette, I.K.; Akdis, C.A. Defective epithelial barrier in chronic rhinosinusitis: The regulation of tight junctions by IFN-γ and IL-4. J. Allergy Clin. Immunol. 2012, 130, 1087–1096.e10. [CrossRef] [PubMed]
39. Fukuoka, A.; Matsushita, K.; Morikawa, T.; Takano, H.; Yoshimoto, T. Diesel exhaust particles exacerbate allergic rhinitis in mice by disrupting the nasal epithelial barrier. Clin. Exp. Allergy 2016, 46, 142–152. [CrossRef] [PubMed]
40. Pauly, M.; Keegstra, K. Biosynthesis of the Plant Cell Wall Matrix Polysaccharide Xyloglucan. Annu. Rev. Plant. Biol. 2016, 67, 235–259. [CrossRef] [PubMed]
41. Urakawa, H.; Mimura, M.; Kajiwara, K. Diversity and versatility of plant seed xyloglucan. Trends Glycosci. Glycotechnol. 2002, 14, 355–376. [CrossRef]
42. Mahajan, H.S.; Tyagi, V.K.; Patil, R.R.; Dusunge, S.B. Thiolated xyloglucan: Synthesis, characterization and evaluation as mucoadhesive in situ gelling agent. Carbohydr. Polym. 2013, 91, 618–625. [CrossRef] [PubMed]
43. Mahajan, H.S.; Tyagi, V.; Lohiya, G.; Nerkar, P. Thermally reversible xyloglucan gels as vehicles for nasal drug delivery. Drug Deliv. 2012, 19, 270–276. [CrossRef] [PubMed]
44. Miyazaki, S.; Suisha, F.; Kawasaki, N.; Shirakawa, M.; Yamatoya, K.; Attwood, D. Thermally reversible xyloglucan gels as vehicles for rectal drug delivery. J. Control. Release 1998, 56, 75–83. [CrossRef]
45. Kulkarni, A.D.; Josh, A.A.; Patil, C.L.; Amale, P.D.; Patel, H.M.; Surana, S.J.; Belgamwar, V.S.; Chaudhari, K.S.; Pardeshi, C.H. Xyloglucan: A functional biomacromolecule for drug delivery applications. Int. J. Biol. Macromol. 2017, 104, 799–812. [CrossRef] [PubMed]
46. Bashir, A.; Sharma, P.K.; Warsi, M.H. Extraction and characterization of xyloglucan (tamarind seed polysaccharide) as pharmaceutical excipient. WJPPS 2016, 6, 2209–2220. [CrossRef]
47. McDougall, G.J.; Fry, S.C. Structure-Activity relationships for xyloglucan oligosaccharides with antiauxin activity. Plant. Physiol. 1989, 89, 883–887. [CrossRef] [PubMed]
48. Alexea, O.; Bacarea, V.; Piqué, N. The combination of oligo- and poly-saccharides and reticulated protein for the control of symptoms of patients with irritable bowel syndrome: Results of a randomized, placebo-controlled, double-blind, parallel group, multicentre clinical trial. United Eur. Gastroenterol. J. 2016, 4, 455–465. [CrossRef] [PubMed]
49. Allegrini, A.; Costantini, M. Gelatine tannate for the treatment of acute diarrhoea in adults. J. Gastroint. Dig. Syst. 2012, 2, 3. [CrossRef]
50. Esteban Carretero, J.; Durbán Reguera, F.; López-Argüeta Alvarez, S.; López Montes, J. A comparative analysis of response to vs. ORS + gelatin tannate pediatric patients with acute diarrhea. Rev. Espan. Enferm. Dig. 2009, 101, 41–48.
51. Manchanda, R.; Arora, S.C.; Manchanda, R. Tamarind seed polysaccharide and its modifications-versatile pharmaceutical excipients-A review. Int. J. PharmTech Res. 2014, 6, 412–420.
52. Satle, A.; Agrawal, S. Solubility enhancement potential of tamarind seed polysaccharide as a solubilizer. Int. J. Curr. Pharm. Res. 2012, 4, 67–73.
53. Sahoo, R.; Sahoo, S. Natural polymer of tamarind seed: A prospective carrier for ocular drug delivery. Eur. Sci. J. 2015, 11, 267–275.
54. Picout, D.R.; Ross-Murphy, S.B.; Errington, N.; Harding, S.E. Pressure cell assisted solubilization of xyloglucans: Tamarind seed polysaccharide and detarium gum. Biomacromolecules 2003, 4, 799–807. [CrossRef] [PubMed]
55. Kozioł, A.; Cybulska, J.; Pieczywek, P.M.; Zdunek, A. Evaluation of Structure and Assembly of Xyloglucan from Tamarind Seed (Tamarindus indica L.) with Atomic Force Microscopy. Food Biophys. 2015, 10, 396–402. [CrossRef] [PubMed]
56. Roy, S.; Pal, K.; Anis, A.; Pramanik, K.; Prabhakar, B. Polymers in mucoadhesive drug-delivery systems: A brief note. Des. Monomer. Polym. 2009, 12, 483–495. [CrossRef]
57. Kumar, A.; Garg, T.; Sarma, G.S.; Rath, G.; Goyal, A.K. Optimization of combinational intranasal drug delivery system for the management of migraine by using statistical design. Eur. J. Pharm. Sci. 2015, 70, 140–151. [CrossRef] [PubMed]
58. Madgulkar, A.R.; Bhalekar, M.R.; Asgaonkar, K.D.; Dikpati, A.A. Synthesis and characterization of a novel mucoadhesive derivative of xyloglucan. Carbohydr. Polym. 2016, 135, 356–362. [CrossRef] [PubMed]
59. Mahajan, H.S.; Deshmukh, S.R. Development and evaluation of gel-forming ocular films based on xyloglucan. Carbohydr. Polym. 2015, 122, 243–247. [CrossRef] [PubMed]
60. York, W.S.; van Halbeek, H.; Darvill, A.G.; Albersheim, P. Structural analysis of xyloglucan oligosaccharides by 1H-n.m.r. spectroscopy and fast-atom-bombardment mass spectrometry. Carbohydr. Res. 1990, 200, 9–31. [CrossRef]
61. Arruda, I.R.S.; Albuquerque, P.B.S.; Santos, G.R.C.; Silva, A.G.; Mourão, P.A.S.; Correia, M.T.S.; Vicente, A.A.; Carneiro-da-Cunha, M.G. Structure and rheological properties of a xyloglucan extracted from Hymenaea courbaril var. courbaril seeds. Int. J. Biol. Macromol. 2015, 73, 31–38. [CrossRef] [PubMed]
62. Gidley, M.J.; Lillford, P.J.; Rowlands, D.W.; Lang, P.; Dentini, M.; Crescenzi, V.; Edwards, M.; Fanutti, C.; Reid, J.S. Structure and solution properties of tamarind-seed polysaccharide. Carbohydr. Res. 1991, 214, 299–314. [CrossRef]
63. Mendes, F.R.S.; Bastos, M.S.R.; Mendes, L.G.; Silva, A.R.A.; Sousa, F.D.; Monteiro-Moreira, A.C.O.; Cheng, H.N.; Biswas, A.; Moreira, R.A. Preparation and evaluation of hemicellulose films and their blends. Food Hydrocoll. 2017, 70, 181–190. [CrossRef]
64. Cozens, D.; Read, R.C. Anti-adhesion methods as novel therapeutics for bacterial infections. Expert Rev. Anti-Infect. Ther. 2012, 10, 1457–1468. [CrossRef] [PubMed]
65. Sattin, S.; Bernardi, A. Glycoconjugates and Glycomimetics as Microbial Anti-Adhesives. Trends Biotechnol. 2016, 34, 483–495. [CrossRef] [PubMed]
66. Rendueles, O.; Kaplan, J.B.; Ghigo, J.M. Antibiofilm polysaccharides. Environ. Microbiol. 2013, 15, 334–346. [CrossRef] [PubMed]
67. Blumberg, J.B.; Basu, A.; Krueger, C.G.; Lila, M.A.; Neto, C.C.; Novotny, J.A.; Reed, J.D.; Rodriguez-Mateos, A.; Toner, C.D. Impact of Cranberries on Gut Microbiota and Cardiometabolic Health: Proceedings of the Cranberry Health Research Conference 2015. Adv. Nutr. 2016, 7, 759S–770S. [CrossRef] [PubMed]
68. Chen, T.; Kim, C.Y.; Kaur, A.; Lamothe, L.; Shaikh, M.; Keshavarzianc, A.; Hamaker, B.R. Dietary fibre-based SCFA mixtures promote both protection and repair of intestinal epithelial barrier function in a Caco-2 cell model. Food Funct. 2017, 8, 1166–1173. [CrossRef] [PubMed]
69. Ojeda, P.; Piqué, N.; Alonso, A.; Delgado, J.; Feo, F.; Igea, J.M.; Navarro, A.; Olaguibel, J.M.; Subiza, J.; Nieto, C.; et al. A topical microemulsion for the prevention of allergic rhinitis symptoms: Results of a randomized, controlled, double-blind, parallel group, multicentre, multinational clinical trial (Nares study). Allergy Asthma Clin. Immunol. 2013, 9, 32. [CrossRef] [PubMed]
70. Katouli, M. Population structure of gut Escherichia coli and its role in development of extra-intestinal infections. Iran. J. Microbiol. 2010, 2, 59–72. [PubMed]
71. Nie, W.; Deters, A.M. Tamarind Seed Xyloglucans Promote Proliferation and Migration of Human Skin Cells through Internalization via Stimulation of Proproliferative Signal Transduction Pathways. Dermatol. Res. Pract. 2013, 2013, 359756. [CrossRef] [PubMed]
72. Bueno, L.; Theodorou, V.; Sekkal, S. Xyloglucan: A new agent to protect the intestinal mucosa and to prevent bacterially mediated alteration of tight junction permeability. In Proceedings of the 22nd United European Gastroenterology (UEG) week, Vienna, Austria, 18–22 October 2014. Abstract P1675.
73. Burgalassi, S.; Panichi, L.; Chetoni, P.; Saettone, M.F.; Boldrini, E. Development of a simple dry eye model in the albino rabbit and evaluation of some tear substitutes. Ophthalmic Res. 1999, 31, 229–235. [CrossRef] [PubMed]
74. Olier, M.; Sekkal, S.; Harkat, C.; Eutamene, H.; Theodorou, V. Evaluation of reticulated gelatin-hibiscus propolis against intestinal comensal species commonly associated with urinary tract infections. Future Microbiol. 2017, 12, 505–513. [CrossRef] [PubMed]
75. Vicario, M.; González-Castro, A.M.; Martínez, C.; Lobo, B.; Pigrau, M.; Guilarte, M.; de Torres, I.; Mosquera, J.L.; Fortea, M.; Sevillano-Aguilera, C.; et al. Increased humoral immunity in the jejunum of diarrhoea-predominant irritable bowel syndrome associated with clinical manifestations. Gut 2015, 64, 1379–1388. [CrossRef] [PubMed]
76. Vandenplas, Y.; Bacarea, A.; Marusteri, M.; Bacarea, V.; Constantin, M.; Manaloche, M. Efficacy and safety of APT198K for the treatment of infantile colic: A pilot study. J. Comp. Eff. Res. 2017, 6, 137–144. [CrossRef]
77. Kezic, S.; Novak, N.; Jakasa, I.; Jungersted, J.M.; Simon, M.; Brandner, J.M.; Middelkamp-Hub, M.A.; Weidinger, S. Skin barrier in atopic dermatitis. Front Biosci. (Landmark Ed) 2014, 19, 542–556. [CrossRef] [PubMed]