An RBD bispecific antibody effectively neutralizes a SARS-CoV-2 Omicron variant.

Potent neutralizing antibodies (nAbs) against SARS-CoV-2 are a promising therapeutic against the ongoing COVID-19 pandemic. However, the continuous emergence of neutralizing antibody escape variants makes it challenging for antibody therapeutics based on monospecific nAbs. Here, we generated an IgG-like bispecific antibody (bsAb), Bi-Nab, based on a pair of human neutralizing antibodies targeting multiple and invariant sites of the spike receptor binding domain (RBD): 35B5 and 32C7. We demonstrated that Bi-Nab exhibited higher binding affinity to the Delta spike protein than its parental antibodies and presented an extended inhibition breadth of preventing RBD binding to angiotensin-converting enzyme 2 (ACE2), the cellular receptor of SARS-CoV-2. In addition, pseudovirus neutralization results showed that Bi-Nab improved the neutralization potency and breadth with a lower half maximum inhibitory concentration (IC50) against wild-type SARS-CoV-2, variants being monitored (VBMs) and variants of concern (VOCs). Notably, the IgG-like Bi-Nab enhanced the neutralizing activity against Omicron variants with potent capabilities for transmission and immune evasion in comparison with its parental monoclonal antibody (mAb) 32C7 and a cocktail (with the lowest IC50 values of 31.6 ng/mL against the Omicron BA.1 and 399.2 ng/mL against the Omicron BA.2), showing evidence of synergistic neutralization potency of Bi-Nab against the Omicron variants. Thus, Bi-Nab represents a feasible and effective strategy against SARS-CoV-2 variants of concern.

Study on time effect of residual pressure and bearing characteristics of jacked pile in saturated silt foundation.

The history of stress in soil mass and pile surface roughness significantly impacts the time effect of residual pressure at the pile end and bearing characteristics of the jacked pile. In this study, the impacts of soil over-consolidation ratio and pile surface roughness on the time effect of residual pressure and bearing characteristics of jacked pile end in saturated silt foundation are explored. Through the independently developed model test device for the vertical bearing characteristics of jacked pile, the driving of jacked pile with different pile surface roughness and static load tests at different resting phases are carried out on saturated silt foundations with different over-consolidation ratios. The model box is cylindrical in shape with a size of 40 cm × 48 cm (inner diameter × height) and is made of transparent tempered glass. The results show that: the increase in surface roughness of jacked pile in saturated silt foundation causes not only the increase in the pile side friction but also the increase in the pile end resistance during the static pressure sinking pile; the change laws on the residual pressure of pile end and limit friction resistance of pile side for jacked pile in saturated silt foundation vary with over-consolidation ratio of soil mass and the pile surface roughness.

A Bispecific Antibody Targeting RBD and S2 Potently Neutralizes SARS-CoV-2 Omicron and Other Variants of Concern.

Emerging severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) variants, especially the Omicron variant, have impaired the efficacy of existing vaccines and most therapeutic antibodies, highlighting the need for additional antibody-based tools that can efficiently neutralize emerging SARS-CoV-2 variants. The use of a "single" agent to simultaneously target multiple distinct epitopes on the spike is desirable in overcoming the neutralizing escape of SARS-CoV-2 variants. Herein, we generated a human-derived IgG-like bispecific antibody (bsAb), Bi-Nab35B5-47D10, which successfully retained parental specificity and simultaneously bound to the two distinct epitopes on receptor-binding domain (RBD) and S2. Bi-Nab35B5-47D10 showed improved spike binding breadth among wild-type (WT) SARS-CoV-2, variants of concern (VOCs), and variants being monitored (VBMs) compared with its parental monoclonal antibodies (MAbs). Furthermore, pseudotyped virus neutralization demonstrated that Bi-Nab35B5-47D10 can efficiently neutralize VBMs, including Alpha (B.1.1.7), Beta (B.1.351), and Kappa (B.1.617.1), as well as VOCs, including Delta (B.1.617.2), Omicron BA.1, and Omicron BA.2. Crucially, Bi-Nab35B5-47D10 substantially improved neutralizing activity against Omicron BA.1 (IC50 = 0.15 nM) and Omicron BA.2 (IC50 = 0.67 nM) compared with its parental MAbs. Therefore, Bi-Nab35B5-47D10 represents a potential effective countermeasure against SARS-CoV-2 Omicron and other variants of concern. IMPORTANCE The new, highly contagious SARS-CoV-2 Omicron variant caused substantial breakthrough infections and has become the dominant strain in countries across the world. Omicron variants usually bear high mutations in the spike protein and exhibit considerable escape of most potent neutralization monoclonal antibodies and reduced efficacy of current COVID-19 vaccines. The development of neutralizing antibodies with potent efficacy against the Omicron variant is still an urgent priority. Here, we generated a bsAb, Bi-Nab35B5-47D10, which simultaneously targets SARS-CoV-2 RBD and S2 and improves the neutralizing potency and breadth against SARS-CoV-2 WT and the tested variants compared with their parental antibodies. Notably, Bi-Nab35B5-47D10 has more potent neutralizing activity against the VOC Omicron pseudotyped virus. Therefore, Bi-Nab35B5-47D10 is a feasible and potentially effective strategy by which to treat and prevent COVID-19.

The expression and clinical value of tumor infiltrating dendritic cells in tumor tissues of patients with esophageal cancer.

BACKGROUND: As dendritic cells (DCs) are the major antigen-presenting cells of the immune system, understanding their role in esophageal cancer is essential for the development of preventative and treatment strategies. This study investigated the expression level and clinical value of tumor infiltrating dendritic cells (TIDCs) in tumor tissues of patients with esophageal cancer. METHODS: From January 2019 to January 2021, 184 patients with esophageal cancer treated were prospectively enrolled as the observation group and 184 patients with benign esophageal tumors were selected as the control group. Tumor tissue samples were obtained and the expression level and phenotypes of the TIDCs were analyzed. The correlation between TIDC expression and clinical characteristics of patients with esophageal cancer was investigated. RESULTS: The density of the TIDCs in the observation group was lower than that in the control group (8.76±2.25 vs. 9.97±2.19; P=0.000). Furthermore, the percentage of major histocompatibility complex-II (MHC-II) positive DCs and the percentage of CD54 positive DCs were relatively lower in the observation group compared to the control group (6.60%±2.12% vs. 9.34%±2.41%; P=0.000 and 7.41%±2.36% vs. 9.98%±2.47%; P=0.000, respectively). Esophageal cancer patients with lymph node metastasis had lower TIDC density, lower percentage of MHC-II positive DCs, and lower percentage of CD54 positive DCs compared to patients without node metastasis (P<0.05). Patients with stage III esophageal cancer also showed significantly lower TIDC density, lower percentage of MHC-II positive DCs, and lower percentage of CD54 positive DCs compared to patients with stage I/II esophageal cancer (P<0.05). Esophageal cancer patients with tumor diameter ≥4 cm presented with decreased TIDC density, decreased percentage of MHC-II positive DCs, and decreased percentage of CD54 positive DCs compared to patients with tumor diameter <4 cm (P<0.05). In addition, the density of TIDCs, the percentage of MHC-II positive DCs, and the percentage of CD54 positive DCs were significantly negatively correlated with the percentage of CD4+ T-lymphocytes and positively correlated with the percentage of CD8+ T-lymphocytes (P<0.05). CONCLUSIONS: Patients with esophageal cancer had low expression and function of TIDCs, and this was related to the imbalance of T-lymphocyte subsets, lymph node metastasis, TNM stage, and lesion size.

Rutin attenuates Sorafenib-induced Chemoresistance and Autophagy in Hepatocellular Carcinoma by regulating BANCR/miRNA-590-5P/OLR1 Axis.

Rutin, the main component of Potentilla discolor Bunge, was proven to exhibit anti-tumor properties. Sorafenib (SO) is conventionally used in chemotherapy against hepatocellular carcinoma (HCC), but acquired resistance developed during long-term therapy limits its benefits. This study aimed to explore the molecular mechanism of rutin in SO-induced autophagy and chemoresistance in HCC. Sixty-eight paired HCC patients who received the same chemotherapy treatment were obtained. We also established two SO resistance cell lines and then utilized high-throughput RNA sequencing to explore their long non-coding RNA (lncRNA) expression profiles. The target microRNA (miRNA) and downstream mRNA were also explored. Our results indicated that rutin treatment attenuates autophagy and BANCR expression in SO resistance cells. Transmission electron microscopy clearly showed a significantly decreased number of autophagosomes after rutin-treated HepG2/SO and HCCLM3/SO cells. BANCR knockdown promotes the sensitivity of SO resistance cells to SO. Further study found that BANCR acts as a molecular sponge of miR-590-5P to sequester miR-590-5P away from oxidized low-density lipoprotein receptor 1 (OLR1) in HCC cells. Furthermore, in vivo study demonstrated that rutin could inhibit autophagy through the BANCR/miRNA-590-5P/OLR1 axis. Our findings suggest that rutin could regulate autophagy by regulating BANCR/miRNA-590-5P/OLR1 axis.

Effects of Antimicrobial peptides on egg production, egg quality and caecal microbiota of hens during the late laying period.

This study was conducted to determine the effects of diet supplementation of laying hens with antimicrobial peptides (AMP) on egg production, egg quality and caecal microbiota. A total of 360 Hy-Line Brown laying hens (72 weeks old) were divided into three groups with four replicates of 30 birds each. The laying hens were fed with the basal diet (Control), the basal diet + 50 mg/kg AMP (group 1) and the basal diet + 100 mg/kg AMP (group 2). The experiment lasted for 45 d. Eggs were collected daily and caecal samples were collected at the end of the experiment. The results showed that AMP supplementation caused a significantly increased laying rate and decreased feed/egg ratio (p ï¼œ .05). Meanwhile, a distinctive difference in cecal microbiota was observed between AMP and control groups and the average values of microbial diversity and richness were lower in the AMP group than in the control group. At the phylum level, the relative abundance of Verrucomicrobia and Cyanobacteria were lower in the AMP group than in the control group. In conclusion, the results indicated that dietary supplementation with AMP can improve egg production and affect the cecal microbial community membership and structure of hens during late laying period.

Metadherin overexpression in perihilar cholangiocarcinoma is associated with lymph node metastasis and poor prognosis.

Metadherin (MTDH) is a protein that is also named astrocyte elevated gene-1, and is highly expressed in a number of different tumor tissues. Although the expression of MTDH is associated with tumor invasion and recurrence, the expression of this protein in perihilar cholangiocarcinoma (PCCA) and its clinical use have not yet been investigated. In the present study, the expression of MTDH in patients with PCCA was investigated in order to determine its clinicopathological use. An immunohistochemical method was used to detect MTDH expression and the epithelial-mesenchymal transition markers E-cadherin and vimentin in 66 cases of PCCA. In addition to the expression of MTDH, the clinical and pathological data and the postoperative outcomes were analyzed. The MTDH positive expression rate was 48.5% (32/66) in PCCA. A significantly higher MTDH expression level was identified in the poor tumor differentiation group compared with the well differentiation group (P=0.007). In the positive lymph node metastasis group, a significantly higher MTDH expression level was revealed compared with the negative lymph node metastasis group (P=0.023). No association was noted with regard to the expression of MTDH and the variables age, sex, tumor diameter, tumor grade and tumor classification stage. Positive MTDH expression was significantly associated with high vimentin expression (P=0.037) compared with negative vimentin expression and inversely associated with positive E-cadherin expression compared with negative E-cadherin expression (P=0.030). Survival analysis suggested that the high MTDH expression group was associated with a worse overall survival (OS) rate and recurrence free survival (RFS) rate compared with the low MTDH expression group (P<0.001 and P=0.01, respectively). Cox regression analysis indicated that the Tumor-Node-Metastasis, surgery margin and high MTDH expression were independent OS and RFS factors for PCCA. MTDH expression may serve an important function in PCCA tumor growth and metastasis. Targeting MTDH may have important therapeutic applications for patients with PCCA.