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Protein & Peptide Letters

Editor-in-Chief

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

Mini-Review Article

Warfare Nerve Agents and Paraoxonase-1 as a Potential Prophylactic Therapy against Intoxication

Author(s): A.R. Satvik Iyengar, Prakash Y. Khandave, Janek Bzdrenga, Florian Nachon, Xavier Brazzolotto and Abhay H. Pande*

Volume 31, Issue 5, 2024

Published on: 03 May, 2024

Page: [345 - 355] Pages: 11

DOI: 10.2174/0109298665284293240409045359

Price: $65

Abstract

Nerve agents are a class of lethal neurotoxic chemicals used in chemical warfare. In this review, we have discussed a brief history of chemical warfare, followed by an exploration of the historical context surrounding nerve agents. The article explores the classification of these agents, their contemporary uses, their toxicity mechanisms, and the disadvantages of the current treatment options for nerve agent poisoning. It then discusses the possible application of enzymes as prophylactics against nerve agent poisoning, outlining the benefits and drawbacks of paraoxonase- 1. Finally, the current studies on paraoxonase-1 are reviewed, highlighting that several challenges need to be addressed in the use of paraoxonase-1 in the actual field and that its potential as a prophylactic antidote against nerve agent poisoning needs to be evaluated. The literature used in this manuscript was searched using various electronic databases, such as PubMed, Google Scholar, Web of Science, Elsevier, Springer, ACS, Google Patent, and books using the keywords chemical warfare agent, butyrylcholinesterase, enzyme, nerve agent, prophylactic, and paraoxonase-1, with the time scale for the analysis of articles between 1960 to 2023. The study has suggested that concerted efforts by researchers and agencies must be made to develop effective countermeasures against NA poisoning and that paraoxonase-1 has suitable properties for the development of efficient prophylaxis against NA poisoning.

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[1]
Gupta, R.C. Introduction.Handbook of Toxicology of Chemical Warfare Agents, 3rd ed; Gupta, R.C., Ed.; Academic Press: Boston, 2020, pp. 3-15.
[http://dx.doi.org/10.1016/B978-0-12-819090-6.00079-9]
[2]
Kloske, M.; Witkiewicz, Z. Novichoks – The A group of organophosphorus chemical warfare agents. Chemosphere, 2019, 221, 672-682.
[http://dx.doi.org/10.1016/j.chemosphere.2019.01.054] [PMID: 30677728]
[3]
Costanzi, S.; Machado, J.H.; Mitchell, M. Nerve agents: What they are, how they work, how to counter them. ACS Chem. Neurosci., 2018, 9(5), 873-885.
[http://dx.doi.org/10.1021/acschemneuro.8b00148] [PMID: 29664277]
[4]
Stojiljković, M. Nerve agents: A clear and present danger to mankind. Scr. Med. (Brno), 2019, 50(3), 109-111.
[http://dx.doi.org/10.5937/scriptamed50-23266]
[5]
Chai, P.R.; Hayes, B.D.; Erickson, T.B.; Boyer, E.W. Novichok agents: A historical, current, and toxicological perspective. Toxicol. Commun., 2018, 2(1), 45-48.
[http://dx.doi.org/10.1080/24734306.2018.1475151] [PMID: 30003185]
[6]
Masson, P.; Nachon, F. Cholinesterase reactivators and bioscavengers for pre- and post-exposure treatments of organophosphorus poisoning. J. Neurochem., 2017, 142(S2), 26-40.
[http://dx.doi.org/10.1111/jnc.14026] [PMID: 28542985]
[7]
Forman, J.E.; Timperley, C.M. Is there a role for green and sustainable chemistry in chemical disarmament and nonproliferation? Curr. Opin. Green Sustain. Chem., 2019, 15, 103-114.
[http://dx.doi.org/10.1016/j.cogsc.2019.01.001]
[8]
Vale, J.A.; Marrs, T.C.; Maynard, R.L. Novichok: A murderous nerve agent attack in the UK. Clin. Toxicol. (Phila.), 2018, 56(11), 1093-1097.
[http://dx.doi.org/10.1080/15563650.2018.1469759] [PMID: 29757015]
[9]
Stone, R. U.K. attack puts nerve agent in the spotlight. Science, 2018, 359(6382), 1314-1315.
[http://dx.doi.org/10.1126/science.359.6382.1314] [PMID: 29567684]
[10]
Steindl, D.; Boehmerle, W.; Körner, R.; Praeger, D.; Haug, M.; Nee, J.; Schreiber, A.; Scheibe, F.; Demin, K.; Jacoby, P.; Tauber, R.; Hartwig, S.; Endres, M.; Eckardt, K.U. Novichok nerve agent poisoning. Lancet, 2021, 397(10270), 249-252.
[http://dx.doi.org/10.1016/S0140-6736(20)32644-1] [PMID: 33357496]
[11]
Jacquet, P.; Rémy, B.; Bross, R.P.T.; van Grol, M.; Gaucher, F.; Chabrière, E.; de Koning, M.C.; Daudé, D. Enzymatic decontamination of G-Type, V-Type and Novichok Nerve Agents. Int. J. Mol. Sci., 2021, 22(15), 8152.
[http://dx.doi.org/10.3390/ijms22158152] [PMID: 34360916]
[12]
Stigler, L.; Köhler, A.; Koller, M.; Job, L.; Escher, B.; Potschka, H.; Thiermann, H.; Skerra, A.; Worek, F.; Wille, T. Post-VX exposure treatment of rats with engineered phosphotriesterases. Arch. Toxicol., 2022, 96(2), 571-583.
[http://dx.doi.org/10.1007/s00204-021-03199-6] [PMID: 34962578]
[13]
Stone, R. Obscure Cold War nerve agents set to be banned. Science, 2019, 366(6464), 404-405.
[http://dx.doi.org/10.1126/science.366.6464.404] [PMID: 31649171]
[14]
Noga, M.; Michalska, A.; Jurowski, K. Review of possible therapies in treatment of novichoks poisoning and HAZMAT/CBRNE approaches: State of the art. J. Clin. Med., 2023, 12(6), 2221.
[http://dx.doi.org/10.3390/jcm12062221] [PMID: 36983219]
[15]
Iyengar, A.R.S.; Pande, A.H. Organophosphate-hydrolyzing enzymes as first-line of defence against nerve agent-poisoning: Perspectives and the road ahead. Protein J., 2016, 35(6), 424-439.
[http://dx.doi.org/10.1007/s10930-016-9686-6] [PMID: 27830420]
[16]
Moshiri, M.; Alizadeh, A.; Balali-Mood, M. Clinical Management of Organophosphorus Nerve Agents’ Poisonings. Basic and Clinical Toxicology of Organophosphorus Compounds; Balali-Mood, M.; Abdollahi, M., Eds.; Springer London: London, 2014, pp. 177-212.
[http://dx.doi.org/10.1007/978-1-4471-5625-3_7]
[17]
Mundu, P.A.; Kumar, M.; Satapathy, R.P.; Mitra, J.K. Organophosphate induced delayed neuropathy: A case report. Int. J. Contemp. Med. Res., 2016, 3, 2289-2291.
[18]
Haley, R.W.; Kramer, G.; Xiao, J.; Dever, J.A.; Teiber, J.F. Evaluation of a gene–environment interaction of PON1 and low-level nerve agent exposure with Gulf War Illness: A prevalence case–control study Drawn from the U.S. Military health survey’s national population sample. Environ. Health Perspect., 2022, 130(5), 057001.
[http://dx.doi.org/10.1289/EHP9009] [PMID: 35543525]
[19]
Sugiyama, A.; Matsuoka, T.; Sakamune, K.; Akita, T.; Makita, R.; Kimura, S.; Kuroiwa, Y.; Nagao, M.; Tanaka, J. The Tokyo subway sarin attack has long-term effects on survivors: A 10-year study started 5 years after the terrorist incident. PLoS One, 2020, 15(6), e0234967.
[http://dx.doi.org/10.1371/journal.pone.0234967] [PMID: 32574198]
[20]
Iyengar, A.R.S.; Pande, A.H. Is human paraoxonase 1 the saviour against the persistent threat of organophosphorus nerve agents? Protein Pept. Lett., 2019, 26(7), 471-478.
[http://dx.doi.org/10.2174/0929866526666190403120259] [PMID: 30942142]
[21]
Jokanović, M.; Prostran, M. Pyridinium oximes as cholinesterase reactivators. Structure-activity relationship and efficacy in the treatment of poisoning with organophosphorus compounds. Curr. Med. Chem., 2009, 16(17), 2177-2188.
[http://dx.doi.org/10.2174/092986709788612729] [PMID: 19519385]
[22]
Doctor, B.P.; Saxena, A. Bioscavengers for the protection of humans against organophosphate toxicity. Chem. Biol. Interact., 2005, 157, 167-171.
[http://dx.doi.org/10.1016/j.cbi.2005.10.024] [PMID: 16293236]
[23]
Boyd, C.E.; Boyd, E.M. The acute toxicity of atropine sulfate. Can. Med. Assoc. J., 1961, 85(23), 1241-1244.
[PMID: 13872140]
[24]
Masson, P. Evolution of and perspectives on therapeutic approaches to nerve agent poisoning. Toxicol. Lett., 2011, 206(1), 5-13.
[http://dx.doi.org/10.1016/j.toxlet.2011.04.006] [PMID: 21524695]
[25]
Calesnick, B.; Christensen, J.A.; Richter, M. Human toxicity of various oximes. 2-Pyridine aldoxime methyl chloride, its methane sulfonate salt, and 1,1′-trimethylenebis-(4-formylpyridinium chloride). Arch. Environ. Health, 1967, 15(5), 599-608.
[http://dx.doi.org/10.1080/00039896.1967.10664975] [PMID: 6066265]
[26]
Worek, F.; Bäcker, M.; Thiermann, H.; Szinicz, L.; Mast, U.; Klimmek, R.; Eyer, P. Reappraisal of indications and limitations of oxime therapy in organophosphate poisoning. Hum. Exp. Toxicol., 1997, 16(8), 466-472.
[http://dx.doi.org/10.1177/096032719701600808] [PMID: 9292287]
[27]
Buckley, N.A.; Eddleston, M.; Szinicz, L. Oximes for acute organophosphate pesticide poisoning. Cochrane Database Syst. Rev., 2005, CD005085(1), CD005085.
[http://dx.doi.org/10.1002/14651858.CD005085] [PMID: 15654704]
[28]
Soukup, O.; Tobin, G.; Kumar, U.K.; Binder, J.; Proska, J.; Jun, D.; Fusek, J.; Kuca, K. Interaction of nerve agent antidotes with cholinergic systems. Curr. Med. Chem., 2010, 17(16), 1708-1718.
[http://dx.doi.org/10.2174/092986710791111260] [PMID: 20345348]
[29]
Bajgar, J.; Fusek, J.; Kassa, J.; Kuca, K.; Jun, D. Chemical aspects of pharmacological prophylaxis against nerve agent poisoning. Curr. Med. Chem., 2009, 16(23), 2977-2986.
[http://dx.doi.org/10.2174/092986709788803088] [PMID: 19689278]
[30]
Kassa, J. Therapeutic and neuroprotective efficacy of pharmacological pretreatment and antidotal treatment of acute tabun or soman poisoning with the emphasis on pretreatment drug PANPAL. Arh. Hig. Rada Toksikol., 2006, 57(4), 427-434.
[PMID: 17265682]
[31]
Timperley, C.M.; Abdollahi, M.; Al-Amri, A.S.; Baulig, A.; Benachour, D.; Borrett, V.; Cariño, F.A.; Geist, M.; Gonzalez, D.; Kane, W.; Kovarik, Z.; Martínez-Álvarez, R.; Fusaro Mourão, N.M.; Neffe, S.; Raza, S.K.; Rubaylo, V.; Suárez, A.G.; Takeuchi, K.; Tang, C.; Trifirò, F.; van Straten, F.M.; Vanninen, P.S.; Vučinić, S.; Zaitsev, V.; Zafar-Uz-Zaman, M.; Zina, M.S.; Holen, S.; Forman, J.E.; Alwan, W.S.; Suri, V. Advice on assistance and protection by the Scientific Advisory Board of the Organisation for the Prohibition of Chemical Weapons: Part 2. On preventing and treating health effects from acute, prolonged, and repeated nerve agent exposure, and the identification of medical countermeasures able to reduce or eliminate the longer term health effects of nerve agents. Toxicology, 2019, 413, 13-23.
[http://dx.doi.org/10.1016/j.tox.2018.11.009] [PMID: 30500381]
[32]
Kanamori-Kataoka, M.; Seto, Y. Paraoxonase activity against nerve gases measured by capillary electrophoresis and characterization of human serum paraoxonase (PON1) polymorphism in the coding region (Q192R). Anal. Biochem., 2009, 385(1), 94-100.
[http://dx.doi.org/10.1016/j.ab.2008.09.044] [PMID: 18952040]
[33]
Myhrer, T.; Aas, P. Pretreatment and prophylaxis against nerve agent poisoning: Are undesirable behavioral side effects unavoidable? Neurosci. Biobehav. Rev., 2016, 71, 657-670.
[http://dx.doi.org/10.1016/j.neubiorev.2016.10.017] [PMID: 27773692]
[34]
Lundy, P.M.; Raveh, L.; Amitai, G. Development of the bisquaternary oxime HI-6 toward clinical use in the treatment of organophosphate nerve agent poisoning. Toxicol. Rev., 2006, 25(4), 231-243.
[http://dx.doi.org/10.2165/00139709-200625040-00004] [PMID: 17288495]
[35]
Nakab, L.; Bardot, I.; Bardot, S.; Simar, S.; Marzin, D.; Nesslany, F. In vitro and in vivo genotoxicity assessment of HI-6 dimethanesulfonate/oxime. Mutat. Res. Genet. Toxicol. Environ. Mutagen., 2014, 762, 30-38.
[http://dx.doi.org/10.1016/j.mrgentox.2013.11.006] [PMID: 24534338]
[36]
Kassa, J.; Kuca, K.; Cabal, J. A comparison of the potency of trimedoxime and other currently available oximes to reactivate tabun-inhibited acetylcholinesterase and eliminate acute toxic effects of tabun. Biomed. Pap. Med. Fac. Univ. Palacky Olomouc Czech Repub., 2005, 149(2), 419-23.
[http://dx.doi.org/10.5507/bp.2005.072]
[37]
Matula, M.; Kucera, T.; Soukup, O.; Pejchal, J. Enzymatic degradation of organophosphorus pesticides and nerve agents by EC: 3.1. 8.2. Catalysts, 2020, 10(12), 1365.
[http://dx.doi.org/10.3390/catal10121365]
[38]
Tawfik, D. Phosphotriesterasess for treating or preventing organophosphate exposure associated damage. WO Patent 2018087759A1, 2005.
[39]
Tawfik, D. Phosphotriesterases for treating or preventing organophosphate exposure associated damage.. US Patent 20190359956A1, 2019.
[40]
Harvey, S.P.; McMahon, L.R.; Berg, F.J. Hydrolysis and enzymatic degradation of Novichok nerve agents. Heliyon, 2020, 6(1), e03153.
[http://dx.doi.org/10.1016/j.heliyon.2019.e03153] [PMID: 32042950]
[41]
Pegan, S. Engineered organophosphorus acid anhydrolases and methods of use thereof. US Patent 20160355792A1, 2016.
[42]
Harvey, S. Mutant organophosphorus acid anhydrolase enzyme having increased catalytic efficiency on V-agents. US Patent 10421952B1, 2019.
[43]
Zhao, S.; Xu, W.; Zhang, W.; Wu, H.; Guang, C.; Mu, W. In-depth biochemical identification of a novel methyl parathion hydrolase from Azohydromonas australica and its high effectiveness in the degradation of various organophosphorus pesticides. Bioresour. Technol., 2021, 323, 124641.
[http://dx.doi.org/10.1016/j.biortech.2020.124641] [PMID: 33429316]
[44]
Melzer, M.; Heidenreich, A.; Dorandeu, F.; Gäb, J.; Kehe, K.; Thiermann, H.; Letzel, T.; Blum, M.M. In vitro and in vivo efficacy of PEGylated diisopropyl fluorophosphatase (DFPase). Drug Test. Anal., 2012, 4(3-4), 262-270.
[http://dx.doi.org/10.1002/dta.363] [PMID: 22174192]
[45]
Lenz, D.E.; Yeung, D.; Smith, J.R.; Sweeney, R.E.; Lumley, L.A.; Cerasoli, D.M. Stoichiometric and catalytic scavengers as protection against nerve agent toxicity: A mini review. Toxicology, 2007, 233(1-3), 31-39.
[http://dx.doi.org/10.1016/j.tox.2006.11.066] [PMID: 17188793]
[46]
Allard, J.L.; Shields, K.A.; Munro, T.P.; Lua, L.H.L. Strategies for developing a recombinant butyrylcholinesterase medical countermeasure for Organophosphorus poisoning. Chem. Biol. Interact., 2022, 363(363), 109996.
[http://dx.doi.org/10.1016/j.cbi.2022.109996] [PMID: 35654125]
[47]
Aharoni, A.; Gaidukov, L.; Yagur, S.; Toker, L.; Silman, I.; Tawfik, D.S. Directed evolution of mammalian paraoxonases PON1 and PON3 for bacterial expression and catalytic specialization. Proc. Natl. Acad. Sci. USA, 2004, 101(2), 482-487.
[http://dx.doi.org/10.1073/pnas.2536901100] [PMID: 14695884]
[48]
Goldsmith, M.; Ashani, Y. Catalytic bioscavengers as countermeasures against organophosphate nerve agents. Chem. Biol. Interact., 2018, 292, 50-64.
[http://dx.doi.org/10.1016/j.cbi.2018.07.006] [PMID: 29990481]
[49]
Nachon, F.; Brazzolotto, X.; Trovaslet, M.; Masson, P. Progress in the development of enzyme-based nerve agent bioscavengers. Chem. Biol. Interact., 2013, 206(3), 536-544.
[http://dx.doi.org/10.1016/j.cbi.2013.06.012] [PMID: 23811386]
[50]
Bigley, A.N.; Raushel, F.M. Catalytic mechanisms for phosphotriesterases. Biochim. Biophys. Acta. Proteins Proteomics, 2013, 1834(1), 443-453.
[http://dx.doi.org/10.1016/j.bbapap.2012.04.004] [PMID: 22561533]
[51]
Reed, B.A.; Sabourin, C.L.; Lenz, D.E. Human butyrylcholinesterase efficacy against nerve agent exposure. J. Biochem. Mol. Toxicol., 2017, 31(5), e21886.
[http://dx.doi.org/10.1002/jbt.21886] [PMID: 28225154]
[52]
Egelkrout, E.; Hayden, C.; Wales, M.; Walker, J.; Novikov, B.; Grimsley, J.; Howard, J. Production of the bioscavenger butyrylcholinesterase in maize. Mol. Breed., 2017, 37(11), 136.
[http://dx.doi.org/10.1007/s11032-017-0731-8]
[53]
Geyer, B.C.; Kannan, L.; Garnaud, P.E.; Broomfield, C.A.; Cadieux, C.L.; Cherni, I.; Hodgins, S.M.; Kasten, S.A.; Kelley, K.; Kilbourne, J.; Oliver, Z.P.; Otto, T.C.; Puffenberger, I.; Reeves, T.E.; Robbins, N., II; Woods, R.R.; Soreq, H.; Lenz, D.E.; Cerasoli, D.M.; Mor, T.S. Plant-derived human butyrylcholinesterase, but not an organophosphorous-compound hydrolyzing variant thereof, protects rodents against nerve agents. Proc. Natl. Acad. Sci. USA, 2010, 107(47), 20251-20256.
[http://dx.doi.org/10.1073/pnas.1009021107] [PMID: 21059932]
[54]
Mukherjee, S.; Gupta, R.D. Organophosphorus nerve agents: Types, toxicity, and treatments. J. Toxicol., 2020, 2020, 1-16.
[http://dx.doi.org/10.1155/2020/3007984] [PMID: 33029136]
[55]
Mee-Hie Cho, C.; Mulchandani, A.; Chen, W. Functional analysis of organophosphorus hydrolase variants with high degradation activity towards organophosphate pesticides. Protein Eng. Des. Sel., 2006, 19(3), 99-105.
[http://dx.doi.org/10.1093/protein/gzj007] [PMID: 16423845]
[56]
Ordentlich, A.; Barak, D.; Sod-Moriah, G.; Kaplan, D.; Mizrahi, D.; Segall, Y.; Kronman, C.; Karton, Y.; Lazar, A.; Marcus, D.; Velan, B.; Shafferman, A. Stereoselectivity toward VX is determined by interactions with residues of the ACYL pocket as well as of the peripheral anionic site of AChE. Biochemistry, 2004, 43(35), 11255-11265.
[http://dx.doi.org/10.1021/bi0490946] [PMID: 15366935]
[57]
Benning, M.M.; Kuo, J.M.; Raushel, F.M.; Holden, H.M. Three-dimensional structure of the binuclear metal center of phosphotriesterase. Biochemistry, 1995, 34(25), 7973-7978.
[http://dx.doi.org/10.1021/bi00025a002] [PMID: 7794910]
[58]
Dong, Y.J.; Bartlam, M.; Sun, L.; Zhou, Y.F.; Zhang, Z.P.; Zhang, C.G.; Rao, Z.; Zhang, X.E. Crystal structure of methyl parathion hydrolase from Pseudomonas sp. WBC-3. J. Mol. Biol., 2005, 353(3), 655-663.
[http://dx.doi.org/10.1016/j.jmb.2005.08.057] [PMID: 16181636]
[59]
Koepke, J.; Scharff, E.I.; Lücke, C.; Rüterjans, H.; Fritzsch, G. Statistical analysis of crystallographic data obtained from squid ganglion DFPase at 0.85 Å resolution. Acta Crystallogr. D Biol. Crystallogr., 2003, 59(10), 1744-1754.
[http://dx.doi.org/10.1107/S0907444903016135] [PMID: 14501113]
[60]
Blum, M.M.; Mustyakimov, M.; Rüterjans, H.; Kehe, K.; Schoenborn, B.P.; Langan, P.; Chen, J.C.H. Rapid determination of hydrogen positions and protonation states of diisopropyl fluorophosphatase by joint neutron and X-ray diffraction refinement. Proc. Natl. Acad. Sci. USA, 2009, 106(3), 713-718.
[http://dx.doi.org/10.1073/pnas.0807842106] [PMID: 19136630]
[61]
Vyas, N.K.; Nickitenko, A.; Rastogi, V.K.; Shah, S.S.; Quiocho, F.A. Structural insights into the dual activities of the nerve agent degrading organophosphate anhydrolase/prolidase. Biochemistry, 2010, 49(3), 547-559.
[http://dx.doi.org/10.1021/bi9011989] [PMID: 20000741]
[62]
Harel, M.; Aharoni, A.; Gaidukov, L.; Brumshtein, B.; Khersonsky, O.; Meged, R.; Dvir, H.; Ravelli, R.B.G.; McCarthy, A.; Toker, L.; Silman, I.; Sussman, J.L.; Tawfik, D.S. Structure and evolution of the serum paraoxonase family of detoxifying and anti-atherosclerotic enzymes. Nat. Struct. Mol. Biol., 2004, 11(5), 412-419.
[http://dx.doi.org/10.1038/nsmb767] [PMID: 15098021]
[63]
Aubert, S.D.; Li, Y.; Raushel, F.M. Mechanism for the hydrolysis of organophosphates by the bacterial phosphotriesterase. Biochemistry, 2004, 43(19), 5707-5715.
[http://dx.doi.org/10.1021/bi0497805] [PMID: 15134445]
[64]
DeFrank, J.J.; Cheng, T.C. Purification and properties of an organophosphorus acid anhydrase from a halophilic bacterial isolate. J. Bacteriol., 1991, 173(6), 1938-1943.
[http://dx.doi.org/10.1128/jb.173.6.1938-1943.1991] [PMID: 2001997]
[65]
Omburo, G.A.; Kuo, J.M.; Mullins, L.S.; Raushel, F.M. Characterization of the ZINC binding site of bacterial phosphotriesterase. J. Biol. Chem., 1992, 267(19), 13278-13283.
[http://dx.doi.org/10.1016/S0021-9258(18)42207-7] [PMID: 1320014]
[66]
Hartleib, J.; Geschwindner, S.; Scharff, E.I.; Rüterjans, H. Role of calcium ions in the structure and function of thedi-isopropylfluorophosphatase from Loligo vulgaris. Biochem. J., 2001, 353(3), 579-589.
[http://dx.doi.org/10.1042/bj3530579] [PMID: 11171055]
[67]
Schenk, G.; Mateen, I.; Ng, T.K.; Pedroso, M.M.; Mitić, N.; Jafelicci, M., Jr; Marques, R.F.C.; Gahan, L.R.; Ollis, D.L. Organophosphate-degrading metallohydrolases: Structure and function of potent catalysts for applications in bioremediation. Coord. Chem. Rev., 2016, 317, 122-131.
[http://dx.doi.org/10.1016/j.ccr.2016.03.006]
[68]
Worek, F.; Seeger, T.; Goldsmith, M.; Ashani, Y.; Leader, H.; Sussman, J.S.; Tawfik, D.; Thiermann, H.; Wille, T. Efficacy of the rePON1 mutant IIG1 to prevent cyclosarin toxicity in vivo and to detoxify structurally different nerve agents in vitro. Arch. Toxicol., 2014, 88(6), 1257-1266.
[http://dx.doi.org/10.1007/s00204-014-1204-z] [PMID: 24477626]
[69]
Worek, F.; Seeger, T.; Reiter, G.; Goldsmith, M.; Ashani, Y.; Leader, H.; Sussman, J.L.; Aggarwal, N.; Thiermann, H.; Tawfik, D.S. Post-exposure treatment of VX poisoned guinea pigs with the engineered phosphotriesterase mutant C23: A proof-of-concept study. Toxicol. Lett., 2014, 231(1), 45-54.
[http://dx.doi.org/10.1016/j.toxlet.2014.09.003] [PMID: 25195526]
[70]
Jun, D.; Musilová, L.; Link, M.; Loiodice, M.; Nachon, F.; Rochu, D.; Renault, F.; Masson, P. Preparation and characterization of methoxy polyethylene glycol-conjugated phosphotriesterase as a potential catalytic bioscavenger against organophosphate poisoning. Chem. Biol. Interact., 2010, 187(1-3), 380-383.
[http://dx.doi.org/10.1016/j.cbi.2010.03.017] [PMID: 20230809]
[71]
Bajaj, P.; Tripathy, R.K.; Aggarwal, G.; Pande, A.H. Human paraoxonase 1 as a pharmacologic agent: Limitations and perspectives. Sci. World J., 2014, 2014, 1-6.
[http://dx.doi.org/10.1155/2014/854391] [PMID: 25386619]
[72]
Taler-Verčič, A.; Goličnik, M.; Bavec, A. The structure and function of Paraoxonase-1 and its comparison to Paraoxonase-2 and -3. Molecules, 2020, 25(24), 5980.
[http://dx.doi.org/10.3390/molecules25245980] [PMID: 33348669]
[73]
Shunmoogam, N.; Naidoo, P.; Chilton, R. Paraoxonase (PON)-1: A brief overview on genetics, structure, polymorphisms and clinical relevance. Vasc. Health Risk Manag., 2018, 14, 137-143.
[http://dx.doi.org/10.2147/VHRM.S165173] [PMID: 29950852]
[74]
Costa, L.G.; Giordano, G.; Furlong, C.E. Pharmacological and dietary modulators of paraoxonase 1 (PON1) activity and expression: The hunt goes on. Biochem. Pharmacol., 2011, 81(3), 337-344.
[http://dx.doi.org/10.1016/j.bcp.2010.11.008] [PMID: 21093416]
[75]
Worek, F.; Thiermann, H.; Wille, T. Catalytic bioscavengers in nerve agent poisoning: A promising approach? Toxicol. Lett., 2016, 244, 143-148.
[http://dx.doi.org/10.1016/j.toxlet.2015.07.012] [PMID: 26200600]
[76]
Gupta, R.D.; Goldsmith, M.; Ashani, Y.; Simo, Y.; Mullokandov, G.; Bar, H.; Ben-David, M.; Leader, H.; Margalit, R.; Silman, I.; Sussman, J.L.; Tawfik, D.S. Directed evolution of hydrolases for prevention of G-type nerve agent intoxication. Nat. Chem. Biol., 2011, 7(2), 120-125.
[http://dx.doi.org/10.1038/nchembio.510] [PMID: 21217689]
[77]
Goldsmith, M.; Ashani, Y.; Simo, Y.; Ben-David, M.; Leader, H.; Silman, I.; Sussman, J.L.; Tawfik, D.S. Evolved stereoselective hydrolases for broad-spectrum G-type nerve agent detoxification. Chem. Biol., 2012, 19(4), 456-466.
[http://dx.doi.org/10.1016/j.chembiol.2012.01.017] [PMID: 22520752]
[78]
Mata, D.G.; Sabnekar, P.; Watson, C.A.; Rezk, P.E.; Chilukuri, N. Assessing the stoichiometric efficacy of mammalian expressed paraoxonase-1 variant I-F11 to afford protection against G-type nerve agents. Chem. Biol. Interact., 2016, 259(Pt B), 233-241.
[http://dx.doi.org/10.1016/j.cbi.2016.04.013] [PMID: 27083144]
[79]
Meek, E.C.; Chambers, H.W.; Pringle, R.B.; Chambers, J.E. The effect of PON1 enhancers on reducing acetylcholinesterase inhibition following organophosphate anticholinesterase exposure in rats. Toxicology, 2015, 336, 79-83.
[http://dx.doi.org/10.1016/j.tox.2015.08.002] [PMID: 26275814]
[80]
Stevens, R.C.; Suzuki, S.M.; Cole, T.B.; Park, S.S.; Richter, R.J.; Furlong, C.E. Engineered recombinant human paraoxonase 1 (rHuPON1) purified from Escherichia coli protects against organophosphate poisoning. Proc. Natl. Acad. Sci. USA, 2008, 105(35), 12780-12784.
[http://dx.doi.org/10.1073/pnas.0805865105] [PMID: 18711144]
[81]
Jia, B.; Jeon, C.O. High-throughput recombinant protein expression in Escherichia coli : Current status and future perspectives. Open Biol., 2016, 6(8), 160196.
[http://dx.doi.org/10.1098/rsob.160196] [PMID: 27581654]
[82]
Bajaj, P.; Tripathy, R.K.; Aggarwal, G.; Pande, A.H. Expression and purification of biologically active recombinant human paraoxonase 1 from inclusion bodies of Escherichia coli. Protein Expr. Purif., 2015, 115, 95-101.
[http://dx.doi.org/10.1016/j.pep.2015.05.011] [PMID: 26003526]
[83]
Pal, A.; Chaudhuri, T.K. Enhancement in the production of recombinant human paraoxonase 1 in Escherichia coli: A comprehensive approach of cellular engineering and optimization of protein folding process in vitro. Int. J. Biol. Macromol., 2022, 221, 1504-1511.
[http://dx.doi.org/10.1016/j.ijbiomac.2022.09.133] [PMID: 36122776]
[84]
Bigley, A.N.; Raushel, F.M. The evolution of phosphotriesterase for decontamination and detoxification of organophosphorus chemical warfare agents. Chem. Biol. Interact., 2019, 308, 80-88.
[http://dx.doi.org/10.1016/j.cbi.2019.05.023] [PMID: 31100274]
[85]
Kirby, S.D.; Norris, J.R.; Richard Smith, J.; Bahnson, B.J.; Cerasoli, D.M. Human paraoxonase double mutants hydrolyze V and G class organophosphorus nerve agents. Chem. Biol. Interact., 2013, 203(1), 181-185.
[http://dx.doi.org/10.1016/j.cbi.2012.10.023] [PMID: 23159884]
[86]
Packer, M.S.; Liu, D.R. Methods for the directed evolution of proteins. Nat. Rev. Genet., 2015, 16(7), 379-394.
[http://dx.doi.org/10.1038/nrg3927] [PMID: 26055155]
[87]
García-Fruitós, E.; Vázquez, E.; Díez-Gil, C.; Corchero, J.L.; Seras-Franzoso, J.; Ratera, I.; Veciana, J.; Villaverde, A. Bacterial inclusion bodies: Making gold from waste. Trends Biotechnol., 2012, 30(2), 65-70.
[http://dx.doi.org/10.1016/j.tibtech.2011.09.003] [PMID: 22037492]
[88]
Kontermann, R.E. Half-life extended biotherapeutics. Expert Opin. Biol. Ther., 2016, 16(7), 903-915.
[http://dx.doi.org/10.1517/14712598.2016.1165661] [PMID: 26967759]
[89]
Iyengar, A.R.S.; Gupta, S.; Jawalekar, S.; Pande, A.H. Protein chimerization: A new frontier for engineering protein therapeutics with improved pharmacokinetics. J. Pharmacol. Exp. Ther., 2019, 370(3), 703-714.
[http://dx.doi.org/10.1124/jpet.119.257063] [PMID: 31010843]
[90]
Dobariya, P.; Adhya, P.; Vaidya, B.; Khandave, P.Y.; Sharma, S.S.; Pande, A.H. Fused human paraoxonase 1 as a prophylactic agent against organophosphate poisoning. Enzyme Microb. Technol., 2023, 165, 110209.
[http://dx.doi.org/10.1016/j.enzmictec.2023.110209] [PMID: 36764031]
[91]
Schellekens, H. The immunogenicity of therapeutic proteins. Discov. Med., 2010, 9(49), 560-564.
[PMID: 20587346]
[92]
De Groot, A.S.; Scott, D.W. Immunogenicity of protein therapeutics. Trends Immunol., 2007, 28(11), 482-490.
[http://dx.doi.org/10.1016/j.it.2007.07.011] [PMID: 17964218]
[93]
Despotović, D.; Aharon, E.; Dubovetskyi, A.; Leader, H.; Ashani, Y.; Tawfik, D.S. A mixture of three engineered phosphotriesterases enables rapid detoxification of the entire spectrum of known threat nerve agents. Protein Eng. Des. Sel., 2019, 32(4), 169-174.
[http://dx.doi.org/10.1093/protein/gzz039] [PMID: 31612205]
[94]
Kirby, S. Phosphotriesterases enzyme tethered monomer. US Patent 20200255811A1, 2020.
[95]
Baker, C.; Garcia, J.S.; Sweeney, R.; Kirby, S. Organophosphate Hydrolase (OPH) designed as a functional monomer. FASEB J., 2018, 32(S1), lb66-lb66.
[http://dx.doi.org/10.1096/fasebj.2018.32.1_supplement.lb66]
[96]
Lee, N.; Yun, H.; Lee, C.; Lee, Y.; Kim, E.; Kim, S.; Jeon, H.; Yu, C.; Rho, J. Engineered recombinant PON1-OPH fusion hybrids: Potentially effective catalytic bioscavengers against organophosphorus nerve agent analogs. J. Microbiol. Biotechnol., 2021, 31(1), 144-153.
[http://dx.doi.org/10.4014/jmb.2006.06044] [PMID: 33144547]
[97]
Garcia, G.E.; Campbell, A.J.; Olson, J.; Moorad-Doctor, D.; Morthole, V.I. Novel oximes as blood–brain barrier penetrating cholinesterase reactivators. Chem. Biol. Interact., 2010, 187(1-3), 199-206.
[http://dx.doi.org/10.1016/j.cbi.2010.02.033] [PMID: 20227398]
[98]
Faiz Norrrahim, M.N.; Idayu Abdul Razak, M.A.; Ahmad Shah, N.A.; Kasim, H.; Wan Yusoff, W.Y.; Halim, N.A.; Mohd Nor, S.A.; Jamal, S.H.; Ong, K.K.; Zin Wan Yunus, W.M.; Knight, V.F.; Mohd Kasim, N.A. Recent developments on oximes to improve the blood brain barrier penetration for the treatment of organophosphorus poisoning: A review. RSC Advances, 2020, 10(8), 4465-4489.
[http://dx.doi.org/10.1039/C9RA08599H] [PMID: 35495228]
[99]
Boado, R.J.; Zhang, Y.; Zhang, Y.; Wang, Y.; Pardridge, W.M. IgG-paraoxonase-1 fusion protein for targeted drug delivery across the human blood-brain barrier. Mol. Pharm., 2008, 5(6), 1037-1043.
[http://dx.doi.org/10.1021/mp800113g] [PMID: 19434854]
[100]
Yan, J.; Wang, M.; Lv, S.; Chen, D.; Wu, Z.; Zhou, D.; Zhang, S.; Lv, J.; Xu, K.; Xu, C.; Wei, Y. SiATG5-loaded cancer cell membrane-fused liposomes induced increased uptake of albumin-bound chemotherapeutics by pancreatic cancer cells. J. Control. Release, 2024, 367, 620-636.
[http://dx.doi.org/10.1016/j.jconrel.2024.01.055] [PMID: 38311244]

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    • Connection Establishedalphaeurekaselec_live_10_06_2022UserAccessCheck.php#24
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      • 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
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      • 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
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      • 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
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      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=140189
      730μsalphaeurekaselec_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
      870μsalphaeurekaselec_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`
      850μsalphaeurekaselec_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
      740μsalphaeurekaselec_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`
      2.47msalphaeurekaselec_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
      2.09msalphaeurekaselec_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` = '140189'
      220μsalphaeurekaselec_live_10_06_2022Keywords.php#43
      Bindings
      • 0: 140189
      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` = '140189'
      5.47msalphaeurekaselec_live_10_06_2022Article.php#1570
      Bindings
      • 0: 140189
      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` = '140189' group by `au`.`author_id` order by `au`.`article_id` asc, `au`.`sequence` asc
      3.93msalphaeurekaselec_live_10_06_2022Author.php#86
      Bindings
      • 0: 140189
      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
      290μsalphaeurekaselec_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
      490μsalphaeurekaselec_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
      29.88msalphaeurekaselec_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
      11.92msalphaeurekaselec_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
      11.03msalphaeurekaselec_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` = 140189 limit 1
      210μsalphaeurekaselec_live_10_06_2022Article.php#744
      Bindings
      • 0: 140189
      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 = 140189 and content_type = 'article' order by status desc limit 1
      250μsalphaeurekaselec_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` = 229679 limit 1
      230μsalphaeurekaselec_live_10_06_2022Meta.php#30
      Bindings
      • 0: 229679
      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
      220μsalphaeurekaselec_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
      260μsalphaeurekaselec_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 = '140189' 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) )
      370μsalphaeurekaselec_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 = '13500' 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) )
      280μsalphaeurekaselec_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 = '3496' 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) )
      280μsalphaeurekaselec_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 <= 309791667 and j.to_ip >=309791667 )) and ((j.from_date <= 1740496343 and j.to_date >= 1740496343 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3496) 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 <= 309791667 and j.to_ip >=309791667 )) and ((j.from_date <= 1740496343 and j.to_date >= 1740496343 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3496) 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 <= 309791667 and j.to_ip >=309791667 )) and ((j.from_date <= 1740496343 and j.to_date >= 1740496343 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3496)
      29.34msalphaeurekaselec_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 <= 309791667 and j.to_ip >=309791667 )) and ((j.from_date <= 1740496343 and j.to_date >= 1740496343 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 13500) 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 <= 309791667 and j.to_ip >=309791667 )) and ((j.from_date <= 1740496343 and j.to_date >= 1740496343 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 13500) 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 <= 309791667 and j.to_ip >=309791667 )) and ((j.from_date <= 1740496343 and j.to_date >= 1740496343 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 13500)
      930μsalphaeurekaselec_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 <= 309791667 and j.to_ip >=309791667 )) and ((j.from_date <= 1740496343 and j.to_date >= 1740496343 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 140189) 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 <= 309791667 and j.to_ip >=309791667 )) and ((j.from_date <= 1740496343 and j.to_date >= 1740496343 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 140189) 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 <= 309791667 and j.to_ip >=309791667 )) and ((j.from_date <= 1740496343 and j.to_date >= 1740496343 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 140189)
      700μsalphaeurekaselec_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` < '345' and is_uploaded = 1 and issue_id = 13500 order by cast(first_page as SIGNED) desc limit 1
      470μsalphaeurekaselec_live_10_06_2022Article.php#1819
      Bindings
      • 0: 345
      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` > '355' and is_uploaded = 1 and issue_id = 13500 order by cast(first_page as SIGNED) asc limit 1
      490μsalphaeurekaselec_live_10_06_2022Article.php#1831
      Bindings
      • 0: 355
      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'
      220μsalphaeurekaselec_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
      290μsalphaeurekaselec_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` = 140189 limit 1
      3.78msalphaeurekaselec_live_10_06_2022ArticleController.php#2506
      Bindings
      • 0: 140189
      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` <= 1740496343 and `b`.`banner_to_date` >= 1740496343 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.56msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 51
      • 3: 1740496343
      • 4: 1740496343
      • 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` <= 1740496343 and `b`.`banner_to_date` >= 1740496343 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.49msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 51
      • 3: 1740496343
      • 4: 1740496343
      • 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='896637190e6464398d6577e1fdff1bfc'
      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
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        ClearShow all
        Date ↕MethodURLData
        #12025-02-25 15:12:23GET/article/140189414361