Generic placeholder image

Current Analytical Chemistry

Author(s): Carlos Polanco*, Vladimir N. Uversky, Alberto Huberman, Enrique Hernandez-Lemus, Mireya Martínez-Garcia, Claudia Pimentel Hernández, Martha Rios Castro, Thomas Buhse, Gilberto Vargas Alarcon, Jorge Alberto Castañón González, Juan Luciano Díaz González, Mauricio Missael Sanchez Díaz, Erika Jeannette López Oliva, Francisco J. Roldan Gomez and Brayans Becerra Luna

DOI: 10.2174/0115734110271243231123160146

DownloadDownload PDF Flyer Cite As
A Bioinformatics Study of the Influenza H5N1 Virus that Infects Wild Fowl and Poultry and, Potentially, Humans

Page: [743 - 764] Pages: 22

  • * (Excluding Mailing and Handling)

Abstract

Introduction: More than sixteen countries are infected with the highly pathogenic avian influenza A-H5N1 virus. As the virus circles the world, it has led to the slaughter of millions of poultry birds as well as the infection of farmed mink in Europe and among seals and grizzly bears on the Northern coast of America; some infected mammals exhibited neurological symptoms like disorientation and blindness, which marks the first large H5N1 outbreak potentially driven by mammal-tomammal transmission that could be poised to spillover into humans its mortality rate in humans exceeds 50%. The virus pandemic potential is continuously monitored to characterize further and analyze its zoonotic potential (PAHO/WHO, March 2023).

Objective: To gain comprehension of the envelope glycoproteins that express H5N1 influenza (hemagglutinin and neuraminidase proteins), computational studies were carried out.

Methods: Calculating each sequence's Protein Intrinsic Disorder Predisposition (PIDP) and Polarity Index Method Profile 2.0 v (PIM 2.0 v) required the employment of multiple computer algorithms.

Results: The analysis of the PIM 2.0 v and PIDP profiles revealed specific patterns within the envelope glycoproteins (neuraminidase and hemagglutinin) of diverse strains of the H5N1 influenza virus. These patterns made it possible to identify structural and morphological similarities.

Conclusion: Using the PIM 2.0 v profile, our computational programs were able to identify the influenza H5N1 virus envelope glycoproteins (hemagglutinin and neuraminidase strains). This study contributes to a better comprehension of this emerging virus.

Graphical Abstract

[1]
Beigel, J.H.; Farrar, J.; Han, A.M.; Hayden, F.G.; Hyer, R.; de Jong, M.D.; Lochindarat, S.; Nguyen, T.K.; Nguyen, T.H.; Tran, T.H.; Nicoll, A.; Touch, S.; Yuen, K.Y. Avian influenza A (H5N1) infection in humans. N. Engl. J. Med., 2005, 353(13), 1374-1385.
[http://dx.doi.org/10.1056/NEJMra052211] [PMID: 16192482]
[2]
Smith, W.; Andrewes, C.H.; Laidlaw, P.P. A virus obtained from influenza patients. Lancet, 1933, 222(5732), 66-68.
[http://dx.doi.org/10.1016/S0140-6736(00)78541-2]
[3]
Colman, P.M.; Varghese, J.N.; Laver, W.G. Structure of the catalytic and antigenic sites in influenza virus neuraminidase. Nature, 1983, 303(5912), 41-44.
[http://dx.doi.org/10.1038/303041a0] [PMID: 6188957]
[4]
Parvin, J.D.; Moscona, A.; Pan, W.T.; Leider, J.M.; Palese, P. Measurement of the mutation rates of animal viruses: Influenza A virus and poliovirus type 1. J. Virol., 1986, 59(2), 377-383.
[http://dx.doi.org/10.1128/jvi.59.2.377-383.1986] [PMID: 3016304]
[5]
World Health Organization Avian Influenza Weekly Update, 2003, 893, 2003. Available from: https://www.ecdc.europa.eu/sites/default/files/documents/Avian%20Influenza%20Overview%20Sep-Dec%202022.pdf
[6]
Bairoch, A.; Apweiler, R.; Wu, C.H.; Barker, W.C.; Boeckmann, B.; Ferro, S.; Gasteiger, E.; Huang, H.; Lopez, R.; Magrane, M.; Martin, M.J.; Natale, D.A.; O’Donovan, C.; Redaschi, N.; Yeh, L.S. The universal protein resource (UniProt). Nucleic Acids Res., 2005, 33(Database issue), D154-D159.
[7]
Mészáros, B. Erdős, G.; Dosztányi, Z. IUPred2A: Context-dependent prediction of protein disorder as a function of redox state and protein binding. Nucleic Acids Res., 2018, 46(W1), W329-W337.
[http://dx.doi.org/10.1093/nar/gky384] [PMID: 29860432]
[8]
Obradovic, Z.; Peng, K.; Vucetic, S.; Radivojac, P.; Dunker, A.K. Exploiting heterogeneous sequence properties improves prediction of protein disorder. Proteins, 2005, 61(S7), 176-182.
[http://dx.doi.org/10.1002/prot.20735] [PMID: 16187360]
[9]
Peng, K.; Radivojac, P.; Vucetic, S.; Dunker, A.K.; Obradovic, Z. Length-dependent prediction of protein intrinsic disorder. BMC Bioinformatics, 2006, 7(1), 208.
[http://dx.doi.org/10.1186/1471-2105-7-208] [PMID: 16618368]
[10]
Romero, P.; Obradovic, Z.; Li, X.; Garner, E.C.; Brown, C.J.; Dunker, A.K. Sequence complexity of disordered protein. Proteins, 2001, 42(1), 38-48.
[http://dx.doi.org/10.1002/1097-0134(20010101)42:1<38:AID-PROT50>3.0.CO;2-3] [PMID: 11093259]
[11]
Xue, B.; Dunbrack, R.L.; Williams, R.W.; Dunker, A.K.; Uversky, V.N. PONDR-FIT: A meta-predictor of intrinsically disordered amino acids. Biochim. Biophys. Acta. Proteins Proteomics, 2010, 1804(4), 996-1010.
[http://dx.doi.org/10.1016/j.bbapap.2010.01.011] [PMID: 20100603]
[12]
Dayhoff, G.W., II; Uversky, V.N. Rapid prediction and analysis of protein intrinsic disorder. Protein Sci., 2022, 31(12), e4496.
[http://dx.doi.org/10.1002/pro.4496] [PMID: 36334049]
[13]
Zhou, J.; Oldfield, C.J.; Yan, W.; Shen, B.; Dunker, A.K. Identification of intrinsic disorder in complexes from the protein data bank. ACS Omega, 2020, 5(29), 17883-17891.
[http://dx.doi.org/10.1021/acsomega.9b03927] [PMID: 32743159]
[14]
Gautam, A.; Singh, H.; Tyagi, A.; Chaudhary, K.; Kumar, R.; Kapoor, P.; Raghava, G.P.S. CPPsite: A curated database of cell penetrating peptides. Database , 2012, 2012(0), bas015.
[http://dx.doi.org/10.1093/database/bas015] [PMID: 22403286]
[15]
Polanco, C.; Castañón-González, J.A.; Uversky, V.N.; Buhse, T.; Samaniego Mendoza, J.L.; Calva, J.J. Electronegativity and intrinsic disorder of preeclampsia-related proteins. Acta Biochim. Pol., 2017, 64(1), 99-111.
[PMID: 27824362]
[16]
Polanco, C.; Huberman, A.; Hernández-Lemus, E.; Uversky, V.N.; Rios Castro, M.; Martínez-Garcia, M.; Vargas-Alarcón, G.; Buhse, T.; Pimentel Hernández, C.; Zazueta, C.; Roldan Gomez, F.R.; López Oliva, E.J. Bioinformatics-based characterization of the variability of MPOX virus proteins. Lett. Drug Des. Discovign., 2024.
[17]
Rajagopalan, K.; Mooney, S.M.; Parekh, N.; Getzenberg, R.H.; Kulkarni, P. A majority of the cancer/testis antigens are intrinsically disordered proteins. J. Cell. Biochem., 2011, 112(11), 3256-3267.
[http://dx.doi.org/10.1002/jcb.23252] [PMID: 21748782]
[18]
Winter, D.J. entrez: An R package for the NCBI eUtils API. R J., 2019, 9(2), 520-526.
[19]
Sealy, J.E.; Howard, W.A.; Molesti, E.; Iqbal, M.; Temperton, N.J.; Banks, J.; Slomka, M.J.; Barclay, W.S.; Long, J.S. Amino acid substitutions in the H5N1 avian influenza haemagglutinin alter pH of fusion and receptor binding to promote a highly pathogenic phenotype in chickens. J. Gen. Virol., 2021, 102(11), 001672.
[http://dx.doi.org/10.1099/jgv.0.001672] [PMID: 34726594]
[20]
Zhang, Y.; Sun, Y.; Sun, H.; Pu, J.; Bi, Y.; Shi, Y.; Lu, X.; Li, J.; Zhu, Q.; Gao, G.F.; Yang, H.; Liu, J. A single amino acid at the hemagglutinin cleavage site contributes to the pathogenicity and neurovirulence of H5N1 influenza virus in mice. J. Virol., 2012, 86(12), 6924-6931.
[http://dx.doi.org/10.1128/JVI.07142-11] [PMID: 22496231]
[21]
de Vries, R.P.; Tzarum, N.; Peng, W.; Thompson, A.J.; Ambepitiya Wickramasinghe, I.N.; de la Pena, A.T.T.; van Breemen, M.J.; Bouwman, K.M.; Zhu, X.; McBride, R.; Yu, W.; Sanders, R.W.; Verheije, M.H.; Wilson, I.A.; Paulson, J.C. A single mutation in taiwanese h6n1 influenza hemagglutinin switches binding to human type receptors. EMBO Mol. Med., 2017, 9(9), 1314-1325.
[http://dx.doi.org/10.15252/emmm.201707726] [PMID: 28694323]
[22]
Han, P.F.; Li, J.; Hu, Y.; Sun, W.; Zhang, S.; Yang, Y.H.; Li, Y.C.; Kang, X.P.; Wu, X.Y.; Zhu, S.Y.; Zhang, Y.; Zhu, Q.Y.; Qin, C.F.; Jiang, T. H5N1 influenza A virus with K193E and G225E double mutations in haemagglutinin is attenuated and immunogenic in mice. J. Gen. Virol., 2015, 96(9), 2522-2530.
[http://dx.doi.org/10.1099/vir.0.000193] [PMID: 25998916]
[23]
Tan, L.; Su, S.; Smith, D.K.; He, S.; Zheng, Y.; Shao, Z.; Ma, J.; Zhu, H.; Zhang, G. A combination of HA and PA mutations enhances virulence in a mouse-adapted H6N6 influenza A virus. J. Virol., 2014, 88(24), 14116-14125.
[http://dx.doi.org/10.1128/JVI.01736-14] [PMID: 25275121]
[24]
Velkov, T.; Ong, C.; Baker, M.A.; Kim, H.; Li, J.; Nation, R.L.; Huang, J.X.; Cooper, M.A.; Rockman, S. The antigenic architecture of the hemagglutinin of influenza H5N1 viruses. Mol. Immunol., 2013, 56(4), 705-719.
[http://dx.doi.org/10.1016/j.molimm.2013.07.010] [PMID: 23933511]
[25]
Li, Z.; Liu, Z.; Ma, C.; Zhang, L.; Su, Y.; Gao, G.F.; Li, Z.; Cui, L.; He, W. Identification of amino acids in highly pathogenic avian influenza H5N1 virus hemagglutinin that determine avian influenza species specificity. Arch. Virol., 2011, 156(10), 1803-1812.
[http://dx.doi.org/10.1007/s00705-011-1056-2] [PMID: 21744000]
[26]
Schrauwen, E.J.A.; Herfst, S.; Leijten, L.M.; van Run, P.; Bestebroer, T.M.; Linster, M.; Bodewes, R.; Kreijtz, J.H.C.M.; Rimmelzwaan, G.F.; Osterhaus, A.D.M.E.; Fouchier, R.A.M.; Kuiken, T.; van Riel, D. The multibasic cleavage site in H5N1 virus is critical for systemic spread along the olfactory and hematogenous routes in ferrets. J. Virol., 2012, 86(7), 3975-3984.
[http://dx.doi.org/10.1128/JVI.06828-11] [PMID: 22278228]
[27]
Suguitan, A.L., Jr; Matsuoka, Y.; Lau, Y.F.; Santos, C.P.; Vogel, L.; Cheng, L.I.; Orandle, M.; Subbarao, K. The multibasic cleavage site of the hemagglutinin of highly pathogenic A/Vietnam/1203/2004 (H5N1) avian influenza virus acts as a virulence factor in a host-specific manner in mammals. J. Virol., 2012, 86(5), 2706-2714.
[http://dx.doi.org/10.1128/JVI.05546-11] [PMID: 22205751]
[28]
Abdelwhab, E.S.M.; Veits, J.; Tauscher, K.; Ziller, M.; Grund, C.; Hassan, M.K.; Shaheen, M.; Harder, T.C.; Teifke, J.; Stech, J.; Mettenleiter, T.C. Progressive glycosylation of the haemagglutinin of avian influenza H5N1 modulates virus replication, virulence and chicken-to-chicken transmission without significant impact on antigenic drift. J. Gen. Virol., 2016, 97(12), 3193-3204.
[http://dx.doi.org/10.1099/jgv.0.000648] [PMID: 27902339]
[29]
Zhang, X.J.; Li, Y.F.; Xiong, L.P.; Chen, S.J.; Peng, D.X.; Liu, X.F. Bing du xue bao. Chin. J. Virol., 2013, 29(5), 495-499.
[30]
Zaraket, H.; Bridges, O.A.; Duan, S.; Baranovich, T.; Yoon, S.W.; Reed, M.L.; Salomon, R.; Webby, R.J.; Webster, R.G.; Russell, C.J. Increased acid stability of the hemagglutinin protein enhances H5N1 influenza virus growth in the upper respiratory tract but is insufficient for transmission in ferrets. J. Virol., 2013, 87(17), 9911-9922.
[http://dx.doi.org/10.1128/JVI.01175-13] [PMID: 23824818]
[31]
Zaraket, H.; Bridges, O.A.; Russell, C.J. The pH of activation of the hemagglutinin protein regulates H5N1 influenza virus replication and pathogenesis in mice. J. Virol., 2013, 87(9), 4826-4834.
[http://dx.doi.org/10.1128/JVI.03110-12] [PMID: 23449784]
[32]
Vongsakul, M.; Kasisith, J.; Noisumdaeng, P.; Puthavathana, P. The difference in IL-1beta, MIP-1alpha, IL-8 and IL-18 production between the infection of PMA activated U937 cells with recombinant vaccinia viruses inserted 2004 H5N1 influenza HA genes and NS genes. Asian Pac. J. Allergy Immunol., 2011, 29(4), 349-356.
[PMID: 22299315]
[33]
Das, P.; Li, J.; Royyuru, A.K.; Zhou, R. Free energy simulations reveal a double mutant avian H5N1 virus hemagglutinin with altered receptor binding specificity. J. Comput. Chem., 2009, 30(11), 1654-1663.
[http://dx.doi.org/10.1002/jcc.21274] [PMID: 19399777]
[34]
Matsuoka, Y.; Swayne, D.E.; Thomas, C.; Rameix-Welti, M.A.; Naffakh, N.; Warnes, C.; Altholtz, M.; Donis, R.; Subbarao, K. Neuraminidase stalk length and additional glycosylation of the hemagglutinin influence the virulence of influenza H5N1 viruses for mice. J. Virol., 2009, 83(9), 4704-4708.
[http://dx.doi.org/10.1128/JVI.01987-08] [PMID: 19225004]
[35]
Floyd, T.; Banyard, A.C.; Lean, F.Z.X.; Byrne, A.M.P.; Fullick, E.; Whittard, E.; Mollett, B.C.; Bexton, S.; Swinson, V.; Macrelli, M.; Lewis, N.S.; Reid, S.M.; Núñez, A.; Duff, J.P.; Hansen, R.; Brown, I.H. Encephalitis and death in wild mammals at a rehabilitation center after infection with highly pathogenic avian influenza A(H5N8) virus, United Kingdom. Emerg. Infect. Dis., 2021, 27(11), 2856-2863.
[http://dx.doi.org/10.3201/eid2711.211225] [PMID: 34670647]
[36]
Oliver, I.; Roberts, J.; Brown, C.S.; Byrne, A.M.; Mellon, D.; Hansen, R.; Banyard, A.C.; James, J.; Donati, M.; Porter, R.; Ellis, J.; Cogdale, J.; Lackenby, A.; Chand, M.; Dabrera, G.; Brown, I.H.; Zambon, M. A case of avian influenza A(H5N1) in England, January 2022. Euro Surveill., 2022, 27(5), 2200061.
[37]
Tammiranta, N.; Isomursu, M.; Fusaro, A.; Nylund, M.; Nokireki, T.; Giussani, E.; Zecchin, B.; Terregino, C.; Gadd, T. Highly pathogenic avian influenza A (H5N1) virus infections in wild carnivores con-nected to mass mortalities of pheasants in Finland. Infect. Genet. Evol., 2023, 111, 105423.
[38]
Xu, Y.; Cao, H.; Liu, H.; Sun, H.; Martin, B.; Zhao, Y.; Wang, Q.; Deng, G.; Xue, J.; Zong, Y.; Zhu, J.; Wen, F.; Long, L.P.; Wong, S.S.; Zhao, N.; Fu, X.; Liao, M.; Hu, G.; Webby, R.; Gao, G.F.; Wan, X.F. Identification of the source of A (H10N8) virus causing human infection. Infect., genet. Evolu., 2015, 30, 159-163.
[39]
Yupiana, Y.; de Vlas, S.J.; Adnan, N.M.; Richardus, J.H. Risk factors of poultry outbreaks and human cases of H5N1 avian influenza virus infection in West Java Province, Indonesia. Int. J. Infect. Dis., 2010, 14(9), e800-e805.
[40]
Fournié, G.; Høg, E.; Barnett, T.; Pfeiffer, D.U.; Mangtani, P. A systematic review and meta-analysis of practices exposing humans to avian influenza viruses, their prevalence, and rationale. Am. J. Trop. Med. Hyg., 2017, 97(2), 376-388.
[http://dx.doi.org/10.4269/ajtmh.17-0014] [PMID: 28749769]
[41]
Angelava, N.A.; Angelava, A.V. Epidemiology, clinical picture, prevention and treatment of Avian influenza Georgian Med. News, 2006, 131(131), 69-76.
[PMID: 16575138]
[42]
Sha, J.; Dong, W.; Liu, S.; Chen, X.; Zhao, N.; Luo, M.; Dong, Y.; Zhang, Z. Differences in the epidemiology of childhood infections with avian influenza a H7N9 and H5N1 viruses. PLoS One, 2016, 11(10), e0161925.
[http://dx.doi.org/10.1371/journal.pone.0161925] [PMID: 27695069]
[43]
Boyd, M.; Clezy, K.; Lindley, R.; Pearce, R. Pandemic influenza: Clinical issues. Med. J. Aust., 2006, 185(S10), S44-S47.
[http://dx.doi.org/10.5694/j.1326-5377.2006.tb00706.x] [PMID: 17115951]
[44]
Mattila, J.M.; Vuorinen, T.; Waris, M.; Antikainen, P.; Heikkinen, T. Oseltamivir treatment of influenza A and B infections in infants. Influenza Other Respir. Viruses, 2021, 15(5), 618-624.
[http://dx.doi.org/10.1111/irv.12862] [PMID: 33939270]
[45]
Malosh, R.E.; Martin, E.T.; Heikkinen, T.; Brooks, W.A.; Whitley, R.J.; Monto, A.S. Efficacy and safety of oseltamivir in children: Systematic review and individual patient data meta-analysis of randomized controlled trials. Clin. Infect. Dis., 2018, 66(10), 1492-1500.
[http://dx.doi.org/10.1093/cid/cix1040] [PMID: 29186364]
[46]
Heinonen, S.; Silvennoinen, H.; Lehtinen, P.; Vainionpää, R.; Vahlberg, T.; Ziegler, T.; Ikonen, N.; Puhakka, T.; Heikkinen, T. Early oseltamivir treatment of influenza in children 1-3 years of age: A randomized controlled trial. Clin. Infect. Dis., 2010, 51(8), 887-894.
[http://dx.doi.org/10.1086/656408] [PMID: 20815736]
[47]
Aoki, F.Y.; Macleod, M.D.; Paggiaro, P.; Carewicz, O.; El Sawy, A.; Wat, C.; Griffiths, M.; Waalberg, E.; Ward, P. Early administration of oral oseltamivir increases the benefits of influenza treatment. J. Antimicrob. Chemother., 2003, 51(1), 123-129.
[http://dx.doi.org/10.1093/jac/dkg007] [PMID: 12493796]
[48]
Kim, J.H.; Drame, M.; Puthanakit, T.; Chiu, N.C.; Supparatpinyo, K.; Huang, L.M.; Chiu, C.H.; Chen, P.Y.; Hwang, K.P.; Danier, J.; Friel, D.; Salaun, B.; Woo, W.; Vaughn, D.W.; Innis, B.; Schuind, A. Immunogenicity and safety of AS03-adjuvanted H5N1 influenza vaccine in children 6-35 months of age. Pediatr. Infect. Dis. J., 2021, 40(9), e333-e339.
[http://dx.doi.org/10.1097/INF.0000000000003247] [PMID: 34285165]
[49]
Chanthavanich, P.; Versage, E.; Van Twuijver, E.; Hohenboken, M. Antibody responses against heterologous A/H5N1 strains for an MF59-adjuvanted cell culture–derived A/H5N1 (aH5N1c) influenza vaccine in healthy pediatric subjects. Vaccine, 2021, 39(47), 6930-6935.
[http://dx.doi.org/10.1016/j.vaccine.2021.10.010] [PMID: 34711436]
[50]
Rehman, S.; Effendi, M.H.; Witaningruma, A.M.; Nnabuikeb, U.E.; Bilal, M.; Abbas, A.; Abbas, R.Z.; Hussain, K. Avian influenza (H5N1) virus, epidemiology and its effects on backyard poultry in Indonesia: A review. F1000 Res., 2022, 11, 1321.
[http://dx.doi.org/10.12688/f1000research.125878.1] [PMID: 36845324]
[51]
Kuiken, T.; Taubenberger, J.K. Pathology of human influenza revisited. Vaccine, 2008, 26(S4), D59-D66.
[http://dx.doi.org/10.1016/j.vaccine.2008.07.025]
[52]
Klenk, H.D. Infection of the endothelium by influenza viruses. Thromb. Haemost., 2005, 94(8), 262-265.
[http://dx.doi.org/10.1160/TH05-04-0264] [PMID: 16113814]
[53]
Mifsud, E.J.; Kuba, M.; Barr, I.G. Innate immune responses to influenza virus infections in the upper respiratory tract. Viruses, 2021, 13(10), 2090.
[http://dx.doi.org/10.3390/v13102090] [PMID: 34696520]
[54]
Koutsakos, M.; Kedzierska, K.; Subbarao, K. Immune responses to avian influenza viruses. J. Immunol., 2019, 202(2), 382-391.
[55]
Zhao, Y.; Huang, F.; Zou, Z.; Bi, Y.; Yang, Y.; Zhang, C.; Liu, Q.; Shang, D.; Yan, Y.; Ju, X.; Mei, S.; Xie, P.; Li, X.; Tian, M.; Tan, S.; Lu, H.; Han, Z.; Liu, K.; Zhang, Y.; Liang, J.; Liang, Z.; Zhang, Q.; Chang, J.; Liu, W.J.; Feng, C.; Li, T.; Zhang, M.Q.; Wang, X.; Gao, G.F.; Liu, Y.; Jin, N.; Jiang, C. Avian influenza viruses suppress innate immunity by inducing trans-transcriptional readthrough via SSU72. Cell. Mol. Immunol., 2022, 19(6), 702-714.
[http://dx.doi.org/10.1038/s41423-022-00843-8] [PMID: 35332300]
[56]
Rimmelzwaan, G.F.; Katz, J.M. Immune responses to infection with H5N1 influenza virus. Virus Res., 2013, 178(1), 44-52.
[http://dx.doi.org/10.1016/j.virusres.2013.05.011] [PMID: 23735534]
[57]
Costa, M.; Goldberger, A.L.; Peng, C.K. Multiscale entropy analysis of biological signals. Phys. Rev. E Stat. Nonlin. Soft Matter Phys., 2005, 71(2), 021906.
[http://dx.doi.org/10.1103/PhysRevE.71.021906] [PMID: 15783351]
[58]
Cilibrasi, R.; Vitányi, P.M.B. Clustering by compression. IEEE Trans. Inf. Theory, 2005, 51(4), 1523-1545.
[http://dx.doi.org/10.1109/TIT.2005.844059]
[59]
Goldberger, A.L.; Amaral, L.A.; Hausdorff, J.M.; Ivanov, P.C. Fractal dynamics in physiology: Alterations with disease and aging. Proc. Natl. Acad. Sci., 2003, 99(S1), 2466-2472.
[60]
Lin, J. Divergence measures based on the Shannon entropy. IEEE Trans. Inf. Theory, 1991, 37(1), 145-151.
[http://dx.doi.org/10.1109/18.61115]