Lack of an appropriate small animal model remains a major hurdle for studying the immunotolerance and immunopathogenesis induced by hepatitis B virus (HBV) infection. In this study, we report a mouse model with sustained HBV viremia after infection with a recombinant adeno-associated virus (AAV) carrying a replicable HBV genome (AAV/HBV). Similar to the clinical HBV carriers, the mice infected with AAV/HBV were sero-negative for antibodies against HBV surface antigen (HBsAg). Immunization with the conventional HBV vaccine in the presence of aluminum adjuvant failed to elicit an immune response against HBV in these mice. To identify a vaccine that can potentially circumvent this tolerance, the TLR9 agonist CpG was added to HBsAg as an adjuvant. Vaccination of mice with HBsAg/CpG induced not only clearance of viremia, but also strong antibody production and T-cell responses. Furthermore, both the DNA replication and protein expression of HBV were significantly reduced in the livers of AAV/HBV-infected mice. Accordingly, AAV/HBV-infected mice may be used as a robust model for investigating the underlying mechanism(s) of HBV immunotolerance and for developing novel immunotherapies to eradicate HBV infections.

Development of therapeutic vaccines/strategies to control chronic hepatitis B virus (HBV) infection (CHB) has been challenging due to HBV-induced tolerance. In this study, we explored strategies for breaking tolerance and restoring the immune response to the HBV surface antigen in tolerant mice. We demonstrated that immune tolerance status is attributed to the level and duration of circulating HBsAg in HBV carrier models. Removal of circulating HBsAg by a monoclonal anti-HBsAg antibody in tolerant mice could gradually reduce tolerance and reestablish B cell and CD4+ T cell responses to subsequent Engerix-B vaccination, producing protective IgG. Furthermore, HBsAg-specific CD8+ T cells induced by the addition of a TLR agonist, resulted in clearance of HBV in both serum and liver. Thus, generation of protective immunity can be achieved by clearing extracellular viral antigen with neutralizing antibodies followed by vaccination.

BackgroundTumor necrosis factor-related apoptosis-inducing ligand (TRAIL) could induce apoptosis of HIV-1-infected monocyte-derived macrophage (MDM), but the molecular mechanisms are not well understood.Methodology/Principal FindingsBy using an HIV-1 Env-pseudotyped virus (HIV-1 PV)-infected MDM cell model we demonstrate that HIV-1 PV infection down-regulates the expression of TRAIL decoy receptor 1 (DcR1) and 2 (DcR2), and cellular FLICE-inhibitory protein (c-FLIP), but dose not affect the expression of death receptor 4 and 5 (DR4, DR5), and Bcl-2 family members in MDM cells. Furthermore, recombinant soluble TRAIL and an agonistic anti-DR5 antibody, AD5-10, treatment stimulates reactive oxygen species (ROS) generation and JNK phosphorylation.Conclusions/SignificanceHIV infection facilitates TRIAL-induced cell death in MDM by down-regulating the expression of TRAIL decoy receptors and intracellular c-FLIP. Meanwhile, the agonistic anti-DR5 antibody, AD5-10, induces apoptosis synergistically with TRAIL in HIV-1-infected cells. ROS generation and JNK phosphorylation are involved in this process. These findings potentiate clinical usage of the combination of TRAIL and AD5-10 in eradication of HIV-infected macrophage and AIDS.

Strong tolerance to HBV surface antigens limits the therapeutic effect of the conventional HBsAg vaccination in both preclinical animal models and patients with chronic hepatitis B (CHB) infection. In contrast, we observed that clinical CHB patients presented less immune tolerance to the preS1 domain of HBV large surface antigen. To study whether targeting the weak tolerance of preS1 region could improve therapy gain, we explored vaccination with the long peptide of preS1 domain for HBV virions clearance. Our study showed that this preS1-polypeptide rather than HBsAg vaccination induced robust immune responses in the HBV carrier mice. The anti-preS1 rapidly cleared HBV virions in vivo and blocked HBV infection to hepatocytes in vitro. Intriguingly, vaccination of preS1-polypeptide even reduced the tolerized status of HBsAg, opening a therapeutic window for the host to respond to the HBsAg vaccine. A sequential administration of antigenically distinct preS1-polypeptide and HBsAg vaccines in HBV carrier mice could finally induce HBsAg-HBsAb serological conversion and clear chronic HBV infection in the carrier mice. These results suggest that preS1 can function as a therapeutic vaccination for the control of CHB.

PurposeTo evaluate the diagnostic value of multidetector CT (MDCT) and its multiplanar reformation (MPR), volume rendering (VR) and virtual bronchoscopy (VB) postprocessing techniques for primary trachea and main bronchus tumors.MethodsDetection results of 31 primary trachea and main bronchus tumors with MDCT and its MPR, VR and VB postprocessing techniques, were analyzed retrospectively with regard to tumor locations, tumor morphologies, extramural invasions of tumors, longitudinal involvements of tumors, morphologies and extents of luminal stenoses, distances between main bronchus tumors and trachea carinae, and internal features of tumors. The detection results were compared with that of surgery and pathology.ResultsDetection results with MDCT and its MPR, VR and VB were consistent with that of surgery and pathology, included tumor locations (tracheae, n = 19; right main bronchi, n = 6; left main bronchi, n = 6), tumor morphologies (endoluminal nodes with narrow bases, n = 2; endoluminal nodes with wide bases, n = 13; both intraluminal and extraluminal masses, n = 16), extramural invasions of tumors (brokethrough only serous membrane, n = 1; 4.0 mm—56.0 mm, n = 14; no clear border with right atelectasis, n = 1), longitudinal involvements of tumors (3.0 mm, n = 1; 5.0 mm—68.0 mm, n = 29; whole right main bronchus wall and trachea carina, n = 1), morphologies of luminal stenoses (irregular, n = 26; circular, n = 3; eccentric, n = 1; conical, n = 1) and extents (mild, n = 5; moderate, n = 7; severe, n = 19), distances between main bronchus tumors and trachea carinae (16.0 mm, n = 1; invaded trachea carina, n = 1; >20.0 mm, n = 10), and internal features of tumors (fairly homogeneous densities with rather obvious enhancements, n = 26; homogeneous density with obvious enhancement, n = 1; homogeneous density without obvious enhancement, n = 1; not enough homogeneous density with obvious enhancement, n = 1; punctate calcification with obvious enhancement, n = 1; low density without obvious enhancement, n = 1).ConclusionMDCT and its MPR, VR and VB images have respective advantages and disadvantages. Their combination could complement to each other to accurately detect locations, natures (benignancy, malignancy or low malignancy), and quantities (extramural invasions, longitudinal involvements, extents of luminal stenoses, distances between main bronchus tumors and trachea carinae) of primary trachea and main bronchus tumors with crucial information for surgical treatment, are highly useful diagnostic methods for primary trachea and main bronchus tumors.

The combination of tris(pyrazolyl)borate cobalt complexes and Lewis base is developed as an efficient catalyst precursor in the homogeneous hydrogenation. A broad substrate scope including carbonyls, alkenes, enamines, and imines is reduced with 60 atm of H 2 at 60 °C. Mechanistic studies support the hydrogenation operates through a frustrated Lewis pair (FLP)-like reduction process. These results highlight the development of novel non-noble metal catalytic processes, when combined with the diverse small molecule activation chemistry associated with FLPs.

In order to improve the working performance of cassava harvester, structural bionic design for its digging shovel was conducted. Taking the oriental mole cricket's paws as bionic prototype, a new structural bionic design method for digging shovel was established, which considers the morphology-configuration-function coupling bionic. A comprehensive performance comparison method was proposed, which is used to select the bionic design schemes. The proposed bionic design method was used to improve digging shovel structure of a digging-pulling style cassava harvester, and nine bionic-type digging shovels were obtained with considering the impact of soil mechanics. After conducting mechanical properties comparative analysis for bionic-type digging shovels, the bionic design rules were summed up, and the optimal design scheme of digging shovel was obtained through combining the proposed comprehensive performance comparison method with Analytic Hierarchy Process (AHP). Studies have shown that bionic design method not only can improve the overall mechanical properties of digging shovel, but also can help to improve the harvesting effect of cassava harvester, which provides a new idea for crops harvesting machinery's structural optimization design.

PurposeTo investigate image quality and radiation dose of CT coronary angiography (CTCA) scanned using automatic tube current modulation (ATCM) and reconstructed by strong adaptive iterative dose reduction three-dimensional (AIDR3D).MethodsEighty-four consecutive CTCA patients were collected for the study. All patients were scanned using ATCM and reconstructed with strong AIDR3D, standard AIDR3D and filtered back-projection (FBP) respectively. Two radiologists who were blinded to the patients' clinical data and reconstruction methods evaluated image quality. Quantitative image quality evaluation included image noise, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR). To evaluate image quality qualitatively, coronary artery is classified into 15 segments based on the modified guidelines of the American Heart Association. Qualitative image quality was evaluated using a 4-point scale. Radiation dose was calculated based on dose-length product.ResultsCompared with standard AIDR3D, strong AIDR3D had lower image noise, higher SNR and CNR, their differences were all statistically significant (P<0.05); compared with FBP, strong AIDR3D decreased image noise by 46.1%, increased SNR by 84.7%, and improved CNR by 82.2%, their differences were all statistically significant (P<0.05 or 0.001). Segments with diagnostic image quality for strong AIDR3D were 336 (100.0%), 486 (96.4%), and 394 (93.8%) in proximal, middle, and distal part respectively; whereas those for standard AIDR3D were 332 (98.8%), 472 (93.7%), 378 (90.0%), respectively; those for FBP were 217 (64.6%), 173 (34.3%), 114 (27.1%), respectively; total segments with diagnostic image quality in strong AIDR3D (1216, 96.5%) were higher than those of standard AIDR3D (1182, 93.8%) and FBP (504, 40.0%); the differences between strong AIDR3D and standard AIDR3D, strong AIDR3D and FBP were all statistically significant (P<0.05 or 0.001). The mean effective radiation dose was (2.55±1.21) mSv.ConclusionCompared with standard AIDR3D and FBP, CTCA with ATCM and strong AIDR3D could significantly improve both quantitative and qualitative image quality.