Abstract
Paclitaxel (taxol), a diterpene natural compound was first extracted from the bark of yew trees. However, the method cannot meet its increasing demand on the market due to unprecedented yew cutting, low amounts of taxol production, the laborious and slow process of taxol extraction. Recently, efforts have been made to develop alternative means of taxol production. Microbial fermentation would be a promising method in the production of taxol at industrial scale. Fungal endophytes have the capacity to produce bioactive compounds and can independently synthesize secondary metabolites similar to those made by the host plants. Optimization of the fermentation culture is one of the most important strategies in increasing taxol production by endophytic fungi supplemented with several substances including carbon sources, nitrogen sources, precursors, inducer and the metabolic bypass inhibitors. Improved fermentation techniques and different biotechnological strategies such as gene cloning, gene transformation, mutations are widely being used on endophytic fungi in order to increase the productivity of the taxol. In this review, the different strategies used to produce taxol from endophytic fungal biotechnology have been discussed.
Similar content being viewed by others
References
Arnold AE, Lutzoni F (2007) Diversity and host range of foliar fungal endophytes: are tropical leaves biodiversity hotspots? Ecology 88(3):541–549
Bacon CW, White JF (2000) Microbial endophytes. Marcel Decker, New York
Beltrametti F, Barucco D, Rossi R, Selva E, Marinelli F (2007) Protoplast fusion and gene recombination in the uncommon Actinomycete Planobispora rosea producing GE2270. J Antibiot 60:447–454
Caruso M, Colombo AL, Fedeli L et al (2000) Isolation of endophytic fungi and actinomycetes taxane producers. Ann Microbiol 50:3–13
Chakravarthi BVSK, Das P, Surendranath K et al (2008) Production of paclitaxel by Fusarium solani isolated from Taxus celebica. J Biosci 33:259–267
Chen YJ, Zhang Z, Wang Y et al (2003) Screening endophytic fungus to produce taxol from Taxus Yunnanensis. Biotechnology 13(2):10–11 (in Chinese)
Chen JH, Liu JJ, Zang GG et al (2004) Screening of taxol-producing endophytic fungi and regulation of fermentation conditions. J Cent South Univ Nat Sci 35(1):65–69
Cheng L, Ma QM, Tao GJ, Tao WY, Wang RM, Yang J, Guo XL (2007) Systemic identification of a paclitaxel producing endophytic fungus. Ind Microbial 4:23–30
Croteau R, Ketchum RB, Long RM, Kaspera R, Wildung MR (2006) Taxol biosynthesis and molecular genetics. Phytochem Rev 5:75–97
Dai WL, Tao WY (2008) Preliminary study on fermentation conditions of taxol-producing endophytic fungus. Chem Ind Eng Prog 27(6):883–886
Das A, Rahman MI, Ferdous AS, Rahman MM, Nahar N, Uddin MA, Islam MR, Khan H (2017) An endophytic basidiomycete Grammothele lineate isolated from orchorus olitorius produces paclitaxel that shows cytotoxicity. PLoS ONE 12(6):e0178612
DeJong JM, Liu Y, Bollon AP et al (2006) Genetic engineering of Taxol biosynthetic genes in Saccharomyces cerevisiae. Biotechnol Bioeng 93:221–224
Deng BW, Liu KH, Chen WQ, Ding XW, Xie XC (2009) Fusarium solani, Tax-3, a new endophytic taxol-producing fungus from Taxus chinensis. World J Microbiol Biotechnol 25:139–143
Diaz PL, Henneli JR, Sucher NJ (2012) Genomic DNA extraction and barcoding of endophytic fungi. Methods Mol Biol 862:171–179
Duong LM, Jeewon R, Lumyong S, Hyde KD (2006) DGGE coupled with ribosomal DNA gene phylogenies reveal uncharacterized fungal phylotypes. Fungal Divers 23:121–138
Eisenreich W, Menhard B, Hylands PJ et al (1996) Studies on the biosynthesis of taxol: the taxane carbon skeleton is not of mevalonoid origin. Proc Natl Acad Sci USA 93(13):6431–6436
Elavarasi A, Rathna GS, Kalaiselvam M (2012) Taxol producing mangrove endophytic fungi Fusarium oxysporum from Rhizophora annamalayana. Asian Pac J Trop Biomed 2(2):S1081–S1085
El-Sayed ASA, Abdel Ghany SE, Ali GS (2017) Genome editing approaches: manipulating of lovastatin and taxol synthesis of filamentous fungi by CRISPR/Cas9 system. Appl Microbiol Biotechnol 101(10):3953–3976
Fatima N, Kondratyuk TP, Park EJ, Marler LE, Jadoon M, Qazi MA, Mirza HM, Khan I, Atiq N, Chang LC, Ahmed S, Pezzuto JM (2016) Endophytic fungi associated with taxus fauna (West Himalayan yew) of Pakistan: potential bioresources for cancer chemopreventiveagents. Pharma Biol 54(11):2547–2554
Flores-Bustamante ZR, Rivera-Orduña FN, Martinez-Cárdenas A, Flores-Cotera LB (2010) Microbial paclitaxel: advances and perspectives. J Antibiot 63(8):460–467
Frense D (2007) Taxanes: perspectives for biotechnological production. Appl Microbiol Biotechnol 73:1233–1240
Gangadevi V, Muthumary J (2007) Taxol, an anticancer drug produced by an endophytic fungus Bartalinia robillardoides Tassi. Isolated from a medicinal plant Aegle marmelos Correa ex Roxb. World J Microbiol Biotechnol. https://doi.org/10.1007/s11274-007-9530-4
Gangadevi V, Muthumary J (2008) Isolation of Colletotrichum gleosporioides a novel endophytic taxol-producing fungus from the leaves of a medicinal plant Justicia gendarussa. Mycol Balc 5:1–4
Gangadevi V, Muthumary J (2009a) A novel endophytic taxol-producing fungus Chaetomella raphigera isolated from a medicinal plant, Terminalia arjuna. Appl Biochem Biotechnol 158(3):675–684
Gangadevi V, Muthumary J (2009b) Taxol production by Pestalotiopsis terminaliae, an endophytic fungus of Terminalia arjuna (arjun tree). Biotechnol Appl Biochem 52(1):9–15
Gangadevi V, Murugan M, Muthumary J (2008) Taxol determination from Pestalotiopsis pauciseta, a fungal endophyte of a medicinal plant. Chin J Biotechnol 24:1433–1438
Garyali S, Kumar Anil, Sudhakara Reddy M (2013) Taxol production by an endophytic fungus Fusarium redolens, isolated from Himalayan Yew. J Microbiol Biotechnol 23(10):1372–1380
Garyali S, Kumar A, Reddy MS (2014) Enhancement of taxol production from endophytic fungus Fusarium redolens. Biotechnol Bioprocess Eng 19(5):908–915
Grothaus PG, Raybould TJ, Bignami GS, Lazo CB, Bymes JB (1993) An enzyme immunoassay for the determination of taxol and taxanes in Taxus sp.tissues and human plasma. J Immunol Methods 158:5–15
Guo LD, Hyde KD, Liew ECY (2000) Identification of endophytic fungi from Livistona chinensis based on morphology and r DNA sequences. New Phytol 147(3):617–630
Guo BH, Wang YC, Zhou XW et al (2006) An endophytic taxol-producing fungus BT2 isolated from Taxus chinensis var. mairei. Afr J Biotechnol 5:875–877
Gupta ML Jr, Bode CJ, Georg GI, Himes RH (2003) Understanding tubulin-axol interactions: mutations that impart taxol binding to yeast tubulin. Proc Natl Acad Sci USA 100:6394–6397
Hao X et al (2013) Taxol producing fungi. In: Ramawat KG, Merillon JM (eds) Natural products. Springer, Berlin, pp 2797–2812
Hartley SE, Gange AC (2009) Impacts of plant symbiotic fungi on herbivores: mutualism in a multitrophic context. Annu Rev Entomol 54:323–342
Hu K, Tan F, Tang K, Zhu S, Wang W (2006) Isolation and screening of endophytic fungi synthesizing taxol from Taxus chinensis var. mairei. J Southwest China Normal Univ (Nat Sci Ed) 31:134–137
Huang Y, Wang J, Li G et al (2001) Antitumor and antifungal activities in endophytic fungi isolated from pharmaceutical plants Taxus mairei, Cephalataxus fortunei and Torreya grandis. FEMS Immunol Med Microbiol 31(2):163–167
Jennewein S, Wildung MR, Chau M et al (2004) Random sequencing of an induced Taxus cell cDNA library for identification of clones involved in Taxol biosynthesis. Proc Natl Acad Sci USA 101(24):9149–9154
Jiang M, Stephanopoulos G, Pfeifer BA (2012) Downstream reactions and engineering in the microbially reconstituted pathway for taxol. Appl Microbiol Biotechnol 94(4):841–849
Kasaei A, Dehkordi MM, Mahjoubi F, Saffar B (2017) Isolation of taxol producing fungi from Iranian yew through molecular approach and their effects on human breast cancer cell line. Curr Microbiol 74(6):702–709
Kathiravan G, Sri Raman V (2010) In vitro taxol production, by Pestalotiopsis breviseta—a first report. Fitoterapia 81:557–564
Kharwar RN, Mishra A, Gond SK et al (2011) Anticancer compounds derived from fungal endophytes: their importance and future challenges. Nat Prod Rep 28:1208–1228
Kumar DSS, Hyde KD (2004) Biodiversity and tissue-recurrence of endophytic fungi in Tripterygium wilfordii. Fungal Divers 17:69–90
Kumaran RS, Hur BK (2009) Screening of species of the endophytic fungus Phomopsis for the production of the anticancer drug taxol. Biotechnol Appl Biochem 54(1):21–30
Kumaran RS, Muthumary J, Hur BK (2008a) Taxol from Phyllosticta citricarpa, a leaf spot fungus of the angiosperm Citrus medica. J Biosci Bioeng 106(1):103–106
Kumaran SR, Muthumari J, Hur BK (2008b) Production of taxol from Phyllosticta spinarum, an endophytic fungus of Cupressus sp. Eng Life Sci 8(4):438–446
Kumaran RS, Muthumary J, Hur BK (2009) Isolation and identification of an anticancer drug, taxol from Phyllosticta tabernaemontanae, a leaf spot fungus of an angiosperm Wrightia tinctoria. J Microbiol 47(1):40–49
Kumaran RS, Kim HJ, Hur BK (2010) Taxol promising fungal endophyte, Pestalotiopsis species isolated from Taxus cuspidata. J Biosci Bioeng 110(5):541–546
Kumaran RC, Jung H, Kim HJ (2011) In vitro screening of taxol, an anticancer drug produced by the fungus, Colletotrichum capsici. Eng Life Sci 11:264–271
Kumaran RS, Choi YK, Lee S, Jeon HJ, Jung H, Kim HJ (2012) Isolation of taxol, an anticancer drug produced by the endophytic fungus, Phoma betae. Afr J Biotechnol 11(4):950–960
Kusari S, Singh S, Jayabaskaran C (2014) Rethinking production of Taxol (paclitaxel) using endophyte biotechnology. Trends Biotechnol 32(6):304–311
Li JY, Strobel G, Sidhu R et al (1996) Endophytic taxol-producing fungi from bald cypress, Taxodium distichum. Microbiology 142(8):2223–2236
Li JY, Sidhu RS, Ford EJ, Long DM, Hess WM, Strobel GA (1998) The induction of taxol production in the endophytic fungus Pericona sp. from Torreya grandifolia. J Ind Microbiol Bio-technol 20:259–264
Li CT, Li Y, Wang Q, Sung C (2008) Taxol production by Fusarium Arthrosporioides isolated from yew, Taxus cuspidata. J Med Biochem 27(4):454–458
Li FL, Qiu DY, Ma XJ et al (2009) Suppression of taxoid 14β-hydroxylase gene expression in Taxus x media via RNA interference. China Biotechnol 29(5):55–60
Li D, Fu D, Zhang Y et al (2017) Isolation, purification, and identification of taxol and related taxanes from taxol-producing fungus Aspergillus niger subsp. taxi. J Microbiol Biotechnol 27(8):1379–1385
Liu WH, Yao B, Zhu SQ et al (2009) Advances in studies on biosynthetic pathway of taxol precursor and its correlative biotechnology. Chin Tradit Herb Drugs 40(8):1327–1331
Mansukhlal CW, Harold LT, Monroe EW, Philip C, Andrew TM (1971) Plant anti-cancer agents. VI. The isolation and structure of taxol, a novel antileukemic and anti-cancer agent from Taxus brevifolia. J Am Chem Soc 93:2325–2327
Meng H, Wang Y, Hua Q et al (2011) In silico analysis and experimental improvement of taxadiene heterologous biosynthesis in Escherichia coli. Biotechnol Bioprocess Eng 16:205–215
Meyer V (2008) Genetic engineering of filamentous fungi—progress, obstacles and future trends. Biotechnol Adv 26:177–185. https://doi.org/10.1016/j.biotechadv.2007.12.001
Miao Z, Wang Y, Yu X, Guo B, Tang K (2009) New endophytic taxane production fungus from T. chinensis. Appl Biochem Microbiol 45:81–86
Michielse CB, Hooykaas PJJ, van den Hodel C, Ram A (2008) Agrobacterium mediated transformation of the filamentous fungus Aspergillus awamori. Nat Protocol 3(10):1671–1678
Mirjalili MH, Farzaneh M, Bonfill M, Rezadoost H, Ghassempour A (2012) Isolation and characterization of Stemphylium sedicola SBU-16 as a new endophytic taxol-producing fungus from Taxus baccata grown in Iran. FEMS Microbiol Lett 328(2):122–129
Miu CD, Hong K (2007) Research progress on the technology of fungi classification. J Anhui Agric Sci 35:6695–6697
Oehme M, Berger U, Brombacher S, Kuhn F, Kolliker S (2002) Trace analysis by HPLC-MS: contamination problems and systematic errors. Trends Anal Chem 21:322–331
Pandey AK, Reddy MS, Suryanarayanan TS (2003) ITS RFLP and ITS sequence analysis of a foliar endophytic Phyllosticta from different tropical trees. Mycol Res 107:439–444. https://doi.org/10.1017/S0953756203007494
Pandi M, Manikandan R, Muthumary J (2010) Anticancer activity of fungal taxol derived from Botryodiplodia theobromae Pat. An endophytic fungus against 7, dimethyl benz(a) anthracene(DMBA) induced mammary gland carcinogenesis in Sprague dawley rats. Biomed Pharmacother 64(1):48–53
Petrini O (1986) Taxonomy of endophytic fungi of aerial plant tissues. Microbiol Plant Microbe Interact 16:580–587
Rohmer M, Knani M, Simonin P et al (1993) Isoprenoid biosynthesis in bacteria: a novel pathway for the early steps leading to isopentenyl diphosphate. Biochem J 295(2):517–524
Sah B, Subban K, Chelliah J (2017) Cloning and sequence analysis of 10-deacetylbaccatin III-10-O-acetyl transferase gene and WRKY1 transcription factor from taxol-producing endophytic fungus Lasiodiplodia theobromea. FEMS Microbiol Lett. https://doi.org/10.1093/femsle/fnx253
Schiff PB, Fant J, Horwitz SB (1979) Promotion of microtubule assembly in vitro by Taxol. Nature 277:665–667
Senthikumaran R, KimHJ Hur BK (2010) Taxol promising fungal endophyte Pestalotiopsis species isolated from taxus cuspidate. J Biosci Bioeng 110(5):541–546
Senthil Kumaran R, Muthumary J, Hur BK (2008) Production of taxol from Phyllosticta spinarum, an endophytic fungus of Cupressus sp. Eng Life Sci 8(4):438–446
Service R (2000) Hazel tree offers a new source of a cancer drug. Science 288:27–28
Shankar Naik B (2009) Taxonomic placement for mycelia sterilia in endophytic fungal research: a molecular approach. Curr Sci 97(9):1276–1277
Shankar Naik B, Shashikala J, Krishnamurthy YL (2006) Study on the diversity of endophytic communities from rice (Oryza sativa L.) and their antagonistic activities in vitro. Microbiol Res 3:290–296
Shankar Naik B, Shashikala J, Krishnamurthy YL (2008) Diversity of endophytic fungal communities in shrubby medicinal plants of Western Ghat region, Southern India. Fungal Ecol 1:89–93
Shrestha K, Strobel GA, Shrivastava SP, Gewali MB (2001) Evidence for paclitaxel from three new endophytic fungi of Himalayan yew of Nepal. Planta Med 67:374–376
Simon JR, Moore PD (1987) Homologous recombination between single stranded DNA and chromosomal genes in Saccharomyces cerevisiae. Mol Cell Biol 7(7):2329–2334
Soliman SSM, Raizada MN (2013) Interactions between co-habitating fungi elicit synthesis of taxol from an endophytic fungus in host Taxus plants. Front Microbiol 4:1–14
Stahlhut R, Park G, Peterson R et al (1999) The occurrence of antitumor diterpene Taxol in Podocarpus gracilor Pilger (Podocarpaceae). Biochem Syst Ecol 27:613–622
Staniek A, Woerdenbag HJ, Kayser O (2009) Taxomyces andreanae: a presumed paclitaxel producer demystified. Planta Med 75:1561–1566
Stierle A, Strobel G, Stierle D (1993) Taxol and taxane production by Taxomyces andreanae, an endophytic fungus of pacific yew. Science 260(5105):214–216
Stierle A, Strobel G, Stierle D, Grothaus P, Bignami G (1995) The search for a taxol-producing microorganism among the endophytic fungi of the Pacific yew, Taxus brevifolia. J Nat Prod 58:1315–1324
Strobel G, Yang XS, Sears J et al (1996a) Taxol from Pestalotiopsis microspora, an endophytic fungus of Taxus wallachiana. Microbiology 142(2):435–440
Strobel GA, Hess WM, Ford E, Sidhu RS, Yang X (1996b) Taxol from fungal endophytes and the issue of biodiversity. J Ind Microbiol 17:417–423
Strobel GA, Hess WM, Li JY, Ford E, Sears J, Sidhu RS, Summerell B (1997) Pestalotiopsis guepinii, a taxol-producing endophyte of the Wollemi pine, Wollemia nobilis. Aust J Bot 45:1073–1082
Strobel GA, Ford E, Li JY et al (1999) Seimatoantlerium tepuiense gen. nov., a unique epiphytic fungus producing taxol from the Venezuelan Guyana. Syst Appl Microbiol 22(3):426–433
Subban K, Singh S, Subramani R, Mthumary J, Chelliah J (2017) Fungal 7-epi- 10-deacetyl taxol peroduced by an endophytic Pestalotiopsis microspora induces apoptosis in human hepatocellular carcinoma cell line (HepG2). BMC Complement Altern Med 17:504
Sun DF, Ran XQ, Wang JF (2008) Isolation and identification of a taxol-producing endophytic fungus from Podocarpus. Acta Microbiol Sin 48(5):589–595
Tian RP, Yang Q, Zhou GL et al (2006) Taxonomic study on a taxol producing fungus isolated from the bark of Taxus chinensis var. mairei. J Wuhan Bot Res 24(6):541–545
Venkatachalam R, Subban K, Paul MJ (2008) Taxol from Botryodiplodia theobromae (BT 115)-an endophytic fungus of Taxus baccata. J Biotechnol 136:189–190
Walker K, Croteau R (2001) Taxol biosynthetic genes. Phytochemistry 58:1–7
Wang Y, Tang KX (2011) A new endophytic taxol- and baccatin III-producing fungus isolated from Taxus chinensis var. mairei. Afr J Biotechnol 10:16379–16386
Wang JF, Li GL, Lu HY et al (2000) Taxol from Tubercularia sp. strain TF5, an endophytic fungus of Taxus mairei. FEMS Microbiol Lett 193(2):249–253
Wang Y, Guo LD, Hyde KD (2005) Taxonomic placements of sterile morphotypes of endophytic fungi from Pinus tabulaeformis (Pinaceae) from northeast China based on rDNA sequences. Fungal Div 20:235–260
Wang Y, Guo B, Miao Z, Tang K (2007) Transformation of taxol producing fungi by restriction enzyme–mediated integratiom (REMI). FEMS Microbiol Lett 273(2):253–259
Wang Y-F, Shi QW, Dong M et al (2011) Natural taxanes: developments since 1828. Chem Rev 111:7652–7709
Wang X, Wang C, Sun YT, Sun CZ, Zhang Y, Wang XH, Zhao K (2015) Taxol produced from endophytic fungi induces apoptosis in human breast, cervical and ovarian cancer cells. Asian Pac J Can Prev 16(1):125–131
Wei YM (2008) Isolation and genetic transformation of taxol-producing endophytic fungi from Taxus. Dissertation, Fudan University, Shanghai, China
Wei Y, Liu L, Zhou X, Tang K (2012) Engineering Taxol biosynthetic pathway for improving Taxol yield in Taxol-producing endophytic fungus EFY-21 (Ozonium sp.). Afr J Biotechnol 11:9094–9101
Xiong ZQ, Yang YY, Zhao N et al (2013) Diversity of endophytic fungi and screening of fungal paclitaxel producer from Anglo jap yew, Taxus x media. BMC Microbiol 13:71
Xu F, Tao WY, Cheng L, Guo LJ (2006) Strain improvement and optimization of the media of taxol-producing fungus Fusarium mairei. Biochem Eng J 31:67–73
Yang SS, Zhou JC (2004) Biology of microorganisms. Science Press, Beijing
Yoo JJ, Eom AH (2012) Molecular identification of endophytic fungi isolated from needle leaves of conifers in Bonyeon mountain, Korea. Mycobiology 40(4):231–235
Yu Y, Hu CH (2007) Separation and identification of a new Taxus chinensis var. mairei endophytic fungus (Bionectria sp.) and the activity of its metabolites. J Southwest Univ Nat Sci Ed 29(6):131–135
Zhang L, Gu S, Shao H, Wei R (1999) Isolation, determination and aroma product characterization of fungus producing iron. Mycosystema 18:49–54
Zhang P, Zhou PP, Yu LJ (2009a) An endophytic taxol-producing fungus from Taxus x media, Aspergillus candidus MD3. FEMS Microbiol Lett 293(2):155–159
Zhang P, Zhou PP, Yu LJ (2009b) An endophytic taxol-producing fungus from Taxus media, Cladosporium cladosporioides MD2. Curr Microbiol 59(3):227–232
Zhao K, Ping W, Zhang L et al (2008) Screening and breeding of high taxol producing fungi by genome shuffling. Sci China C Life Sci 51:222–231
Zhao K, Ping WX, Li Q et al (2009) Aspergillus niger var. taxi, a new species variant of taxol-producing fungus isolated from Taxus cuspidata in China. J Appl Microbiol 107(4):1202–1207
Zhao K, Sun LX, Wang X et al (2011) Screening of high taxol producing fungi by mutagenesis and construction of subtracted cDNA library by Suppression substracted hybridization for differentially expressed genes. Acta Microbiol Sin 51(7):923–933
Zhao K, Lu Y, Yuyan J, Xueling M et al (2016) Advances and prospects of taxol biosynthesis by endophytic fungi. Chin J Biotech 2532(8):1039–1051
Zhou DP, Sun JQ, Yu HY et al (2001) Nodulisporium, a genus new to China. Mycosystema 20(2):148–149
Zhou D, Zhao K, Ping W et al (2005) Study on the mutagenesis of protoplasts from taxol-producing fungus Nodulisporium sylviforme. J Am Sci 1(1):55–62
Zhou XW, Wang ZN, Jiang KJ, Wei M, Lin J, Sun XF, Tang KX (2007) Screening of taxol producing endophytic fungi from Taxus chenensis var mairei. Appl Biochem Microbiol 43:439–443
Zhou XW, Wei YM, Zhu HF, Wang ZN, Lin J, Liu L, Tang KX (2008) Protoplast formation, regeneration and transformation from the taxol-producing fungus Ozonium sp. Afr J Biotechnol 7:2017–2024
Zhou X, Zhu H, Liu L et al (2010) A review: recent advances and future prospects of taxol-producing endophytic fungi. Appl Microbiol Biotechnol. https://doi.org/10.1007/s00253-010-2546-y
Acknowledgements
Authors are grateful to Dr. Syed Abrar for his kind help during preparation of the manuscript. Author also thankful to Kuvempu University for providing the laboratory facilities in Department of Applied Botany, University Grants Commission, India for providing financial support to B. Shankar Naik during the research period.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Ethical statement
N/A.
Conflict of interest
This manuscript described has not been published before; not under consideration for publication anywhere else; and has been approved by all co-authors.
Rights and permissions
About this article
Cite this article
Shankar Naik, B. Developments in taxol production through endophytic fungal biotechnology: a review. Orient Pharm Exp Med 19, 1–13 (2019). https://doi.org/10.1007/s13596-018-0352-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13596-018-0352-8