TC-F 2

Induction of Broadly Cross-Reactive Stalk-Specific Antibody Responses to Influenza Group 1 and Group 2 Hemagglutinins by Natural H7N9 Virus Infection in Humans.[Pubmed:28380622]

J Infect Dis. 2017 Feb 15;215(4):518-528.

Background: The outbreak of novel avian H7N9 influenza virus infections in China in 2013 has demonstrated the continuing threat posed by zoonotic pathogens. Deciphering the immune response during natural infection will guide future vaccine development. Methods: We assessed the induction of heterosubtypic cross-reactive antibodies induced by H7N9 infection against a large panel of recombinant hemagglutinins and neuraminidases by quantitative enzyme-linked immunosorbent assay, and novel chimeric hemagglutinin constructs were used to dissect the anti-stalk or -head humoral immune response. Results: H7N9 infection induced strong antibody responses against divergent H7 hemagglutinins. Interestingly, we also found induction of antibodies against heterosubtypic hemagglutinins from both group 1 and group 2 and a boost in heterosubtypic neutralizing activity in the absence of hemagglutination inhibitory activity. Kinetic monitoring revealed that heterosubtypic binding/neutralizing antibody responses typically appeared and peaked earlier than intrasubtypic responses, likely mediated by memory recall responses. Conclusions: Our results indicate that cross-group binding and neutralizing antibody responses primarily targeting the stalk region can be elicited after natural influenza virus infection. These data support our understanding of the breadth of the postinfection immune response that could inform the design of future, broadly protective influenza virus vaccines.

Ficolin-A/2, acting as a new regulator of macrophage polarization, mediates the inflammatory response in experimental mouse colitis.[Pubmed:28380665]

Immunology. 2017 Aug;151(4):433-450.

Human ficolin-2 (FCN-2) and mouse ficolin-A (FCN-A, a ficolin-2-like molecule in mouse) are activators of the lectin complement pathway, present in normal plasma and usually associated with infectious diseases, but little is known about the role of FCN-A/2 in inflammatory bowel disease (IBD). In our present study, we found that patients with IBD exhibited much higher serum FCN-2 levels than healthy controls. In the dextran sulphate sodium-induced acute colitis mouse model, FCN-A knockout mice showed much milder disease symptoms with less histological damage, lower expression levels of pro-inflammatory cytokines [interleukin-6 (IL-6), IL-1beta and tumour necrosis factor-alpha (TNF-alpha)], chemokines (CXCL1/2/10 and CCL4) and higher levels of the anti-inflammatory cytokine IL-10 compared with wild-type mice. We demonstrated that FCN-A/2 exacerbated the inflammatory pathogenesis of IBD by stimulating M1 polarization through the TLR4/MyD88/MAPK/NF-kappaB signalling pathway in macrophages. Hence, our data suggest that FCN-A/2 may be used as a novel therapeutic target for IBD.

Bicomponent fibrous scaffolds made through dual-source dual-power electrospinning: Dual delivery of rhBMP-2 and Ca-P nanoparticles and enhanced biological performances.[Pubmed:28380671]

J Biomed Mater Res A. 2017 Aug;105(8):2199-2209.

Electrospun scaffolds incorporated with both calcium phosphates (Ca-P) and bone morphogenetic protein-2 (BMP-2) have been used for bone tissue regeneration. However, in most cases BMP-2 and Ca-P were simply mixed and loaded in a monolithic structure, risking low BMP-2 loading level, reduced BMP-2 biological activity, uncontrolled BMP-2 release and inhomogeneous Ca-P distribution. In this investigation, novel bicomponent scaffolds having evenly distributed rhBMP-2-containing fibers and Ca-P nanoparticle-containing fibers were made using an established dual-source dual-power electrospinning technique with the assistance of emulsion electrospinning and blend electrospinning. The release behavior of rhBMP-2 and Ca(2+) ions could be separately tuned and the released rhBMP-2 retained a 68% level for biological activity. MC3T3-E1 cells showed high viability and normal morphology on scaffolds. Compared to monocomponent scaffolds, enhanced cell proliferation, alkaline phosphatase activity, cell mineralization, and gene expression of osteogenic markers were achieved for bicomponent scaffolds due to the synergistic effect of rhBMP-2 and Ca-P nanoparticles. Bicomponent scaffolds with a double mass elicited further enhanced cell adhesion, spreading, proliferation, and osteogenic differentiation. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2199-2209, 2017.

Integrated analysis of non-coding RNA and mRNA expression profiles of 2 pig breeds differing in muscle traits.[Pubmed:28380516]

J Anim Sci. 2017 Mar;95(3):1092-1103.

Production of high-quality meat is important to satisfy the consumer and allow the pork industry to be competitive. It is evident that different muscle fiber types in different breeds greatly influence the pork quality, but the underlying molecular mechanism remains unclear. We used Ribo-Zero RNA-Seq and miRNA-Seq to examine global expressions of protein-coding transcripts and non-coding RNAs including miRNA, lncRNA, and circRNA in the longissimus dorsi of Landrace and Lantang pigs. Of the 22,469 identified coding transcripts, only 547 candidates were differentially expressed, including 461 upregulated and 86 downregulated transcripts in the Lantang pigs compared with Landrace. Gene ontology analysis of these differentially-expressed transcripts further revealed 17 genes involved in myogenesis. In addition, 5,566 lncRNA and 4,360 circRNA candidates were found to be differentially expressed. Of these, 3,976 lncRNAs and 1,401 circRNAs were upregulated in the Lantang library, while 1,590 lncRNAs and 2,959 circRNAs were downregulated. Of the differentially expressed circRNAs, 236 candidates were edited from 93 functional hosting-genes related to myogenesis. We found 96 showed upregulation and 140 showed downregulation. By analyzing Ribo-Zero RNA-Seq data in combination with matched miRNA profiles, we identified 68 sponge modulators participating in 26 miRNA-mediated ceRNA interactions, including 19 lncRNAs, 40 circRNAs, and 9 mRNAs. Our study uncovered a novel post-transcriptional regulation layer which could help in the understanding of the mechanisms that underlie porcine myofiber development in different breeds.

Identification of potent, noncovalent fatty acid amide hydrolase (FAAH) inhibitors.[Pubmed:21392988]

Bioorg Med Chem Lett. 2011 Apr 15;21(8):2492-6.

Starting from a series of ureas that were determined to be mechanism-based inhibitors of FAAH, several spirocyclic ureas and lactams were designed and synthesized. These efforts identified a series of novel, noncovalent FAAH inhibitors with in vitro potency comparable to known covalent FAAH inhibitors. The mechanism of action for these compounds was determined through a combination of SAR and co-crystallography with rat FAAH.

Discovery and molecular basis of potent noncovalent inhibitors of fatty acid amide hydrolase (FAAH).[Pubmed:21502526]

Proc Natl Acad Sci U S A. 2011 May 3;108(18):7379-84.

Fatty acid amide hydrolase (FAAH), an amidase-signature family member, is an integral membrane enzyme that degrades lipid amides including the endogenous cannabinoid anandamide and the sleep-inducing molecule oleamide. Both genetic knock out and pharmacological administration of FAAH inhibitors in rodent models result in analgesic, anxiolytic, and antiinflammatory phenotypes. Targeting FAAH activity, therefore, presents a promising new therapeutic strategy for the treatment of pain and other neurological-related or inflammatory disorders. Nearly all FAAH inhibitors known to date attain their binding potency through a reversible or irreversible covalent modification of the nucleophile Ser241 in the unusual Ser-Ser-Lys catalytic triad. Here, we report the discovery and mechanism of action of a series of ketobenzimidazoles as unique and potent noncovalent FAAH inhibitors. Compound 2, a representative of these ketobenzimidazoles, was designed from a series of ureas that were identified from high-throughput screening. While urea compound 1 is characterized as an irreversible covalent inhibitor, the cocrystal structure of FAAH complexed with compound 2 reveals that these ketobenzimidazoles, though containing a carbonyl moiety, do not covalently modify Ser241. These inhibitors achieve potent inhibition of FAAH activity primarily from shape complementarity to the active site and through numerous hydrophobic interactions. These noncovalent compounds exhibit excellent selectivity and good pharmacokinetic properties. The discovery of this distinctive class of inhibitors opens a new avenue for modulating FAAH activity through nonmechanism-based inhibition.