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The pandemic of COVID-19 caused by SARS-CoV-2 continues to spread around the world. Mutant strains of SARS-CoV-2 are constantly emerging. At present, Omicron variants have become mainstream. In this work, we carried out a systematic and comprehensive analysis of the reported spike protein antibodies, counting the antibodies epitopes and genotypes. We further comprehensively analyzed the impact of Omicron mutations on antibody epitopes and classified these antibodies according to their binding patterns. We found that the epitopes of one class of antibodies were significantly less affected by Omicron mutations than other classes. Binding and virus neutralization experiments show that such antibodies can effectively inhibit the immune escape of Omicron. Cryo-EM results show that this class of antibodies utilizes a conserved mechanism to neutralize SARS-CoV-2. Our results greatly help us deeply understand the impact of Omicron mutations. At the same time, it also provides guidance and insights for developing Omicron antibodies and vaccines.
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The SARS-CoV-2 Omicron variant has become the dominant SARS-CoV-2 variant around the world and exhibits immune escape to current COVID-19 vaccines to some extent due to its numerous spike mutations. Here, we evaluated the immune responses to booster vaccination with intramuscular adenovirus-vectored vaccine (Ad5-nCoV), aerosolized Ad5-nCoV, a recombinant protein subunit vaccine (ZF2001) or homologous inactivated vaccine (CoronaVac) in those who received two doses of inactivated COVID-19 vaccines 6 months prior. We found that the Ad5-nCoV booster induced potent neutralizing activity against the wild-type virus and Omicron variant, while aerosolized Ad5-nCoV generated the greatest neutralizing antibody responses against the Omicron variant at day 28 after booster vaccination, at 14.1-fold that of CoronaVac, 5.6-fold that of ZF2001 and 2.0-fold that of intramuscular Ad5-nCoV. Similarly, the aerosolized Ad5-nCoV booster produced the greatest IFN{gamma} T-cell response at day 14 after booster vaccination. The IFN{gamma} T-cell response to aerosolized Ad5-nCoV was 12.8-fold for CoronaVac, 16.5-fold for ZF2001, and 5.0-fold for intramuscular Ad5-nCoV. Aerosolized Ad5-nCoV booster also produced the greatest spike-specific B cell response. Our findings suggest that inactivated vaccine recipients should consider adenovirus-vectored vaccine boosters in China and that aerosolized Ad5-nCoV may provide a more efficient alternative in response to the spread of the Omicron variant.
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The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents a global public health threat. Most research on therapeutics against SARS-CoV-2 focused on the receptor binding domain (RBD) of the Spike (S) protein, whereas the vulnerable epitopes and functional mechanism of non-RBD regions are poorly understood. Here we isolated and characterized monoclonal antibodies (mAbs) derived from convalescent COVID-19 patients. An mAb targeting the N-terminal domain (NTD) of the SARS-CoV-2 S protein, named 4A8, exhibits high neutralization potency against both authentic and pseudotyped SARS-CoV-2, although it does not block the interaction between angiotensin-converting enzyme 2 (ACE2) receptor and S protein. The cryo-EM structure of the SARS-CoV-2 S protein in complex with 4A8 has been determined to an overall resolution of 3.1 Angstrom and local resolution of 3.4 Angstrom for the 4A8-NTD interface, revealing detailed interactions between the NTD and 4A8. Our functional and structural characterizations discover a new vulnerable epitope of the S protein and identify promising neutralizing mAbs as potential clinical therapy for COVID-19.
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Given the increasing exploitation of antibodies in different contexts such as molecular diagnostics and therapeutics, it would be beneficial to unravel properties of antigen-antibody interaction with modeling of computational protein-protein docking, especially, in the absence of a cocrystal structure. However, obtaining a native-like antigen-antibody structure remains challenging due in part to failing to reliably discriminate accurate from inaccurate structures among tens of thousands of decoys after computational docking with existing scoring function. We hypothesized that some important physicochemical and energetic features could be used to describe antigen-antibody interfaces and identify native-like antigen-antibody structure. We prepared a dataset, a subset of Protein-Protein Docking Benchmark Version 4.0, comprising 37 nonredundant 3D structures of antigen-antibody complexes, and used it to train and test multivariate logistic regression equation which took several important physicochemical and energetic features of decoys as dependent variables. Our results indicate that the ability to identify native-like structures of our method is superior to ZRANK and ZDOCK score for the subset of antigen-antibody complexes. And then, we use our method in workflow of predicting epitope of anti-Ebola glycoprotein monoclonal antibody-4G7 and identify three accurate residues in its epitope.
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Aim To study the effects of Free Anthra-quinone from Rhubarb (FAR)on myocardial CTGF and collagen expression and interstitial fibrosis in dia-betic rats.Methods The male SD rats were randomly divided into normal group (CON),diabetic cardiomy-opathy group (DCM) and FAR treatment group (FAR).Streptozocin was intraperitoneally injected in-to the animals in the latter 2 groups to induce diabetic rat model.The model was expected to be stable for 2 weeks before the treatment.At the end of the 8th week in treatment,fasting plasma glucose and heart mass in-dex were measured.Masson staining was used to ob-serve the myocardial fibrosis.RT-PCR was used to de-tect the mRNA levels of CTGF,procollagen type Ⅰand collagen type Ⅲ.Immunohistochemical method was used to detect the content of CTGF.ELISA was used to detect the depositions of collagen type I and collagen type Ⅲ. Results Compared with CON group,fasting plasma glucose,heart mass index,the degree of myocardial fibrosis,and the expressions of CTGF,collagen type I and collagen type Ⅲ in left ven-tricular myocardial tissue of DCM group were signifi-cantly increased. However, compared with DCM group,fasting plasma glucose,heart mass index,the degree of myocardial fibrosis,and the expressions of CTGF,collagen type I and collagen type Ⅲ in left ven-tricular myocardial tissue of FAR-treated rats were sig-nificantly decreased.Conclusion FAR retards the process of myocardial fibrosis in diabetic rats by down-regulating the expression of CTGF,reducing the syn-thesis and depositions of collagen type I and collagen type Ⅲ.
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Objective To investigate effect of sitagliptin ( SIT) on the expression of inducible nitric oxide synthase ( iNOS) and nitric oxide ( NO) in type 2 diabetic nephropathy.Methods 30 rats were randomly divided into normal group (NC group), diabetic nephropathy group (DN group) and sitagliptin treatment group (SIT group).The type 2 diabetes mellitus (T2DM) rats were induced by a high fat diet (HFD) plus repeated low dose streptozocin (STZ) injections.At the end of the 12th week in treatment,there were 6 rats in each group, the NO level was determined by Griess method.mRNA levels of iNOS RT-PCR was detect ed by.The expression of iNOS protein was detected by western blot and immunohistochemical method. ResuIts Compared with the NC group, the expression of iNOS and NO of DN group increased significantly.However, compared with DN group, the expression of iNOS and NO of SIT group decreased significantly.ConcIusion SIT can decrease the expression of iNOS and NO, which implies SIT may protect the type 2 diabetic kidney.
