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Current Drug Metabolism

Editor-in-Chief

ISSN (Print): 1389-2002
ISSN (Online): 1875-5453

Review Article

Framework Nucleic Acids: A Promising Vehicle for Small Molecular Cargos

Author(s): Junjiang Zhang, Jiayin Li, Lei Sui and Yanjing Li*

Volume 24, Issue 5, 2023

Published on: 14 February, 2023

Page: [353 - 366] Pages: 14

DOI: 10.2174/1389200224666230120124402

Price: $65

Abstract

Framework nucleic acids (FNAs), which are a series of self-assembled DNA nanostructures, are highly versatile tools for engineering intelligent molecular delivery vehicles. Owing to their precise and controllable design and construction, excellent programmability and functionality, as well as favorable intercalation between DNA and small molecules, FNAs provide a promising approach for small molecule delivery. This review discusses the advantages, applications, and current challenges of FNAs for the delivery of small molecular cargo. First, the physicochemical and biological properties that make FNAs favorable for the transport of small molecules are introduced. Thereafter, the classification of loaded cargos and the mechanism of combination between small molecules and FNAs are summarized in detail, and recent research on FNA-based delivery systems and their applications are highlighted. Finally, the challenges and prospects of FNA nanocarriers are discussed to advance their exploitation and clinical adoption.

Graphical Abstract

[1]
Seeman, N.C. Nucleic acid junctions and lattices. J. Theor. Biol., 1982, 99(2), 237-247.
[http://dx.doi.org/10.1016/0022-5193(82)90002-9] [PMID: 6188926]
[2]
Winfree, E.; Liu, F.; Wenzler, L.A.; Seeman, N.C. Design and self-assembly of two-dimensional DNA crystals. Nature, 1998, 394(6693), 539-544.
[http://dx.doi.org/10.1038/28998] [PMID: 9707114]
[3]
Yan, H.; Park, S.H.; Finkelstein, G.; Reif, J.H.; LaBean, T.H. DNA-templated self-assembly of protein arrays and highly conductive nanowires. Science, 2003, 301(5641), 1882-1884.
[http://dx.doi.org/10.1126/science.1089389] [PMID: 14512621]
[4]
Zheng, J.; Birktoft, J.J.; Chen, Y.; Wang, T.; Sha, R.; Constantinou, P.E.; Ginell, S.L.; Mao, C.; Seeman, N.C. From molecular to macroscopic via the rational design of a self-assembled 3D DNA crystal. Nature, 2009, 461(7260), 74-77.
[http://dx.doi.org/10.1038/nature08274] [PMID: 19727196]
[5]
Goodman, R.P.; Schaap, I.A.T.; Tardin, C.F.; Erben, C.M.; Berry, R.M.; Schmidt, C.F.; Turberfield, A.J. Rapid chiral assembly of rigid DNA building blocks for molecular nanofabrication. Science, 2005, 310(5754), 1661-1665.
[http://dx.doi.org/10.1126/science.1120367] [PMID: 16339440]
[6]
Zhang, T.; Tian, T.; Lin, Y. Functionalizing framework nucleic-acid-based nanostructures for biomedical application. Adv. Mater., 2022, 34(46), 2107820.
[http://dx.doi.org/10.1002/adma.202107820] [PMID: 34787933]
[7]
Schüller, V.J.; Heidegger, S.; Sandholzer, N.; Nickels, P.C.; Suhartha, N.A.; Endres, S.; Bourquin, C.; Liedl, T. Cellular immunostimulation by CpG-sequence-coated DNA origami structures. ACS Nano, 2011, 5(12), 9696-9702.
[http://dx.doi.org/10.1021/nn203161y] [PMID: 22092186]
[8]
Shen, X.; Jiang, Q.; Wang, J.; Dai, L.; Zou, G.; Wang, Z.G.; Chen, W.Q.; Jiang, W.; Ding, B. Visualization of the intracellular location and stability of DNA origami with a label-free fluorescent probe. Chem. Commun. (Camb.), 2012, 48(92), 11301-11303.
[http://dx.doi.org/10.1039/c2cc36185j] [PMID: 23073289]
[9]
Rothemund, P.W.K. Folding DNA to create nanoscale shapes and patterns. Nature, 2006, 440(7082), 297-302.
[http://dx.doi.org/10.1038/nature04586] [PMID: 16541064]
[10]
Douglas, S.M.; Dietz, H.; Liedl, T.; Högberg, B.; Graf, F.; Shih, W.M. Self-assembly of DNA into nanoscale three-dimensional shapes. Nature, 2009, 459(7245), 414-418.
[http://dx.doi.org/10.1038/nature08016] [PMID: 19458720]
[11]
Andersen, E.S.; Dong, M.; Nielsen, M.M.; Jahn, K.; Subramani, R.; Mamdouh, W.; Golas, M.M.; Sander, B.; Stark, H.; Oliveira, C.L.P.; Pedersen, J.S.; Birkedal, V.; Besenbacher, F.; Gothelf, K.V.; Kjems, J. Self-assembly of a nanoscale DNA box with a controllable lid. Nature, 2009, 459(7243), 73-76.
[http://dx.doi.org/10.1038/nature07971] [PMID: 19424153]
[12]
Benson, E.; Mohammed, A.; Gardell, J.; Masich, S.; Czeizler, E.; Orponen, P.; Högberg, B. DNA rendering of polyhedral meshes at the nanoscale. Nature, 2015, 523(7561), 441-444.
[http://dx.doi.org/10.1038/nature14586] [PMID: 26201596]
[13]
Wei, B.; Dai, M.; Yin, P. Complex shapes self-assembled from single-stranded DNA tiles. Nature, 2012, 485(7400), 623-626.
[http://dx.doi.org/10.1038/nature11075] [PMID: 22660323]
[14]
Tikhomirov, G.; Petersen, P.; Qian, L. Fractal assembly of micrometre-scale DNA origami arrays with arbitrary patterns. Nature, 2017, 552(7683), 67-71.
[http://dx.doi.org/10.1038/nature24655] [PMID: 29219965]
[15]
Douglas, S.M.; Marblestone, A.H.; Teerapittayanon, S.; Vazquez, A.; Church, G.M.; Shih, W.M. Rapid prototyping of 3D DNA-origami shapes with caDNAno. Nucleic Acids Res., 2009, 37(15), 5001-5006.
[http://dx.doi.org/10.1093/nar/gkp436] [PMID: 19531737]
[16]
Gustafson, R.; Källmén, H. Alcohol effects on cognitive and personality style in women with special reference to primary and secondary process. Alcohol. Clin. Exp. Res., 1989, 13(5), 644-648.
[http://dx.doi.org/10.1111/j.1530-0277.1989.tb00397.x] [PMID: 2688462]
[17]
Liu, Z.; Li, Y.; Tian, C.; Mao, C. A smart DNA tetrahedron that isothermally assembles or dissociates in response to the solution pH value changes. Biomacromolecules, 2013, 14(6), 1711-1714.
[http://dx.doi.org/10.1021/bm400426f] [PMID: 23647463]
[18]
Ge, Z.; Gu, H.; Li, Q.; Fan, C. Concept and development of framework nucleic acids. J. Am. Chem. Soc., 2018, 140(51), 17808-17819.
[http://dx.doi.org/10.1021/jacs.8b10529] [PMID: 30516961]
[19]
Veneziano, R.; Ratanalert, S.; Zhang, K.; Zhang, F.; Yan, H.; Chiu, W.; Bathe, M. Designer nanoscale DNA assemblies programmed from the top down. Science, 2016, 352(6293), 1534.
[http://dx.doi.org/10.1126/science.aaf4388] [PMID: 27229143]
[20]
Mokhtarzadeh, A.; Vahidnezhad, H.; Youssefian, L.; Mosafer, J.; Baradaran, B.; Uitto, J. Applications of spherical nucleic acid nanoparticles as delivery systems. Trends Mol. Med., 2019, 25(12), 1066-1079.
[http://dx.doi.org/10.1016/j.molmed.2019.08.012] [PMID: 31703931]
[21]
Kollmann, F.; Ramakrishnan, S.; Shen, B.; Grundmeier, G.; Kostiainen, M.A.; Linko, V.; Keller, A. Superstructure-dependent loading of DNA origami nanostructures with a groove-binding drug. ACS Omega, 2018, 3(8), 9441-9448.
[http://dx.doi.org/10.1021/acsomega.8b00934] [PMID: 31459078]
[22]
Ramakrishnan, S.; Ijäs, H.; Linko, V.; Keller, A. Structural stability of DNA origami nanostructures under application-specific conditions. Comput. Struct. Biotechnol. J., 2018, 16, 342-349.
[http://dx.doi.org/10.1016/j.csbj.2018.09.002] [PMID: 30305885]
[23]
Castro, C.E.; Kilchherr, F.; Kim, D.N.; Shiao, E.L.; Wauer, T.; Wortmann, P.; Bathe, M.; Dietz, H. A primer to scaffolded DNA origami. Nat. Methods, 2011, 8(3), 221-229.
[http://dx.doi.org/10.1038/nmeth.1570] [PMID: 21358626]
[24]
Perrault, S.D.; Shih, W.M. Virus-inspired membrane encapsulation of DNA nanostructures to achieve in vivo stability. ACS Nano, 2014, 8(5), 5132-5140.
[http://dx.doi.org/10.1021/nn5011914] [PMID: 24694301]
[25]
Mikkilä, J.; Eskelinen, A.P.; Niemelä, E.H.; Linko, V.; Frilander, M.J.; Törmä, P.; Kostiainen, M.A. Virus-encapsulated DNA origami nanostructures for cellular delivery. Nano Lett., 2014, 14(4), 2196-2200.
[http://dx.doi.org/10.1021/nl500677j] [PMID: 24627955]
[26]
Ahmadi, Y.; De Llano, E.; Barišić, I. (Poly)cation-induced protection of conventional and wireframe DNA origami nanostructures. Nanoscale, 2018, 10(16), 7494-7504.
[http://dx.doi.org/10.1039/C7NR09461B] [PMID: 29637957]
[27]
Zeng, Y.; Liu, J.; Yang, S.; Liu, W.; Xu, L.; Wang, R. Time-lapse live cell imaging to monitor doxorubicin release from DNA origami nanostructures. J. Mater. Chem. B Mater. Biol. Med., 2018, 6(11), 1605-1612.
[http://dx.doi.org/10.1039/C7TB03223D] [PMID: 30221004]
[28]
Shi, S.; Li, Y.; Zhang, T.; Xiao, D.; Tian, T.; Chen, T.; Zhang, Y.; Li, X.; Lin, Y. Biological effect of differently sized tetrahedral framework nucleic acids: Endocytosis, proliferation, migration, and biodistribution. ACS Appl. Mater. Interfaces, 2021, 13(48), 57067-57074.
[http://dx.doi.org/10.1021/acsami.1c20657] [PMID: 34802237]
[29]
Tian, T.; Zhang, C.; Li, J.; Liu, Y.; Wang, Y.; Ke, X. Proteomic exploration of endocytosis of framework nucleic acids. Small, 2021, 17(23), e2100837.
[30]
Liang, L.; Li, J.; Li, Q.; Huang, Q.; Shi, J.; Yan, H.; Fan, C. Single-particle tracking and modulation of cell entry pathways of a tetrahedral DNA nanostructure in live cells. Angew. Chem. Int. Ed., 2014, 53(30), 7745-7750.
[http://dx.doi.org/10.1002/anie.201403236] [PMID: 24827912]
[31]
Tian, T.; Zhang, T.; Zhou, T.; Lin, S.; Shi, S.; Lin, Y. Synthesis of an ethyleneimine/tetrahedral DNA nanostructure complex and its potential application as a multi-functional delivery vehicle. Nanoscale, 2017, 9(46), 18402-18412.
[http://dx.doi.org/10.1039/C7NR07130B] [PMID: 29147695]
[32]
Li, Q.; Zhao, D.; Shao, X.; Lin, S.; Xie, X.; Liu, M.; Ma, W.; Shi, S.; Lin, Y. Aptamer-modified tetrahedral DNA nanostructure for tumor-targeted drug delivery. ACS Appl. Mater. Interfaces, 2017, 9(42), 36695-36701.
[http://dx.doi.org/10.1021/acsami.7b13328] [PMID: 28991436]
[33]
Wiraja, C.; Zhu, Y.; Lio, D.C.S.; Yeo, D.C.; Xie, M.; Fang, W.; Li, Q.; Zheng, M.; Van Steensel, M.; Wang, L.; Fan, C.; Xu, C. Framework nucleic acids as programmable carrier for transdermal drug delivery. Nat. Commun., 2019, 10(1), 1147.
[http://dx.doi.org/10.1038/s41467-019-09029-9] [PMID: 30850596]
[34]
Hasanzadeh, M.; Shadjou, N. Pharmacogenomic study using bio- and nanobioelectrochemistry: Drug–DNA interaction. Mater. Sci. Eng. C, 2016, 61, 1002-1017.
[http://dx.doi.org/10.1016/j.msec.2015.12.020] [PMID: 26838928]
[35]
Ijäs, H.; Shen, B.; Heuer-Jungemann, A.; Keller, A.; Kostiainen, M.A.; Liedl, T.; Ihalainen, J.A.; Linko, V. Unraveling the interaction between doxorubicin and DNA origami nanostructures for customizable chemotherapeutic drug release. Nucleic Acids Res., 2021, 49(6), 3048-3062.
[http://dx.doi.org/10.1093/nar/gkab097] [PMID: 33660776]
[36]
Zhang, Q.; Jiang, Q.; Li, N.; Dai, L.; Liu, Q.; Song, L.; Wang, J.; Li, Y.; Tian, J.; Ding, B.; Du, Y. DNA origami as an in vivo drug delivery vehicle for cancer therapy. ACS Nano, 2014, 8(7), 6633-6643.
[http://dx.doi.org/10.1021/nn502058j] [PMID: 24963790]
[37]
Zhao, Y.X.; Shaw, A.; Zeng, X.; Benson, E.; Nyström, A.M.; Högberg, B. DNA origami delivery system for cancer therapy with tunable release properties. ACS Nano, 2012, 6(10), 8684-8691.
[http://dx.doi.org/10.1021/nn3022662] [PMID: 22950811]
[38]
Ge, Z.; Guo, L.; Wu, G.; Li, J.; Sun, Y.; Hou, Y. DNA origami-enabled engineering of ligand-drug conjugates for targeted drug delivery. Small, 2020, 16(16), e1904857.
[39]
Sun, P.; Zhang, N.; Tang, Y.; Yang, Y.; Chu, X.; Zhao, Y. SL2B aptamer and folic acid dual-targeting DNA nanostructures for synergic biological effect with chemotherapy to combat colorectal cancer. Int. J. Nanomedicine, 2017, 12, 2657-2672.
[http://dx.doi.org/10.2147/IJN.S132929] [PMID: 28435250]
[40]
Liu, M.; Ma, W.; Zhao, D.; Li, J.; Li, Q.; Liu, Y.; Hao, L.; Lin, Y. Enhanced penetrability of a tetrahedral framework nucleic acid by modification with iRGD for DOX-targeted delivery to triple-negative breast cancer. ACS Appl. Mater. Interfaces, 2021, 13(22), 25825-25835.
[http://dx.doi.org/10.1021/acsami.1c07297] [PMID: 34038071]
[41]
Xia, Z.; Wang, P.; Liu, X.; Liu, T.; Yan, Y.; Yan, J.; Zhong, J.; Sun, G.; He, D. Tumor-penetrating peptide-modified DNA tetrahedron for targeting drug delivery. Biochemistry, 2016, 55(9), 1326-1331.
[http://dx.doi.org/10.1021/acs.biochem.5b01181] [PMID: 26789283]
[42]
Shi, S.; Fu, W.; Lin, S.; Tian, T.; Li, S.; Shao, X.; Zhang, Y.; Zhang, T.; Tang, Z.; Zhou, Y.; Lin, Y.; Cai, X. Targeted and effective glioblastoma therapy via aptamer-modified tetrahedral framework nucleic acid-paclitaxel nanoconjugates that can pass the blood brain barrier. Nanomedicine, 2019, 21, 102061.
[http://dx.doi.org/10.1016/j.nano.2019.102061] [PMID: 31344499]
[43]
Xie, X.; Shao, X.; Ma, W.; Zhao, D.; Shi, S.; Li, Q.; Lin, Y. Overcoming drug-resistant lung cancer by paclitaxel loaded tetrahedral DNA nanostructures. Nanoscale, 2018, 10(12), 5457-5465.
[http://dx.doi.org/10.1039/C7NR09692E] [PMID: 29484330]
[44]
Zhong, Y.F.; Cheng, J.; Liu, Y.; Luo, T.; Wang, Y.; Jiang, K. DNA nanostructures as Pt(IV) prodrug delivery systems to combat chemoresistance. Small, 2020, 16(38), e2003646.
[45]
Jorge, A.F.; Aviñó, A.; Pais, A.A.C.C.; Eritja, R.; Fàbrega, C. DNA-based nanoscaffolds as vehicles for 5-fluoro-2'-deoxyuridine oligomers in colorectal cancer therapy. Nanoscale, 2018, 10(15), 7238-7249.
[http://dx.doi.org/10.1039/C7NR08442K] [PMID: 29632908]
[46]
Ma, W.; Yang, Y.; Zhu, J.; Jia, W.; Zhang, T.; Liu, Z. Biomimetic nanoerythrosome-coated aptamer-DNA tetrahedron/maytansine conjugates: pH-responsive and targeted cytotoxicity for HER2-positive breast cancer. Advanced materials, 2022, 2022, e2109609.
[47]
Zhuang, X.; Ma, X.; Xue, X.; Jiang, Q.; Song, L.; Dai, L.; Zhang, C.; Jin, S.; Yang, K.; Ding, B.; Wang, P.C.; Liang, X.J. A photosensitizer-loaded DNA origami nanosystem for photodynamic therapy. ACS Nano, 2016, 10(3), 3486-3495.
[http://dx.doi.org/10.1021/acsnano.5b07671] [PMID: 26950644]
[48]
Shaukat, A.; Anaya-Plaza, E.; Julin, S.; Linko, V.; Torres, T.; de la Escosura, A.; Kostiainen, M.A. Phthalocyanine–DNA origami complexes with enhanced stability and optical properties. Chem. Commun., 2020, 56(53), 7341-7344.
[http://dx.doi.org/10.1039/D0CC01916J] [PMID: 32483566]
[49]
Kim, K.R.; Bang, D.; Ahn, D.R. Nano-formulation of a photosensitizer using a DNA tetrahedron and its potential for in vivo photodynamic therapy. Biomater. Sci., 2016, 4(4), 605-609.
[http://dx.doi.org/10.1039/C5BM00467E] [PMID: 26674121]
[50]
Wright, G.D. Antibiotic adjuvants: Rescuing antibiotics from resistance. Trends Microbiol., 2016, 24(11), 862-871.
[http://dx.doi.org/10.1016/j.tim.2016.06.009] [PMID: 27430191]
[51]
Bhattacharya, P.; Mukherjee, S.; Mandal, S.M. Fluoroquinolone antibiotics show genotoxic effect through DNA-binding and oxidative damage. Spectrochim. Acta A Mol. Biomol. Spectrosc., 2020, 227, 117634.
[http://dx.doi.org/10.1016/j.saa.2019.117634] [PMID: 31756649]
[52]
Halley, P.D.; Lucas, C.R.; McWilliams, E.M.; Webber, M.J.; Patton, R.A.; Kural, C. Daunorubicin-loaded DNA origami nanostructures circumvent drug-resistance mechanisms in a leukemia model. Small, 2016, 12(3), 308-320.
[53]
Sun, Y.; Li, S.; Zhang, Y.; Li, Q.; Xie, X.; Zhao, D.; Tian, T.; Shi, S.; Meng, L.; Lin, Y. Tetrahedral framework nucleic acids loading ampicillin improve the drug susceptibility against methicillin-resistant Staphylococcus aureus. ACS Appl. Mater. Interfaces, 2020, 12(33), 36957-36966.
[http://dx.doi.org/10.1021/acsami.0c11249] [PMID: 32814381]
[54]
Sun, Y.; Liu, Y.; Zhang, B.; Shi, S.; Zhang, T.; Zhao, D.; Tian, T.; Li, Q.; Lin, Y. Erythromycin loaded by tetrahedral framework nucleic acids are more antimicrobial sensitive against Escherichia coli (E. coli). Bioact. Mater., 2021, 6(8), 2281-2290.
[http://dx.doi.org/10.1016/j.bioactmat.2020.12.027] [PMID: 33553815]
[55]
Mela, I.; Vallejo-Ramirez, P.P.; Makarchuk, S.; Christie, G.; Bailey, D.; Henderson, R.M.; Sugiyama, H.; Endo, M.; Kaminski, C.F. DNA nanostructures for targeted antimicrobial delivery. Angew. Chem. Int. Ed., 2020, 59(31), 12698-12702.
[http://dx.doi.org/10.1002/anie.202002740] [PMID: 32297692]
[56]
Pastor, R.F.; Restani, P.; Di Lorenzo, C.; Orgiu, F.; Teissedre, P.L.; Stockley, C.; Ruf, J.C.; Quini, C.I.; Garcìa Tejedor, N.; Gargantini, R.; Aruani, C.; Prieto, S.; Murgo, M.; Videla, R.; Penissi, A.; Iermoli, R.H. Resveratrol, human health and winemaking perspectives. Crit. Rev. Food Sci. Nutr., 2019, 59(8), 1237-1255.
[http://dx.doi.org/10.1080/10408398.2017.1400517] [PMID: 29206058]
[57]
Xu, M.; Pirtskhalava, T.; Farr, J.N.; Weigand, B.M.; Palmer, A.K.; Weivoda, M.M.; Inman, C.L.; Ogrodnik, M.B.; Hachfeld, C.M.; Fraser, D.G.; Onken, J.L.; Johnson, K.O.; Verzosa, G.C.; Langhi, L.G.P.; Weigl, M.; Giorgadze, N.; LeBrasseur, N.K.; Miller, J.D.; Jurk, D.; Singh, R.J.; Allison, D.B.; Ejima, K.; Hubbard, G.B.; Ikeno, Y.; Cubro, H.; Garovic, V.D.; Hou, X.; Weroha, S.J.; Robbins, P.D.; Niedernhofer, L.J.; Khosla, S.; Tchkonia, T.; Kirkland, J.L. Senolytics improve physical function and increase lifespan in old age. Nat. Med., 2018, 24(8), 1246-1256.
[http://dx.doi.org/10.1038/s41591-018-0092-9] [PMID: 29988130]
[58]
Srinivasan, K. Biological activities of red pepper (Capsicum annuum) and its pungent principle capsaicin: A review. Crit. Rev. Food Sci. Nutr., 2016, 56(9), 1488-1500.
[http://dx.doi.org/10.1080/10408398.2013.772090] [PMID: 25675368]
[59]
Ma, N.; Zhang, Z.; Liao, F.; Jiang, T.; Tu, Y. The birth of artemisinin. Pharmacol. Ther., 2020, 216, 107658.
[http://dx.doi.org/10.1016/j.pharmthera.2020.107658] [PMID: 32777330]
[60]
Hussain, I.; Fatima, S.; Siddiqui, S.; Ahmed, S.; Tabish, M. Exploring the binding mechanism of β-resorcylic acid with calf thymus DNA: Insights from multi-spectroscopic, thermodynamic and bioinformatics approaches. Spectrochim. Acta A Mol. Biomol. Spectrosc., 2021, 260, 119952.
[http://dx.doi.org/10.1016/j.saa.2021.119952] [PMID: 34052761]
[61]
Platella, C.; Mazzini, S.; Napolitano, E.; Mattio, L.M.; Beretta, G.L.; Zaffaroni, N.; Pinto, A.; Montesarchio, D.; Dallavalle, S. Plant-derived stilbenoids as DNA-binding agents: From monomers to dimers. Chemistry, 2021, 27(34), 8832-8845.
[http://dx.doi.org/10.1002/chem.202101229] [PMID: 33890349]
[62]
Sirong, S.; Yang, C.; Taoran, T.; Songhang, L.; Shiyu, L.; Yuxin, Z.; Xiaoru, S.; Tao, Z.; Yunfeng, L.; Xiaoxiao, C. Effects of tetrahedral framework nucleic acid/wogonin complexes on osteoarthritis. Bone Res., 2020, 8(1), 6.
[http://dx.doi.org/10.1038/s41413-019-0077-4] [PMID: 32047705]
[63]
Zhang, M.; Zhang, X.; Tian, T.; Zhang, Q.; Wen, Y.; Zhu, J.; Xiao, D.; Cui, W.; Lin, Y. Anti-inflammatory activity of curcumin-loaded tetrahedral framework nucleic acids on acute gouty arthritis. Bioact. Mater., 2022, 8, 368-380.
[http://dx.doi.org/10.1016/j.bioactmat.2021.06.003] [PMID: 34541407]
[64]
Li, Y.; Gao, S.; Shi, S.; Xiao, D.; Peng, S.; Gao, Y.; Zhu, Y.; Lin, Y. Tetrahedral framework nucleic acid-based delivery of resveratrol alleviates insulin resistance: From innate to adaptive immunity. Nano-Micro Lett., 2021, 13(1), 86.
[http://dx.doi.org/10.1007/s40820-021-00614-6] [PMID: 34138319]
[65]
Cui, W.; Yang, X.; Chen, X.; Xiao, D.; Zhu, J.; Zhang, M.; Qin, X.; Ma, X.; Lin, Y. Treating LRRK2-Related Parkinson’s disease by inhibiting the mtor signaling pathway to restore autophagy. Adv. Funct. Mater., 2021, 31(38), 2105152.
[http://dx.doi.org/10.1002/adfm.202105152]
[66]
Xu, T.; Yu, S.; Sun, Y.; Wu, S.; Gao, D.; Wang, M. DNA origami frameworks enabled self-protective siRNA delivery for dual enhancement of chemo-photothermal combination therapy. Small, 2021, 17(46), e2101780.
[67]
Bhatia, D.; Arumugam, S.; Nasilowski, M.; Joshi, H.; Wunder, C.; Chambon, V.; Prakash, V.; Grazon, C.; Nadal, B.; Maiti, P.K.; Johannes, L.; Dubertret, B.; Krishnan, Y. Quantum dot-loaded monofunctionalized DNA icosahedra for single-particle tracking of endocytic pathways. Nat. Nanotechnol., 2016, 11(12), 1112-1119.
[http://dx.doi.org/10.1038/nnano.2016.150] [PMID: 27548358]
[68]
Leamon, C.; Reddy, J.A. Folate-targeted chemotherapy. Adv. Drug Deliv. Rev., 2004, 56(8), 1127-1141.
[http://dx.doi.org/10.1016/j.addr.2004.01.008] [PMID: 15094211]
[69]
Ko, S.; Liu, H.; Chen, Y.; Mao, C. DNA nanotubes as combinatorial vehicles for cellular delivery. Biomacromolecules, 2008, 9(11), 3039-3043.
[http://dx.doi.org/10.1021/bm800479e] [PMID: 18821795]
[70]
Pal, S.; Rakshit, T. Folate-functionalized DNA origami for targeted delivery of doxorubicin to triple-negative breast cancer. Front Chem., 2021, 9, 721105.
[http://dx.doi.org/10.3389/fchem.2021.721105] [PMID: 34485245]
[71]
Raniolo, S.; Vindigni, G.; Ottaviani, A.; Unida, V.; Iacovelli, F.; Manetto, A.; Figini, M.; Stella, L.; Desideri, A.; Biocca, S. Selective targeting and degradation of doxorubicin-loaded folate-functionalized DNA nanocages. Nanomedicine, 2018, 14(4), 1181-1190.
[http://dx.doi.org/10.1016/j.nano.2018.02.002] [PMID: 29458213]
[72]
Jiang, D.; Sun, Y.; Li, J.; Li, Q.; Lv, M.; Zhu, B.; Tian, T.; Cheng, D.; Xia, J.; Zhang, L.; Wang, L.; Huang, Q.; Shi, J.; Fan, C. Multiple-armed tetrahedral DNA nanostructures for tumor-targeting, dual-modality in vivo imaging. ACS Appl. Mater. Interfaces, 2016, 8(7), 4378-4384.
[http://dx.doi.org/10.1021/acsami.5b10792] [PMID: 26878704]
[73]
Bu, Y.Z.; Xu, J.R.; Luo, Q.; Chen, M.; Mu, L.M.; Lu, W.L. A precise nanostructure of folate-overhung mitoxantrone DNA tetrahedron for targeted capture leukemia. Nanomaterials (Basel), 2020, 10(5), 951.
[http://dx.doi.org/10.3390/nano10050951] [PMID: 32429472]
[74]
Zhu, G.; Chen, X. Aptamer-based targeted therapy. Adv. Drug Deliv. Rev., 2018, 134, 65-78.
[http://dx.doi.org/10.1016/j.addr.2018.08.005] [PMID: 30125604]
[75]
Wu, L.; Wang, Y.; Xu, X.; Liu, Y.; Lin, B.; Zhang, M.; Zhang, J.; Wan, S.; Yang, C.; Tan, W. Aptamer-based detection of circulating targets for precision medicine. Chem. Rev., 2021, 121(19), 12035-12105.
[http://dx.doi.org/10.1021/acs.chemrev.0c01140] [PMID: 33667075]
[76]
Tong, X.; Ga, L.; Ai, J.; Wang, Y. Progress in cancer drug delivery based on AS1411 oriented nanomaterials. J. Nanobiotechnology, 2022, 20(1), 57.
[http://dx.doi.org/10.1186/s12951-022-01240-z] [PMID: 35101048]
[77]
Li, H.; Liu, J.; Gu, H. Targeting nucleolin to obstruct vasculature feeding with an intelligent DNA nanorobot. J. Cell. Mol. Med., 2019, 23(3), 2248-2250.
[http://dx.doi.org/10.1111/jcmm.14127] [PMID: 30592140]
[78]
Chang, M.; Yang, C.S.; Huang, D.M. Aptamer-conjugated DNA icosahedral nanoparticles as a carrier of doxorubicin for cancer therapy. ACS Nano, 2011, 5(8), 6156-6163.
[http://dx.doi.org/10.1021/nn200693a] [PMID: 21732610]
[79]
Douglas, S.M.; Bachelet, I.; Church, G.M. A logic-gated nanorobot for targeted transport of molecular payloads. Science, 2012, 335(6070), 831-834.
[http://dx.doi.org/10.1126/science.1214081] [PMID: 22344439]
[80]
Liang, H.; Shi, Y.; Kou, Z.; Peng, Y.; Chen, W.; Li, X.; Li, S.; Wang, Y.; Wang, F.; Zhang, X. Inhibition of BACE1 activity by a DNA aptamer in an Alzheimer’s disease cell model. PLoS One, 2015, 10(10), e0140733.
[http://dx.doi.org/10.1371/journal.pone.0140733] [PMID: 26473367]
[81]
Ji, M.L.; Jiang, H.; Wu, F.; Geng, R.; Ya, L.K.; Lin, Y.C. Precise targeting of miR-141/200c cluster in chondrocytes attenuates osteoarthritis development. Ann. Rheum. Dis., 2021, 80(3), 356-366.
[PMID: 33109602]
[82]
Luo, Z.W.; Li, F.X.Z.; Liu, Y.W.; Rao, S.S.; Yin, H.; Huang, J.; Chen, C.Y.; Hu, Y.; Zhang, Y.; Tan, Y.J.; Yuan, L.Q.; Chen, T.H.; Liu, H.M.; Cao, J.; Liu, Z.Z.; Wang, Z.X.; Xie, H. Aptamer-functionalized exosomes from bone marrow stromal cells target bone to promote bone regeneration. Nanoscale, 2019, 11(43), 20884-20892.
[http://dx.doi.org/10.1039/C9NR02791B] [PMID: 31660556]
[83]
Tian, T.; Li, J.; Xie, C.; Sun, Y.; Lei, H.; Liu, X.; Xia, J.; Shi, J.; Wang, L.; Lu, W.; Fan, C. Targeted imaging of brain tumors with a framework nucleic acid probe. ACS Appl. Mater. Interfaces, 2018, 10(4), 3414-3420.
[http://dx.doi.org/10.1021/acsami.7b17927] [PMID: 29299920]
[84]
Tian, T.; Zhang, H.X.; He, C.P.; Fan, S.; Zhu, Y.L.; Qi, C.; Huang, N.P.; Xiao, Z.D.; Lu, Z.H.; Tannous, B.A.; Gao, J. Surface functionalized exosomes as targeted drug delivery vehicles for cerebral ischemia therapy. Biomaterials, 2018, 150, 137-149.
[http://dx.doi.org/10.1016/j.biomaterials.2017.10.012] [PMID: 29040874]
[85]
Bari, E.; Serra, M.; Paolillo, M.; Bernardi, E.; Tengattini, S.; Piccinini, F.; Lanni, C.; Sorlini, M.; Bisbano, G.; Calleri, E.; Torre, M.L.; Perteghella, S. Silk fibroin nanoparticle functionalization with Arg-Gly-Asp cyclopentapeptide promotes active targeting for tumor site-specific delivery. Cancers, 2021, 13(5), 1185.
[http://dx.doi.org/10.3390/cancers13051185] [PMID: 33803385]
[86]
Zhang, Y.; Pan, V.; Li, X.; Yang, X.; Li, H.; Wang, P. Dynamic DNA Structures. Small, 2019, 15(26), e1900228.
[87]
Li, J.; Zhang, Y.; Sun, J.; Ouyang, J.; Na, N. SiRNA-templated 3D framework nucleic acids for chemotactic recognition, and programmable and visualized precise delivery for synergistic cancer therapy. Chem. Sci., 2021, 12(46), 15353-15361.
[http://dx.doi.org/10.1039/D1SC04249A] [PMID: 34976356]
[88]
Zhang, P.; Ouyang, Y.; Sohn, Y.S.; Nechushtai, R.; Pikarsky, E.; Fan, C.; Willner, I. pH- and miRNA-responsive DNA-tetrahedra/metal–organic framework conjugates: Functional sense-and-treat carriers. ACS Nano, 2021, 15(4), 6645-6657.
[http://dx.doi.org/10.1021/acsnano.0c09996] [PMID: 33787219]
[89]
Juul, S.; Iacovelli, F.; Falconi, M.; Kragh, S.L.; Christensen, B.; Frøhlich, R.; Franch, O.; Kristoffersen, E.L.; Stougaard, M.; Leong, K.W.; Ho, Y.P.; Sørensen, E.S.; Birkedal, V.; Desideri, A.; Knudsen, B.R. Temperature-controlled encapsulation and release of an active enzyme in the cavity of a self-assembled DNA nanocage. ACS Nano, 2013, 7(11), 9724-9734.
[http://dx.doi.org/10.1021/nn4030543] [PMID: 24168393]
[90]
Franch, O.; Iacovelli, F.; Falconi, M.; Juul, S.; Ottaviani, A.; Benvenuti, C.; Biocca, S.; Ho, Y.P.; Knudsen, B.R.; Desideri, A. DNA hairpins promote temperature controlled cargo encapsulation in a truncated octahedral nanocage structure family. Nanoscale, 2016, 8(27), 13333-13341.
[http://dx.doi.org/10.1039/C6NR01806H] [PMID: 27341703]
[91]
Jiang, Q.; Song, C.; Nangreave, J.; Liu, X.; Lin, L.; Qiu, D.; Wang, Z.G.; Zou, G.; Liang, X.; Yan, H.; Ding, B. DNA origami as a carrier for circumvention of drug resistance. J. Am. Chem. Soc., 2012, 134(32), 13396-13403.
[http://dx.doi.org/10.1021/ja304263n] [PMID: 22803823]
[92]
Kim, K.R.; Kim, D.R.; Lee, T.; Yhee, J.Y.; Kim, B.S.; Kwon, I.C.; Ahn, D.R. Drug delivery by a self-assembled DNA tetrahedron for overcoming drug resistance in breast cancer cells. Chem. Commun., 2013, 49(20), 2010-2012.
[http://dx.doi.org/10.1039/c3cc38693g] [PMID: 23380739]
[93]
Liu, J.; Song, L.; Liu, S.; Zhao, S.; Jiang, Q.; Ding, B. A tailored DNA nanoplatform for synergistic RNAi-/chemotherapy of multidrug-resistant tumors. Angew. Chem. Int. Ed., 2018, 57(47), 15486-15490.
[http://dx.doi.org/10.1002/anie.201809452] [PMID: 30288887]
[94]
Pan, Q.; Nie, C.; Hu, Y.; Yi, J.; Liu, C.; Zhang, J.; He, M.; He, M.; Chen, T.; Chu, X. Aptamer-functionalized DNA origami for targeted codelivery of antisense oligonucleotides and doxorubicin to enhance therapy in drug-resistant cancer cells. ACS Appl. Mater. Interfaces, 2020, 12(1), 400-409.
[http://dx.doi.org/10.1021/acsami.9b20707] [PMID: 31815420]
[95]
Wang, Z.; Song, L.; Liu, Q.; Tian, R.; Shang, Y.; Liu, F.; Liu, S.; Zhao, S.; Han, Z.; Sun, J.; Jiang, Q.; Ding, B. A tubular DNA nanodevice as a siRNA/Chemo-drug co-delivery vehicle for combined cancer therapy. Angew. Chem. Int. Ed., 2021, 60(5), 2594-2598.
[http://dx.doi.org/10.1002/anie.202009842] [PMID: 33089613]
[96]
Zhu, J.; Yang, Y.; Ma, W.; Wang, Y.; Chen, L.; Xiong, H.; Yin, C.; He, Z.; Fu, W.; Xu, R.; Lin, Y. Antiepilepticus effects of tetrahedral framework nucleic acid via inhibition of gliosis-induced downregulation of glutamine synthetase and increased AMPAR internalization in the postsynaptic membrane. Nano Lett., 2022, 22(6), 2381-2390.
[http://dx.doi.org/10.1021/acs.nanolett.2c00025] [PMID: 35266400]
[97]
Gao, Y.; Chen, X.; Tian, T.; Zhang, T.; Gao, S.; Zhang, X. A lysosome-activated tetrahedral nanobox for encapsulated siRNA delivery. Advanced materials, 2022, 2022, e2201731.
[98]
Zhang, B.; Tian, T.; Xiao, D.; Gao, S.; Cai, X.; Lin, Y. Facilitating in situ tumor imaging with a tetrahedral DNA framework-enhanced hybridization chain reaction probe. Adv. Funct. Mater., 2022, 32(16), 2109728.
[http://dx.doi.org/10.1002/adfm.202109728]
[99]
Wang, Y.; Li, Y.; Gao, S.; Yu, X.; Chen, Y.; Lin, Y. Tetrahedral framework nucleic acids can alleviate taurocholate-induced severe acute pancreatitis and its subsequent multiorgan injury in mice. Nano Lett., 2022, 22(4), 1759-1768.
[http://dx.doi.org/10.1021/acs.nanolett.1c05003] [PMID: 35138113]
[100]
Zhou, M.; Zhang, T.; Zhang, B.; Zhang, X.; Gao, S.; Zhang, T. A DNA nanostructure-based neuroprotectant against neuronal apoptosis via inhibiting toll-like receptor 2 signaling pathway in acute ischemic stroke. ACS Nano, 2021, 16(1), 1456-1470.
[PMID: 34967217]
[101]
Maezawa, T.; Ohtsuki, S.; Hidaka, K.; Sugiyama, H.; Endo, M.; Takahashi, Y.; Takakura, Y.; Nishikawa, M. DNA density-dependent uptake of DNA origami-based two-or three-dimensional nanostructures by immune cells. Nanoscale, 2020, 12(27), 14818-14824.
[http://dx.doi.org/10.1039/D0NR02361B] [PMID: 32633313]
[102]
Tseng, C.Y.; Wang, W.X.; Douglas, T.R.; Chou, L.Y.T. Engineering DNA nanostructures to manipulate immune receptor signaling and immune cell fates. Adv. Healthc. Mater., 2022, 11(4), 2101844.
[http://dx.doi.org/10.1002/adhm.202101844] [PMID: 34716686]
[103]
Yang, G.; Koo, J.E.; Lee, H.E.; Shin, S.W.; Um, S.H.; Lee, J.Y. Immunostimulatory activity of Y-shaped DNA nanostructures mediated through the activation of TLR9. Biomed. Pharmacother., 2019, 112, 108657.
[104]
Li, J.; Yao, Y.; Wang, Y.; Xu, J.; Zhao, D.; Liu, M. Modulation of the crosstalk between schwann cells and macrophages for nerve regeneration: A therapeutic strategy based on multifunctional tetrahedral framework nucleic acids system. Advanced Materials, 2022, 220513.
[http://dx.doi.org/10.1002/adma.202202513]
[105]
Qin, H.; Zhao, A.; Fu, X. Small molecules for reprogramming and transdifferentiation. Cell. Mol. Life Sci., 2017, 74(19), 3553-3575.
[http://dx.doi.org/10.1007/s00018-017-2586-x] [PMID: 28698932]
[106]
Li, J.; Lai, Y.; Li, M.; Chen, X.; Zhou, M.; Wang, W.; Li, J.; Cui, W.; Zhang, G.; Wang, K.; Liu, L.; Lin, Y. Repair of infected bone defect with clindamycin-tetrahedral DNA nanostructure complex-loaded 3D bioprinted hybrid scaffold. Chem. Eng. J., 2022, 435, 134855.
[http://dx.doi.org/10.1016/j.cej.2022.134855]

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      • 9. middleware::check_user_access:24
      • 10. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
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      • 11. middleware::check_user_access:24
      • 12. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 14. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
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      • 11. middleware::check_user_access:27
      • 12. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 14. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
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      Backtrace
      • 14. app/Models/UserAccess/UserAccess.php:784
      • 15. middleware::check_user_access:114
      • 16. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 18. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
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      1.05msalphaeurekaselec_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` = 15 limit 1
      2.02msalphaeurekaselec_live_10_06_2022Journal.php#64
      Bindings
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      • 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=15) and sj.journal_id!=15 group by `j`.`nid`) as `aggregate_table`
      1.95msalphaeurekaselec_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=15) and sj.journal_id!=15 group by `j`.`nid` order by `j`.`journal_id` asc limit 10 offset 0
      1.37msalphaeurekaselec_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=15) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid`) as `aggregate_table`
      10.52msalphaeurekaselec_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=15) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid` order by `v`.`ebook_volume_id` desc limit 10 offset 0
      2.65msalphaeurekaselec_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` = '128980'
      290μsalphaeurekaselec_live_10_06_2022Keywords.php#43
      Bindings
      • 0: 128980
      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` = '128980'
      6.92msalphaeurekaselec_live_10_06_2022Article.php#1570
      Bindings
      • 0: 128980
      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` = '128980' group by `au`.`author_id` order by `au`.`article_id` asc, `au`.`sequence` asc
      5.05msalphaeurekaselec_live_10_06_2022Author.php#86
      Bindings
      • 0: 128980
      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
      570μsalphaeurekaselec_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
      760μsalphaeurekaselec_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 = 15 and i.is_uploaded = 1 order by v.volume_name+0 desc, i.title+0 desc limit 1
      63.7msalphaeurekaselec_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 = 15 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      37.12msalphaeurekaselec_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 = 15 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      10.81msalphaeurekaselec_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` = 128980 limit 1
      230μsalphaeurekaselec_live_10_06_2022Article.php#744
      Bindings
      • 0: 128980
      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 = 128980 and content_type = 'article' order by status desc limit 1
      310μsalphaeurekaselec_live_10_06_2022Article.php#751
      Backtrace
      • 11. app/Models/Article.php:751
      • 12. app/Http/Controllers/ArticleController.php:2094
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `node_meta` where `nid` = 212965 limit 1
      240μsalphaeurekaselec_live_10_06_2022Meta.php#30
      Bindings
      • 0: 212965
      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
      260μsalphaeurekaselec_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` = 'CDM' and (h.proposal_closing_date = 0 OR TO_DAYS(FROM_UNIXTIME(h.proposal_closing_date)) >= TO_DAYS(NOW())) order by `h`.`manuscript` asc
      300μsalphaeurekaselec_live_10_06_2022Article.php#2025
      Bindings
      • 0: CDM
      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 = '128980' 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) )
      400μsalphaeurekaselec_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 = '12731' 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) )
      430μsalphaeurekaselec_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 = '3327' 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) )
      370μsalphaeurekaselec_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 <= 314549955 and j.to_ip >=314549955 )) and ((j.from_date <= 1740514580 and j.to_date >= 1740514580 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3327) 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 <= 314549955 and j.to_ip >=314549955 )) and ((j.from_date <= 1740514580 and j.to_date >= 1740514580 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3327) 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 <= 314549955 and j.to_ip >=314549955 )) and ((j.from_date <= 1740514580 and j.to_date >= 1740514580 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3327)
      13.19msalphaeurekaselec_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 <= 314549955 and j.to_ip >=314549955 )) and ((j.from_date <= 1740514580 and j.to_date >= 1740514580 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 12731) 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 <= 314549955 and j.to_ip >=314549955 )) and ((j.from_date <= 1740514580 and j.to_date >= 1740514580 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 12731) 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 <= 314549955 and j.to_ip >=314549955 )) and ((j.from_date <= 1740514580 and j.to_date >= 1740514580 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 12731)
      670μsalphaeurekaselec_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 <= 314549955 and j.to_ip >=314549955 )) and ((j.from_date <= 1740514580 and j.to_date >= 1740514580 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 128980) 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 <= 314549955 and j.to_ip >=314549955 )) and ((j.from_date <= 1740514580 and j.to_date >= 1740514580 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 128980) 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 <= 314549955 and j.to_ip >=314549955 )) and ((j.from_date <= 1740514580 and j.to_date >= 1740514580 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 128980)
      760μsalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ArticleController.php:2329
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `article` where `first_page` < '353' and is_uploaded = 1 and issue_id = 12731 order by cast(first_page as SIGNED) desc limit 1
      520μsalphaeurekaselec_live_10_06_2022Article.php#1819
      Bindings
      • 0: 353
      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` > '366' and is_uploaded = 1 and issue_id = 12731 order by cast(first_page as SIGNED) asc limit 1
      470μsalphaeurekaselec_live_10_06_2022Article.php#1831
      Bindings
      • 0: 366
      Backtrace
      • 14. app/Models/Article.php:1831
      • 15. app/Http/Controllers/ArticleController.php:2472
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select `language_id` from `multilanguage` where `short_code` = 'en'
      220μsalphaeurekaselec_live_10_06_2022ArticleController.php#2497
      Bindings
      • 0: en
      Backtrace
      • 14. app/Http/Controllers/ArticleController.php:2497
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:206
    • select `source_lang_label`, `target_lang_label` from `multilanguage_labels` where `target_lang_id` = 1
      280μsalphaeurekaselec_live_10_06_2022MultiLanguage.php#23
      Bindings
      • 0: 1
      Backtrace
      • 13. app/Models/MultiLanguage.php:23
      • 14. app/Http/Controllers/ArticleController.php:2498
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select `id` from `multilanguage_article` where `article_id` = 128980 limit 1
      2.88msalphaeurekaselec_live_10_06_2022ArticleController.php#2506
      Bindings
      • 0: 128980
      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` = 15 and `b`.`banner_from_date` <= 1740514580 and `b`.`banner_to_date` >= 1740514580 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.35msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 15
      • 3: 1740514580
      • 4: 1740514580
      • 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` = 15 and `b`.`banner_from_date` <= 1740514580 and `b`.`banner_to_date` >= 1740514580 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.4msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 15
      • 3: 1740514580
      • 4: 1740514580
      • 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='63e9140026b39f907e6f99d6925317ad'
      250μsalphaeurekaselec_live_10_06_2022Cart.php#271
      Backtrace
      • 15. app/Models/Cart.php:271
      • 16. view::layouts._header:260
      • 18. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 20. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
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        status_text
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        ClearShow all
        Date ↕MethodURLData
        #12025-02-25 20:16:20GET/article/128980414361