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Combinatorial Chemistry & High Throughput Screening

Editor-in-Chief

ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

Research Article

In Silico Drug Target Discovery Through Proteome Mining from M. tuberculosis: An Insight into Antivirulent Therapy

Author(s): Shreya Bhattacharya, Puja Ghosh, Debasmita Banerjee, Arundhati Banerjee and Sujay Ray*

Volume 23, Issue 3, 2020

Page: [253 - 268] Pages: 16

DOI: 10.2174/1386207323666200219120903

Price: $65

Abstract

Aim and Objective: One of the challenges to conventional therapies against Mycobacterium tuberculosis is the development of multi-drug resistant pathogenic strains. This study was undertaken to explore new therapeutic targets for the revolutionary antivirulence therapy utilizing the pathogen’s essential hypothetical proteins, serving as virulence factors, which is the essential first step in novel drug designing.

Methods: Functional annotations of essential hypothetical proteins from Mycobacterium tuberculosis (H37Rv strain) were performed through domain annotation, Gene Ontology analysis, physicochemical characterization and prediction of subcellular localization. Virulence factors among the essential hypothetical proteins were predicted, among which pathogen-specific drug target candidates, non-homologous to human and gut microbiota, were identified. This was followed by druggability and spectrum analysis of the identified targets.

Results and Conclusion: The study successfully assigned functions of 83 essential hypothetical proteins of Mycobacterium tuberculosis, among which 25 were identified as virulence factors. Out of 25, 12 virulence factors were observed as potential pathogen-specific drug target candidates. Nine potential targets had druggable properties and rest three were considered as novel targets. Exploration of these targets will provide new insights into future drug development. Characterization of subcellular localizations revealed that most of the predicted targets were cytoplasmic which could be ideal for intracellular drugs, while two drug targets were membranebound, ideal for vaccines. Spectrum analysis identified one broad-spectrum and 11 narrowspectrum targets. This study would, therefore, instigate designing novel therapeutics for antivirulence therapy, which have the potential to serve as revolutionary treatment instead of conventional antibiotic therapies to overcome the lethality of antibiotic-resistant strains.

Keywords: Mycobacterium tuberculosis, essential hypothetical proteins, domain characterization, gene ontology, subcellular localization prediction, therapeutic target identification, druggability analysis, spectrum analysis.

« Previous
[1]
Gordon, S.V.; Parish, T. Microbe Profile: Mycobacterium tuberculosis: Humanity’s deadly microbial foe. Microbiology, 2018, 164(4), 437-439.
[http://dx.doi.org/10.1099/mic.0.000601] [PMID: 29465344]
[2]
Dye, C. Global epidemiology of tuberculosis. Lancet, 2006, 367(9514), 938-940.
[http://dx.doi.org/10.1016/S0140-6736(06)68384-0] [PMID: 16546542]
[3]
Global tuberculosis report. 2018.https://www.who.int/tb/publications/global_report/en/ [accessed May 16, 2019]
[4]
Almeida Da Silva, P.E.; Palomino, J.C. Molecular basis and mechanisms of drug resistance in Mycobacterium tuberculosis: classical and new drugs. J. Antimicrob. Chemother., 2011, 66(7), 1417-1430.
[http://dx.doi.org/10.1093/jac/dkr173] [PMID: 21558086]
[5]
Pinto, L.; Menzies, D. Treatment of drug-resistant tuberculosis. Infect. Drug Resist., 2011, 4, 129-135.
[PMID: 21904458]
[6]
What is multidrug-resistant tuberculosis (MDR-TB) and how do we control it? Available at . https://www.who.int/features/qa/79/en/ (accessed on May 16, 2019).
[7]
Goldman, R.C.; Plumley, K.V.; Laughon, B.E. The evolution of extensively drug resistant tuberculosis (XDR-TB): history, status and issues for global control. Infect. Disord. Drug Targets, 2007, 7(2), 73-91.
[http://dx.doi.org/10.2174/187152607781001844] [PMID: 17970220]
[8]
Velayati, A.A.; Masjedi, M.R.; Farnia, P.; Tabarsi, P.; Ghanavi, J.; ZiaZarifi, A.H.; Hoffner, S.E. Emergence of new forms of totally drug-resistant tuberculosis bacilli: super extensively drug-resistant tuberculosis or totally drug-resistant strains in iran. Chest, 2009, 136(2), 420-425.
[http://dx.doi.org/10.1378/chest.08-2427] [PMID: 19349380]
[9]
Bakheet, T.M.; Doig, A.J. Properties and identification of human protein drug targets. Bioinformatics, 2009, 25(4), 451-457.
[http://dx.doi.org/10.1093/bioinformatics/btp002] [PMID: 19164304]
[10]
Gazi, M.A.; Kibria, M.G.; Mahfuz, M.; Islam, M.R.; Ghosh, P.; Afsar, M.N.A.; Khan, M.A.; Ahmed, T. Functional, structural and epitopic prediction of hypothetical proteins of Mycobacterium tuberculosis H37Rv: An in silico approach for prioritizing the targets. Gene, 2016, 591(2), 442-455.
[http://dx.doi.org/10.1016/j.gene.2016.06.057] [PMID: 27374154]
[11]
Bifani, P.; Moghazeh, S.; Shopsin, B.; Driscoll, J.; Ravikovitch, A.; Kreiswirth, B.N. Molecular characterization of Mycobacterium tuberculosis H37Rv/Ra variants: distinguishing the mycobacterial laboratory strain. J. Clin. Microbiol., 2000, 38(9), 3200-3204.
[http://dx.doi.org/10.1128/JCM.38.9.3200-3204.2000] [PMID: 10970357]
[12]
Cole, S.T.; Brosch, R.; Parkhill, J.; Garnier, T.; Churcher, C.; Harris, D.; Gordon, S.V.; Eiglmeier, K.; Gas, S.; Barry, C.E., III; Tekaia, F.; Badcock, K.; Basham, D.; Brown, D.; Chillingworth, T.; Connor, R.; Davies, R.; Devlin, K.; Feltwell, T.; Gentles, S.; Hamlin, N.; Holroyd, S.; Hornsby, T.; Jagels, K.; Krogh, A.; McLean, J.; Moule, S.; Murphy, L.; Oliver, K.; Osborne, J.; Quail, M.A.; Rajandream, M-A.; Rogers, J.; Rutter, S.; Seeger, K.; Skelton, J.; Squares, R.; Squares, S.; Sulston, J.E.; Taylor, K.; Whitehead, S.; Barrell, B.G. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature, 1998, 393(6685), 537-544.
[http://dx.doi.org/10.1038/31159] [PMID: 9634230]
[13]
Luo, H.; Lin, Y.; Gao, F.; Zhang, C.T.; Zhang, R. DEG 10, an update of the database of essential genes that includes both protein-coding genes and noncoding genomic elements. Nucleic Acids Res., 2014, 42(Database issue), D574-D580.
[http://dx.doi.org/10.1093/nar/gkt1131] [PMID: 24243843]
[14]
Shahbaaz, M.; Bisetty, K.; Ahmad, F.; Hassan, M.I. Current Advances in the Identification and Characterization of Putative Drug and Vaccine Targets in the Bacterial Genomes. Curr. Top. Med. Chem., 2016, 16(9), 1040-1069.
[http://dx.doi.org/10.2174/1568026615666150825143307] [PMID: 26303422]
[15]
Cegelski, L.; Marshall, G.R.; Eldridge, G.R.; Hultgren, S.J. The biology and future prospects of antivirulence therapies. Nat. Rev. Microbiol., 2008, 6(1), 17-27.
[http://dx.doi.org/10.1038/nrmicro1818] [PMID: 18079741]
[16]
Garland, M.; Loscher, S.; Bogyo, M. Chemical Strategies To Target Bacterial Virulence. Chem. Rev., 2017, 117(5), 4422-4461.
[http://dx.doi.org/10.1021/acs.chemrev.6b00676] [PMID: 28234447]
[17]
Imperi, F.; Massai, F.; Facchini, M.; Frangipani, E.; Visaggio, D.; Leoni, L.; Bragonzi, A.; Visca, P. Repurposing the antimycotic drug flucytosine for suppression of Pseudomonas aeruginosa pathogenicity. Proc. Natl. Acad. Sci. USA, 2013, 110(18), 7458-7463.
[http://dx.doi.org/10.1073/pnas.1222706110] [PMID: 23569238]
[18]
Branden, C.; Tooze, J. Introduction to Protein Structure; Garland: New York, 1998.
[19]
Finn, R.D.; Coggill, P.; Eberhardt, R.Y.; Eddy, S.R.; Mistry, J.; Mitchell, A.L.; Potter, S.C.; Punta, M.; Qureshi, M.; Sangrador-Vegas, A.; Salazar, G.A.; Tate, J.; Bateman, A. The Pfam protein families database: towards a more sustainable future. Nucleic Acids Res., 2016, 44(D1), D279-D285.
[http://dx.doi.org/10.1093/nar/gkv1344] [PMID: 26673716]
[20]
Mitchell, A.L.; Attwood, T.K.; Babbitt, P.C.; Blum, M.; Bork, P.; Bridge, A.; Brown, S.D.; Chang, H-Y.; El-Gebali, S.; Fraser, M.I.; Gough, J.; Haft, D.R.; Huang, H.; Letunic, I.; Lopez, R.; Luciani, A.; Madeira, F.; Marchler-Bauer, A.; Mi, H.; Natale, D.A.; Necci, M.; Nuka, G.; Orengo, C.; Pandurangan, A.P.; Paysan-Lafosse, T.; Pesseat, S.; Potter, S.C.; Qureshi, M.A.; Rawlings, N.D.; Redaschi, N.; Richardson, L.J.; Rivoire, C.; Salazar, G.A.; Sangrador-Vegas, A.; Sigrist, C.J.A.; Sillitoe, I.; Sutton, G.G.; Thanki, N.; Thomas, P.D.; Tosatto, S.C.E.; Yong, S-Y.; Finn, R.D. InterPro in 2019: improving coverage, classification and access to protein sequence annotations. Nucleic Acids Res., 2019, 47(D1), D351-D360.
[http://dx.doi.org/10.1093/nar/gky1100] [PMID: 30398656]
[21]
Koskinen, P.; Törönen, P.; Nokso-Koivisto, J.; Holm, L. PANNZER: high-throughput functional annotation of uncharacterized proteins in an error-prone environment. Bioinformatics, 2015, 31(10), 1544-1552.
[http://dx.doi.org/10.1093/bioinformatics/btu851] [PMID: 25653249]
[22]
Schomburg, I.; Chang, A.; Schomburg, D. BRENDA, enzyme data and metabolic information. Nucleic Acids Res., 2002, 30(1), 47-49.
[http://dx.doi.org/10.1093/nar/30.1.47] [PMID: 11752250]
[23]
Gasteiger, E.; Hoogland, C.; Gattiker, A.; Duvaud, S.; Wilkins, M.R.; Appel, R.D.; Bairoch, A. Protein Identification and Analysis Tools on the ExPASy Server. In: The Proteomics Protocols Handbook; Humana Press, 2005; pp. 571-607.
[http://dx.doi.org/10.1385/1-59259-890-0:571]
[24]
Kyte, J.; Doolittle, R.F. A simple method for displaying the hydropathic character of a protein. J. Mol. Biol., 1982, 157(1), 105-132.
[http://dx.doi.org/10.1016/0022-2836(82)90515-0] [PMID: 7108955]
[25]
Yu, N.Y.; Wagner, J.R.; Laird, M.R.; Melli, G.; Rey, S.; Lo, R.; Dao, P.; Sahinalp, S.C.; Ester, M.; Foster, L.J.; Brinkman, F.S.L. PSORTb 3.0: improved protein subcellular localization prediction with refined localization subcategories and predictive capabilities for all prokaryotes. Bioinformatics, 2010, 26(13), 1608-1615.
[http://dx.doi.org/10.1093/bioinformatics/btq249] [PMID: 20472543]
[26]
Hirokawa, T.; Boon-Chieng, S.; Mitaku, S. SOSUI: classification and secondary structure prediction system for membrane proteins. Bioinformatics, 1998, 14(4), 378-379.
[http://dx.doi.org/10.1093/bioinformatics/14.4.378] [PMID: 9632836]
[27]
Garg, A.; Gupta, D. VirulentPred: a SVM based prediction method for virulent proteins in bacterial pathogens. BMC Bioinformatics, 2008, 9, 62.
[http://dx.doi.org/10.1186/1471-2105-9-62] [PMID: 18226234]
[28]
Altschul, S.F.; Gish, W.; Miller, W.; Myers, E.W.; Lipman, D.J. Basic local alignment search tool. J. Mol. Biol., 1990, 215(3), 403-410.
[http://dx.doi.org/10.1016/S0022-2836(05)80360-2] [PMID: 2231712]
[29]
Lin, L.; Zhang, J. Role of intestinal microbiota and metabolites on gut homeostasis and human diseases. BMC Immunol., 2017, 18(1), 2.
[http://dx.doi.org/10.1186/s12865-016-0187-3] [PMID: 28061847]
[30]
Shende, G.; Haldankar, H.; Barai, R.S.; Bharmal, M.H.; Shetty, V.; Idicula-Thomas, S. PBIT: Pipeline Builder for Identification of drug Targets for infectious diseases. Bioinformatics, 2017, 33(6), 929-931.
[PMID: 28039165]
[31]
Bento, A.P.; Gaulton, A.; Hersey, A.; Bellis, L.J.; Chambers, J.; Davies, M.; Krüger, F.A.; Light, Y.; Mak, L.; McGlinchey, S.; Nowotka, M.; Papadatos, G.; Santos, R.; Overington, J.P. The ChEMBL bioactivity database: an update. Nucleic Acids Res., 2014, 42(Database issue), D1083-D1090.
[http://dx.doi.org/10.1093/nar/gkt1031] [PMID: 24214965]
[32]
Crowther, G.J.; Shanmugam, D.; Carmona, S.J.; Doyle, M.A.; Hertz-Fowler, C.; Berriman, M.; Nwaka, S.; Ralph, S.A.; Roos, D.S.; Van Voorhis, W.C.; Agüero, F. Identification of attractive drug targets in neglected-disease pathogens using an in silico approach. PLoS Negl. Trop. Dis., 2010, 4(8) e804
[http://dx.doi.org/10.1371/journal.pntd.0000804] [PMID: 20808766]
[33]
McGuffin, L.J.; Bryson, K.; Jones, D.T. The PSIPRED protein structure prediction server. Bioinformatics, 2000, 16(4), 404-405.
[http://dx.doi.org/10.1093/bioinformatics/16.4.404] [PMID: 10869041]
[34]
Erzberger, J.P.; Berger, J.M. Evolutionary relationships and structural mechanisms of AAA+ proteins. Annu. Rev. Biophys. Biomol. Struct., 2006, 35, 93-114.
[http://dx.doi.org/10.1146/annurev.biophys.35.040405.101933] [PMID: 16689629]
[35]
Blackwood, J.K.; Rzechorzek, N.J.; Abrams, A.S.; Maman, J.D.; Pellegrini, L.; Robinson, N.P. Structural and functional insights into DNA-end processing by the archaeal HerA helicase-NurA nuclease complex. Nucleic Acids Res., 2012, 40(7), 3183-3196.
[http://dx.doi.org/10.1093/nar/gkr1157] [PMID: 22135300]
[36]
Brennan, R.G. The winged-helix DNA-binding motif: another helix-turn-helix takeoff. Cell, 1993, 74(5), 773-776.
[http://dx.doi.org/10.1016/0092-8674(93)90456-Z] [PMID: 8374950]
[37]
Kang, C-M.; Nyayapathy, S.; Lee, J-Y.; Suh, J-W.; Husson, R.N. Wag31, a homologue of the cell division protein DivIVA, regulates growth, morphology and polar cell wall synthesis in mycobacteria. Microbiology, 2008, 154(Pt 3), 725-735.
[http://dx.doi.org/10.1099/mic.0.2007/014076-0] [PMID: 18310019]
[38]
Korotkova, N.; Freire, D.; Phan, T.H.; Ummels, R.; Creekmore, C.C.; Evans, T.J.; Wilmanns, M.; Bitter, W.; Parret, A.H.A.; Houben, E.N.G.; Korotkov, K.V. Structure of the Mycobacterium tuberculosis type VII secretion system chaperone EspG5 in complex with PE25-PPE41 dimer. Mol. Microbiol., 2014, 94(2), 367-382.
[http://dx.doi.org/10.1111/mmi.12770] [PMID: 25155747]
[39]
Deochand, D.K.; Grove, A.; Mar, R. MarR family transcription factors: dynamic variations on a common scaffold. Crit. Rev. Biochem. Mol. Biol., 2017, 52(6), 595-613.
[http://dx.doi.org/10.1080/10409238.2017.1344612] [PMID: 28670937]
[40]
Serafini, A.; Pisu, D.; Palù, G.; Rodriguez, G.M.; Manganelli, R. The ESX-3 secretion system is necessary for iron and zinc homeostasis in Mycobacterium tuberculosis. PLoS One, 2013, 8(10) e78351
[http://dx.doi.org/10.1371/journal.pone.0078351] [PMID: 24155985]
[41]
Chevalier, B.S.; Stoddard, B.L. Homing endonucleases: structural and functional insight into the catalysts of intron/intein mobility. Nucleic Acids Res., 2001, 29(18), 3757-3774.
[http://dx.doi.org/10.1093/nar/29.18.3757] [PMID: 11557808]
[42]
Wei, W.; Zhang, S.; Fleming, J.; Chen, Y.; Li, Z.; Fan, S.; Liu, Y.; Wang, W.; Wang, T.; Liu, Y.; Ren, B.; Wang, M.; Jiao, J.; Chen, Y.; Zhou, Y.; Zhou, Y.; Gu, S.; Zhang, X.; Wan, L.; Chen, T.; Zhou, L.; Chen, Y.; Zhang, X-E.; Li, C.; Zhang, H.; Bi, L. Mycobacterium tuberculosis type III-A CRISPR/Cas system crRNA and its maturation have atypical features. FASEB J., 2019, 33(1), 1496-1509.
[http://dx.doi.org/10.1096/fj.201800557RR] [PMID: 29979631]
[43]
Keasling, J.D.; Bertsch, L.; Kornberg, A. Guanosine pentaphosphate phosphohydrolase of Escherichia coli is a long-chain exopolyphosphatase. Proc. Natl. Acad. Sci. USA, 1993, 90(15), 7029-7033.
[http://dx.doi.org/10.1073/pnas.90.15.7029] [PMID: 8394006]
[44]
Miallau, L.; Faller, M.; Chiang, J.; Arbing, M.; Guo, F.; Cascio, D.; Eisenberg, D. Structure and proposed activity of a member of the VapBC family of toxin-antitoxin systems. VapBC-5 from Mycobacterium tuberculosis. J. Biol. Chem., 2009, 284(1), 276-283.
[http://dx.doi.org/10.1074/jbc.M805061200] [PMID: 18952600]
[45]
Akoh, C.C.; Lee, G-C.; Liaw, Y.C.; Huang, T.H.; Shaw, J-F. GDSL family of serine esterases/lipases. Prog. Lipid Res., 2004, 43(6), 534-552.
[http://dx.doi.org/10.1016/j.plipres.2004.09.002] [PMID: 15522763]
[46]
Choe, L.H.; Chen, W.; Lee, K.H. Proteome analysis of factor for inversion stimulation (Fis) overproduction in Escherichia coli. Electrophoresis, 1999, 20(4-5), 798-805.
[http://dx.doi.org/10.1002/(SICI)1522-2683(19990101)20:4/5<798:AID-ELPS798>3.0.CO;2-F] [PMID: 10344250]
[47]
Marrakchi, H.; Zhang, Y-M.; Rock, C.O. Mechanistic diversity and regulation of Type II fatty acid synthesis. Biochem. Soc. Trans., 2002, 30(Pt 6), 1050-1055.
[http://dx.doi.org/10.1042/bst0301050] [PMID: 12440970]
[48]
Pearce, M.J.; Mintseris, J.; Ferreyra, J.; Gygi, S.P.; Darwin, K.H. Ubiquitin-like protein involved in the proteasome pathway of Mycobacterium tuberculosis. Science, 2008, 322(5904), 1104-1107.
[http://dx.doi.org/10.1126/science.1163885] [PMID: 18832610]
[49]
Hamma, T.; Ferré-D’Amaré, A.R. Pseudouridine synthases. Chem. Biol., 2006, 13(11), 1125-1135.
[http://dx.doi.org/10.1016/j.chembiol.2006.09.009] [PMID: 17113994]
[50]
Scopes, R.K. Protein Purification: Principles and Practice; Springer-Verlag New York, 1982.
[51]
Marra, A. Can virulence factors be viable antibacterial targets? Expert Rev. Anti Infect. Ther., 2004, 2(1), 61-72.
[http://dx.doi.org/10.1586/14787210.2.1.61] [PMID: 15482172]
[52]
Bieler, S.; Soto, C. β-sheet breakers for Alzheimer’s disease therapy. Curr. Drug Targets, 2004, 5(6), 553-558.
[http://dx.doi.org/10.2174/1389450043345290] [PMID: 15270201]
[53]
Rivas, A.; Vidal, R.L.; Hetz, C. Targeting the unfolded protein response for disease intervention. Expert Opin. Ther. Targets, 2015, 19(9), 1203-1218.
[http://dx.doi.org/10.1517/14728222.2015.1053869] [PMID: 26166159]
[54]
Kremer, L.; Gurcha, S.S.; Bifani, P.; Hitchen, P.G.; Baulard, A.; Morris, H.R.; Dell, A.; Brennan, P.J.; Besra, G.S. Characterization of a putative α-mannosyltransferase involved in phosphatidylinositol trimannoside biosynthesis in Mycobacterium tuberculosis. Biochem. J., 2002, 363(Pt 3), 437-447.
[http://dx.doi.org/10.1042/bj3630437] [PMID: 11964144]
[55]
Jankute, M.; Cox, J.A.; Harrison, J.; Besra, G.S. Assembly of the mycobacterial cell wall. Annu. Rev. Microbiol., 2015, 69, 405-423.
[http://dx.doi.org/10.1146/annurev-micro-091014-104121] [PMID: 26488279]
[56]
Lea-Smith, D.J.; Martin, K.L.; Pyke, J.S.; Tull, D.; McConville, M.J.; Coppel, R.L.; Crellin, P.K. Analysis of a new mannosyltransferase required for the synthesis of phosphatidylinositol mannosides and lipoarbinomannan reveals two lipomannan pools in corynebacterineae. J. Biol. Chem., 2008, 283(11), 6773-6782.
[http://dx.doi.org/10.1074/jbc.M707139200] [PMID: 18178556]
[57]
Melander, R.J.; Melander, C. The challenge of overcoming antibiotic resistance: an adjuvant approach? ACS Infect. Dis., 2017, 3(8), 559-563.
[http://dx.doi.org/10.1021/acsinfecdis.7b00071] [PMID: 28548487]
[58]
Phan, T.H.; van Leeuwen, L.M.; Kuijl, C.; Ummels, R.; van Stempvoort, G.; Rubio-Canalejas, A.; Piersma, S.R.; Jiménez, C.R.; van der Sar, A.M.; Houben, E.N.G.; Bitter, W.; Esp, H. EspH is a hypervirulence factor for Mycobacterium marinum and essential for the secretion of the ESX-1 substrates EspE and EspF. PLoS Pathog., 2018, 14(8) e1007247
[http://dx.doi.org/10.1371/journal.ppat.1007247] [PMID: 30102741]
[59]
Abbehausen, C. Zinc finger domains as therapeutic targets for metal-based compounds - an update. Metallomics, 2019, 11(1), 15-28.
[http://dx.doi.org/10.1039/C8MT00262B] [PMID: 30303505]
[60]
Masamba, P.; Adenowo, A.F.; Oyinloye, B.E.; Kappo, A.P. Universal stress proteins as new targets for environmental and therapeutic interventions of schistosomiasis. Int. J. Environ. Res. Public Health, 2016, 13(10), 972.
[http://dx.doi.org/10.3390/ijerph13100972] [PMID: 27706050]
[61]
Waack, U.; Johnson, T.L.; Chedid, K.; Xi, C.; Simmons, L.A.; Mobley, H.L.T.; Sandkvist, M. Targeting the type II secretion system: development, optimization, and validation of a high-throughput screen for the identification of small molecule inhibitors. Front. Cell. Infect. Microbiol., 2017, 7, 380.
[http://dx.doi.org/10.3389/fcimb.2017.00380] [PMID: 28894700]
[62]
Yang, J.; Suzuki, M.; McCarty, D.R. Essential role of conserved DUF177A protein in plastid 23S rRNA accumulation and plant embryogenesis. J. Exp. Bot., 2016, 67(18), 5447-5460.
[http://dx.doi.org/10.1093/jxb/erw311] [PMID: 27574185]
[63]
Lambert, M.; Jambon, S.; Depauw, S.; David-Cordonnier, M-H. Targeting transcription factors for cancer treatment. Molecules, 2018, 23(6), 1479.
[http://dx.doi.org/10.3390/molecules23061479] [PMID: 29921764]
[64]
Grainger, D.C.; Busby, S.J. Global regulators of transcription in Escherichia coli: mechanisms of action and methods for study. Adv. Appl. Microbiol., 2008, 65, 93-113.
[http://dx.doi.org/10.1016/S0065-2164(08)00604-7] [PMID: 19026863]
[65]
Golkar, Z.; Rochelle, L. Crisprs/Cas9 may provide new method for drug discovery and development. J. Mol. Biomark. Diagn., 2016, 7(280), 10-4172.
[http://dx.doi.org/10.4172/2155-9929.1000280]
[66]
Louwen, R.; Staals, R.H.J.; Endtz, H.P.; van Baarlen, P.; van der Oost, J. The role of CRISPR-Cas systems in virulence of pathogenic bacteria. Microbiol. Mol. Biol. Rev., 2014, 78(1), 74-88.
[http://dx.doi.org/10.1128/MMBR.00039-13] [PMID: 24600041]

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    App\Http\Controllers\ArticleController@GetArticleDetails
    namespace
    App\Http\Controllers
    where
    as
    article
    file
    app/Http/Controllers/ArticleController.php:1974-2510
    37 statements were executed, 4 of which were duplicates, 33 unique. Show only duplicated220ms
    • 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 ('309684047','',1,1739988051,1739988051) ON DUPLICATE KEY UPDATE visitor_count=visitor_count + 1, updated_on=1739988051
      1.55msalphaeurekaselec_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 ('309684047','/article/104652',1,1739988051,1739988051)
      220μsalphaeurekaselec_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 >= 309684047 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309684047) 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 >= 309684047 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309684047) 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 >= 309684047 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309684047) 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 >= 309684047 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309684047) 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 >= 309684047 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309684047) 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 >= 309684047 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309684047) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_trail WHERE to_ip >= 309684047 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309684047) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_corporate WHERE to_ip >= 309684047 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309684047) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_token WHERE to_ip >= 309684047 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309684047) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_trail WHERE to_ip >= 309684047 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309684047) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_corporate WHERE to_ip >= 309684047 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309684047) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_token WHERE to_ip >= 309684047 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309684047) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_trail WHERE to_ip >= 309684047 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309684047) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_corporate WHERE to_ip >= 309684047 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309684047) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_token WHERE to_ip >= 309684047 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309684047) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_disease_corporate WHERE to_ip >= 309684047 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 309684047) limit 1
      18.39msalphaeurekaselec_live_10_06_2022UserAccess.php#784
      Bindings
      • 0: 309684047
      • 1: 309684047
      • 2: 309684047
      • 3: 309684047
      • 4: 309684047
      • 5: 309684047
      • 6: 309684047
      • 7: 309684047
      • 8: 309684047
      • 9: 309684047
      • 10: 309684047
      • 11: 309684047
      • 12: 309684047
      • 13: 309684047
      • 14: 309684047
      • 15: 309684047
      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=104652
      940μsalphaeurekaselec_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` = 8 limit 1
      34.42msalphaeurekaselec_live_10_06_2022Journal.php#64
      Bindings
      • 0: 8
      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=8) and sj.journal_id!=8 group by `j`.`nid`) as `aggregate_table`
      1.61msalphaeurekaselec_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=8) and sj.journal_id!=8 group by `j`.`nid` order by `j`.`journal_id` asc limit 10 offset 0
      1.29msalphaeurekaselec_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=8) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid`) as `aggregate_table`
      3.41msalphaeurekaselec_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=8) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid` order by `v`.`ebook_volume_id` desc limit 10 offset 0
      2.87msalphaeurekaselec_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` = '104652'
      320μsalphaeurekaselec_live_10_06_2022Keywords.php#43
      Bindings
      • 0: 104652
      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` = '104652'
      2.9msalphaeurekaselec_live_10_06_2022Article.php#1570
      Bindings
      • 0: 104652
      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` = '104652' group by `au`.`author_id` order by `au`.`article_id` asc, `au`.`sequence` asc
      2.77msalphaeurekaselec_live_10_06_2022Author.php#86
      Bindings
      • 0: 104652
      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
      340μsalphaeurekaselec_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
      700μsalphaeurekaselec_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 = 8 and i.is_uploaded = 1 order by v.volume_name+0 desc, i.title+0 desc limit 1
      40.32msalphaeurekaselec_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 = 8 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      17.21msalphaeurekaselec_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 = 8 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      13.41msalphaeurekaselec_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` = 104652 limit 1
      330μsalphaeurekaselec_live_10_06_2022Article.php#744
      Bindings
      • 0: 104652
      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 = 104652 and content_type = 'article' order by status desc limit 1
      2.49msalphaeurekaselec_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 a.nid article_nid,a.title article_title,j.title journal_title from content_by_diseases cd inner join article a on a.article_id=cd.content_id inner join journal j on j.journal_id=a.journal_id where cd.pid = 295 and cd.sub_disease_id = 607 and content_id!=104652 and cd.content_type = 'article' order by rand() limit 20
      45.84msalphaeurekaselec_live_10_06_2022Article.php#769
      Backtrace
      • 11. app/Models/Article.php:769
      • 12. app/Http/Controllers/ArticleController.php:2098
      • 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` = 179543 limit 1
      280μsalphaeurekaselec_live_10_06_2022Meta.php#30
      Bindings
      • 0: 179543
      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
      230μsalphaeurekaselec_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` = 'CCHTS' and (h.proposal_closing_date = 0 OR TO_DAYS(FROM_UNIXTIME(h.proposal_closing_date)) >= TO_DAYS(NOW())) order by `h`.`manuscript` asc
      310μsalphaeurekaselec_live_10_06_2022Article.php#2025
      Bindings
      • 0: CCHTS
      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 = '104652' 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) )
      360μsalphaeurekaselec_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 = '9784' 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) )
      310μsalphaeurekaselec_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 = '2700' 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) )
      260μsalphaeurekaselec_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 <= 309684047 and j.to_ip >=309684047 )) and ((j.from_date <= 1739988051 and j.to_date >= 1739988051 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2700) 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 <= 309684047 and j.to_ip >=309684047 )) and ((j.from_date <= 1739988051 and j.to_date >= 1739988051 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2700) 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 <= 309684047 and j.to_ip >=309684047 )) and ((j.from_date <= 1739988051 and j.to_date >= 1739988051 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2700)
      19.29msalphaeurekaselec_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 <= 309684047 and j.to_ip >=309684047 )) and ((j.from_date <= 1739988051 and j.to_date >= 1739988051 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 9784) 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 <= 309684047 and j.to_ip >=309684047 )) and ((j.from_date <= 1739988051 and j.to_date >= 1739988051 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 9784) 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 <= 309684047 and j.to_ip >=309684047 )) and ((j.from_date <= 1739988051 and j.to_date >= 1739988051 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 9784)
      610μsalphaeurekaselec_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 <= 309684047 and j.to_ip >=309684047 )) and ((j.from_date <= 1739988051 and j.to_date >= 1739988051 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 104652) 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 <= 309684047 and j.to_ip >=309684047 )) and ((j.from_date <= 1739988051 and j.to_date >= 1739988051 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 104652) 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 <= 309684047 and j.to_ip >=309684047 )) and ((j.from_date <= 1739988051 and j.to_date >= 1739988051 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 104652)
      550μsalphaeurekaselec_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` < '253' and is_uploaded = 1 and issue_id = 9784 order by cast(first_page as SIGNED) desc limit 1
      510μsalphaeurekaselec_live_10_06_2022Article.php#1819
      Bindings
      • 0: 253
      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` > '268' and is_uploaded = 1 and issue_id = 9784 order by cast(first_page as SIGNED) asc limit 1
      370μsalphaeurekaselec_live_10_06_2022Article.php#1831
      Bindings
      • 0: 268
      Backtrace
      • 14. app/Models/Article.php:1831
      • 15. app/Http/Controllers/ArticleController.php:2472
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select `language_id` from `multilanguage` where `short_code` = 'en'
      160μsalphaeurekaselec_live_10_06_2022ArticleController.php#2497
      Bindings
      • 0: en
      Backtrace
      • 14. app/Http/Controllers/ArticleController.php:2497
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:206
    • select `source_lang_label`, `target_lang_label` from `multilanguage_labels` where `target_lang_id` = 1
      170μsalphaeurekaselec_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` = 104652 limit 1
      2.42msalphaeurekaselec_live_10_06_2022ArticleController.php#2506
      Bindings
      • 0: 104652
      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` = 8 and `b`.`banner_from_date` <= 1739988051 and `b`.`banner_to_date` >= 1739988051 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.11msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 8
      • 3: 1739988051
      • 4: 1739988051
      • 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` = 8 and `b`.`banner_from_date` <= 1739988051 and `b`.`banner_to_date` >= 1739988051 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.06msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 8
      • 3: 1739988051
      • 4: 1739988051
      • 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='37886ba687b979b8d091d05a0d2db94b'
      220μsalphaeurekaselec_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
        kuXHprAtlFIx44ZfiUodmJ9k7GUXkVb7QHnQDLXB
        uc_cart_id
        37886ba687b979b8d091d05a0d2db94b
        _previous
        array:1 [ "url" => "http://alpha.eurekaselect.com/article/104652" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /article/104652
        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=eyJpdiI6IkVJSm8zZlJjWkhLSjdEcm0zWHZ4UGc9PSIsInZhbHVlIjoiUHpoNTRKQjNpSDlySzNuMGdzSkE2NjJ5YnIrRHVzT1IzNlhCNVcyQnkwOD0iLCJtYWMiOiI0NzA0MTNkZDY3NjljYjc3NzFlMTBkZTI0OWIxNzhkZjdiNjBmZTYzMzM5OWZhMjRmODJmMzUwOGZjNDVkNDVjIiwidGFnIjoiIn0%3Dwayfindertarget=eyJpdiI6IkVJSm8zZlJjWkhLSjdEcm0zWHZ4UGc9PSIsInZhbHVlIjoiUHpoNTRKQjNpSDlySzNuMGdzSkE2NjJ5YnIrRHVzT1IzNlhCNVcyQnkwOD0iLCJtYWMiOiI0NzA0MTNkZDY3Njlj" ] "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 ]
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