Generic placeholder image

Protein & Peptide Letters

Editor-in-Chief

ISSN (Print): 0929-8665
ISSN (Online): 1875-5305

Letter Article

Structural Plasticity of EAK-16 Peptide Inducing Vesicle Membrane Leakage

Author(s): Abdul Majid *, Farah Naz and Muhammad Hassan Khaskheli

Volume 27, Issue 8, 2020

Page: [801 - 807] Pages: 7

DOI: 10.2174/0929866527666200129141116

Price: $65

Abstract

Background: Ionic complementary peptide EAK-16 has been studies for anticancer drug delivery application. This is a 16 residues, short sequence peptide has ability to trosnform into micro/nanoparticle via self-assembly. However, it is still not clear that how this can bind with cell membrane to induce membrane leakage or delivering their cargo inside cell membrane.

Objective: The main objective of this work was to understand behaviour of secondary structure conformation of peptide in solution and at lipid membrane interfaces and membrane permeability of synthetic ionic complementary peptide EAK-16. The corresponding secondary structure conformation was evaluated.

Methods: We performed biophysical investigation to probe the interaction of synthesised ionic complementary peptide (EAK-16) with dimyristoylphospholcholine (DMPC) and dimyristoylphosphoserine (DMPS) membrane interfaces. The folding behaviours of EAK-16 were studied with Circular Dichroism (CD) spectroscopy. Membrane leakage with peptide was confirmed with calcein leakage assay.

Results: Our finding of this study showed that in aqueous phase EAK-16 was predominantly folded into β-sheets. The temperature could alter the β-sheets. However, in DMPC and DMPS membrane interfaces, EAK-16 adopted helical conformation. EAK-16 has preference in perturbing anionic compared Zwitterionic lipid vesicles. This study proposed that hydrophobic grooves of EAK-16 might be a key in the association with lipid bilayers. Secondly, a charge distribution of ionic residues would also support the orientation at lipid bilayers. This peptide membrane association would facilitate the membrane destabilisation.

Conclusion: This study demonstrated the supporting evidence that EAK-16 could interact with lipid membranes and conforming to helical structure, while the helical conformation induced the lipid membrane leakage. Overall, this study provides a physical rationale that ionic complementary peptide can be a useful tool for designing and development of novel antibiotics and anticancer agents along its previous drug delivery applications.

Keywords: Ionic complementary peptide, peptide membrane interaction, membrane permeability, peptide folding, structurefunction of peptide, zwitterionic lipid vesicles.

« Previous
Graphical Abstract

[1]
Dufourc, E.J.; Buchoux, S.; Toupé, J.; Sani, M.A.; Jean-François, F.; Khemtémourian, L.; Grélard, A.; Loudet-Courrèges, C.; Laguerre, M.; Elezgaray, J.; Desbat, B.; Odaert, B. Membrane interacting peptides: From killers to helpers. Curr. Protein Pept. Sci., 2012, 13(7), 620-631.
[http://dx.doi.org/10.2174/138920312804142138] [PMID: 23116443]
[2]
Vineeth Kumar, T.V.; Sanil, G. A review of the mechanism of action of amphibian antimicrobial peptides focusing on peptide-membrane interaction and membrane curvature. Curr. Protein Pept. Sci., 2017, 18(12), 1263-1272.
[http://dx.doi.org/10.2174/1389203718666170710114932] [PMID: 28699512]
[3]
Wang, G. Tool developments for structure-function studies of host defense peptides. Protein Pept. Lett., 2007, 14(1), 57-69.
[http://dx.doi.org/10.2174/092986607779117182] [PMID: 17266652]
[4]
Iwasaki, A.; Medzhitov, R. Control of adaptive immunity by the innate immune system. Nat. Immunol., 2015, 16(4), 343-353.
[http://dx.doi.org/10.1038/ni.3123] [PMID: 25789684]
[5]
Moynihan, K.D.; Opel, C.F.; Szeto, G.L.; Tzeng, A.; Zhu, E.F.; Engreitz, J.M.; Williams, R.T.; Rakhra, K.; Zhang, M.H.; Rothschilds, A.M.; Kumari, S.; Kelly, R.L.; Kwan, B.H.; Abraham, W.; Hu, K.; Mehta, N.K.; Kauke, M.J.; Suh, H.; Cochran, J.R.; Lauffenburger, D.A.; Wittrup, K.D.; Irvine, D.J. Eradication of large established tumors in mice by combination immunotherapy that engages innate and adaptive immune responses. Nat. Med., 2016, 22(12), 1402-1410.
[http://dx.doi.org/10.1038/nm.4200] [PMID: 27775706]
[6]
Hall, C.W.; Mah, T-F. Molecular mechanisms of biofilm-based antibiotic resistance and tolerance in pathogenic bacteria. FEMS Microbiol. Rev., 2017, 41(3), 276-301.
[http://dx.doi.org/10.1093/femsre/fux010] [PMID: 28369412]
[7]
Falanga, A.; Lombardi, L.; Franci, G.; Vitiello, M.; Iovene, M.R.; Morelli, G.; Galdiero, M.; Galdiero, S. Marine antimicrobial peptides: Nature provides templates for the design of novel compounds against pathogenic bacteria. Int. J. Mol. Sci., 2016, 17(5), 785.
[http://dx.doi.org/10.3390/ijms17050785] [PMID: 27213366]
[8]
Andersson, D.I.; Hughes, D.; Kubicek-Sutherland, J.Z. Mechanisms and consequences of bacterial resistance to antimicrobial peptides. Drug Resist. Updat., 2016, 26, 43-57.
[http://dx.doi.org/10.1016/j.drup.2016.04.002] [PMID: 27180309]
[9]
Oliveira, M.D.; Franco, O.L.; Nascimento, J.M.; de Melo, C.P.; Andrade, C.A. Mechanistic aspects of peptide-membrane interactions determined by optical, dielectric and piezoelectric techniques: An overview. Curr. Protein Pept. Sci., 2013, 14(7), 543-555.
[http://dx.doi.org/10.2174/13892037113149990070] [PMID: 23968347]
[10]
Wang, J.; Liu, K.; Xing, R.; Yan, X. Peptide self-assembly: Thermodynamics and kinetics. Chem. Soc. Rev., 2016, 45(20), 5589-5604.
[http://dx.doi.org/10.1039/C6CS00176A] [PMID: 27487936]
[11]
Sun, L.; Zheng, C.; Webster, T.J. Self-assembled peptide nanomaterials for biomedical applications: Promises and pitfalls. Int. J. Nanomedicine, 2016, 12, 73-86.
[http://dx.doi.org/10.2147/IJN.S117501] [PMID: 28053525]
[12]
Edgar, J.Y.C.; Wang, H. Introduction for design of nanoparticle based drug delivery systems. Curr. Pharm. Des., 2017, 23(14), 2108-2112.
[http://dx.doi.org/10.2174/1381612822666161025154003] [PMID: 27784242]
[13]
Hong, Y.; Lau, L.S.; Legge, R.L.; Chen, P. Critical self-assembly concentration of an ionic-complementary peptide EAK16-I. J. Adhes., 2004, 80(10-11), 913-931.
[http://dx.doi.org/10.1080/00218460490508616]
[14]
Dathe, M.; Schümann, M.; Wieprecht, T.; Winkler, A.; Beyermann, M.; Krause, E.; Matsuzaki, K.; Murase, O.; Bienert, M. Peptide helicity and membrane surface charge modulate the balance of electrostatic and hydrophobic interactions with lipid bilayers and biological membranes. Biochemistry, 1996, 35(38), 12612-12622.
[http://dx.doi.org/10.1021/bi960835f] [PMID: 8823199]
[15]
Greenfield, N.J. Using circular dichroism spectra to estimate protein secondary structure. Nat. Protoc., 2006, 1(6), 2876-2890.
[http://dx.doi.org/10.1038/nprot.2006.202] [PMID: 17406547]
[16]
Neuhaus, F.C.; Baddiley, J. A continuum of anionic charge: Structures and functions of D-alanyl-teichoic acids in gram-positive bacteria. Microbiol. Mol. Biol. Rev., 2003, 67(4), 686-723.
[http://dx.doi.org/10.1128/MMBR.67.4.686-723.2003] [PMID: 14665680]
[17]
Lee, T-H.; Hall, K.N.; Aguilar, M.I.K.; Aguilar, M-I. Antimicrobial peptide structure and mechanism of action: A focus on the role of membrane structure. Curr. Top. Med. Chem., 2016, 16(1), 25-39.
[http://dx.doi.org/10.2174/1568026615666150703121700] [PMID: 26139112]
[18]
Reed, J.; Reed, T.A. A set of constructed type spectra for the practical estimation of peptide secondary structure from circular dichroism. Anal. Biochem., 1997, 254(1), 36-40.
[http://dx.doi.org/10.1006/abio.1997.2355] [PMID: 9398343]
[19]
Xu, D.; Zhang, Y. Ab initio protein structure assembly using continuous structure fragments and optimized knowledge-based force field. Proteins, 2012, 80(7), 1715-1735.
[http://dx.doi.org/10.1002/prot.24065] [PMID: 22411565]
[20]
Prenner, E.J.; Lewis, R.N.; McElhaney, R.N. The interaction of the antimicrobial peptide gramicidin S with lipid bilayer model and biological membranes. Biochim. Biophys. Acta, 1999, 1462(1-2), 201-221.
[http://dx.doi.org/10.1016/S0005-2736(99)00207-2] [PMID: 10590309]
[21]
Herrera, A.I.; Tomich, J.M.; Prakash, O. Membrane interacting peptides: A review. Curr. Protein Pept. Sci., 2016, 17(8), 827-841.
[http://dx.doi.org/10.2174/1389203717666160526123821] [PMID: 27226195]
[22]
Sani, M-A.; Separovic, F. How membrane-active peptides get into lipid membranes. Acc. Chem. Res., 2016, 49(6), 1130-1138.
[http://dx.doi.org/10.1021/acs.accounts.6b00074] [PMID: 27187572]
[23]
Mika, J.T.; Moiset, G.; Cirac, A.D.; Feliu, L.; Bardají, E.; Planas, M.; Sengupta, D.; Marrink, S.J.; Poolman, B. Structural basis for the enhanced activity of cyclic antimicrobial peptides: the case of BPC194. Biochim. Biophys. Acta, 2011, 1808(9), 2197-2205.
[http://dx.doi.org/10.1016/j.bbamem.2011.05.001] [PMID: 21586269]
[24]
Bond, P.J.; Holyoake, J.; Ivetac, A.; Khalid, S.; Sansom, M.S.P. Coarse-grained molecular dynamics simulations of membrane proteins and peptides. J. Struct. Biol., 2007, 157(3), 593-605.
[http://dx.doi.org/10.1016/j.jsb.2006.10.004] [PMID: 17116404]
[25]
Sato, H.; Feix, J.B. Peptide-membrane interactions and mechanisms of membrane destruction by amphipathic α-helical antimicrobial peptides. Biochim. Biophys. Acta, 2006, 1758(9), 1245-1256.
[http://dx.doi.org/10.1016/j.bbamem.2006.02.021] [PMID: 16697975]
[26]
Berditsch, M.; Jäger, T.; Strempel, N.; Schwartz, T.; Overhage, J.; Ulrich, A.S. Synergistic effect of membrane-active peptides polymyxin B and gramicidin S on multidrug-resistant strains and biofilms of Pseudomonas aeruginosa. Antimicrob. Agents Chemother., 2015, 59(9), 5288-5296.
[http://dx.doi.org/10.1128/AAC.00682-15] [PMID: 26077259]
[27]
Lins, L.; Charloteaux, B.; Thomas, A.; Brasseur, R. Computational study of lipid-destabilizing protein fragments: Towards a comprehensive view of tilted peptides. Proteins, 2001, 44(4), 435-447.
[http://dx.doi.org/10.1002/prot.1109] [PMID: 11484221]
[28]
Mishig-Ochir, T.; Gombosuren, D.; Jigjid, A.; Tuguldur, B.; Chuluunbaatar, G.; Urnukhsaikhan, E.; Pathak, C.; Lee, B.J. Cellular membrane composition requirement by antimicrobial and anticancer peptide GA-K4. Protein Pept. Lett., 2017, 24(3), 197-205.
[http://dx.doi.org/10.2174/0929866523666161216123509] [PMID: 27993125]
[29]
Deslouches, B.; Di, Y.P. Antimicrobial peptides with selective antitumor mechanisms: Prospect for anticancer applications. Oncotarget, 2017, 8(28), 46635-46651.
[http://dx.doi.org/10.18632/oncotarget.16743] [PMID: 28422728]
[30]
Strömstedt, A.A.; Ringstad, L.; Schmidtchen, A.; Malmsten, M. Malmsten, interaction between amphiphilic peptides and phospholipid membranes. Curr. Opin. Colloid Interface Sci., 2010, 15(6), 467-478.
[http://dx.doi.org/10.1016/j.cocis.2010.05.006]
[31]
Alvares, D.S.; Fanani, M.L.; Ruggiero Neto, J.; Wilke, N. The interfacial properties of the peptide Polybia-MP1 and its interaction with DPPC are modulated by lateral electrostatic attractions. Biochim. Biophys. Acta, 2016, 1858(2), 393-402.
[http://dx.doi.org/10.1016/j.bbamem.2015.12.010] [PMID: 26673092]
[32]
Cutrona, K.J.; Kaufman, B.A.; Figueroa, D.M.; Elmore, D.E. Role of arginine and lysine in the antimicrobial mechanism of histone-derived antimicrobial peptides. FEBS Lett., 2015, 589(24 Pt B), 3915-3920.
[http://dx.doi.org/10.1016/j.febslet.2015.11.002] [PMID: 26555191]
[33]
Lee, I.H.; Zhao, C.; Nguyen, T.; Menzel, L.; Waring, A.J.; Sherman, M.A.; Lehrer, R.I. Clavaspirin, an antibacterial and haemolytic peptide from Styela clava. J. Pept. Res., 2001, 58(6), 445-456.
[http://dx.doi.org/10.1034/j.1399-3011.2001.10975.x] [PMID: 12005415]
[34]
Nicolas, P.; Mor, A. Peptides as weapons against microorganisms in the chemical defense system of vertebrates. Annu. Rev. Microbiol., 1995, 49(1), 277-304.
[http://dx.doi.org/10.1146/annurev.mi.49.100195.001425] [PMID: 8561461]
[35]
Jang, W.S.; Kim, K.N.; Lee, Y.S.; Nam, M.H.; Lee, I.H. Halocidin: A new antimicrobial peptide from hemocytes of the solitary tunicate, Halocynthia aurantium. FEBS Lett., 2002, 521(1-3), 81-86.
[http://dx.doi.org/10.1016/S0014-5793(02)02827-2] [PMID: 12067731]
[36]
Guidotti, G.; Brambilla, L.; Rossi, D. Cell-penetrating peptides: From basic research to clinics. Trends Pharmacol. Sci., 2017, 38(4), 406-424.
[http://dx.doi.org/10.1016/j.tips.2017.01.003] [PMID: 28209404]
[37]
Poger, D.; Pöyry, S.; Mark, A.E. Could Cardiolipin protect membranes against the action of certain antimicrobial peptides? Aurein 1.2, a case study. ACS Omega, 2018, 3(12), 16453-16464.
[http://dx.doi.org/10.1021/acsomega.8b02710] [PMID: 30613806]
[38]
Qian, S.; Rai, D. Interaction of aurein 1.2 and charged lipid bilayers. Biophys. J., 2017, 112(3), 378-379.
[http://dx.doi.org/10.1016/j.bpj.2016.11.2058]
[39]
Ulmschneider, J.P. Charged antimicrobial peptides can translocate across membranes without forming channel-like pores. Biophys. J., 2017, 113(1), 73-81.
[http://dx.doi.org/10.1016/j.bpj.2017.04.056] [PMID: 28700927]

Rights & Permissions Print Cite
© 2025 Bentham Science Publishers | Privacy Policy
Request history8.2.27PHP Version494msRequest Duration28MBMemory UsageGET article/{article_id}/{param?}Route
  • warninglog[15:39:07] LOG.warning: Optional parameter $article_id declared before required parameter $request i...
  • warninglog[15:39:08] LOG.warning: trim(): Passing null to parameter #1 ($string) of type string is deprecated ...
  • warninglog[15:39:08] LOG.warning: Function strftime() is deprecated in /home/alphaeurekaselec/public_html/stor...
  • Booting (95.19ms)time
  • Application (399ms)time
  • 1 x Application (80.72%)
    399ms
    1 x Booting (19.28%)
    95.19ms
    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 duplicated297ms
    • 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 ('59765840','',1,1740497947,1740497947) ON DUPLICATE KEY UPDATE visitor_count=visitor_count + 1, updated_on=1740497947
      1.31msalphaeurekaselec_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 ('59765840','/article/104050',1,1740497947,1740497947)
      280μsalphaeurekaselec_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 >= 59765840 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59765840) 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 >= 59765840 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59765840) 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 >= 59765840 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59765840) 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 >= 59765840 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59765840) 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 >= 59765840 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59765840) 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 >= 59765840 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59765840) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_trail WHERE to_ip >= 59765840 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59765840) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_corporate WHERE to_ip >= 59765840 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59765840) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_token WHERE to_ip >= 59765840 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59765840) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_trail WHERE to_ip >= 59765840 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59765840) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_corporate WHERE to_ip >= 59765840 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59765840) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_token WHERE to_ip >= 59765840 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59765840) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_trail WHERE to_ip >= 59765840 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59765840) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_corporate WHERE to_ip >= 59765840 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59765840) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_token WHERE to_ip >= 59765840 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59765840) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_disease_corporate WHERE to_ip >= 59765840 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59765840) limit 1
      21.37msalphaeurekaselec_live_10_06_2022UserAccess.php#784
      Bindings
      • 0: 59765840
      • 1: 59765840
      • 2: 59765840
      • 3: 59765840
      • 4: 59765840
      • 5: 59765840
      • 6: 59765840
      • 7: 59765840
      • 8: 59765840
      • 9: 59765840
      • 10: 59765840
      • 11: 59765840
      • 12: 59765840
      • 13: 59765840
      • 14: 59765840
      • 15: 59765840
      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=104050
      2.25msalphaeurekaselec_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` = 51 limit 1
      6.17msalphaeurekaselec_live_10_06_2022Journal.php#64
      Bindings
      • 0: 51
      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=51) and sj.journal_id!=51 group by `j`.`nid`) as `aggregate_table`
      1.27msalphaeurekaselec_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=51) and sj.journal_id!=51 group by `j`.`nid` order by `j`.`journal_id` asc limit 10 offset 0
      1.06msalphaeurekaselec_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=51) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid`) as `aggregate_table`
      101msalphaeurekaselec_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=51) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid` order by `v`.`ebook_volume_id` desc limit 10 offset 0
      38.78msalphaeurekaselec_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` = '104050'
      8.62msalphaeurekaselec_live_10_06_2022Keywords.php#43
      Bindings
      • 0: 104050
      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` = '104050'
      590μsalphaeurekaselec_live_10_06_2022Article.php#1570
      Bindings
      • 0: 104050
      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` = '104050' group by `au`.`author_id` order by `au`.`article_id` asc, `au`.`sequence` asc
      4.19msalphaeurekaselec_live_10_06_2022Author.php#86
      Bindings
      • 0: 104050
      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
      390μsalphaeurekaselec_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 = 51 and i.is_uploaded = 1 order by v.volume_name+0 desc, i.title+0 desc limit 1
      51.01msalphaeurekaselec_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 = 51 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      20.51msalphaeurekaselec_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 = 51 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      18.59msalphaeurekaselec_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` = 104050 limit 1
      280μsalphaeurekaselec_live_10_06_2022Article.php#744
      Bindings
      • 0: 104050
      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 = 104050 and content_type = 'article' order by status desc limit 1
      350μsalphaeurekaselec_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` = 178810 limit 1
      270μsalphaeurekaselec_live_10_06_2022Meta.php#30
      Bindings
      • 0: 178810
      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
      320μsalphaeurekaselec_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` = 'PPL' and (h.proposal_closing_date = 0 OR TO_DAYS(FROM_UNIXTIME(h.proposal_closing_date)) >= TO_DAYS(NOW())) order by `h`.`manuscript` asc
      1.8msalphaeurekaselec_live_10_06_2022Article.php#2025
      Bindings
      • 0: PPL
      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 = '104050' 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) )
      410μsalphaeurekaselec_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 = '10093' 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 = '2694' 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) )
      310μsalphaeurekaselec_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 <= 59765840 and j.to_ip >=59765840 )) and ((j.from_date <= 1740497948 and j.to_date >= 1740497948 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2694) 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 <= 59765840 and j.to_ip >=59765840 )) and ((j.from_date <= 1740497948 and j.to_date >= 1740497948 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2694) 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 <= 59765840 and j.to_ip >=59765840 )) and ((j.from_date <= 1740497948 and j.to_date >= 1740497948 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2694)
      2.49msalphaeurekaselec_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 <= 59765840 and j.to_ip >=59765840 )) and ((j.from_date <= 1740497948 and j.to_date >= 1740497948 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 10093) 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 <= 59765840 and j.to_ip >=59765840 )) and ((j.from_date <= 1740497948 and j.to_date >= 1740497948 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 10093) 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 <= 59765840 and j.to_ip >=59765840 )) and ((j.from_date <= 1740497948 and j.to_date >= 1740497948 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 10093)
      840μsalphaeurekaselec_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 <= 59765840 and j.to_ip >=59765840 )) and ((j.from_date <= 1740497948 and j.to_date >= 1740497948 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 104050) 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 <= 59765840 and j.to_ip >=59765840 )) and ((j.from_date <= 1740497948 and j.to_date >= 1740497948 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 104050) 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 <= 59765840 and j.to_ip >=59765840 )) and ((j.from_date <= 1740497948 and j.to_date >= 1740497948 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 104050)
      860μsalphaeurekaselec_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` < '801' and is_uploaded = 1 and issue_id = 10093 order by cast(first_page as SIGNED) desc limit 1
      780μsalphaeurekaselec_live_10_06_2022Article.php#1819
      Bindings
      • 0: 801
      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` > '807' and is_uploaded = 1 and issue_id = 10093 order by cast(first_page as SIGNED) asc limit 1
      600μsalphaeurekaselec_live_10_06_2022Article.php#1831
      Bindings
      • 0: 807
      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'
      1.48msalphaeurekaselec_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
      310μsalphaeurekaselec_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` = 104050 limit 1
      3.83msalphaeurekaselec_live_10_06_2022ArticleController.php#2506
      Bindings
      • 0: 104050
      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` = 51 and `b`.`banner_from_date` <= 1740497948 and `b`.`banner_to_date` >= 1740497948 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.75msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 51
      • 3: 1740497948
      • 4: 1740497948
      • 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` = 51 and `b`.`banner_from_date` <= 1740497948 and `b`.`banner_to_date` >= 1740497948 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.46msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 51
      • 3: 1740497948
      • 4: 1740497948
      • 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='52f320c193d82ae97a70b7a91cce00bb'
      270μsalphaeurekaselec_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
        BdE2Lq9747HhuYeuEaLjJNNZzIK0ftZuF9Z0SwxK
        uc_cart_id
        52f320c193d82ae97a70b7a91cce00bb
        _previous
        array:1 [ "url" => "http://alpha.eurekaselect.com/article/104050" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /article/104050
        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=eyJpdiI6ImtsanFmY0dkaXB3RHZoYXBxQ2RSZkE9PSIsInZhbHVlIjoiT2orYjZ4NTN1N3JUdXRqQVpGOVVOWklaT25yOXpuc2pmaEN3NXg0ZmxjRT0iLCJtYWMiOiJhYmZmMWJjZmE1ODM0MGQ4Yzk2ZGE0NDdlYzhmZDNjODY3MDdmNTQxN2IzMGNjZTIzOGQ5ZjQzZmFiZDE5OTAxIiwidGFnIjoiIn0%3Dwayfindertarget=eyJpdiI6ImtsanFmY0dkaXB3RHZoYXBxQ2RSZkE9PSIsInZhbHVlIjoiT2orYjZ4NTN1N3JUdXRqQVpGOVVOWklaT25yOXpuc2pmaEN3NXg0ZmxjRT0iLCJtYWMiOiJhYmZmMWJjZmE1ODM0" ] "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, 25 Feb 2025 15:39:08 GMT" ] "set-cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6IlVXK2dUcndDdVBFbjZaSDVYRXkrelE9PSIsInZhbHVlIjoiUEUvWHl4NWR2WWpTcDVHY25EL2FZeXE2MWx0Q0ZVV2NWQWt2ZmV6T1VVYUdxU3E3WEtRK2tRcTM5d0w4Q1pBNmsvWFltQ1JFOVNEYUc1MTFMSGdoRHgxL0dZREpRNWZIdW52V2h2YlFhR2pRL0oyR3IyNEFjeHZYTU1jYTZoQi8iLCJtYWMiOiI5NmU5YmVjMzk1NmQzNmE1MTM4NzgwNDE5YjAxZTgwZjk0ZDUzMDgyN2Y5ZDhmNTE2M2JmYmMyMjlmZjE4MjY2IiwidGFnIjoiIn0%3D; expires=Fri, 28 Feb 2025 03:39:08 GMT; Max-Age=216000; path=/; secure; samesite=laxXSRF-TOKEN=eyJpdiI6IlVXK2dUcndDdVBFbjZaSDVYRXkrelE9PSIsInZhbHVlIjoiUEUvWHl4NWR2WWpTcDVHY25EL2FZeXE2MWx0Q0ZVV2NWQWt2ZmV6T1VVYUdxU3E3WEtRK2tRcTM5d0w4Q1pBNmsvWFltQ" 1 => "alphaeurekaselectnet_session=eyJpdiI6ImxGbkRVcFArVW95TFNJYzBZRVBOR1E9PSIsInZhbHVlIjoiYU1CZzJiQlFObVdxZHRQWVRrLzd6UVFIUDBUck9BRC8xUkluc0VHS3NUcUdYazJ2Q3NQeWgvTzkwRVFSb3VuY3RTUCt2OHEwaytkS0IrZ2ROTjVPazhETVVwUm00L2dYanJKd095SjAxK1BxeC9yekdGVURibGUzVDhSMUsrOG4iLCJtYWMiOiIxYzhiNDUxOGY1YTY2ODk5YTllMDc5MzY2OWU5NmNmZDI3Mjk1ZjgyZTE0ZWZkY2UzZGEwN2RkODRmZjE2OTk2IiwidGFnIjoiIn0%3D; path=/; secure; httponly; samesite=laxalphaeurekaselectnet_session=eyJpdiI6ImxGbkRVcFArVW95TFNJYzBZRVBOR1E9PSIsInZhbHVlIjoiYU1CZzJiQlFObVdxZHRQWVRrLzd6UVFIUDBUck9BRC8xUkluc0VHS3NUcUdYazJ2Q3NQeWgvTzk" ] "Set-Cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6IlVXK2dUcndDdVBFbjZaSDVYRXkrelE9PSIsInZhbHVlIjoiUEUvWHl4NWR2WWpTcDVHY25EL2FZeXE2MWx0Q0ZVV2NWQWt2ZmV6T1VVYUdxU3E3WEtRK2tRcTM5d0w4Q1pBNmsvWFltQ1JFOVNEYUc1MTFMSGdoRHgxL0dZREpRNWZIdW52V2h2YlFhR2pRL0oyR3IyNEFjeHZYTU1jYTZoQi8iLCJtYWMiOiI5NmU5YmVjMzk1NmQzNmE1MTM4NzgwNDE5YjAxZTgwZjk0ZDUzMDgyN2Y5ZDhmNTE2M2JmYmMyMjlmZjE4MjY2IiwidGFnIjoiIn0%3D; expires=Fri, 28-Feb-2025 03:39:08 GMT; path=/; secureXSRF-TOKEN=eyJpdiI6IlVXK2dUcndDdVBFbjZaSDVYRXkrelE9PSIsInZhbHVlIjoiUEUvWHl4NWR2WWpTcDVHY25EL2FZeXE2MWx0Q0ZVV2NWQWt2ZmV6T1VVYUdxU3E3WEtRK2tRcTM5d0w4Q1pBNmsvWFltQ" 1 => "alphaeurekaselectnet_session=eyJpdiI6ImxGbkRVcFArVW95TFNJYzBZRVBOR1E9PSIsInZhbHVlIjoiYU1CZzJiQlFObVdxZHRQWVRrLzd6UVFIUDBUck9BRC8xUkluc0VHS3NUcUdYazJ2Q3NQeWgvTzkwRVFSb3VuY3RTUCt2OHEwaytkS0IrZ2ROTjVPazhETVVwUm00L2dYanJKd095SjAxK1BxeC9yekdGVURibGUzVDhSMUsrOG4iLCJtYWMiOiIxYzhiNDUxOGY1YTY2ODk5YTllMDc5MzY2OWU5NmNmZDI3Mjk1ZjgyZTE0ZWZkY2UzZGEwN2RkODRmZjE2OTk2IiwidGFnIjoiIn0%3D; path=/; secure; httponlyalphaeurekaselectnet_session=eyJpdiI6ImxGbkRVcFArVW95TFNJYzBZRVBOR1E9PSIsInZhbHVlIjoiYU1CZzJiQlFObVdxZHRQWVRrLzd6UVFIUDBUck9BRC8xUkluc0VHS3NUcUdYazJ2Q3NQeWgvTzk" ] ]
        session_attributes
        0 of 0
        array:5 [ "_token" => "BdE2Lq9747HhuYeuEaLjJNNZzIK0ftZuF9Z0SwxK" "uc_cart_id" => "52f320c193d82ae97a70b7a91cce00bb" "_previous" => array:1 [ "url" => "http://alpha.eurekaselect.com/article/104050" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-25 15:39:08GET/article/104050314361