Severity: Warning
Message: file_get_contents(https://...@gmail.com&api_key=61f08fa0b96a73de8c900d749fcb997acc09): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
Filename: helpers/my_audit_helper.php
Line Number: 143
Backtrace:
File: /var/www/html/application/helpers/my_audit_helper.php
Line: 143
Function: file_get_contents
File: /var/www/html/application/helpers/my_audit_helper.php
Line: 209
Function: simplexml_load_file_from_url
File: /var/www/html/application/helpers/my_audit_helper.php
Line: 994
Function: getPubMedXML
File: /var/www/html/application/helpers/my_audit_helper.php
Line: 3134
Function: GetPubMedArticleOutput_2016
File: /var/www/html/application/controllers/Detail.php
Line: 574
Function: pubMedSearch_Global
File: /var/www/html/application/controllers/Detail.php
Line: 488
Function: pubMedGetRelatedKeyword
File: /var/www/html/index.php
Line: 316
Function: require_once
We report the development of a well-defined flagellin-based nanoparticle stimulator and also provide a new mechanism of action model explaining how flagellin-triggered innate immunity has evolved to favor localized rather than potentially debilitating systemic immune stimulation. Cell-free protein synthesis (CFPS) was used to facilitate mutational analysis and precisely orientated display of flagellin on Hepatitis B core (HBc) protein virus-like particles (VLPs). The need for product stability and an understanding of mechanism of action motivated investigations indicating that the D0 domain of flagellin is sensitive to amino acid sequence independent hydrolysis - apparently due to the need for structural flexibility during natural flagellin polymerization. When D0-stabilized flagellin was attached to HBc VLPs with the D0 domain facing outward, flagellin's tendency to polymerize caused the VLPs to precipitate. However, attaching the D0 domain to the VLP surface produced a stable nanoparticle adjuvant. Surprisingly, attaching only 2 flagellins per VLP provided the same 1 pM potency as did VLPs with about 33 attached flagellins suggesting that the TLR5 receptor is highly effective in delivering its intracellular signal. These observations suggest that flagellin's protease sensitivity, tendency to aggregate, and very high affinity for TLR5 receptors limit its systemic distribution to favor localized immune stimulation.
Download full-text PDF |
Source |
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4709591 | PMC |
http://dx.doi.org/10.1038/srep18379 | DOI Listing |
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