Review Article

功能失调蛋白分解代谢对巨噬细胞胆固醇处理的影响

卷 26, 期 9, 2019

页: [1631 - 1643] 页: 13

弟呕挨: 10.2174/0929867325666180326165234

价格: $65

摘要

巨噬细胞中的蛋白质分解代谢主要通过自噬-溶酶体降解、泛素-蛋白酶体系统和钙蛋白酶来完成,在动脉粥样硬化血管中受到干扰。此外,越来越多的证据表明蛋白质分解代谢缺陷会干扰巨噬细胞中胆固醇的处理。事实上,自噬减少有助于动脉粥样硬化巨噬细胞中胆固醇的沉积,并随后由于脂质滴分解代谢受损和死亡细胞的有效清除有限而导致易受损害的动脉粥样硬化斑块的形成。蛋白酶体负责降解ATP结合盒转运蛋白,从而导致巨噬细胞胆固醇流出受损。传统钙蛋白酶的过度激活有助于功能蛋白的过度加工,从而加速受体介导的氧化低密度脂蛋白(LDL)的摄取,并减缓胆固醇的排出。此外,calpain-6是巨噬细胞中的一种非常规的非保护性calpain,它能增强本地低密度脂蛋白的胞饮作用,并减弱死亡细胞的体外清除。在这里,我们集中在最近的进展,了解有缺陷的蛋白质分解代谢如何与巨噬细胞胆固醇处理和随后的动脉粥样硬化有关。

关键词: 动脉粥样硬化、低密度脂蛋白、清除剂受体、胞饮作用、传出细胞增多、胆固醇外流;三磷酸腺苷结合盒转运蛋白。

[1]
Puente, X.S.; Sánchez, L.M.; Overall, C.M.; López-Otín, C. Human and mouse proteases: A comparative genomic approach. Nat. Rev. Genet., 2003, 4(7), 544-558.
[2]
Rawlings, N.D.; Barrett, A.J.; Bateman, A. MEROPS: The peptidase database. Nucleic Acids Res., 2010, 38(Database issue), D227-D233.
[3]
Mizushima, N.; Komatsu, M. Autophagy: renovation of cells and tissues. Cell, 2011, 147(4), 728-741.
[4]
Tanaka, K.; Matsuda, N. Proteostasis and neurodegeneration: the roles of proteasomal degradation and autophagy. Biochim. Biophys. Acta, 2014, 1843(1), 197-204.
[5]
Qureshi, N.; Vogel, S.N.; Van Way, C., III; Papasian, C.J.; Qureshi, A.A.; Morrison, D.C. The proteasome: a central regulator of inflammation and macrophage function. Immunol. Res., 2005, 31(3), 243-260.
[6]
Vieira, O.; Escargueil-Blanc, I.; Jürgens, G.; Borner, C.; Almeida, L.; Salvayre, R.; Nègre-Salvayre, A. Oxidized LDLs alter the activity of the ubiquitin-proteasome pathway: potential role in oxidized LDL-induced apoptosis. FASEB J., 2000, 14(3), 532-542.
[7]
Martinet, W.; De Bie, M.; Schrijvers, D.M.; De Meyer, G.R.; Herman, A.G.; Kockx, M.M. 7-ketocholesterol induces protein ubiquitination, myelin figure formation, and light chain 3 processing in vascular smooth muscle cells. Arterioscler. Thromb. Vasc. Biol., 2004, 24(12), 2296-2301.
[8]
Miyazaki, T.; Miyazaki, A. Emerging roles of calpain proteolytic systems in macrophage cholesterol handling. Cell. Mol. Life Sci., 2017, 74(16), 3011-3021.
[9]
Miyazaki, T.; Miyazaki, A. Dysregulation of calpain proteolytic systems underlies degenerative vascular disorders. J. Atheroscler. Thromb., 2018, 25(1), 1-15.
[10]
Miyazaki, T.; Koya, T.; Kigawa, Y.; Oguchi, T.; Lei, X.F.; Kim-Kaneyama, J.R.; Miyazaki, A. Calpain and atherosclerosis. J. Atheroscler. Thromb., 2013, 20(3), 228-237.
[11]
Levine, B.; Kroemer, G. Autophagy in the pathogenesis of disease. Cell, 2008, 132(1), 27-42.
[12]
Maiuri, M.C.; Zalckvar, E.; Kimchi, A.; Kroemer, G. Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat. Rev. Mol. Cell Biol., 2007, 8(9), 741-752.
[13]
Lavandero, S.; Chiong, M.; Rothermel, B.A.; Hill, J.A. Autophagy in cardiovascular biology. J. Clin. Invest., 2015, 125(1), 55-64.
[14]
Razani, B.; Feng, C.; Coleman, T.; Emanuel, R.; Wen, H.; Hwang, S.; Ting, J.P.; Virgin, H.W.; Kastan, M.B.; Semenkovich, C.F. Autophagy links inflammasomes to atherosclerotic progression. Cell Metab., 2012, 15(4), 534-544.
[15]
Liao, X.; Sluimer, J.C.; Wang, Y.; Subramanian, M.; Brown, K.; Pattison, J.S.; Robbins, J.; Martinez, J.; Tabas, I. Macrophage autophagy plays a protective role in advanced atherosclerosis. Cell Metab., 2012, 15(4), 545-553.
[16]
Sijts, E.J.; Kloetzel, P.M. The role of the proteasome in the generation of MHC class I ligands and immune responses. Cell. Mol. Life Sci., 2011, 68(9), 1491-1502.
[17]
DeSalle, L.M.; Pagano, M. Regulation of the G1 to S transition by the ubiquitin pathway. FEBS Lett., 2001, 490(3), 179-189.
[18]
Kimura, Y.; Tanaka, K. Regulatory mechanisms involved in the control of ubiquitin homeostasis. J. Biochem., 2010, 147(6), 793-798.
[19]
Zheng, Q.; Huang, T.; Zhang, L.; Zhou, Y.; Luo, H.; Xu, H.; Wang, X. Dysregulation of ubiquitin-proteasome system in neurodegenerative diseases. Front. Aging Neurosci., 2016, 8, 303.
[20]
Herrmann, J.; Lerman, L.O.; Lerman, A. On to the road to degradation: Atherosclerosis and the proteasome. Cardiovasc. Res., 2010, 85(2), 291-302.
[21]
Herrmann, J.; Soares, S.M.; Lerman, L.O.; Lerman, A. Potential role of the ubiquitin-proteasome system in atherosclerosis: Aspects of a protein quality disease. J. Am. Coll. Cardiol., 2008, 51(21), 2003-2010.
[22]
Herrmann, J.; Saguner, A.M.; Versari, D.; Peterson, T.E.; Chade, A.; Olson, M.; Lerman, L.O.; Lerman, A. Chronic proteasome inhibition contributes to coronary atherosclerosis. Circ. Res., 2007, 101(9), 865-874.
[23]
Versari, D.; Herrmann, J.; Gössl, M.; Mannheim, D.; Sattler, K.; Meyer, F.B.; Lerman, L.O.; Lerman, A. Dysregulation of the ubiquitin-proteasome system in human carotid atherosclerosis. Arterioscler. Thromb. Vasc. Biol., 2006, 26(9), 2132-2139.
[24]
Brand, K.; Eisele, T.; Kreusel, U.; Page, M.; Page, S.; Haas, M.; Gerling, A.; Kaltschmidt, C.; Neumann, F.J.; Mackman, N.; Baeurele, P.A.; Walli, A.K.; Neumeier, D. Dysregulation of monocytic nuclear factor-kappa B by oxidized low-density lipoprotein. Arterioscler. Thromb. Vasc. Biol., 1997, 17(10), 1901-1909.
[25]
Wilck, N.; Fechner, M.; Dreger, H.; Hewing, B.; Arias, A.; Meiners, S.; Baumann, G.; Stangl, V.; Stangl, K.; Ludwig, A. Attenuation of early atherogenesis in low-density lipoprotein receptor-deficient mice by proteasome inhibition. Arterioscler. Thromb. Vasc. Biol., 2012, 32(6), 1418-1426.
[26]
Ross, R. Atherosclerosis-an inflammatory disease. N. Engl. J. Med., 1999, 340(2), 115-126.
[27]
Goll, D.E.; Thompson, V.F.; Li, H.; Wei, W.; Cong, J. The calpain system. Physiol. Rev., 2003, 83(3), 731-801.
[28]
Ono, Y.; Sorimachi, H. Calpains: An elaborate proteolytic system. Biochim. Biophys. Acta, 2012, 1824(1), 224-236.
[29]
Ono, Y.; Saido, T.C.; Sorimachi, H. Calpain research for drug discovery: Challenges and potential. Nat. Rev. Drug Discov., 2016, 15(12), 854-876.
[30]
Miyazaki, T.; Ohata, H.; Yamamoto, M.; Momose, K. Spontaneous and flow-induced Ca2+ transients in retracted regions in endothelial cells. Biochem. Biophys. Res. Commun., 2001, 281(1), 172-179.
[31]
Miyazaki, T.; Honda, K.; Ohata, H. m-Calpain antagonizes RhoA overactivation and endothelial barrier dysfunction under disturbed shear conditions. Cardiovasc. Res., 2010, 85(3), 530-541.
[32]
Miyazaki, T.; Taketomi, Y.; Takimoto, M.; Lei, X.F.; Arita, S.; Kim-Kaneyama, J.R.; Arata, S.; Ohata, H.; Ota, H.; Murakami, M.; Miyazaki, A. m-Calpain induction in vascular endothelial cells on human and mouse atheromas and its roles in VE-cadherin disorganization and atherosclerosis. Circulation, 2011, 124(23), 2522-2532.
[33]
Subramanian, V.; Uchida, H.A.; Ijaz, T.; Moorleghen, J.J.; Howatt, D.A.; Balakrishnan, A. Calpain inhibition attenuates angiotensin II-induced abdominal aortic aneurysms and atherosclerosis in low-density lipoprotein receptor-deficient mice. J. Cardiovasc. Pharmacol., 2012, 59(1), 66-76.
[34]
Howatt, D.A.; Balakrishnan, A.; Moorleghen, J.J.; Muniappan, L.; Rateri, D.L.; Uchida, H.A.; Takano, J.; Saido, T.C.; Chishti, A.H.; Baud, L.; Subramanian, V. Leukocyte calpain deficiency reduces angiotensin II-Induced inflammation and atherosclerosis but not abdominal aortic aneurysms in mice. Arterioscler. Thromb. Vasc. Biol., 2016, 36(5), 835-845.
[35]
Miyazaki, T.; Tonami, K.; Hata, S.; Aiuchi, T.; Ohnishi, K.; Lei, X.F.; Kim-Kaneyama, J.R.; Takeya, M.; Itabe, H.; Sorimachi, H.; Kurihara, H.; Miyazaki, A. Calpain-6 confers atherogenicity to macrophages by dysregulating pre-mRNA splicing. J. Clin. Invest., 2016, 126(9), 3417-3432.
[36]
Tonami, K.; Hata, S.; Ojima, K.; Ono, Y.; Kurihara, Y.; Amano, T.; Sato, T.; Kawamura, Y.; Kurihara, H.; Sorimachi, H. Calpain-6 deficiency promotes skeletal muscle development and regeneration. PLoS Genet., 2013, 9(8), e1003668.
[37]
Dear, N.; Matena, K.; Vingron, M.; Boehm, T. A new subfamily of vertebrate calpains lacking a calmodulin-like domain: Implications for calpain regulation and evolution. Genomics, 1997, 45(1), 175-184.
[38]
Brown, M.S.; Goldstein, J.L. Lipoprotein metabolism in the macrophage: Implications for cholesterol deposition in atherosclerosis. Annu. Rev. Biochem., 1983, 52, 223-261.
[39]
Moore, K.J.; Sheedy, F.J.; Fisher, E.A. Macrophages in atherosclerosis: A dynamic balance. Nat. Rev. Immunol., 2013, 13(10), 709-721.
[40]
Chang, T.Y.; Chang, C.C.; Ohgami, N.; Yamauchi, Y. Cholesterol sensing, trafficking, and esterification. Annu. Rev. Cell Dev. Biol., 2006, 22, 129-157.
[41]
Yokoyama, S. Assembly of high density lipoprotein by the ABCA1/apolipoprotein pathway. Curr. Opin. Lipidol., 2005, 16(3), 269-279.
[42]
Silvestre-Roig, C.; de Winther, M.P.; Weber, C.; Daemen, M.J.; Lutgens, E.; Soehnlein, O. Atherosclerotic plaque destabilization: mechanisms, models, and therapeutic strategies. Circ. Res., 2014, 114(1), 214-226.
[43]
Steinberg, D.; Parthasarathy, S.; Carew, T.E.; Khoo, J.C.; Witztum, J.L. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N. Engl. J. Med., 1989, 320(14), 915-924.
[44]
Kunjathoor, V.V.; Febbraio, M.; Podrez, E.A.; Moore, K.J.; Andersson, L.; Koehn, S.; Rhee, J.S.; Silverstein, R.; Hoff, H.F.; Freeman, M.W. Scavenger receptors class A-I/II and CD36 are the principal receptors responsible for the uptake of modified low density lipoprotein leading to lipid loading in macrophages. J. Biol. Chem., 2002, 277(51), 49982-49988.
[45]
Bonilla, D.L.; Bhattacharya, A.; Sha, Y.; Xu, Y.; Xiang, Q.; Kan, A.; Jagannath, C.; Komatsu, M.; Eissa, N.T. Autophagy regulates phagocytosis by modulating the expression of scavenger receptors. Immunity, 2013, 39(3), 537-547.
[46]
Wang, X.; Li, L.; Niu, X.; Dang, X.; Li, P.; Qu, L.; Bi, X.; Gao, Y.; Hu, Y.; Li, M.; Qiao, W.; Peng, Z.; Pan, L. mTOR enhances foam cell formation by suppressing the autophagy pathway. DNA Cell Biol., 2014, 33(4), 198-204.
[47]
Liu, X.; Tang, Y.; Cui, Y.; Zhang, H.; Zhang, D. Autophagy is associated with cell fate in the process of macrophage-derived foam cells formation and progress. J. Biomed. Sci., 2016, 23(1), 57.
[48]
Zhao, J.F.; Ching, L.C.; Huang, Y.C.; Chen, C.Y.; Chiang, A.N.; Kou, Y.R.; Shyue, S.K.; Lee, T.S. Molecular mechanism of curcumin on the suppression of cholesterol accumulation in macrophage foam cells and atherosclerosis. Mol. Nutr. Food Res., 2012, 56(5), 691-701.
[49]
Yang, X.; Yin, M.; Yu, L.; Lu, M.; Wang, H.; Tang, F.; Zhang, Y. Simvastatin inhibited oxLDL-induced proatherogenic effects through calpain-1-PPARγ-CD36 pathway. Can. J. Physiol. Pharmacol., 2016, 94(12), 1336-1343.
[50]
Steinbrecher, U.P.; Lougheed, M. Scavenger receptor-independent stimulation of cholesterol esterification in macrophages by low density lipoprotein extracted from human aortic intima. Arterioscler. Thromb., 1992, 12(5), 608-625.
[51]
Manning-Tobin, J.J.; Moore, K.J.; Seimon, T.A.; Bell, S.A.; Sharuk, M.; Alvarez-Leite, J.I.; de Winther, M.P.; Tabas, I.; Freeman, M.W. Loss of SR-A and CD36 activity reduces atherosclerotic lesion complexity without abrogating foam cell formation in hyperlipidemic mice. Arterioscler. Thromb. Vasc. Biol., 2009, 29(1), 19-26.
[52]
Kruth, H.S. Receptor-independent fluid-phase pinocytosis mechanisms for induction of foam cell formation with native low-density lipoprotein particles. Curr. Opin. Lipidol., 2011, 22(5), 386-393.
[53]
Buono, C.; Anzinger, J.J.; Amar, M.; Kruth, H.S. Fluorescent pegylated nanoparticles demonstrate fluid-phase pinocytosis by macrophages in mouse atherosclerotic lesions. J. Clin. Invest., 2009, 119(5), 1373-1381.
[54]
Kruth, H.S.; Jones, N.L.; Huang, W.; Zhao, B.; Ishii, I.; Chang, J.; Combs, C.A.; Malide, D.; Zhang, W.Y. Macropinocytosis is the endocytic pathway that mediates macrophage foam cell formation with native low density lipoprotein. J. Biol. Chem., 2005, 280(3), 2352-2360.
[55]
Barthwal, M.K.; Anzinger, J.J.; Xu, Q.; Bohnacker, T.; Wymann, M.P.; Kruth, H.S. Fluid-phase pinocytosis of native low density lipoprotein promotes murine M-CSF differentiated macrophage foam cell formation. PLoS One, 2013, 8(3), e58054.
[56]
Anzinger, J.J.; Chang, J.; Xu, Q.; Buono, C.; Li, Y.; Leyva, F.J.; Park, B.C.; Greene, L.E.; Kruth, H.S. Native low-density lipoprotein uptake by macrophage colony-stimulating factor-differentiated human macrophages is mediated by macropinocytosis and micropinocytosis. Arterioscler. Thromb. Vasc. Biol., 2010, 30(10), 2022-2031.
[57]
Steckelberg, A.L.; Boehm, V.; Gromadzka, A.M.; Gehring, N.H. CWC22 connects pre-mRNA splicing and exon junction complex assembly. Cell Reports, 2012, 2(3), 454-461.
[58]
Fujii, M.; Kawai, K.; Egami, Y.; Araki, N. Dissecting the roles of Rac1 activation and deactivation in macropinocytosis using microscopic photo-manipulation. Sci. Rep., 2013, 3, 2385.
[59]
Gordon, D.J.; Rifkind, B.M. High-density lipoprotein--the clinical implications of recent studies. N. Engl. J. Med., 1989, 321(19), 1311-1316.
[60]
Ho, Y.K.; Brown, M.S.; Goldstein, J.L. Hydrolysis and excretion of cytoplasmic cholesteryl esters by macrophages: stimulation by high density lipoprotein and other agents. J. Lipid Res., 1980, 21(4), 391-398.
[61]
Ouimet, M.; Franklin, V.; Mak, E.; Liao, X.; Tabas, I.; Marcel, Y.L. Autophagy regulates cholesterol efflux from macrophage foam cells via lysosomal acid lipase. Cell Metab., 2011, 13(6), 655-667.
[62]
Ouimet, M.; Ediriweera, H.; Afonso, M.S.; Ramkhelawon, B.; Singaravelu, R.; Liao, X.; Bandler, R.C.; Rahman, K.; Fisher, E.A.; Rayner, K.J.; Pezacki, J.P.; Tabas, I.; Moore, K.J. MicroRNA-33 regulates macrophage autophagy in atherosclerosis. Arterioscler. Thromb. Vasc. Biol., 2017, 37(6), 1058-1067.
[63]
Feinberg, M.W.; Moore, K.J. MicroRNA regulation of atherosclerosis. Circ. Res., 2016, 118(4), 703-720.
[64]
Hsieh, V.; Kim, M.J.; Gelissen, I.C.; Brown, A.J.; Sandoval, C.; Hallab, J.C.; Kockx, M.; Traini, M.; Jessup, W.; Kritharides, L. Cellular cholesterol regulates ubiquitination and degradation of the cholesterol export proteins ABCA1 and ABCG1. J. Biol. Chem., 2014, 289(11), 7524-7536.
[65]
Aleidi, S.M.; Howe, V.; Sharpe, L.J.; Yang, A.; Rao, G.; Brown, A.J.; Gelissen, I.C. The E3 ubiquitin ligases, HUWE1 and NEDD4-1, are involved in the post-translational regulation of the ABCG1 and ABCG4 lipid transporters. J. Biol. Chem., 2015, 290(40), 24604-24613.
[66]
Ogura, M.; Ayaori, M.; Terao, Y.; Hisada, T.; Iizuka, M.; Takiguchi, S.; Uto-Kondo, H.; Yakushiji, E.; Nakaya, K.; Sasaki, M.; Komatsu, T.; Ozasa, H.; Ohsuzu, F.; Ikewaki, K. Proteasomal inhibition promotes ATP-binding cassette transporter A1 (ABCA1) and ABCG1 expression and cholesterol efflux from macrophages in vitro and in vivo. Arterioscler. Thromb. Vasc. Biol., 2011, 31(9), 1980-1987.
[67]
Wang, N.; Chen, W.; Linsel-Nitschke, P.; Martinez, L.O.; Agerholm-Larsen, B.; Silver, D.L.; Tall, A.R. A PEST sequence in ABCA1 regulates degradation by calpain protease and stabilization of ABCA1 by apoA-I. J. Clin. Invest., 2003, 111(1), 99-107.
[68]
Lu, R.; Arakawa, R.; Ito-Osumi, C.; Iwamoto, N.; Yokoyama, S. ApoA-I facilitates ABCA1 recycle/accumulation to cell surface by inhibiting its intracellular degradation and increases HDL generation. Arterioscler. Thromb. Vasc. Biol., 2008, 28(10), 1820-1824.
[69]
Okoro, E.U.; Guo, Z.; Yang, H. Akt isoform-dependent regulation of ATP-binding cassette A1 expression by apolipoprotein E. Biochem. Biophys. Res. Commun., 2016, 477(1), 123-128.
[70]
Liu, X.Y.; Lu, Q.; Ouyang, X.P.; Tang, S.L.; Zhao, G.J.; Lv, Y.C.; He, P.P.; Kuang, H.J.; Tang, Y.Y.; Fu, Y.; Zhang, D.W.; Tang, C.K. Apelin-13 increases expression of ATP-binding cassette transporter A1 via activating protein kinase C α signaling in THP-1 macrophage-derived foam cells. Atherosclerosis, 2013, 226(2), 398-407.
[71]
Lu, Q.; Tang, S.L.; Liu, X.Y.; Zhao, G.J.; Ouyang, X.P.; Lv, Y.C.; He, P.P.; Yao, F.; Chen, W.J.; Tang, Y.Y.; Zhang, M.; Zhang, D.W.; Yin, K.; Tang, C.K. Tertiary-butylhydroquinone upregulates expression of ATP-binding cassette transporter A1 via nuclear factor E2-related factor 2/heme oxygenase-1 signaling in THP-1 macrophage-derived foam cells. Circ. J., 2013, 77(9), 2399-2408.
[72]
Hossain, M.A.; Ngeth, S.; Chan, T.; Oda, M.N.; Francis, G.A. Lipid-bound apolipoproteins in tyrosyl radical-oxidized HDL stabilize ABCA1 like lipid-free apolipoprotein A-I. BMC Biochem., 2012, 13, 1.
[73]
Wu, C.A.; Tsujita, M.; Hayashi, M.; Yokoyama, S. Probucol inactivates ABCA1 in the plasma membrane with respect to its mediation of apolipoprotein binding and high density lipoprotein assembly and to its proteolytic degradation. J. Biol. Chem., 2004, 279(29), 30168-30174.
[74]
Arakawa, R.; Tsujita, M.; Iwamoto, N.; Ito-Ohsumi, C.; Lu, R.; Wu, C.A.; Shimizu, K.; Aotsuka, T.; Kanazawa, H.; Abe-Dohmae, S.; Yokoyama, S. Pharmacological inhibition of ABCA1 degradation increases HDL biogenesis and exhibits antiatherogenesis. J. Lipid Res., 2009, 50(11), 2299-2305.
[75]
Yakushiji, E.; Ayaori, M.; Nishida, T.; Shiotani, K.; Takiguchi, S.; Nakaya, K.; Uto-Kondo, H.; Ogura, M.; Sasaki, M.; Yogo, M.; Komatsu, T.; Lu, R.; Yokoyama, S.; Ikewaki, K. Probucol-oxidized products, spiroquinone and diphenoquinone, promote reverse cholesterol transport in mice. Arterioscler. Thromb. Vasc. Biol., 2016, 36(4), 591-597.
[76]
Wang, L.; Palme, V.; Rotter, S.; Schilcher, N.; Cukaj, M.; Wang, D.; Ladurner, A.; Heiss, E.H.; Stangl, H.; Dirsch, V.M.; Atanasov, A.G. Piperine inhibits ABCA1 degradation and promotes cholesterol efflux from THP-1-derived macrophages. Mol. Nutr. Food Res., 2017, 61(4), 1500960.
[77]
Tanaka, N.; Abe-Dohmae, S.; Iwamoto, N.; Fitzgerald, M.L.; Yokoyama, S. Helical apolipoproteins of high-density lipoprotein enhance phagocytosis by stabilizing ATP-binding cassette transporter A7. J. Lipid Res., 2010, 51(9), 2591-2599.
[78]
Lin, C.Y.; Lee, T.S.; Chen, C.C.; Chang, C.A.; Lin, Y.J.; Hsu, Y.P.; Ho, L.T. Endothelin-1 exacerbates lipid accumulation by increasing the protein degradation of the ATP-binding cassette transporter G1 in macrophages. J. Cell. Physiol., 2011, 226(8), 2198-2205.
[79]
Zhao, J.F.; Shyue, S.K.; Lee, T.S. Excess Nitric Oxide Activates TRPV1-Ca(2+)-Calpain Signaling and Promotes PEST-dependent Degradation of Liver X Receptor α. Int. J. Biol. Sci., 2016, 12(1), 18-29.
[80]
Hozoji, M.; Munehira, Y.; Ikeda, Y.; Makishima, M.; Matsuo, M.; Kioka, N.; Ueda, K. Direct interaction of nuclear liver X receptor-beta with ABCA1 modulates cholesterol efflux. J. Biol. Chem., 2008, 283(44), 30057-30063.
[81]
Silvestre-Roig, C.; de Winther, M.P.; Weber, C.; Daemen, M.J.; Lutgens, E.; Soehnlein, O. Atherosclerotic plaque destabilization: mechanisms, models, and therapeutic strategies. Circ. Res., 2014, 114(1), 214-226.
[82]
Ortega-Gómez, A.; Perretti, M.; Soehnlein, O. Resolution of inflammation: An integrated view. EMBO Mol. Med., 2013, 5(5), 661-674.
[83]
Thorp, E.; Vaisar, T.; Subramanian, M.; Mautner, L.; Blobel, C.; Tabas, I. Shedding of the Mer tyrosine kinase receptor is mediated by ADAM17 protein through a pathway involving reactive oxygen species, protein kinase Cδ, and p38 mitogen-activated protein kinase (MAPK). J. Biol. Chem., 2011, 286(38), 33335-33344.
[84]
Sather, S.; Kenyon, K.D.; Lefkowitz, J.B.; Liang, X.; Varnum, B.C.; Henson, P.M.; Graham, D.K. A soluble form of the Mer receptor tyrosine kinase inhibits macrophage clearance of apoptotic cells and platelet aggregation. Blood, 2007, 109(3), 1026-1033.
[85]
Ravichandran, K.S. Beginnings of a good apoptotic meal: The find-me and eat-me signaling pathways. Immunity, 2011, 35(4), 445-455.
[86]
Driscoll, W.S.; Vaisar, T.; Tang, J.; Wilson, C.L.; Raines, E.W. Macrophage ADAM17 deficiency augments CD36-dependent apoptotic cell uptake and the linked anti-inflammatory phenotype. Circ. Res., 2013, 113(1), 52-61.
[87]
Teplova, I.; Lozy, F.; Price, S.; Singh, S.; Barnard, N.; Cardiff, R.D.; Birge, R.B.; Karantza, V. ATG proteins mediate efferocytosis and suppress inflammation in mammary involution. Autophagy, 2013, 9(4), 459-475.
[88]
Tao, H.; Yancey, P.G.; Babaev, V.R.; Blakemore, J.L.; Zhang, Y.; Ding, L.; Fazio, S.; Linton, M.F. Macrophage SR-BI mediates efferocytosis via Src/PI3K/Rac1 signaling and reduces atherosclerotic lesion necrosis. J. Lipid Res., 2015, 56(8), 1449-1460.
[89]
Miyazaki, T.; Taketomi, Y.; Saito, Y.; Hosono, T.; Lei, X.F.; Kim-Kaneyama, J.R.; Arata, S.; Takahashi, H.; Murakami, M.; Miyazaki, A. Calpastatin counteracts pathological angiogenesis by inhibiting suppressor of cytokine signaling 3 degradation in vascular endothelial cells. Circ. Res., 2015, 116(7), 1170-1181.
[90]
Tsai, J.C.; Lin, Y.W.; Huang, C.Y.; Lin, C.Y.; Tsai, Y.T.; Shih, C.M.; Lee, C.Y.; Chen, Y.H.; Li, C.Y.; Chang, N.C.; Lin, F.Y.; Tsai, C.S. The role of calpain-myosin 9-Rab7b pathway in mediating the expression of Toll-like receptor 4 in platelets: a novel mechanism involved in α-granules trafficking. PLoS One, 2014, 9(1), e85833.
[91]
Zhang, D.W.; Lagace, T.A.; Garuti, R.; Zhao, Z.; McDonald, M.; Horton, J.D.; Cohen, J.C.; Hobbs, H.H. Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation. J. Biol. Chem., 2007, 282(25), 18602-18612.
[92]
Giunzioni, I.; Tavori, H.; Covarrubias, R.; Major, A.S.; Ding, L.; Zhang, Y.; DeVay, R.M.; Hong, L.; Fan, D.; Predazzi, I.M.; Rashid, S.; Linton, M.F.; Fazio, S. Local effects of human PCSK9 on the atherosclerotic lesion. J. Pathol., 2016, 238(1), 52-62.
[93]
Maxwell, K.N.; Fisher, E.A.; Breslow, J.L. Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment. Proc. Natl. Acad. Sci. USA, 2005, 102(6), 2069-2074.
[94]
Wang, Y.; Huang, Y.; Hobbs, H.H.; Cohen, J.C. Molecular characterization of proprotein convertase subtilisin/kexin type 9-mediated degradation of the LDLR. J. Lipid Res., 2012, 53(9), 1932-1943.
[95]
Martinet, W.; De Loof, H.; De Meyer, G.R. mTOR inhibition: a promising strategy for stabilization of atherosclerotic plaques. Atherosclerosis, 2014, 233(2), 601-607.
[96]
Chen, W.Q.; Zhong, L.; Zhang, L.; Ji, X.P.; Zhang, M.; Zhao, Y.X.; Zhang, C.; Zhang, Y. Oral rapamycin attenuates inflammation and enhances stability of atherosclerotic plaques in rabbits independent of serum lipid levels. Br. J. Pharmacol., 2009, 156(6), 941-951.
[97]
Pakala, R.; Stabile, E.; Jang, G.J.; Clavijo, L.; Waksman, R. Rapamycin attenuates atherosclerotic plaque progression in apolipoprotein E knockout mice: inhibitory effect on monocyte chemotaxis. J. Cardiovasc. Pharmacol., 2005, 46(4), 481-486.
[98]
Zhao, L.; Ding, T.; Cyrus, T.; Cheng, Y.; Tian, H.; Ma, M.; Falotico, R.; Praticò, D. Low-dose oral sirolimus reduces atherogenesis, vascular inflammation and modulates plaque composition in mice lacking the LDL receptor. Br. J. Pharmacol., 2009, 156(5), 774-785.
[99]
Xie, J.; Wang, X.; Proud, C.G. mTOR inhibitors in cancer therapy. F1000Res., 2016, 5(F1000 Faculty Rev), 2078.
[http://dx.doi.org/10.12688/f1000research.9207.1]
[100]
Huang, L.; Chen, C.H. Proteasome regulators: Activators and inhibitors. Curr. Med. Chem., 2009, 16(8), 931-939.
[101]
Seo, H.; Sonntag, K.C.; Kim, W.; Cattaneo, E.; Isacson, O. Proteasome activator enhances survival of Huntington’s disease neuronal model cells. PLoS One, 2007, 2(2), e238.

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Request history8.2.27PHP Version367msRequest Duration28MBMemory UsageGET article/{article_id}/{param?}Route
  • warninglog[03:12:17] LOG.warning: Optional parameter $article_id declared before required parameter $request i...
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  • Booting (103ms)time
  • Application (263ms)time
  • 1 x Application (71.78%)
    263ms
    1 x Booting (28.21%)
    103ms
    14 templates were rendered
    • articlearticle.blade.php#?blade
    • includes.article_top_bannerarticle_top_banner.blade.php#?blade
    • includes.article_referencearticle_reference.blade.php#?blade
    • export_citation_formexport_citation_form.blade.php#?blade
    • includes.article_bottom_bannerarticle_bottom_banner.blade.php#?blade
    • includes.inc_related_journalsinc_related_journals.blade.php#?blade
    • includes.inc_related_ebooksinc_related_ebooks.blade.php#?blade
    • includes.journal_rightmenujournal_rightmenu.blade.php#?blade
    • includes.journal_right_bannerjournal_right_banner.blade.php#?blade
    • layouts.appapp.blade.php#?blade
    • layouts._login_access_login_access.blade.php#?blade
    • layouts._header_header.blade.php#?blade
    • layouts._main_menu_main_menu.blade.php#?blade
    • layouts._footer_menu_footer_menu.blade.php#?blade
    uri
    GET article/{article_id}/{param?}
    middleware
    web, check_user_access
    controller
    App\Http\Controllers\ArticleController@GetArticleDetails
    namespace
    App\Http\Controllers
    where
    as
    article
    file
    app/Http/Controllers/ArticleController.php:1974-2510
    41 statements were executed, 4 of which were duplicates, 37 unique. Show only duplicated191ms
    • Connection Establishedalphaeurekaselec_live_10_06_2022UserAccessCheck.php#24
      Backtrace
      • 9. middleware::check_user_access:24
      • 10. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 11. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 12. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 13. vendor/laravel/framework/src/Illuminate/Foundation/Http/Middleware/VerifyCsrfToken.php:88
    • INSERT INTO visitor_ip_address (ip_address,visitor_agent,visitor_count, created_on,updated_on) VALUES ('221948497','',1,1739848337,1739848337) ON DUPLICATE KEY UPDATE visitor_count=visitor_count + 1, updated_on=1739848337
      1.03msalphaeurekaselec_live_10_06_2022UserAccessCheck.php#24
      Backtrace
      • 11. middleware::check_user_access:24
      • 12. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 14. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 15. vendor/laravel/framework/src/Illuminate/Foundation/Http/Middleware/VerifyCsrfToken.php:88
    • INSERT INTO visitor_ip_address_detail (ip_address,visitor_url,visitor_count, created_on,updated_on) VALUES ('221948497','/article/89306/cn',1,1739848337,1739848337)
      210μsalphaeurekaselec_live_10_06_2022UserAccessCheck.php#27
      Backtrace
      • 11. middleware::check_user_access:27
      • 12. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 14. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 15. vendor/laravel/framework/src/Illuminate/Foundation/Http/Middleware/VerifyCsrfToken.php:88
    • (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_journal_volume_trail WHERE to_ip >= 221948497 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221948497) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_journal_volume_corporate WHERE to_ip >= 221948497 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221948497) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_journal_volume_token WHERE to_ip >= 221948497 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221948497) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_ebook_volume_trail WHERE to_ip >= 221948497 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221948497) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_ebook_volume_corporate WHERE to_ip >= 221948497 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221948497) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_ebook_volume_token WHERE to_ip >= 221948497 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221948497) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_trail WHERE to_ip >= 221948497 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221948497) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_corporate WHERE to_ip >= 221948497 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221948497) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_token WHERE to_ip >= 221948497 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221948497) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_trail WHERE to_ip >= 221948497 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221948497) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_corporate WHERE to_ip >= 221948497 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221948497) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_token WHERE to_ip >= 221948497 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221948497) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_trail WHERE to_ip >= 221948497 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221948497) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_corporate WHERE to_ip >= 221948497 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221948497) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_token WHERE to_ip >= 221948497 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221948497) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_disease_corporate WHERE to_ip >= 221948497 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 221948497) limit 1
      16.74msalphaeurekaselec_live_10_06_2022UserAccess.php#784
      Bindings
      • 0: 221948497
      • 1: 221948497
      • 2: 221948497
      • 3: 221948497
      • 4: 221948497
      • 5: 221948497
      • 6: 221948497
      • 7: 221948497
      • 8: 221948497
      • 9: 221948497
      • 10: 221948497
      • 11: 221948497
      • 12: 221948497
      • 13: 221948497
      • 14: 221948497
      • 15: 221948497
      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=89306
      610μsalphaeurekaselec_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` = 25 limit 1
      720μsalphaeurekaselec_live_10_06_2022Journal.php#64
      Bindings
      • 0: 25
      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=25) and sj.journal_id!=25 group by `j`.`nid`) as `aggregate_table`
      1.31msalphaeurekaselec_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=25) and sj.journal_id!=25 group by `j`.`nid` order by `j`.`journal_id` asc limit 10 offset 0
      1.11msalphaeurekaselec_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=25) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid`) as `aggregate_table`
      3.39msalphaeurekaselec_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=25) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid` order by `v`.`ebook_volume_id` desc limit 10 offset 0
      2.89msalphaeurekaselec_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` = '89306'
      1.57msalphaeurekaselec_live_10_06_2022Keywords.php#43
      Bindings
      • 0: 89306
      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` = '89306'
      4.79msalphaeurekaselec_live_10_06_2022Article.php#1570
      Bindings
      • 0: 89306
      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` = '89306' group by `au`.`author_id` order by `au`.`article_id` asc, `au`.`sequence` asc
      2.76msalphaeurekaselec_live_10_06_2022Author.php#86
      Bindings
      • 0: 89306
      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
      500μsalphaeurekaselec_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 = 25 and i.is_uploaded = 1 order by v.volume_name+0 desc, i.title+0 desc limit 1
      31.75msalphaeurekaselec_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 = 25 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      40.35msalphaeurekaselec_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 = 25 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      33.86msalphaeurekaselec_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` = 89306 limit 1
      740μsalphaeurekaselec_live_10_06_2022Article.php#744
      Bindings
      • 0: 89306
      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 = 89306 and content_type = 'article' order by status desc limit 1
      950μsalphaeurekaselec_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 = 258 and cd.sub_disease_id = 426 and content_id!=89306 and cd.content_type = 'article' order by rand() limit 20
      10.12msalphaeurekaselec_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` = 160747 limit 1
      220μsalphaeurekaselec_live_10_06_2022Meta.php#30
      Bindings
      • 0: 160747
      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
      200μsalphaeurekaselec_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` = 'CMC' and (h.proposal_closing_date = 0 OR TO_DAYS(FROM_UNIXTIME(h.proposal_closing_date)) >= TO_DAYS(NOW())) order by `h`.`manuscript` asc
      350μsalphaeurekaselec_live_10_06_2022Article.php#2025
      Bindings
      • 0: CMC
      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 = '89306' 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) )
      350μsalphaeurekaselec_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 = '9118' 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 = '2572' 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) )
      240μsalphaeurekaselec_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 <= 221948497 and j.to_ip >=221948497 )) and ((j.from_date <= 1739848338 and j.to_date >= 1739848338 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2572) 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 <= 221948497 and j.to_ip >=221948497 )) and ((j.from_date <= 1739848338 and j.to_date >= 1739848338 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2572) 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 <= 221948497 and j.to_ip >=221948497 )) and ((j.from_date <= 1739848338 and j.to_date >= 1739848338 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2572)
      11.7msalphaeurekaselec_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 <= 221948497 and j.to_ip >=221948497 )) and ((j.from_date <= 1739848338 and j.to_date >= 1739848338 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 9118) 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 <= 221948497 and j.to_ip >=221948497 )) and ((j.from_date <= 1739848338 and j.to_date >= 1739848338 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 9118) 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 <= 221948497 and j.to_ip >=221948497 )) and ((j.from_date <= 1739848338 and j.to_date >= 1739848338 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 9118)
      570μsalphaeurekaselec_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 <= 221948497 and j.to_ip >=221948497 )) and ((j.from_date <= 1739848338 and j.to_date >= 1739848338 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 89306) 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 <= 221948497 and j.to_ip >=221948497 )) and ((j.from_date <= 1739848338 and j.to_date >= 1739848338 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 89306) 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 <= 221948497 and j.to_ip >=221948497 )) and ((j.from_date <= 1739848338 and j.to_date >= 1739848338 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 89306)
      540μsalphaeurekaselec_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` < '1631' and is_uploaded = 1 and issue_id = 9118 order by cast(first_page as SIGNED) desc limit 1
      490μsalphaeurekaselec_live_10_06_2022Article.php#1819
      Bindings
      • 0: 1631
      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` > '1643' and is_uploaded = 1 and issue_id = 9118 order by cast(first_page as SIGNED) asc limit 1
      400μsalphaeurekaselec_live_10_06_2022Article.php#1831
      Bindings
      • 0: 1643
      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` = 'cn'
      180μsalphaeurekaselec_live_10_06_2022ArticleController.php#2486
      Bindings
      • 0: cn
      Backtrace
      • 14. app/Http/Controllers/ArticleController.php:2486
      • 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` = 2
      190μsalphaeurekaselec_live_10_06_2022MultiLanguage.php#23
      Bindings
      • 0: 2
      Backtrace
      • 13. app/Models/MultiLanguage.php:23
      • 14. app/Http/Controllers/ArticleController.php:2487
      • 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 `multilanguage_article` where (`language_id` = 2 and `article_id` = 89306)
      5.66msalphaeurekaselec_live_10_06_2022ArticleController.php#2488
      Bindings
      • 0: 2
      • 1: 89306
      Backtrace
      • 15. app/Http/Controllers/ArticleController.php:2488
      • 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
      • 19. vendor/laravel/framework/src/Illuminate/Routing/Route.php:206
    • select `keyword` from `multilanguage_keywords` where (`language_id` = 2 and `article_id` = 89306)
      3.03msalphaeurekaselec_live_10_06_2022ArticleController.php#2489
      Bindings
      • 0: 2
      • 1: 89306
      Backtrace
      • 14. app/Http/Controllers/ArticleController.php:2489
      • 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 CONCAT_WS(' ',au.first_name, ' ', ifnull(au.initials,''), ' ', au.last_name) as authors, CONCAT_WS(' ',au.last_name, ', ', ifnull(au.initials,''), ' ', au.first_name) as authorsRIS, CONCAT_WS(' ',au.last_name, ' ', ifnull(au.initials,''), ' ', au.first_name) as authorsCiteAs , `au`.*, (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 `multilanguage_authors` as `au` left join `multilanguage_author_affiliation` as `af` on `au`.`id` = `af`.`author_id` where `au`.`article_id` = 89306 group by `au`.`id` order by `au`.`article_id` asc, `au`.`sequence` asc
      5.85msalphaeurekaselec_live_10_06_2022MultiLangAuthor.php#30
      Bindings
      • 0: 89306
      Backtrace
      • 13. app/Models/MultiLangAuthor.php:30
      • 14. app/Http/Controllers/ArticleController.php:2493
      • 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 `multilanguage_journal`.`title` from `multilanguage_journal` where `multilanguage_journal`.`journal_id` = 25 and `language_id` = 2
      220μsalphaeurekaselec_live_10_06_2022ArticleController.php#2495
      Bindings
      • 0: 25
      • 1: 2
      Backtrace
      • 13. app/Http/Controllers/ArticleController.php:2495
      • 14. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 15. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:206
    • select `id` from `multilanguage_article` where `article_id` = 89306 limit 1
      2.38msalphaeurekaselec_live_10_06_2022ArticleController.php#2506
      Bindings
      • 0: 89306
      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` = 25 and `b`.`banner_from_date` <= 1739848338 and `b`.`banner_to_date` >= 1739848338 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.36msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 25
      • 3: 1739848338
      • 4: 1739848338
      • 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` = 25 and `b`.`banner_from_date` <= 1739848338 and `b`.`banner_to_date` >= 1739848338 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.12msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 25
      • 3: 1739848338
      • 4: 1739848338
      • 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='445575c70be0bec5305207c331f0ce8c'
      250μsalphaeurekaselec_live_10_06_2022Cart.php#271
      Backtrace
      • 15. app/Models/Cart.php:271
      • 16. view::layouts._header:260
      • 18. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 20. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
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        ClearShow all
        Date ↕MethodURLData
        #12025-02-18 03:12:18GET/article/89306/cn314413