Generic placeholder image

Infectious Disorders - Drug Targets

Editor-in-Chief

ISSN (Print): 1871-5265
ISSN (Online): 2212-3989

Review Article

Insights into Ebola Virus VP35 and VP24 Interferon Inhibitory Functions and their Initial Exploitation as Drug Targets

Author(s): Elisa Fanunza, Aldo Frau, Angela Corona and Enzo Tramontano*

Volume 19, Issue 4, 2019

Page: [362 - 374] Pages: 13

DOI: 10.2174/1871526519666181123145540

Price: $65

Abstract

Upon viral infection, the interferon (IFN) system triggers potent antiviral mechanisms limiting viral growth and spread. Hence, to sustain their infection, viruses evolved efficient counteracting strategies to evade IFN control. Ebola virus (EBOV), member of the family Filoviridae, is one of the most virulent and deadly pathogen ever faced by humans. The etiological agent of the Ebola Virus Disease (EVD), EBOV can be undoubtedly considered the perfect example of a powerful inhibitor of the host organism immune response activation. Particularly, the efficacious suppression of the IFN cascade contributes to disease progression and severity. Among the EBOVencoded proteins, the Viral Proteins 35 (VP35) and 24 (VP24) are responsible for the EBOV extreme virulence, representing the core of such inhibitory function through which EBOV determines its very effective shield to the cellular immune defenses. VP35 inhibits the activation of the cascade leading to IFN production, while VP24 inhibits the activation of the IFN-stimulated genes. A number of studies demonstrated that both VP35 and VP24 is validated target for drug development. Insights into the structural characteristics of VP35 and VP24 domains revealed crucial pockets exploitable for drug development. Considered the lack of therapy for EVD, restoring the immune activation is a promising approach for drug development. In the present review, we summarize the importance of VP35 and VP24 proteins in counteracting the host IFN cellular response and discuss their potential as druggable viral targets as a promising approach toward attenuation of EBOV virulence.

Keywords: Ebola virus, Interferon, IFN production, IFN signaling, VP35, VP24, small molecules and FDA approved drugs.

Graphical Abstract

[1]
Feldmann, H.; Geisbert, T.W. Ebola haemorrhagic fever. Lancet, 2011, 377(9768), 849-862.
[http://dx.doi.org/10.1016/S0140-6736(10)60667-8] [PMID: 21084112]
[2]
Wan, W.; Kolesnikova, L.; Clarke, M.; Koehler, A.; Noda, T.; Becker, S.; Briggs, J.A.G. Structure and assembly of the Ebola virus nucleocapsid. Nature, 2017, 551(7680), 394-397.
[http://dx.doi.org/10.1038/nature24490] [PMID: 29144446]
[3]
Baseler, L.; Chertow, D.S.; Johnson, K.M.; Feldmann, H.; Morens, D.M. The Pathogenesis of Ebola Virus Disease. Annu. Rev. Pathol., 2017, 12, 387-418.
[http://dx.doi.org/10.1146/annurev-pathol-052016-100506] [PMID: 27959626]
[4]
Bray, M. Pathogenesis of viral hemorrhagic fever. Curr. Opin. Immunol., 2005, 17(4), 399-403.
[http://dx.doi.org/10.1016/j.coi.2005.05.001] [PMID: 15955687]
[5]
Basler, C.F.; Wang, X.; Mühlberger, E.; Volchkov, V.; Paragas, J.; Klenk, H.D.; García-Sastre, A.; Palese, P. The Ebola virus VP35 protein functions as a type I IFN antagonist. Proc. Natl. Acad. Sci. USA, 2000, 97(22), 12289-12294.
[http://dx.doi.org/10.1073/pnas.220398297] [PMID: 11027311]
[6]
Reid, S.P.; Leung, L.W.; Hartman, A.L.; Martinez, O.; Shaw, M.L.; Carbonnelle, C.; Volchkov, V.E.; Nichol, S.T.; Basler, C.F.D. Ebola virus VP24 binds karyopherin alpha1 and blocks STAT1 nuclear accumulation. J. Virol., 2006, 80(11), 5156-5167.
[http://dx.doi.org/10.1128/JVI.02349-05] [PMID: 16698996]
[7]
Mateo, M.; Reid, S.P.; Leung, L.W.; Basler, C.F.; Volchkov, V.E. Ebolavirus VP24 binding to karyopherins is required for inhibition of interferon signaling. J. Virol., 2010, 84(2), 1169-1175.
[http://dx.doi.org/10.1128/JVI.01372-09] [PMID: 19889762]
[8]
Luthra, P.; Ramanan, P.; Mire, C.E.; Weisend, C.; Tsuda, Y.; Yen, B.; Liu, G.; Leung, D.W.; Geisbert, T.W.; Ebihara, H.; Amarasinghe, G.K.; Basler, C.F. Mutual antagonism between the Ebola virus VP35 protein and the RIG-I activator PACT determines infection outcome. Cell Host Microbe, 2013, 14(1), 74-84.
[http://dx.doi.org/10.1016/j.chom.2013.06.010] [PMID: 23870315]
[9]
Leung, D.W.; Prins, K.C.; Borek, D.M.; Farahbakhsh, M.; Tufariello, J.M.; Ramanan, P.; Nix, J.C.; Helgeson, L.A.; Otwinowski, Z.; Honzatko, R.B.; Basler, C.F.; Amarasinghe, G.K. Structural basis for dsRNA recognition and interferon antagonism by Ebola VP35. Nat. Struct. Mol. Biol., 2010, 17(2), 165-172.
[http://dx.doi.org/10.1038/nsmb.1765] [PMID: 20081868]
[10]
Leung, D.W.; Ginder, N.D.; Fulton, D.B.; Nix, J.; Basler, C.F.; Honzatko, R.B.; Amarasinghe, G.K. Structure of the Ebola VP35 interferon inhibitory domain. Proc. Natl. Acad. Sci. USA, 2009, 106(2), 411-416.
[http://dx.doi.org/10.1073/pnas.0807854106] [PMID: 19122151]
[11]
Basler, C.F. Innate immune evasion by filoviruses. Virology, 2015, 479-480, 122-130.
[http://dx.doi.org/10.1016/j.virol.2015.03.030] [PMID: 25843618]
[12]
Zinzula, L.; Esposito, F.; Mühlberger, E.; Trunschke, M.; Conrad, D.; Piano, D.; Tramontano, E. Purification and functional characterization of the full length recombinant Ebola virus VP35 protein expressed in E. coli. Protein Expr. Purif., 2009, 66(1), 113-119.
[http://dx.doi.org/10.1016/j.pep.2009.02.008] [PMID: 19233284]
[13]
Zinzula, L.; Esposito, F.; Pala, D.; Tramontano, E. dsRNA binding characterization of full length recombinant wild type and mutants Zaire ebolavirus VP35. Antiviral Res., 2012, 93(3), 354-363.
[http://dx.doi.org/10.1016/j.antiviral.2012.01.005] [PMID: 22289166]
[14]
Zinzula, L.; Tramontano, E. Strategies of highly pathogenic RNA viruses to block dsRNA detection by RIG-I-like receptors: hide, mask, hit. Antiviral Res., 2013, 100(3), 615-635.
[http://dx.doi.org/10.1016/j.antiviral.2013.10.002] [PMID: 24129118]
[15]
Basler, C.F.; Mikulasova, A.; Martinez-Sobrido, L.; Paragas, J.; Mühlberger, E.; Bray, M.; Klenk, H.D.; Palese, P.; García-Sastre, A. The Ebola virus VP35 protein inhibits activation of interferon regulatory factor 3. J. Virol., 2003, 77(14), 7945-7956.
[http://dx.doi.org/10.1128/JVI.77.14.7945-7956.2003] [PMID: 12829834]
[16]
Prins, K.C.; Delpeut, S.; Leung, D.W.; Reynard, O.; Volchkova, V.A.; Reid, S.P.; Ramanan, P.; Cárdenas, W.B.; Amarasinghe, G.K.; Volchkov, V.E.; Basler, C.F. Mutations abrogating VP35 interaction with double-stranded RNA render Ebola virus avirulent in guinea pigs. J. Virol., 2010, 84(6), 3004-3015.
[http://dx.doi.org/10.1128/JVI.02459-09] [PMID: 20071589]
[17]
Ramanan, P.; Shabman, R.S.; Brown, C.S.; Amarasinghe, G.K.; Basler, C.F.; Leung, D.W.; Amarasinghe, G.K. Filoviral immune evasion mechanisms. Viruses, 2011, 3(9), 1634-1649.
[http://dx.doi.org/10.3390/v3091634] [PMID: 21994800]
[18]
Cannas, V.; Daino, G.L.; Corona, A.; Esposito, F.; Tramontano, E. A Luciferase Reporter Gene Assay to Measure Ebola Virus Viral Protein 35 - Associated Inhibition of Double-Stranded RNA – Stimulated, Retinoic Acid – Inducible Gene 1 – Mediated Induction of Interferon. β. J. Infect. Dis., 2015, 212, S277-S281.
[19]
Fanunza, E.; Frau, A.; Sgarbanti, M.; Orsatti, R.; Corona, A.; Tramontano, E. Development and Validation of a Novel Dual Luciferase Reporter Gene Assay to Quantify Ebola Virus VP24 Inhibition of IFN Signaling. Viruses, 2018, 10(2), 98.
[http://dx.doi.org/10.3390/v10020098] [PMID: 29495311]
[20]
Hartman, A.L.; Bird, B.H.; Towner, J.S.; Antoniadou, Z-A.; Zaki, S.R.; Nichol, S.T. Inhibition of IRF-3 activation by VP35 is critical for the high level of virulence of ebola virus. J. Virol., 2008, 82(6), 2699-2704.
[http://dx.doi.org/10.1128/JVI.02344-07] [PMID: 18199658]
[21]
Reid, S.P.; Ca, W.B.; Basler, C.F. Homo-Oligomerization Facilitates the Interferon-Antagonist Activity of the Ebolavirus VP35 Protein., 2005, 341, 179-189.
[http://dx.doi.org/10.1016/j.virol.2005.06.044]
[22]
Reid, S.P.; Valmas, C.; Martinez, O.; Sanchez, F.M.; Basler, C.F. Ebola virus VP24 proteins inhibit the interaction of NPI-1 subfamily karyopherin α proteins with activated STAT1. J. Virol., 2007, 81(24), 13469-13477.
[http://dx.doi.org/10.1128/JVI.01097-07] [PMID: 17928350]
[23]
Ebihara, H.; Takada, A.; Kobasa, D.; Jones, S.; Neumann, G.; Theriault, S.; Bray, M.; Feldmann, H.; Kawaoka, Y. Molecular determinants of Ebola virus virulence in mice. PLoS Pathog., 2006, 2(7)e73
[http://dx.doi.org/10.1371/journal.ppat.0020073] [PMID: 16848640]
[24]
Mateo, M.; Carbonnelle, C.; Reynard, O.; Kolesnikova, L.; Nemirov, K.; Page, A.; Volchkova, V.A.; Volchkov, V.E. VP24 is a molecular determinant of Ebola virus virulence in guinea pigs. J. Infect. Dis., 2011, 204(Suppl. 3), S1011-S1020.
[http://dx.doi.org/10.1093/infdis/jir338] [PMID: 21987737]
[25]
Leung, D.W.; Prins, K.C.; Basler, C.F.; Amarasinghe, G.K. Ebolavirus VP35 is a multifunctional virulence factor. Virulence, 2010, 1(6), 526-531.
[http://dx.doi.org/10.4161/viru.1.6.12984] [PMID: 21178490]
[26]
Fanunza, E.; Frau, A.; Corona, A.; Tramontano, E. Antiviral Agents Against Ebola Virus Infection: Repositioning Old Drugs and Finding Novel Small Molecules. In: Annual Reports in Medicinal Chemistry,2018.
[27]
Haller, O.; Kochs, G.; Weber, F. The interferon response circuit: induction and suppression by pathogenic viruses. Virology, 2006, 344(1), 119-130.
[http://dx.doi.org/10.1016/j.virol.2005.09.024] [PMID: 16364743]
[28]
Ma, D.Y.; Suthar, M.S. Mechanisms of innate immune evasion in re-emerging RNA viruses. Curr. Opin. Virol., 2015, 12, 26-37.
[http://dx.doi.org/10.1016/j.coviro.2015.02.005] [PMID: 25765605]
[29]
Kühl, A.; Pöhlmann, S. How Ebola virus counters the interferon system. Zoonoses Public Health, 2012, 59(Suppl. 2), 116-131.
[http://dx.doi.org/10.1111/j.1863-2378.2012.01454.x] [PMID: 22958256]
[30]
Schneider, W.M.; Chevillotte, M.D.; Rice, C.M. Interferon-stimulated genes: a complex web of host defenses. Annu. Rev. Immunol., 2014, 32, 513-545.
[http://dx.doi.org/10.1146/annurev-immunol-032713-120231] [PMID: 24555472]
[31]
Weber, M.; Weber, F. RIG-I-like receptors and negative-strand RNA viruses: RLRly bird catches some worms. Cytokine Growth Factor Rev., 2014, 25(5), 621-628.
[http://dx.doi.org/10.1016/j.cytogfr.2014.05.004] [PMID: 24894317]
[32]
Gerlier, D.; Lyles, D.S. Interplay between innate immunity and negative-strand RNA viruses: towards a rational model. Microbiol. Mol. Biol. Rev., 2011, 75(3), 468-490.
[http://dx.doi.org/10.1128/MMBR.00007-11] [PMID: 21885681]
[33]
Yoneyama, M.; Kikuchi, M.; Natsukawa, T.; Shinobu, N.; Imaizumi, T.; Miyagishi, M.; Taira, K.; Akira, S.; Fujita, T. RNA Helicase RIG-I Has an Essential Function in Double-Stranded RNA-Induced Innate Antiviral Responses., 2004, 5, 730.
[34]
Sarkar, S.N.; Peters, K.L.; Elco, C.P.; Sakamoto, S.; Pal, S.; Sen, G.C. Novel roles of TLR3 tyrosine phosphorylation and PI3 kinase in double-stranded RNA signaling. Nat. Struct. Mol. Biol., 2004, 11(11), 1060-1067.
[http://dx.doi.org/10.1038/nsmb847] [PMID: 15502848]
[35]
Fitzgerald, K.A.; McWhirter, S.M.; Faia, K.L.; Rowe, D.C.; Latz, E.; Golenbock, D.T.; Coyle, A.J.; Liao, S-M.; Maniatis, T. IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nat. Immunol., 2003, 4(5), 491-496.
[http://dx.doi.org/10.1038/ni921] [PMID: 12692549]
[36]
Sharma, S.; TenOever, B.R.; Grandvaux, N.; Zhou, G.P.; Lin, R.; Hiscott, J. Triggering the Interferon Antiviral Response through an IKK-Related Pathway. Science, 2003, 300, 1148-1151.
[37]
Yamamoto, A.; Seya, T.; Oshiumi, H.; Shingai, M.; Seto, Y.; Matsumoto, M.; Funami, K.; Tanabe, M. Receptor 3 in Human Dendritic Cells Subcellular Localization of Toll-Like Subcellular Localization of Toll-Like Receptor 3 in Human Dendritic Cells 1. J Immunol Ref. J. Immunol., 2003, 171, 3154-3162.
[http://dx.doi.org/10.4049/jimmunol.171.6.3154]
[38]
Kawai, T.; Takahashi, K.; Sato, S.; Coban, C.; Kumar, H.; Kato, H.; Ishii, K.J.; Takeuchi, O.; Akira, S. IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nat. Immunol., 2005, 6(10), 981-988.
[http://dx.doi.org/10.1038/ni1243] [PMID: 16127453]
[39]
Meylan, E.; Curran, J.; Hofmann, K.; Moradpour, D.; Binder, M.; Bartenschlager, R.; Tschopp, J. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature, 2005, 437(7062), 1167-1172.
[http://dx.doi.org/10.1038/nature04193] [PMID: 16177806]
[40]
Seth, R.B.; Sun, L.; Ea, C.K.; Chen, Z.J. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell, 2005, 122(5), 669-682.
[http://dx.doi.org/10.1016/j.cell.2005.08.012] [PMID: 16125763]
[41]
Xu, L.G.; Wang, Y.Y.; Han, K.J.; Li, L.Y.; Zhai, Z.; Shu, H.B. VISA is an adapter protein required for virus-triggered IFN-β signaling. Mol. Cell, 2005, 19(6), 727-740.
[http://dx.doi.org/10.1016/j.molcel.2005.08.014] [PMID: 16153868]
[42]
Johnson, C.L.; Gale, M. Jr CARD games between virus and host get a new player. Trends Immunol., 2006, 27(1), 1-4.
[http://dx.doi.org/10.1016/j.it.2005.11.004] [PMID: 16309964]
[43]
Liu, H.M.; Loo, Y.M.; Horner, S.M.; Zornetzer, G.A.; Katze, M.G.; Gale, M., Jr The mitochondrial targeting chaperone 14-3-3ε regulates a RIG-I translocon that mediates membrane association and innate antiviral immunity. Cell Host Microbe, 2012, 11(5), 528-537.
[http://dx.doi.org/10.1016/j.chom.2012.04.006] [PMID: 22607805]
[44]
Gack, M.U.; Shin, Y.C.; Joo, C.; Urano, T.; Liang, C.; Sun, L.; Takeuchi, O.; Akira, S.; Chen, Z.; Inoue, S.; Jung, J.U. TRIM25 RING-Finger E3 Ubiquitin Ligase Is Essential for RIG-I-Mediated Antiviral Activity 446,, 916-920. 2007.
[45]
Hou, F.; Sun, L.; Zheng, H.; Skaug, B.; Jiang, Q.X.; Chen, Z.J. MAVS forms functional prion-like aggregates to activate and propagate antiviral innate immune response. Cell, 2011, 146(3), 448-461.
[http://dx.doi.org/10.1016/j.cell.2011.06.041] [PMID: 21782231]
[46]
Oganesyan, G.; Saha, S.K.; Guo, B.; He, J.Q.; Shahangian, A.; Zarnegar, B.; Perry, A.; Cheng, G. Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response. Nature, 2006, 439(7073), 208-211.
[http://dx.doi.org/10.1038/nature04374] [PMID: 16306936]
[47]
Zhao, T.; Yang, L.; Sun, Q.; Arguello, M.; Ballard, D.W.; Hiscott, J.; Lin, R. The NEMO adaptor bridges the nuclear factor-kappaB and interferon regulatory factor signaling pathways. Nat. Immunol., 2007, 8(6), 592-600.
[http://dx.doi.org/10.1038/ni1465] [PMID: 17468758]
[48]
Belgnaoui, S.M.; Paz, S.; Samuel, S.; Goulet, M.L.; Sun, Q.; Kikkert, M.; Iwai, K.; Dikic, I.; Hiscott, J.; Lin, R. Linear ubiquitination of NEMO negatively regulates the interferon antiviral response through disruption of the MAVS-TRAF3 complex. Cell Host Microbe, 2012, 12(2), 211-222.
[http://dx.doi.org/10.1016/j.chom.2012.06.009] [PMID: 22901541]
[49]
Wang, L.; Li, S.; Dorf, M.E. NEMO binds ubiquitinated TANK-binding kinase 1 (TBK1) to regulate innate immune responses to RNA viruses. PLoS One, 2012, 7(9)e43756
[http://dx.doi.org/10.1371/journal.pone.0043756] [PMID: 23028469]
[50]
Ishikawa, H.; Barber, G.N. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature, 2008, 455(7213), 674-678.
[http://dx.doi.org/10.1038/nature07317] [PMID: 18724357]
[51]
Sun, W.; Li, Y.; Chen, L.; Chen, H.; You, F.; Zhou, X.; Zhou, Y.; Zhai, Z.; Chen, D.; Jiang, Z. ERIS, an endoplasmic reticulum IFN stimulator, activates innate immune signaling through dimerization. Proc. Natl. Acad. Sci. USA, 2009, 106(21), 8653-8658.
[http://dx.doi.org/10.1073/pnas.0900850106] [PMID: 19433799]
[52]
Zhong, B.; Yang, Y.; Li, S.; Wang, Y.Y.; Li, Y.; Diao, F.; Lei, C.; He, X.; Zhang, L.; Tien, P.; Shu, H.B. The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation. Immunity, 2008, 29(4), 538-550.
[http://dx.doi.org/10.1016/j.immuni.2008.09.003] [PMID: 18818105]
[53]
Panne, D.; Maniatis, T.; Harrison, S.C. An atomic model of the interferon-β enhanceosome. Cell, 2007, 129(6), 1111-1123.
[http://dx.doi.org/10.1016/j.cell.2007.05.019] [PMID: 17574024]
[54]
Platanias, L.C. Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat. Rev. Immunol., 2005, 5(5), 375-386.
[http://dx.doi.org/10.1038/nri1604] [PMID: 15864272]
[55]
Stark, G.R.; Kerr, I.M.; Williams, B.R.G.; Silverman, R.H.; Schreiber, R.D. How cells respond to interferons. Annu. Rev. Biochem., 1998, 67, 227-264.
[http://dx.doi.org/10.1146/annurev.biochem.67.1.227] [PMID: 9759489]
[56]
van Boxel-Dezaire, A.H.; Rani, M.R.S.; Stark, G.R. Complex modulation of cell type-specific signaling in response to type I interferons. Immunity, 2006, 25(3), 361-372.
[http://dx.doi.org/10.1016/j.immuni.2006.08.014] [PMID: 16979568]
[57]
Stancato, L.F.; David, M.; Carter-Su, C.; Larner, A.C.; Pratt, W.B. Preassociation of STAT1 with STAT2 and STAT3 in separate signalling complexes prior to cytokine stimulation. J. Biol. Chem., 1996, 271(8), 4134-4137.
[http://dx.doi.org/10.1074/jbc.271.8.4134] [PMID: 8626752]
[58]
Tang, X.; Gao, J.S.; Guan, Y.J.; McLane, K.E.; Yuan, Z.L.; Ramratnam, B.; Chin, Y.E. Acetylation-dependent signal transduction for type I interferon receptor. Cell, 2007, 131(1), 93-105.
[http://dx.doi.org/10.1016/j.cell.2007.07.034] [PMID: 17923090]
[59]
Yan, H.; Krishnan, K.; Greenlund, A.C.; Gupta, S.; Lim, J.T.; Schreiber, R.D.; Schindler, C.W.; Krolewski, J.J. Phosphorylated interferon-alpha receptor 1 subunit (IFNaR1) acts as a docking site for the latent form of the 113 kDa STAT2 protein. EMBO J., 1996, 15(5), 1064-1074.
[http://dx.doi.org/10.1002/j.1460-2075.1996.tb00444.x] [PMID: 8605876]
[60]
Fu, X.Y.; Kessler, D.S.; Veals, S.A.; Levy, D.E.; Darnell, J.E., Jr ISGF3, the transcriptional activator induced by interferon alpha, consists of multiple interacting polypeptide chains. Proc. Natl. Acad. Sci. USA, 1990, 87(21), 8555-8559.
[http://dx.doi.org/10.1073/pnas.87.21.8555] [PMID: 2236065]
[61]
Chen, X.; Vinkemeier, U.; Zhao, Y.; Jeruzalmi, D.; Darnell, J.E., Jr; Kuriyan, J. Crystal structure of a tyrosine phosphorylated STAT-1 dimer bound to DNA. Cell, 1998, 93(5), 827-839.
[http://dx.doi.org/10.1016/S0092-8674(00)81443-9] [PMID: 9630226]
[62]
McBride, K.M.; Banninger, G.; McDonald, C.; Reich, N.C. Regulated nuclear import of the STAT1 transcription factor by direct binding of importin-α. EMBO J., 2002, 21(7), 1754-1763.
[http://dx.doi.org/10.1093/emboj/21.7.1754] [PMID: 11927559]
[63]
Xu, W.; Edwards, M.R.; Borek, D.M.; Feagins, A.R.; Mittal, A.; Pappu, R. V; Leung, D.W.; Basler, C.F.; Amarasinghe, G.K. Ebola Virus VP24 Targets a Unique NLS Binding Site on Karyopherin Alpha 5 to Selectively Compete with Nuclear Import of Phosphorylated STAT1, 2015, 16, 187-200.
[64]
Fink, K.; Grandvaux, N. STAT2 and IRF9: Beyond ISGF3. JAK-STAT, 2013, 2(4)e27521
[http://dx.doi.org/10.4161/jkst.27521] [PMID: 24498542]
[65]
Kessler, D.S.; Levy, D.E.; Darnell, J.E., Jr Two interferon-induced nuclear factors bind a single promoter element in interferon-stimulated genes. Proc. Natl. Acad. Sci. USA, 1988, 85(22), 8521-8525.
[http://dx.doi.org/10.1073/pnas.85.22.8521] [PMID: 2460869]
[66]
Harcourt, B.H.; Sanchez, A.; Offermann, M.K. Ebola virus inhibits induction of genes by double-stranded RNA in endothelial cells. Virology, 1998, 252(1), 179-188.
[http://dx.doi.org/10.1006/viro.1998.9446] [PMID: 9875327]
[67]
Harcourt, B.H.; Sanchez, A.; Offermann, M.K. Ebola virus selectively inhibits responses to interferons, but not to interleukin-1beta, in endothelial cells. J. Virol., 1999, 73(4), 3491-3496.
[PMID: 10074208]
[68]
Cárdenas, W.B.; Loo, Y-M.; Gale, M., Jr; Hartman, A.L.; Kimberlin, C.R.; Martínez-Sobrido, L.; Saphire, E.O.; Basler, C.F. Ebola virus VP35 protein binds double-stranded RNA and inhibits alpha/beta interferon production induced by RIG-I signaling. J. Virol., 2006, 80(11), 5168-5178.
[http://dx.doi.org/10.1128/JVI.02199-05] [PMID: 16698997]
[69]
Mühlberger, E.; Weik, M.; Volchkov, V.E.; Klenk, H.D.; Becker, S. Comparison of the transcription and replication strategies of marburg virus and Ebola virus by using artificial replication systems. J. Virol., 1999, 73(3), 2333-2342.
[PMID: 9971816]
[70]
Mühlberger, E. Filovirus replication and transcription. Future Virol., 2007, 2(2), 205-215.
[http://dx.doi.org/10.2217/17460794.2.2.205] [PMID: 24093048]
[71]
Le Sage, V. Cinti, A.; McCarthy, S.; Amorim, R.; Rao, S.; Daino, G.L.; Tramontano, E.; Branch, D.R.; Mouland, A.J. Ebola virus VP35 blocks stress granule assembly. Virology, 2017, 502, 73-83.
[http://dx.doi.org/10.1016/j.virol.2016.12.012] [PMID: 28013103]
[72]
Versteeg, G.A.; García-Sastre, A. Viral tricks to grid-lock the type I interferon system. Curr. Opin. Microbiol., 2010, 13(4), 508-516.
[http://dx.doi.org/10.1016/j.mib.2010.05.009] [PMID: 20538505]
[73]
Ramaswamy, V.K.; Di Palma, F.; Vargiu, A.V.; Corona, A.; Piano, D.; Ruggerone, P.; Zinzula, L.; Tramontano, E. Insights into the homo-oligomerization properties of N-terminal coiled-coil domain of Ebola virus VP35 protein. Virus Res., 2018, 247, 61-70.
[http://dx.doi.org/10.1016/j.virusres.2018.02.003] [PMID: 29427597]
[74]
Zinzula, L.; István, N.; Massimiliano, O.; Elisabeth, W-S.; Andreas, B.; Wolfgang, B. Structures of Ebola and Reston Virus VP35 Oligomerization Domains and Comparative Biophysical Characterization in All Ebolavirus Species. Structure, 2019, 27(1), 39-54.
[PMID: 30482729]
[75]
Leung, D.W.; Borek, D.; Farahbakhsh, M.; Ramanan, P.; Nix, J.C.; Wang, T.; Prins, K.C.; Otwinowski, Z.; Honzatko, R.B.; Helgeson, L.A.; Basler, C.F.; Amarasinghe, G.K. Crystallization and preliminary X-ray analysis of Ebola VP35 interferon inhibitory domain mutant proteins. Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun., 2010, 66(Pt 6), 689-692.
[http://dx.doi.org/10.1107/S1744309110013266] [PMID: 20516601]
[76]
Kimberlin, C.R.; Bornholdt, Z.A.; Li, S.; Woods, V.L., Jr; MacRae, I.J.; Saphire, E.O. Ebolavirus VP35 uses a bimodal strategy to bind dsRNA for innate immune suppression. Proc. Natl. Acad. Sci. USA, 2010, 107(1), 314-319.
[http://dx.doi.org/10.1073/pnas.0910547107] [PMID: 20018665]
[77]
Feng, Z.; Cerveny, M.; Yan, Z.; He, B. The VP35 protein of Ebola virus inhibits the antiviral effect mediated by double-stranded RNA-dependent protein kinase PKR. J. Virol., 2007, 81(1), 182-192.
[http://dx.doi.org/10.1128/JVI.01006-06] [PMID: 17065211]
[78]
Hartman, A.L.; Ling, L.; Nichol, S.T.; Hibberd, M.L. Whole-genome expression profiling reveals that inhibition of host innate immune response pathways by Ebola virus can be reversed by a single amino acid change in the VP35 protein. J. Virol., 2008, 82(11), 5348-5358.
[http://dx.doi.org/10.1128/JVI.00215-08] [PMID: 18353943]
[79]
Hartman, A.L.; Towner, J.S.; Nichol, S.T. A C-Terminal Basic Amino Acid Motif of Zaire Ebolavirus VP35 Is Essential for Type I Interferon Antagonism and Displays High Identity with the RNABinding Domain of Another Interferon Antagonist. NS1 Protein of Influenza A Virus, 2004, 328, 177-184.
[http://dx.doi.org/10.1016/j.virol.2004.07.006]
[80]
Hartman, A.L.; Dover, J.E.; Towner, J.S.; Nichol, S.T. Reverse Genetic Generation of Recombinant Zaire Ebola Viruses Containing Disrupted IRF-3 Inhibitory Domains Results in Attenuated Virus Growth In Vitro and Higher Levels of IRF-3 Activation without Inhibiting Viral Transcription or Replication., 2006, 80, 6430-6440.
[http://dx.doi.org/10.1128/JVI.00044-06]]
[81]
Zinzula, L.; Tramontano, E. Strategies of highly pathogenic RNA viruses to block dsRNA detection by RIG-I-like receptors: hide, mask, hit. Antiviral Res., 2013, 100(3), 615-635.
[http://dx.doi.org/10.1016/j.antiviral.2013.10.002] [PMID: 24129118]
[82]
Prins, K.C.; Cárdenas, W.B.; Basler, C.F. Ebola virus protein VP35 impairs the function of interferon regulatory factor-activating kinases IKKepsilon and TBK-1. J. Virol., 2009, 83(7), 3069-3077.
[http://dx.doi.org/10.1128/JVI.01875-08] [PMID: 19153231]
[83]
Chang, T.H.; Kubota, T.; Matsuoka, M.; Jones, S.; Bradfute, S.B.; Bray, M.; Ozato, K. Ebola Zaire virus blocks type I interferon production by exploiting the host SUMO modification machinery. PLoS Pathog., 2009, 5(6)e1000493
[http://dx.doi.org/10.1371/journal.ppat.1000493] [PMID: 19557165]
[84]
Chen, Z.J.; Sun, L.J. Nonproteolytic functions of ubiquitin in cell signaling. Mol. Cell, 2009, 33(3), 275-286.
[http://dx.doi.org/10.1016/j.molcel.2009.01.014] [PMID: 19217402]
[85]
Oudshoorn, D.; Versteeg, G.A.; Kikkert, M. Regulation of the innate immune system by ubiquitin and ubiquitin-like modifiers. Cytokine Growth Factor Rev., 2012, 23(6), 273-282.
[http://dx.doi.org/10.1016/j.cytogfr.2012.08.003] [PMID: 22964110]
[86]
Rajsbaum, R.; García-Sastre, A. Viral evasion mechanisms of early antiviral responses involving regulation of ubiquitin pathways. Trends Microbiol., 2013, 21(8), 421-429.
[http://dx.doi.org/10.1016/j.tim.2013.06.006] [PMID: 23850008]
[87]
Bharaj, P.; Atkins, C.; Luthra, P.; Giraldo, M.I.; Dawes, B.E.; Miorin, L.; Johnson, J.R.; Krogan, N.J.; Basler, C.F.; Freiberg, A.N.; Rajsbaum, R. The host E3-ubiquitin ligase TRIM6 ubiquitinates the ebola virus VP35 protein and promotes virus replication. J. Virol., 2017, 91(18)e00833
[88]
Rajsbaum, R.; Versteeg, G.A.; Schmid, S.; Maestre, A.M.; Belicha-Villanueva, A.; Martínez-Romero, C.; Patel, J.R.; Morrison, J.; Pisanelli, G.; Miorin, L.; Laurent-Rolle, M.; Moulton, H.M.; Stein, D.A.; Fernandez-Sesma, A.; tenOever, B.R.; García-Sastre, A. Unanchored K48-linked polyubiquitin synthesized by the E3-ubiquitin ligase TRIM6 stimulates the interferon-IKKε kinase-mediated antiviral response. Immunity, 2014, 40(6), 880-895.
[http://dx.doi.org/10.1016/j.immuni.2014.04.018] [PMID: 24882218]
[89]
Schümann, M.; Gantke, T.; Mühlberger, E. Ebola virus VP35 antagonizes PKR activity through its C-terminal interferon inhibitory domain. J. Virol., 2009, 83(17), 8993-8997.
[http://dx.doi.org/10.1128/JVI.00523-09] [PMID: 19515768]
[90]
Zhang, P.; Samuel, C.E. Induction of protein kinase PKR-dependent activation of interferon regulatory factor 3 by vaccinia virus occurs through adapter IPS-1 signaling. J. Biol. Chem., 2008, 283(50), 34580-34587.
[http://dx.doi.org/10.1074/jbc.M807029200] [PMID: 18927075]
[91]
McAllister, C.S.; Samuel, C.E. The RNA-activated protein kinase enhances the induction of interferon-β and apoptosis mediated by cytoplasmic RNA sensors. J. Biol. Chem., 2009, 284(3), 1644-1651.
[http://dx.doi.org/10.1074/jbc.M807888200] [PMID: 19028691]
[92]
Dalet, A.; Gatti, E.; Pierre, P. Integration of PKR-dependent translation inhibition with innate immunity is required for a coordinated anti-viral response. FEBS Lett., 2015, 589(14), 1539-1545.
[http://dx.doi.org/10.1016/j.febslet.2015.05.006] [PMID: 25979169]
[93]
Mateo, M.; Carbonnelle, C.; Martinez, M.J.; Reynard, O.; Page, A.; Volchkova, V.A.; Volchkov, V.E. Knockdown of Ebola virus VP24 impairs viral nucleocapsid assembly and prevents virus replication. J. Infect. Dis., 2011, 204(Suppl. 3), S892-S896.
[http://dx.doi.org/10.1093/infdis/jir311] [PMID: 21987766]
[94]
Huang, Y.; Xu, L.; Sun, Y.; Nabel, G.J. The assembly of Ebola virus nucleocapsid requires virion-associated proteins 35 and 24 and posttranslational modification of nucleoprotein. Mol. Cell, 2002, 10(2), 307-316.
[http://dx.doi.org/10.1016/S1097-2765(02)00588-9] [PMID: 12191476]
[95]
Han, Z.; Boshra, H.; Sunyer, J.O.; Zwiers, S.H.; Paragas, J.; Harty, R.N. Biochemical and functional characterization of the Ebola virus VP24 protein: implications for a role in virus assembly and budding. J. Virol., 2003, 77(3), 1793-1800.
[http://dx.doi.org/10.1128/JVI.77.3.1793-1800.2003] [PMID: 12525613]
[96]
Noda, T.; Ebihara, H.; Muramoto, Y.; Fujii, K.; Takada, A.; Sagara, H.; Jin, H.K.; Kida, H.; Feldmann, H.; Kawaoka, Y. Assembly and Budding of Ebolavirus. PLoS Pathog., 2006, 2(9)e99
[97]
Noda, T.; Halfmann, P.; Sagara, H.; Kawaoka, Y. Regions in Ebola virus VP24 that are important for nucleocapsid formation. J. Infect. Dis., 2007, 196(Suppl. 2), S247-S250.
[http://dx.doi.org/10.1086/520596] [PMID: 17940956]
[98]
Watanabe, S.; Watanabe, T.; Noda, T.; Takada, A.; Feldmann, H.; Jasenosky, L.D.; Kawaoka, Y. Production of novel ebola virus-like particles from cDNAs: an alternative to ebola virus generation by reverse genetics. J. Virol., 2004, 78(2), 999-1005.
[http://dx.doi.org/10.1128/JVI.78.2.999-1005.2004] [PMID: 14694131]
[99]
Watanabe, S.; Noda, T.; Halfmann, P.; Jasenosky, L.; Kawaoka, Y. Ebola virus (EBOV) VP24 inhibits transcription and replication of the EBOV genome. J. Infect. Dis., 2007, 196(Suppl. 2), S284-S290.
[http://dx.doi.org/10.1086/520582] [PMID: 17940962]
[100]
Zhang, A.P.P.; Bornholdt, Z.A.; Liu, T.; Abelson, D.M.; Lee, D.E.; Li, S.; Woods, V.L., Jr; Saphire, E.O. The ebola virus interferon antagonist VP24 directly binds STAT1 and has a novel, pyramidal fold. PLoS Pathog., 2012, 8(2)e1002550
[http://dx.doi.org/10.1371/journal.ppat.1002550] [PMID: 22383882]
[101]
Halfmann, P.; Neumann, G.; Kawaoka, Y. The Ebolavirus VP24 Protein Blocks Phosphorylation of P38 Mitogen-Activated Protein Kinase., 2011, 204, 953-956.
[http://dx.doi.org/10.1093/infdis/jir325]
[102]
Iversen, P.L.; Warren, T.K.; Wells, J.B.; Garza, N.L.; Mourich, D.V.; Welch, L.S.; Panchal, R.G.; Bavari, S. Discovery and early development of AVI-7537 and AVI-7288 for the treatment of Ebola virus and Marburg virus infections. Viruses, 2012, 4(11), 2806-2830.
[http://dx.doi.org/10.3390/v4112806] [PMID: 23202506]
[103]
Warren, T.K.; Whitehouse, C.A.; Wells, J.; Welch, L.; Heald, A.E.; Charleston, J.S.; Sazani, P.; Reid, P.; Iversen, P.L. A Single Phosphorodiamidate Morpholino Oligomer Targeting VP24 Protects Rhesus Monkeys against Lethal Ebola Virus Infection., 2015, 6, 1-4.
[http://dx.doi.org/10.1128/mBio.02344-14]
[104]
Ren, J.X.; Zhang, R.T.; Zhang, H.; Cao, X.S.; Liu, L.K.; Xie, Y. Identification of novel VP35 inhibitors: Virtual screening driven new scaffolds. Biomed. Pharmacother., 2016, 84, 199-207.
[http://dx.doi.org/10.1016/j.biopha.2016.09.034] [PMID: 27657828]
[105]
Glanzer, J.G.; Byrne, B.M.; McCoy, A.M.; James, B.J.; Frank, J.D.; Oakley, G.G. In silico and in vitro methods to identify ebola virus VP35-dsRNA inhibitors. Bioorg. Med. Chem., 2016, 24(21), 5388-5392.
[http://dx.doi.org/10.1016/j.bmc.2016.08.065] [PMID: 27642076]
[106]
Tambunan, U.S.F.; Siregar, S.; Toepak, E.P. Ebola Viral Protein 24 (VP24) Inhibitor Discovery by In Silico Fragment-Based Design. Int. J. GEOMATE Spec. Issue Sci. Eng. Environ., 2018, 15, 59-64.
[http://dx.doi.org/10.21660/2018.49.3534]
[107]
Seesuay, W.; Jittavisutthikul, S.; Sae-Lim, N.; Sookrung, N.; Sakolvaree, Y.; Chaicumpa, W. Human transbodies that interfere with the functions of Ebola virus VP35 protein in genome replication and transcription and innate immune antagonism. Emerg. Microbes Infect., 2018, 7(1), 41.
[http://dx.doi.org/10.1038/s41426-018-0031-3] [PMID: 29568066]
[108]
Shah, R.; Panda, P.K.; Patel, P.; Mumbai, N.; Farm, A.; Road, G.D. Pharmacophore based virtual screening and molecular docking studies of inherited compounds. World J. Pharm. Pharm. Sci., 2015, 4, 1268-1282.
[109]
Darapaneni, V. Virion Protein 24 of Ebola Virus as a Potential Drug Target. Am. J. Curr. Microbiol., 2014, 3, 14-22.
[110]
Chakraborty, S.; Rao, B.J.; Asgeirsson, B.; Dandekar, A.M. Correlating the Ability of VP24 Protein from Ebola and Marburg Viruses to Bind Human Karyopherin to Their Immune Suppression Mechanism and Pathogenicity Using Computational Methods. F1000 Res., 2015, 3, 1-17.
[111]
Song, X.; Lu, L.Y.; Passioura, T.; Suga, H. Macrocyclic peptide inhibitors for the protein-protein interaction of Zaire Ebola virus protein 24 and karyopherin alpha 5. Org. Biomol. Chem., 2017, 15(24), 5155-5160.
[http://dx.doi.org/10.1039/C7OB00012J] [PMID: 28574091]
[112]
Pleško, S.; Volk, H.; Lukšič, M.; Podlipnik, Č. In Silico Study of Plant Polyphenols’ Interactions with VP24-Ebola Virus Membrane-associated Protein. Acta Chim. Slov., 2015, 62(3), 555-564.
[http://dx.doi.org/10.17344/acsi.2015.1505] [PMID: 26454589]
[113]
Raj, U.; Varadwaj, P.K. Flavonoids as Multi-target Inhibitors for Proteins Associated with Ebola Virus: In Silico Discovery Using Virtual Screening and Molecular Docking Studies. Interdiscip. Sci., 2016, 8(2), 132-141.
[http://dx.doi.org/10.1007/s12539-015-0109-8] [PMID: 26286008]
[114]
Madrid, P.B.; Chopra, S.; Manger, I.D.; Gilfillan, L.; Keepers, T.R.; Shurtleff, A.C.; Green, C.E.; Iyer, L.V.; Dilks, H.H.; Davey, R.A.; Kolokoltsov, A.A.; Carrion, R., Jr; Patterson, J.L.; Bavari, S.; Panchal, R.G.; Warren, T.K.; Wells, J.B.; Moos, W.H.; Burke, R.L.L.; Tanga, M.J. A systematic screen of FDA-approved drugs for inhibitors of biological threat agents. PLoS One, 2013, 8(4)e60579
[http://dx.doi.org/10.1371/journal.pone.0060579] [PMID: 23577127]
[115]
Ekins, S.; Freundlich, J.S.; Coffee, M. A common feature pharmacophore for FDA-approved drugs inhibiting the Ebola virus. F1000 Res., 2014, 3, 277.
[http://dx.doi.org/10.12688/f1000research.5741.1] [PMID: 25653841]
[116]
Gignoux, E.; Azman, A.S.; de Smet, M.; Azuma, P.; Massaquoi, M.; Job, D.; Tiffany, A.; Petrucci, R.; Sterk, E.; Potet, J.; Suzuki, M.; Kurth, A.; Cannas, A.; Bocquin, A.; Strecker, T.; Logue, C.; Pottage, T.; Yue, C.; Cabrol, J.C.; Serafini, M.; Ciglenecki, I. Effect of Artesunate-Amodiaquine on Mortality Related to Ebola Virus Disease. N. Engl. J. Med., 2016, 374(1), 23-32.
[http://dx.doi.org/10.1056/NEJMoa1504605] [PMID: 26735991]
[117]
Bishop, B.M. Potential and emerging treatment options for Ebola virus disease. Ann. Pharmacother., 2015, 49(2), 196-206.
[http://dx.doi.org/10.1177/1060028014561227] [PMID: 25414384]
[118]
Dowall, S.D.; Bosworth, A.; Watson, R.; Bewley, K.; Taylor, I.; Rayner, E.; Hunter, L.; Pearson, G.; Easterbrook, L.; Pitman, J.; Hewson, R.; Carroll, M.W. Chloroquine inhibited Ebola virus replication in vitro but failed to protect against infection and disease in the in vivo guinea pig model. J. Gen. Virol., 2015, 96(12), 3484-3492.
[http://dx.doi.org/10.1099/jgv.0.000309] [PMID: 26459826]
[119]
Falzarano, D.; Safronetz, D.; Prescott, J.; Marzi, A.; Feldmann, F.; Feldmann, H. Lack of protection against ebola virus from chloroquine in mice and hamsters. Emerg. Infect. Dis., 2015, 21(6), 1065-1067.
[http://dx.doi.org/10.3201/eid2106.150176] [PMID: 25988934]
[120]
Zhao, Z.; Martin, C.; Fan, R.; Bourne, P.E.; Xie, L. Drug repurposing to target Ebola virus replication and virulence using structural systems pharmacology. BMC Bioinformatics, 2016, 17, 90.
[http://dx.doi.org/10.1186/s12859-016-0941-9] [PMID: 26887654]
[121]
Di Petrillo, A.; Fais, A.; Pintus, F.; Santos-Buelga, C.; González-Paramás, A.M.; Piras, V.; Orrù, G.; Mameli, A.; Tramontano, E.; Frau, A. Broad-range potential of Asphodelus microcarpus leaves extract for drug development. BMC Microbiol., 2017, 17(1), 159.
[http://dx.doi.org/10.1186/s12866-017-1068-5] [PMID: 28709400]
[122]
Daino, G.L.; Frau, A.; Sanna, C.; Rigano, D.; Distinto, S.; Madau, V.; Esposito, F.; Fanunza, E.; Bianco, G.; Taglialatela-Scafati, O.; Zinzula, L.; Maccioni, E.; Corona, A.; Tramontano, E. Identification of Myricetin as an Ebola Virus VP35-Double-Stranded RNA Interaction Inhibitor through a Novel Fluorescence-Based Assay. Biochemistry, 2018, 57(44), 6367-6378.
[http://dx.doi.org/10.1021/acs.biochem.8b00892] [PMID: 30298725]
[123]
Baikerikar, S. Curcumin and Natural Derivatives Inhibit Ebola Viral Proteins: An In silico Approach. Pharmacognosy Res., 2017, 9(Suppl. 1), S15-S22.
[http://dx.doi.org/10.4103/pr.pr_30_17] [PMID: 29333037]
[124]
Setlur, A.S.; Naik, S.Y.; Skariyachan, S. Herbal Lead as Ideal Bioactive Compounds Against Probable Drug Targets of Ebola Virus in Comparison with Known Chemical Analogue: A Computational Drug Discovery Perspective. Interdiscip. Sci., 2017, 9(2), 254-277.
[http://dx.doi.org/10.1007/s12539-016-0149-8] [PMID: 26857866]
[125]
Todorov, D.; Hinkov, A.; Shishkova, K.; Shishkov, S. Antiviral Potential of Bulgarian Medicinal Plants. Phytochem. Rev., 2014, 13, 525-538.
[http://dx.doi.org/10.1007/s11101-014-9357-1]
[126]
Makau, J.N.; Watanabe, K.; Kobayashi, N. Anti-influenza activity of Alchemilla mollis extract: possible virucidal activity against influenza virus particles. Drug Discov. Ther., 2013, 7(5), 189-195.
[http://dx.doi.org/10.5582/ddt.2013.v7.5.189] [PMID: 24270383]
[127]
Willför, S.; Ali, M.; Karonen, M.; Reunanen, M.; Arfan, M.; Harlamow, R. Extractives in Bark of Different Conifer Species Growing in Pakistan. Holzforschung, 2009, 63, 551-558.
[http://dx.doi.org/10.1515/HF.2009.095]
[128]
Kaul, T.N.; Middleton, E., Jr; Ogra, P.L. Antiviral effect of flavonoids on human viruses. J. Med. Virol., 1985, 15(1), 71-79.
[http://dx.doi.org/10.1002/jmv.1890150110] [PMID: 2981979]
[129]
Chery, J.; Petri, A.; Wagschal, A.; Lim, S-Y.; Cunningham, J.; Vasudevan, S.; Kauppinen, S.; Näär, A.M. Development of locked nucleic acid antisense oligonucleotides targeting ebola viral proteins and host factor niemann-pick C1. Nucleic Acid Ther., 2018, 28(5), 273-284.
[http://dx.doi.org/10.1089/nat.2018.0722] [PMID: 30133337]
[130]
Tanaka, K.; Kasahara, Y.; Miyamoto, Y.; Okuda, T.; Kasai, T.; Onodera, K.; Kuwahara, M.; Oka, M.; Yoneda, Y.; Obika, S. Development of oligonucleotide-based antagonists of Ebola virus protein 24 inhibiting its interaction with karyopherin alpha 1. Org. Biomol. Chem., 2018, 16(24), 4456-4463.
[http://dx.doi.org/10.1039/C8OB00706C] [PMID: 29850750]
[131]
Parren, P.W.; Geisbert, T.W.; Maruyama, T.; Jahrling, P.B.; Burton, D.R. Pre- and postexposure prophylaxis of Ebola virus infection in an animal model by passive transfer of a neutralizing human antibody. J. Virol., 2002, 76(12), 6408-6412.
[http://dx.doi.org/10.1128/JVI.76.12.6408-6412.2002] [PMID: 12021376]
[132]
Qiu, X.; Wong, G.; Audet, J.; Bello, A.; Fernando, L.; Alimonti, J.B.; Fausther-Bovendo, H.; Wei, H.; Aviles, J.; Hiatt, E.; Johnson, A.; Morton, J.; Swope, K.; Bohorov, O.; Bohorova, N.; Goodman, C.; Kim, D.; Pauly, M.H.; Velasco, J.; Pettitt, J.; Olinger, G.G.; Whaley, K.; Xu, B.; Strong, J.E.; Zeitlin, L.; Kobinger, G.P. Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp. Nature, 2014, 514(7520), 47-53.
[http://dx.doi.org/10.1038/nature13777] [PMID: 25171469]
[133]
Pettitt, J.; Zeitlin, L.; Kim, D.H.; Working, C.; Johnson, J.C.; Bohorov, O.; Bratcher, B.; Hiatt, E.; Hume, S.D.; Johnson, A.K.; Morton, J.; Pauly, M.H.; Whaley, K.J.; Ingram, M.F.; Zovanyi, A.; Heinrich, M.; Piper, A.; Zelko, J.; Olinger, G.G. Therapeutic intervention of Ebola virus infection in rhesus macaques with the MB-003 monoclonal antibody cocktail. Sci. Transl. Med., 2013, 5(199)199ra113
[http://dx.doi.org/10.1126/scitranslmed.3006608] [PMID: 23966302]
[134]
de La Vega, M-A.; Wong, G.; Kobinger, G.P.; Qiu, X. The multiple roles of sGP in Ebola pathogenesis. Viral Immunol., 2015, 28(1), 3-9.
[http://dx.doi.org/10.1089/vim.2014.0068] [PMID: 25354393]
[135]
Corti, D.; Misasi, J.; Mulangu, S.; Stanley, D.A.; Kanekiyo, M.; Wollen, S.; Ploquin, A.; Doria-Rose, N.A.; Staupe, R.P.; Bailey, M.; Shi, W.; Choe, M.; Marcus, H.; Thompson, E.A.; Cagigi, A.; Silacci, C.; Fernandez-Rodriguez, B.; Perez, L.; Sallusto, F.; Vanzetta, F.; Agatic, G.; Cameroni, E.; Kisalu, N.; Gordon, I.; Ledgerwood, J.E.; Mascola, J.R.; Graham, B.S.; Muyembe-Tamfun, J.J.; Trefry, J.C.; Lanzavecchia, A.; Sullivan, N.J. Protective Monotherapy against Lethal Ebola Virus Infection by a Potently Neutralizing Antibody. Science (80-.), 2016, 351(6279), 1339-1342.
[http://dx.doi.org/10.1126/science.aad5224]
[136]
Forthal, D.N. Functions of Antibodies. Microbiol. Spectr., 2014, 2(4), 1-17.
[PMID: 25215264]
[137]
Kristensen, M.; Birch, D.; Mørck Nielsen, H. Applications and Challenges for Use of Cell-Penetrating Peptides as Delivery Vectors for Peptide and Protein Cargos. Int. J. Mol. Sci., 2016, 17(2), 185.
[http://dx.doi.org/10.3390/ijms17020185] [PMID: 26840305]
[138]
Liu, J.; Gaj, T.; Patterson, J.T.; Sirk, S.J.; Barbas, C.F. III Cell-penetrating peptide-mediated delivery of TALEN proteins via bioconjugation for genome engineering. PLoS One, 2014, 9(1)e85755
[http://dx.doi.org/10.1371/journal.pone.0085755] [PMID: 24465685]

Rights & Permissions Print Cite
© 2025 Bentham Science Publishers | Privacy Policy
Request history8.2.27PHP Version1.16sRequest Duration28MBMemory UsageGET article/{article_id}/{param?}Route
  • warninglog[20:13:59] LOG.warning: Optional parameter $article_id declared before required parameter $request i...
  • warninglog[20:13:59] LOG.warning: trim(): Passing null to parameter #1 ($string) of type string is deprecated ...
  • warninglog[20:13:59] LOG.warning: Function strftime() is deprecated in /home/alphaeurekaselec/public_html/stor...
  • Booting (200ms)time
  • Application (957ms)time
  • 1 x Application (82.73%)
    957ms
    1 x Booting (17.27%)
    200ms
    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
    37 statements were executed, 4 of which were duplicates, 33 unique. Show only duplicated835ms
    • 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 ('59397798','',1,1740773639,1740773639) ON DUPLICATE KEY UPDATE visitor_count=visitor_count + 1, updated_on=1740773639
      1.51msalphaeurekaselec_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 ('59397798','/article/94748',1,1740773639,1740773639)
      290μsalphaeurekaselec_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 >= 59397798 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59397798) 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 >= 59397798 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59397798) 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 >= 59397798 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59397798) 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 >= 59397798 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59397798) 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 >= 59397798 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59397798) 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 >= 59397798 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59397798) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_trail WHERE to_ip >= 59397798 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59397798) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_corporate WHERE to_ip >= 59397798 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59397798) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_token WHERE to_ip >= 59397798 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59397798) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_trail WHERE to_ip >= 59397798 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59397798) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_corporate WHERE to_ip >= 59397798 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59397798) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_token WHERE to_ip >= 59397798 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59397798) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_trail WHERE to_ip >= 59397798 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59397798) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_corporate WHERE to_ip >= 59397798 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59397798) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_token WHERE to_ip >= 59397798 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59397798) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_disease_corporate WHERE to_ip >= 59397798 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59397798) limit 1
      191msalphaeurekaselec_live_10_06_2022UserAccess.php#784
      Bindings
      • 0: 59397798
      • 1: 59397798
      • 2: 59397798
      • 3: 59397798
      • 4: 59397798
      • 5: 59397798
      • 6: 59397798
      • 7: 59397798
      • 8: 59397798
      • 9: 59397798
      • 10: 59397798
      • 11: 59397798
      • 12: 59397798
      • 13: 59397798
      • 14: 59397798
      • 15: 59397798
      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=94748
      9.52msalphaeurekaselec_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` = 54 limit 1
      1.14msalphaeurekaselec_live_10_06_2022Journal.php#64
      Bindings
      • 0: 54
      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=54) and sj.journal_id!=54 group by `j`.`nid`) as `aggregate_table`
      10.39msalphaeurekaselec_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=54) and sj.journal_id!=54 group by `j`.`nid` order by `j`.`journal_id` asc limit 10 offset 0
      1.59msalphaeurekaselec_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=54) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid`) as `aggregate_table`
      8.14msalphaeurekaselec_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=54) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid` order by `v`.`ebook_volume_id` desc limit 10 offset 0
      7.29msalphaeurekaselec_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` = '94748'
      16.31msalphaeurekaselec_live_10_06_2022Keywords.php#43
      Bindings
      • 0: 94748
      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` = '94748'
      9.98msalphaeurekaselec_live_10_06_2022Article.php#1570
      Bindings
      • 0: 94748
      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` = '94748' group by `au`.`author_id` order by `au`.`article_id` asc, `au`.`sequence` asc
      8.23msalphaeurekaselec_live_10_06_2022Author.php#86
      Bindings
      • 0: 94748
      Backtrace
      • 13. app/Models/Author.php:86
      • 14. app/Http/Controllers/ArticleController.php:2533
      • 15. app/Http/Controllers/ArticleController.php:2035
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select `bo`.* from `bundle_offer` as `bo` where `bo`.`bundle_status` = 'A' order by `bo`.`bundle_id` desc
      890μsalphaeurekaselec_live_10_06_2022BundleOffer.php#57
      Bindings
      • 0: A
      Backtrace
      • 13. app/Models/BundleOffer.php:57
      • 14. app/Http/Controllers/ArticleController.php:2535
      • 15. app/Http/Controllers/ArticleController.php:2035
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select `subtitle` from `journal` where `continues_publication_journal` = 1
      770μsalphaeurekaselec_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 = 54 and i.is_uploaded = 1 order by v.volume_name+0 desc, i.title+0 desc limit 1
      76.68msalphaeurekaselec_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 = 54 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      99.59msalphaeurekaselec_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 = 54 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      20msalphaeurekaselec_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` = 94748 limit 1
      16.49msalphaeurekaselec_live_10_06_2022Article.php#744
      Bindings
      • 0: 94748
      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 = 94748 and content_type = 'article' order by status desc limit 1
      23.44msalphaeurekaselec_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 = 281 and cd.sub_disease_id = 523 and content_id!=94748 and cd.content_type = 'article' order by rand() limit 20
      210msalphaeurekaselec_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` = 167703 limit 1
      1.01msalphaeurekaselec_live_10_06_2022Meta.php#30
      Bindings
      • 0: 167703
      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
      1.51msalphaeurekaselec_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` = 'IDDT' and (h.proposal_closing_date = 0 OR TO_DAYS(FROM_UNIXTIME(h.proposal_closing_date)) >= TO_DAYS(NOW())) order by `h`.`manuscript` asc
      760μsalphaeurekaselec_live_10_06_2022Article.php#2025
      Bindings
      • 0: IDDT
      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 = '94748' 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) )
      2.84msalphaeurekaselec_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 = '9537' 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) )
      860μsalphaeurekaselec_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 = '2604' 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) )
      690μsalphaeurekaselec_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 <= 59397798 and j.to_ip >=59397798 )) and ((j.from_date <= 1740773639 and j.to_date >= 1740773639 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2604) 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 <= 59397798 and j.to_ip >=59397798 )) and ((j.from_date <= 1740773639 and j.to_date >= 1740773639 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2604) 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 <= 59397798 and j.to_ip >=59397798 )) and ((j.from_date <= 1740773639 and j.to_date >= 1740773639 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2604)
      75.44msalphaeurekaselec_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 <= 59397798 and j.to_ip >=59397798 )) and ((j.from_date <= 1740773639 and j.to_date >= 1740773639 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 9537) 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 <= 59397798 and j.to_ip >=59397798 )) and ((j.from_date <= 1740773639 and j.to_date >= 1740773639 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 9537) 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 <= 59397798 and j.to_ip >=59397798 )) and ((j.from_date <= 1740773639 and j.to_date >= 1740773639 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 9537)
      1.52msalphaeurekaselec_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 <= 59397798 and j.to_ip >=59397798 )) and ((j.from_date <= 1740773639 and j.to_date >= 1740773639 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 94748) 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 <= 59397798 and j.to_ip >=59397798 )) and ((j.from_date <= 1740773639 and j.to_date >= 1740773639 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 94748) 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 <= 59397798 and j.to_ip >=59397798 )) and ((j.from_date <= 1740773639 and j.to_date >= 1740773639 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 94748)
      900μsalphaeurekaselec_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` < '362' and is_uploaded = 1 and issue_id = 9537 order by cast(first_page as SIGNED) desc limit 1
      720μsalphaeurekaselec_live_10_06_2022Article.php#1819
      Bindings
      • 0: 362
      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` > '374' and is_uploaded = 1 and issue_id = 9537 order by cast(first_page as SIGNED) asc limit 1
      670μsalphaeurekaselec_live_10_06_2022Article.php#1831
      Bindings
      • 0: 374
      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'
      250μsalphaeurekaselec_live_10_06_2022ArticleController.php#2497
      Bindings
      • 0: en
      Backtrace
      • 14. app/Http/Controllers/ArticleController.php:2497
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:206
    • select `source_lang_label`, `target_lang_label` from `multilanguage_labels` where `target_lang_id` = 1
      310μsalphaeurekaselec_live_10_06_2022MultiLanguage.php#23
      Bindings
      • 0: 1
      Backtrace
      • 13. app/Models/MultiLanguage.php:23
      • 14. app/Http/Controllers/ArticleController.php:2498
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select `id` from `multilanguage_article` where `article_id` = 94748 limit 1
      3.64msalphaeurekaselec_live_10_06_2022ArticleController.php#2506
      Bindings
      • 0: 94748
      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` = 54 and `b`.`banner_from_date` <= 1740773639 and `b`.`banner_to_date` >= 1740773639 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      22.24msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 54
      • 3: 1740773639
      • 4: 1740773639
      • 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` = 54 and `b`.`banner_from_date` <= 1740773639 and `b`.`banner_to_date` >= 1740773639 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      8.37msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 54
      • 3: 1740773639
      • 4: 1740773639
      • 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='679be9ef5433a79204c5940bd7b45a7c'
      360μsalphaeurekaselec_live_10_06_2022Cart.php#271
      Backtrace
      • 15. app/Models/Cart.php:271
      • 16. view::layouts._header:291
      • 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
        JYgutB2T0PJCKrFIlQ0LUU8FCa9oGi0a8LUl3osA
        uc_cart_id
        679be9ef5433a79204c5940bd7b45a7c
        _previous
        array:1 [ "url" => "http://alpha.eurekaselect.com/article/94748" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /article/94748
        status_code
        200
        
        status_text
        OK
        format
        html
        content_type
        text/html; charset=UTF-8
        request_query
        []
        
        request_request
        []
        
        request_headers
        0 of 0
        array:8 [ "accept-encoding" => array:1 [ 0 => "gzip, deflate" ] "accept" => array:1 [ 0 => "text/html,application/xhtml+xml,application/xml;q=0.9,image/avif,image/webp,image/apng,*/*;q=0.8,application/signed-exchange;v=b3;q=0.7" ] "user-agent" => array:1 [ 0 => "Mozilla/5.0 AppleWebKit/537.36 (KHTML, like Gecko; compatible; ClaudeBot/1.0; +claudebot@anthropic.com)" ] "upgrade-insecure-requests" => array:1 [ 0 => "1" ] "cache-control" => array:1 [ 0 => "no-cache" ] "pragma" => array:1 [ 0 => "no-cache" ] "connection" => array:1 [ 0 => "keep-alive" ] "host" => array:1 [ 0 => "alpha.eurekaselect.com" ] ]
        request_cookies
        []
        
        response_headers
        0 of 0
        array:5 [ "content-type" => array:1 [ 0 => "text/html; charset=UTF-8" ] "cache-control" => array:1 [ 0 => "no-cache, private" ] "date" => array:1 [ 0 => "Fri, 28 Feb 2025 20:13:59 GMT" ] "set-cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6IkwwaTl2V2xhclVGaVBmTWFOd0R4Z3c9PSIsInZhbHVlIjoiQnBvMERCTXUzUVpkeHIvL09wZHIwTzllNWRWQS9UcSt6NkQ3RVVqL3FwcDV0ckhFaU9GdHMreHJJa2VKQ0pBOUZGL1ZLWGQ3S3M1SlVIOUdzQ1k2OS9qUmZ0SiswVWlVZE1hbXdick9wcTVYVGJNTlJXRTN1UGtsN0ZjU1hReWIiLCJtYWMiOiJiOTYyZGQzMjY3OTc4MjkxOWZiNjY3MmE1YTMyYjg2MzcyOGIxODdiMjdjNGUyZjk0ODJkZTRhMzY2NjIwN2FkIiwidGFnIjoiIn0%3D; expires=Mon, 03 Mar 2025 08:14:00 GMT; Max-Age=216000; path=/; secure; samesite=laxXSRF-TOKEN=eyJpdiI6IkwwaTl2V2xhclVGaVBmTWFOd0R4Z3c9PSIsInZhbHVlIjoiQnBvMERCTXUzUVpkeHIvL09wZHIwTzllNWRWQS9UcSt6NkQ3RVVqL3FwcDV0ckhFaU9GdHMreHJJa2VKQ0pBOUZGL1ZLW" 1 => "alphaeurekaselectnet_session=eyJpdiI6Imh2akNxNHZmbkVDczYwbjNKazBLa2c9PSIsInZhbHVlIjoicEppNm1iNDluM2w2KzNvMlJ4UDJtRmlHclBCdkswYUFULzZLeDZmcVFLRXZIV1NqSm1LOUZ6eVlyb3owaWkzU1A0M2l1NG1RVTZhZEZ2ZDlMVEpmcGtiYTlmWUlrSUNJTG8vb3c5T05EU0cyb0gvVzZ4ekVvZnhhMDZ0RlRXVDAiLCJtYWMiOiJhOTE4NjFhYWNhNGVmZTBmMGY4NTc5YzNhOGI0MzcxODVkMzUxNWVhNzIxNWIyYzJjYzljNDg5OTBjNGFkNDQyIiwidGFnIjoiIn0%3D; path=/; secure; httponly; samesite=laxalphaeurekaselectnet_session=eyJpdiI6Imh2akNxNHZmbkVDczYwbjNKazBLa2c9PSIsInZhbHVlIjoicEppNm1iNDluM2w2KzNvMlJ4UDJtRmlHclBCdkswYUFULzZLeDZmcVFLRXZIV1NqSm1LOUZ6eVl" ] "Set-Cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6IkwwaTl2V2xhclVGaVBmTWFOd0R4Z3c9PSIsInZhbHVlIjoiQnBvMERCTXUzUVpkeHIvL09wZHIwTzllNWRWQS9UcSt6NkQ3RVVqL3FwcDV0ckhFaU9GdHMreHJJa2VKQ0pBOUZGL1ZLWGQ3S3M1SlVIOUdzQ1k2OS9qUmZ0SiswVWlVZE1hbXdick9wcTVYVGJNTlJXRTN1UGtsN0ZjU1hReWIiLCJtYWMiOiJiOTYyZGQzMjY3OTc4MjkxOWZiNjY3MmE1YTMyYjg2MzcyOGIxODdiMjdjNGUyZjk0ODJkZTRhMzY2NjIwN2FkIiwidGFnIjoiIn0%3D; expires=Mon, 03-Mar-2025 08:14:00 GMT; path=/; secureXSRF-TOKEN=eyJpdiI6IkwwaTl2V2xhclVGaVBmTWFOd0R4Z3c9PSIsInZhbHVlIjoiQnBvMERCTXUzUVpkeHIvL09wZHIwTzllNWRWQS9UcSt6NkQ3RVVqL3FwcDV0ckhFaU9GdHMreHJJa2VKQ0pBOUZGL1ZLW" 1 => "alphaeurekaselectnet_session=eyJpdiI6Imh2akNxNHZmbkVDczYwbjNKazBLa2c9PSIsInZhbHVlIjoicEppNm1iNDluM2w2KzNvMlJ4UDJtRmlHclBCdkswYUFULzZLeDZmcVFLRXZIV1NqSm1LOUZ6eVlyb3owaWkzU1A0M2l1NG1RVTZhZEZ2ZDlMVEpmcGtiYTlmWUlrSUNJTG8vb3c5T05EU0cyb0gvVzZ4ekVvZnhhMDZ0RlRXVDAiLCJtYWMiOiJhOTE4NjFhYWNhNGVmZTBmMGY4NTc5YzNhOGI0MzcxODVkMzUxNWVhNzIxNWIyYzJjYzljNDg5OTBjNGFkNDQyIiwidGFnIjoiIn0%3D; path=/; secure; httponlyalphaeurekaselectnet_session=eyJpdiI6Imh2akNxNHZmbkVDczYwbjNKazBLa2c9PSIsInZhbHVlIjoicEppNm1iNDluM2w2KzNvMlJ4UDJtRmlHclBCdkswYUFULzZLeDZmcVFLRXZIV1NqSm1LOUZ6eVl" ] ]
        session_attributes
        0 of 0
        array:5 [ "_token" => "JYgutB2T0PJCKrFIlQ0LUU8FCa9oGi0a8LUl3osA" "uc_cart_id" => "679be9ef5433a79204c5940bd7b45a7c" "_previous" => array:1 [ "url" => "http://alpha.eurekaselect.com/article/94748" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-28 20:14:00GET/article/94748314371