Generic placeholder image

Mini-Reviews in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1389-5575
ISSN (Online): 1875-5607

Review Article

Antimicrobial Peptides: Vestiges of Past or Modern Therapeutics?

Author(s): Jyotsna Bhatt Mitra, Veerendra K. Sharma, Mukesh Kumar and Archana Mukherjee*

Volume 20, Issue 3, 2020

Page: [183 - 195] Pages: 13

DOI: 10.2174/1389557519666191125121407

Price: $65

Abstract

The ubiquitous occurrence of Antimicrobial Peptides (AMPs) in all domains of life emphasizes their crucial role as ancient mediators of host defense. Despite their antiquity and prolonged history of exposure to pathogens, endogenous AMPs continue to serve as effective antibiotics. An "evolutionary arms race" between host and pathogen resulted in structural diversity of AMPs, leading these molecules to retain activity against a wide range of pathogens, including antibiotic-resistant microbes. As the menace of antibiotic resistance continues to render most antibiotics ineffective against pathogens, the search for novel drug candidates has taken the center stage. The ability of AMPs to combat antibiotic-resistant microbes gave rise to a remarkable surge of interest in AMPs as potential therapeutics. Apart from being effective antimicrobials, AMPs have also found application as probes suitable for in-situ diagnosis of infection. Here, we review the evolutionary history of AMPs, their structural diversity, and mechanism of interaction with microbial membranes. We also summarize the role of AMPs as modern pharmaceuticals and challenges to this development.

Keywords: Antimicrobial Peptides (AMP), AMP evolution, AMP prevalence, structure-function relations, infection imaging agents, Ubiquicidin (UBI).

Graphical Abstract

[1]
Zhang, L.J.; Gallo, R.L. Antimicrobial peptides. Current. Biol., 2016, 26(1), R14-R19.
[2]
Kimbrell, D.A.; Beutler, B. The evolution and genetics of innate immunity. Nat. Rev. Genet., 2001, 2(4), 256-267.
[http://dx.doi.org/10.1038/35066006] [PMID: 11283698]
[3]
Indian Network for Surveillance of Antimicrobial Resistance (INSAR) group, India. Methicillin resistant Staphylococcus aureus (MRSA) in India: prevalence & susceptibility pattern. Indian J. Med. Res., 2013, 137(2), 363-369.
[PMID: 23563381]
[4]
Ventola, C.L. The antibiotic resistance crisis: part 1: causes and threats. P&T, 2015, 40(4), 277-283.
[PMID: 25859123]
[5]
Udwadia, Z.F.; Amale, R.A.; Ajbani, K.K.; Rodrigues, C. Totally drug-resistant tuberculosis in India. Clin. Infect. Dis., 2012, 54(4), 579-581.
[http://dx.doi.org/10.1093/cid/cir889] [PMID: 22190562]
[6]
Velayati, A.A.; Masjedi, M.R.; Farnia, P.; Tabarsi, P.; Ghanavi, J.; ZiaZarifi, A.H.; Hoffner, S.E. Emergence of new forms of totally drug-resistant tuberculosis bacilli: super extensively drug-resistant tuberculosis or totally drug-resistant strains in iran. Chest, 2009, 136(2), 420-425.
[http://dx.doi.org/10.1378/chest.08-2427] [PMID: 19349380]
[7]
Kumar, P.; Kizhakkedathu, J.N.; Straus, S.K. Antimicrobial Peptides: Diversity, mechanism of action and strategies to improve the activity and biocompatibility In vivo. Biomolecules, 2018, 8(1), 4.
[http://dx.doi.org/10.3390/biom8010004] [PMID: 29351202]
[8]
Wang, G.; Li, X.; Wang, Z. APD2: the updated antimicrobial peptide database and its application in peptide design. Nucleic Acids Res., 2009, 37(Database issue), D933-D937.
[http://dx.doi.org/10.1093/nar/gkn823] [PMID: 18957441]
[9]
Waghu, F.H.; Barai, R.S.; Gurung, P.; Idicula-Thomas, S. CAMPR3: a database on sequences, structures and signatures of antimicrobial peptides. Nucleic Acids Res., 2016, 44(D1), D1094-D1097.
[http://dx.doi.org/10.1093/nar/gkv1051] [PMID: 26467475]
[10]
Wiesner, J.; Vilcinskas, A. Antimicrobial peptides: the ancient arm of the human immune system. Virulence, 2010, 1(5), 440-464.
[http://dx.doi.org/10.4161/viru.1.5.12983] [PMID: 21178486]
[11]
Sumi, C.D.; Yang, B.W.; Yeo, I.C.; Hahm, Y.T. Antimicrobial peptides of the genus Bacillus: a new era for antibiotics. Can. J. Microbiol., 2015, 61(2), 93-103.
[http://dx.doi.org/10.1139/cjm-2014-0613] [PMID: 25629960]
[12]
Weissman, K.J. The structural biology of biosynthetic megaenzymes. Nat. Chem. Biol., 2015, 11(9), 660-670.
[http://dx.doi.org/10.1038/nchembio.1883] [PMID: 26284673]
[13]
Riley, M.A.; Wertz, J.E. Bacteriocins: evolution, ecology, and application. Annu. Rev. Microbiol., 2002, 56, 117-137.
[http://dx.doi.org/10.1146/annurev.micro.56.012302.161024] [PMID: 12142491]
[14]
Yang, S.C.; Lin, C-H.; Sung, C.T.; Fang, J-Y. Antibacterial activities of bacteriocins: application in foods and pharmaceuticals. Front. Microbiol., 2014, 5, 241.
[PMID: 24904554]
[15]
Heng, N. C. K.; Wescombe, P. A.; Burton, J. P.; Jack, R. W.; Tagg, J. R. The Diversity of bacteriocins in gram-positive bacteria. 2007, 45-92.
[http://dx.doi.org/ 10.1007/978-3-540-36604-1_4]
[16]
Nes, I.F.; Brede, D.A.; Diep, D.B. Handbook of Biologically Active Peptides, 2nd ed; Bacterial/Antibiotic Peptides, 2013, pp. 85-92.
[http://dx.doi.org/10.1016/B978-0-12-385095-9.00016-6]
[17]
Cotter, P.D.; Hill, C.; Ross, R.P. Bacteriocins: developing innate immunity for food. Nat. Rev. Microbiol., 2005, 3(10), 777-788.
[http://dx.doi.org/10.1038/nrmicro1273] [PMID: 16205711]
[18]
Liou, J.W.; Hung, Y-J.; Yang, C-H.; Chen, Y-C. The antimicrobial activity of gramicidin A is associated with hydroxyl radical formation. PLoS One, 2015, 10(1)e0117065
[http://dx.doi.org/10.1371/journal.pone.0117065] [PMID: 25622083]
[19]
Mylonakis, E.; Podsiadlowski, L.; Muhammed, M.; Vilcinskas, A. Diversity, evolution and medical applications of insect antimicrobial peptides. Philos. Trans. R. Soc. Lond. B Biol. Sci., 2016, 371(1695), 20150290 .
[http://dx.doi.org/10.1098/rstb.2015.0290] [PMID: 27160593]
[20]
Tassanakajon, A.; Somboonwiwat, K.; Amparyup, P. Sequence diversity and evolution of antimicrobial peptides in invertebrates. Dev. Comp. Immunol., 2015, 48(2), 324-341.
[http://dx.doi.org/10.1016/j.dci.2014.05.020] [PMID: 24950415]
[21]
Harris, F.; Dennison, R.S., and; A. , Phoenix D. Anionic antimicrobial peptides from eukaryotic organisms and their mechanisms of action. Curr. Chem. Biol., 2011, 5(2), 142-153.
[http://dx.doi.org/10.2174/2212796811105020142]
[22]
Phoenix, D.A.; Dennison, S.R.; Harris, F. Antimicrobial peptides; John Wiley & Sons, 2012.
[23]
Cooper, M.D.; Alder, M.N. The evolution of adaptive immune systems. Cell, 2006, 124(4), 815-822.
[http://dx.doi.org/10.1016/j.cell.2006.02.001] [PMID: 16497590]
[24]
Tennessen, J.A. Molecular evolution of animal antimicrobial peptides: widespread moderate positive selection. J. Evol. Biol., 2005, 18(6), 1387-1394.
[http://dx.doi.org/10.1111/j.1420-9101.2005.00925.x] [PMID: 16313451]
[25]
Bulet, P.; Stöcklin, R.; Menin, L. Anti-microbial peptides: from invertebrates to vertebrates. Immunol. Rev., 2004, 198, 169-184.
[http://dx.doi.org/10.1111/j.0105-2896.2004.0124.x] [PMID: 15199962]
[26]
Jenssen, H.; Hamill, P.; Hancock, R.E.W. Peptide antimicrobial agents. Clin. Microbiol. Rev., 2006, 19(3), 491-511.
[http://dx.doi.org/10.1128/CMR.00056-05] [PMID: 16847082]
[27]
Tam, J.P.; Wang, S.; Wong, K.H.; Tan, W.L. Antimicrobial Peptides from Plants. Pharmaceuticals (Basel), 2015, 8(4), 711-757.
[http://dx.doi.org/10.3390/ph8040711] [PMID: 26580629]
[28]
Kindt, T. Goldsby, R.; Osborne, B.; Kuby, J. Kuby Immunology; W. H. Freeman, 2007.
[29]
Russell, P.J. Genetics: A molecular approach; Pearson. Education, 2010.
[30]
Spurgin, L.G.; Richardson, D.S. How pathogens drive genetic diversity: MHC, mechanisms and misunderstandings. Proc. Biol. Sci., 2010, 277(1684), 979-988.
[http://dx.doi.org/10.1098/rspb.2009.2084] [PMID: 20071384]
[31]
Wagner, A. Selection and gene duplication: A view from the genome. Genom. Biol., 2002, 3, reviews1012.1.
[32]
Goraya, J.; Wang, Y.; Li, Z.; O’Flaherty, M.; Knoop, F.C.; Platz, J.E.; Conlon, J.M. Peptides with antimicrobial activity from four different families isolated from the skins of the North American frogs Rana luteiventris, Rana berlandieri and Rana pipiens. Eur. J. Biochem., 2000, 267(3), 894-900.
[http://dx.doi.org/10.1046/j.1432-1327.2000.01074.x] [PMID: 10651828]
[33]
Yu, H.; Lu, Y.; Qiao, X.; Wei, L.; Fu, T.; Cai, S.; Wang, C.; Liu, X.; Zhong, S.; Wang, Y. Novel cathelicidins from pigeon highlights evolutionary convergence in avain cathelicidins and functions in modulation of innate immunity. Sci. Rep., 2015, 5, 11082.
[http://dx.doi.org/10.1038/srep11082] [PMID: 26194630]
[34]
Xiao, Y.; Cai, Y.; Bommineni, Y.R.; Fernando, S.C.; Prakash, O.; Gilliland, S.E.; Zhang, G. Identification and functional characterization of three chicken cathelicidins with potent antimicrobial activity. J. Biol. Chem., 2006, 281(5), 2858-2867.
[http://dx.doi.org/10.1074/jbc.M507180200] [PMID: 16326712]
[35]
Wang, Y.; Lu, Z.; Feng, F.; Zhu, W.; Guang, H.; Liu, J.; He, W.; Chi, L.; Li, Z.; Yu, H. Molecular cloning and characterization of novel cathelicidin-derived myeloid antimicrobial peptide from Phasianus colchicus. Dev. Comp. Immunol., 2011, 35(3), 314-322.
[http://dx.doi.org/10.1016/j.dci.2010.10.004] [PMID: 20955730]
[36]
Sackton, T.B.; Lazzaro, B.P.; Schlenke, T.A.; Evans, J.D.; Hultmark, D.; Clark, A.G. Dynamic evolution of the innate immune system in Drosophila. Nat. Genet., 2007, 39(12), 1461-1468.
[http://dx.doi.org/10.1038/ng.2007.60] [PMID: 17987029]
[37]
Zhu, S.; Gao, B. Positive selection in cathelicidin host defense peptides: adaptation to exogenous pathogens or endogenous receptors? Heredity, 2017, 118(5), 453-465.
[http://dx.doi.org/10.1038/hdy.2016.117] [PMID: 27925615]
[38]
Nguyen, L.T.; Haney, E.F.; Vogel, H.J. The expanding scope of antimicrobial peptide structures and their modes of action. Trends Biotechnol., 2011, 29(9), 464-472.
[http://dx.doi.org/10.1016/j.tibtech.2011.05.001] [PMID: 21680034]
[39]
Yount, N.Y.; Weaver, D.C.; Lee, E.Y.; Lee, M.W.; Wang, H.; Chan, L.C.; Wong, G.C.L.; Yeaman, M.R. Unifying structural signature of eukaryotic α-helical host defense peptides. Proc. Natl. Acad. Sci. USA, 2019, 116(14), 6944-6953.
[http://dx.doi.org/ 10.1073/pnas.1819250116] [PMID: 30877253]
[40]
Wimley, W.C. Describing the mechanism of antimicrobial peptide action with the interfacial activity model. ACS Chem. Biol., 2010, 5(10), 905-917.
[http://dx.doi.org/10.1021/cb1001558] [PMID: 20698568]
[41]
Huang, Y.; Huang, J.; Chen, Y. Alpha-helical cationic antimicrobial peptides: relationships of structure and function. Protein Cell, 2010, 1(2), 143-152.
[http://dx.doi.org/10.1007/s13238-010-0004-3] [PMID: 21203984]
[42]
Giangaspero, A.; Sandri, L.; Tossi, A. Amphipathic alpha helical antimicrobial peptides. Eur. J. Biochem., 2001, 268(21), 5589-5600.
[http://dx.doi.org/10.1046/j.1432-1033.2001.02494.x] [PMID: 11683882]
[43]
Bessalle, R.; Kapitkovsky, A.; Gorea, A.; Shalit, I.; Fridkin, M. All-D-magainin: chirality, antimicrobial activity and proteolytic resistance. FEBS Lett., 1990, 274(1-2), 151-155.
[http://dx.doi.org/10.1016/0014-5793(90)81351-N] [PMID: 2253768]
[44]
Merrifield, E.L.; Mitchell, S.A.; Ubach, J.; Boman, H.G.; Andreu, D.; Merrifield, R.B. D-enantiomers of 15-residue cecropin A-melittin hybrids. Int. J. Pept. Protein Res., 1995, 46(3-4), 214-220.
[http://dx.doi.org/10.1111/j.1399-3011.1995.tb00592.x] [PMID: 8537174]
[45]
Le, C-F.; Fang, C-M.; Sekaran, S.D. Intracellular targeting mechanisms by antimicrobial peptides. Antimicrob. Agents Chemother., 2017, 61(4), e02340-e16.
[http://dx.doi.org/10.1128/AAC.02340-16] [PMID: 28167546]
[46]
Xhindoli, D.; Pacor, S.; Benincasa, M.; Scocchi, M.; Gennaro, R.; Tossi, A. A pore-forming antibacterial peptide and host-cell modulato. Biochimica et Biophysica Acta (BBA) - Biomembranes, 2016, 1858 Pore-Forming Toxins: Cellular Effects and Biotech Applications., 546-566.
[47]
Paterson, D.J.; Tassieri, M.; Reboud, J.; Wilson, R.; Cooper, J.M. Lipid topology and electrostatic interactions underpin lytic activity of linear cationic antimicrobial peptides in membranes. Proc. Natl. Acad. Sci. USA, 2017, 114(40), E8324-E8332.
[http://dx.doi.org/10.1073/pnas.1704489114] [PMID: 28931578]
[48]
Huang, H.W. Action of antimicrobial peptides: two-state model. Biochemistry, 2000, 39(29), 8347-8352.
[http://dx.doi.org/10.1021/bi000946l] [PMID: 10913240]
[49]
Melo, M.N.; Ferre, R.; Castanho, M.A.R.B. Antimicrobial peptides: linking partition, activity and high membrane-bound concentrations. Nat. Rev. Microbiol., 2009, 7(3), 245-250.
[http://dx.doi.org/10.1038/nrmicro2095] [PMID: 19219054]
[50]
Rai, D.K.; Qian, S. Interaction of the antimicrobial peptide aurein 1.2 and charged lipid bilayer. Sci. Rep., 2017, 7(1), 3719.
[http://dx.doi.org/10.1038/s41598-017-03795-6] [PMID: 28623332]
[51]
Sharma, V.K.; Mamontov, E.; Anunciado, D.B.; O’Neill, H.; Urban, V.S. Effect of antimicrobial peptide on the dynamics of phosphocholine membrane: role of cholesterol and physical state of bilayer. Soft Matter, 2015, 11(34), 6755-6767.
[http://dx.doi.org/10.1039/C5SM01562F] [PMID: 26212615]
[52]
Sharma, V.K.; Mamontov, E.; Tyagi, M.; Qian, S.; Rai, D.K.; Urban, V.S. Dynamical and phase behavior of a phospholipid membrane altered by an antimicrobial peptide at low concentration. J. Phys. Chem. Lett., 2016, 7(13), 2394-2401.
[http://dx.doi.org/10.1021/acs.jpclett.6b01006] [PMID: 27232190]
[53]
Sharma, V.K.; Qian, S. Effect of an antimicrobial peptide on lateral segregation of lipids: A structure and dynamics study by neutron scattering. Langmuir, 2019, 35(11), 4152-4160.
[http://dx.doi.org/10.1021/acs.langmuir.8b04158] [PMID: 30720281]
[54]
Tossi, A.; Sandri, L.; Giangaspero, A. Amphipathic, α-helical antimicrobial peptides. Biopolymers, 2000, 55(1), 4-30.
[http://dx.doi.org/10.1002/1097-0282(2000)55:1<4:AID-BIP30>3.0.CO;2-M] [PMID: 10931439]
[55]
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 a-helical antimicrobial peptide with improved cell-selective and potent anti-biofilm activity. Scientific Report, 2016, 6 27271216[pmid], 27394
[http://dx.doi.org/10.1038/srep27394]
[56]
Jiang, Z.; Vasil, A.I.; Hale, J.D.; Hancock, R.E.W.; Vasil, M.L.; Hodges, R.S. Effects of net charge and the number of positively charged residues on the biological activity of amphipathic α-helical cationic antimicrobial peptides. Biopolymers, 2008, 90(3), 369-383.
[http://dx.doi.org/10.1002/bip.20911] [PMID: 18098173]
[57]
Xiong, M.; Lee, M.W.; Mansbach, R.A.; Song, Z.; Bao, Y.; Peek, R.M., Jr; Yao, C.; Chen, L-F.; Ferguson, A.L.; Wong, G.C.L.; Cheng, J. Helical antimicrobial polypeptides with radial amphiphilicity. Proc. Natl. Acad. Sci. USA, 2015, 112(43), 13155-13160.
[http://dx.doi.org/10.1073/pnas.1507893112] [PMID: 26460016]
[58]
Oren, Z.; Shai, Y. Selective lysis of bacteria but not mammalian cells by diastereomers of melittin: structure-function study. Biochemistry, 1997, 36(7), 1826-1835.
[http://dx.doi.org/10.1021/bi962507l] [PMID: 9048567]
[59]
Sengupta, D.; Leontiadou, H.; Mark, A.E.; Marrink, S.J. Toroidal pores formed by antimicrobial peptides show significant disorder. Biochim. Biophys. Acta, 2008, 1778(10), 2308-2317.
[http://dx.doi.org/10.1016/j.bbamem.2008.06.007] [PMID: 18602889]
[60]
Leontiadou, H.; Mark, A.E.; Marrink, S.J. Antimicrobial peptides in action. J. Am. Chem. Soc., 2006, 128(37), 12156-12161.
[http://dx.doi.org/10.1021/ja062927q] [PMID: 16967965]
[61]
Ulaeto, D.O.; Morris, C.J.; Fox, M.A.; Gumbleton, M.; Beck, K. Destabilization of α-Helical structure in solution improves bactericidal activity of antimicrobial peptides: Opposite effects on bacterial and viral targets. Antimicrob. Agents Chemother., 2016, 60(4), 1984-1991.
[http://dx.doi.org/10.1128/AAC.02146-15] [PMID: 26824944]
[62]
Chen, Y.; Mant, C.T.; Hodges, R.S. Determination of stereochemistry stability coefficients of amino acid side-chains in an amphipathic α-helix. J. Pept. Res., 2002, 59(1), 18-33.
[http://dx.doi.org/10.1046/j.1397-002x.2001.10994.x] [PMID: 11906604]
[63]
Matsuzaki, K.; Nakamura, A.; Murase, O.; Sugishita, K.; Fujii, N.; Miyajima, K. Modulation of magainin 2-lipid bilayer interactions by peptide charge. Biochemistry, 1997, 36(8), 2104-2111.
[http://dx.doi.org/10.1021/bi961870p] [PMID: 9047309]
[64]
Lee, M.T.; Sun, T-L.; Hung, W-C.; Huang, H.W. Process of inducing pores in membranes by melittin. Proc. Natl. Acad. Sci. USA, 2013, 110(35), 14243-14248.
[http://dx.doi.org/10.1073/pnas.1307010110] [PMID: 23940362]
[65]
Pieta, P.; Mirza, J.; Lipkowski, J. Direct visualization of the alamethicin pore formed in a planar phospholipid matrix. Proc. Natl. Acad. Sci. USA, 2012, 109(52), 21223-21227.
[http://dx.doi.org/10.1073/pnas.1201559110] [PMID: 23236158]
[66]
Pino-Angeles, A.; Lazaridis, T. Effects of peptide charge, orientation, and concentration on melittin transmembrane pores. Biophys. J., 2018, 114(12), 2865-2874.
[http://dx.doi.org/10.1016/j.bpj.2018.05.006] [PMID: 29925023]
[67]
Rathinakumar, R.; Walkenhorst, W.F.; Wimley, W.C. Broad-spectrum antimicrobial peptides by rational combinatorial design and high-throughput screening: the importance of interfacial activity. J. Am. Chem. Soc., 131, 7609-7617. 2009
[68]
Pino-Angeles, A.; Leveritt, J.M., III; Lazaridis, T. Pore structure and synergy in antimicrobial peptides of the magainin family. PLOS Comput. Biol., 2016, 12(1) e1004570
[http://dx.doi.org/10.1371/journal.pcbi.1004570] [PMID: 26727376]
[69]
Han, M.; Mei, Y.; Khant, H.; Ludtke, S.J. Characterization of antibiotic peptide pores using cryo-EM and comparison to neutron scattering. Biophys. J., 2009, 97(1), 164-172.
[http://dx.doi.org/10.1016/j.bpj.2009.04.039] [PMID: 19580754]
[70]
Wiener, M.C.; White, S.H. Structure of a fluid dioleoylphosphatidylcholine bilayer determined by joint refinement of x-ray and neutron diffraction data. III. Complete structure. Biophys. J., 1992, 61(2), 434-447.
[http://dx.doi.org/10.1016/S0006-3495(92)81849-0] [PMID: 1547331]
[71]
Tang, M.; Hong, M. Structure and mechanism of beta-hairpin antimicrobial peptides in lipid bilayers from solid-state NMR spectroscopy. Mol. Biosyst., 2009, 5(4), 317-322.
[http://dx.doi.org/10.1039/b820398a] [PMID: 19396367]
[72]
Skerlavaj, B.; Romeo, D.; Gennaro, R. Rapid membrane permeabilization and inhibition of vital functions of gram-negative bacteria by bactenecins. Infect. Immun., 1990, 58(11), 3724-3730.
[PMID: 2228243]
[73]
Madhongsa, K.; Pasan, S.; Phophetleb, O.; Nasompag, S.; Thammasirirak, S.; Daduang, S.; Taweechaisupapong, S.; Lomize, A.L.; Patramanon, R. Antimicrobial action of the cyclic peptide bactenecin on Burkholderia pseudomallei correlates with efficient membrane permeabilization. PLoS Negl. Trop. Dis., 2013, 7(6)e2267
[http://dx.doi.org/10.1371/journal.pntd.0002267] [PMID: 23785532]
[74]
Gifford, J.L.; Hunter, H.N.; Vogel, H.J. Lactoferricin: a lactoferrin-derived peptide with antimicrobial, antiviral, antitumor and immunological properties. Cell. Mol. Life Sci., 2005, 62(22), 2588-2598.
[http://dx.doi.org/10.1007/s00018-005-5373-z] [PMID: 16261252]
[75]
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]
[76]
Oishi, O.; Yamashita, S.; Nishimoto, E.; Lee, S.; Sugihara, G.; Ohno, M. Conformations and orientations of aromatic amino acid residues of tachyplesin I in phospholipid membranes. Biochemistry, 1997, 36, 4352-4359.
[77]
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]
[78]
Hill, C..; Yee, J.; Selsted, M.; Eisenberg, D. Crystal structure of defensin HNP-3, an amphiphilic dimer: mechanisms of membrane permeabilization. Science, 1991, 251, 1481-1485.
[79]
Wimley, W.C.; Selsted, M.E.; White, S.H. Interactions between human defensins and lipid bilayers: evidence for formation of multimeric pores. Protein Sci., 1994, 3(9), 1362-1373.
[http://dx.doi.org/10.1002/pro.5560030902] [PMID: 7833799]
[80]
Bonucci, A.; Balducci, E.; Pistolesi, S.; Pogni, R. The defensins-lipid interaction: Insights on the binding states of the human antimicrobial peptide HNP-1 to model bacterial membranes’ Biochimica et Biophysica Acta (BBA). Biomembranes, 2013, 1828, 758-764.
[http://dx.doi.org/10.1016/j.bbamem.2012.11.011] [PMID: 23159481]
[81]
Rokitskaya, T.I.; Kolodkin, N.I.; Kotova, E.A.; Antonenko, Y.N. Indolicidin action on membrane permeability: carrier mechanism versus pore formation. Biochim. Biophys. Acta, 2011, 1808(1), 91-97.
[http://dx.doi.org/10.1016/j.bbamem.2010.09.005] [PMID: 20851098]
[82]
Marchand, C.; Krajewski, K.; Lee, H-F.; Antony, S.; Johnson, A.A.; Amin, R.; Roller, P.; Kvaratskhelia, M.; Pommier, Y. Covalent binding of the natural antimicrobial peptide indolicidin to DNA abasic sites. Nucleic Acids Res., 2006, 34(18), 5157-5165.
[http://dx.doi.org/10.1093/nar/gkl667] [PMID: 16998183]
[83]
Yang, S.T.; Shin, S.Y.; Hahm, K.S.; Kim, J.I. Different modes in antibiotic action of tritrpticin analogs, cathelicidin-derived Trp-rich and Pro/Arg-rich peptides. Biochim. Biophys. Acta, 2006, 1758(10), 1580-1586.
[http://dx.doi.org/10.1016/j.bbamem.2006.06.007] [PMID: 16859636]
[84]
Schibli, D.J.; Nguyen, L.T.; Kernaghan, S.D.; Rekdal, Ø.; Vogel, H.J. Structure-function analysis of tritrpticin analogs: potential relationships between antimicrobial activities, model membrane interactions, and their micelle-bound NMR structures. Biophys. J., 2006, 91(12), 4413-4426.
[http://dx.doi.org/10.1529/biophysj.106.085837] [PMID: 16997878]
[85]
Mochon, A.B.; Liu, H. The antimicrobial peptide histatin-5 causes a spatially restricted disruption on the Candida albicans surface, allowing rapid entry of the peptide into the cytoplasm. PLoS Pathog., 2008, 4(10)e1000190
[http://dx.doi.org/10.1371/journal.ppat.1000190] [PMID: 18974864]
[86]
Velkov, T.; Roberts, K.D.; Nation, R.L.; Thompson, P.E.; Li, J. Pharmacology of polymyxins: new insights into an ‘old’ class of antibiotics. Future Microbiol., 2013, 8(6), 711-724.
[http://dx.doi.org/10.2217/fmb.13.39] [PMID: 23701329]
[87]
Guleri, A.; Utili, R.; Dohmen, P.; Petrosillo, N.; Piper, C.; Pathan, R.; Hamed, K. Daptomycin for the treatment of infective endocarditis: Results from European Cubicin® Outcomes Registry and Experience (EU-CORE). Infect. Dis. Ther., 2015, 4(3), 283-296.
[http://dx.doi.org/10.1007/s40121-015-0075-9] [PMID: 26168988]
[88]
Wenzler, E.; Bunnell, K.L.; Danziger, L.H. Clinical use of the polymyxins: the tale of the fox and the cat. Int. J. Antimicrob. Agents, 2018, 51(5), 700-706.
[http://dx.doi.org/10.1016/j.ijantimicag.2017.12.023] [PMID: 29305954]
[89]
Marr, A.K.; Gooderham, W.J.; Hancock, R.E. Antibacterial peptides for therapeutic use: obstacles and realistic outlook. Curr. Opin. Pharmacol., 2006, 6(5), 468-472.
[http://dx.doi.org/10.1016/j.coph.2006.04.006] [PMID: 16890021]
[90]
Fuente-Núñez. C; Silva, O.P.; Lu, T.K.; Octavio Luiz Franco, O.L. Antimicrobial peptides: Role in human disease and potential as immunotherapies. Pharmaco. Therapeut, 2017, 178, 132-140.
[91]
AlMatar, M.; Makky, E.A.; Yakıcı, G.; Var, I.; Kayar, B.; Köksal, F. Antimicrobial peptides as an alternative to anti-tuberculosis drugs. Pharmacol. Res., 2018, 128, 288-305.
[http://dx.doi.org/10.1016/j.phrs.2017.10.011] [PMID: 29079429]
[92]
Elad, S.; Epstein, J.B.; Raber-Durlacher, J.; Donnelly, P.; Strahilevitz, J. The antimicrobial effect of Iseganan HCl oral solution in patients receiving stomatotoxic chemotherapy: analysis from a multicenter, double-blind, placebo-controlled, randomized, phase III clinical trial. J. Oral Pathol. Med., 2012, 41(3), 229-234.
[http://dx.doi.org/10.1111/j.1600-0714.2011.01094.x] [PMID: 22077420]
[93]
Velden, W.J.; van Iersel, T.M.; Blijlevens, N.M.; Donnelly, J.P. Safety and tolerability of the antimicrobial peptide human lactoferrin 1-11 (hLF1-11). BMC Med., 2009, 8, 44.
[94]
Grönberg, A.; Mahlapuu, M.; Ståhle, M.; Whately-Smith, C.; Rollman, O. Treatment with LL-37 is safe and effective in enhancing healing of hard-to-heal venous leg ulcers: A randomized, placebo-controlled clinical trial.
[http://dx.doi.org/10.1111/wrr.12211]
[95]
Wiig, M.E.; Dahlin, L.B.; Fridén, J.; Hagberg, L.; Larsen, S.E.; Wiklund, K.; Mahlapuu, M. PXL01 in sodium hyaluronate for improvement of hand recovery after flexor tendon repair surgery: randomized controlled trial. PLoS One, 2014, 9(10)e110735
[http://dx.doi.org/10.1371/journal.pone.0110735] [PMID: 25340801]
[96]
Domingues, M.M.; Santos, N.C.; Castanho, M.A. Antimicrobial peptide rBPI21: a translational overview from bench to clinical studies. Curr. Protein Pept. Sci., 2012, 13(7), 611-619.
[http://dx.doi.org/10.2174/138920312804142101] [PMID: 23116442]
[97]
Fox, J.L. Antimicrobial peptides stage a comeback. Nat. Biotechnol., 2013, 31(5), 379-382.
[http://dx.doi.org/10.1038/nbt.2572] [PMID: 23657384]
[98]
Ji, H.X.; Zou, Y.L.; Duan, J.J.; Jia, Z.R.; Li, X.J.; Wang, Z.; Li, L.; Li, Y.W.; Liu, G.Y.; Tong, M.Q.; Li, X.Y.; Zhang, G.H.; Dai, X.R.; He, L.; Li, Z.Y.; Cao, C.; Yang, Y. The synthetic melanocortin (CKPV)2 exerts anti-fungal and anti-inflammatory effects against Candida albicans vaginitis via inducing macrophage M2 polarization. PLoS One, 2013, 8(2)e56004
[http://dx.doi.org/10.1371/journal.pone.0056004] [PMID: 23457491]
[99]
Gordon, Y.J.; Romanowski, E.G.; McDermott, A.M. A review of antimicrobial peptides and their therapeutic potential as anti-infective drugs. Curr. Eye Res., 2005, 30(7), 505-515.
[http://dx.doi.org/10.1080/02713680590968637] [PMID: 16020284]
[100]
Kavanagh, K.; Dowd, S. Histatins: antimicrobial peptides with therapeutic potential. J. Pharm. Pharmacol., 2004, 56(3), 285-289.
[http://dx.doi.org/10.1211/0022357022971] [PMID: 15025852]
[101]
Reinhardt, A.; Neundorf, I. Design and Application of Antimicrobial Peptide Conjugates. Int. J. Mol. Sci, 2016, 17(5), 701 pii: E701.
[http://dx.doi.org/10.3390/ijms17050701]
[102]
Piotrowska, U.; Sobczak, M.; Oledzka, E. Current state of a dual behaviour of antimicrobial peptides-Therapeutic agents and promising delivery vectors. Chem. Biol. Drug Des., 2017, 90(6), 1079-1093.
[http://dx.doi.org/10.1111/cbdd.13031] [PMID: 28548370]
[103]
Dikid, T.; Jain, S.K.; Sharma, A.; Kumar, A.; Narain, J.P. Emerging & re-emerging infections in India: an overview. Indian J. Med. Res., 2013, 138(1), 19-31.
[PMID: 24056553]
[104]
Palestro, C.J. Radionuclide imaging of infection: in search of the grail. J. Nucl. Med., 2009, 50(5), 671-673.
[http://dx.doi.org/10.2967/jnumed.108.058297] [PMID: 19372472]
[105]
Lupetti, A.; Welling, M.M.; Pauwels, E.K.; Nibbering, P.H. Radiolabelled antimicrobial peptides for infection detection. Lancet Infect. Dis., 2003, 3(4), 223-229.
[http://dx.doi.org/10.1016/S1473-3099(03)00579-6] [PMID: 12679265]
[106]
Ostovar, A.; Assadi, M.; Vahdat, K.; Nabipour, I.; Javadi, H.; Eftekhari, M.; Assadi, M. A pooled analysis of diagnostic value of (99m)Tc-ubiquicidin (UBI) scintigraphy in detection of an infectious process. Clin. Nucl. Med., 2013, 38(6), 413-416.
[http://dx.doi.org/10.1097/RLU.0b013e3182867d56] [PMID: 23652406]
[107]
Shinto, A.S.; Mukherjee, A.; Karuppusamy, K.K.; Joseph, J.; Bhatt, J.; Korde, A.; Upadhya, I.; Arjun, C.; Samuel, G.; Dash, A. Clinical utility of 99mTc-ubiquicidin (29-41) as an adjunct to bone scan in differentiating infected versus noninfected loosening of prosthesis before revision surgery. Nucl. Med. Commun., 2017, 38(4), 285-290.
[http://dx.doi.org/10.1097/MNM.0000000000000648] [PMID: 28244975]
[108]
Mukherjee, A.; Bhatt, J.; Shinto, A.; Korde, A.; Kumar, M.; Kamaleshwaran, K.; Joseph, J.; Sarma, H.D.; Dash, A. 68Ga-NOTA-ubiquicidin fragment for PET imaging of infection: From bench to bedside. J. Pharm. Biomed. Anal., 2018, 159, 245-251.
[http://dx.doi.org/10.1016/j.jpba.2018.06.064] [PMID: 29990892]
[109]
Welling, M.M.; Nibbering, P.H.; Paulusma-Annema, A.; Hiemstra, P.S.; Pauwels, E.K.; Calame, W. Imaging of bacterial infections with 99mTc-labeled human neutrophil peptide-1. J. Nucl. Med., 1999, 40(12), 2073-2080.
[PMID: 10616888]
[110]
Welling, M.M.; Lupetti, A.; Balter, H.S.; Lanzzeri, S.; Souto, B.; Rey, A.M.; Savio, E.O.; Paulusma-Annema, A.; Pauwels, E.K.; Nibbering, P.H. 99mTc-labeled antimicrobial peptides for detection of bacterial and Candida albicans infections. J. Nucl. Med., 2001, 42(5), 788-794.
[PMID: 11337578]
[111]
Brouwer, C.P.; Welling, M.M. Various routes of administration of (99m)Tc-labeled synthetic lactoferrin antimicrobial peptide hLF 1-11 enables monitoring and effective killing of multidrug-resistant Staphylococcus aureus infections in mice. Peptides, 2008, 29(7), 1109-1117.
[http://dx.doi.org/10.1016/j.peptides.2008.03.003] [PMID: 18423795]
[112]
Brouwer, C.P.J.M.; Sarda-Mantel, L.; Meulemans, A.; Le Guludec, D.; Welling, M.M. The use of technetium-99m radiolabeled human antimicrobial peptides for infection specific imaging. Mini Rev. Med. Chem., 2008, 8(10), 1039-1052.
[http://dx.doi.org/10.2174/138955708785740670] [PMID: 18782056]

Rights & Permissions Print Cite
© 2025 Bentham Science Publishers | Privacy Policy
Request history8.2.27PHP Version263msRequest Duration28MBMemory UsageGET article/{article_id}/{param?}Route
  • warninglog[03:01:12] LOG.warning: Optional parameter $article_id declared before required parameter $request i...
  • warninglog[03:01:12] LOG.warning: trim(): Passing null to parameter #1 ($string) of type string is deprecated ...
  • warninglog[03:01:12] LOG.warning: Function strftime() is deprecated in /home/alphaeurekaselec/public_html/stor...
  • Booting (101ms)time
  • Application (162ms)time
  • 1 x Application (61.54%)
    162ms
    1 x Booting (38.46%)
    101ms
    14 templates were rendered
    • articlearticle.blade.php#?blade
    • includes.article_top_bannerarticle_top_banner.blade.php#?blade
    • includes.article_referencearticle_reference.blade.php#?blade
    • export_citation_formexport_citation_form.blade.php#?blade
    • includes.article_bottom_bannerarticle_bottom_banner.blade.php#?blade
    • includes.inc_related_journalsinc_related_journals.blade.php#?blade
    • includes.inc_related_ebooksinc_related_ebooks.blade.php#?blade
    • includes.journal_rightmenujournal_rightmenu.blade.php#?blade
    • includes.journal_right_bannerjournal_right_banner.blade.php#?blade
    • layouts.appapp.blade.php#?blade
    • layouts._login_access_login_access.blade.php#?blade
    • layouts._header_header.blade.php#?blade
    • layouts._main_menu_main_menu.blade.php#?blade
    • layouts._footer_menu_footer_menu.blade.php#?blade
    uri
    GET article/{article_id}/{param?}
    middleware
    web, check_user_access
    controller
    App\Http\Controllers\ArticleController@GetArticleDetails
    namespace
    App\Http\Controllers
    where
    as
    article
    file
    app/Http/Controllers/ArticleController.php:1974-2510
    36 statements were executed, 4 of which were duplicates, 32 unique. Show only duplicated87.69ms
    • Connection Establishedalphaeurekaselec_live_10_06_2022UserAccessCheck.php#24
      Backtrace
      • 9. middleware::check_user_access:24
      • 10. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 11. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 12. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 13. vendor/laravel/framework/src/Illuminate/Foundation/Http/Middleware/VerifyCsrfToken.php:88
    • INSERT INTO visitor_ip_address (ip_address,visitor_agent,visitor_count, created_on,updated_on) VALUES ('59755419','',1,1739847672,1739847672) ON DUPLICATE KEY UPDATE visitor_count=visitor_count + 1, updated_on=1739847672
      970μsalphaeurekaselec_live_10_06_2022UserAccessCheck.php#24
      Backtrace
      • 11. middleware::check_user_access:24
      • 12. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 14. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 15. vendor/laravel/framework/src/Illuminate/Foundation/Http/Middleware/VerifyCsrfToken.php:88
    • INSERT INTO visitor_ip_address_detail (ip_address,visitor_url,visitor_count, created_on,updated_on) VALUES ('59755419','/article/102580',1,1739847672,1739847672)
      140μsalphaeurekaselec_live_10_06_2022UserAccessCheck.php#27
      Backtrace
      • 11. middleware::check_user_access:27
      • 12. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 14. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 15. vendor/laravel/framework/src/Illuminate/Foundation/Http/Middleware/VerifyCsrfToken.php:88
    • (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_journal_volume_trail WHERE to_ip >= 59755419 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59755419) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_journal_volume_corporate WHERE to_ip >= 59755419 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59755419) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_journal_volume_token WHERE to_ip >= 59755419 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59755419) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_ebook_volume_trail WHERE to_ip >= 59755419 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59755419) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_ebook_volume_corporate WHERE to_ip >= 59755419 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59755419) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_ebook_volume_token WHERE to_ip >= 59755419 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59755419) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_trail WHERE to_ip >= 59755419 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59755419) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_corporate WHERE to_ip >= 59755419 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59755419) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_token WHERE to_ip >= 59755419 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59755419) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_trail WHERE to_ip >= 59755419 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59755419) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_corporate WHERE to_ip >= 59755419 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59755419) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_token WHERE to_ip >= 59755419 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59755419) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_trail WHERE to_ip >= 59755419 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59755419) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_corporate WHERE to_ip >= 59755419 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59755419) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_token WHERE to_ip >= 59755419 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59755419) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_disease_corporate WHERE to_ip >= 59755419 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59755419) limit 1
      12.34msalphaeurekaselec_live_10_06_2022UserAccess.php#784
      Bindings
      • 0: 59755419
      • 1: 59755419
      • 2: 59755419
      • 3: 59755419
      • 4: 59755419
      • 5: 59755419
      • 6: 59755419
      • 7: 59755419
      • 8: 59755419
      • 9: 59755419
      • 10: 59755419
      • 11: 59755419
      • 12: 59755419
      • 13: 59755419
      • 14: 59755419
      • 15: 59755419
      Backtrace
      • 14. app/Models/UserAccess/UserAccess.php:784
      • 15. middleware::check_user_access:114
      • 16. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 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=102580
      700μsalphaeurekaselec_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` = 56 limit 1
      1.32msalphaeurekaselec_live_10_06_2022Journal.php#64
      Bindings
      • 0: 56
      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=56) and sj.journal_id!=56 group by `j`.`nid`) as `aggregate_table`
      1.23msalphaeurekaselec_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=56) and sj.journal_id!=56 group by `j`.`nid` order by `j`.`journal_id` asc limit 10 offset 0
      920μsalphaeurekaselec_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=56) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid`) as `aggregate_table`
      1.46msalphaeurekaselec_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=56) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid` order by `v`.`ebook_volume_id` desc limit 10 offset 0
      1.36msalphaeurekaselec_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` = '102580'
      300μsalphaeurekaselec_live_10_06_2022Keywords.php#43
      Bindings
      • 0: 102580
      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` = '102580'
      4.15msalphaeurekaselec_live_10_06_2022Article.php#1570
      Bindings
      • 0: 102580
      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` = '102580' group by `au`.`author_id` order by `au`.`article_id` asc, `au`.`sequence` asc
      2.16msalphaeurekaselec_live_10_06_2022Author.php#86
      Bindings
      • 0: 102580
      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
      230μsalphaeurekaselec_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
      430μsalphaeurekaselec_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 = 56 and i.is_uploaded = 1 order by v.volume_name+0 desc, i.title+0 desc limit 1
      26.9msalphaeurekaselec_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 = 56 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      11.84msalphaeurekaselec_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 = 56 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      10.89msalphaeurekaselec_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` = 102580 limit 1
      210μsalphaeurekaselec_live_10_06_2022Article.php#744
      Bindings
      • 0: 102580
      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 = 102580 and content_type = 'article' order by status desc limit 1
      220μsalphaeurekaselec_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 * from `node_meta` where `nid` = 176959 limit 1
      160μsalphaeurekaselec_live_10_06_2022Meta.php#30
      Bindings
      • 0: 176959
      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
      190μsalphaeurekaselec_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` = 'MRMC' and (h.proposal_closing_date = 0 OR TO_DAYS(FROM_UNIXTIME(h.proposal_closing_date)) >= TO_DAYS(NOW())) order by `h`.`manuscript` asc
      310μsalphaeurekaselec_live_10_06_2022Article.php#2025
      Bindings
      • 0: MRMC
      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 = '102580' 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) )
      340μsalphaeurekaselec_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 = '9590' 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) )
      270μsalphaeurekaselec_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 = '2708' 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) )
      240μsalphaeurekaselec_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 <= 59755419 and j.to_ip >=59755419 )) and ((j.from_date <= 1739847672 and j.to_date >= 1739847672 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2708) 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 <= 59755419 and j.to_ip >=59755419 )) and ((j.from_date <= 1739847672 and j.to_date >= 1739847672 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2708) 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 <= 59755419 and j.to_ip >=59755419 )) and ((j.from_date <= 1739847672 and j.to_date >= 1739847672 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2708)
      1.47msalphaeurekaselec_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 <= 59755419 and j.to_ip >=59755419 )) and ((j.from_date <= 1739847672 and j.to_date >= 1739847672 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 9590) 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 <= 59755419 and j.to_ip >=59755419 )) and ((j.from_date <= 1739847672 and j.to_date >= 1739847672 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 9590) 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 <= 59755419 and j.to_ip >=59755419 )) and ((j.from_date <= 1739847672 and j.to_date >= 1739847672 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 9590)
      530μsalphaeurekaselec_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 <= 59755419 and j.to_ip >=59755419 )) and ((j.from_date <= 1739847672 and j.to_date >= 1739847672 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 102580) 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 <= 59755419 and j.to_ip >=59755419 )) and ((j.from_date <= 1739847672 and j.to_date >= 1739847672 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 102580) 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 <= 59755419 and j.to_ip >=59755419 )) and ((j.from_date <= 1739847672 and j.to_date >= 1739847672 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 102580)
      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` < '183' and is_uploaded = 1 and issue_id = 9590 order by cast(first_page as SIGNED) desc limit 1
      420μsalphaeurekaselec_live_10_06_2022Article.php#1819
      Bindings
      • 0: 183
      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` > '195' and is_uploaded = 1 and issue_id = 9590 order by cast(first_page as SIGNED) asc limit 1
      350μsalphaeurekaselec_live_10_06_2022Article.php#1831
      Bindings
      • 0: 195
      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` = 'en'
      160μsalphaeurekaselec_live_10_06_2022ArticleController.php#2497
      Bindings
      • 0: en
      Backtrace
      • 14. app/Http/Controllers/ArticleController.php:2497
      • 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` = 1
      230μsalphaeurekaselec_live_10_06_2022MultiLanguage.php#23
      Bindings
      • 0: 1
      Backtrace
      • 13. app/Models/MultiLanguage.php:23
      • 14. app/Http/Controllers/ArticleController.php:2498
      • 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 `id` from `multilanguage_article` where `article_id` = 102580 limit 1
      2.37msalphaeurekaselec_live_10_06_2022ArticleController.php#2506
      Bindings
      • 0: 102580
      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` = 56 and `b`.`banner_from_date` <= 1739847672 and `b`.`banner_to_date` >= 1739847672 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.09msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 56
      • 3: 1739847672
      • 4: 1739847672
      • 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` = 56 and `b`.`banner_from_date` <= 1739847672 and `b`.`banner_to_date` >= 1739847672 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.04msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 56
      • 3: 1739847672
      • 4: 1739847672
      • 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='25f5e21c83a1e03010569328e2a1f0e8'
      210μsalphaeurekaselec_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\MultiLanguage
    1MultiLanguage.php#?
        _token
        zmGLhyRkxkqoLZphgXFWUz8u3Bfz2IpfdeSVgJqU
        uc_cart_id
        25f5e21c83a1e03010569328e2a1f0e8
        _previous
        array:1 [ "url" => "http://alpha.eurekaselect.com/article/102580" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /article/102580
        status_code
        200
        
        status_text
        OK
        format
        html
        content_type
        text/html; charset=UTF-8
        request_query
        []
        
        request_request
        []
        
        request_headers
        0 of 0
        array:9 [ "cookie" => array:1 [ 0 => "wayfindertarget=eyJpdiI6Im9QblNmZ2lxcTlNa1dpTTZNL1c2OGc9PSIsInZhbHVlIjoibmE4eE92VVkrS1NEUWFyOVR2N1d1STVoT3BXLyt5WThzN1BLemZnRk1zVT0iLCJtYWMiOiJiZTgyNGNjNmJlNjlmMWEzYTM3NGRmYTc0NWUzNDFmMDZlMDQwMGZmNmY1YzI4YjdlMTQ1ODBlNGQyNGRmM2ZkIiwidGFnIjoiIn0%3Dwayfindertarget=eyJpdiI6Im9QblNmZ2lxcTlNa1dpTTZNL1c2OGc9PSIsInZhbHVlIjoibmE4eE92VVkrS1NEUWFyOVR2N1d1STVoT3BXLyt5WThzN1BLemZnRk1zVT0iLCJtYWMiOiJiZTgyNGNjNmJlNjlm" ] "accept-encoding" => array:1 [ 0 => "gzip, deflate" ] "accept" => array:1 [ 0 => "text/html,application/xhtml+xml,application/xml;q=0.9,image/avif,image/webp,image/apng,*/*;q=0.8,application/signed-exchange;v=b3;q=0.7" ] "user-agent" => array:1 [ 0 => "Mozilla/5.0 AppleWebKit/537.36 (KHTML, like Gecko; compatible; ClaudeBot/1.0; +claudebot@anthropic.com)" ] "upgrade-insecure-requests" => array:1 [ 0 => "1" ] "cache-control" => array:1 [ 0 => "no-cache" ] "pragma" => array:1 [ 0 => "no-cache" ] "connection" => array:1 [ 0 => "keep-alive" ] "host" => array:1 [ 0 => "alpha.eurekaselect.com" ] ]
        request_cookies
        0 of 0
        array:1 [ "wayfindertarget" => null ]
        response_headers
        0 of 0
        array:5 [ "content-type" => array:1 [ 0 => "text/html; charset=UTF-8" ] "cache-control" => array:1 [ 0 => "no-cache, private" ] "date" => array:1 [ 0 => "Tue, 18 Feb 2025 03:01:12 GMT" ] "set-cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6IllZTWJ4bUNNRkVhVUpKTTJLK2ZoZ1E9PSIsInZhbHVlIjoiZCtDVnVEdHV2N3ZZRldoTFduWUQ2ZEtDRWpwYXNwVGE3a2V2RUsxd05iTEQwblBMT1g3NFByZ004N2dUODlsUDFVS0ZocFgrTDFUK1ZyQXVXQXN4ZkNhc09WdGpVc0xLMS9Kbi9wOFRBNVhWSW80TzZhKzBsaFdOeFI0Uy9UZ1QiLCJtYWMiOiI4NDc3NjUzODllMDkzYzUyODA2NzJjMTJiMjA3NDk0MTY2MjczYjdhYmJmMjIwNzM1OTk5MDVlYTQ4NjA0NDhkIiwidGFnIjoiIn0%3D; expires=Thu, 20 Feb 2025 15:01:12 GMT; Max-Age=216000; path=/; secure; samesite=laxXSRF-TOKEN=eyJpdiI6IllZTWJ4bUNNRkVhVUpKTTJLK2ZoZ1E9PSIsInZhbHVlIjoiZCtDVnVEdHV2N3ZZRldoTFduWUQ2ZEtDRWpwYXNwVGE3a2V2RUsxd05iTEQwblBMT1g3NFByZ004N2dUODlsUDFVS0Zoc" 1 => "alphaeurekaselectnet_session=eyJpdiI6IjZ6UGlLM3g5QmlueWZBK1ZJTmtVT2c9PSIsInZhbHVlIjoiRVVmVHRuNWw2WGRuQWdnTUJnM3RiUFg5TDVRTnJ0bWlMNVZLb2xWbE4xcXBqQXpRN1ZjT3lJdE5DVXVVeDY3WksrcENidkFRYS9JNnYrdHBwYktXeTRqRmpESkZtd2JhQ29jRGkySStNclp1aWxhZHB4MFczdnc5VFRKQ0VDNHoiLCJtYWMiOiJhM2I5Mzc1ZGUzZjljNTBlY2E4NWE0YTY4MjIwNGU4MWU3MGJlN2M5MDExMGFlYzE0MjYxMDA5OTJiNjVjOTYzIiwidGFnIjoiIn0%3D; path=/; secure; httponly; samesite=laxalphaeurekaselectnet_session=eyJpdiI6IjZ6UGlLM3g5QmlueWZBK1ZJTmtVT2c9PSIsInZhbHVlIjoiRVVmVHRuNWw2WGRuQWdnTUJnM3RiUFg5TDVRTnJ0bWlMNVZLb2xWbE4xcXBqQXpRN1ZjT3lJdE5" ] "Set-Cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6IllZTWJ4bUNNRkVhVUpKTTJLK2ZoZ1E9PSIsInZhbHVlIjoiZCtDVnVEdHV2N3ZZRldoTFduWUQ2ZEtDRWpwYXNwVGE3a2V2RUsxd05iTEQwblBMT1g3NFByZ004N2dUODlsUDFVS0ZocFgrTDFUK1ZyQXVXQXN4ZkNhc09WdGpVc0xLMS9Kbi9wOFRBNVhWSW80TzZhKzBsaFdOeFI0Uy9UZ1QiLCJtYWMiOiI4NDc3NjUzODllMDkzYzUyODA2NzJjMTJiMjA3NDk0MTY2MjczYjdhYmJmMjIwNzM1OTk5MDVlYTQ4NjA0NDhkIiwidGFnIjoiIn0%3D; expires=Thu, 20-Feb-2025 15:01:12 GMT; path=/; secureXSRF-TOKEN=eyJpdiI6IllZTWJ4bUNNRkVhVUpKTTJLK2ZoZ1E9PSIsInZhbHVlIjoiZCtDVnVEdHV2N3ZZRldoTFduWUQ2ZEtDRWpwYXNwVGE3a2V2RUsxd05iTEQwblBMT1g3NFByZ004N2dUODlsUDFVS0Zoc" 1 => "alphaeurekaselectnet_session=eyJpdiI6IjZ6UGlLM3g5QmlueWZBK1ZJTmtVT2c9PSIsInZhbHVlIjoiRVVmVHRuNWw2WGRuQWdnTUJnM3RiUFg5TDVRTnJ0bWlMNVZLb2xWbE4xcXBqQXpRN1ZjT3lJdE5DVXVVeDY3WksrcENidkFRYS9JNnYrdHBwYktXeTRqRmpESkZtd2JhQ29jRGkySStNclp1aWxhZHB4MFczdnc5VFRKQ0VDNHoiLCJtYWMiOiJhM2I5Mzc1ZGUzZjljNTBlY2E4NWE0YTY4MjIwNGU4MWU3MGJlN2M5MDExMGFlYzE0MjYxMDA5OTJiNjVjOTYzIiwidGFnIjoiIn0%3D; path=/; secure; httponlyalphaeurekaselectnet_session=eyJpdiI6IjZ6UGlLM3g5QmlueWZBK1ZJTmtVT2c9PSIsInZhbHVlIjoiRVVmVHRuNWw2WGRuQWdnTUJnM3RiUFg5TDVRTnJ0bWlMNVZLb2xWbE4xcXBqQXpRN1ZjT3lJdE5" ] ]
        session_attributes
        0 of 0
        array:5 [ "_token" => "zmGLhyRkxkqoLZphgXFWUz8u3Bfz2IpfdeSVgJqU" "uc_cart_id" => "25f5e21c83a1e03010569328e2a1f0e8" "_previous" => array:1 [ "url" => "http://alpha.eurekaselect.com/article/102580" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-18 03:01:12GET/article/102580314361