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Pharmaceutical Nanotechnology

Editor-in-Chief

ISSN (Print): 2211-7385
ISSN (Online): 2211-7393

Commentary

Advances and Perspectives of Pharmaceutical Nanotechnology in mRNA Therapy

Author(s): Hui Cheng and Zongjin Li*

Volume 10, Issue 5, 2022

Published on: 06 October, 2022

Page: [328 - 333] Pages: 6

DOI: 10.2174/2211738510666220825145124

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Acta Biomater 2021,131,1-15 10.1016/j.actbio.2021.06.020 34133982 Boo S.H.; Kim Y.K.; The emerging role of RNA modifications in the regulation of mRNA stability. Exp Mol Med 2020,52(3),400-408 10.1038/s12276-020-0407-z 32210357 Chaudhary N.; Weissman D.; Whitehead K.A.; mRNA vaccines for infectious diseases: Principles, delivery and clinical translation. Nat Rev Drug Discov 2021,20(11),817-838 10.1038/s41573-021-00283-5 34433919 Eygeris Y.; Gupta M.; Kim J.; Sahay G.; Chemistry of lipid nanoparticles for RNA delivery. Acc Chem Res 2022,55(1),2-12 10.1021/acs.accounts.1c00544 34850635 Ryals R.C.; Patel S.; Acosta C.; McKinney M.; Pennesi M.E.; Sahay G.; The effects of PEGylation on LNP based mRNA delivery to the eye. PLoS One 2020,15(10),e0241006 10.1371/journal.pone.0241006 33119640 Hassett K.J.; Higgins J.; Woods A.; Impact of lipid nanoparticle size on mRNA vaccine immunogenicity. J Control Release 2021,335,237-246 10.1016/j.jconrel.2021.05.021 34019945 Chen S.; Tam Y.Y.C.; Lin P.J.C.; Sung M.M.H.; Tam Y.K.; Cullis P.R.; Influence of particle size on the in vivo potency of lipid nanoparticle formula-tions of siRNA. J Control Release 2016,235,236-244 10.1016/j.jconrel.2016.05.059 27238441 Cabral H.; Matsumoto Y.; Mizuno K.; Accumulation of sub-100 nm polymeric micelles in poorly permeable tumours depends on size. Nat Nanotechnol 2011,6(12),815-823 10.1038/nnano.2011.166 22020122 Kim M.; Jeong M.; Hur S.; Engineered ionizable lipid nanoparticles for targeted delivery of RNA therapeutics into different types of cells in the liver. Sci Adv 2021,7(9),eabf4398 10.1126/sciadv.abf4398 33637537 Hersh A.M.; Alomari S.; Tyler B.M.; Crossing the blood-brain barrier: Advances in nanoparticle technology for drug delivery in neuro-oncology. Int J Mol Sci 2022,23(8),4153 10.3390/ijms23084153 35456971 Renukaradhya G.J.; Narasimhan B.; Mallapragada S.K.; Respiratory nanoparticle-based vaccines and challenges associated with animal models and translation. J Control Release 2015,219,622-631 10.1016/j.jconrel.2015.09.047 26410807 Kowalski P.S.; Rudra A.; Miao L.; Anderson D.G.; Delivering the messenger: Advances in technologies for therapeutic mRNA delivery. Mol Ther 2019,27(4),710-728 10.1016/j.ymthe.2019.02.012 30846391 Park J.W.; Lagniton P.N.P.; Liu Y.; Xu R.H.; mRNA vaccines for COVID-19: What, why and how. Int J Biol Sci 2021,17(6),1446-1460 10.7150/ijbs.59233 33907508 Gaviria M.; Kilic B.; A network analysis of COVID-19 mRNA vaccine patents. Nat Biotechnol 2021,39(5),546-548 10.1038/s41587-021-00912-9 33981074 Vu M.N.; Kelly H.G.; Kent S.J.; Wheatley A.K.; Current and future nanoparticle vaccines for COVID-19. EBioMedicine 2021,74,103699 10.1016/j.ebiom.2021.103699 34801965 Wang L.; Wang Y.; Li Z.; Nanoparticle-based tumor theranostics with molecular imaging. Curr Pharm Biotechnol 2013,14(7),683-692 10.2174/1389201014666131226111248 24372235 Berraondo P.; Martini P.G.V.; Avila M.A.; Fontanellas A.; Messenger RNA therapy for rare genetic metabolic diseases. Gut 2019,68(7),1323-1330 10.1136/gutjnl-2019-318269 30796097 Damase T.R.; Sukhovershin R.; Boada C.; Taraballi F.; Pettigrew R.I.; Cooke J.P.; The limitless future of RNA therapeutics. Front Bioeng Biotechnol 2021,9,628137 10.3389/fbioe.2021.628137 33816449 Chabanovska O.; Galow A.M.; David R.; Lemcke H.; mRNA - A game changer in regenerative medicine, cell-based therapy and reprogramming strategies. Adv Drug Deliv Rev 2021,179,114002 10.1016/j.addr.2021.114002 34653534 Scheideler M.; Vidakovic I.; Prassl R.; Lipid nanocarriers for microRNA delivery. Chem Phys Lipids 2020,226,104837 10.1016/j.chemphyslip.2019.104837 31689410 Inoue J.; Inazawa J.; Cancer-associated miRNAs and their therapeutic potential. J Hum Genet 2021,66(9),937-945 10.1038/s10038-021-00938-6 34088973 Rupaimoole R.; Slack F.J.; MicroRNA therapeutics: Towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov 2017,16(3),203-222 10.1038/nrd.2016.246 28209991 Deng S.; Zhao Q.; Zhen L.; Neonatal heart-enriched miR-708 promotes proliferation and stress resistance of cardiomyocytes in rodents. Theranostics 2017,7(7),1953-1965 10.7150/thno.16478 28638481 Peng B.; Chen Y.; Leong K.W.; MicroRNA delivery for regenerative medicine. Adv Drug Deliv Rev 2015,88,108-122 10.1016/j.addr.2015.05.014 26024978 Ghatak S.; Li J.; Chan Y.C.; AntihypoxamiR functionalized gramicidin lipid nanoparticles rescue against ischemic memory improving cutaneous wound healing. Nanomedicine 2016,12(7),1827-1831 10.1016/j.nano.2016.03.004 27033464 Bejerano T.; Etzion S.; Elyagon S.; Etzion Y.; Cohen S.; Nanoparticle delivery of miRNA-21 mimic to cardiac macrophages improves myocar-dial remodeling after myocardial infarction. Nano Lett 2018,18(9),5885-5891 10.1021/acs.nanolett.8b02578 30141949 Takeda Y.S.; Wang M.; Deng P.; Xu Q.; Synthetic bioreducible lipid-based nanoparticles for miRNA delivery to mesenchymal stem cells to induce neuronal differentiation. Bioeng Transl Med 2016,1(2),160-167 10.1002/btm2.10021 29313011 Lee S.W.L.; Paoletti C.; Campisi M.; MicroRNA delivery through nanoparticles. J Control Release 2019,313,80-95 10.1016/j.jconrel.2019.10.007 31622695 Tabatabaei S.N.; Derbali R.M.; Yang C.; Co-delivery of miR-181a and melphalan by lipid nanoparticles for treatment of seeded retinoblas-toma. J Control Release 2019,298,177-185 10.1016/j.jconrel.2019.02.014 30776396 Yuan H.; Peng Y.M.; Long Z.Y.; Wu S.X.; Zhou Y.F.; Lipid nanoparticles co-loaded with miRNA-22 and methotrexate for enhanced anti-inflammatory response in rheumatoid arthritis. Biosci Rep 2020,BSR20201735 10.1042/BSR20201735 32808648 Bhardwaj P.; Bhatia E.; Sharma S.; Ahamad N.; Banerjee R.; Advancements in prophylactic and therapeutic nanovaccines. Acta Biomater 2020,108,1-21 10.1016/j.actbio.2020.03.020 32268235 Schoenmaker L.; Witzigmann D.; Kulkarni J.A.; mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability. Int J Pharm 2021,601,120586 10.1016/j.ijpharm.2021.120586 33839230 Blumenthal K.G.; Phadke N.A.; Bates D.W.; Safety surveillance of COVID-19 mRNA vaccines through the vaccine safety datalink. JAMA 2021,326(14),1375-1377 10.1001/jama.2021.14808 34477809 Duan Y.; Wang S.; Zhang Q.; Gao W.; Zhang L.; Nanoparticle approaches against SARS-CoV-2 infection. Curr Opin Solid State Mater Sci 2021,25(6),100964 10.1016/j.cossms.2021.100964 34729031 Deshmukh S.P.; Patil S.M.; Mullani S.B.; Delekar S.D.; Silver nanoparticles as an effective disinfectant: A review. Mater Sci Eng C 2019,97,954-965 10.1016/j.msec.2018.12.102 30678983 Draz M.S.; Shafiee H.; Applications of gold nanoparticles in virus detection. Theranostics 2018,8(7),1985-2017 10.7150/thno.23856 29556369 Halfpenny K.C.; Wright D.W.; Nanoparticle detection of respiratory infection. Wiley Interdiscip Rev Nanomed Nanobiotechnol 2010,2(3),277-290 10.1002/wnan.83 20201109 Ai X.; Wang D.; Honko A.; Surface glycan modification of cellular nanosponges to promote SARS-CoV-2 inhibition. J Am Chem Soc 2021,143(42),17615-17621 10.1021/jacs.1c07798 34647745 Zhang Q.; Honko A.; Zhou J.; Cellular nanosponges inhibit SARS-CoV-2 infectivity. Nano Lett 2020,20(7),5570-5574 10.1021/acs.nanolett.0c02278 32551679 Horejs C.; From lipids to lipid nanoparticles to mRNA vaccines. Nat Rev Mater 2021,6(12),1075-1076 10.1038/s41578-021-00379-9 34567796 Gao C.; Wang Y.; mRNA metabolism in cardiac development and disease: Life after transcription. Physiol Rev 2020,100(2),673-694 10.1152/physrev.00007.2019 31751167 Fukushima Y.; Uchida S.; Imai H.; Treatment of ischemic neuronal death by introducing brain-derived neurotrophic factor mRNA using polyplex nanomicelle. Biomaterials 2021,270,120681 10.1016/j.biomaterials.2021.120681 33517206 Yang T.; Poenisch M.; Khanal R.; Therapeutic HNF4A mRNA attenuates liver fibrosis in a preclinical model. J Hepatol 2021,75(6),1420-1433 10.1016/j.jhep.2021.08.011 34453962 Cheng Q.; Wei T.; Farbiak L.; Johnson L.T.; Dilliard S.A.; Siegwart D.J.; Selective organ targeting (SORT) nanoparticles for tissue-specific mRNA delivery and CRISPR-Cas gene editing. Nat Nanotechnol 2020,15(4),313-320 10.1038/s41565-020-0669-6 32251383

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      • 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
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      • 11. middleware::check_user_access:24
      • 12. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 14. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 15. vendor/laravel/framework/src/Illuminate/Foundation/Http/Middleware/VerifyCsrfToken.php:88
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      Backtrace
      • 11. middleware::check_user_access:27
      • 12. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 14. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 15. vendor/laravel/framework/src/Illuminate/Foundation/Http/Middleware/VerifyCsrfToken.php:88
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      • 7: 316567616
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      • 11: 316567616
      • 12: 316567616
      • 13: 316567616
      • 14: 316567616
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      Backtrace
      • 14. app/Models/UserAccess/UserAccess.php:784
      • 15. middleware::check_user_access:114
      • 16. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 18. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
    • 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=125850
      700μsalphaeurekaselec_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` = 133 limit 1
      820μsalphaeurekaselec_live_10_06_2022Journal.php#64
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      • 14. app/Models/Journal.php:64
      • 15. app/Http/Controllers/ArticleController.php:2516
      • 16. app/Http/Controllers/ArticleController.php:2035
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select count(*) as aggregate from (select j.nid as journal_nid,j.flyer_link,j.title ,j.issn,j.eissn,j.keyword, j.journal_id as journal_id, j.subtitle, j.image_file_name,j.description,j.journal_insight_url,j.doi from `subject_journal` as `sj` inner join `journal` as `j` on `j`.`journal_id` = `sj`.`journal_id` where j.journal_status=1 and subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=133) and sj.journal_id!=133 group by `j`.`nid`) as `aggregate_table`
      1.04msalphaeurekaselec_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=133) and sj.journal_id!=133 group by `j`.`nid` order by `j`.`journal_id` asc limit 10 offset 0
      810μsalphaeurekaselec_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=133) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid`) as `aggregate_table`
      1.27msalphaeurekaselec_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=133) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid` order by `v`.`ebook_volume_id` desc limit 10 offset 0
      1.09msalphaeurekaselec_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` = '125850'
      710μsalphaeurekaselec_live_10_06_2022Keywords.php#43
      Bindings
      • 0: 125850
      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` = '125850'
      2.18msalphaeurekaselec_live_10_06_2022Article.php#1570
      Bindings
      • 0: 125850
      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` = '125850' group by `au`.`author_id` order by `au`.`article_id` asc, `au`.`sequence` asc
      1.75msalphaeurekaselec_live_10_06_2022Author.php#86
      Bindings
      • 0: 125850
      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
      240μsalphaeurekaselec_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
      440μsalphaeurekaselec_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 = 133 and i.is_uploaded = 1 order by v.volume_name+0 desc, i.title+0 desc limit 1
      24.5msalphaeurekaselec_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 = 133 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      4.23msalphaeurekaselec_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 = 133 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      2.82msalphaeurekaselec_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` = 125850 limit 1
      210μsalphaeurekaselec_live_10_06_2022Article.php#744
      Bindings
      • 0: 125850
      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 = 125850 and content_type = 'article' order by status desc limit 1
      240μsalphaeurekaselec_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` = 207999 limit 1
      180μsalphaeurekaselec_live_10_06_2022Meta.php#30
      Bindings
      • 0: 207999
      Backtrace
      • 14. app/Models/Meta.php:30
      • 15. app/Http/Controllers/ArticleController.php:2101
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select `bo`.* from `bundle_offer` as `bo` where `bo`.`bundle_status` = 'A' order by `bo`.`bundle_id` desc
      210μsalphaeurekaselec_live_10_06_2022BundleOffer.php#57
      Bindings
      • 0: A
      Backtrace
      • 13. app/Models/BundleOffer.php:57
      • 14. app/Http/Controllers/ArticleController.php:2108
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `tbl_ht_submission` as `h` where `h`.`subtitle` = 'PNT' and (h.proposal_closing_date = 0 OR TO_DAYS(FROM_UNIXTIME(h.proposal_closing_date)) >= TO_DAYS(NOW())) order by `h`.`manuscript` asc
      260μsalphaeurekaselec_live_10_06_2022Article.php#2025
      Bindings
      • 0: PNT
      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 = '125850' 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) )
      380μsalphaeurekaselec_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 * from `article` where `first_page` < '328' and is_uploaded = 1 and issue_id = 12062 order by cast(first_page as SIGNED) desc limit 1
      420μsalphaeurekaselec_live_10_06_2022Article.php#1819
      Bindings
      • 0: 328
      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` > '333' and is_uploaded = 1 and issue_id = 12062 order by cast(first_page as SIGNED) asc limit 1
      410μsalphaeurekaselec_live_10_06_2022Article.php#1831
      Bindings
      • 0: 333
      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'
      180μsalphaeurekaselec_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
      200μsalphaeurekaselec_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` = 125850 limit 1
      2.44msalphaeurekaselec_live_10_06_2022ArticleController.php#2506
      Bindings
      • 0: 125850
      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` = 133 and `b`.`banner_from_date` <= 1740497461 and `b`.`banner_to_date` >= 1740497461 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.2msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 133
      • 3: 1740497461
      • 4: 1740497461
      • 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` = 133 and `b`.`banner_from_date` <= 1740497461 and `b`.`banner_to_date` >= 1740497461 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.17msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 133
      • 3: 1740497461
      • 4: 1740497461
      • 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='70a32941262275bebe68239656e007e3'
      230μsalphaeurekaselec_live_10_06_2022Cart.php#271
      Backtrace
      • 15. app/Models/Cart.php:271
      • 16. view::layouts._header:260
      • 18. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 20. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    App\Models\MultiLanguage
    1MultiLanguage.php#?
        _token
        bO2X9u5Q1JoaMeyCA5YXXgBBt4mfqv82wb35bZkE
        uc_cart_id
        70a32941262275bebe68239656e007e3
        _previous
        array:1 [ "url" => "https://alpha.eurekaselect.com/article/125850" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /article/125850
        status_code
        200
        
        status_text
        OK
        format
        html
        content_type
        text/html; charset=UTF-8
        request_query
        []
        
        request_request
        []
        
        request_headers
        0 of 0
        array:17 [ "x-https" => array:1 [ 0 => "1" ] "host" => array:1 [ 0 => "alpha.eurekaselect.com" ] "priority" => array:1 [ 0 => "u=0, i" ] "cookie" => array:1 [ 0 => "wayfindertarget=eyJpdiI6Ik9oanEreXpFTGJpOXpjUkZkNWR3VkE9PSIsInZhbHVlIjoiVW15cGFqVmR3OVN1enVGQlpNV3A1T1IwcnJPSklsZXIrb1BaMVJNUlpibz0iLCJtYWMiOiIwMjZlZjI4YjFjNTJiMTIwMzdlYjllNTRmZTlmMTA3MTJiMzA2NGRjOWE2YzhmYjZiZjMwNmI3Zjg3NjQ3MDdlIiwidGFnIjoiIn0%3Dwayfindertarget=eyJpdiI6Ik9oanEreXpFTGJpOXpjUkZkNWR3VkE9PSIsInZhbHVlIjoiVW15cGFqVmR3OVN1enVGQlpNV3A1T1IwcnJPSklsZXIrb1BaMVJNUlpibz0iLCJtYWMiOiIwMjZlZjI4YjFjNTJi" ] "accept-encoding" => array:1 [ 0 => "gzip, deflate, br, zstd" ] "sec-fetch-dest" => array:1 [ 0 => "document" ] "sec-fetch-user" => array:1 [ 0 => "?1" ] "sec-fetch-mode" => array:1 [ 0 => "navigate" ] "sec-fetch-site" => array:1 [ 0 => "none" ] "accept" => array:1 [ 0 => "text/html,application/xhtml+xml,application/xml;q=0.9,image/avif,image/webp,image/apng,*/*;q=0.8,application/signed-exchange;v=b3;q=0.7" ] "user-agent" => array:1 [ 0 => "Mozilla/5.0 AppleWebKit/537.36 (KHTML, like Gecko; compatible; ClaudeBot/1.0; +claudebot@anthropic.com)" ] "upgrade-insecure-requests" => array:1 [ 0 => "1" ] "sec-ch-ua-platform" => array:1 [ 0 => ""Windows"" ] "sec-ch-ua-mobile" => array:1 [ 0 => "?0" ] "sec-ch-ua" => array:1 [ 0 => ""HeadlessChrome";v="129", "Not=A?Brand";v="8", "Chromium";v="129"" ] "cache-control" => array:1 [ 0 => "no-cache" ] "pragma" => array:1 [ 0 => "no-cache" ] ]
        request_cookies
        0 of 0
        array:1 [ "wayfindertarget" => null ]
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