STAT1 participates in the induction of substance P expression in airway epithelial cells by respiratory syncytial virus.

PURPOSE: The regulation effect and mechanism of respiratory syncytial virus (RSV) infection on the expression of tachykinin substance P (SP) in airway epithelial cells was investigated. METHODS: The regulation of SP expression by RSV was investigated in the BEAS-2B airway epithelial cell line. RT-qPCR, immunofluorescence, and ELISA assay were used to examine the expression of the SP encoding gene TAC1, the intracellular SP protein expression, and the extracellular SP secretion. RESULTS: The mRNA expression of TAC1 and the intracellular SP protein level in BEAS-2B cells were significantly enhanced by RSV infection with multiplicity of infection (MOI) values of both 1 and 0.1 at 48 hours post infection. Heat-inactivated and UV-inactivated RSV, but not live RSV, significantly induced SP secretion in both control BEAS-2B cells and CX3CR1 receptor knockout cells without affecting the TAC1 gene expression or cell viability. RSV G protein (2-10 µg/ml) and fractalkine (10-50 ng/ml), both CX3CR1 receptor ligands, did not affect SP secretion in BEAS-2B cells. Inhibition of STAT1 phosphorylation by fludarabine (1 µM) markedly reduced the RSV-induced TAC1 gene expression and antagonized the inhibition of RSV replication by interferon-α in BEAS-2B cells. CONCLUSIONS: STAT1 participates in RSV infection-induced SP expression in airway epithelial cells.

aFGF Targeted Mediated by Novel Nanoparticles-Microbubble Complex Combined With Ultrasound-Targeted Microbubble Destruction attenuates Doxorubicin-Induced Heart Failure via Anti-Apoptosis and Promoting Cardiac Angiogenesis.

The purpose of this study was to evaluate the protective effect of acidic fibroblast growth factor targeted mediated by novel nanoparticles-cationic lipid microbubbles complex (aFGF-NP + CPMBs) combined with ultrasound targeted microbubble destruction (UTMD)on doxorubicin-induced heart failure (HF)and its mechanism. Heart failure rats induced by intraperitoneal injection with doxorubicin (DOX) to achieve cummulative dose of 15mg/kg for continuous 6 weeks showed left ventricular dysfunction, seriously oxidative stress, cardiomyocyte apoptosis, and decrease of myocardial vascular density. In contrast, aFGF-NP + CPMBs combined with UTMD therapy (3ug/kg, caudal vein injection, twice a week, 6weeks)prominently ameliorated left ventricular dysfunction by increased ejection fraction (EF) and fractional shortening (FS), decreased brain natriuretic peptide (BNP); strengthened the ability of antioxidant stress confirmed by increasing the activity of SOD and reducing the production of MDA; exerted the effect of anti-cardiomyocyte apoptosis and promotion angiogenesis by inhibited Bax expression and increased Bcl-2 expression and platelet endothelial cell adhesion molecule (CD31) expression. Taken together, the research suggested that aFGF targeted mediated by novel nanoparticles-cationic lipid microbubbles complex combined with UTMD should be a promising targeted treatment for heart failure.

Structure of Schlafen13 reveals a new class of tRNA/rRNA- targeting RNase engaged in translational control.

Cleavage of transfer (t)RNA and ribosomal (r)RNA are critical and conserved steps of translational control for cells to overcome varied environmental stresses. However, enzymes that are responsible for this event have not been fully identified in high eukaryotes. Here, we report a mammalian tRNA/rRNA-targeting endoribonuclease: SLFN13, a member of the Schlafen family. Structural study reveals a unique pseudo-dimeric U-pillow-shaped architecture of the SLFN13 N'-domain that may clamp base-paired RNAs. SLFN13 is able to digest tRNAs and rRNAs in vitro, and the endonucleolytic cleavage dissevers 11 nucleotides from the 3'-terminus of tRNA at the acceptor stem. The cytoplasmically localised SLFN13 inhibits protein synthesis in 293T cells. Moreover, SLFN13 restricts HIV replication in a nucleolytic activity-dependent manner. According to these observations, we term SLFN13 RNase S13. Our study provides insights into the modulation of translational machinery in high eukaryotes, and sheds light on the functional mechanisms of the Schlafen family.

Ephrin receptor A2 is an epithelial cell receptor for Epstein-Barr virus entry.

Epstein-Barr virus (EBV) is causally associated with nasopharyngeal carcinoma, 10% of gastric carcinoma and various B cell lymphomas 1 . EBV infects both B cells and epithelial cells 2 . Recently, we reported that epidermal growth factor and Neuropilin 1 markedly enhanced EBV entry into nasopharyngeal epithelial cells 3 . However, knowledge of how EBV infects epithelial cells remains incomplete. To understand the mechanisms through which EBV infects epithelial cells, we integrated microarray and RNA interference screen analyses and found that Ephrin receptor A2 (EphA2) is important for EBV entry into the epithelial cells. EphA2 short interfering RNA knockdown or CRISPR-Cas9 knockout markedly reduced EBV epithelial cell infection, which was mostly restored by EphA2 complementary DNA rescue. EphA2 overexpression increased epithelial cell EBV infection. Soluble EphA2 protein, antibodies against EphA2, soluble EphA2 ligand EphrinA1, or the EphA2 inhibitor 2,5-dimethylpyrrolyl benzoic acid efficiently blocked EBV epithelial cell infection. Mechanistically, EphA2 interacted with EBV entry proteins gH/gL and gB to facilitate EBV internalization and fusion. The EphA2 Ephrin-binding domain and fibronectin type III repeats domain were essential for EphA2-mediated EBV infection, while the intracellular domain was dispensable. This is distinct from Kaposi's sarcoma-associated herpesvirus infection through EphA2 4 . Taken together, our results identify EphA2 as a critical player for EBV epithelial cell entry.

Author Correction: Ephrin receptor A2 is an epithelial cell receptor for Epstein-Barr virus entry.

In the version of this Letter originally published, the authors reported on the use of 2,5-dimethylpyrrolyl benzoic acid to block Ephrin receptors. In 2011, it was reported that newly synthesized 2,5-dimethylpyrrolyl benzoic acid lacked the previously reported EphA2 antagonizing activity1. However, the purchased compound did in fact have the activity initially reported, suggesting that an uncharacterized alteration occurred during storage. The authors therefore wish to clarify that the compound used in their study should be more accurately referred to as a 2,5-dimethylpyrrolyl benzoic acid derivative. All references to 2,5-dimethylpyrrolyl benzoic acid in the Letter have now been changed to reflect this.Although 2,5-dimethylpyrrolyl benzoic acid derivatives have been reported to have off-target effects2, as do most small-molecule inhibitors, the multiple complementary methods and techniques used demonstrate that EphA2 is a key Epstein-Barr virus epithelial cell receptor. The conclusions of the study are therefore unchanged.

[Correlation of Her-2 overexpression with endocrine status and response to tamoxifen treatment in patients with breast cancer].

OBJECTIVE: To investigate the correlation of Her-2 overexpression with endocrine status and response to tamoxifen treatment in patients with breast cancer. METHODS: Immunohistochemistry was used to measure the expression of estrogen receptor (ER), progesterone receptor (PR), Her-2, p53, proliferating cell nuclear antigen (PCNA) in 4773 consecutive in-hospitalized patients with primary breast cancer confirmed by pathological examination of the resected specimens, all females, aged 50 (15 - 92), and were followed up for 42 months on average. 1090 if then received tamoxifen (TAM), an anti-estrogen agent, post-operationally. The correlation of Her-2 overexpression with other factors was analyzed. RESULTS: (1) The Her-2 overexpression rate was 26.6%. Her-2 overexpression was significantly negatively correlated with expressions of ER and PR (both P < 0.01). (2) The general 3-year disease-free survival (DFS) rate of those treated with TAM was 92.7%; and the 3-year GFS rate of the subgroup of the TAM-treated patients with Her-1 overexpression was 91.2%, significantly lower than that of those without Her-2 overexpression (93.4%, P = 0.004). (3) The 3-year DFS rate premenopausal patients with Her-2 overexpression was 91.8%, not significantly different from that of those without Her-2 overexpression (92.6%, P > 0.05), however, the 3-year DFS rate of the postmenopausal patients with Her-2 overexpression was 90.4%, significantly lower than that of those without Her-2 overexpression (92.6%, P = 0.010). (4) The 3-year DFS rate of the axillary lymph node-positive patients with Her-2 overexpression was 89.1%, significantly lower than that without Her-2 overexpression (92.3%, P = 0.037). (5) In the premenopausal patients there was no significant difference in the 3-year DFS rate between the lymph node-negative patients with and without Her-2 overexpression (P > 0.05). However, in the postmenopausal lymph node positive patients the 3-year DFS rate of those with Her-2 overexpression was 88.7%, significantly lower than that of those without Her-2 overexpression (92.2%, P = 0.0069). CONCLUSION: ER and PR are independent factors of Her-2 expression. Her-2 overexpression signifies resistance to TAM treatment. The response to TAM is not influenced by the Her-2 expression and axillary lymph node metastasis status in the premenopausal patients, and is not influenced by the Her-2 expression level in the postmenopausal patients.

[Treatment of skeletal Class II adult patients with microscrew implant anchorage and multi-loop edgewise arch wire].

OBJECTIVE: To evaluate the effects and mechanisms of the microscrew implant anchorage (MIA) combined with multi-loop edgewise arch wire (MEAW) technique in the treatment of skeletal Class II adult patients. METHODS: Eleven adult patients with skeletal Class II high-angle malocclusions were treated with fixed appliances. The spaces were closed by the springs from the MIA to the hook on the archwire. The height of the hook and the direction of the force were different according to the intrusion and retraction of upper anterior teeth. In the finishing stage, MEAW technique and modified class II elastics (from the first loop of MEAW to the MIA) were used for final detailing. Cephalometric analysis was used to evaluate the effect after treatment. RESULTS: After treatment, the decrease of SNA, ANB and FMA were (2.86 +/- 1.05) degrees , (2.82 +/- 0.96) degrees and (2.95 +/- 1.35) degrees , respectively. The torque control of upper anterior teeth was good. The protrusion of lower incisors and the molar extrusion were avoided. The upper molars were moved distally by (3.00 +/- 2.19) mm. CONCLUSIONS: The treatment of adult patients with skeletal Class II high angle malocclusions with MIA and MEAW technique could not only improve the facial esthetics but also avoided the common side effects of traditional Class II elastics.