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Current Molecular Medicine

Editor-in-Chief

ISSN (Print): 1566-5240
ISSN (Online): 1875-5666

Review Article

Molecular Links Between Alzheimer's Disease and Gastrointestinal Microbiota: Emphasis on Helicobacter pylori Infection Involvement

Author(s): Taxiarchis Katsinelos, Michael Doulberis, Stergios A Polyzos, Apostolis Papaefthymiou, Panagiotis Katsinelos and Jannis Kountouras*

Volume 20, Issue 1, 2020

Page: [3 - 12] Pages: 10

DOI: 10.2174/1566524019666190917125917

Price: $65

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease and the main form of dementia, characterized by progressive cognitive decline and detrimental consequences in both personal-family and global level. Within this narrative review, we provide recent molecular aspects of Tau, a microtubule AD-associated protein, as well as amyloid beta, involved in AD pathophysiology. Moreover, we provide additional emerging data from basic research as well as clinical studies indicating an implicating role of gastrointestinal microbiota (GI-M), including Helicobacter pylori infection (Hp-I), in AD pathophysiology. Likewise, we identified through a molecular prism the current evidence of AD pathogenesis as well as its linkage with GI-M and emphasizing the role of Hp-I. All in all, additional large-scale studies are required for the further clarification of AD pathophysiology and its connection with GI-M and Hp-I, so as novel therapies on molecular basis become available.

Keywords: Alzheimer's disease, tauopathies, amyloid beta, gastrointestinal microbiota, Helicobacter pylori, hyperphosphorylation.

[1]
Tobore TO. On the Etiopathogenesis and Pathophysiology of Alzheimer’s disease: A comprehensive theoretical review. J Alzheimers Dis 2019; 68(2): 417-37.
[http://dx.doi.org/10.3233/JAD-181052] [PMID: 30775973]
[2]
Doulberis M, Kotronis G, Thomann R, et al. Review: Impact of Helicobacter pylori on Alzheimer’s disease: What do we know so far? Helicobacter 2018; 23(1): 1-18.
[http://dx.doi.org/10.1111/hel.12454] [PMID: 29181894]
[3]
Jan AT, Azam M, Rahman S, et al. Perspective insights into disease progression, diagnostics, and therapeutic approaches in Alzheimer’s disease: a judicious update. Front Aging Neurosci 2017; 9: 356.
[http://dx.doi.org/10.3389/fnagi.2017.00356] [PMID: 29163138]
[4]
Hu X, Wang T, Jin F. Alzheimer’s disease and gut microbiota. Sci China Life Sci 2016; 59(10): 1006-23.
[http://dx.doi.org/10.1007/s11427-016-5083-9] [PMID: 27566465]
[5]
Qiu C, Fratiglioni L. Aging without dementia is achievable: Current evidence from epidemiological research. J Alzheimers Dis 2018; 62(3): 933-42.
[http://dx.doi.org/10.3233/JAD-171037] [PMID: 29562544]
[6]
WHO. First WHO ministerial conference on global action against dementia: meeting report. Geneva World Heal Organ 2015.
[7]
International Center at NIH F. March April. Global health matters newsletter 2015.
[8]
Kountouras J, Boziki M, Gavalas E, et al. Five-year survival after Helicobacter pylori eradication in Alzheimer disease patients. Cogn Behav Neurol 2010; 23(3): 199-204.
[http://dx.doi.org/10.1097/WNN.0b013e3181df3034] [PMID: 20829670]
[9]
Waldemar G, Dubois B, Emre M, et al. Recommendations for the diagnosis and management of Alzheimer’s disease and other disorders associated with dementia: EFNS guideline. Eur J Neurol 2007; 14(1): e1-e26.
[http://dx.doi.org/10.1111/j.1468-1331.2006.01605.x] [PMID: 17222085]
[10]
McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011.
[http://dx.doi.org/10.1016/j.jalz.2011.03.005]
[11]
Holtzman DM, Morris JC, Goate AM. Alzheimer’s disease: the challenge of the second century. Sci Transl Med 2011; 63(77): 77-1.
[http://dx.doi.org/10.1126/scitranslmed.3002369]
[12]
Winblad B, Amouyel P, Andrieu S, et al. Defeating Alzheimer’s disease and other dementias: a priority for European science and society. Lancet Neurol 2016; 15(5): 455-532.
[http://dx.doi.org/10.1016/S1474-4422(16)00062-4]
[13]
Schneider LS, Mangialasche F, Andreasen N, et al. Clinical trials and late-stage drug development for Alzheimer’s disease: an appraisal from 1984 to 2014. J Intern Med 2014; 275(3): 251-83.
[14]
Ittner LM, Götz J. Amyloid-β and tau--a toxic pas de deux in Alzheimer’s disease. Nat Rev Neurosci 2011; 12(2): 65-72.
[http://dx.doi.org/10.1038/nrn2967] [PMID: 21193853]
[15]
Sadigh-Eteghad S, Sabermarouf B, Majdi A, Talebi M, Farhoudi M, Mahmoudi J. Amyloid-beta: a crucial factor in Alzheimer’s disease. Med Princ Pract 2015; 24(1): 1-10.
[http://dx.doi.org/10.1159/000369101]
[16]
De Strooper B, Saftig P, Craessaerts K, et al. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 1998; 391(6665): 387-90.
[http://dx.doi.org/10.1038/34910] [PMID: 9450754]
[17]
Vassar R, Bennett BD, Babu-Khan S, et al. Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 1999; 22286(5440): 735-41.
[http://dx.doi.org/10.1126/science.286.5440.735]
[18]
Sowade RF, Jahn TR. Seed-induced acceleration of amyloid-β mediated neurotoxicity in vivo. Nat Commun 2017; 118(1): 512.
[http://dx.doi.org/10.1038/s41467-017-00579-4]
[19]
Kayed R, Head E, Thompson JL, et al. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 2003; 300(5618): 486-9.
[http://dx.doi.org/10.1126/science.1079469] [PMID: 12702875]
[20]
Heneka MT, Carson MJ, El Khoury J, et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol 2015; 14(4): 388-405.
[http://dx.doi.org/10.1016/S1474-4422(15)70016-5]
[21]
Lee VM, Goedert M, Trojanowski JQ. Neurodegenerative tauopathies. Annu Rev Neurosci 2001; 24(1): 1121-59.
[http://dx.doi.org/10.1146/annurev.neuro.24.1.1121] [PMID: 11520930]
[22]
Rudrabhatla P, Jaffe H, Pant HC. Direct evidence of phosphorylated neuronal intermediate filament proteins in neurofibrillary tangles (NFTs): phosphoproteomics of Alzheimer’s NFTs. FASEB J 2011; 25(11): 3896-905.
[http://dx.doi.org/10.1096/fj.11-181297] [PMID: 21828286]
[23]
Andreadis A, Brown WM, Kosik KS. Structure and novel exons of the human tau gene. Biochemistry 1992; 331(43): 10626-33.
[http://dx.doi.org/10.1021/bi00158a027]
[24]
Wang Y, Mandelkow E. Tau in physiology and pathology. Nat Rev Neurosci 2016; 17(1): 5-21.
[http://dx.doi.org/10.1038/nrn.2015.1] [PMID: 26631930]
[25]
Rosenberg KJ, Ross JL, Feinstein HE, Feinstein SC, Israelachvili J. Complementary dimerization of microtubule-associated tau protein: Implications for microtubule bundling and tau-mediated pathogenesis. Proc Natl Acad Sci USA 2008; 27105(21): 7445-50.
[26]
Buée L, Bussière T, Buée-Scherrer V, Delacourte A, Hof PR. Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Brain Res Rev 2000; 33(1): 95-130.
[http://dx.doi.org/10.1016/S0165-0173(00)00019-9] [PMID: 10967355]
[27]
Götz J, Ittner LM. Animal models of Alzheimer’s disease and frontotemporal dementia. Nat Rev Neurosci 2008; 9(7): 532-44.
[http://dx.doi.org/10.1038/nrn2420] [PMID: 18568014]
[28]
Hasegawa M, Morishima-Kawashima M, Takio K, Suzuki M, Titani K, Ihara Y. Protein sequence and mass spectrometric analyses of tau in the Alzheimer’s disease brain. J Biol Chem 1992; 267(24): 17047-54.
[PMID: 1512244]
[29]
Köpke E, Tung YC, Shaikh S, Alonso AC, Iqbal K, Grundke-Iqbal I. Microtubule-associated protein tau. Abnormal phosphorylation of a non-paired helical filament pool in Alzheimer disease. J Biol Chem 1993; 268(32): 24374-84.
[PMID: 8226987]
[30]
Alonso A, Zaidi T, Novak M, Grundke-Iqbal I, Iqbal K. Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments. Proc Natl Acad Sci USA 2001; 98(12): 6923-8.
[http://dx.doi.org/10.1073/pnas.121119298] [PMID: 11381127]
[31]
Arendt T, Stieler J, Strijkstra AM, et al. Reversible paired helical filament-like phosphorylation of tau is an adaptive process associated with neuronal plasticity in hibernating animals. J Neurosci 2003; 623(18): 6972-81.
[32]
Berriman J, Serpell LC, Oberg KA, Fink AL, Goedert M, Crowther RA. Tau filaments from human brain and from in vitro assembly of recombinant protein show cross-beta structure. Proc Natl Acad Sci USA 2003; 22100(15): 9034-8.
[33]
Fitzpatrick AWP, Falcon B, He S, et al. Cryo-EM structures of tau filaments from Alzheimer’s disease. Nature 2017; 547(7662): 185-90. Available from: http://www.nature.com/doifinder/10.1038/nature23002
[http://dx.doi.org/10.1038/nature23002] [PMID: 28678775]
[34]
Mukrasch MD, von Bergen M, Biernat J, et al. The “jaws” of the tau-microtubule interaction. J Biol Chem 2007; 20282(16): 12230-9.
[35]
Kadavath H, Hofele RV, Biernat J, et al. Tau stabilizes microtubules by binding at the interface between tubulin heterodimers. Proc Natl Acad Sci USA 2015; 112(24): 7501-6.
[http://dx.doi.org/10.1073/pnas.1504081112] [PMID: 26034266]
[36]
Wischik CM, Novak M, Thøgersen HC, et al. Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci USA 1988; Jun 85(12): 4506-10.
[http://dx.doi.org/10.1073/pnas.85.12.4506]
[37]
Wegmann S, Medalsy ID, Mandelkow E, Müller DJ. The fuzzy coat of pathological human Tau fibrils is a two-layered polyelectrolyte brush. Proc Natl Acad Sci USA 2013; 110(4): E313-21.
[http://dx.doi.org/10.1073/pnas.1212100110] [PMID: 23269837]
[38]
Harada A, Oguchi K, Okabe S, et al. Altered microtubule organization in small-calibre axons of mice lacking tau protein. Nature 1994; 369(6480): 488-91.
[http://dx.doi.org/10.1038/369488a0] [PMID: 8202139]
[39]
Hoover BR, Reed MN, Su J, et al. Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron 2010; 68(6): 1067-81.
[http://dx.doi.org/10.1016/j.neuron.2010.11.030] [PMID: 21172610]
[40]
Goedert M, Eisenberg DS, Crowther RA. Propagation of Tau aggregates and neurodegeneration. Annu Rev Neurosci 2017; Aug 2340(1): 189-210.
[http://dx.doi.org/10.1146/annurev-neuro-072116-031153210]
[41]
Jack CR, Holtzman DM. Biomarker modeling of Alzheimer’s disease. Neuron 2013; 80(6): 1347-58.
[http://dx.doi.org/10.1016/j.neuron.2013.12.003]
[42]
Iba M, McBride JD, Guo JL, Zhang B, Trojanowski JQ, Lee VM-Y. Tau pathology spread in PS19 tau transgenic mice following locus coeruleus (LC) injections of synthetic tau fibrils is determined by the LC’s afferent and efferent connections. Acta Neuropathol 2015; 130(3): 349-62.
[http://dx.doi.org/10.1007/s00401-015-1458-4] [PMID: 26150341]
[43]
Clavaguera F, Bolmont T, Crowther RA, et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol 2009; 11(7): 909-13.
[http://dx.doi.org/10.1038/ncb1901] [PMID: 19503072]
[44]
Clavaguera F, Akatsu H, Fraser G, et al. Brain homogenates from human tauopathies induce tau inclusions in mouse brain. Proc Natl Acad Sci USA 2013; 110(23): 9535-40.
[http://dx.doi.org/10.1073/pnas.1301175110]
[45]
Iba M, Guo JL, McBride JD, Zhang B, Trojanowski JQ, Lee VM-Y. Synthetic tau fibrils mediate transmission of neurofibrillary tangles in a transgenic mouse model of Alzheimer’s-like tauopathy. J Neurosci 2013; Jan 1633(3): 1024-37.
[46]
Guo JL, Narasimhan S, Changolkar L, et al. Unique pathological tau conformers from Alzheimer’s brains transmit tau pathology in nontransgenic mice. J Exp Med 2016; 213(12): 2635-54.
[http://dx.doi.org/10.1084/jem.20160833] [PMID: 27810929]
[47]
Fagan AM, Mintun MA, Shah AR, et al. Cerebrospinal fluid tau and ptau(181) increase with cortical amyloid deposition in cognitively normal individuals: implications for future clinical trials of Alzheimer’s disease. EMBO Mol Med 2009; 1(8-9): 371-80.
[48]
De Vos A, Bjerke M, Brouns R, et al. Neurogranin and tau in cerebrospinal fluid and plasma of patients with acute ischemic stroke. BMC Neurol 2017; 3017(1): 170.
[http://dx.doi.org/10.1186/s12883-017-0945-8]
[49]
Galasko D, Chang L, Motter R, et al. High cerebrospinal fluid tau and low amyloid beta42 levels in the clinical diagnosis of Alzheimer disease and relation to apolipoprotein E genotype. Arch Neurol 1998; 55(7): 937-45.
[http://dx.doi.org/10.1001/archneur.55.7.937] [PMID: 9678311]
[50]
Shaw LM, Vanderstichele H, Knapik-Czajka M, et al. Cerebrospinal fluid biomarker signature in Alzheimer’s disease neuroimaging initiative subjects. Ann Neurol 2009; 65(4): 403-13.
[http://dx.doi.org/10.1002/ana.21610] [PMID: 19296504]
[51]
Visser PJ, Verhey F, Knol DL, et al. Prevalence and prognostic value of CSF markers of Alzheimer’s disease pathology in patients with subjective cognitive impairment or mild cognitive impairment in the DESCRIPA study: a prospective cohort study. Lancet Neurol 2009; 8(7): 619-27.
[http://dx.doi.org/10.1016/S1474-4422(09)70139-5]
[52]
Mattsson N, Zetterberg H, Hansson O, et al. CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA 2009; 302(4): 385-93.
[http://dx.doi.org/10.1001/jama.2009.1064] [PMID: 19622817]
[53]
Mohamed NV, Herrou T, Plouffe V, Piperno N, Leclerc N. Spreading of tau pathology in Alzheimer’s disease by cell-to-cell transmission. Eur J Neurosci 2013; 37(12): 1939-48.
[http://dx.doi.org/10.1111/ejn.12229] [PMID: 23773063]
[54]
Pooler AM, Phillips EC, Lau DHW, Noble W, Hanger DP. Physiological release of endogenous tau is stimulated by neuronal activity. EMBO Rep 2013; 14(4): 389-94.
[http://dx.doi.org/10.1038/embor.2013.15]
[55]
Rabouille C. Pathways of Unconventional Protein Secretion. Trends Cell Biol 2017; 27(3): 230-40.
[http://dx.doi.org/10.1016/j.tcb.2016.11.007] [PMID: 27989656]
[56]
Dimou E, Nickel W. Unconventional mechanisms of eukaryotic protein secretion. Curr Biol 2018; 2328(8): R406-10.
[http://dx.doi.org/10.1016/j.cub.2017.11.074]
[57]
Wang Y, Balaji V, Kaniyappan S, et al. The release and trans-synaptic transmission of Tau via exosomes. Mol Neurodegener 2017; 12(1): 5.
[http://dx.doi.org/10.1186/s13024-016-0143-y] [PMID: 28086931]
[58]
Katsinelos T, Zeitler M, Dimou E, et al. Unconventional secretion mediates the trans-cellular spreading of Tau. Cell Rep 2018; 23(7): 2039-55.
[http://dx.doi.org/10.1016/j.celrep.2018.04.056] [PMID: 29768203]
[59]
Merezhko M, Brunello CA, Yan X, et al. Secretion of Tau via an unconventional non-vesicular mechanism. Cell Rep 2018; 25(8): 2027-2035.e4.
[http://dx.doi.org/10.1016/j.celrep.2018.10.078] [PMID: 30463001]
[60]
Fulop T, Witkowski JM, Bourgade K, et al. Can an infection hypothesis explain the beta amyloid hypothesis of Alzheimer’s disease? Front Aging Neurosci 2018; 10(July): 224.
[http://dx.doi.org/10.3389/fnagi.2018.00224] [PMID: 30087609]
[61]
Eimer WA, Vijaya Kumar DK, Navalpur Shanmugam NK, et al. Alzheimer’s Disease-associated β-amyloid is rapidly seeded by herpesviridae to protect against brain infection. Neuron 2018; 99(1): 56-63.e3.
[http://dx.doi.org/10.1016/j.neuron.2018.06.030] [PMID: 30001512]
[62]
Soscia SJ, Kirby JE, Washicosky KJ, et al. The Alzheimer’s disease-associated amyloid beta-protein is an antimicrobial peptide. PLoS One 2010; 5(3)e9505
[http://dx.doi.org/10.1371/journal.pone.0009505] [PMID: 20209079]
[63]
Kumar DKV, Choi SH, Washicosky KJ, et al. Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease. Sci Transl Med 2016; 8(340)340ra72
[http://dx.doi.org/10.1126/scitranslmed.aaf1059] [PMID: 27225182]
[64]
White MR, Kandel R, Tripathi S, et al. Alzheimer’s associated β-amyloid protein inhibits influenza A virus and modulates viral interactions with phagocytes. PLoS One 2014; 9(7)e101364
[http://dx.doi.org/10.1371/journal.pone.0101364] [PMID: 24988208]
[65]
Gosztyla ML, Brothers HM, Robinson SR. Alzheimer’s Amyloid-β is an Antimicrobial Peptide: A Review of the Evidence. J Alzheimers Dis 2018; 62(4): 1495-506.
[http://dx.doi.org/10.3233/JAD-171133] [PMID: 29504537]
[66]
Kountouras J, Boziki M, Polyzos SA, Katsinelos P, et al. The emerging role of Helicobacter Pylori-induced metabolic gastrointestinal dysmotility and neurodegeneration. Curr Mol Med 2017; Feb 717(6): 389-404.
[67]
Deretzi G, Kountouras J, Polyzos SA, et al. Gastrointestinal immune system and brain dialogue implicated in neuroinflammatory and neurodegenerative diseases. Curr Mol Med 2011; 11(8): 696-707.
[http://dx.doi.org/10.2174/156652411797536660] [PMID: 21902649]
[68]
Jiang C, Li G, Huang P, Liu Z, Zhao B. The gut microbiota and Alzheimer’s disease. J Alzheimers Dis 2017; 58(1): 1-15.
[http://dx.doi.org/10.3233/JAD-161141] [PMID: 28372330]
[69]
Vogt NM, Romano KA, Darst BF, et al. The gut microbiota-derived metabolite trimethylamine N-oxide is elevated in Alzheimer’s disease. Alzheimers Res Ther 2018; 10(1): 124.
[http://dx.doi.org/10.1186/s13195-018-0451-2] [PMID: 30579367]
[70]
Doulberis M, Kotronis G, Gialamprinou D, Kountouras J, Katsinelos P. Non-alcoholic fatty liver disease: An update with special focus on the role of gut microbiota. Metabolism 2017; 71: 182-97.
[http://dx.doi.org/10.1016/j.metabol.2017.03.013] [PMID: 28521872]
[71]
Minter MR, Zhang C, Leone V, et al. Antibiotic-induced perturbations in gut microbial diversity influences neuro-inflammation and amyloidosis in a murine model of Alzheimer’s disease. Sci Rep 2016; 6: 30028.
[http://dx.doi.org/10.1038/srep30028] [PMID: 27443609]
[72]
Wu S-C, Cao Z-S, Chang K-M, Juang J-L. Intestinal microbial dysbiosis aggravates the progression of Alzheimer’s disease in Drosophila. Nat Commun 2017; 8(1): 24.
[http://dx.doi.org/10.1038/s41467-017-00040-6] [PMID: 28634323]
[73]
Clemente JC, Ursell LK, Parfrey LW, Knight R. The impact of the gut microbiota on human health: an integrative view. Cell 2012; 148(6): 1258-70.
[http://dx.doi.org/10.1016/j.cell.2012.01.035] [PMID: 22424233]
[74]
Alkasir R, Li J, Li X, Jin M, Zhu B. Human gut microbiota: the links with dementia development. Protein Cell 2017; 8(2): 90-102.
[http://dx.doi.org/10.1007/s13238-016-0338-6] [PMID: 27866330]
[75]
Friedland RP, Chapman MR. The role of microbial amyloid in neurodegeneration. PLoS Pathog 2017; 13(12)e1006654
[http://dx.doi.org/10.1371/journal.ppat.1006654] [PMID: 29267402]
[76]
Zhuang Z-Q, Shen L-L, Li W-W, et al. Gut microbiota is altered in patients with Alzheimer’s disease. J Alzheimers Dis 2018; 63(4): 1337-46.
[http://dx.doi.org/10.3233/JAD-180176] [PMID: 29758946]
[77]
Saji N, Niida S, Murotani K, et al. Analysis of the relationship between the gut microbiome and dementia: a cross-sectional study conducted in Japan. Sci Rep 2019; 9(1): 1008.
[http://dx.doi.org/10.1038/s41598-018-38218-7] [PMID: 30700769]
[78]
Vogt NM, Kerby RL, Dill-McFarland KA, et al. Gut microbiome alterations in Alzheimer’s disease. Sci Rep 2017; 7(1): 13537.
[http://dx.doi.org/10.1038/s41598-017-13601-y] [PMID: 29051531]
[79]
Cattaneo A, Cattane N, Galluzzi S, et al. Association of brain amyloidosis with pro-inflammatory gut bacterial taxa and peripheral inflammation markers in cognitively impaired elderly. Neurobiol Aging 2017; 49: 60-8.
[http://dx.doi.org/10.1016/j.neurobiolaging.2016.08.019] [PMID: 27776263]
[80]
MahmoudianDehkordi S, Arnold M, Nho K, et al. Altered bile acid profile associates with cognitive impairment in Alzheimer’s disease-An emerging role for gut microbiome. Alzheimers Dement 2019; 15(1): 76-92.
[81]
Lee Y-L, Hu H-Y, Huang L-Y, Chou P, Chu D. Periodontal disease associated with higher risk of dementia: population-based cohort study in Taiwan. J Am Geriatr Soc 2017; 65(9): 1975-80.
[http://dx.doi.org/10.1111/jgs.14944] [PMID: 28598507]
[82]
Hayashi K, Hasegawa Y, Takemoto Y, et al. Continuous intracerebroventricular injection of Porphyromonas gingivalis lipopolysaccharide induces systemic organ dysfunction in a mouse model of Alzheimer’s disease. Exp Gerontol 2019; 120(February): 1-5.
[http://dx.doi.org/10.1016/j.exger.2019.02.007] [PMID: 30786259]
[83]
Choi S, Kim K, Chang J, et al. Association of chronic periodontitis on Alzheimer’s disease or vascular dementia. J Am Geriatr Soc 2019; 67(6): 1234-9.
[http://dx.doi.org/10.1111/jgs.15828] [PMID: 30874308]
[84]
Roubaud-Baudron C, Krolak-Salmon P, Quadrio I, Mégraud F, Salles N. Impact of chronic Helicobacter pylori infection on Alzheimer’s disease: preliminary results. Neurobiol Aging 2012; 33(5)1009.e11
[http://dx.doi.org/10.1016/j.neurobiolaging.2011.10.021] [PMID: 22133280]
[85]
Beydoun MA, Beydoun HA, Shroff MR, Kitner-Triolo MH, Zonderman AB. Helicobacter pylori seropositivity and cognitive performance among US adults: evidence from a large national survey. Psychosom Med 2013; 75(5): 486-96.
[http://dx.doi.org/10.1097/PSY.0b013e31829108c3]
[86]
Boziki M, Polyzos SA, Deretzi G, et al. A potential impact of Helicobacter pylori-related galectin-3 in neurodegeneration. Neurochem Int 2018; 113: 137-51.
[http://dx.doi.org/10.1016/j.neuint.2017.12.003] [PMID: 29246761]
[87]
Rea K, Dinan TG, Cryan JF. The microbiome: A key regulator of stress and neuroinflammation. Neurobiol Stress 2016; 4: 23-33.
[http://dx.doi.org/10.1016/j.ynstr.2016.03.001] [PMID: 27981187]
[88]
Zárate-Bladés CR, Horai R, Caspi RR. Regulation of autoimmunity by the microbiome. DNA Cell Biol 2016; 35(9): 455-8.
[http://dx.doi.org/10.1089/dna.2016.3432] [PMID: 27463238]
[89]
Stanisavljević S, Lukić J, Soković S, et al. Correlation of gut microbiota composition with resistance to experimental autoimmune encephalomyelitis in rats. Front Microbiol 2016; 7(December): 2005.
[http://dx.doi.org/10.3389/fmicb.2016.02005] [PMID: 28018327]
[90]
Tükel C, Wilson RP, Nishimori JH, Pezeshki M, Chromy BA, Bäumler AJ. Responses to amyloids of microbial and host origin are mediated through toll-like receptor 2. Cell Host Microbe 2009; 6(1): 45-53.
[http://dx.doi.org/10.1016/j.chom.2009.05.020] [PMID: 19616765]
[91]
Holmes C. Review: systemic inflammation and Alzheimer’s disease. Neuropathol Appl Neurobiol 2013; 39(1): 51-68.
[http://dx.doi.org/10.1111/j.1365-2990.2012.01307.x] [PMID: 23046210]
[92]
César Machado MC, da Silva FP. Intestinal barrier dysfunction in human pathology and aging. Curr Pharm Des 2016; 722(30): 4645-50.
[93]
Jakobsson HE, Rodríguez-Piñeiro AM, Schütte A, et al. The composition of the gut microbiota shapes the colon mucus barrier. EMBO Rep 2015; 16(2): 164-77.
[http://dx.doi.org/10.15252/embr.201439263] [PMID: 25525071]
[94]
Kowalski K, Mulak A. Brain-gut-microbiota axis in Alzheimer’s disease. J Neurogastroenterol Motil 2019; 25(1): 48-60.
[http://dx.doi.org/10.5056/jnm18087] [PMID: 30646475]
[95]
Bostanciklioğlu M. The role of gut microbiota in pathogenesis of Alzheimer’s disease. J Appl Microbiol 2019; 127(4): 954-67.
[http://dx.doi.org/10.1111/jam.14264] [PMID: 30920075]
[96]
Chen R, Wu P, Cai Z, et al. Puerariae Lobatae radix with chuanxiong Rhizoma for treatment of cerebral ischemic stroke by remodeling gut microbiota to regulate the brain-gut barriers. J Nutr Biochem 2019; 65: 101-14.
[http://dx.doi.org/10.1016/j.jnutbio.2018.12.004] [PMID: 30710886]
[97]
Marungruang N, Arévalo Sureda E, Lefrançoise A, et al. Impact of dietary induced precocious gut maturation on cecal microbiota and its relation to the blood-brain barrier during the postnatal period in rats. Neurogastroenterol Motil 2018; 30(6)e13285
[http://dx.doi.org/10.1111/nmo.13285] [PMID: 29327435]
[98]
Roy Sarkar S, Banerjee S. Gut microbiota in neurodegenerative disorders. J Neuroimmunol 2019; 328: 98-104.
[http://dx.doi.org/10.1016/j.jneuroim.2019.01.004]
[99]
Cheng Y, Bai F. The association of Tau with mitochondrial dysfunction in Alzheimer’s disease. Front Neurosci 2018; 12: 163.
[http://dx.doi.org/10.3389/fnins.2018.00163] [PMID: 29623026]
[100]
Syeda T, Sanchez-Tapia M, Pinedo-Vargas L, et al. Bioactive food abates metabolic and synaptic alterations by modulation of gut microbiota in a mouse model of Alzheimer’s disease. J Alzheimers Dis 2018; 66(4): 1657-82.
[http://dx.doi.org/10.3233/JAD-180556] [PMID: 30475761]
[101]
Li J, Perez-Perez GI. Helicobacter pylori the latent human pathogen or an ancestral commensal organism. Front Microbiol 2018; 9(Apr): 609.
[http://dx.doi.org/10.3389/fmicb.2018.00609] [PMID: 29666614]
[102]
Franceschi F, Ojetti V, Candelli M, et al. Microbes and Alzheimer’ disease: lessons from H. pylori and GUT microbiota. Eur Rev Med Pharmacol Sci 2019; 23(1): 426-30.
[PMID: 30657587]
[103]
He C, Yang Z, Lu N. Imbalance of gastrointestinal microbiota in the pathogenesis of helicobacter pylori-associated diseases. Helicobacter 2016; 21(5): 337-48.
[http://dx.doi.org/10.1111/hel.12297] [PMID: 26876927]
[104]
Bruno G, Rocco G, Zaccari P, Porowska B, Mascellino MT, Severi C. Helicobacter pylori Infection and gastric dysbiosis: can probiotics administration be useful to treat this condition? Can J Infect Dis Med Microbiol = J Can des Mal Infect la Microbiol medicale 2018.
[105]
Shen L, Liu L, Ji H-F. Alzheimer’s disease histological and behavioral manifestations in transgenic mice correlate with specific gut microbiome state. J Alzheimers Dis 2017; 56(1): 385-90.
[http://dx.doi.org/10.3233/JAD-160884] [PMID: 27911317]
[106]
Katan M, Moon YP, Paik MC, Sacco RL, Wright CB, Elkind MSV. Infectious burden and cognitive function: the Northern Manhattan Study. Neurology 2013; 80(13): 1209-15.
[http://dx.doi.org/10.1212/WNL.0b013e3182896e79] [PMID: 23530151]
[107]
Wright CB, Gardener H, Dong C, et al. Infectious burden and cognitive decline in the northern manhattan study. J Am Geriatr Soc 2015; 63(8): 1540-5.
[http://dx.doi.org/10.1111/jgs.13557] [PMID: 26289683]
[108]
Xu Y, Wang Q, Liu Y, Cui R, Lu K, Zhao Y. Association between Helicobacter pylori infection and carotid atherosclerosis in patients with vascular dementia. J Neurol Sci 2016; 362: 73-7.
[http://dx.doi.org/10.1016/j.jns.2016.01.025] [PMID: 26944122]
[109]
Swardfager W, Lanctôt K, Rothenburg L, Wong A, Cappell J, Herrmann N. A meta-analysis of cytokines in Alzheimer’s disease. Biol Psychiatry 2010; 68(10): 930-41.
[http://dx.doi.org/10.1016/j.biopsych.2010.06.012] [PMID: 20692646]
[110]
Beydoun MA, Beydoun HA, Elbejjani M, Dore GA, Zonderman AB. Helicobacter pylori seropositivity and its association with incident all-cause and Alzheimer’s disease dementia in large national surveys. Alzheimers Dement 2018; 14(9): 1148-58.
[http://dx.doi.org/10.1016/j.jalz.2018.04.009] [PMID: 30201100]
[111]
Kountouras J, Mylopoulos N, Chatzopoulos D, et al. Eradication of Helicobacter pylori may be beneficial in the management of chronic open-angle glaucoma. Arch Intern Med 2002; 162(11): 1237-44.
[http://dx.doi.org/10.1001/archinte.162.11.1237] [PMID: 12038941]
[112]
Kountouras J, Zavos C, Gavalas E, Boziki M, Chatzopoulos D, Katsinelos P. Normal-tension glaucoma and Alzheimer’s disease: Helicobacter pylori as a possible common underlying risk factor. Med Hypotheses 2007; 68(1): 228-9.
[http://dx.doi.org/10.1016/j.mehy.2006.07.008] [PMID: 16978795]
[113]
Supajatura V, Ushio H, Wada A, et al. Cutting edge: VacA, a vacuolating cytotoxin of Helicobacter pylori, directly activates mast cells for migration and production of proinflammatory cytokines. J Immunol 2002; 168(6): 2603-7.
[http://dx.doi.org/10.4049/jimmunol.168.6.2603] [PMID: 11884423]
[114]
McKittrick CM, Lawrence CE, Carswell HVO. Mast cells promote blood brain barrier breakdown and neutrophil infiltration in a mouse model of focal cerebral ischemia. J Cereb Blood Flow Metab 2015; 35(4): 638-47. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25564235
[http://dx.doi.org/10.1038/jcbfm.2014.239] [PMID: 25564235]
[115]
Wang X-L, Zeng J, Feng J, et al. Helicobacter pylori filtrate impairs spatial learning and memory in rats and increases β-amyloid by enhancing expression of presenilin-2. Front Aging Neurosci 2014; 6(April): 66.
[http://dx.doi.org/10.3389/fnagi.2014.00066] [PMID: 24782763]
[116]
Wang X-L, Zeng J, Yang Y, et al. Helicobacter pylori filtrate induces Alzheimer-like tau hyperphosphorylation by activating glycogen synthase kinase-3β. J Alzheimers Dis 2015; 43(1): 153-65.
[http://dx.doi.org/10.3233/JAD-140198] [PMID: 25079798]

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Request history8.2.27PHP Version386msRequest Duration28MBMemory UsageGET article/{article_id}/{param?}Route
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    • 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
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      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
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      150μsalphaeurekaselec_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
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      • 7: 59584110
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      • 10: 59584110
      • 11: 59584110
      • 12: 59584110
      • 13: 59584110
      • 14: 59584110
      • 15: 59584110
      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=100847
      670μsalphaeurekaselec_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` = 23 limit 1
      780μsalphaeurekaselec_live_10_06_2022Journal.php#64
      Bindings
      • 0: 23
      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=23) and sj.journal_id!=23 group by `j`.`nid`) as `aggregate_table`
      820μsalphaeurekaselec_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=23) and sj.journal_id!=23 group by `j`.`nid` order by `j`.`journal_id` asc limit 10 offset 0
      720μsalphaeurekaselec_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=23) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid`) as `aggregate_table`
      2.84msalphaeurekaselec_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=23) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid` order by `v`.`ebook_volume_id` desc limit 10 offset 0
      2.43msalphaeurekaselec_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` = '100847'
      250μsalphaeurekaselec_live_10_06_2022Keywords.php#43
      Bindings
      • 0: 100847
      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` = '100847'
      3.62msalphaeurekaselec_live_10_06_2022Article.php#1570
      Bindings
      • 0: 100847
      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` = '100847' group by `au`.`author_id` order by `au`.`article_id` asc, `au`.`sequence` asc
      750μsalphaeurekaselec_live_10_06_2022Author.php#86
      Bindings
      • 0: 100847
      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
      210μsalphaeurekaselec_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
      430μsalphaeurekaselec_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 = 23 and i.is_uploaded = 1 order by v.volume_name+0 desc, i.title+0 desc limit 1
      26.34msalphaeurekaselec_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 = 23 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      11.81msalphaeurekaselec_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 = 23 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      10.09msalphaeurekaselec_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` = 100847 limit 1
      190μsalphaeurekaselec_live_10_06_2022Article.php#744
      Bindings
      • 0: 100847
      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 = 100847 and content_type = 'article' order by status desc limit 1
      250μsalphaeurekaselec_live_10_06_2022Article.php#751
      Backtrace
      • 11. app/Models/Article.php:751
      • 12. app/Http/Controllers/ArticleController.php:2094
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select 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 = 518 and content_id!=100847 and cd.content_type = 'article' order by rand() limit 20
      47.73msalphaeurekaselec_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` = 174927 limit 1
      310μsalphaeurekaselec_live_10_06_2022Meta.php#30
      Bindings
      • 0: 174927
      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
      210μsalphaeurekaselec_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` = 'CMM' and (h.proposal_closing_date = 0 OR TO_DAYS(FROM_UNIXTIME(h.proposal_closing_date)) >= TO_DAYS(NOW())) order by `h`.`manuscript` asc
      280μsalphaeurekaselec_live_10_06_2022Article.php#2025
      Bindings
      • 0: CMM
      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 = '100847' and content_type = 'a' and ( (from_date <= CURDATE() and to_date >= CURDATE() and perpetual= 0) or (from_date is null and to_date is null and perpetual= 1) )
      360μsalphaeurekaselec_live_10_06_2022ContentAccess.php#647
      Backtrace
      • 11. app/Models/ContentAccess.php:647
      • 12. app/Http/Controllers/ArticleController.php:2186
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select count(*) as total_count, content_type_access_id as access_type from journal_access where content_type_id = '9499' 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) )
      270μsalphaeurekaselec_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 = '2689' 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) )
      250μsalphaeurekaselec_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 <= 59584110 and j.to_ip >=59584110 )) and ((j.from_date <= 1739834676 and j.to_date >= 1739834676 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2689) 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 <= 59584110 and j.to_ip >=59584110 )) and ((j.from_date <= 1739834676 and j.to_date >= 1739834676 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2689) 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 <= 59584110 and j.to_ip >=59584110 )) and ((j.from_date <= 1739834676 and j.to_date >= 1739834676 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2689)
      4.18msalphaeurekaselec_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 <= 59584110 and j.to_ip >=59584110 )) and ((j.from_date <= 1739834676 and j.to_date >= 1739834676 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 9499) 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 <= 59584110 and j.to_ip >=59584110 )) and ((j.from_date <= 1739834676 and j.to_date >= 1739834676 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 9499) 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 <= 59584110 and j.to_ip >=59584110 )) and ((j.from_date <= 1739834676 and j.to_date >= 1739834676 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 9499)
      800μsalphaeurekaselec_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 <= 59584110 and j.to_ip >=59584110 )) and ((j.from_date <= 1739834676 and j.to_date >= 1739834676 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 100847) 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 <= 59584110 and j.to_ip >=59584110 )) and ((j.from_date <= 1739834676 and j.to_date >= 1739834676 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 100847) 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 <= 59584110 and j.to_ip >=59584110 )) and ((j.from_date <= 1739834676 and j.to_date >= 1739834676 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 100847)
      800μsalphaeurekaselec_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` < '3' and is_uploaded = 1 and issue_id = 9499 order by cast(first_page as SIGNED) desc limit 1
      640μsalphaeurekaselec_live_10_06_2022Article.php#1819
      Bindings
      • 0: 3
      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` > '12' and is_uploaded = 1 and issue_id = 9499 order by cast(first_page as SIGNED) asc limit 1
      600μsalphaeurekaselec_live_10_06_2022Article.php#1831
      Bindings
      • 0: 12
      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'
      230μsalphaeurekaselec_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
      270μsalphaeurekaselec_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` = 100847 limit 1
      2.86msalphaeurekaselec_live_10_06_2022ArticleController.php#2506
      Bindings
      • 0: 100847
      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` = 23 and `b`.`banner_from_date` <= 1739834676 and `b`.`banner_to_date` >= 1739834676 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.3msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 23
      • 3: 1739834676
      • 4: 1739834676
      • 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` = 23 and `b`.`banner_from_date` <= 1739834676 and `b`.`banner_to_date` >= 1739834676 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.1msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 23
      • 3: 1739834676
      • 4: 1739834676
      • 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='5dcc9a5974e5b279324cbc099b8f4662'
      190μsalphaeurekaselec_live_10_06_2022Cart.php#271
      Backtrace
      • 15. app/Models/Cart.php:271
      • 16. view::layouts._header:260
      • 18. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 20. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    App\Models\MultiLanguage
    1MultiLanguage.php#?
    App\Models\MultiLangArticle
    1MultiLangArticle.php#?
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        cppDcpXgNlzicspDLuUN5YK1n2vuZQ9lNbBxt0kE
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        PHPDEBUGBAR_STACK_DATA
        []
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        status_code
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        status_text
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        request_cookies
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        response_headers
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        ClearShow all
        Date ↕MethodURLData
        #12025-02-17 23:24:36GET/article/100847314372