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Current Stem Cell Research & Therapy

Editor-in-Chief

ISSN (Print): 1574-888X
ISSN (Online): 2212-3946

Mini-Review Article

Advances in iPSC Technology in Neural Disease Modeling, Drug Screening, and Therapy

Author(s): Sihan Dai, Linhui Qiu, Vishnu Priya Veeraraghavan, Chia-Lin Sheu* and Ullas Mony*

Volume 19, Issue 6, 2024

Published on: 19 July, 2023

Page: [809 - 819] Pages: 11

DOI: 10.2174/1574888X18666230608105703

Price: $65

Abstract

Neurodegenerative disorders (NDs) including Alzheimer’s Disease, Parkinson’s Disease, Amyotrophic Lateral Sclerosis (ALS), and Huntington's disease are all incurable and can only be managed with drugs for the associated symptoms. Animal models of human illnesses help to advance our understanding of the pathogenic processes of diseases. Understanding the pathogenesis as well as drug screening using appropriate disease models of neurodegenerative diseases (NDs) are vital for identifying novel therapies. Human-derived induced pluripotent stem cell (iPSC) models can be an efficient model to create disease in a dish and thereby can proceed with drug screening and identifying appropriate drugs. This technology has many benefits, including efficient reprogramming and regeneration potential, multidirectional differentiation, and the lack of ethical concerns, which open up new avenues for studying neurological illnesses in greater depth. The review mainly focuses on the use of iPSC technology in neuronal disease modeling, drug screening, and cell therapy.

Graphical Abstract

[1]
Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007; 131(5): 861-72.
[http://dx.doi.org/10.1016/j.cell.2007.11.019] [PMID: 18035408]
[2]
Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006; 126(4): 663-76.
[http://dx.doi.org/10.1016/j.cell.2006.07.024] [PMID: 16904174]
[3]
Wu Z, Chen J, Ren J, et al. Generation of pig induced pluripotent stem cells with a drug-inducible system. J Mol Cell Biol 2009; 1(1): 46-54.
[http://dx.doi.org/10.1093/jmcb/mjp003] [PMID: 19502222]
[4]
Chiang CH, Wu WW, Li HY, et al. Enhanced antioxidant capacity of dental pulp-derived iPSC-differentiated hepatocytes and liver regeneration by injectable HGF-releasing hydrogel in fulminant hepatic failure. Cell Transplant 2015; 24(3): 541-59.
[http://dx.doi.org/10.3727/096368915X686986] [PMID: 25668102]
[5]
Vlahos K, Sourris K, Mayberry R, et al. Generation of iPSC lines from peripheral blood mononuclear cells from 5 healthy adults. Stem Cell Res 2019; 34: 101380.
[http://dx.doi.org/10.1016/j.scr.2018.101380] [PMID: 30605840]
[6]
Kim Y, Park N, Rim YA, et al. Establishment of a complex skin structure via layered co-culture of keratinocytes and fibroblasts derived from induced pluripotent stem cells. Stem Cell Res Ther 2018; 9(1): 217.
[http://dx.doi.org/10.1186/s13287-018-0958-2] [PMID: 30103800]
[7]
Li X, Xu R, Tu X, et al. Differentiation of Neural Crest Stem Cells in Response to Matrix Stiffness and TGF-β1 in Vascular Regeneration. Stem Cells Dev 2020; 29(4): 249-56.
[http://dx.doi.org/10.1089/scd.2019.0161] [PMID: 31701817]
[8]
Shi Y, Inoue H, Wu JC, Yamanaka S. Induced pluripotent stem cell technology: a decade of progress. Nat Rev Drug Discov 2017; 16(2): 115-30.
[http://dx.doi.org/10.1038/nrd.2016.245] [PMID: 27980341]
[9]
Begley CG, Ellis LM. Raise standards for preclinical cancer research. Nature 2012; 483(7391): 531-3.
[http://dx.doi.org/10.1038/483531a] [PMID: 22460880]
[10]
Paik DT, Chandy M, Wu JC. Patient and Disease–Specific Induced Pluripotent Stem Cells for Discovery of Personalized Cardiovascular Drugs and Therapeutics. Pharmacol Rev 2020; 72(1): 320-42.
[http://dx.doi.org/10.1124/pr.116.013003] [PMID: 31871214]
[11]
Komor AC, Kim YB, Packer MS, Zuris JA, Liu DR. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature 2016; 533(7603): 420-4.
[http://dx.doi.org/10.1038/nature17946] [PMID: 27096365]
[12]
Dawson TM, Golde TE, Lagier-Tourenne C. Animal models of neurodegenerative diseases. Nat Neurosci 2018; 21(10): 1370-9.
[http://dx.doi.org/10.1038/s41593-018-0236-8] [PMID: 30250265]
[13]
Doss MX, Sachinidis A. Current challenges of iPSC-based disease modeling and therapeutic implications. Cells 2019; 8(5): 403.
[http://dx.doi.org/10.3390/cells8050403] [PMID: 31052294]
[14]
Zhao M, Nakada Y, Wei Y, et al. Cyclin D2 overexpression enhances the efficacy of human induced pluripotent stem cell–derived cardiomyocytes for myocardial repair in a swine model of myocardial infarction. Circulation 2021; 144(3): 210-28.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.120.049497] [PMID: 33951921]
[15]
Kimbrel EA, Lanza R. Current status of pluripotent stem cells: moving the first therapies to the clinic. Nat Rev Drug Discov 2015; 14(10): 681-92.
[http://dx.doi.org/10.1038/nrd4738] [PMID: 26391880]
[16]
Scudellari M. How iPS cells changed the world. Nature 2016; 534(7607): 310-2.
[http://dx.doi.org/10.1038/534310a] [PMID: 27306170]
[17]
Onos KD, Sukoff Rizzo SJ, Howell GR, Sasner M. Toward more predictive genetic mouse models of Alzheimer’s disease. Brain Res Bull 2016; 122: 1-11.
[http://dx.doi.org/10.1016/j.brainresbull.2015.12.003] [PMID: 26708939]
[18]
Penney J, Ralvenius WT, Tsai LH. Modeling Alzheimer’s disease with iPSC-derived brain cells. Mol Psychiatry 2020; 25(1): 148-67.
[http://dx.doi.org/10.1038/s41380-019-0468-3] [PMID: 31391546]
[19]
Tam KY, Ju Y. Pathological mechanisms and therapeutic strategies for Alzheimer’s disease. Neural Regen Res 2022; 17(3): 543-9.
[http://dx.doi.org/10.4103/1673-5374.320970] [PMID: 34380884]
[20]
Scheltens P, De Strooper B, Kivipelto M, et al. Alzheimer’s disease. Lancet 2021; 397(10284): 1577-90.
[http://dx.doi.org/10.1016/S0140-6736(20)32205-4] [PMID: 33667416]
[21]
William F Goure GAK. Targeting the proper amyloid-beta neuronal toxins: A path forward for Alzheimer’s disease immuno therapeutics. Alz Res Therapy 2014; 6: 42.
[22]
Busche MA, Wegmann S, Dujardin S, et al. Tau impairs neural circuits, dominating amyloid-β effects, in Alzheimer models in vivo. Nat Neurosci 2019; 22(1): 57-64.
[http://dx.doi.org/10.1038/s41593-018-0289-8] [PMID: 30559471]
[23]
Goedert M. Alzheimer’s and Parkinson’s diseases: The prion concept in relation to assembled Aβ, tau, and α-synuclein. Science 2015; 349(6248): 1255555.
[http://dx.doi.org/10.1126/science.1255555] [PMID: 26250687]
[24]
Jeong S. Molecular and cellular basis of neurodegeneration in Alzheimer’s Disease. Mol Cells 2017; 40(9): 613-20.
[PMID: 28927263]
[25]
Goetzl EJ, Kapogiannis D, Schwartz JB, et al. Decreased synaptic proteins in neuronal exosomes of frontotemporal dementia and Alzheimer’s disease. FASEB J 2016; 30(12): 4141-8.
[http://dx.doi.org/10.1096/fj.201600816R] [PMID: 27601437]
[26]
Duncan T, Valenzuela M. Alzheimer’s disease, dementia, and stem cell therapy. Stem Cell Res Ther 2017; 8(1): 111.
[http://dx.doi.org/10.1186/s13287-017-0567-5] [PMID: 28494803]
[27]
Jonsson T, Stefansson H, Steinberg S, et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med 2013; 368(2): 107-16.
[http://dx.doi.org/10.1056/NEJMoa1211103] [PMID: 23150908]
[28]
Lin YT, Seo J, Gao F, et al. APOE4 causes widespread molecular and cellular alterations associated with alzheimer’s disease phenotypes in human ipsc-derived brain cell types. Neuron 2018; 98(6): 1141-1154.e7.
[http://dx.doi.org/10.1016/j.neuron.2018.05.008] [PMID: 29861287]
[29]
Kunkle BW, et al. Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates A beta, tau, immunity and lipid processing. Nat Genet 2019; 51(9): 1423-4.
[http://dx.doi.org/10.1038/s41588-019-0495-7] [PMID: 31417202]
[30]
Huang K, Marcora E, Pimenova AA, et al. A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer’s disease. Nat Neurosci 2017; 20(8): 1052-61.
[http://dx.doi.org/10.1038/nn.4587] [PMID: 28628103]
[31]
Kondo T, Asai M, Tsukita K, et al. Modeling Alzheimer’s disease with iPSCs reveals stress phenotypes associated with intracellular Aβ and differential drug responsiveness. Cell Stem Cell 2013; 12(4): 487-96.
[http://dx.doi.org/10.1016/j.stem.2013.01.009] [PMID: 23434393]
[32]
Gonzalez C, Armijo E, Bravo-Alegria J, Becerra-Calixto A, Mays CE, Soto C. Modeling amyloid beta and tau pathology in human cerebral organoids. Mol Psychiatry 2018; 23(12): 2363-74.
[http://dx.doi.org/10.1038/s41380-018-0229-8] [PMID: 30171212]
[33]
Park JC, Jang SY, Lee D, et al. A logical network-based drug-screening platform for Alzheimer’s disease representing pathological features of human brain organoids. Nat Commun 2021; 12(1): 280.
[http://dx.doi.org/10.1038/s41467-020-20440-5] [PMID: 33436582]
[34]
Chang KH, Lee-Chen GJ, Huang CC, et al. Modeling Alzheimer’s disease by induced pluripotent stem cells carrying APP D678H mutation. Mol Neurobiol 2019; 56(6): 3972-83.
[http://dx.doi.org/10.1007/s12035-018-1336-x] [PMID: 30238389]
[35]
Ochalek A, Mihalik B, Avci HX, et al. Neurons derived from sporadic Alzheimer’s disease iPSCs reveal elevated TAU hyperphosphorylation, increased amyloid levels, and GSK3B activation. Alzheimers Res Ther 2017; 9(1): 90.
[http://dx.doi.org/10.1186/s13195-017-0317-z] [PMID: 29191219]
[36]
van der Kant R, Langness VF, Herrera CM, et al. Cholesterol metabolism is a druggable axis that independently regulates Tau and amyloid-β in iPSC-derived Alzheimer’s disease neurons. Cell Stem Cell 2019; 24(3): 363-375.e9.
[http://dx.doi.org/10.1016/j.stem.2018.12.013] [PMID: 30686764]
[37]
Kondo T, Imamura K, Funayama M, et al. iPSC-based compound screening and in vitro trials identify a synergistic anti-amyloid β combination for Alzheimer’s Disease. Cell Rep 2017; 21(8): 2304-12.
[http://dx.doi.org/10.1016/j.celrep.2017.10.109] [PMID: 29166618]
[38]
Vuidel A, Cousin L, Weykopf B, et al. High-content phenotyping of Parkinson’s disease patient stem cell-derived midbrain dopaminergic neurons using machine learning classification. Stem Cell Reports 2022; 17(10): 2349-64.
[http://dx.doi.org/10.1016/j.stemcr.2022.09.001] [PMID: 36179692]
[39]
Du F, Yu Q, Chen A, Chen D, Yan SS. Astrocytes attenuate mitochondrial dysfunctions in human dopaminergic neurons derived from iPSC. Stem Cell Reports 2018; 10(2): 366-74.
[http://dx.doi.org/10.1016/j.stemcr.2017.12.021] [PMID: 29396183]
[40]
Magistrelli L, Ferrari M, Furgiuele A, et al. Polymorphisms of dopamine receptor genes and Parkinson’s Disease: Clinical relevance and future perspectives. Int J Mol Sci 2021; 22(7): 3781.
[http://dx.doi.org/10.3390/ijms22073781] [PMID: 33917417]
[41]
Lee D, Dallapiazza R, De Vloo P, Lozano A. Current surgical treatments for Parkinson’s disease and potential therapeutic targets. Neural Regen Res 2018; 13(8): 1342-5.
[http://dx.doi.org/10.4103/1673-5374.235220] [PMID: 30106037]
[42]
Jaiswal MK. Riluzole and edaravone: A tale of two amyotrophic lateral sclerosis drugs. Med Res Rev 2019; 39(2): 733-48.
[http://dx.doi.org/10.1002/med.21528] [PMID: 30101496]
[43]
Osaki T, Uzel SGM, Kamm RD. Microphysiological 3D model of amyotrophic lateral sclerosis (ALS) from human iPS-derived muscle cells and optogenetic motor neurons. Sci Adv 2018; 4(10): eaat5847.
[http://dx.doi.org/10.1126/sciadv.aat5847] [PMID: 30324134]
[44]
Okano H, Yasuda D, Fujimori K, Morimoto S, Takahashi S. Ropinirole, a new ALS drug candidate developed using iPSCs. Trends Pharmacol Sci 2020; 41(2): 99-109.
[http://dx.doi.org/10.1016/j.tips.2019.12.002] [PMID: 31926602]
[45]
Lopez-Gonzalez R, Lu Y, Gendron TF, et al. Poly(GR) in C9ORF72 -related als/ftd compromises mitochondrial function and increases oxidative stress and dna damage in ipsc-derived motor neurons. Neuron 2016; 92(2): 383-91.
[http://dx.doi.org/10.1016/j.neuron.2016.09.015] [PMID: 27720481]
[46]
Maezawa I, Jin LW. Rett syndrome microglia damage dendrites and synapses by the elevated release of glutamate. J Neurosci 2010; 30(15): 5346-56.
[http://dx.doi.org/10.1523/JNEUROSCI.5966-09.2010] [PMID: 20392956]
[47]
Rodrigues FB, Duarte GS, Costa J, Ferreira JJ, Wild EJ. Tetrabenazine versus deutetrabenazine for huntington’s disease: twins or distant cousins? Mov Disord Clin Pract (Hoboken) 2017; 4(4): 582-5.
[http://dx.doi.org/10.1002/mdc3.12483] [PMID: 28920068]
[48]
Kordasiewicz HB, Stanek LM, Wancewicz EV, et al. Sustained therapeutic reversal of Huntington’s disease by transient repression of huntingtin synthesis. Neuron 2012; 74(6): 1031-44.
[http://dx.doi.org/10.1016/j.neuron.2012.05.009] [PMID: 22726834]
[49]
Park HJ, Jeon J, Choi J, et al. Human iPSC‐derived neural precursor cells differentiate into multiple cell types to delay disease progression following transplantation into YAC128 Huntington’s disease mouse model. Cell Prolif 2021; 54(8): e13082.
[http://dx.doi.org/10.1111/cpr.13082] [PMID: 34152047]
[50]
Hasselmann J, Coburn MA, England W, et al. Development of a chimeric model to study and manipulate human microglia In Vivo. Neuron 2019; 103(6): 1016-1033.e10.
[http://dx.doi.org/10.1016/j.neuron.2019.07.002] [PMID: 31375314]
[51]
Day JO, Mullin S. The genetics of Parkinson’s Disease and implications for clinical practice. Genes 2021; 12(7): 1006.
[http://dx.doi.org/10.3390/genes12071006] [PMID: 34208795]
[52]
Pierzchlińska A, Droździk M, Białecka M. A possible role for HMG-CoA reductase inhibitors and its association with HMGCR Genetic variation in Parkinson’s Disease. Int J Mol Sci 2021; 22(22): 12198.
[http://dx.doi.org/10.3390/ijms222212198] [PMID: 34830081]
[53]
Palermo G, Giannoni S, Bellini G, Siciliano G, Ceravolo R. Dopamine transporter imaging, current status of a potential biomarker: A comprehensive review. Int J Mol Sci 2021; 22(20): 11234.
[http://dx.doi.org/10.3390/ijms222011234] [PMID: 34681899]
[54]
Pajares M, I Rojo A, Manda G, Boscá L, Cuadrado A. Inflammation in Parkinson’s Disease: Mechanisms and therapeutic implications. Cells 2020; 9(7): 1687.
[http://dx.doi.org/10.3390/cells9071687] [PMID: 32674367]
[55]
Yang P, Pavlovic D, Waldvogel H, et al. String vessel formation is increased in the brain of Parkinson Disease. J Parkinsons Dis 2015; 5(4): 821-36.
[http://dx.doi.org/10.3233/JPD-140454] [PMID: 26444086]
[56]
Reynolds RH, Botía J, Nalls MA, et al. Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson’s disease heritability. NPJ Parkinsons Dis 2019; 5(1): 6.
[http://dx.doi.org/10.1038/s41531-019-0076-6] [PMID: 31016231]
[57]
Booth HDE, Hirst WD, Wade-Martins R. The role of astrocyte dysfunction in Parkinson’s disease pathogenesis. Trends Neurosci 2017; 40(6): 358-70.
[http://dx.doi.org/10.1016/j.tins.2017.04.001] [PMID: 28527591]
[58]
Pons-Espinal M, Blasco-Agell L, Consiglio A. Dissecting the non-neuronal cell contribution to Parkinson’s disease pathogenesis using induced pluripotent stem cells. Cell Mol Life Sci 2021; 78(5): 2081-94.
[http://dx.doi.org/10.1007/s00018-020-03700-x] [PMID: 33210214]
[59]
Schneider JS, Kortagere S. Current concepts in treating mild cognitive impairment in Parkinson’s disease. Neuropharmacology 2022; 203: 108880.
[http://dx.doi.org/10.1016/j.neuropharm.2021.108880] [PMID: 34774549]
[60]
Osman M, Ryterska A, Karimi K, et al. The effects of dopaminergic medication on dynamic decision making in Parkinson’s disease. Neuropsychologia 2014; 53: 157-64.
[http://dx.doi.org/10.1016/j.neuropsychologia.2013.10.024] [PMID: 24269857]
[61]
Stoddard-Bennett T, Reijo Pera R. Treatment of Parkinson’s Disease through personalized medicine and induced pluripotent stem cells. Cells 2019; 8(1): 26.
[http://dx.doi.org/10.3390/cells8010026] [PMID: 30621042]
[62]
Brown RH, Al-Chalabi A. Amyotrophic lateral sclerosis. N Engl J Med 2017; 377(2): 162-72.
[http://dx.doi.org/10.1056/NEJMra1603471] [PMID: 28700839]
[63]
Csobonyeiova M, Polak S, Nicodemou A, Danisovic L. Induced pluripotent stem cells in modeling and cell-based therapy of amyotrophic lateral sclerosis. J Physiol Pharmacol 2017; 68(5): 649-57.
[PMID: 29375039]
[64]
Wobst HJ, Mack KL, Brown DG, Brandon NJ, Shorter J. The clinical trial landscape in amyotrophic lateral sclerosis—Past, present, and future. Med Res Rev 2020; 40(4): 1352-84.
[http://dx.doi.org/10.1002/med.21661] [PMID: 32043626]
[65]
Zarei S, Carr K, Reiley L, et al. A comprehensive review of amyotrophic lateral sclerosis. Surg Neurol Int 2015; 6(1): 171.
[http://dx.doi.org/10.4103/2152-7806.169561] [PMID: 26629397]
[66]
Sever B, Ciftci H, DeMirci H, et al. Comprehensive research on past and future therapeutic strategies devoted to treatment of amyotrophic lateral sclerosis. Int J Mol Sci 2022; 23(5): 2400.
[http://dx.doi.org/10.3390/ijms23052400] [PMID: 35269543]
[67]
Jankovic M, Novakovic I, Gamil Anwar Dawod P, et al. Current concepts on genetic aspects of mitochondrial dysfunction in amyotrophic lateral sclerosis. Int J Mol Sci 2021; 22(18): 9832.
[http://dx.doi.org/10.3390/ijms22189832] [PMID: 34575995]
[68]
Devlin AC, Burr K, Borooah S, et al. Human iPSC-derived motoneurons harbouring TARDBP or C9ORF72 ALS mutations are dysfunctional despite maintaining viability. Nat Commun 2015; 6(1): 5999.
[http://dx.doi.org/10.1038/ncomms6999] [PMID: 25580746]
[69]
Steinbeck JA, Jaiswal MK, Calder EL, et al. Functional connectivity under optogenetic control allows modeling of human neuromuscular disease. Cell Stem Cell 2016; 18(1): 134-43.
[http://dx.doi.org/10.1016/j.stem.2015.10.002] [PMID: 26549107]
[70]
Pradat PF, Bruneteau G, Gonzalez de Aguilar JL, et al. Muscle Nogo-a expression is a prognostic marker in lower motor neuron syndromes. Ann Neurol 2007; 62(1): 15-20.
[http://dx.doi.org/10.1002/ana.21122] [PMID: 17455292]
[71]
Lin CY, et al. Extracellular Pgk1 enhances neurite outgrowth of motoneurons through Nogo66/NgR-independent targeting of NogoA. eLife 2019; 8.
[72]
Chang CY, Ting HC, Liu CA, et al. Induced Pluripotent Stem Cell (iPSC)-based neurodegenerative disease models for phenotype recapitulation and drug screening. Molecules 2020; 25(8): 2000.
[http://dx.doi.org/10.3390/molecules25082000] [PMID: 32344649]
[73]
López-Cortés A, Echeverría-Garcés G, Ramos-Medina MJ. Molecular pathogenesis and new therapeutic dimensions for spinal muscular atrophy. Biology 2022; 11(6): 894.
[http://dx.doi.org/10.3390/biology11060894] [PMID: 35741415]
[74]
Ogino S, Wilson RB. Spinal muscular atrophy: molecular genetics and diagnostics. Expert Rev Mol Diagn 2004; 4(1): 15-29.
[http://dx.doi.org/10.1586/14737159.4.1.15] [PMID: 14711346]
[75]
Feldkötter M, Schwarzer V, Wirth R, Wienker TF, Wirth B. Quantitative analyses of SMN1 and SMN2 based on real-time lightCycler PCR: fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy. Am J Hum Genet 2002; 70(2): 358-68.
[http://dx.doi.org/10.1086/338627] [PMID: 11791208]
[76]
Zhou M, Hu Z, Qiu L, et al. Seamless genetic conversion of SMN2 to SMN1 via CRISPR/Cpf1 and single-stranded oligodeoxynucleotides in spinal muscular atrophy patient-specific induced pluripotent stem cells. Hum Gene Ther 2018; 29(11): 1252-63.
[http://dx.doi.org/10.1089/hum.2017.255] [PMID: 29598153]
[77]
Coovert D, Le TT, McAndrew PE, et al. The survival motor neuron protein in spinal muscular atrophy. Hum Mol Genet 1997; 6(8): 1205-14.
[http://dx.doi.org/10.1093/hmg/6.8.1205] [PMID: 9259265]
[78]
Lorson CL, Hahnen E, Androphy EJ, Wirth B. A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. Proc Natl Acad Sci USA 1999; 96(11): 6307-11.
[http://dx.doi.org/10.1073/pnas.96.11.6307] [PMID: 10339583]
[79]
Hauser S, Schuster S, Heuten E, et al. Comparative transcriptional profiling of motor neuron disorder-associated genes in various human cell culture models. Front Cell Dev Biol 2020; 8: 544043.
[http://dx.doi.org/10.3389/fcell.2020.544043] [PMID: 33072739]
[80]
Andoh-Noda T, Inouye MO, Miyake K, Kubota T, Okano H, Akamatsu W. Modeling rett syndrome using human induced pluripotent stem cells. CNS Neurol Disord Drug Targets 2016; 15(5): 544-50.
[http://dx.doi.org/10.2174/1871527315666160413120156] [PMID: 27071793]
[81]
Marchetto MCN, Carromeu C, Acab A, et al. A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. Cell 2010; 143(4): 527-39.
[http://dx.doi.org/10.1016/j.cell.2010.10.016] [PMID: 21074045]
[82]
Bourgeron T. From the genetic architecture to synaptic plasticity in autism spectrum disorder. Nat Rev Neurosci 2015; 16(9): 551-63.
[http://dx.doi.org/10.1038/nrn3992] [PMID: 26289574]
[83]
Avior Y, Sagi I, Benvenisty N. Pluripotent stem cells in disease modelling and drug discovery. Nat Rev Mol Cell Biol 2016; 17(3): 170-82.
[http://dx.doi.org/10.1038/nrm.2015.27] [PMID: 26818440]
[84]
Barral S, Kurian MA. Utility of induced pluripotent stem cells for the study and treatment of genetic diseases: focus on childhood neurological disorders. Front Mol Neurosci 2016; 9: 78.
[http://dx.doi.org/10.3389/fnmol.2016.00078] [PMID: 27656126]
[85]
Di Giorgio FP, Boulting GL, Bobrowicz S, Eggan KC. Human embryonic stem cell-derived motor neurons are sensitive to the toxic effect of glial cells carrying an ALS-causing mutation. Cell Stem Cell 2008; 3(6): 637-48.
[http://dx.doi.org/10.1016/j.stem.2008.09.017] [PMID: 19041780]
[86]
Di Giorgio FP, Carrasco MA, Siao MC, Maniatis T, Eggan K. Non–cell autonomous effect of glia on motor neurons in an embryonic stem cell–based ALS model. Nat Neurosci 2007; 10(5): 608-14.
[http://dx.doi.org/10.1038/nn1885] [PMID: 17435754]
[87]
Lindvall O, Kokaia Z. Stem cells for the treatment of neurological disorders. Nature 2006; 441(7097): 1094-6.
[http://dx.doi.org/10.1038/nature04960] [PMID: 16810245]
[88]
Chiaradia I, Lancaster MA. Brain organoids for the study of human neurobiology at the interface of in vitro and in vivo. Nat Neurosci 2020; 23(12): 1496-508.
[http://dx.doi.org/10.1038/s41593-020-00730-3] [PMID: 33139941]
[89]
Yoshida S, Miwa H, Kawachi T, Kume S, Takahashi K. Generation of intestinal organoids derived from human pluripotent stem cells for drug testing. Sci Rep 2020; 10(1): 5989.
[http://dx.doi.org/10.1038/s41598-020-63151-z] [PMID: 32249832]
[90]
Ebert AD, Yu J, Rose FF Jr, et al. Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature 2009; 457(7227): 277-80.
[http://dx.doi.org/10.1038/nature07677] [PMID: 19098894]
[91]
Sareen D, Ebert AD, Heins BM, McGivern JV, Ornelas L, Svendsen CN. Inhibition of apoptosis blocks human motor neuron cell death in a stem cell model of spinal muscular atrophy. PLoS One 2012; 7(6): e39113.
[http://dx.doi.org/10.1371/journal.pone.0039113] [PMID: 22723941]
[92]
Wang ZB, Zhang X, Li XJ. Recapitulation of spinal motor neuron-specific disease phenotypes in a human cell model of spinal muscular atrophy. Cell Res 2013; 23(3): 378-93.
[http://dx.doi.org/10.1038/cr.2012.166] [PMID: 23208423]
[93]
Ohuchi K, Funato M, Kato Z, et al. Established stem cell model of spinal muscular atrophy is applicable in the evaluation of the efficacy of thyrotropin-releasing hormone analog. Stem Cells Transl Med 2016; 5(2): 152-63.
[http://dx.doi.org/10.5966/sctm.2015-0059] [PMID: 26683872]
[94]
Naryshkin NA, Weetall M, Dakka A, et al. SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy. Science 2014; 345(6197): 688-93.
[http://dx.doi.org/10.1126/science.1250127] [PMID: 25104390]
[95]
Porensky PN, Mitrpant C, McGovern VL, et al. A single administration of morpholino antisense oligomer rescues spinal muscular atrophy in mouse. Hum Mol Genet 2012; 21(7): 1625-38.
[http://dx.doi.org/10.1093/hmg/ddr600] [PMID: 22186025]
[96]
Zanetta C, Nizzardo M, Simone C, et al. Molecular therapeutic strategies for spinal muscular atrophies: current and future clinical trials. Clin Ther 2014; 36(1): 128-40.
[http://dx.doi.org/10.1016/j.clinthera.2013.11.006] [PMID: 24360800]
[97]
Zanetta C, Riboldi G, Nizzardo M, et al. Molecular, genetic and stem cell‐mediated therapeutic strategies for spinal muscular atrophy (SMA). J Cell Mol Med 2014; 18(2): 187-96.
[http://dx.doi.org/10.1111/jcmm.12224] [PMID: 24400925]
[98]
Hua Y, Sahashi K, Rigo F, et al. Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model. Nature 2011; 478(7367): 123-6.
[http://dx.doi.org/10.1038/nature10485] [PMID: 21979052]
[99]
Nizzardo M, Simone C, Salani S, et al. Effect of combined systemic and local morpholino treatment on the spinal muscular atrophy Δ7 mouse model phenotype. Clin Ther 2014; 36(3): 340-356.e5.
[http://dx.doi.org/10.1016/j.clinthera.2014.02.004] [PMID: 24636820]
[100]
Nizzardo M, Simone C, Dametti S, et al. Spinal muscular atrophy phenotype is ameliorated in human motor neurons by SMN increase via different novel RNA therapeutic approaches. Sci Rep 2015; 5(1): 11746.
[http://dx.doi.org/10.1038/srep11746] [PMID: 26123042]
[101]
Chaytow H, Faller KME, Huang YT, Gillingwater TH. Spinal muscular atrophy: From approved therapies to future therapeutic targets for personalized medicine. Cell Rep Med 2021; 2(7): 100346.
[http://dx.doi.org/10.1016/j.xcrm.2021.100346] [PMID: 34337562]
[102]
Ross CA, Poirier MA. Protein aggregation and neurodegenerative disease. Nat Med 2004; 10(S7) (Suppl.): S10-7.
[http://dx.doi.org/10.1038/nm1066] [PMID: 15272267]
[103]
Soto C, Pritzkow S. Protein misfolding, aggregation, and conformational strains in neurodegenerative diseases. Nat Neurosci 2018; 21(10): 1332-40.
[http://dx.doi.org/10.1038/s41593-018-0235-9] [PMID: 30250260]
[104]
Mohandas E, Rajmohan V. Frontotemporal dementia: An updated overview. Indian J Psychiatry 51(s1): 65-9.
[PMID: 21416021]
[105]
Bocchetta M, Malpetti M, Todd EG, Rowe JB, Rohrer JD. Looking beneath the surface: the importance of subcortical structures in frontotemporal dementia. Brain Commun 2021; 3(3): fcab158.
[http://dx.doi.org/10.1093/braincomms/fcab158] [PMID: 34458729]
[106]
Nakamura M, Shiozawa S, Tsuboi D, et al. Pathological progression induced by the frontotemporal dementia-associated r406w tau mutation in patient-derived iPSCs. Stem Cell Reports 2019; 13(4): 684-99.
[http://dx.doi.org/10.1016/j.stemcr.2019.08.011] [PMID: 31543469]
[107]
Kühn R, Mahajan A, Canoll P, Hargus G. Human induced pluripotent stem cell models of frontotemporal dementia with tau pathology. Front Cell Dev Biol 2021; 9: 766773.
[http://dx.doi.org/10.3389/fcell.2021.766773] [PMID: 34858989]
[108]
Bocchetta M, Gordon E, Manning E, et al. Detailed volumetric analysis of the hypothalamus in behavioral variant frontotemporal dementia. J Neurol 2015; 262(12): 2635-42.
[http://dx.doi.org/10.1007/s00415-015-7885-2] [PMID: 26338813]
[109]
Honson NS, Kuret J. Tau aggregation and toxicity in tauopathic neurodegenerative diseases. J Alzheimers Dis 2008; 14(4): 417-22.
[http://dx.doi.org/10.3233/JAD-2008-14409] [PMID: 18688092]
[110]
Liu F, Gong CX. Tau exon 10 alternative splicing and tauopathies. Mol Neurodegener 2008; 3(1): 8.
[http://dx.doi.org/10.1186/1750-1326-3-8] [PMID: 18616804]
[111]
Camp JG, Badsha F, Florio M, et al. Human cerebral organoids recapitulate gene expression programs of fetal neocortex development. Proc Natl Acad Sci USA 2015; 112(51): 15672-7.
[http://dx.doi.org/10.1073/pnas.1520760112] [PMID: 26644564]
[112]
Imamura K, Sahara N, Kanaan NM, et al. Calcium dysregulation contributes to neurodegeneration in FTLD patient iPSC-derived neurons. Sci Rep 2016; 6(1): 34904.
[http://dx.doi.org/10.1038/srep34904] [PMID: 27721502]
[113]
Medda X, Mertens L, Versweyveld S, et al. Development of a scalable, high-throughput-compatible assay to detect tau aggregates using ipsc-derived cortical neurons maintained in a three-dimensional culture format. SLAS Discov 2016; 21(8): 804-15.
[http://dx.doi.org/10.1177/1087057116638029] [PMID: 26984927]
[114]
Silva MC, Ferguson FM, Cai Q, et al. Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models. eLife 2019; 8: e45457.
[http://dx.doi.org/10.7554/eLife.45457] [PMID: 30907729]
[115]
Krishnan G, Raitcheva D, Bartlett D, et al. Poly(GR) and poly(GA) in cerebrospinal fluid as potential biomarkers for C9ORF72-ALS/FTD. Nat Commun 2022; 13(1): 2799.
[http://dx.doi.org/10.1038/s41467-022-30387-4] [PMID: 35589711]
[116]
Valdez C, Wong YC, Schwake M, Bu G, Wszolek ZK, Krainc D. Progranulin-mediated deficiency of cathepsin D results in FTD and NCL-like phenotypes in neurons derived from FTD patients. Hum Mol Genet 2017; 26(24): 4861-72.
[http://dx.doi.org/10.1093/hmg/ddx364] [PMID: 29036611]
[117]
Dafinca R, Scaber J, Ababneh N, et al. C9orf72 hexanucleotide expansions are associated with altered endoplasmic reticulum calcium homeostasis and stress granule formation in induced pluripotent stem cell-derived neurons from patients with amyotrophic lateral sclerosis and frontotemporal dementia. Stem Cells 2016; 34(8): 2063-78.
[http://dx.doi.org/10.1002/stem.2388] [PMID: 27097283]
[118]
Ehrlich M, Hallmann AL, Reinhardt P, et al. Distinct neurodegenerative changes in an induced pluripotent stem cell model of frontotemporal dementia linked to mutant TAU protein. Stem Cell Reports 2015; 5(1): 83-96.
[http://dx.doi.org/10.1016/j.stemcr.2015.06.001] [PMID: 26143746]
[119]
Melamed Z, López-Erauskin J, Baughn MW, et al. Premature polyadenylation-mediated loss of stathmin-2 is a hallmark of TDP-43-dependent neurodegeneration. Nat Neurosci 2019; 22(2): 180-90.
[http://dx.doi.org/10.1038/s41593-018-0293-z] [PMID: 30643298]
[120]
Kim M, Kim HJ, Koh W, et al. Modeling of frontotemporal dementia using iPSC technology. Int J Mol Sci 2020; 21(15): 5319.
[http://dx.doi.org/10.3390/ijms21155319] [PMID: 32727073]
[121]
López-Pousa S, Calvó-Perxas L, Lejarreta S, et al. Use of antidementia drugs in frontotemporal lobar degeneration. Am J Alzheimers Dis Other Demen 2012; 27(4): 260-6.
[http://dx.doi.org/10.1177/1533317512447887] [PMID: 22605780]
[122]
Chen SD, Li HQ, Cui M, Dong Q, Yu JT. Pluripotent stem cells for neurodegenerative disease modeling: an expert view on their value to drug discovery. Expert Opin Drug Discov 2020; 15(9): 1081-94.
[http://dx.doi.org/10.1080/17460441.2020.1767579] [PMID: 32425128]
[123]
Huber N, Korhonen S, Hoffmann D, et al. Deficient neurotransmitter systems and synaptic function in frontotemporal lobar degeneration—Insights into disease mechanisms and current therapeutic approaches. Mol Psychiatry 2022; 27(3): 1300-9.
[http://dx.doi.org/10.1038/s41380-021-01384-8] [PMID: 34799692]
[124]
Haenseler W, Rajendran L. Concise review: Modeling neurodegenerative diseases with human pluripotent stem cell-derived microglia. Stem Cells 2019; 37(6): 724-30.
[http://dx.doi.org/10.1002/stem.2995] [PMID: 30801863]
[125]
Chen X, Han X, Blanchi B, et al. Graded and pan-neural disease phenotypes of Rett Syndrome linked with dosage of functional MeCP2. Protein Cell 2021; 12(8): 639-52.
[http://dx.doi.org/10.1007/s13238-020-00773-z] [PMID: 32851591]
[126]
Gomes AR, Fernandes TG, Cabral JMS, Diogo MM. Modeling rett syndrome with human pluripotent stem cells: Mechanistic outcomes and future clinical perspectives. Int J Mol Sci 2021; 22(7): 3751.
[http://dx.doi.org/10.3390/ijms22073751] [PMID: 33916879]
[127]
Smirnov K, Stroganova T, Molholm S, Sysoeva O. Reviewing evidence for the relationship of EEG abnormalities and RTT phenotype paralleled by insights from animal studies. Int J Mol Sci 2021; 22(10): 5308.
[http://dx.doi.org/10.3390/ijms22105308] [PMID: 34069993]
[128]
Leonard H, Gold W, Samaco R, Sahin M, Benke T, Downs J. Improving clinical trial readiness to accelerate development of new therapeutics for Rett syndrome. Orphanet J Rare Dis 2022; 17(1): 108.
[http://dx.doi.org/10.1186/s13023-022-02240-w] [PMID: 35246185]
[129]
Cheffer A, Flitsch LJ, Krutenko T, et al. Human stem cell-based models for studying autism spectrum disorder-related neuronal dysfunction. Mol Autism 2020; 11(1): 99.
[http://dx.doi.org/10.1186/s13229-020-00383-w] [PMID: 33308283]
[130]
Balachandar V, Dhivya V, Gomathi M, Mohanadevi S, Venkatesh B, Geetha B. A review of Rett syndrome (RTT) with induced pluripotent stem cells. Stem Cell Investig 2016; 3: 52.
[http://dx.doi.org/10.21037/sci.2016.09.05] [PMID: 27777941]
[131]
Gomathi M, Padmapriya S, Balachandar V. Drug studies on Rett Syndrome: From bench to bedside. J Autism Dev Disord 2020; 50(8): 2740-64.
[http://dx.doi.org/10.1007/s10803-020-04381-y] [PMID: 32016693]
[132]
Caron NS, Wright GEB, Hayden MR. Huntington Disease. GeneReviewsSeattle, WA 1993.
[133]
Roos RAC. Huntington’s disease: a clinical review. Orphanet J Rare Dis 2010; 5(1): 40.
[http://dx.doi.org/10.1186/1750-1172-5-40] [PMID: 21171977]
[134]
MacDonald M. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 1993; 72(6): 971-83.
[http://dx.doi.org/10.1016/0092-8674(93)90585-E] [PMID: 8458085]
[135]
Ross CA, Tabrizi SJ. Huntington’s disease: from molecular pathogenesis to clinical treatment. Lancet Neurol 2011; 10(1): 83-98.
[http://dx.doi.org/10.1016/S1474-4422(10)70245-3] [PMID: 21163446]
[136]
Conforti P, et al. Faulty neuronal determination and cell polarization are reverted by modulating HD early phenotypes. Proc Natl Acad Sci USA 2018; 115(9): E2148-8.
[PMID: 29463700]
[137]
Csobonyeiova M, Polák Š. Recent overview of the use of iPSCs Huntington's Disease modeling and therapy. Int J Mol Sci 2020; 21(6): 2239.
[http://dx.doi.org/10.3390/ijms21062239] [PMID: 32213859]
[138]
Bachoud-Lévi AC, Ferreira J, Massart R, et al. International guidelines for the treatment of Huntington’s Disease. Front Neurol 2019; 10: 710.
[http://dx.doi.org/10.3389/fneur.2019.00710] [PMID: 31333565]
[139]
Kaplan A, Stockwell BR. Therapeutic approaches to preventing cell death in Huntington disease. Prog Neurobiol 2012; 99(3): 262-80.
[http://dx.doi.org/10.1016/j.pneurobio.2012.08.004] [PMID: 22967354]
[140]
Coppen EM, Roos RAC. Current pharmacological approaches to reduce chorea in Huntington’s Disease. Drugs 2017; 77(1): 29-46.
[http://dx.doi.org/10.1007/s40265-016-0670-4] [PMID: 27988871]
[141]
Safety, tolerability, and efficacy of PBT2 in Huntington’s disease: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol 2015; 14(1): 39-47.
[http://dx.doi.org/10.1016/S1474-4422(14)70262-5] [PMID: 25467848]
[142]
Jeon I, Lee N, Li JY, et al. Neuronal properties, in vivo effects, and pathology of a Huntington’s disease patient-derived induced pluripotent stem cells. Stem Cells 2012; 30(9): 2054-62.
[http://dx.doi.org/10.1002/stem.1135] [PMID: 22628015]
[143]
La Spada AR, Weydt P, Pineda VV. Huntington’s Disease Pathogenesis: Mechanisms and Pathways.Neurobiology of Huntington’s Disease: Applications to Drug Discovery. CRC Press,Taylor and FrancisBoca Raton, FL 2011.
[PMID: 21882412]
[144]
Ward JM, La Spada AR. The expanding world of stem cell modeling of Huntington’s disease: creating tools with a promising future. Genome Med 2012; 4(8): 68.
[http://dx.doi.org/10.1186/gm369] [PMID: 22943447]

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      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` = 60 limit 1
      1.15msalphaeurekaselec_live_10_06_2022Journal.php#64
      Bindings
      • 0: 60
      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=60) and sj.journal_id!=60 group by `j`.`nid`) as `aggregate_table`
      1.3msalphaeurekaselec_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=60) and sj.journal_id!=60 group by `j`.`nid` order by `j`.`journal_id` asc limit 10 offset 0
      1.12msalphaeurekaselec_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=60) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid`) as `aggregate_table`
      7.18msalphaeurekaselec_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=60) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid` order by `v`.`ebook_volume_id` desc limit 10 offset 0
      6.41msalphaeurekaselec_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` = '132400'
      330μsalphaeurekaselec_live_10_06_2022Keywords.php#43
      Bindings
      • 0: 132400
      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` = '132400'
      5.61msalphaeurekaselec_live_10_06_2022Article.php#1570
      Bindings
      • 0: 132400
      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` = '132400' group by `au`.`author_id` order by `au`.`article_id` asc, `au`.`sequence` asc
      4.42msalphaeurekaselec_live_10_06_2022Author.php#86
      Bindings
      • 0: 132400
      Backtrace
      • 13. app/Models/Author.php:86
      • 14. app/Http/Controllers/ArticleController.php:2533
      • 15. app/Http/Controllers/ArticleController.php:2035
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select `bo`.* from `bundle_offer` as `bo` where `bo`.`bundle_status` = 'A' order by `bo`.`bundle_id` desc
      340μsalphaeurekaselec_live_10_06_2022BundleOffer.php#57
      Bindings
      • 0: A
      Backtrace
      • 13. app/Models/BundleOffer.php:57
      • 14. app/Http/Controllers/ArticleController.php:2535
      • 15. app/Http/Controllers/ArticleController.php:2035
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select `subtitle` from `journal` where `continues_publication_journal` = 1
      740μsalphaeurekaselec_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 = 60 and i.is_uploaded = 1 order by v.volume_name+0 desc, i.title+0 desc limit 1
      47.97msalphaeurekaselec_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 = 60 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      19.4msalphaeurekaselec_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 = 60 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      9.88msalphaeurekaselec_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` = 132400 limit 1
      390μsalphaeurekaselec_live_10_06_2022Article.php#744
      Bindings
      • 0: 132400
      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 = 132400 and content_type = 'article' order by status desc limit 1
      360μsalphaeurekaselec_live_10_06_2022Article.php#751
      Backtrace
      • 11. app/Models/Article.php:751
      • 12. app/Http/Controllers/ArticleController.php:2094
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `node_meta` where `nid` = 217789 limit 1
      280μsalphaeurekaselec_live_10_06_2022Meta.php#30
      Bindings
      • 0: 217789
      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
      470μsalphaeurekaselec_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` = 'CSCRT' and (h.proposal_closing_date = 0 OR TO_DAYS(FROM_UNIXTIME(h.proposal_closing_date)) >= TO_DAYS(NOW())) order by `h`.`manuscript` asc
      400μsalphaeurekaselec_live_10_06_2022Article.php#2025
      Bindings
      • 0: CSCRT
      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 = '132400' 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) )
      550μsalphaeurekaselec_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 = '13037' 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) )
      480μsalphaeurekaselec_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 = '3453' 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) )
      440μsalphaeurekaselec_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 <= 309695154 and j.to_ip >=309695154 )) and ((j.from_date <= 1740775683 and j.to_date >= 1740775683 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3453) 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 <= 309695154 and j.to_ip >=309695154 )) and ((j.from_date <= 1740775683 and j.to_date >= 1740775683 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3453) 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 <= 309695154 and j.to_ip >=309695154 )) and ((j.from_date <= 1740775683 and j.to_date >= 1740775683 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3453)
      158msalphaeurekaselec_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 <= 309695154 and j.to_ip >=309695154 )) and ((j.from_date <= 1740775684 and j.to_date >= 1740775684 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 13037) 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 <= 309695154 and j.to_ip >=309695154 )) and ((j.from_date <= 1740775684 and j.to_date >= 1740775684 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 13037) 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 <= 309695154 and j.to_ip >=309695154 )) and ((j.from_date <= 1740775684 and j.to_date >= 1740775684 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 13037)
      1.04msalphaeurekaselec_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 <= 309695154 and j.to_ip >=309695154 )) and ((j.from_date <= 1740775684 and j.to_date >= 1740775684 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 132400) 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 <= 309695154 and j.to_ip >=309695154 )) and ((j.from_date <= 1740775684 and j.to_date >= 1740775684 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 132400) 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 <= 309695154 and j.to_ip >=309695154 )) and ((j.from_date <= 1740775684 and j.to_date >= 1740775684 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 132400)
      980μsalphaeurekaselec_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` < '809' and is_uploaded = 1 and issue_id = 13037 order by cast(first_page as SIGNED) desc limit 1
      680μsalphaeurekaselec_live_10_06_2022Article.php#1819
      Bindings
      • 0: 809
      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` > '819' and is_uploaded = 1 and issue_id = 13037 order by cast(first_page as SIGNED) asc limit 1
      1.07msalphaeurekaselec_live_10_06_2022Article.php#1831
      Bindings
      • 0: 819
      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
      290μsalphaeurekaselec_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` = 132400 limit 1
      2.97msalphaeurekaselec_live_10_06_2022ArticleController.php#2506
      Bindings
      • 0: 132400
      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` = 60 and `b`.`banner_from_date` <= 1740775684 and `b`.`banner_to_date` >= 1740775684 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.49msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 60
      • 3: 1740775684
      • 4: 1740775684
      • 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` = 60 and `b`.`banner_from_date` <= 1740775684 and `b`.`banner_to_date` >= 1740775684 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.54msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 60
      • 3: 1740775684
      • 4: 1740775684
      • 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='c7ad7497d3f158a6bba8746ddd37fe77'
      290μsalphaeurekaselec_live_10_06_2022Cart.php#271
      Backtrace
      • 15. app/Models/Cart.php:271
      • 16. view::layouts._header:291
      • 18. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 20. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    App\Models\MultiLanguage
    1MultiLanguage.php#?
        _token
        durtkBoFF2aRJlTGuInbQUM9h9ZRnNaYL64LPnd8
        uc_cart_id
        c7ad7497d3f158a6bba8746ddd37fe77
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        status_code
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        status_text
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        request_cookies
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        response_headers
        0 of 0
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        ClearShow all
        Date ↕MethodURLData
        #12025-02-28 20:48:04GET/article/132400414361