Generic placeholder image

Current Organic Synthesis

Editor-in-Chief

ISSN (Print): 1570-1794
ISSN (Online): 1875-6271

Review Article

The Recent Progresses in Chemical Synthesis of Proteins with Site-Specific Lysine Post-translational Modifications

Author(s): Zhipeng A. Wang*

Volume 16, Issue 3, 2019

Page: [369 - 384] Pages: 16

DOI: 10.2174/1570179416666190328233918

Price: $65

Abstract

In the past two decades, a plethora of lysine (Lys) posttranslational modifications (PTMs) has been discovered on proteins, major groups are acylation, alkylation, and ubiquitination. Although considered biologically important, functional annotation of proteins with Lys PTMs has largely fallen behind the discovery. One grand challenge of characterizing proteins with PTMs is the procurement of homogenously modified proteins. To resolve this obstacle, sophisticated methods have been developed. These include total synthesis, semisynthesis that is based on native chemical ligation, expressed protein ligation, and enzyme-catalyzed peptide ligation, and the amber-suppression based noncanonical amino acid mutagenesis technique that may need to couple with follow-up bioorthogonal chemistry. This review summarizes currently identified significant PTMs and chemical biology methods for their installation in proteins. We hope that the current review will provide helpful insights and critical perspectives to this important research frontier.

Keywords: Post-translational modifications, protein chemical modifications, bioorthogonal reaction, non-Canonical amino acid, Lysine, chemical biology methods.

Graphical Abstract

[1]
Zhao, Y.; Jensen, O.N. Modification-specific proteomics: Strategies for characterization of post-translational modifications using enrichment techniques. Proteomics, 2009, 9, 4632-4641.
[2]
Choudhary, C.; Weinert, B.T.; Nishida, Y.; Verdin, E.; Mann, M. The growing landscape of lysine acetylation links metabolism and cell signalling. Nat. Rev. Mol. Cell Biol., 2014, 15(8), 536-550.
[3]
Müller, M.M.; Muir, T.W. Histones: at the crossroads of peptide and protein chemistry. Chem. Rev., 2014, 115(6), 2296-2349.
[4]
Zhang, Y.; Reinberg, D. Transcription regulation by histone methylation: interplay between different covalent modifications of the core histone tails. Genes Dev., 2001, 15, 2343-2360.
[5]
Greer, E.L.; Shi, Y. Histone methylation: a dynamic mark in health, disease and inheritance. Nat. Rev. Genet., 2012, 13(5), 343-357.
[6]
Chuikov, S.; Kurash, J.K.; Wilson, J.R.; Xiao, B.; Justin, N.; Ivanov, G.S.; McKinney, K.; Tempst, P.; Prives, C.; Gamblin, S.J. Regulation of p53 activity through lysine methylation. Nature, 2004, 432(7015), 353-360.
[7]
Hamamoto, R.; Saloura, V.; Nakamura, Y. Critical roles of non-histone protein lysine methylation in human tumorigenesis. Nat. Rev. Cancer, 2015, 15(2), 110-124.
[8]
Phillips, D.M. Acetyl groups as N-terminal aubstituents in calf-thymus histones. Biochem. J., 1961, 80(3), 40.
[9]
Manohar, M.; Mooney, A.M.; North, J.A.; Nakkula, R.J.; Picking, J.W.; Edon, A.; Fishel, R.; Poirier, M.G.; Ottesen, J.J. Acetylation of histone H3 at the nucleosome dyad alters DNA-histone binding. J. Biol. Chem., 2009, 284(35), 23312-23321.
[10]
Spange, S.; Wagner, T.; Heinzel, T.; Krämer, O.H. Acetylation of non-histone proteins modulates cellular signalling at multiple levels. Int. J. Biochem. Cell Biol., 2009, 41(1), 185-198.
[11]
Kothapalli, N.; Camporeale, G.; Kueh, A.; Chew, Y.C.; Oommen, A.M.; Griffin, J.B.; Zempleni, J. Biological functions of biotinylated histones. J. Nutr. Biochem., 2005, 16(7), 446-448.
[12]
Peng, C.; Lu, Z.; Xie, Z.; Cheng, Z.; Chen, Y.; Tan, M.; Luo, H.; Zhang, Y.; He, W.; Yang, K.; Zhao, Y. The first identification of lysine malonylation substrates and its regulatory enzyme. Mol. Cell. Proteomics, 2011, 10(12), M111. 012658.
[13]
Zhang, Z.; Tan, M.; Xie, Z.; Dai, L.; Chen, Y.; Zhao, Y. Identification of lysine succinylation as a new post-translational modification. Nat. Chem. Biol., 2011, 7(1), 58-63.
[14]
Tan, M.; Peng, C.; Anderson, K.A.; Chhoy, P.; Xie, Z.; Dai, L.; Park, J.; Chen, Y.; Huang, H.; Zhang, Y.; Ro, J.; Wagner, G.R.; Green, M.F.; Madsen, A.S.; Schmiesing, J.; Peterson, B.S.; Xu, G.; Ilkayeva, O.R.; Muehlbauer, M.J.; Braulke, T.; Muhlhausen, C.; Backos, D.S.; Olsen, C.A.; McGuire, P.J.; Pletcher, S.D.; Lombard, D.B.; Hirschey, M.D.; Zhao, Y. Lysine glutarylation is a protein posttranslational modification regulated by SIRT5. Cell Metab., 2014, 19(4), 605-617.
[15]
Dai, L.; Peng, C.; Montellier, E.; Lu, Z.; Chen, Y.; Ishii, H.; Debernardi, A.; Buchou, T.; Rousseaux, S.; Jin, F. Lysine 2-hydroxyisobutyrylation is a widely distributed active histone mark. Nat. Chem. Biol., 2014, 10(5), 365-370.
[16]
Jin, J.; He, B.; Zhang, X.; Lin, H.; Wang, Y. SIRT2 reverses 4-oxononanoyl lysine modification on histones. J. Am. Chem. Soc., 2016, 138(38), 12304-12307.
[17]
Xie, Z.; Zhang, D.; Chung, D.; Tang, Z.; Huang, H.; Dai, L.; Qi, S.; Li, J.; Colak, G.; Chen, Y.; Xia, C.; Peng, C.; Ruan, H.; Kirkey, M.; Wang, D.; Jensen, L.M.; Kwon, O.K.; Lee, S.; Pletcher, S.D.; Tan, M.; Lombard, D.B.; White, K.P.; Zhao, H.; Li, J.; Roeder, R.G.; Yang, X.; Zhao, Y. Metabolic regulation of gene expression by histone lysine β-hydroxybutyrylation. Mol. Cell, 2016, 62(2), 194-206.
[18]
Huang, H.; Zhang, D.; Wang, Y.; Perez-Neut, M.; Han, Z.; Zheng, Y.G.; Hao, Q.; Zhao, Y. Lysine benzoylation is a histone mark regulated by SIRT2. Nat. Commun., 2018, 9, Article number 3374.
[19]
Zhipeng, A. Wang; Li, M.; Li, H.; Liu, Z.; Li, Y.; Zheng, J.-S. Chemical (Semi-) synthesis and applications of lysine post-translationally modified proteins. Chin. J. Org. Chem., 2018, 38, 2400.
[20]
Liu, W.S.R.; Wang, Y.S.; Wan, W. Synthesis of proteins with defined posttranslational modifications using the genetic noncanonical amino acid incorporation approach. Mol. Biosyst., 2011, 7(1), 38-47.
[21]
Wang, Z-P.; Wang, Y-H.; Chu, G-C.; Shi, J.; Li, Y-M. The study of the chemical synthesis and preparation of histone with post-translational modifications. Curr. Org. Synth., 2015, 12(2), 150-162.
[22]
Wang, Z.; Ding, X.; Li, S.; Shi, J.; Li, Y. Engineered fluorescence tags for in vivo protein labelling. RSC Adv, 2014, 4(14), 7235-7245.
[23]
Tate, E.W. Recent advances in chemical proteomics: exploring the post-translational proteome. J. Chem. Biol., 2008, 1, 17-26.
[24]
Li, J-B.; Tang, S.; Zheng, J-S.; Tian, C-L.; Liu, L. Removable backbone modification method for the chemical synthesis of membrane proteins. Acc. Chem. Res., 2017, 50(5), 1143-1153.
[25]
Wang, Z.; Xu, W.; Liu, L.; Zhu, T.F. A synthetic molecular system capable of mirror-image genetic replication and transcription. Nat. Chem., 2016, 8(7), 698.
[26]
Dawson, P.E.; Kent, S.B.H. Synthesis of native proteins by chemical ligation. Annu. Rev. Biochem., 2000, 69(1), 923-960.
[27]
Muir, T.W.; Sondhi, D.; Cole, P.A. Expressed protein ligation: a general method for protein engineering. Proc. Natl. Acad. Sci. USA, 1998, 95(12), 6705-6710.
[28]
Zheng, J-S.; Tang, S.; Huang, Y-C.; Liu, L. Development of new thioester equivalents for protein chemical synthesis. Acc. Chem. Res., 2013, 46(11), 2475-2484.
[29]
Zheng, J-S.; He, Y.; Zuo, C.; Cai, X-Y.; Tang, S.; Wang, Z.A.; Zhang, L-H.; Tian, C-L.; Liu, L. Robust chemical synthesis of membrane proteins through a general method of removable backbone modification. J. Am. Chem. Soc., 2016, 138(10), 3553-3561.
[30]
Chen, X.; Tang, S.; Zheng, J-S.; Zhao, R.; Wang, Z-P.; Shao, W.; Chang, H-N.; Cheng, J-Y.; Zhao, H.; Liu, L. Chemical synthesis of a two-photon-activatable chemokine and photon-guided lymphocyte migration in vivo. Nat. Commun., 2015, 6, 1-9.
[31]
Fang, G.M.; Li, Y.M.; Shen, F.; Huang, Y.C.; Li, J.B.; Lin, Y.; Cui, H.K.; Liu, L. Protein chemical synthesis by ligation of peptide hydrazides. Angew. Chem. Int. Ed., 2011, 50(33), 7645-7649.
[32]
Pan, M.; Gao, S.; Zheng, Y.; Tan, X.; Lan, H.; Tan, X.; Sun, D.; Lu, L.; Wang, T.; Zheng, Q.; Liu, L. Quasi-racemic X-ray structures of K27-linked ubiquitin chains prepared by total chemical synthesis. J. Am. Chem. Soc., 2016, 138(23), 7429-7435.
[33]
Li, J.; Li, Y.; He, Q.; Li, Y.; Li, H.; Liu, L. One-pot native chemical ligation of peptide hydrazides enables total synthesis of modified histones. Org. Biomol. Chem., 2014, 12(29), 5435-5441.
[34]
Morgan, M.T.; Haj-Yahya, M.; Ringel, A.E.; Bandi, P.; Brik, A.; Wolberger, C. Structural basis for histone H2B deubiquitination by the SAGA DUB module. Science, 2016, 351(6274), 725-728.
[35]
Tang, S.; Liang, L.J.; Si, Y.Y.; Gao, S.; Wang, J.X.; Liang, J.; Mei, Z.; Zheng, J.S.; Liu, L. Practical chemical synthesis of atypical ubiquitin chains by using an isopeptide-linked ub isomer. Angew. Chem. Int. Ed., 2017, 56(43), 13333-13337.
[36]
Moyle, P.M.; Muir, T.W. Method for the synthesis of mono-ADP-ribose conjugated peptides. J. Am. Chem. Soc., 2010, 132(45), 15878-15880.
[37]
Kee, J-M.; Villani, B.; Carpenter, L.R.; Muir, T.W. Development of stable phosphohistidine analogues. J. Am. Chem. Soc., 2010, 132(41), 14327-14329.
[38]
Hsu, W.W.; Wu, B.; Liu, W.R. Sirtuins 1 and 2 are universal histone deacetylases. ACS Chem. Biol., 2016, 11, 792-799.
[39]
Wu, Y-W.; Goody, R.S. Probing protein function by chemical modification. J. Pept. Sci., 2010, 16, 514-523.
[40]
Eftekhari-Sis, B.; Zirak, M. Chemistry of α-oxoesters: a powerful tool for the synthesis of heterocycles. Chem. Rev., 2014, 115(1), 151-264.
[41]
Zheng, M.; Zheng, L.; Zhang, P.; Li, J.; Zhang, Y. Development of bioorthogonal reactions and their applications in bioconjugation. Molecules, 2015, 20, 3190-3205.
[42]
Best, M.D. Click chemistry and bioorthogonal reactions: unprecedented selectivity in the labeling of biological molecules. Biochemistry, 2009, 48, 6571-6584.
[43]
Chalker, J.M.; Bernardes, G.A.J.; Davis, B.G.A. “tag-and-modify” approach to site-selective protein modification. Acc. Chem. Res., 2011, 44(9), 730-741.
[44]
Dawson, P.E.; Muir, T.W.; Clark-Lewis, I.; Kent, S.B. Synthesis of proteins by native chemical ligation. Science, 1994, 266(5186), 776-779.
[45]
Zuo, C.; Tang, S.; Zheng, J.S. Chemical synthesis and biophysical applications of membrane proteins. J. Pept. Sci., 2015, 21(7), 540-549.
[46]
Guo, Q-Y.; Zhang, L-H.; Zuo, C.; Huang, D-L.; Wang, Z.A.; Zheng, J-S.; Tian, C-L. Channel activity of mirror-image M2 proton channel of influenza A virus is blocked by achiral or chiral inhibitors. Protein & Cell, 2018, 10(3), 211-216.
[47]
Wu, M.; Hayward, D.; Kalin, J.H.; Song, Y.; Schwabe, J.W.; Cole, P.A. Lysine-14 acetylation of histone H3 in chromatin confers resistance to the deacetylase and demethylase activities of an epigenetic silencing complex. eLife, 2018, 7, e37231.
[48]
Zheng, J-S.; Tang, S.; Qi, Y-K.; Wang, Z-P.; Liu, L. Chemical synthesis of proteins using peptide hydrazides as thioester surrogates. Nat. Protoc., 2013, 8(12), 2483-2495.
[49]
He, S.; Bauman, D.; Davis, J.S.; Loyola, A.; Nishioka, K.; Gronlund, J.L.; Reinberg, D.; Meng, F.Y.; Kelleher, N.; McCafferty, D.G. Facile synthesis of site-specifically acetylated and methylated histone proteins: Reagents for evaluation of the histone code hypothesis. Proc. Natl. Acad. Sci. USA, 2003, 100(21), 12033-12038.
[50]
Kawakami, T.; Akai, Y.; Fujimoto, H.; Kita, C.; Aoki, Y.; Konishi, T.; Waseda, M.; Takemura, L.; Aimoto, S. Sequential peptide ligation by combining the Cys-Pro Ester (CPE) and thioester methods and its application to the synthesis of histone H3 containing a trimethyl lysine residue. Bull. Chem. Soc. Jpn., 2013, 86(6), 690-697.
[51]
Jbara, M.; Guttmann-Raviv, N.; Maity, S.K.; Ayoub, N.; Brik, A. Total chemical synthesis of methylated analogues of histone 3 revealed KDM4D as a potential regulator of H3K79me3. Biorg. Med. Chem., 2017, 25(18), 4966-4970.
[52]
Kwon, Y.T.; Ciechanover, A. The ubiquitin code in the ubiquitin-proteasome system and autophagy. Trends Biochem. Sci., 2017, 42(11), 873-886.
[53]
Mali, S.M.; Singh, S.K.; Eid, E.; Brik, A. Ubiquitin signaling: Chemistry comes to the rescue. J. Am. Chem. Soc., 2017, 139(14), 4971-4986.
[54]
Kumar, K.A.; Spasser, L.; Ohayon, S.; Erlich, L.A.; Brik, A. Expeditious chemical synthesis of ubiquitinated peptides employing orthogonal protection and native chemical ligation. Bioconjugate. Chem., 2011, 22(2), 137-143.
[55]
Siman, P.; Karthikeyan, S.V.; Nikolov, M.; Fischle, W.; Brik, A. Convergent chemical synthesis of histone H2B Protein for the site-specific ubiquitination at Lys34. Angew. Chem. Int. Ed., 2013, 52(31), 8059-8063.
[56]
Li, J.; He, Q.; Liu, Y.; Liu, S.; Tang, S.; Li, C.; Sun, D.; Li, X.; Zhou, M.; Zhu, P. Chemical synthesis of K34-ubiquitylated H2B for nucleosome reconstitution and single-particle cryo-electron microscopy structural analysis. ChemBioChem, 2017, 18, 176-180.
[57]
McGinty, R.K.; Kim, J.; Chatterjee, C.; Roeder, R.G.; Muir, T.W. Chemically ubiquitylated histone H2B stimulates hDot1L-mediated intranucleosomal methylation. Nature, 2008, 453(7196), 812-816.
[58]
McGinty, R.K.; Kohn, M.; Chatterjee, C.; Chiang, K.P.; Pratt, M.R.; Muir, T.W. Structure-activity analysis of semisynthetic nucleosomes: mechanistic insights into the stimulation of Dot1L by ubiquitylated histone H2B. ACS Chem. Biol., 2009, 4(11), 958-968.
[59]
Chatterjee, C.; McGinty, R.K.; Fierz, B.; Muir, T.W. Disulfide-directed histone ubiquitylation reveals plasticity in hDot1L activation. Nat. Chem. Biol., 2010, 6(4), 267-269.
[60]
Wojcik, F.; Dann, G.P.; Beh, L.Y.; Debelouchina, G.T.; Hofmann, R.; Muir, T.W. Functional crosstalk between histone H2B ubiquitylation and H2A modifications and variants. Nat. Commun., 2018, 9(1), 1394.
[61]
Liang, J.; Zhang, L.; Tan, X.L.; Qi, Y.K.; Feng, S.; Deng, H.; Yan, Y.; Zheng, J.S.; Liu, L.; Tian, C.L. Chemical synthesis of diubiquitin-based photoaffinity probes for selectively profiling ubiquitin-binding proteins. Angew. Chem. Int. Ed., 2017, 129(10), 2788-2792.
[62]
Bondalapati, S.; Eid, E.; Mali, S.M.; Wolberger, C.; Brik, A. Total chemical synthesis of SUMO-2-Lys63-linked diubiquitin hybrid chains assisted by removable solubilizing tags. Chem. Sci., 2017, 8, 4027-4034.
[63]
Liang, L-J.; Si, Y.; Tang, S.; Huang, D.; Wang, Z.A.; Tian, C.; Zheng, J-S. Biochemical properties of K11, 48-branched ubiquitin chains. Chin. Chem. Lett., 2018, 29, 1155-1159.
[64]
Si, Y-Y.; Liang, L-J.; Tang, S.; Qi, Y-K.; Huang, Y.; Zheng, J-S. One-pot ligation strategy for atypical ubiquitin chains synthesis by using the trifluoroacetamidomethyl-protected isopeptide-linked Ub (Tfacm-isoUb) unit. Tetrahedron Lett., 2018, 59(3), 268-271.
[65]
Qi, Y-K.; He, Q-Q.; Ai, H-S.; Li, J-B.; Zheng, J-S. Convergent total synthesis of histone H2B protein with site-specific ubiquitination at Lys120. Synlett, 2017, 28(15), 1907-1912.
[66]
Li, J.; He, Q.; Liu, Y.; Liu, S.; Tang, S.; Li, C.; Sun, D.; Li, X.; Zhou, M.; Zhu, P. Chemical synthesis of K34-ubiquitylated H2B for nucleosome reconstitution and single-particle cryo-electron microscopy structural analysis. ChemBioChem, 2017, 18(2), 176-180.
[67]
Luo, J.; Li, M.; Tang, Y.; Laszkowska, M.; Roeder, R.G.; Gu, W. Acetylation of p53 augments its site-specific DNA binding both in vitro and in vivo. Proc. Natl. Acad. Sci. USA, 2004, 101(8), 2259-2264.
[68]
Li, M.; Luo, J.; Brooks, C.L.; Gu, W. Acetylation of p53 inhibits its ubiquitination by Mdm2. J. Biol. Chem., 2002, 277(52), 50607-50611.
[69]
Tang, Y.; Zhao, W.; Chen, Y.; Zhao, Y.; Gu, W. Acetylation is indispensable for p53 activation. Cell, 2008, 133(4), 612-626.
[70]
Martino, F.; Kueng, S.; Robinson, P.; Tsai-Pflugfelder, M.; van Leeuwen, F.; Ziegler, M.; Cubizolles, F.; Cockell, M.M.; Rhodes, D.; Gasser, S.M. Reconstitution of yeast silent chromatin: Multiple contact sites and O-AADPR binding load SIR complexes onto nucleosomes in vitro. Mol. Cell, 2009, 33(3), 323-334.
[71]
Nguyen, D.P.; Garcia Alai, M.M.; Kapadnis, P.B.; Neumann, H.; Chin, J.W. Genetically encoding N(epsilon)-methyl-L-lysine in recombinant histones. J. Am. Chem. Soc., 2009, 131(40), 14194-14195.
[72]
Yin, J.; Liu, F.; Li, X.H.; Walsh, C.T. Labeling proteins with small molecules by site-specific posttranslational modification. J. Am. Chem. Soc., 2004, 126(25), 7754-7755.
[73]
Scheffner, M.; Nuber, U.; Huibregtse, J.M. Protein ubiquitination involving an E1-E2-E3 enzyme ubiquitin thioester cascade. Nature, 1995, 373(6509), 81.
[74]
Park, S.; Krist, D.T.; Statsyuk, A.V. Protein ubiquitination and formation of polyubiquitin chains without ATP, E1 and E2 enzymes. Chem. Sci, 2015, 6(3), 1770-1779.
[75]
Wang, X.A.; Kurra, Y.; Huang, Y.; Lee, Y.J.; Liu, W.R. E1-Catalyzed ubiquitin C-terminal amidation for the facile synthesis of deubiquitinase substrates. ChemBioChem, 2014, 15(1), 37-41.
[76]
Faggiano, S.; Menon, R.P.; Kelly, G.P.; McCormick, J.; Todi, S.V.; Scaglione, K.M.; Paulson, H.L.; Pastore, A. Enzymatic production of mono-ubiquitinated proteins for structural studies: The example of the Josephin domain of ataxin-3. FEBS Open Bio, 2013, 3(1), 453-458.
[77]
Komander, D.; Rape, M. The ubiquitin code. Annu. Rev. Biochem., 2012, 81, 203-229.
[78]
Foley, T.L.; Burkart, M.D. Site-specific protein modification: advances and applications. Curr. Opin. Chem. Biol., 2007, 11(1), 12-19.
[79]
Dempsey, D.R.; Jiang, H.; Kalin, J.H.; Chen, Z.; Cole, P.A. Site-specific protein labeling with NHS-esters and the analysis of ubiquitin ligase mechanisms. J. Am. Chem. Soc., 2018, 140(30), 9374-9378.
[80]
Wang, Z-P.A.; Tian, C-L.; Zheng, J-S. The recent developments and applications of traceless-staudinger reaction in the chemical biology study. RSC Adv, 2015, 5, 107192-107199.
[81]
Lang, K.; Chin, J.W. Bioorthogonal reactions for labeling proteins. ACS Chem. Biol., 2014, 9(1), 16-20.
[82]
Baslé, E.; Joubert, N.; Pucheault, M. Protein chemical modification on endogenous amino acids. Chem. Biol., 2010, 17(3), 213-227.
[83]
Davis, B.G. Mimicking posttranslational modifications of proteins. Science, 2004, 303(5657), 480-482.
[84]
Li, Y.; Yang, M.; Huang, Y.; Song, X.; Liu, L.; Chen, P.R. Genetically encoded alkenyl–pyrrolysine analogues for thiol–ene reaction mediated site-specific protein labeling. Chem. Sci., 2012, 3, 2766-2770.
[85]
Simon, M.D.; Chu, F.; Racki, L.R.; Cecile, C.; Burlingame, A.L.; Panning, B.; Narlikar, G.J.; Shokat, K.M. The site-specific installation of methyl-lysine analogs into recombinant histones. Cell, 2007, 128(5), 1003-1012.
[86]
van Kasteren, S.I.; Kramer, H.B.; Jensen, H.H.; Campbell, S.J.; Kirkpatrick, J.; Oldham, N.J.; Anthony, D.C.; Davis, B.G. Expanding the diversity of chemical protein modification allows post-translational mimicry. Nature, 2007, 446(7139), 1105-1109.
[87]
Li, F.P.; Allahverdi, A.; Yang, R.L.; Lua, G.B.J.; Zhang, X.H.; Cao, Y.; Korolev, N.; Nordenskiold, L.; Liu, C.F. A direct method for site-specific protein acetylation. Angew. Chem. Int. Ed., 2011, 50(41), 9611-9614.
[88]
Bhat, S.; Hwang, Y.; Gibson, M.D.; Morgan, M.T.; Taverna, S.D.; Zhao, Y.; Wolberger, C.; Poirier, M.G.; Cole, P.A. Hydrazide mimics for protein lysine acylation to assess nucleosome dynamics and deubiquitinase action. J. Am. Chem. Soc., 2018, 140(30), 9478-9485.
[89]
Willey, J.M.; van der Donk, W.A. Lantibiotics: Peptides of diverse structure and function. Annu. Rev. Microbiol., 2007, 61, 477-501.
[90]
Bar-Or, R.; Rael, L.T.; Bar-Or, D. Dehydroalanine derived from cysteine is a common post-translational modification in human serum albumin. Rapid Commun. Mass Spectrom., 2008, 22(5), 711-716.
[91]
Hashimoto, K.; Sakai, M.; Okuno, T.; Shirahama, H. beta-phenylseleno-alanine as a dehydroalanine precursor-efficient synthesis of alternariolide (AM-toxin I) (May, pg 1139, 1996). Chem. Commun., 1996, (15), 1849-1849.
[92]
Seebeck, F.P.; Szostak, J.W. Ribosomal synthesis of dehydroalanine-containing peptides. J. Am. Chem. Soc., 2006, 128(22), 7150-7151.
[93]
Okeley, N.M.; Zhu, Y.T.; van der Donk, W.A. Facile chemoselective synthesis of dehydroalanine-containing peptides. Org. Lett., 2000, 2(23), 3603-3606.
[94]
Bernardes, G.J.; Chalker, J.M.; Errey, J.C.; Davis, B.G. Facile conversion of cysteine and alkyl cysteines to dehydroalanine on protein surfaces: versatile and switchable access to functionalized proteins. J. Am. Chem. Soc., 2008, 130(15), 5052-5053.
[95]
Chalker, J.M.; Gunnoo, S.B.; Boutureira, O.; Gerstberger, S.C.; Fernández-González, M.; Bernardes, G.J.; Griffin, L.; Hailu, H.; Schofield, C.J.; Davis, B.G. Methods for converting cysteine to dehydroalanine on peptides and proteins. Chem. Sci., 2011, 2(9), 1666-1676.
[96]
Wang, Z.U.; Wang, Y-S.; Pai, P-J.; Russell, W.K.; Russell, D.H.; Liu, W.R. A facile method to synthesize histones with posttranslational modification mimics. Biochemistry, 2012, 51(26), 5232-5234.
[97]
Yang, A.; Ha, S.; Ahn, J.; Kim, R.; Kim, S.; Lee, Y.; Kim, J.; Söll, D.; Lee, H-Y.; Park, H-S. A chemical biology route to site-specific authentic protein modifications. Science, 2016, 354(6312), 623-626.
[98]
Wright, T.H.; Bower, B.J.; Chalker, J.M.; Bernardes, G.J.; Wiewiora, R.; Ng, W-L.; Raj, R.; Faulkner, S.; Vallée, M.R.J.; Phanumartwiwath, A.; Davis, B.G. Posttranslational mutagenesis: A chemical strategy for exploring protein side-chain diversity. Science, 2016, 354(6312), aag1465.
[99]
Wang, L.; Brock, A.; Herberich, B.; Schultz, P.G. Expanding the genetic code of Escherichia coli. Science, 2001, 292(5516), 498-500.
[100]
Ambrogelly, A.; Gundllapalli, S.; Herring, S.; Polycarpo, C.; Frauer, C.; Söll, D. Pyrrolysine is not hardwired for cotranslational insertion at UAG codons. Proc. Natl. Acad. Sci. USA, 2007, 104(9), 3141-3146.
[101]
Namy, O.; Zhou, Y.; Gundllapalli, S.; Polycarpo, C.R.; Denise, A.; Rousset, J-P.; Söll, D.; Ambrogelly, A. Adding pyrrolysine to the Escherichia coli genetic code. FEBS Lett., 2007, 581(27), 5282-5288.
[102]
Hancock, S.M.; Uprety, R.; Deiters, A.; Chin, J.W. Expanding the genetic code of yeast for incorporation of diverse unnatural amino acids via a pyrrolysyl-tRNA synthetase/tRNA pair. J. Am. Chem. Soc., 2010, 132(42), 14819-14824.
[103]
Mukai, T.; Kobayashi, T.; Hino, N.; Yanagisawa, T.; Sakamoto, K.; Yokoyama, S. Adding l-lysine derivatives to the genetic code of mammalian cells with engineered pyrrolysyl-tRNA synthetases. Biochem. Biophys. Res. Commun., 2008, 371(4), 818-822.
[104]
Greiss, S.; Chin, J.W. Expanding the genetic code of an animal. J. Am. Chem. Soc., 2011, 133(36), 14196-14199.
[105]
Neumann, H.; Peak-Chew, S.Y.; Chin, J.W. Genetically encoding Nε-acetyllysine in recombinant proteins. Nat. Chem. Biol., 2008, 4(4), 232-234.
[106]
Neumann, H.; Hancock, S.M.; Buning, R.; Routh, A.; Chapman, L.; Somers, J.; Owen-Hughes, T.; van Noort, J.; Rhodes, D.; Chin, J.W. A method for genetically installing site-specific acetylation in recombinant histones defines the effects of H3 K56 acetylation. Mol. Cell, 2009, 36(1), 153-163.
[107]
Kim, C.H.; Kang, M.; Kim, H.J.; Chatterjee, A.; Schultz, P.G. Site-specific incorporation of epsilon-N-crotonyllysine into histones. Angew. Chem. Int. Ed., 2012, 51(29), 7246-7249.
[108]
Gattner, M.J.; Vrabel, M.; Carell, T. Synthesis of epsilon-N-propionyl-, epsilon-N-butyryl-, and epsilon-N-crotonyl-lysine containing histone H3 using the pyrrolysine system. Chem. Commun. (Camb.), 2013, 49(4), 379-381.
[109]
Lee, Y-J.; Wu, B.; Raymond, J.E.; Zeng, Y.; Fang, X.; Wooley, K.L.; Liu, W.R. A genetically encoded acrylamide functionality. ACS Chem. Biol., 2013, 8(8), 1664-1670.
[110]
Xiao, H.; Xuan, W.; Shao, S.; Liu, T.; Schultz, P.G. Genetic incorporation of ε-N-2-hydroxyisobutyryl-lysine into recombinant histones. ACS Chem. Biol., 2015, 10(7), 1599-1603.
[111]
Dumas, A.; Lercher, L.; Spicer, C.D.; Davis, B.G. Designing logical codon reassignment–Expanding the chemistry in biology. Chem. Sci., 2015, 6(1), 50-69.
[112]
Rogerson, D.T.; Sachdeva, A.; Wang, K.; Haq, T.; Kazlauskaite, A.; Hancock, S.M.; Huguenin-Dezot, N.; Muqit, M.M.K.; Fry, A.M.; Bayliss, R.; Chin, J.W. Efficient genetic encoding of phosphoserine and its nonhydrolyzable analog. Nat. Chem. Biol., 2015, 11, 496-506.
[113]
Bertozzi, C.R. A decade of bioorthogonal chemistry. Acc. Chem. Res., 2011, 44(9), 651-653.
[114]
Zhang, G.; Zheng, S.; Liu, H.; Chen, P.R. Illuminating biological processes through site-specific protein labeling. Chem. Soc. Rev., 2015, 44, 3405-3417.
[115]
Chin, J.W.; Santoro, S.W.; Martin, A.B.; King, D.S.; Wang, L.; Schultz, P.G. Addition of p-Azido-l-phenylalanine to the Genetic Code of Escherichia coli. J. Am. Chem. Soc., 2002, 124(31), 9026-9027.
[116]
Li, J.; Chen, P.R. Development and application of bond cleavage reactions in bioorthogonal chemistry. Nat. Chem. Biol., 2016, 12(3), 129-137.
[117]
Ai, H.W.; Lee, J.W.; Schultz, P.G. A method to site-specifically introduce methyllysine into proteins in E. coli. Chem. Commun. (Camb.), 2010, 46(30), 5506-5508.
[118]
Wang, Y-S.; Wu, B.; Wang, Z.; Huang, Y.; Wan, W.; Russell, W.K.; Pai, P-J.; Moe, Y.N.; Russell, D.H.; Liu, W.R. A genetically encoded photocaged Nε-methyl-l-lysine. Mol. Biosyst., 2010, 6(9), 1557-1560.
[119]
Gautier, A.; Deiters, A.; Chin, J.W. Light-activated kinases enable temporal dissection of signaling networks in living cells. J. Am. Chem. Soc., 2011, 133(7), 2124-2127.
[120]
Hemphill, J.; Chou, C.; Chin, J.W.; Deiters, A. Genetically encoded light-activated transcription for spatiotemporal control of gene expression and gene silencing in mammalian cells. J. Am. Chem. Soc., 2013, 135, 13433-13439.
[121]
Nguyen, D.P.; Alai, M.M.G.; Virdee, S.; Chin, J.W. Genetically directing ɛ-N, N-dimethyl-l-lysine in recombinant histones. Chem. Biol., 2010, 17(10), 1072-1076.
[122]
Virdee, S.; Ye, Y.; Nguyen, D.P.; Komander, D.; Chin, J.W. Engineered diubiquitin synthesis reveals Lys29-isopeptide specificity of an OTU deubiquitinase. Nat. Chem. Biol., 2010, 6(10), 750-757.
[123]
Zhang, G.; Li, J.; Xie, R.; Fan, X.; Liu, Y.; Zheng, S.; Ge, Y.; Chen, P.R. Bioorthogonal chemical activation of kinases in living systems. ACS Cent. Sci., 2016, 2, 325-331.
[124]
Spicer, C.D.; Davis, B.G. Selective chemical protein modification. Nat. Commun., 2014, 5, 1-14.
[125]
Li, X.; Fekner, T.; Ottesen, J.J.; Chan, M.K. A pyrrolysine analogue for site-specific protein ubiquitination. Angew. Chem. Int. Ed., 2009, 121(48), 9348-9351.
[126]
Nguyen, D.P.; Elliott, T.; Holt, M.; Muir, T.W.; Chin, J.W. Genetically encoded 1, 2-aminothiols facilitate rapid and site-specific protein labeling via a bio-orthogonal cyanobenzothiazole condensation. J. Am. Chem. Soc., 2011, 133(30), 11418-11421.
[127]
Virdee, S.; Kapadnis, P.B.; Elliott, T.; Lang, K.; Madrzak, J.; Nguyen, D.P.; Riechmann, L.; Chin, J.W. Traceless and site-specific ubiquitination of recombinant proteins. J. Am. Chem. Soc., 2011, 133(28), 10708-10711.
[128]
Amamoto, Y.; Aoi, Y.; Nagashima, N.; Suto, H.; Yoshidome, D.; Arimura, Y.; Osakabe, A.; Kato, D.; Kurumizaka, H.; Kawashima, S.A. Synthetic posttranslational modifications: Chemical catalyst-driven regioselective histone acylation of native chromatin. J. Am. Chem. Soc., 2017, 139(22), 7568-7576.
[129]
Chatterjee, C.; McGinty, R.K.; Pellois, J.P.; Muir, T.W. Auxiliary-mediated site-specific peptide ubiquitylation. Angew. Chem. Int. Ed., 2007, 119(16), 2872-2876.
[130]
Weller, C.E.; Huang, W.; Chatterjee, C. Facile synthesis of native and protease-resistant ubiquitylated peptides. ChemBioChem, 2014, 15(9), 1263-1267.
[131]
Weller, C.E.; Dhall, A.; Ding, F.; Linares, E.; Whedon, S.D.; Senger, N.A.; Tyson, E.L.; Bagert, J.D.; Li, X.; Augusto, O.; Chatterjee, C. Aromatic thiol-mediated cleavage of N–O bonds enables chemical ubiquitylation of folded proteins. Nat. Commun., 2016, 7, 12979.
[132]
Wang, Z.A.; Liu, W.R. Proteins with site-specific lysine methylation. Chem. Eur. J., 2017, 23(49), 11732-11737.
[133]
Wang, Z.A.; Zeng, Y.; Kurra, Y.; Wang, X.; Tharp, J.M.; Vatansever, E.C.; Hsu, W.W.; Dai, S.; Fang, X.; Liu, W.R. A Genetically Encoded Allysine for the Synthesis of Proteins with Site-Specific Lysine Dimethylation. Angew. Chem. Int. Ed., 2017, 56(1), 212-216.
[134]
Wang, Z.A.; Kurra, Y.; Wang, X.; Zeng, Y.; Lee, Y-J.; Sharma, V.; Lin, H.; Dai, S.Y.; Liu, W.R. A versatile approach for site-specific lysine acylation in proteins. Angew. Chem. Int. Ed., 2017, 56(6), 1643-1647.
[135]
Ngo, J.T.; Schuman, E.M.; Tirrell, D.A. Mutant methionyl-tRNA synthetase from bacteria enables site-selective N-terminal labeling of proteins expressed in mammalian cells. Proc. Natl. Acad. Sci. USA, 2013, 110(13), 4992-4997.
[136]
Mahdavi, A.; Segall-Shapiro, T.H.; Kou, S.; Jindal, G.A.; Hoff, K.G.; Liu, S.; Chitsaz, M.; Ismagilov, R.F.; Silberg, J.J.; Tirrell, D.A. A genetically encoded AND gate for cell-targeted metabolic labeling of proteins. J. Am. Chem. Soc., 2013, 135(8), 2979-2982.
[137]
Yang, R.; Bi, X.; Li, F.; Cao, Y.; Liu, C-F. Native chemical ubiquitination using a genetically incorporated azidonorleucine. Chem. Commun., 2014, 50(59), 7971-7974.
[138]
Gong, Y.; Pan, L. Recent advances in bioorthogonal reactions for site-specific protein labeling and engineering. Tetrahedron Lett., 2015, 56, 2123-2132.
[139]
Bowman, G.D.; Poirier, M.G. Post-translational modifications of histones that influence nucleosome dynamics. Chem. Rev., 2015, 115(6), 2274.
[140]
Sueoka, T.; Koyama, K.; Hayashi, G.; Okamoto, A. Chemistry-driven epigenetic investigation of histone and DNA modifications. Chem. Rec., 2018, 18(12), 1727-1744.
[141]
Fareghi-Alamdari, R.; Mansouri, F.; Golestanzadeh, M.; Zekri, N. Recent developments in the synthesis of antioxidant derivatives using recoverable and/or nano-catalysts. Curr. Org. Chem., 2018, 22(14), 1373-1419.
[142]
Eftekhari-Sis, B.; Zirak, M. α-Imino esters in organic synthesis: Recent advances. Chem. Rev., 2017, 117(12), 8326-8419.
[143]
Ngo, J.T.; Tirrell, D.A. Noncanonical amino acids in the interrogation of cellular protein synthesis. Acc. Chem. Res., 2011, 44(9), 677-685.
[144]
Lang, K.; Chin, J.W. Cellular incorporation of unnatural amino acids and bioorthogonal labeling of proteins. Chem. Rev., 2014, 114(9), 4764-4806.
[145]
Delgado-Andrade, C. Carboxymethyl-lysine: thirty years of investigation in the field of AGE formation. Food Funct., 2016, 7(1), 46-57.
[146]
Park, M.H. The post-translational synthesis of a polyamine-derived amino acid, hypusine, in the eukaryotic translation initiation factor 5A (eIF5A). J. Biochem., 2006, 139(2), 161-169.
[147]
Lang, K.; Davis, L.; Torres-Kolbus, J.; Chou, C.J.; Deiters, A.; Chin, J.W. Genetically encoded norbornene directs site-specific cellular protein labelling via a rapid bioorthogonal reaction. Nat. Chem., 2012, 4(4), 298-304.
[148]
Mohammadi, O.; Golestanzadeh, M.; Abdouss, M. Recent advances in organic reactions catalyzed by graphene oxide and sulfonated graphene as heterogeneous nanocatalysts: A review. New J. Chem., 2017, 41(20), 11471-11497.
[149]
Murar, C.E.; Thuaud, F.; Bode, J.W. KAHA ligations that form aspartyl aldehyde residues as synthetic handles for protein modification and purification. J. Am. Chem. Soc., 2014, 136(52), 18140-18148.
[150]
Hao, Z.; Hong, S.; Chen, X.; Chen, P.R. Introducing bioorthogonal functionalities into proteins in living cells. Acc. Chem. Res., 2011, 44(9), 742-751.
[151]
Krall, N.; da Cruz, F.P.; Boutureira, O.; Bernardes, G.J.L. Site-selective protein-modification chemistry for basic biology and drug development. Nat. Chem., 2016, 8(2), 102-112.

Rights & Permissions Print Cite
© 2025 Bentham Science Publishers | Privacy Policy
Request history8.2.27PHP Version511msRequest Duration28MBMemory UsageGET article/{article_id}/{param?}Route
  • warninglog[02:57:21] LOG.warning: Optional parameter $article_id declared before required parameter $request i...
  • warninglog[02:57:21] LOG.warning: trim(): Passing null to parameter #1 ($string) of type string is deprecated ...
  • warninglog[02:57:21] LOG.warning: Function strftime() is deprecated in /home/alphaeurekaselec/public_html/stor...
  • Booting (102ms)time
  • Application (409ms)time
  • 1 x Application (80%)
    409ms
    1 x Booting (19.99%)
    102ms
    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 duplicated329ms
    • 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 ('314525270','',1,1739847441,1739847441) ON DUPLICATE KEY UPDATE visitor_count=visitor_count + 1, updated_on=1739847441
      1.07msalphaeurekaselec_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 ('314525270','/article/97657',1,1739847441,1739847441)
      230μsalphaeurekaselec_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 >= 314525270 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314525270) 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 >= 314525270 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314525270) 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 >= 314525270 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314525270) 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 >= 314525270 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314525270) 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 >= 314525270 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314525270) 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 >= 314525270 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314525270) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_trail WHERE to_ip >= 314525270 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314525270) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_corporate WHERE to_ip >= 314525270 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314525270) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_token WHERE to_ip >= 314525270 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314525270) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_trail WHERE to_ip >= 314525270 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314525270) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_corporate WHERE to_ip >= 314525270 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314525270) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_token WHERE to_ip >= 314525270 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314525270) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_trail WHERE to_ip >= 314525270 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314525270) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_corporate WHERE to_ip >= 314525270 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314525270) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_token WHERE to_ip >= 314525270 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314525270) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_disease_corporate WHERE to_ip >= 314525270 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 314525270) limit 1
      14.54msalphaeurekaselec_live_10_06_2022UserAccess.php#784
      Bindings
      • 0: 314525270
      • 1: 314525270
      • 2: 314525270
      • 3: 314525270
      • 4: 314525270
      • 5: 314525270
      • 6: 314525270
      • 7: 314525270
      • 8: 314525270
      • 9: 314525270
      • 10: 314525270
      • 11: 314525270
      • 12: 314525270
      • 13: 314525270
      • 14: 314525270
      • 15: 314525270
      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=97657
      4.11msalphaeurekaselec_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` = 34 limit 1
      1.09msalphaeurekaselec_live_10_06_2022Journal.php#64
      Bindings
      • 0: 34
      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=34) and sj.journal_id!=34 group by `j`.`nid`) as `aggregate_table`
      600μsalphaeurekaselec_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=34) and sj.journal_id!=34 group by `j`.`nid` order by `j`.`journal_id` asc limit 10 offset 0
      530μsalphaeurekaselec_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=34) 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=34) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid` order by `v`.`ebook_volume_id` desc limit 10 offset 0
      1.2msalphaeurekaselec_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` = '97657'
      340μsalphaeurekaselec_live_10_06_2022Keywords.php#43
      Bindings
      • 0: 97657
      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` = '97657'
      6.73msalphaeurekaselec_live_10_06_2022Article.php#1570
      Bindings
      • 0: 97657
      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` = '97657' group by `au`.`author_id` order by `au`.`article_id` asc, `au`.`sequence` asc
      950μsalphaeurekaselec_live_10_06_2022Author.php#86
      Bindings
      • 0: 97657
      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
      370μsalphaeurekaselec_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
      720μsalphaeurekaselec_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 = 34 and i.is_uploaded = 1 order by v.volume_name+0 desc, i.title+0 desc limit 1
      32.25msalphaeurekaselec_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 = 34 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      161msalphaeurekaselec_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 = 34 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      69.41msalphaeurekaselec_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` = 97657 limit 1
      330μsalphaeurekaselec_live_10_06_2022Article.php#744
      Bindings
      • 0: 97657
      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 = 97657 and content_type = 'article' order by status desc limit 1
      360μsalphaeurekaselec_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` = 171115 limit 1
      250μsalphaeurekaselec_live_10_06_2022Meta.php#30
      Bindings
      • 0: 171115
      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
      270μsalphaeurekaselec_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` = 'COS' and (h.proposal_closing_date = 0 OR TO_DAYS(FROM_UNIXTIME(h.proposal_closing_date)) >= TO_DAYS(NOW())) order by `h`.`manuscript` asc
      370μsalphaeurekaselec_live_10_06_2022Article.php#2025
      Bindings
      • 0: COS
      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 = '97657' 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) )
      430μsalphaeurekaselec_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 = '9148' 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) )
      390μsalphaeurekaselec_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 = '2584' 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) )
      380μsalphaeurekaselec_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 <= 314525270 and j.to_ip >=314525270 )) and ((j.from_date <= 1739847441 and j.to_date >= 1739847441 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2584) 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 <= 314525270 and j.to_ip >=314525270 )) and ((j.from_date <= 1739847441 and j.to_date >= 1739847441 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2584) 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 <= 314525270 and j.to_ip >=314525270 )) and ((j.from_date <= 1739847441 and j.to_date >= 1739847441 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2584)
      11.64msalphaeurekaselec_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 <= 314525270 and j.to_ip >=314525270 )) and ((j.from_date <= 1739847441 and j.to_date >= 1739847441 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 9148) 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 <= 314525270 and j.to_ip >=314525270 )) and ((j.from_date <= 1739847441 and j.to_date >= 1739847441 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 9148) 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 <= 314525270 and j.to_ip >=314525270 )) and ((j.from_date <= 1739847441 and j.to_date >= 1739847441 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 9148)
      790μsalphaeurekaselec_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 <= 314525270 and j.to_ip >=314525270 )) and ((j.from_date <= 1739847441 and j.to_date >= 1739847441 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 97657) 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 <= 314525270 and j.to_ip >=314525270 )) and ((j.from_date <= 1739847441 and j.to_date >= 1739847441 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 97657) 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 <= 314525270 and j.to_ip >=314525270 )) and ((j.from_date <= 1739847441 and j.to_date >= 1739847441 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 97657)
      760μsalphaeurekaselec_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` < '369' and is_uploaded = 1 and issue_id = 9148 order by cast(first_page as SIGNED) desc limit 1
      700μsalphaeurekaselec_live_10_06_2022Article.php#1819
      Bindings
      • 0: 369
      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` > '384' and is_uploaded = 1 and issue_id = 9148 order by cast(first_page as SIGNED) asc limit 1
      600μsalphaeurekaselec_live_10_06_2022Article.php#1831
      Bindings
      • 0: 384
      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'
      260μsalphaeurekaselec_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
      280μsalphaeurekaselec_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` = 97657 limit 1
      4.03msalphaeurekaselec_live_10_06_2022ArticleController.php#2506
      Bindings
      • 0: 97657
      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` = 34 and `b`.`banner_from_date` <= 1739847441 and `b`.`banner_to_date` >= 1739847441 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.37msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 34
      • 3: 1739847441
      • 4: 1739847441
      • 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` = 34 and `b`.`banner_from_date` <= 1739847441 and `b`.`banner_to_date` >= 1739847441 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.21msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 34
      • 3: 1739847441
      • 4: 1739847441
      • 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='a0aa7393f85359cbd34916ce5269e1cc'
      250μsalphaeurekaselec_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
        TN3HtrvrI7xGGKPW7iMplJ0hZHNFnocsigB3sCtY
        uc_cart_id
        a0aa7393f85359cbd34916ce5269e1cc
        _previous
        array:1 [ "url" => "http://alpha.eurekaselect.com/article/97657" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /article/97657
        status_code
        200
        
        status_text
        OK
        format
        html
        content_type
        text/html; charset=UTF-8
        request_query
        []
        
        request_request
        []
        
        request_headers
        0 of 0
        array:9 [ "cookie" => array:1 [ 0 => "wayfindertarget=eyJpdiI6Ik5VZ205VkdmbmRmdkVCUTNwN0s3V2c9PSIsInZhbHVlIjoiRjJQMUc1T1R0dHAvUUdLTXQ5NFppcmxnbUZlcUdqajk5Z0ZuWkFEOHMyYz0iLCJtYWMiOiJlMjZiNDEyMDViOGIxOTI5ODFhNDIyZjViMWJjY2RiZmVhZWY4YTc5ZjI5YWFmYmRkMjMzZjNmZTcwYWM3OTYwIiwidGFnIjoiIn0%3Dwayfindertarget=eyJpdiI6Ik5VZ205VkdmbmRmdkVCUTNwN0s3V2c9PSIsInZhbHVlIjoiRjJQMUc1T1R0dHAvUUdLTXQ5NFppcmxnbUZlcUdqajk5Z0ZuWkFEOHMyYz0iLCJtYWMiOiJlMjZiNDEyMDViOGIx" ] "accept-encoding" => array:1 [ 0 => "gzip, deflate" ] "accept" => array:1 [ 0 => "text/html,application/xhtml+xml,application/xml;q=0.9,image/avif,image/webp,image/apng,*/*;q=0.8,application/signed-exchange;v=b3;q=0.7" ] "user-agent" => array:1 [ 0 => "Mozilla/5.0 AppleWebKit/537.36 (KHTML, like Gecko; compatible; ClaudeBot/1.0; +claudebot@anthropic.com)" ] "upgrade-insecure-requests" => array:1 [ 0 => "1" ] "cache-control" => array:1 [ 0 => "no-cache" ] "pragma" => array:1 [ 0 => "no-cache" ] "connection" => array:1 [ 0 => "keep-alive" ] "host" => array:1 [ 0 => "alpha.eurekaselect.com" ] ]
        request_cookies
        0 of 0
        array:1 [ "wayfindertarget" => null ]
        response_headers
        0 of 0
        array:5 [ "content-type" => array:1 [ 0 => "text/html; charset=UTF-8" ] "cache-control" => array:1 [ 0 => "no-cache, private" ] "date" => array:1 [ 0 => "Tue, 18 Feb 2025 02:57:21 GMT" ] "set-cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6InBNL2s3cUFIbmdydzNJMHdoT3Q5Wnc9PSIsInZhbHVlIjoiM29VTGllMzZ1Nitqb3RFMXRBMTZhMmI1ZXUxdzZCQmNCcFZrQXRrVWQ2MDFVcU5iMmcvZ1VDaHcrWGpvbUVWNmE2eEFpQmVFdTBja3BOTGh0NGp1TWI3SkxtOWpjeTlBR01XaVp6bVk1b29pZy9BakhWbUgxL2MzN082TiszQVMiLCJtYWMiOiI4YzllMmUwYjk3ZGQ2YzJlMzVjOTNhZTU4YTgxOTAwMTdlNGQ0YzEyYmRiOGQxNTIxZTUyYzY5MGNlODM3ZDlmIiwidGFnIjoiIn0%3D; expires=Thu, 20 Feb 2025 14:57:21 GMT; Max-Age=216000; path=/; secure; samesite=laxXSRF-TOKEN=eyJpdiI6InBNL2s3cUFIbmdydzNJMHdoT3Q5Wnc9PSIsInZhbHVlIjoiM29VTGllMzZ1Nitqb3RFMXRBMTZhMmI1ZXUxdzZCQmNCcFZrQXRrVWQ2MDFVcU5iMmcvZ1VDaHcrWGpvbUVWNmE2eEFpQ" 1 => "alphaeurekaselectnet_session=eyJpdiI6IlFBaWdzTnVBYUo3TW5pTnBNMWpuQ3c9PSIsInZhbHVlIjoialdjY2IySmx4ODh4SlppM3JWOVIxazNscCs4WkZhYzluL2VwRkoxZnFGUWxmTlZuREo2aU01YytBWDhvaUZZK2U5b2N4a0pwUVNoUTZWUFk3SHJKTW5oejBGRCs1U1dnUC9zN0hmcGluMTM0QUFxVmR6MC9YUEJDMXNNK2JqbXciLCJtYWMiOiJkNzk1ZDdmZGE0YmI1NWUyMWVkYWYxOThhODljM2U3MDFhYWMwNGRlMmMwYjJlYTgzZmJiMWJmNDE0MmZiY2JjIiwidGFnIjoiIn0%3D; path=/; secure; httponly; samesite=laxalphaeurekaselectnet_session=eyJpdiI6IlFBaWdzTnVBYUo3TW5pTnBNMWpuQ3c9PSIsInZhbHVlIjoialdjY2IySmx4ODh4SlppM3JWOVIxazNscCs4WkZhYzluL2VwRkoxZnFGUWxmTlZuREo2aU01Yyt" ] "Set-Cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6InBNL2s3cUFIbmdydzNJMHdoT3Q5Wnc9PSIsInZhbHVlIjoiM29VTGllMzZ1Nitqb3RFMXRBMTZhMmI1ZXUxdzZCQmNCcFZrQXRrVWQ2MDFVcU5iMmcvZ1VDaHcrWGpvbUVWNmE2eEFpQmVFdTBja3BOTGh0NGp1TWI3SkxtOWpjeTlBR01XaVp6bVk1b29pZy9BakhWbUgxL2MzN082TiszQVMiLCJtYWMiOiI4YzllMmUwYjk3ZGQ2YzJlMzVjOTNhZTU4YTgxOTAwMTdlNGQ0YzEyYmRiOGQxNTIxZTUyYzY5MGNlODM3ZDlmIiwidGFnIjoiIn0%3D; expires=Thu, 20-Feb-2025 14:57:21 GMT; path=/; secureXSRF-TOKEN=eyJpdiI6InBNL2s3cUFIbmdydzNJMHdoT3Q5Wnc9PSIsInZhbHVlIjoiM29VTGllMzZ1Nitqb3RFMXRBMTZhMmI1ZXUxdzZCQmNCcFZrQXRrVWQ2MDFVcU5iMmcvZ1VDaHcrWGpvbUVWNmE2eEFpQ" 1 => "alphaeurekaselectnet_session=eyJpdiI6IlFBaWdzTnVBYUo3TW5pTnBNMWpuQ3c9PSIsInZhbHVlIjoialdjY2IySmx4ODh4SlppM3JWOVIxazNscCs4WkZhYzluL2VwRkoxZnFGUWxmTlZuREo2aU01YytBWDhvaUZZK2U5b2N4a0pwUVNoUTZWUFk3SHJKTW5oejBGRCs1U1dnUC9zN0hmcGluMTM0QUFxVmR6MC9YUEJDMXNNK2JqbXciLCJtYWMiOiJkNzk1ZDdmZGE0YmI1NWUyMWVkYWYxOThhODljM2U3MDFhYWMwNGRlMmMwYjJlYTgzZmJiMWJmNDE0MmZiY2JjIiwidGFnIjoiIn0%3D; path=/; secure; httponlyalphaeurekaselectnet_session=eyJpdiI6IlFBaWdzTnVBYUo3TW5pTnBNMWpuQ3c9PSIsInZhbHVlIjoialdjY2IySmx4ODh4SlppM3JWOVIxazNscCs4WkZhYzluL2VwRkoxZnFGUWxmTlZuREo2aU01Yyt" ] ]
        session_attributes
        0 of 0
        array:5 [ "_token" => "TN3HtrvrI7xGGKPW7iMplJ0hZHNFnocsigB3sCtY" "uc_cart_id" => "a0aa7393f85359cbd34916ce5269e1cc" "_previous" => array:1 [ "url" => "http://alpha.eurekaselect.com/article/97657" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-18 02:57:21GET/article/97657314361