ABSTRACT
The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been endangering worldwide public health and economy. SARS-CoV-2 infects a variety of tissues where the known receptor ACE2 is low or almost absent, suggesting the existence of alternative pathways for virus entry. Here, we performed a genome-wide barcoded-CRISPRa screen to identify novel host factors that enable SARS-CoV-2 infection. In addition to known host proteins, i.e. ACE2, TMPRSS2 and NRP1, we identified multiple host components, among which LDLRAD3, TMEM30A and CLEC4G were confirmed as functional receptors for SARS-CoV-2. All these membrane proteins bind directly to spikes N-terminal domain (NTD). Their essential and physiological roles have all been confirmed in either neuron or liver cells. In particular, LDLRAD3 and CLEC4G mediate SARS-CoV-2 entry and infection in a fashion independent of ACE2. The identification of the novel receptors and entry mechanisms could advance our understanding of the multiorgan tropism of SARS-CoV-2, and may shed light on the development of the therapeutic countermeasures against COVID-19.
ABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its emerging variants of concern (VOC), such as Delta (B.1.617.2) and Omicron (B.1.1.529), has continued to drive the worldwide pandemic. Therefore, there is a high demand for vaccines with enhanced efficacy, high thermostability, superior design flexibility, and fast manufacturing speed. Here, we report a circular RNA (circRNA) vaccine that encodes the trimeric RBD of SARS-CoV-2 Spike protein. Without the need of nucleotide modification, 5-capping or 3-polyadenylation, circRNA could be rapidly produced via in vitro transcription and is highly thermostable whether stored in naked or lipid-nanoparticle (LNP)-encapsulated format. LNP-encapsulated circRNARBD elicited potent neutralizing antibodies and T cell responses, providing robust protection against Beta (B.1.351) and native viruses in mice and rhesus macaques, respectively. Notably, circRNA vaccine enabled higher and more durable antigen production than 1m{Psi}-modified mRNA vaccine, eliciting a higher proportion of neutralizing antibodies and stronger Th1-biased immune responses. Importantly, we found that circRNARBD-Omicron vaccine induced effective neutralizing antibodies against only Omicron but not Delta variant. By contrast, circRNARBD-Delta could elicit high level of neutralizing antibodies against both Delta and Omicron. Following two doses of either native- or Delta-specific vaccination, circRNARBD-Delta, but not Omicron or Beta vaccines, could effectively boost the neutralizing antibodies against both Delta and Omicron variants. These results suggest that circRNARBD-Delta is a favorable choice for vaccination to provide a broad-spectrum protection against the current variants of concern of SARS-CoV-2.
ABSTRACT
Objective: To evaluate the efficacy of postoperative radiotherapy in the treatment of parotid gland carcinoma. Methods: Eighty-six postoperated patients with parotid gland carcinoma( 7 in stage Ⅰ, 28 in stage Ⅱ, 33 in stage Ⅲ and 18 in stage Ⅳ) were radiated by 60Co ?-ray or linear accelerator X-ray combined with electron beam. All patients were diagnosed by pathology and followed up for more than 5 years. Results: The five year survival rate and the local control rate were 73.3% and 87.2% respectively. Poor prognosis was observed in the cases with the neoplastic classification of undifferentiated carcinoma, sequamous cell carcinoma and malignant pleomorphic adenoma, but the better prognosis was obtained in the cases with acinic cell carcinoma and mucoepidermoid carcinoma. Poor prognosis was observed in the cases with stage Ⅲ and Ⅳ of clinical stage. Radiotherapy undertaken in 2 weeks after surgical operation gave higher 5- year survival ratio( 83.8%). The group given 51～60 Gy radiation showed 82.9% of five- year survival rate. Conclusion: The combination of surgery with radiation is effective in the treatment of parotid gland carcinoma.Radiation of 51～60 Gy 2 weeks after operation may result in better prognosis. Neoplastic type and clinical stage are important factors for prognosis.
