Review Article

青蛙皮肤肽抗感染治疗的潜力:Esculentin-1a(1-21)NH2的病例。

卷 27, 期 9, 2020

页: [1405 - 1419] 页: 15

弟呕挨: 10.2174/0929867326666190722095408

价格: $65

摘要

抗菌肽(AMPs)是先天免疫的关键效应物,代表了开发新抗菌药物的有前途的分子。但是,为了实现这一目标,需要克服一些问题:(i)高浓度时的细胞毒性作用; (ii)生物稳定性差,并且(iii)难以到达目标位置。蛙皮是AMPs最丰富的天然仓库之一,多年来,已从中分离出许多肽,对其进行了表征和分类,包括temporins,brevinins,Nigrocins和esculentins几个家族。在这篇综述中,我们总结了属于esculentin-1家族的肽的分离/表征如何推动我们设计具有强大抗菌作用和免疫调节特性的类似物esculentin-1a(1-21)NH2。该肽具有广泛的活性,特别是针对机会性革兰氏阴性菌铜绿假单胞菌。我们描述了该肽的结构特征和体外/体内生物学特性,以及用于改善其生物学特性的策略。其中:(i)设计一种带有D氨基酸的非对映异构体,以减少该肽的细胞毒性并提高其半衰期; (ii)肽与金纳米颗粒的共价缀合或将其封装到聚(丙交酯-共-乙交酯)纳米颗粒中; (iii)将肽固定在生物医学装置(例如硅水凝胶隐形眼镜)上以获得能够减少微生物生长和附着的抗菌表面。总结迄今为止所取得的最佳结果,本综述追溯了导致这些蛙皮AMP朝着基于肽的药物走向临床用途的所有步骤。

关键词: 抗菌肽,铜绿假单胞菌,先天免疫,金纳米颗粒,隐形眼镜,D-氨基酸,伤口愈合。

[1]
Boto, A.; Pérez de la Lastra, J.M.; González, C.C. The road from host-defense peptides to a new generation of antimicrobial drugs. Molecules, 2018, 23(2), E311
[http://dx.doi.org/10.3390/molecules23020311] [PMID: 29389911]
[2]
Ageitos, J.M.; Sánchez-Pérez, A.; Calo-Mata, P.; Villa, T.G. Antimicrobial peptides (AMPs): Ancient compounds that represent novel weapons in the fight against bacteria. Biochem. Pharmacol., 2017, 133, 117-138.
[http://dx.doi.org/10.1016/j.bcp.2016.09.018] [PMID: 27663838]
[3]
Maróti, G.; Kereszt, A.; Kondorosi, E.; Mergaert, P. Natural roles of antimicrobial peptides in microbes, plants and animals. Res. Microbiol., 2011, 162(4), 363-374.
[http://dx.doi.org/10.1016/j.resmic.2011.02.005] [PMID: 21320593]
[4]
Tang, S.S.; Prodhan, Z.H.; Biswas, S.K.; Le, C.F.; Sekaran, S.D. Antimicrobial peptides from different plant sources: Isolation, characterisation, and purification. Phytochemistry, 2018, 154, 94-105.
[http://dx.doi.org/10.1016/j.phytochem.2018.07.002] [PMID: 30031244]
[5]
Faye, I.; Lindberg, B.G. Towards a paradigm shift in innate immunity-seminal work by Hans G. Boman and co-workers. Philos. Trans. R. Soc. Lond. B Biol. Sci., 2016, 371(1695), 371.
[http://dx.doi.org/10.1098/rstb.2015.0303] [PMID: 27160604]
[6]
Lehrer, R.I. Primate defensins. Nat. Rev. Microbiol., 2004, 2(9), 727-738.
[http://dx.doi.org/10.1038/nrmicro976] [PMID: 15372083]
[7]
Berkowitz, B.A.; Bevins, C.L.; Zasloff, M.A. Magainins: a new family of membrane-active host defense peptides. Biochem. Pharmacol., 1990, 39(4), 625-629.
[http://dx.doi.org/10.1016/0006-2952(90)90138-B] [PMID: 1689576]
[8]
Steckbeck, J.D.; Deslouches, B.; Montelaro, R.C. Antimicrobial peptides: new drugs for bad bugs? Expert Opin. Biol. Ther., 2014, 14(1), 11-14.
[http://dx.doi.org/10.1517/14712598.2013.844227] [PMID: 24206062]
[9]
Sharma, K.; Aaghaz, S.; Shenmar, K.; Jain, R. Short antimicrobial peptides. Recent Pat Antiinfect Drug Discov, 2018, 13(1), 12-52.
[http://dx.doi.org/10.2174/1574891X13666180628105928] [PMID: 29952266]
[10]
Pasupuleti, M.; Schmidtchen, A.; Malmsten, M. Antimicrobial peptides: key components of the innate immune system. Crit. Rev. Biotechnol., 2012, 32(2), 143-171.
[http://dx.doi.org/10.3109/07388551.2011.594423] [PMID: 22074402]
[11]
Ganz, T. Defensins: antimicrobial peptides of innate immunity. Nat. Rev. Immunol., 2003, 3(9), 710-720.
[http://dx.doi.org/10.1038/nri1180] [PMID: 12949495]
[12]
Brogden, K.A.; Ackermann, M.; McCray, P.B. Jr.; Tack, B.F. Antimicrobial peptides in animals and their role in host defences. Int. J. Antimicrob. Agents, 2003, 22(5), 465-478.
[http://dx.doi.org/10.1016/S0924-8579(03)00180-8] [PMID: 14602364]
[13]
Boman, H.G. Antibacterial peptides: key components needed in immunity. Cell, 1991, 65(2), 205-207.
[http://dx.doi.org/10.1016/0092-8674(91)90154-Q] [PMID: 2015623]
[14]
Hancock, R.E.; Diamond, G. The role of cationic antimicrobial peptides in innate host defences. Trends Microbiol., 2000, 8(9), 402-410.
[http://dx.doi.org/10.1016/S0966-842X(00)01823-0] [PMID: 10989307]
[15]
Zasloff, M. Antimicrobial peptides of multicellular organisms. Nature, 2002, 415(6870), 389-395.
[http://dx.doi.org/10.1038/415389a] [PMID: 11807545]
[16]
Mangoni, M.L.; McDermott, A.M.; Zasloff, M. Antimicrobial peptides and wound healing: biological and therapeutic considerations. Exp. Dermatol., 2016, 25(3), 167-173.
[http://dx.doi.org/10.1111/exd.12929] [PMID: 26738772]
[17]
Bals, R. Epithelial antimicrobial peptides in host defense against infection. Respir. Res., 2000, 1(3), 141-150.
[http://dx.doi.org/10.1186/rr25] [PMID: 11667978]
[18]
Huang, H.W.; Charron, N.E. Understanding membrane-active antimicrobial peptides. Q. Rev. Biophys., 2017, 50e10
[http://dx.doi.org/10.1017/S0033583517000087] [PMID: 29233222]
[19]
Mangoni, M.L.; Papo, N.; Saugar, J.M.; Barra, D.; Shai, Y.; Simmaco, M.; Rivas, L. Effect of natural L- to D-amino acid conversion on the organization, membrane binding, and biological function of the antimicrobial peptides bombinins H. Biochemistry, 2006, 45(13), 4266-4276.
[http://dx.doi.org/10.1021/bi052150y] [PMID: 16566601]
[20]
Nicolas, P.; El Amri, C. The dermaseptin superfamily: a gene-based combinatorial library of antimicrobial peptides. Biochim. Biophys. Acta, 2009, 1788(8), 1537-1550.
[http://dx.doi.org/10.1016/j.bbamem.2008.09.006] [PMID: 18929530]
[21]
Wang, G. Post-translational modifications of natural antimicrobial peptides and strategies for peptide engineering. Curr. Biotechnol., 2012, 1(1), 72-79.
[http://dx.doi.org/10.2174/2211550111201010072] [PMID: 24511461]
[22]
Thaiss, C.A.; Levy, M.; Itav, S.; Elinav, E. Integration of innate immune signaling. Trends Immunol., 2016, 37(2), 84-101.
[http://dx.doi.org/10.1016/j.it.2015.12.003] [PMID: 26755064]
[23]
Hemshekhar, M.; Anaparti, V.; Mookherjee, N. Functions of cationic host defense peptides in immunity. Pharmaceuticals (Basel), 2016, 9(3), E40
[http://dx.doi.org/10.3390/ph9030040] [PMID: 27384571]
[24]
Davidson, D.J.; Currie, A.J.; Reid, G.S.; Bowdish, D.M.; MacDonald, K.L.; Ma, R.C.; Hancock, R.E.; Speert, D.P. The cationic antimicrobial peptide LL-37 modulates dendritic cell differentiation and dendritic cell-induced T cell polarization. J. Immunol., 2004, 172(2), 1146-1156.
[http://dx.doi.org/10.4049/jimmunol.172.2.1146] [PMID: 14707090]
[25]
Afacan, N.J.; Yeung, A.T.; Pena, O.M.; Hancock, R.E. Therapeutic potential of host defense peptides in antibiotic-resistant infections. Curr. Pharm. Des., 2012, 18(6), 807-819.
[http://dx.doi.org/10.2174/138161212799277617] [PMID: 22236127]
[26]
Mookherjee, N.; Hancock, R.E. Cationic host defence peptides: innate immune regulatory peptides as a novel approach for treating infections. Cell. Mol. Life Sci., 2007, 64(7-8), 922-933.
[http://dx.doi.org/10.1007/s00018-007-6475-6] [PMID: 17310278]
[27]
Rinaldi, A.C. Antimicrobial peptides from amphibian skin: an expanding scenario. Curr. Opin. Chem. Biol., 2002, 6(6), 799-804.
[http://dx.doi.org/10.1016/S1367-5931(02)00401-5] [PMID: 12470734]
[28]
Hancock, R.E.; Sahl, H.G. Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nat. Biotechnol., 2006, 24(12), 1551-1557.
[http://dx.doi.org/10.1038/nbt1267] [PMID: 17160061]
[29]
Powers, J.P.; Hancock, R.E. The relationship between peptide structure and antibacterial activity. Peptides, 2003, 24(11), 1681-1691.
[http://dx.doi.org/10.1016/j.peptides.2003.08.023] [PMID: 15019199]
[30]
Mojsoska, B.; Jenssen, H. Peptides and peptidomimetics for antimicrobial drug design. Pharmaceuticals (Basel), 2015, 8(3), 366-415.
[http://dx.doi.org/10.3390/ph8030366] [PMID: 26184232]
[31]
Mahlapuu, M.; Håkansson, J.; Ringstad, L.; Björn, C. Antimicrobial peptides: an emerging category of therapeutic agents. Front. Cell. Infect. Microbiol., 2016, 6, 194.
[http://dx.doi.org/10.3389/fcimb.2016.00194] [PMID: 28083516]
[32]
Hall, K.; Aguilar, M.I. Surface plasmon resonance spectroscopy for studying the membrane binding of antimicrobial peptides. Methods Mol. Biol., 2010, 627, 213-223.
[http://dx.doi.org/10.1007/978-1-60761-670-2_14] [PMID: 20217624]
[33]
Ehrenstein, G.; Lecar, H. Electrically gated ionic channels in lipid bilayers. Q. Rev. Biophys., 1977, 10(1), 1-34.
[http://dx.doi.org/10.1017/S0033583500000123] [PMID: 327501]
[34]
Zhang, L.; Rozek, A.; Hancock, R.E. Interaction of cationic antimicrobial peptides with model membranes. J. Biol. Chem., 2001, 276(38), 35714-35722.
[http://dx.doi.org/10.1074/jbc.M104925200] [PMID: 11473117]
[35]
Brogden, K.A. Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? Nat. Rev. Microbiol., 2005, 3(3), 238-250.
[http://dx.doi.org/10.1038/nrmicro1098] [PMID: 15703760]
[36]
Shai, Y. Mode of action of membrane active antimicrobial peptides. Biopolymers, 2002, 66(4), 236-248.
[http://dx.doi.org/10.1002/bip.10260] [PMID: 12491537]
[37]
Bechinger, B.; Gorr, S.U. Antimicrobial peptides: mechanisms of action and resistance. J. Dent. Res., 2017, 96(3), 254-260.
[http://dx.doi.org/10.1177/0022034516679973] [PMID: 27872334]
[38]
Conlon, J.M. Structural diversity and species distribution of host-defense peptides in frog skin secretions. Cell. Mol. Life Sci., 2011, 68(13), 2303-2315.
[http://dx.doi.org/10.1007/s00018-011-0720-8] [PMID: 21560068]
[39]
Wang, G.; Li, X.; Wang, Z. APD3: the antimicrobial peptide database as a tool for research and education. Nucleic Acids Res., 2016, 44(D1), D1087-D1093.
[http://dx.doi.org/10.1093/nar/gkv1278] [PMID: 26602694]
[40]
Xu, X.; Lai, R. The chemistry and biological activities of peptides from amphibian skin secretions. Chem. Rev., 2015, 115(4), 1760-1846.
[http://dx.doi.org/10.1021/cr4006704] [PMID: 25594509]
[41]
Mangoni, M.L. Temporins, anti-infective peptides with expanding properties. Cell. Mol. Life Sci., 2006, 63(9), 1060-1069.
[http://dx.doi.org/10.1007/s00018-005-5536-y] [PMID: 16572270]
[42]
Conlon, J.M. The contribution of skin antimicrobial peptides to the system of innate immunity in anurans. Cell Tissue Res., 2011, 343(1), 201-212.
[http://dx.doi.org/10.1007/s00441-010-1014-4] [PMID: 20640445]
[43]
Conlon, J.M.; Kolodziejek, J.; Nowotny, N. Antimicrobial peptides from the skins of North American frogs. Biochim. Biophys. Acta, 2009, 1788(8), 1556-1563.
[http://dx.doi.org/10.1016/j.bbamem.2008.09.018] [PMID: 18983817]
[44]
Pantic, J.M.; Jovanovic, I.P.; Radosavljevic, G.D.; Arsenijevic, N.N.; Conlon, J.M.; Lukic, M.L. The potential of frog skin-derived peptides for development into therapeutically-valuable immunomodulatory agents. Molecules, 2017, 22(12), E2071
[http://dx.doi.org/10.3390/molecules22122071] [PMID: 29236056]
[45]
Park, J.M.; Jung, J.E.; Lee, B.J. Antimicrobial peptides from the skin of a Korean frog, Rana rugosa. Biochem. Biophys. Res. Commun., 1995, 209(2), 775.
[http://dx.doi.org/10.1006/bbrc.1995.1567] [PMID: 7733950]
[46]
Conlon, J.M.; Kolodziejek, J.; Nowotny, N. Antimicrobial peptides from ranid frogs: taxonomic and phylogenetic markers and a potential source of new therapeutic agents. Biochim. Biophys. Acta, 2004, 1696(1), 1-14.
[http://dx.doi.org/10.1016/j.bbapap.2003.09.004] [PMID: 14726199]
[47]
Matutte, B.; Storey, K.B.; Knoop, F.C.; Conlon, J.M. Induction of synthesis of an antimicrobial peptide in the skin of the freeze-tolerant frog, Rana sylvatica, in response to environmental stimuli. FEBS Lett., 2000, 483(2-3), 135-138.
[http://dx.doi.org/10.1016/S0014-5793(00)02102-5] [PMID: 11042268]
[48]
Yan, H.; Hancock, R.E. Synergistic interactions between mammalian antimicrobial defense peptides. Antimicrob. Agents Chemother., 2001, 45(5), 1558-1560.
[http://dx.doi.org/10.1128/AAC.45.5.1558-1560.2001] [PMID: 11302828]
[49]
Rosenfeld, Y.; Barra, D.; Simmaco, M.; Shai, Y.; Mangoni, M.L. A synergism between temporins toward Gram-negative bacteria overcomes resistance imposed by the lipopolysaccharide protective layer. J. Biol. Chem., 2006, 281(39), 28565-28574.
[http://dx.doi.org/10.1074/jbc.M606031200] [PMID: 16867990]
[50]
Merlino, F.; Carotenuto, A.; Casciaro, B.; Martora, F.; Loffredo, M.R.; Di Grazia, A.; Yousif, A.M.; Brancaccio, D.; Palomba, L.; Novellino, E.; Galdiero, M.; Iovene, M.R.; Mangoni, M.L.; Grieco, P. Glycine-replaced derivatives of [Pro3,DLeu9]TL, a temporin L analogue: Evaluation of antimicrobial, cytotoxic and hemolytic activities. Eur. J. Med. Chem., 2017, 139, 750-761.
[http://dx.doi.org/10.1016/j.ejmech.2017.08.040] [PMID: 28863356]
[51]
Mangoni, M.L.; Grazia, A.D.; Cappiello, F.; Casciaro, B.; Luca, V. Naturally occurring peptides from Rana temporaria: Antimicrobial properties and more. Curr. Top. Med. Chem., 2016, 16(1), 54-64.
[http://dx.doi.org/10.2174/1568026615666150703121403] [PMID: 26139114]
[52]
Musale, V.; Casciaro, B.; Mangoni, M.L.; Abdel-Wahab, Y.H.A.; Flatt, P.R.; Conlon, J.M. Assessment of the potential of temporin peptides from the frog Rana temporaria (Ranidae) as anti-diabetic agents. J. Pept. Sci., 2018, 24(2)
[http://dx.doi.org/10.1002/psc.3065] [PMID: 29349894]
[53]
Marcocci, M.E.; Amatore, D.; Villa, S.; Casciaro, B.; Aimola, P.; Franci, G.; Grieco, P.; Galdiero, M.; Palamara, A.T.; Mangoni, M.L.; Nencioni, L. The amphibian antimicrobial peptide temporin B inhibits in vitro herpes simplex virus 1 infection. Antimicrob. Agents Chemother., 2018, 62(5), e02367
[http://dx.doi.org/10.1128/AAC.02367-17] [PMID: 29483113]
[54]
Musale, V.; Abdel-Wahab, Y.H.A.; Flatt, P.R.; Conlon, J.M.; Mangoni, M.L. Insulinotropic, glucose-lowering, and beta-cell anti-apoptotic actions of peptides related to esculentin-1a(1-21).NH2. Amino Acids, 2018, 50(6), 723-734.
[http://dx.doi.org/10.1007/s00726-018-2551-5] [PMID: 29549522]
[55]
Conlon, J.M. Reflections on a systematic nomenclature for antimicrobial peptides from the skins of frogs of the family Ranidae. Peptides, 2008, 29(10), 1815-1819.
[http://dx.doi.org/10.1016/j.peptides.2008.05.029] [PMID: 18585417]
[56]
Basir, Y.J.; Knoop, F.C.; Dulka, J.; Conlon, J.M. Multiple antimicrobial peptides and peptides related to bradykinin and neuromedin N isolated from skin secretions of the pickerel frog, Rana palustris. Biochim. Biophys. Acta, 2000, 1543(1), 95-105.
[http://dx.doi.org/10.1016/S0167-4838(00)00191-6] [PMID: 11087945]
[57]
Ali, M.F.; Lips, K.R.; Knoop, F.C.; Fritzsch, B.; Miller, C.; Conlon, J.M. Antimicrobial peptides and protease inhibitors in the skin secretions of the crawfish frog, Rana areolata. Biochim. Biophys. Acta, 2002, 1601(1), 55-63.
[http://dx.doi.org/10.1016/S1570-9639(02)00432-6] [PMID: 12429503]
[58]
Wang, H.; Yu, Z.; Hu, Y.; Yu, H.; Ran, R.; Xia, J.; Wang, D.; Yang, S.; Yang, X.; Liu, J. Molecular cloning and characterization of antimicrobial peptides from skin of the broad-folded frog, Hylarana latouchii. Biochimie, 2012, 94(6), 1317-1326.
[http://dx.doi.org/10.1016/j.biochi.2012.02.032] [PMID: 22426384]
[59]
Li, J.; Xu, X.; Xu, C.; Zhou, W.; Zhang, K.; Yu, H.; Zhang, Y.; Zheng, Y.; Rees, H.H.; Lai, R.; Yang, D.; Wu, J. Anti-infection peptidomics of amphibian skin. Mol. Cell. Proteomics, 2007, 6(5), 882-894.
[http://dx.doi.org/10.1074/mcp.M600334-MCP200] [PMID: 17272268]
[60]
Iwakoshi-Ukena, E.; Ukena, K.; Okimoto, A.; Soga, M.; Okada, G.; Sano, N.; Fujii, T.; Sugawara, Y.; Sumida, M. Identification and characterization of antimicrobial peptides from the skin of the endangered frog Odorrana ishikawae. Peptides, 2011, 32(4), 670-676.
[http://dx.doi.org/10.1016/j.peptides.2010.12.013] [PMID: 21193000]
[61]
Marenah, L.; Flatt, P.R.; Orr, D.F.; Shaw, C.; Abdel-Wahab, Y.H. Skin secretions of Rana saharica frogs reveal antimicrobial peptides esculentins-1 and -1B and brevinins-1E and -2EC with novel insulin releasing activity. J. Endocrinol., 2006, 188(1), 1-9.
[http://dx.doi.org/10.1677/joe.1.06293] [PMID: 16394170]
[62]
Conlon, J.M.; Meetani, M.A.; Coquet, L.; Jouenne, T.; Leprince, J.; Vaudry, H.; Kolodziejek, J.; Nowotny, N.; King, J.D. Antimicrobial peptides from the skin secretions of the New World frogs Lithobates capito and Lithobates warszewitschii (Ranidae). Peptides, 2009, 30(10), 1775-1781.
[http://dx.doi.org/10.1016/j.peptides.2009.07.011] [PMID: 19635516]
[63]
Conlon, J.M.; Kolodziejek, J.; Mechkarska, M.; Coquet, L.; Leprince, J.; Jouenne, T.; Vaudry, H.; Nielsen, P.F.; Nowotny, N.; King, J.D. Host defense peptides from Lithobates forreri, Hylarana luctuosa, and Hylarana signata (Ranidae): phylogenetic relationships inferred from primary structures of ranatuerin-2 and brevinin-2 peptides. Comp. Biochem. Physiol. Part D Genomics Proteomics, 2014, 9, 49-57.
[http://dx.doi.org/10.1016/j.cbd.2014.01.002] [PMID: 24463457]
[64]
Simmaco, M.; Mignogna, G.; Barra, D.; Bossa, F. Novel antimicrobial peptides from skin secretion of the European frog Rana esculenta. FEBS Lett., 1993, 324(2), 159-161.
[http://dx.doi.org/10.1016/0014-5793(93)81384-C] [PMID: 8508915]
[65]
Simmaco, M.; Mignogna, G.; Barra, D.; Bossa, F. Antimicrobial peptides from skin secretions of Rana esculenta. Molecular cloning of cDNAs encoding esculentin and brevinins and isolation of new active peptides. J. Biol. Chem., 1994, 269(16), 11956-11961.
[PMID: 8163497]
[66]
Wang, Y.; Zhang, Y.; Lee, W.H.; Yang, X.; Zhang, Y. Novel peptides from skins of amphibians showed broad-spectrum antimicrobial activities. Chem. Biol. Drug Des., 2016, 87(3), 419-424.
[http://dx.doi.org/10.1111/cbdd.12672] [PMID: 26452973]
[67]
Ponti, D.; Mignogna, G.; Mangoni, M.L.; De Biase, D.; Simmaco, M.; Barra, D. Expression and activity of cyclic and linear analogues of esculentin-1, an anti-microbial peptide from amphibian skin. Eur. J. Biochem., 1999, 263(3), 921-927.
[http://dx.doi.org/10.1046/j.1432-1327.1999.00597.x] [PMID: 10469159]
[68]
Segura, A.; Moreno, M.; Molina, A.; García-Olmedo, F. Novel defensin subfamily from spinach (Spinacia oleracea). FEBS Lett., 1998, 435(2-3), 159-162.
[http://dx.doi.org/10.1016/S0014-5793(98)01060-6] [PMID: 9762899]
[69]
Ponti, D.; Mangoni, M.L.; Mignogna, G.; Simmaco, M.; Barra, D. An amphibian antimicrobial peptide variant expressed in Nicotiana tabacum confers resistance to phytopathogens. Biochem. J., 2003, 370(Pt 1), 121-127.
[http://dx.doi.org/10.1042/bj20021444] [PMID: 12435273]
[70]
Orivel, J.; Redeker, V.; Le Caer, J.P.; Krier, F.; Revol-Junelles, A.M.; Longeon, A.; Chaffotte, A.; Dejean, A.; Rossier, J. Ponericins, new antibacterial and insecticidal peptides from the venom of the ant Pachycondyla goeldii. J. Biol. Chem., 2001, 276(21), 17823-17829.
[http://dx.doi.org/10.1074/jbc.M100216200] [PMID: 11279030]
[71]
Mangoni, M.L.; Fiocco, D.; Mignogna, G.; Barra, D.; Simmaco, M. Functional characterisation of the 1-18 fragment of esculentin-1b, an antimicrobial peptide from Rana esculenta. Peptides, 2003, 24(11), 1771-1777.
[http://dx.doi.org/10.1016/j.peptides.2003.07.029] [PMID: 15019209]
[72]
Islas-Rodrìguez, A.E.; Marcellini, L.; Orioni, B.; Barra, D.; Stella, L.; Mangoni, M.L. Esculentin 1-21: a linear antimicrobial peptide from frog skin with inhibitory effect on bovine mastitis-causing bacteria. J. Pept. Sci., 2009, 15(9), 607-614.
[http://dx.doi.org/10.1002/psc.1148] [PMID: 19507197]
[73]
Loffredo, M.R.; Ghosh, A.; Harmouche, N.; Casciaro, B.; Luca, V.; Bortolotti, A.; Cappiello, F.; Stella, L.; Bhunia, A.; Bechinger, B.; Mangoni, M.L. Membrane perturbing activities and structural properties of the frog-skin derived peptide Esculentin-1a(1-21)NH2 and its Diastereomer Esc(1-21)-1c: Correlation with their antipseudomonal and cytotoxic activity. Biochim. Biophys. Acta Biomembr., 2017, 1859(12), 2327-2339.
[http://dx.doi.org/10.1016/j.bbamem.2017.09.009] [PMID: 28912103]
[74]
Di Grazia, A.; Cappiello, F.; Cohen, H.; Casciaro, B.; Luca, V.; Pini, A.; Di, Y.P.; Shai, Y.; Mangoni, M.L. D-Amino acids incorporation in the frog skin-derived peptide esculentin-1a(1-21)NH2 is beneficial for its multiple functions. Amino Acids, 2015, 47(12), 2505-2519.
[http://dx.doi.org/10.1007/s00726-015-2041-y] [PMID: 26162435]
[75]
Klaas, I.C.; Zadoks, R.N. An update on environmental mastitis: Challenging perceptions. Transbound. Emerg. Dis., 2018, 65(Suppl. 1), 166-185.
[http://dx.doi.org/10.1111/tbed.12704] [PMID: 29083115]
[76]
Luca, V.; Stringaro, A.; Colone, M.; Pini, A.; Mangoni, M.L. Esculentin(1-21), an amphibian skin membrane-active peptide with potent activity on both planktonic and biofilm cells of the bacterial pathogen Pseudomonas aeruginosa. Cell. Mol. Life Sci., 2013, 70(15), 2773-2786.
[http://dx.doi.org/10.1007/s00018-013-1291-7] [PMID: 23503622]
[77]
Parkins, M.D.; Somayaji, R.; Waters, V.J. Epidemiology, biology, and impact of clonal Pseudomonas aeruginosa infections in cystic fibrosis. Clin. Microbiol. Rev., 2018, 31(4), e00019-e18.
[http://dx.doi.org/10.1128/CMR.00019-18] [PMID: 30158299]
[78]
Cappiello, F.; Casciaro, B.; Mangoni, M.L. A novel in vitro wound healing assay to evaluate cell migration. J. Vis. Exp., 2018, (133)
[http://dx.doi.org/10.3791/56825] [PMID: 29608162]
[79]
Cappiello, F.; Di Grazia, A.; Segev-Zarko, L.A.; Scali, S.; Ferrera, L.; Galietta, L.; Pini, A.; Shai, Y.; Di, Y.P.; Mangoni, M.L. Esculentin-1a-derived peptides promote clearance of Pseudomonas aeruginosa internalized in bronchial cells of cystic fibrosis patients and lung cell migration: biochemical properties and a plausible mode of action. Antimicrob. Agents Chemother., 2016, 60(12), 7252-7262.
[http://dx.doi.org/10.1128/AAC.00904-16] [PMID: 27671059]
[80]
Kolar, S.S.N.; Luca, V.; Baidouri, H.; Mannino, G.; McDermott, A.M.; Mangoni, M.L. Esculentin-1a(1-21)NH2: a frog skin-derived peptide for microbial keratitis. Cell. Mol. Life Sci., 2015, 72(3), 617-627.
[http://dx.doi.org/10.1007/s00018-014-1694-0] [PMID: 25086859]
[81]
Casciaro, B.; Cappiello, F.; Cacciafesta, M.; Mangoni, M.L. Promising approaches to optimize the biological properties of the antimicrobial peptide Esculentin-1a(1-21)Nh2: amino acids substitution and conjugation to nanoparticles. Front Chem., 2017, 5, 26.
[http://dx.doi.org/10.3389/fchem.2017.00026] [PMID: 28487853]
[82]
Jia, F.; Wang, J.; Peng, J.; Zhao, P.; Kong, Z.; Wang, K.; Yan, W.; Wang, R. D-amino acid substitution enhances the stability of antimicrobial peptide polybia-CP. Acta Biochim. Biophys. Sin. (Shanghai), 2017, 49(10), 916-925.
[http://dx.doi.org/10.1093/abbs/gmx091] [PMID: 28981608]
[83]
Saint Jean, K.D.; Henderson, K.D.; Chrom, C.L.; Abiuso, L.E.; Renn, L.M.; Caputo, G.A. Effects of hydrophobic amino acid substitutions on antimicrobial peptide behavior. Probiotics Antimicrob. Proteins, 2018, 10(3), 408-419.
[http://dx.doi.org/10.1007/s12602-017-9345-z] [PMID: 29103131]
[84]
Junior, E.F.C.; Guimarães, C.F.R.C.; Franco, L.L.; Alves, R.J.; Kato, K.C.; Martins, H.R.; de Souza Filho, J.D.; Bemquerer, M.P.; Munhoz, V.H.O.; Resende, J.M.; Verly, R.M. Glycotriazole-peptides derived from the peptide HSP1: synergistic effect of triazole and saccharide rings on the antifungal activity. Amino Acids, 2017, 49(8), 1389-1400.
[http://dx.doi.org/10.1007/s00726-017-2441-2] [PMID: 28573520]
[85]
Albada, H.B.; Prochnow, P.; Bobersky, S.; Langklotz, S.; Schriek, P.; Bandow, J.E.; Metzler-Nolte, N. Tuning the activity of a short arg-trp antimicrobial Peptide by lipidation of a C- or N-terminal lysine side-chain. ACS Med. Chem. Lett., 2012, 3(12), 980-984.
[http://dx.doi.org/10.1021/ml300148v] [PMID: 24900420]
[86]
Zhang, S.K.; Song, J.W.; Gong, F.; Li, S.B.; Chang, H.Y.; Xie, H.M.; Gao, H.W.; Tan, Y.X.; Ji, S.P. Design of an α-helical antimicrobial peptide with improved cell-selective and potent anti-biofilm activity. Sci. Rep., 2016, 6, 27394.
[http://dx.doi.org/10.1038/srep27394] [PMID: 27271216]
[87]
Huang, Y.; He, L.; Li, G.; Zhai, N.; Jiang, H.; Chen, Y. Role of helicity of α-helical antimicrobial peptides to improve specificity. Protein Cell, 2014, 5(8), 631-642.
[http://dx.doi.org/10.1007/s13238-014-0061-0] [PMID: 24805306]
[88]
Biondi, B.; Casciaro, B.; Di Grazia, A.; Cappiello, F.; Luca, V.; Crisma, M.; Mangoni, M.L. Effects of Aib residues insertion on the structural-functional properties of the frog skin-derived peptide esculentin-1a(1-21)NH2. Amino Acids, 2017, 49(1), 139-150.
[http://dx.doi.org/10.1007/s00726-016-2341-x] [PMID: 27726008]
[89]
Buommino, E.; Carotenuto, A.; Antignano, I.; Bellavita, R.; Casciaro, B.; Loffredo, M.R.; Merlino, F.; Novellino, E.; Mangoni, M.L.; Nocera, F.P.; Brancaccio, D.; Punzi, P.; Roversi, D.; Ingenito, R.; Bianchi, E.; Grieco, P. The Outcomes of decorated prolines in the discovery of antimicrobial peptides from Temporin-L. ChemMedChem, 2019, 14(13), 1283-1290.
[http://dx.doi.org/10.1002/cmdc.201900221] [PMID: 31087626]
[90]
Izadpanah, M.; Khalili, H. Antibiotic regimens for treatment of infections due to multidrug-resistant Gram-negative pathogens: An evidence-based literature review. J. Res. Pharm. Pract., 2015, 4(3), 105-114.
[http://dx.doi.org/10.4103/2279-042X.162360] [PMID: 26312249]
[91]
Casciaro, B.; Loffredo, M.R.; Luca, V.; Verrusio, W.; Cacciafesta, M.; Mangoni, M.L. Esculentin-1a derived antipseudomonal peptides: limited induction of resistance and synergy with aztreonam. Protein Pept. Lett., 2018, 25(12), 1155-1162.
[http://dx.doi.org/10.2174/0929866525666181101104649] [PMID: 30381056]
[92]
Davies, J.; Spiegelman, G.B.; Yim, G. The world of subinhibitory antibiotic concentrations. Curr. Opin. Microbiol., 2006, 9(5), 445-453.
[http://dx.doi.org/10.1016/j.mib.2006.08.006] [PMID: 16942902]
[93]
Andersson, D.I.; Hughes, D. Microbiological effects of sublethal levels of antibiotics. Nat. Rev. Microbiol., 2014, 12(7), 465-478.
[http://dx.doi.org/10.1038/nrmicro3270] [PMID: 24861036]
[94]
Kaplan, J.B. Antibiotic-induced biofilm formation. Int. J. Artif. Organs, 2011, 34(9), 737-751.
[http://dx.doi.org/10.5301/ijao.5000027] [PMID: 22094552]
[95]
Berditsch, M.; Afonin, S.; Vladimirova, T.; Wadhwani, P.; Ulrich, A.S. Antimicrobial peptides can enhance the risk of persistent infections. Front. Immunol., 2012, 3, 222.
[http://dx.doi.org/10.3389/fimmu.2012.00222] [PMID: 22870073]
[96]
Casciaro, B.; Lin, Q.; Afonin, S.; Loffredo, M.R.; de Turris, V.; Middel, V.; Ulrich, A.S.; Di, Y.P.; Mangoni, M.L. Inhibition of Pseudomonas aeruginosa biofilm formation and expression of virulence genes by selective epimerization in the peptide Esculentin-1a(1-21)NH2. FEBS J., 2019, 286(19), 3874-3891.
[http://dx.doi.org/10.1111/febs.14940] [PMID: 31144441]
[97]
Peschel, A.; Sahl, H.G. The co-evolution of host cationic antimicrobial peptides and microbial resistance. Nat. Rev. Microbiol., 2006, 4(7), 529-536.
[http://dx.doi.org/10.1038/nrmicro1441] [PMID: 16778838]
[98]
Hong, J.; Hu, J.; Ke, F. experimental induction of bacterial resistance to the antimicrobial peptide Tachyplesin I and investigation of the resistance mechanisms. Antimicrob. Agents Chemother., 2016, 60(10), 6067-6075.
[http://dx.doi.org/10.1128/AAC.00640-16] [PMID: 27480861]
[99]
St Helen, G.; Holland, N.T.; Balmes, J.R.; Hall, D.B.; Bernert, J.T.; Vena, J.E.; Wang, J.S.; Naeher, L.P. Utility of urinary Clara cell protein (CC16) to demonstrate increased lung epithelial permeability in non-smokers exposed to outdoor secondhand smoke. J. Expo. Sci. Environ. Epidemiol., 2013, 23(2), 183-189.
[http://dx.doi.org/10.1038/jes.2012.68] [PMID: 22805990]
[100]
Chen, C.; Mangoni, M.L.; Di, Y.P. In vivo therapeutic efficacy of frog skin-derived peptides against Pseudomonas aeruginosa-induced pulmonary infection. Sci. Rep., 2017, 7(1), 8548.
[http://dx.doi.org/10.1038/s41598-017-08361-8] [PMID: 28819175]
[101]
Rai, A.; Pinto, S.; Velho, T.R.; Ferreira, A.F.; Moita, C.; Trivedi, U.; Evangelista, M.; Comune, M.; Rumbaugh, K.P.; Simões, P.N.; Moita, L.; Ferreira, L. One-step synthesis of high-density peptide-conjugated gold nanoparticles with antimicrobial efficacy in a systemic infection model. Biomaterials, 2016, 85, 99-110.
[http://dx.doi.org/10.1016/j.biomaterials.2016.01.051] [PMID: 26866877]
[102]
Torres, L.M.F.C.; Almeida, M.T.; Santos, T.L.; Marinho, L.E.S.; de Mesquita, J.P.; da Silva, L.M.; Dos Santos, W.T.P.; Martins, H.R.; Kato, K.C.; Alves, E.S.F.; Liao, L.M.; de Magalhães, M.T.Q.; de Mendonça, F.G.; Pereira, F.V.; Resende, J.M.; Bemquerer, M.P.; Rodrigues, M.A.; Verly, R.M. Antimicrobial alumina nanobiostructures of disulfide- and triazole-linked peptides: Synthesis, characterization, membrane interactions and biological activity. Colloids Surf. B Biointerfaces, 2019, 177, 94-104.
[http://dx.doi.org/10.1016/j.colsurfb.2019.01.052] [PMID: 30711763]
[103]
Dutta, D.; Willcox, M.D. Antimicrobial contact lenses and lens cases: a review. Eye Contact Lens, 2014, 40(5), 312-324.
[http://dx.doi.org/10.1097/ICL.0000000000000056] [PMID: 25083781]
[104]
Kamaruzzaman, N.F.; Tan, L.P.; Hamdan, R.H.; Choong, S.S.; Wong, W.K.; Gibson, A.J.; Chivu, A.; Pina, M.F. Antimicrobial polymers: the potential replacement of existing antibiotics? Int. J. Mol. Sci., 2019, 20(11), E2747
[http://dx.doi.org/10.3390/ijms20112747] [PMID: 31167476]
[105]
Elahi, N.; Kamali, M.; Baghersad, M.H. Recent biomedical applications of gold nanoparticles: A review. Talanta, 2018, 184, 537-556.
[http://dx.doi.org/10.1016/j.talanta.2018.02.088] [PMID: 29674080]
[106]
Casciaro, B.; Moros, M.; Rivera-Fernández, S.; Bellelli, A.; de la Fuente, J.M.; Mangoni, M.L. Gold-nanoparticles coated with the antimicrobial peptide esculentin-1a(1-21)NH2 as a reliable strategy for antipseudomonal drugs. Acta Biomater., 2017, 47, 170-181.
[http://dx.doi.org/10.1016/j.actbio.2016.09.041] [PMID: 27693686]
[107]
Ciofu, O.; Tolker-Nielsen, T. Tolerance and resistance of Pseudomonas aeruginosa biofilms to antimicrobial agents-How P. aeruginosa Can Escape Antibiotics. Front. Microbiol., 2019, 10, 913.
[http://dx.doi.org/10.3389/fmicb.2019.00913] [PMID: 31130925]
[108]
d’Angelo, I.; Casciaro, B.; Miro, A.; Quaglia, F.; Mangoni, M.L.; Ungaro, F. Overcoming barriers in Pseudomonas aeruginosa lung infections: Engineered nanoparticles for local delivery of a cationic antimicrobial peptide. Colloids Surf. B Biointerfaces, 2015, 135, 717-725.
[http://dx.doi.org/10.1016/j.colsurfb.2015.08.027] [PMID: 26340361]
[109]
d’Angelo, I.; Quaglia, F.; Ungaro, F. PLGA carriers for inhalation: where do we stand, where are we headed? Ther. Deliv., 2015, 6(10), 1139-1144.
[http://dx.doi.org/10.4155/tde.15.37] [PMID: 26606854]
[110]
Debnath, S.K.; Saisivam, S.; Omri, A. PLGA Ethionamide Nanoparticles for Pulmonary Delivery: Development and in vivo evaluation of dry powder inhaler. J. Pharm. Biomed. Anal., 2017, 145, 854-859.
[http://dx.doi.org/10.1016/j.jpba.2017.07.051] [PMID: 28826144]
[111]
Tang, J.; Li, J.; Li, G.; Zhang, H.; Wang, L.; Li, D.; Ding, J. Spermidine-mediated poly(lactic-co-glycolic acid) nanoparticles containing fluorofenidone for the treatment of idiopathic pulmonary fibrosis. Int. J. Nanomedicine, 2017, 12, 6687-6704.
[http://dx.doi.org/10.2147/IJN.S140569] [PMID: 28932114]
[112]
Semete, B.; Booysen, L.; Lemmer, Y.; Kalombo, L.; Katata, L.; Verschoor, J.; Swai, H.S. In vivo evaluation of the biodistribution and safety of PLGA nanoparticles as drug delivery systems. Nanomedicine (Lond.), 2010, 6(5), 662-671.
[http://dx.doi.org/10.1016/j.nano.2010.02.002] [PMID: 20230912]
[113]
Casciaro, B.; d’Angelo, I.; Zhang, X.; Loffredo, M.R.; Conte, G.; Cappiello, F.; Quaglia, F.; Di, Y.P.; Ungaro, F.; Mangoni, M.L. Poly(lactide- co-glycolide) nanoparticles for prolonged therapeutic efficacy of esculentin-1a-derived antimicrobial peptides against pseudomonas aeruginosa lung infection: in vitro and in vivo studies. Biomacromolecules, 2019, 20(5), 1876-1888.
[http://dx.doi.org/10.1021/acs.biomac.8b01829] [PMID: 31013061]
[114]
Subedi, D.; Vijay, A.K.; Willcox, M. Overview of mechanisms of antibiotic resistance in Pseudomonas aeruginosa: an ocular perspective. Clin. Exp. Optom., 2018, 101(2), 162-171.
[http://dx.doi.org/10.1111/cxo.12621] [PMID: 29044738]
[115]
Casciaro, B.; Dutta, D.; Loffredo, M.R.; Marcheggiani, S.; McDermott, A.M.; Willcox, M.D.; Mangoni, M.L. Esculentin-1a derived peptides kill Pseudomonas aeruginosa biofilm on soft contact lenses and retain antibacterial activity upon immobilization to the lens surface. Biopolymers, 2017, 110(5), e23074
[http://dx.doi.org/10.1002/bip.23074] [PMID: 29086910]

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      • 17. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 18. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
    • SELECT at.type_name, p.copyright, p.publisher_location,m.month,y.year, a.publish_on, a.nid article_nid,a.article_id, a.pmid, a.issue_id, a.title, a.abstract,a.podcast,a.altmetric_score,a.altmetric_url,a.kudos_url, a.page_count, a.first_page, a.elocator, a.last_page, i.publication_date, a.file_name, a.file_path, a.doi, a.is_epub,a.epub_type, a.volume_id, a.is_uploaded, a.editor_choice, a.is_epub, j.image_file_name, a.article_no, a.art_type AS article_type, a.supplementary_filename,a.html_filename,a.prc_filename,a.epub_filename, a.graph_abs_lg_filename, a.graph_abs_sm_filename, a.oa_image_lg_filename, a.oa_image_sm_filename, j.journal_banner,a.animated_abstract,a.erratum_in,a.erratum_for, (CASE WHEN a.issue_id =0 THEN j.epub_price ELSE j.price END) AS sell_price, j.epub_price, j.nid AS jour_nid, j.title AS journal_title, j.issn, j.eissn,j.journal_id, j.subtitle AS jour_subtitle, v.volume_id,v.volume_name AS volume, v.year_id, i.title AS issue, i.month_id ,i.type issue_type, j.subtitle,j.formerly_title, ac.subtitle AS epub_title,a.crossmark_enabled,a.text_mining_urls,a.license_urls,a.created, a.receivedate, a.revisedate, a.acceptdate,js.js_title FROM article a LEFT JOIN article_section ac ON a.is_epub = ac.art_sec_id LEFT JOIN journal_section js ON a.js_id = js.js_id LEFT JOIN article_type at ON a.art_type = at.art_type_id LEFT JOIN issue i ON a.issue_id = i.issue_id LEFT JOIN month m ON m.id = i.month_id LEFT JOIN volume v ON v.volume_id = a.volume_id INNER JOIN year y ON y.id = v.year_id INNER JOIN journal j ON j.journal_id = a.journal_id INNER JOIN publisher p ON p.publisher_id = j.publisher_id WHERE a.article_id=99795
      980μsalphaeurekaselec_live_10_06_2022Article.php#408
      Backtrace
      • 11. app/Models/Article.php:408
      • 12. app/Http/Controllers/ArticleController.php:2515
      • 13. app/Http/Controllers/ArticleController.php:2035
      • 14. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 15. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select * from `journal` where `journal_id` = 25 limit 1
      1.04msalphaeurekaselec_live_10_06_2022Journal.php#64
      Bindings
      • 0: 25
      Backtrace
      • 14. app/Models/Journal.php:64
      • 15. app/Http/Controllers/ArticleController.php:2516
      • 16. app/Http/Controllers/ArticleController.php:2035
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select count(*) as aggregate from (select j.nid as journal_nid,j.flyer_link,j.title ,j.issn,j.eissn,j.keyword, j.journal_id as journal_id, j.subtitle, j.image_file_name,j.description,j.journal_insight_url,j.doi from `subject_journal` as `sj` inner join `journal` as `j` on `j`.`journal_id` = `sj`.`journal_id` where j.journal_status=1 and subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=25) and sj.journal_id!=25 group by `j`.`nid`) as `aggregate_table`
      2msalphaeurekaselec_live_10_06_2022Subject.php#200
      Backtrace
      • 16. app/Models/Subject.php:200
      • 17. app/Http/Controllers/ArticleController.php:2517
      • 18. app/Http/Controllers/ArticleController.php:2035
      • 19. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 20. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select j.nid as journal_nid,j.flyer_link,j.title ,j.issn,j.eissn,j.keyword, j.journal_id as journal_id, j.subtitle, j.image_file_name,j.description,j.journal_insight_url,j.doi from `subject_journal` as `sj` inner join `journal` as `j` on `j`.`journal_id` = `sj`.`journal_id` where j.journal_status=1 and subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=25) and sj.journal_id!=25 group by `j`.`nid` order by `j`.`journal_id` asc limit 10 offset 0
      1.12msalphaeurekaselec_live_10_06_2022Subject.php#200
      Backtrace
      • 14. app/Models/Subject.php:200
      • 15. app/Http/Controllers/ArticleController.php:2517
      • 16. app/Http/Controllers/ArticleController.php:2035
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select count(*) as aggregate from (select v.nid as volume_id,e.nid,e.title,v.issn,v.eissn,v.isbn,v.eisbn,e.ebook_id, v.image_file_name,v.file_path,v.flyer_link,v.ebook_volume_id, v.volume_name,v.doi,v.year_id,v.introduction from `subject_ebook` as `se` inner join `ebook` as `e` on `e`.`ebook_id` = `se`.`ebook_id` inner join `ebook_volume` as `v` on `v`.`ebook_id` = `se`.`ebook_id` inner join `year` as `y` on `y`.`id` = `v`.`year_id` where subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=25) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid`) as `aggregate_table`
      4.09msalphaeurekaselec_live_10_06_2022Subject.php#220
      Backtrace
      • 16. app/Models/Subject.php:220
      • 17. app/Http/Controllers/ArticleController.php:2518
      • 18. app/Http/Controllers/ArticleController.php:2035
      • 19. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 20. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select v.nid as volume_id,e.nid,e.title,v.issn,v.eissn,v.isbn,v.eisbn,e.ebook_id, v.image_file_name,v.file_path,v.flyer_link,v.ebook_volume_id, v.volume_name,v.doi,v.year_id,v.introduction from `subject_ebook` as `se` inner join `ebook` as `e` on `e`.`ebook_id` = `se`.`ebook_id` inner join `ebook_volume` as `v` on `v`.`ebook_id` = `se`.`ebook_id` inner join `year` as `y` on `y`.`id` = `v`.`year_id` where subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=25) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid` order by `v`.`ebook_volume_id` desc limit 10 offset 0
      6.25msalphaeurekaselec_live_10_06_2022Subject.php#220
      Backtrace
      • 14. app/Models/Subject.php:220
      • 15. app/Http/Controllers/ArticleController.php:2518
      • 16. app/Http/Controllers/ArticleController.php:2035
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select * from `keywords` where `article_id` = '99795'
      2.35msalphaeurekaselec_live_10_06_2022Keywords.php#43
      Bindings
      • 0: 99795
      Backtrace
      • 13. app/Models/Keywords.php:43
      • 14. app/Http/Controllers/ArticleController.php:2519
      • 15. app/Http/Controllers/ArticleController.php:2035
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select * from `article_citation` where `article_id` = '99795'
      4.63msalphaeurekaselec_live_10_06_2022Article.php#1570
      Bindings
      • 0: 99795
      Backtrace
      • 13. app/Models/Article.php:1570
      • 14. app/Http/Controllers/ArticleController.php:2520
      • 15. app/Http/Controllers/ArticleController.php:2035
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select CONCAT_WS(' ',au.first_name, ' ', ifnull(au.initials,''), ' ', au.last_name) as authors, CONCAT(au.last_name, IFNULL(CONCAT(' ', au.initials), ''), ' ', au.first_name) AS authorsRIS, CONCAT_WS(' ',au.last_name, ' ', ifnull(au.initials,''), ' ', au.first_name) as authorsCiteAs, CONCAT_WS(' ',au.first_name, IFNULL(CONCAT(' ', au.initials), ''), IFNULL(CONCAT(' ', au.last_name), '')) as authorsmodal , `au`.*, `af`.`ror_id`, `af`.`institution`, `af`.`department`, `af`.`country`, `af`.`city`, `af`.`address`, (GROUP_CONCAT(TRIM(BOTH ', ' FROM CONCAT(ifnull(concat(af.institution,','),''), ifnull(concat(af.department,','),''), ifnull(concat(af.address,','),''), ifnull(concat(af.city,','),''), ifnull(concat(af.country,','),''), ifnull(concat(af.postal_code,','),''), ifnull(concat(af.phone,','),''), ifnull(concat(af.fax,','),''))) SEPARATOR '|')) as `author_affiliation`, (GROUP_CONCAT(TRIM(BOTH ', ' FROM CONCAT(ifnull(concat(af.web_view,','),''))) SEPARATOR '|')) as `web_view` from `author` as `au` left join `author_affiliation` as `af` on `au`.`author_id` = `af`.`author_id` where `au`.`article_id` = '99795' group by `au`.`author_id` order by `au`.`article_id` asc, `au`.`sequence` asc
      3.5msalphaeurekaselec_live_10_06_2022Author.php#86
      Bindings
      • 0: 99795
      Backtrace
      • 13. app/Models/Author.php:86
      • 14. app/Http/Controllers/ArticleController.php:2533
      • 15. app/Http/Controllers/ArticleController.php:2035
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select `bo`.* from `bundle_offer` as `bo` where `bo`.`bundle_status` = 'A' order by `bo`.`bundle_id` desc
      320μsalphaeurekaselec_live_10_06_2022BundleOffer.php#57
      Bindings
      • 0: A
      Backtrace
      • 13. app/Models/BundleOffer.php:57
      • 14. app/Http/Controllers/ArticleController.php:2535
      • 15. app/Http/Controllers/ArticleController.php:2035
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select `subtitle` from `journal` where `continues_publication_journal` = 1
      710μsalphaeurekaselec_live_10_06_2022Article.php#1960
      Bindings
      • 0: 1
      Backtrace
      • 13. app/Models/Article.php:1960
      • 14. app/Http/Controllers/ArticleController.php:2062
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • Select j.subtitle, v.volume_id as volume_id,v.year_id,y.year as year,v.volume_name, v.total_no_of_issues, i.issue_id as issue_id,i.title as issue, i.publication_date as issue_pub_date from journal j join volume v on j.journal_id = v.journal_id join issue i on v.volume_id = i.volume_id join article a on a.issue_id = i.issue_id join year y on v.year_id = y.id where j.journal_id = 25 and i.is_uploaded = 1 order by v.volume_name+0 desc, i.title+0 desc limit 1
      47.98msalphaeurekaselec_live_10_06_2022Issue.php#298
      Backtrace
      • 11. app/Models/Issue.php:298
      • 12. app/Http/Controllers/ArticleController.php:2068
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select a.nid,a.publish_on, a.pmid,a.article_id,a.doi,j.journal_id,j.subtitle,v.volume_name,a.volume_id as volume_id, a.issue_id,a.title,first_page, last_page, page_count,abstract,ifnull(is_abstract,"y"),asec.title as article_section,at.type_name as article_type_name, a.article_id as ArticleID ,is_epub,epub_price,epub_type,a.created, y.year from `article` as `a` left join `article_section` as `asec` on `asec`.`art_sec_id` = `a`.`is_epub` left join `article_type` as `at` on `at`.`art_type_id` = `a`.`art_type` left join `journal` as `j` on `j`.`journal_id` = `a`.`journal_id` inner join `volume` as `v` on `a`.`volume_id` = `v`.`volume_id` inner join `year` as `y` on `v`.`year_id` = `y`.`id` where a.article_status != "W" and a.is_epub = 1 and a.journal_id = 25 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      39.01msalphaeurekaselec_live_10_06_2022Article.php#528
      Backtrace
      • 13. app/Models/Article.php:528
      • 14. app/Http/Controllers/ArticleController.php:2070
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select a.nid,a.publish_on, a.pmid,a.article_id,a.doi,j.journal_id,j.subtitle,v.volume_name,a.volume_id as volume_id, a.issue_id,a.title,first_page, last_page, page_count,abstract,ifnull(is_abstract,"y"),asec.title as article_section,at.type_name as article_type_name, a.article_id as ArticleID ,is_epub,epub_price,epub_type,a.created, y.year from `article` as `a` left join `article_section` as `asec` on `asec`.`art_sec_id` = `a`.`is_epub` left join `article_type` as `at` on `at`.`art_type_id` = `a`.`art_type` left join `journal` as `j` on `j`.`journal_id` = `a`.`journal_id` inner join `volume` as `v` on `a`.`volume_id` = `v`.`volume_id` inner join `year` as `y` on `v`.`year_id` = `y`.`id` where a.article_status != "W" and a.is_epub = 4 and a.journal_id = 25 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      25.83msalphaeurekaselec_live_10_06_2022Article.php#528
      Backtrace
      • 13. app/Models/Article.php:528
      • 14. app/Http/Controllers/ArticleController.php:2071
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select pdf, html, epub, prc from `article_metrics` where `article_id` = 99795 limit 1
      900μsalphaeurekaselec_live_10_06_2022Article.php#744
      Bindings
      • 0: 99795
      Backtrace
      • 14. app/Models/Article.php:744
      • 15. app/Http/Controllers/ArticleController.php:2091
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from content_by_diseases where content_id = 99795 and content_type = 'article' order by status desc limit 1
      270μsalphaeurekaselec_live_10_06_2022Article.php#751
      Backtrace
      • 11. app/Models/Article.php:751
      • 12. app/Http/Controllers/ArticleController.php:2094
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select a.nid article_nid,a.title article_title,j.title journal_title from content_by_diseases cd inner join article a on a.article_id=cd.content_id inner join journal j on j.journal_id=a.journal_id where cd.pid = 295 and cd.sub_disease_id = 300 and content_id!=99795 and cd.content_type = 'article' order by rand() limit 20
      124msalphaeurekaselec_live_10_06_2022Article.php#769
      Backtrace
      • 11. app/Models/Article.php:769
      • 12. app/Http/Controllers/ArticleController.php:2098
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `node_meta` where `nid` = 173672 limit 1
      290μsalphaeurekaselec_live_10_06_2022Meta.php#30
      Bindings
      • 0: 173672
      Backtrace
      • 14. app/Models/Meta.php:30
      • 15. app/Http/Controllers/ArticleController.php:2101
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select `bo`.* from `bundle_offer` as `bo` where `bo`.`bundle_status` = 'A' order by `bo`.`bundle_id` desc
      260μsalphaeurekaselec_live_10_06_2022BundleOffer.php#57
      Bindings
      • 0: A
      Backtrace
      • 13. app/Models/BundleOffer.php:57
      • 14. app/Http/Controllers/ArticleController.php:2108
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `tbl_ht_submission` as `h` where `h`.`subtitle` = 'CMC' and (h.proposal_closing_date = 0 OR TO_DAYS(FROM_UNIXTIME(h.proposal_closing_date)) >= TO_DAYS(NOW())) order by `h`.`manuscript` asc
      420μsalphaeurekaselec_live_10_06_2022Article.php#2025
      Bindings
      • 0: CMC
      Backtrace
      • 13. app/Models/Article.php:2025
      • 14. app/Http/Controllers/ArticleController.php:2112
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select count(*) as total_count, content_type_access_id as access_type from journal_access where content_type_id = '99795' and content_type = 'a' and ( (from_date <= CURDATE() and to_date >= CURDATE() and perpetual= 0) or (from_date is null and to_date is null and perpetual= 1) )
      400μsalphaeurekaselec_live_10_06_2022ContentAccess.php#647
      Backtrace
      • 11. app/Models/ContentAccess.php:647
      • 12. app/Http/Controllers/ArticleController.php:2186
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select count(*) as total_count, content_type_access_id as access_type from journal_access where content_type_id = '9759' and content_type = 'i' and ( (from_date <= CURDATE() and to_date >= CURDATE() and perpetual= 0) or (from_date is null and to_date is null and perpetual= 1) )
      360μsalphaeurekaselec_live_10_06_2022ContentAccess.php#647
      Backtrace
      • 11. app/Models/ContentAccess.php:647
      • 12. app/Http/Controllers/ArticleController.php:2207
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select count(*) as total_count, content_type_access_id as access_type from journal_access where content_type_id = '2698' and content_type = 'v' and ( (from_date <= CURDATE() and to_date >= CURDATE() and perpetual= 0) or (from_date is null and to_date is null and perpetual= 1) )
      300μsalphaeurekaselec_live_10_06_2022ContentAccess.php#647
      Backtrace
      • 11. app/Models/ContentAccess.php:647
      • 12. app/Http/Controllers/ArticleController.php:2231
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"volume" as access_level,"" as issue_id,"" as article_id from `user_access_journal_volume_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 314448117 and j.to_ip >=314448117 )) and ((j.from_date <= 1740496017 and j.to_date >= 1740496017 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2698) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"volume" as access_level,"" as issue_id,"" as article_id from `user_access_journal_volume_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 314448117 and j.to_ip >=314448117 )) and ((j.from_date <= 1740496017 and j.to_date >= 1740496017 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2698) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"volume" as access_level,"" as issue_id,"" as article_id from `user_access_journal_volume_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 314448117 and j.to_ip >=314448117 )) and ((j.from_date <= 1740496017 and j.to_date >= 1740496017 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2698)
      23.36msalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ArticleController.php:2272
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"issue" as access_level,j.issue_id,"" as article_id from `user_access_issue_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 314448117 and j.to_ip >=314448117 )) and ((j.from_date <= 1740496017 and j.to_date >= 1740496017 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 9759) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"issue" as access_level,j.issue_id,"" as article_id from `user_access_issue_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 314448117 and j.to_ip >=314448117 )) and ((j.from_date <= 1740496017 and j.to_date >= 1740496017 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 9759) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"issue" as access_level,j.issue_id,"" as article_id from `user_access_issue_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 314448117 and j.to_ip >=314448117 )) and ((j.from_date <= 1740496017 and j.to_date >= 1740496017 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 9759)
      630μsalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ArticleController.php:2297
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"article" as access_level, j.issue_id, j.article_id from `user_access_article_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 314448117 and j.to_ip >=314448117 )) and ((j.from_date <= 1740496017 and j.to_date >= 1740496017 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 99795) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"article" as access_level, j.issue_id, j.article_id from `user_access_article_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 314448117 and j.to_ip >=314448117 )) and ((j.from_date <= 1740496017 and j.to_date >= 1740496017 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 99795) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"article" as access_level, j.issue_id, j.article_id from `user_access_article_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 314448117 and j.to_ip >=314448117 )) and ((j.from_date <= 1740496017 and j.to_date >= 1740496017 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 99795)
      540μsalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ArticleController.php:2329
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `article` where `first_page` < '1405' and is_uploaded = 1 and issue_id = 9759 order by cast(first_page as SIGNED) desc limit 1
      520μsalphaeurekaselec_live_10_06_2022Article.php#1819
      Bindings
      • 0: 1405
      Backtrace
      • 14. app/Models/Article.php:1819
      • 15. app/Http/Controllers/ArticleController.php:2470
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `article` where `last_page` > '1419' and is_uploaded = 1 and issue_id = 9759 order by cast(first_page as SIGNED) asc limit 1
      460μsalphaeurekaselec_live_10_06_2022Article.php#1831
      Bindings
      • 0: 1419
      Backtrace
      • 14. app/Models/Article.php:1831
      • 15. app/Http/Controllers/ArticleController.php:2472
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select `language_id` from `multilanguage` where `short_code` = 'cn'
      200μsalphaeurekaselec_live_10_06_2022ArticleController.php#2486
      Bindings
      • 0: cn
      Backtrace
      • 14. app/Http/Controllers/ArticleController.php:2486
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:206
    • select `source_lang_label`, `target_lang_label` from `multilanguage_labels` where `target_lang_id` = 2
      290μsalphaeurekaselec_live_10_06_2022MultiLanguage.php#23
      Bindings
      • 0: 2
      Backtrace
      • 13. app/Models/MultiLanguage.php:23
      • 14. app/Http/Controllers/ArticleController.php:2487
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `multilanguage_article` where (`language_id` = 2 and `article_id` = 99795)
      5.94msalphaeurekaselec_live_10_06_2022ArticleController.php#2488
      Bindings
      • 0: 2
      • 1: 99795
      Backtrace
      • 15. app/Http/Controllers/ArticleController.php:2488
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
      • 19. vendor/laravel/framework/src/Illuminate/Routing/Route.php:206
    • select `keyword` from `multilanguage_keywords` where (`language_id` = 2 and `article_id` = 99795)
      7.62msalphaeurekaselec_live_10_06_2022ArticleController.php#2489
      Bindings
      • 0: 2
      • 1: 99795
      Backtrace
      • 14. app/Http/Controllers/ArticleController.php:2489
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:206
    • select CONCAT_WS(' ',au.first_name, ' ', ifnull(au.initials,''), ' ', au.last_name) as authors, CONCAT_WS(' ',au.last_name, ', ', ifnull(au.initials,''), ' ', au.first_name) as authorsRIS, CONCAT_WS(' ',au.last_name, ' ', ifnull(au.initials,''), ' ', au.first_name) as authorsCiteAs , `au`.*, (GROUP_CONCAT(TRIM(BOTH ', ' FROM CONCAT(ifnull(concat(af.institution,','),''), ifnull(concat(af.department,','),''), ifnull(concat(af.address,','),''), ifnull(concat(af.city,','),''), ifnull(concat(af.country,','),''), ifnull(concat(af.postal_code,','),''), ifnull(concat(af.phone,','),''), ifnull(concat(af.fax,','),''))) SEPARATOR '|')) as `author_affiliation`, (GROUP_CONCAT(TRIM(BOTH ', ' FROM CONCAT(ifnull(concat(af.web_view,','),''))) SEPARATOR '|')) as `web_view` from `multilanguage_authors` as `au` left join `multilanguage_author_affiliation` as `af` on `au`.`id` = `af`.`author_id` where `au`.`article_id` = 99795 group by `au`.`id` order by `au`.`article_id` asc, `au`.`sequence` asc
      11.79msalphaeurekaselec_live_10_06_2022MultiLangAuthor.php#30
      Bindings
      • 0: 99795
      Backtrace
      • 13. app/Models/MultiLangAuthor.php:30
      • 14. app/Http/Controllers/ArticleController.php:2493
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select `multilanguage_journal`.`title` from `multilanguage_journal` where `multilanguage_journal`.`journal_id` = 25 and `language_id` = 2
      1.53msalphaeurekaselec_live_10_06_2022ArticleController.php#2495
      Bindings
      • 0: 25
      • 1: 2
      Backtrace
      • 13. app/Http/Controllers/ArticleController.php:2495
      • 14. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 15. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:206
    • select `id` from `multilanguage_article` where `article_id` = 99795 limit 1
      2.06msalphaeurekaselec_live_10_06_2022ArticleController.php#2506
      Bindings
      • 0: 99795
      Backtrace
      • 16. app/Http/Controllers/ArticleController.php:2506
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 19. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
      • 20. vendor/laravel/framework/src/Illuminate/Routing/Route.php:206
    • select b.banner_link, b.banner_name, b.banner_script, b.banner_remarks, b.banner_file_name, b.banner_placement, bd.content_type, bd.content_id from `tbl_banner` as `b` inner join `tbl_banner_detail` as `bd` on `bd`.`banner_id` = `b`.`banner_id` inner join `users` as `u` on `u`.`id` = `b`.`updated_by` inner join `journal` as `j` on `j`.`journal_id` = `bd`.`content_id` where `b`.`banner_journal` = 1 and `bd`.`content_type` = 'J' and `bd`.`content_id` = 25 and `b`.`banner_from_date` <= 1740496017 and `b`.`banner_to_date` >= 1740496017 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.55msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 25
      • 3: 1740496017
      • 4: 1740496017
      • 5: A
      Backtrace
      • 13. app/Models/Banner.php:95
      • 14. app/Http/helpers.php:404
      • 17. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 18. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    • select b.banner_link, b.banner_name, b.banner_script, b.banner_remarks, b.banner_file_name, b.banner_placement, bd.content_type, bd.content_id from `tbl_banner` as `b` inner join `tbl_banner_detail` as `bd` on `bd`.`banner_id` = `b`.`banner_id` inner join `users` as `u` on `u`.`id` = `b`.`updated_by` inner join `journal` as `j` on `j`.`journal_id` = `bd`.`content_id` where `b`.`banner_journal` = 1 and `bd`.`content_type` = 'J' and `bd`.`content_id` = 25 and `b`.`banner_from_date` <= 1740496017 and `b`.`banner_to_date` >= 1740496017 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.63msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 25
      • 3: 1740496017
      • 4: 1740496017
      • 5: A
      Backtrace
      • 13. app/Models/Banner.php:95
      • 14. app/Http/helpers.php:404
      • 17. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 18. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    • select count(*) as aggregate from `uc_cart_products` where cart_id='951dd0cac16aecdb0b687eb18096ca1b'
      300μsalphaeurekaselec_live_10_06_2022Cart.php#271
      Backtrace
      • 15. app/Models/Cart.php:271
      • 16. view::layouts._header:260
      • 18. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 20. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    App\Models\MultiLangArticle
    2MultiLangArticle.php#?
    App\Models\MultiLanguage
    1MultiLanguage.php#?
        _token
        wei8yNbFuD8VbuT5yCTwgEBnegxjQVD2LTR1Ovwy
        uc_cart_id
        951dd0cac16aecdb0b687eb18096ca1b
        _previous
        array:1 [ "url" => "http://alpha.eurekaselect.com/article/99795/cn" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /article/99795/cn
        status_code
        200
        
        status_text
        OK
        format
        html
        content_type
        text/html; charset=UTF-8
        request_query
        []
        
        request_request
        []
        
        request_headers
        0 of 0
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        request_cookies
        0 of 0
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        response_headers
        0 of 0
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