Generic placeholder image

Protein & Peptide Letters

Editor-in-Chief

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

Letter Article

Antioxidant Responses are Crucial for Defense against Misfolded Human Z-Type α1-Antitrypsin

Author(s): Hana Im* and Jaeyeon Lim

Volume 29, Issue 5, 2022

Published on: 22 April, 2022

Page: [384 - 391] Pages: 8

DOI: 10.2174/0929866529666220321151913

Price: $65

Abstract

Background: The Z-type variant of human α1-antitrypsin is involved in liver cirrhosis and pulmonary emphysema. Due to its slow folding characteristics, this variant accumulates folding intermediates and forms protein aggregates within hepatocytes. Misfolded proteins may induce oxidative stress and subsequent cell death.

Objective: The potential application of antioxidant response signaling pathway and antioxidants to cope with Z-type α1-antitrypsin-induced oxidative stress was evaluated.

Methods: Overexpression of Z-type α1-antitrypsin in Saccharomyces cerevisiae provoked oxidative stress and increased susceptibility to oxidative challenges such as hydrogen peroxide treatment. Deletion of antioxidant-response genes, including yap1, skn7, sod2, tsa1, and pst2, exacerbated the slow growth phenotype of Z-type α1-antitrypsin-expressing cells. Antioxidant treatment alleviated oxidative stress and cytotoxicity induced by Z-type α1-antitrypsin.

Results: Our results show that cellular antioxidant capacity is crucial to protection against misfolded Z-type α1-antitrypsin.

Conclusion: The information obtained here may be used to prevent oxidative stress caused by misfolded proteins, which are associated with several degenerative diseases, including amyotrophic lateral sclerosis and Parkinson’s disease.

Keywords: α1-Antitrypsin, antioxidant, antitrypsin variant, misfolded protein, protein folding, oxidative stress.

Graphical Abstract

[1]
Carrell, R.W.; Jeppsson, J-O.; Laurell, C-B.; Brennan, S.O.; Owen, M.C.; Vaughan, L.; Boswell, D.R. Structure and variation of human α 1-antitrypsin. Nature, 1982, 298(5872), 329-334.
[http://dx.doi.org/10.1038/298329a0] [PMID: 7045697]
[2]
Creighton, T.E. Protein folding. Up the kinetic pathway. Nature, 1992, 356(6366), 194-195.
[http://dx.doi.org/10.1038/356194a0] [PMID: 1552936]
[3]
Giacopuzzi, E.; Laffranchi, M.; Berardelli, R.; Ravasio, V.; Ferrarotti, I.; Gooptu, B.; Borsani, G.; Fra, A. Real-world clinical applicability of pathogenicity predictors assessed on SERPINA1 mutations in alpha-1-antitrypsin deficiency. Hum. Mutat., 2018, 39(9), 1203-1213.
[http://dx.doi.org/10.1002/humu.23562] [PMID: 29882371]
[4]
Stein, P.E.; Carrell, R.W. What do dysfunctional serpins tell us about molecular mobility and disease? Nat. Struct. Biol., 1995, 2(2), 96-113.
[http://dx.doi.org/10.1038/nsb0295-96] [PMID: 7749926]
[5]
Perlmutter, D.H. Liver injury in α1-antitrypsin deficiency: An aggregated protein induces mitochondrial injury. J. Clin. Invest., 2002, 110(11), 1579-1583.
[http://dx.doi.org/10.1172/JCI0216787] [PMID: 12464659]
[6]
Eriksson, S.; Carlson, J.; Velez, R. Risk of cirrhosis and primary liver cancer in α 1-antitrypsin deficiency. N. Engl. J. Med., 1986, 314(12), 736-739.
[http://dx.doi.org/10.1056/NEJM198603203141202] [PMID: 3485248]
[7]
Yu, M-H.; Lee, K.N.; Kim, J. The Z type variation of human α 1-antitrypsin causes a protein folding defect. Nat. Struct. Biol., 1995, 2(5), 363-367.
[http://dx.doi.org/10.1038/nsb0595-363] [PMID: 7664092]
[8]
Mahadeva, R.; Chang, W.S.; Dafforn, T.R.; Oakley, D.J.; Foreman, R.C.; Calvin, J.; Wight, D.G.; Lomas, D.A. Heteropolymerization of S, I, and Z α1-antitrypsin and liver cirrhosis. J. Clin. Invest., 1999, 103(7), 999-1006.
[http://dx.doi.org/10.1172/JCI4874] [PMID: 10194472]
[9]
Singh, A.; Kukreti, R.; Saso, L.; Kukreti, S. Oxidative stress: A key modulator in neurodegenerative diseases. Molecules, 2019, 24(8), 1583.
[http://dx.doi.org/10.3390/molecules24081583] [PMID: 31013638]
[10]
Barnham, K.J.; Masters, C.L.; Bush, A.I. Neurodegenerative diseases and oxidative stress. Nat. Rev. Drug Discov., 2004, 3(3), 205-214.
[http://dx.doi.org/10.1038/nrd1330] [PMID: 15031734]
[11]
Ikawa, M.; Okazawa, H.; Tsujikawa, T.; Matsunaga, A.; Yamamura, O.; Mori, T.; Hamano, T.; Kiyono, Y.; Nakamoto, Y.; Yoneda, M. Increased oxidative stress is related to disease severity in the ALS motor cortex: A PET study. Neurology, 2015, 84(20), 2033-2039.
[http://dx.doi.org/10.1212/WNL.0000000000001588] [PMID: 25904686]
[12]
Basso, M.; Samengo, G.; Nardo, G.; Massignan, T.; D’Alessandro, G.; Tartari, S.; Cantoni, L.; Marino, M.; Cheroni, C.; De Biasi, S.; Giordana, M.T.; Strong, M.J.; Estevez, A.G.; Salmona, M.; Bendotti, C.; Bonetto, V. Characterization of detergent-insoluble proteins in ALS indicates a causal link between nitrative stress and aggregation in pathogenesis. PLoS One, 2009, 4(12), e8130.
[http://dx.doi.org/10.1371/journal.pone.0008130] [PMID: 19956584]
[13]
Tu, B.P.; Weissman, J.S. Oxidative protein folding in eukaryotes: Mechanisms and consequences. J. Cell Biol., 2004, 164(3), 341-346.
[http://dx.doi.org/10.1083/jcb.200311055] [PMID: 14757749]
[14]
Lüth, H.J.; Holzer, M.; Gärtner, U.; Staufenbiel, M.; Arendt, T. Expression of endothelial and inducible NOS-isoforms is increased in Alzheimer’s disease, in APP23 transgenic mice and after experimental brain lesion in rat: Evidence for an induction by amyloid pathology. Brain Res., 2001, 913(1), 57-67.
[http://dx.doi.org/10.1016/S0006-8993(01)02758-5] [PMID: 11532247]
[15]
Malhotra, J.D.; Miao, H.; Zhang, K.; Wolfson, A.; Pennathur, S.; Pipe, S.W.; Kaufman, R.J. Antioxidants reduce endoplasmic reticulum stress and improve protein secretion. Proc. Natl. Acad. Sci. USA, 2008, 105(47), 18525-18530.
[http://dx.doi.org/10.1073/pnas.0809677105] [PMID: 19011102]
[16]
Papp, E.; Száraz, P.; Korcsmáros, T.; Csermely, P. Changes of endoplasmic reticulum chaperone complexes, redox state, and impaired protein disulfide reductase activity in misfolding α1-antitrypsin transgenic mice. FASEB J., 2006, 20(7), 1018-1020.
[http://dx.doi.org/10.1096/fj.05-5065fje] [PMID: 16571774]
[17]
Tenreiro, S.; Outeiro, T.F. Simple is good: Yeast models of neurodegeneration. FEMS Yeast Res., 2010, 10(8), 970-979.
[http://dx.doi.org/10.1111/j.1567-1364.2010.00649.x] [PMID: 20579105]
[18]
Jung, C-H.; Kim, Y-H.; Lee, K. Im, H. Retarded protein folding of the human Z-type α1-antitrypsin variant is suppressed by Cpr2p. Biochem. Biophys. Res. Commun., 2014, 445(1), 191-195.
[http://dx.doi.org/10.1016/j.bbrc.2014.01.156] [PMID: 24502947]
[19]
Adams, A.; Gottschling, D.E.; Kaiser, C.A.; Stearns, T. Techniques and protocols: High-efficiency transformation of yeast.Methods in Yeast Genetics; Dickerson, M.M., Ed.; Cold Spring Harbor Press: Cold Spring Harbor, N.Y., 1997, pp. 99-102.
[20]
Wang, H.; Joseph, J.A. Quantifying cellular oxidative stress by dichlorofluorescein assay using microplate reader. Free Radic. Biol. Med., 1999, 27(5-6), 612-616.
[http://dx.doi.org/10.1016/S0891-5849(99)00107-0] [PMID: 10490282]
[21]
Morgan, B.A.; Banks, G.R.; Toone, W.M.; Raitt, D.; Kuge, S.; Johnston, L.H. The Skn7 response regulator controls gene expression in the oxidative stress response of the budding yeast Saccharomyces cerevisiae. EMBO J., 1997, 16(5), 1035-1044.
[http://dx.doi.org/10.1093/emboj/16.5.1035] [PMID: 9118942]
[22]
Kuge, S.; Jones, N.; Nomoto, A. Regulation of yAP-1 nuclear localization in response to oxidative stress. EMBO J., 1997, 16(7), 1710-1720.
[http://dx.doi.org/10.1093/emboj/16.7.1710] [PMID: 9130715]
[23]
Lee, J.; Godon, C.; Lagniel, G.; Spector, D.; Garin, J.; Labarre, J.; Toledano, M.B. Yap1 and Skn7 control two specialized oxidative stress response regulons in yeast. J. Biol. Chem., 1999, 274(23), 16040-16046.
[http://dx.doi.org/10.1074/jbc.274.23.16040] [PMID: 10347154]
[24]
Marcus, N.Y.; Blomenkamp, K.; Ahmad, M.; Teckman, J.H. Oxidative stress contributes to liver damage in a murine model of alpha-1-antitrypsin deficiency. Exp. Biol. Med. (Maywood), 2012, 237(10), 1163-1172.
[http://dx.doi.org/10.1258/ebm.2012.012106] [PMID: 23104507]
[25]
van Dam, L.; Dansen, T.B. Cross-talk between redox signalling and protein aggregation. Biochem. Soc. Trans., 2020, 48(2), 379-397.
[http://dx.doi.org/10.1042/BST20190054] [PMID: 32311028]
[26]
Haynes, C.M.; Titus, E.A.; Cooper, A.A. Degradation of misfolded proteins prevents ER-derived oxidative stress and cell death. Mol. Cell, 2004, 15(5), 767-776.
[http://dx.doi.org/10.1016/j.molcel.2004.08.025] [PMID: 15350220]
[27]
Cuozzo, J.W.; Kaiser, C.A. Competition between glutathione and protein thiols for disulphide-bond formation. Nat. Cell Biol., 1999, 1(3), 130-135.
[http://dx.doi.org/10.1038/11047] [PMID: 10559898]
[28]
Milhavet, O.; McMahon, H.E.; Rachidi, W.; Nishida, N.; Katamine, S.; Mangé, A.; Arlotto, M.; Casanova, D.; Riondel, J.; Favier, A.; Lehmann, S. Prion infection impairs the cellular response to oxidative stress. Proc. Natl. Acad. Sci. USA, 2000, 97(25), 13937-13942.
[http://dx.doi.org/10.1073/pnas.250289197] [PMID: 11095725]
[29]
Deniaud, A. Sharaf el dein, O.; Maillier, E.; Poncet, D.; Kroemer, G.; Lemaire, C.; Brenner, C. Endoplasmic reticulum stress induces calcium-dependent permeability transition, mitochondrial outer membrane permeabilization and apoptosis. Oncogene, 2008, 27(3), 285-299.
[http://dx.doi.org/10.1038/sj.onc.1210638] [PMID: 17700538]
[30]
Teckman, J.H.; An, J.K.; Blomenkamp, K.; Schmidt, B.; Perlmutter, D. Mitochondrial autophagy and injury in the liver in alpha 1-antitrypsin deficiency. Am. J. Physiol. Gastrointest. Liver Physiol., 2004, 286(5), G851-G862.
[http://dx.doi.org/10.1152/ajpgi.00175.2003] [PMID: 14684378]
[31]
Vargas, M.R.; Johnson, D.A.; Sirkis, D.W.; Messing, A.; Johnson, J.A. Nrf2 activation in astrocytes protects against neurodegeneration in mouse models of familial amyotrophic lateral sclerosis. J. Neurosci., 2008, 28(50), 13574-13581.
[http://dx.doi.org/10.1523/JNEUROSCI.4099-08.2008] [PMID: 19074031]
[32]
Kuge, S.; Jones, N. YAP1 dependent activation of TRX2 is essential for the response of Saccharomyces cerevisiae to oxidative stress by hydroperoxides. EMBO J., 1994, 13(3), 655-664.
[http://dx.doi.org/10.1002/j.1460-2075.1994.tb06304.x] [PMID: 8313910]
[33]
Brombacher, K.; Fischer, B.B.; Rüfenacht, K.; Eggen, R.I.L. The role of Yap1p and Skn7p-mediated oxidative stress response in the defence of Saccharomyces cerevisiae against singlet oxygen. Yeast, 2006, 23(10), 741-750.
[http://dx.doi.org/10.1002/yea.1392] [PMID: 16862604]
[34]
Thorpe, G.W.; Fong, C.S.; Alic, N.; Higgins, V.J.; Dawes, I.W. Cells have distinct mechanisms to maintain protection against different reactive oxygen species: Oxidative-stress-response genes. Proc. Natl. Acad. Sci. USA, 2004, 101(17), 6564-6569.
[http://dx.doi.org/10.1073/pnas.0305888101] [PMID: 15087496]
[35]
Krems, B.; Charizanis, C.; Entian, K.D. Mutants of Saccharomyces cerevisiae sensitive to oxidative and osmotic stress. Curr. Genet., 1995, 27(5), 427-434.
[http://dx.doi.org/10.1007/BF00311211] [PMID: 7586028]
[36]
Harrison, F.E.; Allard, J.; Bixler, R.; Usoh, C.; Li, L.; May, J.M.; McDonald, M.P. Antioxidants and cognitive training interact to affect oxidative stress and memory in APP/PSEN1 mice. Nutr. Neurosci., 2009, 12(5), 203-218.
[http://dx.doi.org/10.1179/147683009X423364] [PMID: 19761651]
[37]
Holmay, M.J.; Terpstra, M.; Coles, L.D.; Mishra, U.; Ahlskog, M.; Öz, G.; Cloyd, J.C.; Tuite, P.J. N-Acetylcysteine boosts brain and blood glutathione in Gaucher and Parkinson diseases. Clin. Neuropharmacol., 2013, 36(4), 103-106.
[http://dx.doi.org/10.1097/WNF.0b013e31829ae713] [PMID: 23860343]
[38]
Niedzielska, E.; Smaga, I.; Gawlik, M.; Moniczewski, A.; Stankowicz, P.; Pera, J.; Filip, M. Oxidative stress in neurodegenerative diseases. Mol. Neurobiol., 2016, 53(6), 4094-4125.
[http://dx.doi.org/10.1007/s12035-015-9337-5] [PMID: 26198567]
[39]
Feng, Z.; Qin, C.; Chang, Y.; Zhang, J.T. Early melatonin supplementation alleviates oxidative stress in a transgenic mouse model of Alzheimer’s disease. Free Radic. Biol. Med., 2006, 40(1), 101-109.
[http://dx.doi.org/10.1016/j.freeradbiomed.2005.08.014] [PMID: 16337883]
[40]
Festjens, N.; Kalai, M.; Smet, J.; Meeus, A.; Van Coster, R.; Saelens, X.; Vandenabeele, P. Butylated hydroxyanisole is more than a reactive oxygen species scavenger. Cell Death Differ., 2006, 13(1), 166-169.
[http://dx.doi.org/10.1038/sj.cdd.4401746] [PMID: 16138110]
[41]
Eftekhari, A.; Dizaj, S.M.; Chodari, L.; Sunar, S.; Hasanzadeh, A.; Ahmadian, E.; Hasanzadeh, M. The promising future of nano-antioxidant therapy against environmental pollutants induced-toxicities. Biomed. Pharmacother., 2018, 103, 1018-1027.
[http://dx.doi.org/10.1016/j.biopha.2018.04.126] [PMID: 29710659]
[42]
Ahmadian, E.; Eftekhari, A.; Kavetskyy, T.; Khosroushahi, A.Y.; Turksoy, V.A.; Khalilov, R. Effects of quercetin loaded nanostructured lipid carriers on the paraquat-induced toxicity in human lymphocytes. Pestic. Biochem. Physiol., 2020, 167, 104586.
[http://dx.doi.org/10.1016/j.pestbp.2020.104586] [PMID: 32527420]
[43]
Dodson, M.; de la Vega, M.R.; Cholanians, A.B.; Schmidlin, C.J.; Chapman, E.; Zhang, D.D. Modulating NRF2 in disease: Timing is everything. Annu. Rev. Pharmacol. Toxicol., 2019, 59(1), 555-575.
[http://dx.doi.org/10.1146/annurev-pharmtox-010818-021856] [PMID: 30256716]
[44]
Stephen, D.W.; Rivers, S.L.; Jamieson, D.J. The role of the YAP1 and YAP2 genes in the regulation of the adaptive oxidative stress responses of Saccharomyces cerevisiae. Mol. Microbiol., 1995, 16(3), 415-423.
[http://dx.doi.org/10.1111/j.1365-2958.1995.tb02407.x] [PMID: 7565103]
[45]
Jung, C-H.; Lim, J.H.; Lee, K. Im, H. An endoplasmic reticulum cyclophilin Cpr5p rescues Z-type α1-antitrypsin from retarded folding. Bull. Korean Chem. Soc., 2014, 35(9), 2781-2786.
[http://dx.doi.org/10.5012/bkcs.2014.35.9.2781]
[46]
Lim, J.; Lee, K.; Im, H. Reinforcement of the unfolded protein response mitigates cytotoxicity induced by human Z-type α1-antitrypsin. Bull. Korean Chem. Soc., 2021, 42(6), 900-906.
[http://dx.doi.org/10.1002/bkcs.12289]

Rights & Permissions Print Cite
© 2025 Bentham Science Publishers | Privacy Policy
Request history8.2.27PHP Version517msRequest Duration28MBMemory UsageGET article/{article_id}/{param?}Route
  • warninglog[16:58:23] LOG.warning: Optional parameter $article_id declared before required parameter $request i...
  • warninglog[16:58:23] LOG.warning: Function strftime() is deprecated in /home/alphaeurekaselec/public_html/stor...
  • warninglog[16:58:23] LOG.warning: trim(): Passing null to parameter #1 ($string) of type string is deprecated ...
  • warninglog[16:58:23] LOG.warning: Function strftime() is deprecated in /home/alphaeurekaselec/public_html/stor...
  • Booting (146ms)time
  • Application (372ms)time
  • 1 x Application (71.87%)
    372ms
    1 x Booting (28.12%)
    146ms
    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 duplicated262ms
    • 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 ('59799503','',1,1740675503,1740675503) ON DUPLICATE KEY UPDATE visitor_count=visitor_count + 1, updated_on=1740675503
      2.92msalphaeurekaselec_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 ('59799503','/article/121766',1,1740675503,1740675503)
      5.7msalphaeurekaselec_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 >= 59799503 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59799503) 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 >= 59799503 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59799503) 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 >= 59799503 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59799503) 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 >= 59799503 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59799503) 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 >= 59799503 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59799503) 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 >= 59799503 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59799503) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_trail WHERE to_ip >= 59799503 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59799503) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_corporate WHERE to_ip >= 59799503 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59799503) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_token WHERE to_ip >= 59799503 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59799503) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_trail WHERE to_ip >= 59799503 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59799503) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_corporate WHERE to_ip >= 59799503 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59799503) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_token WHERE to_ip >= 59799503 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59799503) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_trail WHERE to_ip >= 59799503 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59799503) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_corporate WHERE to_ip >= 59799503 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59799503) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_token WHERE to_ip >= 59799503 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59799503) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_disease_corporate WHERE to_ip >= 59799503 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59799503) limit 1
      18.61msalphaeurekaselec_live_10_06_2022UserAccess.php#784
      Bindings
      • 0: 59799503
      • 1: 59799503
      • 2: 59799503
      • 3: 59799503
      • 4: 59799503
      • 5: 59799503
      • 6: 59799503
      • 7: 59799503
      • 8: 59799503
      • 9: 59799503
      • 10: 59799503
      • 11: 59799503
      • 12: 59799503
      • 13: 59799503
      • 14: 59799503
      • 15: 59799503
      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=121766
      1.11msalphaeurekaselec_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
      2.26msalphaeurekaselec_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`
      1msalphaeurekaselec_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
      840μsalphaeurekaselec_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`
      9.04msalphaeurekaselec_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
      11.18msalphaeurekaselec_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` = '121766'
      1.63msalphaeurekaselec_live_10_06_2022Keywords.php#43
      Bindings
      • 0: 121766
      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` = '121766'
      2.72msalphaeurekaselec_live_10_06_2022Article.php#1570
      Bindings
      • 0: 121766
      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` = '121766' group by `au`.`author_id` order by `au`.`article_id` asc, `au`.`sequence` asc
      2.76msalphaeurekaselec_live_10_06_2022Author.php#86
      Bindings
      • 0: 121766
      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
      890μsalphaeurekaselec_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
      1.18msalphaeurekaselec_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
      91.45msalphaeurekaselec_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
      31.06msalphaeurekaselec_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
      20.75msalphaeurekaselec_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` = 121766 limit 1
      7.83msalphaeurekaselec_live_10_06_2022Article.php#744
      Bindings
      • 0: 121766
      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 = 121766 and content_type = 'article' order by status desc limit 1
      4.79msalphaeurekaselec_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` = 202489 limit 1
      3.66msalphaeurekaselec_live_10_06_2022Meta.php#30
      Bindings
      • 0: 202489
      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
      6.61msalphaeurekaselec_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
      890μsalphaeurekaselec_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 = '121766' 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) )
      1.07msalphaeurekaselec_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 = '11589' 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) )
      620μsalphaeurekaselec_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 = '3176' 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) )
      1.28msalphaeurekaselec_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 <= 59799503 and j.to_ip >=59799503 )) and ((j.from_date <= 1740675503 and j.to_date >= 1740675503 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3176) 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 <= 59799503 and j.to_ip >=59799503 )) and ((j.from_date <= 1740675503 and j.to_date >= 1740675503 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3176) 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 <= 59799503 and j.to_ip >=59799503 )) and ((j.from_date <= 1740675503 and j.to_date >= 1740675503 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3176)
      17.2msalphaeurekaselec_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 <= 59799503 and j.to_ip >=59799503 )) and ((j.from_date <= 1740675503 and j.to_date >= 1740675503 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 11589) 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 <= 59799503 and j.to_ip >=59799503 )) and ((j.from_date <= 1740675503 and j.to_date >= 1740675503 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 11589) 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 <= 59799503 and j.to_ip >=59799503 )) and ((j.from_date <= 1740675503 and j.to_date >= 1740675503 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 11589)
      920μsalphaeurekaselec_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 <= 59799503 and j.to_ip >=59799503 )) and ((j.from_date <= 1740675503 and j.to_date >= 1740675503 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 121766) 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 <= 59799503 and j.to_ip >=59799503 )) and ((j.from_date <= 1740675503 and j.to_date >= 1740675503 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 121766) 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 <= 59799503 and j.to_ip >=59799503 )) and ((j.from_date <= 1740675503 and j.to_date >= 1740675503 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 121766)
      3.06msalphaeurekaselec_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` < '384' and is_uploaded = 1 and issue_id = 11589 order by cast(first_page as SIGNED) desc limit 1
      730μsalphaeurekaselec_live_10_06_2022Article.php#1819
      Bindings
      • 0: 384
      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` > '391' and is_uploaded = 1 and issue_id = 11589 order by cast(first_page as SIGNED) asc limit 1
      680μsalphaeurekaselec_live_10_06_2022Article.php#1831
      Bindings
      • 0: 391
      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'
      240μsalphaeurekaselec_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
      260μsalphaeurekaselec_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` = 121766 limit 1
      3.36msalphaeurekaselec_live_10_06_2022ArticleController.php#2506
      Bindings
      • 0: 121766
      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` <= 1740675503 and `b`.`banner_to_date` >= 1740675503 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.58msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 51
      • 3: 1740675503
      • 4: 1740675503
      • 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` <= 1740675503 and `b`.`banner_to_date` >= 1740675503 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.71msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 51
      • 3: 1740675503
      • 4: 1740675503
      • 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='d921c7912e4fba51c34dba2088716e4d'
      340μsalphaeurekaselec_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
        MOlu2qn7hqQKufveIDtOhFgFmnAh5XGzmq7mfkfu
        uc_cart_id
        d921c7912e4fba51c34dba2088716e4d
        _previous
        array:1 [ "url" => "http://alpha.eurekaselect.com/article/121766" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /article/121766
        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:8 [ "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
        []
        
        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 => "Thu, 27 Feb 2025 16:58:23 GMT" ] "set-cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6IjJ5NFpTZWxMdkdiZzdZSW1GYmliWEE9PSIsInZhbHVlIjoiMUo5SGhxZ1FMVEJKbUdTU1d2QzBpY1BYU0g5K2cwcE9nTGFlTTl1SlJpZytTZjFCM0N3NkxZQ2FZQ2VQZGZxSVZiZ0EwK0hOdjcxR0ZnaGN1RnFJZFJGRE1MMnk4S29zb1hCVmQzSjIvRFNuZFEzYWZPMGM2aGNOajRqNEI3bjIiLCJtYWMiOiJlYzcwZjUyYjFjNzE5MzAzOTcxYzEwZmYxYTJiNmU5NDM3MzdhNDQyZmExOGIxMGRhZTk0MDczMmNjZjkyMmIyIiwidGFnIjoiIn0%3D; expires=Sun, 02 Mar 2025 04:58:23 GMT; Max-Age=216000; path=/; secure; samesite=laxXSRF-TOKEN=eyJpdiI6IjJ5NFpTZWxMdkdiZzdZSW1GYmliWEE9PSIsInZhbHVlIjoiMUo5SGhxZ1FMVEJKbUdTU1d2QzBpY1BYU0g5K2cwcE9nTGFlTTl1SlJpZytTZjFCM0N3NkxZQ2FZQ2VQZGZxSVZiZ0EwK" 1 => "alphaeurekaselectnet_session=eyJpdiI6InN2MHIrMUNyaHJYNWE4dmlKOUFyZnc9PSIsInZhbHVlIjoiMzE4VkFFM3R5VENpY2tta2dHYzJ3MjVJL1dxbzVGdnZUWmhxR3JjT1ZzTlRyTkVXbXF3RnN0YXJ2NllVQjhoT1BvRFRNQjdrMXd6d2dPc0lOWjIvM0puS3R6SE5JQXNoclV0STJRSk9PakRGdlZjUThiTUV0VklTN2hPb2tYcUIiLCJtYWMiOiJjYTk1ZmU3NjAwNDgzOGM4NjIyMTY4YmRhZDU3NWYxMGNlOTg0YmI2MmZlY2Y3M2E1NDQwNzMzNzFhNWZkNDA5IiwidGFnIjoiIn0%3D; path=/; secure; httponly; samesite=laxalphaeurekaselectnet_session=eyJpdiI6InN2MHIrMUNyaHJYNWE4dmlKOUFyZnc9PSIsInZhbHVlIjoiMzE4VkFFM3R5VENpY2tta2dHYzJ3MjVJL1dxbzVGdnZUWmhxR3JjT1ZzTlRyTkVXbXF3RnN0YXJ" ] "Set-Cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6IjJ5NFpTZWxMdkdiZzdZSW1GYmliWEE9PSIsInZhbHVlIjoiMUo5SGhxZ1FMVEJKbUdTU1d2QzBpY1BYU0g5K2cwcE9nTGFlTTl1SlJpZytTZjFCM0N3NkxZQ2FZQ2VQZGZxSVZiZ0EwK0hOdjcxR0ZnaGN1RnFJZFJGRE1MMnk4S29zb1hCVmQzSjIvRFNuZFEzYWZPMGM2aGNOajRqNEI3bjIiLCJtYWMiOiJlYzcwZjUyYjFjNzE5MzAzOTcxYzEwZmYxYTJiNmU5NDM3MzdhNDQyZmExOGIxMGRhZTk0MDczMmNjZjkyMmIyIiwidGFnIjoiIn0%3D; expires=Sun, 02-Mar-2025 04:58:23 GMT; path=/; secureXSRF-TOKEN=eyJpdiI6IjJ5NFpTZWxMdkdiZzdZSW1GYmliWEE9PSIsInZhbHVlIjoiMUo5SGhxZ1FMVEJKbUdTU1d2QzBpY1BYU0g5K2cwcE9nTGFlTTl1SlJpZytTZjFCM0N3NkxZQ2FZQ2VQZGZxSVZiZ0EwK" 1 => "alphaeurekaselectnet_session=eyJpdiI6InN2MHIrMUNyaHJYNWE4dmlKOUFyZnc9PSIsInZhbHVlIjoiMzE4VkFFM3R5VENpY2tta2dHYzJ3MjVJL1dxbzVGdnZUWmhxR3JjT1ZzTlRyTkVXbXF3RnN0YXJ2NllVQjhoT1BvRFRNQjdrMXd6d2dPc0lOWjIvM0puS3R6SE5JQXNoclV0STJRSk9PakRGdlZjUThiTUV0VklTN2hPb2tYcUIiLCJtYWMiOiJjYTk1ZmU3NjAwNDgzOGM4NjIyMTY4YmRhZDU3NWYxMGNlOTg0YmI2MmZlY2Y3M2E1NDQwNzMzNzFhNWZkNDA5IiwidGFnIjoiIn0%3D; path=/; secure; httponlyalphaeurekaselectnet_session=eyJpdiI6InN2MHIrMUNyaHJYNWE4dmlKOUFyZnc9PSIsInZhbHVlIjoiMzE4VkFFM3R5VENpY2tta2dHYzJ3MjVJL1dxbzVGdnZUWmhxR3JjT1ZzTlRyTkVXbXF3RnN0YXJ" ] ]
        session_attributes
        0 of 0
        array:5 [ "_token" => "MOlu2qn7hqQKufveIDtOhFgFmnAh5XGzmq7mfkfu" "uc_cart_id" => "d921c7912e4fba51c34dba2088716e4d" "_previous" => array:1 [ "url" => "http://alpha.eurekaselect.com/article/121766" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-27 16:58:23GET/article/121766414361