The omicron variant of SARS-CoV-2 has been spreading rapidly across the globe. The virus-surface spike protein plays a critical role in the cell entry and immune evasion of SARS-CoV-2. Here we ...determined the 3.0 Å cryo-EM structure of the omicron spike protein ectodomain. In contrast to the original strain of SARS-CoV-2 where the receptor-binding domain (RBD) of the spike protein takes a mixture of open ("standing up") and closed ("lying down") conformations, the omicron spike molecules are predominantly in the open conformation, with one upright RBD ready for receptor binding. The open conformation of the omicron spike is stabilized by enhanced inter-domain and inter-subunit packing, which involves new mutations in the omicron strain. Moreover, the omicron spike has undergone extensive mutations in RBD regions where known neutralizing antibodies target, allowing the omicron variant to escape immune surveillance aimed at the original viral strain. The stable open conformation of the omicron spike sheds light on the cell entry and immune evasion mechanisms of the omicron variant.
Cell entry mechanisms of SARS-CoV-2 Shang, Jian; Wan, Yushun; Luo, Chuming ...
Proceedings of the National Academy of Sciences - PNAS,
05/2020, Letnik:
117, Številka:
21
Journal Article
Recenzirano
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A novel severe acute respiratory syndrome (SARS)-like coronavirus (SARS-CoV-2) is causing the global coronavirus disease 2019 (COVID-19) pandemic. Understanding how SARS-CoV-2 enters human cells is a ...high priority for deciphering its mystery and curbing its spread. A virus surface spike protein mediates SARS-CoV-2 entry into cells. To fulfill its function, SARS-CoV-2 spike binds to its receptor human ACE2 (hACE2) through its receptor-binding domain (RBD) and is proteolytically activated by human proteases. Here we investigated receptor binding and protease activation of SARS-CoV-2 spike using biochemical and pseudovirus entry assays. Our findings have identified key cell entry mechanisms of SARS-CoV-2. First, SARS-CoV-2 RBD has higher hACE2 binding affinity than SARS-CoV RBD, supporting efficient cell entry. Second, paradoxically, the hACE2 binding affinity of the entire SARS-CoV-2 spike is comparable to or lower than that of SARS-CoV spike, suggesting that SARS-CoV-2 RBD, albeit more potent, is less exposed than SARS-CoV RBD. Third, unlike SARS-CoV, cell entry of SARS-CoV-2 is preactivated by proprotein convertase furin, reducing its dependence on target cell proteases for entry. The high hACE2 binding affinity of the RBD, furin preactivation of the spike, and hidden RBD in the spike potentially allow SARS-CoV-2 to maintain efficient cell entry while evading immune surveillance. These features may contribute to the wide spread of the virus. Successful intervention strategies must target both the potency of SARS-CoV-2 and its evasiveness.
A novel severe acute respiratory syndrome (SARS)-like coronavirus (SARS-CoV-2) recently emerged and is rapidly spreading in humans, causing COVID-19
. A key to tackling this pandemic is to understand ...the receptor recognition mechanism of the virus, which regulates its infectivity, pathogenesis and host range. SARS-CoV-2 and SARS-CoV recognize the same receptor-angiotensin-converting enzyme 2 (ACE2)-in humans
. Here we determined the crystal structure of the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 (engineered to facilitate crystallization) in complex with ACE2. In comparison with the SARS-CoV RBD, an ACE2-binding ridge in SARS-CoV-2 RBD has a more compact conformation; moreover, several residue changes in the SARS-CoV-2 RBD stabilize two virus-binding hotspots at the RBD-ACE2 interface. These structural features of SARS-CoV-2 RBD increase its ACE2-binding affinity. Additionally, we show that RaTG13, a bat coronavirus that is closely related to SARS-CoV-2, also uses human ACE2 as its receptor. The differences among SARS-CoV-2, SARS-CoV and RaTG13 in ACE2 recognition shed light on the potential animal-to-human transmission of SARS-CoV-2. This study provides guidance for intervention strategies that target receptor recognition by SARS-CoV-2.
We report a new macromolecular architecture of dual functional block copolymer brushes on commercial thin-film composite (TFC) membranes for integrated “defending” and “attacking” strategies against ...biofouling. Mussel-inspired catechol chemistry is used for a convenient immobilization of initiator molecules to the membrane surface with the aid of polydopamine (PDA). Zwitterionic polymer brushes with strong hydration capacity and quaternary ammonium salt (QAS) polymer brushes with bactericidal ability are sequentially grafted on TFC membranes via activators regenerated by electron transfer–atom transfer radical polymerization (ARGET-ATRP), an environmentally benign and controlled polymerization method. Measurement of membrane intrinsic transport properties in reverse osmosis experiments shows that the modified TFC membrane maintains the same water permeability and salt selectivity as the pristine TFC membrane. Chemical force microscopy and protein/bacterial adhesion studies are carried out for a comprehensive evaluation of the biofouling resistance and antimicrobial ability, demonstrating low biofouling propensity and excellent bacterial inactivation for the modified TFC membrane. We conclude that this polymer architecture, with complementary “defending” and “attacking” capabilities, can effectively prevent the attachment of biofoulants and formation of biofilms and thereby significantly mitigate biofouling on TFC membranes.
Curcumin, the active component of turmeric, has been shown to protect against carcinogenesis and prevent tumor development. However, little is known about its anti-tumor mechanism in small cell lung ...cancer (SCLC). In this study, we found that curcumin can inhibit SCLC cell proliferation, cell cycle, migration, invasion and angiogenesis through suppression of the STAT3. SCLC cells were treated with curcumin (15 µmol/L) and the results showed that curcumin was effective in inhibiting STAT3 phosphorylation to downregulate of an array of STAT3 downstream targets ,which contributed to suppression of cell proliferation, loss of colony formation, depression of cell migration and invasion. Curcumin also suppressed the expression of proliferative proteins (Survivin, Bcl-X(L) and Cyclin B1), and invasive proteins (VEGF, MMP-2, MMP-7 and ICAM-1). Knockdown of STAT3 expression by siRNA was able to induce anti-invasive effects in vitro. In contrast, activation of STAT3 upstream of interleukin 6 (IL-6) leads to the increased cell proliferation ,cell survival, angiogenesis, invasion, migration and tumor growth. Our findings illustrate the biologic significance of IL-6/JAK/STAT3 signaling in SCLC progression and provide novel evidence that the pathway may be a new potential target for therapy of SCLC. It was concluded that curcumin is a potent agent in the inhibition of STAT3 with favorable pharmacological activity,and curcumin may have translational potential as an effective cancer therapeutic or preventive agent for SCLC.
A key challenge of photoregulated living radical polymerization is developing efficient and robust photocatalysts. Now carbon dots (CDs) have been exploited for the first time as metal‐free ...photocatalysts for visible‐light‐regulated reversible addition–fragmentation chain‐transfer (RAFT) polymerization. Screening of diverse heteroatom‐doped CDs suggested that the P‐ and S‐doped CDs were effective photocatalysts for RAFT polymerization under mild visible light following a photoinduced electron transfer (PET) involved oxidative quenching mechanism. PET‐RAFT polymerization of various monomers with temporal control, narrow dispersity (Đ≈1.04), and chain‐end fidelity was achieved. Besides, it was demonstrated that the CD‐catalyzed PET‐RAFT polymerization was effectively performed under natural solar irradiation.
Carbon dots (CDs) are presented as a class of metal‐free photocatalysts for photo‐induced electron transfer (PET) reversible addition–fragmentation chain‐transfer (RAFT) polymerization under natural sunlight.
Network intrusion detection system (NIDS) is a commonly used tool to detect attacks and protect networks, while one of its general limitations is the false positive issue. On the basis of our ...comparative experiments and analysis for the characteristics of the particle swarm optimization (PSO) and Xgboost, this paper proposes the PSO-Xgboost model given its overall higher classification accuracy than other alternative models such like Xgboost, Random Forest, Bagging and Adaboost. Firstly, a classification model based on Xgboost is constructed, and then PSO is used to adaptively search for the optimal structure of Xgboost. The benchmark NSL-KDD dataset is used to evaluate the proposed model. Our experimental results demonstrate that PSO-Xgboost model outperforms other comparative models in precision, recall, macro-average (macro) and mean average precision (mAP), especially when identifying minority groups of attacks like U2R and R2L. This work also provides experimental arguments for the application of swarm intelligence in NIDS.
miRNAs play important roles in gene regulation, and their dysregulation is associated with many diseases, including epithelial ovarian cancer (EOC). In this study, we determined the expression and ...function of miR-590-3p in EOC. miR-590-3p levels were higher in high-grade carcinoma when compared with low-grade or tumors with low malignant potential. Interestingly, plasma levels of miR-590-3p were significantly higher in patients with EOC than in subjects with benign gynecologic disorders. Transient transfection of miR-590-3p mimics or stable transfection of mir-590 increased cell proliferation, migration, and invasion.
studies revealed that mir-590 accelerated tumor growth and metastasis. Using a cDNA microarray, we identified forkhead box A2 (FOXA2) and versican (VCAN) as top downregulated and upregulated genes by mir-590, respectively. miR-590-3p targeted FOXA2 3' UTR to suppress its expression. In addition, knockdown or knockout of FOXA2 enhanced cell proliferation, migration, and invasion. Overexpression of FOXA2 decreased, whereas knockout of FOXA2 increased VCAN mRNA and protein levels, which was due to direct binding and regulation of the VCAN gene by FOXA2. Interrogation of the TCGA ovarian cancer database revealed a negative relationship between FOXA2 and VCAN mRNA levels in EOC tumors, and high FOXA2/low VCAN mRNA levels in tumors positively correlated with patient survival. Finally, overexpression of FOXA2 or silencing of VCAN reversed the effects of mir-590. These findings demonstrate that miR-590-3p promotes EOC development via a novel FOXA2-VCAN pathway.
Low FOXA2/high VCAN levels mediate the tumor-promoting effects of miR-590-3p and negatively correlate with ovarian cancer survival.
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Solar‐driven water evaporation and valuable fuel generation is an environmentally friendly and sustainable way for clean water and energy production. However, a few bottlenecks for practical ...applications are high‐cost, low productivity, and severe sunlight angle dependence. Herein, solar evaporation with enhanced photocatalytic capacity that is light direction insensitive and of efficiency breakthrough by virtue of a three‐dimensional (3D) photothermal catalytic spherical isotopic evaporator is demonstrated. A homogeneous layer of microfluidic blow spun polyamide nanofibers loaded with efficient light absorber of polypyrrole nanoparticles conformally wraps onto a lightweight, thermal insulating plastic sphere, featuring favorable interfacial solar heating and efficient water transportation. The 3D spherical geometry not only guarantees the omnidirectional solar absorbance by the light‐facing hemisphere, but also keeps the other hemisphere under shadow to harvest energy from the warmer environment. As a result, the light‐to‐vapor efficiency exceeds the theoretical limit, reaching 217% and 156% under 1 and 2 sun, respectively. Simultaneously, CO2 photoreduction with generated steam reveals a favorable clean fuels production rate using photocatalytic spherical evaporator by secondary growth of Cu2O nanoparticles. Finally, an outdoor demonstration manifests a high evaporation rate and easy‐to‐perform construction on‐site, providing a promising opportunity for efficient and decentralized water and clean fuel production.
A three‐dimensional (3D) photothermal catalytic spherical evaporator with double‐layer structure that enables the theoretical light‐to‐vapor efficiency limits breakthrough and efficient clean fuels production. The isotropy of spherical structure exhibits the omnidirectional light absorption, reducing the influence of natural light incident angle on solar evaporation rate and circumventing the trade‐off between water condensation and photocatalytic reaction, which is significant for practical applications.
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