Human infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) and there is no cure currently. The 3CL protease (3CLpro) is a highly ...conserved protease which is indispensable for CoVs replication, and is a promising target for development of broad-spectrum antiviral drugs. In this study we investigated the anti-SARS-CoV-2 potential of Shuanghuanglian preparation, a Chinese traditional patent medicine with a long history for treating respiratory tract infection in China. We showed that either the oral liquid of Shuanghuanglian, the lyophilized powder of Shuanghuanglian for injection or their bioactive components dose-dependently inhibited SARS-CoV-2 3CLpro as well as the replication of SARS-CoV-2 in Vero E6 cells. Baicalin and baicalein, two ingredients of Shuanghuanglian, were characterized as the first noncovalent, nonpeptidomimetic inhibitors of SARS-CoV-2 3CLpro and exhibited potent antiviral activities in a cell-based system. Remarkably, the binding mode of baicalein with SARS-CoV-2 3CLpro determined by X-ray protein crystallography was distinctly different from those of known 3CLpro inhibitors. Baicalein was productively ensconced in the core of the substrate-binding pocket by interacting with two catalytic residues, the crucial S1/S2 subsites and the oxyanion loop, acting as a "shield" in front of the catalytic dyad to effectively prevent substrate access to the catalytic dyad within the active site. Overall, this study provides an example for exploring the in vitro potency of Chinese traditional patent medicines and effectively identifying bioactive ingredients toward a specific target, and gains evidence supporting the in vivo studies of Shuanghuanglian oral liquid as well as two natural products for COVID-19 treatment.
Capturing CO2 and subsequently converting into valuable chemicals has attracted extensive attention. Herein, a series of biomass‐based N‐rich porous carbon materials with high specific surface area ...and pore volume were prepared using biomass waste soybean dregs as precursors. The nitrogen content was up to 4 % with different forms in the carbon skeleton such as pyridine‐N, pyrrole‐N. The synergistic effect of ultra‐micropore (pore size <0.7 nm) and N‐containing groups endowed the materials with a high CO2 adsorption capacity, reaching 6.3 and 3.6 mmol g−1 at 0 and 25 °C under atmospheric pressure, respectively. In addition, the sufficient interaction between N‐containing groups and CO2 was demonstrated by solid‐state nuclear magnetic resonance spectroscopy, and the captured CO2 was possibly activated in the form of carbamate, which is conducive to subsequent conversion. Therefore, the supported catalyst with the as‐synthetic porous carbon material as the carrier and ZnII as catalytic sites was prepared and successfully applied for carboxylative cyclization of propargylic amine with CO2 to afford the 3‐benzyl‐5‐methyleneoxazolidin‐2‐one. The results showed that CO2 capture and in‐situ conversion work effectively to produce highly value‐added chemicals. In this process, the captured CO2 could be activated and fixed into chemicals in mild conditions. More importantly, the energy consumption in CO2 desorption and adsorbent regeneration could be avoided. The valorization of both solid waste and CO2 to valuable chemicals provides an elegant strategy of killing three birds with one stone.
Capture and convert: Biomass‐based N‐rich porous carbon materials and their supported zinc catalysts are successfully applied to carboxylative cyclization of propargylic amine with CO2 under mild conditions, efficiently combining CO2 capture and in‐situ conversion. This protocol can pave an alternative avenue to integrate CO2 valorization with biomass waste treatment to produce valuable chemicals.
Abstract
The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) urgently needs an effective cure. 3CL protease (3CL
pro
) ...is a highly conserved cysteine proteinase that is indispensable for coronavirus replication, providing an attractive target for developing broad-spectrum antiviral drugs. Here we describe the discovery of myricetin, a flavonoid found in many food sources, as a non-peptidomimetic and covalent inhibitor of the SARS-CoV-2 3CL
pro
. Crystal structures of the protease bound with myricetin and its derivatives unexpectedly revealed that the pyrogallol group worked as an electrophile to covalently modify the catalytic cysteine. Kinetic and selectivity characterization together with theoretical calculations comprehensively illustrated the covalent binding mechanism of myricetin with the protease and demonstrated that the pyrogallol can serve as an electrophile warhead. Structure-based optimization of myricetin led to the discovery of derivatives with good antiviral activity and the potential of oral administration. These results provide detailed mechanistic insights into the covalent mode of action by pyrogallol-containing natural products and a template for design of non-peptidomimetic covalent inhibitors against 3CL
pro
s, highlighting the potential of pyrogallol as an alternative warhead in design of targeted covalent ligands.
Yang and Lee investigated phase transitions in terms of zeros of partition functions, namely, Yang-Lee zeros Phys. Rev. 87, 404 (1952)PHRVAO0031-899X10.1103/PhysRev.87.404; Phys. Rev. 87, 410 ...(1952)PHRVAO0031-899X10.1103/PhysRev.87.410. We show that the essential singularity in the superconducting gap is directly related to the number of roots of the partition function of a BCS superconductor. Those zeros are found to be distributed on a semicircle in the complex plane of the interaction strength due to the Fermi-surface instability. A renormalization-group analysis shows that the semicircle theorem holds for a generic quantum many-body system with a marginal coupling, in sharp contrast with the Lee-Yang circle theorem for the Ising spin system. This indicates that the geometry of Yang-Lee zeros is directly connected to the Fermi-surface instability. Furthermore, we unveil the nonunitary criticality in BCS superconductivity that emerges at each individual Yang-Lee zero due to exceptional points and presents a universality class distinct from that of the conventional Yang-Lee edge singularity.
SARS-CoV-2 variants of concern (VOC) B.1.1.7 (alpha) and B.1.351 (beta) show increased transmissibility and enhanced antibody neutralization resistance. Here we demonstrate in K18-hACE2 transgenic ...mice that B.1.1.7 and B.1.351 are 100-fold more lethal than the original SARS-CoV-2 bearing 614D. B.1.1.7 and B.1.351 cause more severe organ lesions in K18-hACE2 mice than early SARS-CoV-2 strains bearing 614D or 614G, with B.1.1.7 and B.1.351 infection resulting in distinct tissue-specific cytokine signatures, significant D-dimer depositions in vital organs and less pulmonary hypoxia signaling before death. However, K18-hACE2 mice with prior infection of early SARS-CoV-2 strains or intramuscular immunization of viral spike or receptor binding domain are resistant to the lethal reinfection of B.1.1.7 or B.1.351, despite having reduced neutralization titers against these VOC than early strains. Our results thus distinguish pathogenic patterns in K18-hACE2 mice caused by B.1.1.7 and B.1.351 infection from those induced by early SARS-CoV-2 strains, and help inform potential medical interventions for combating COVID-19.
Abstract
Electrical manipulation of spins is essential to design state-of-the-art spintronic devices and commonly relies on the spin current injected from a second heavy-metal material. The fact that ...chiral antiferromagnets produce spin current inspires us to explore the magnetization switching of chiral spins using self-generated spin torque. Here, we demonstrate the electric switching of noncollinear antiferromagnetic state in Mn
3
Sn by observing a crossover from conventional spin-orbit torque to the self-generated spin torque when increasing the MgO thickness in Ta/MgO/Mn
3
Sn polycrystalline films. The spin current injection from the Ta layer can be controlled and even blocked by varying the MgO thickness, but the switching sustains even at a large MgO thickness. Furthermore, the switching polarity reverses when the MgO thickness exceeds around 3 nm, which cannot be explained by the spin-orbit torque scenario due to spin current injection from the Ta layer. Evident current-induced switching is also observed in MgO/Mn
3
Sn and Ti/Mn
3
Sn bilayers, where external injection of spin Hall current to Mn
3
Sn is negligible. The inter-grain spin-transfer torque induced by spin-polarized current explains the experimental observations. Our findings provide an alternative pathway for electrical manipulation of non-collinear antiferromagnetic state without resorting to the conventional bilayer structure.
Objective:
The present study was designed to identify potential diagnostic markers for acute myocardial infarction (AMI) and determine the significance of immune cell infiltration in this pathology.
...Methods:
Two publicly available gene expression profiles (GSE66360 and GSE48060 datasets) from human AMI and control samples were downloaded from the GEO database. Differentially expressed genes (DEGs) were screened between 80 AMI and 71 control samples. The LASSO regression model and support vector machine recursive feature elimination (SVM-RFE) analysis were performed to identify candidate biomarkers. The area under the receiver operating characteristic curve (AUC) value was obtained and used to evaluate discriminatory ability. The expression level and diagnostic value of the biomarkers in AMI were further validated in the GSE60993 dataset (17 AMI patients and 7 controls). The compositional patterns of the 22 types of immune cell fraction in AMI were estimated based on the merged cohorts using CIBERSORT.
Results:
A total of 27 genes were identified. The identified DEGs were mainly involved in carbohydrate binding, Kawasaki disease, atherosclerosis, and arteriosclerotic cardiovascular disease. Gene sets related to atherosclerosis signaling, primary immunodeficiency, IL-17, and TNF signaling pathways were differentially activated in AMI compared with the control. IL1R2, IRAK3, and THBD were identified as diagnostic markers of AMI (AUC = 0.877) and validated in the GSE60993 dataset (AUC = 0.941). Immune cell infiltration analysis revealed that IL1R2, IRAK3, and THBD were correlated with M2 macrophages, neutrophils, monocytes, CD4
+
resting memory T cells, activated natural killer (NK) cells, and gamma delta T cells.
Conclusion:
IL1R2, IRAK3, and THBD can be used as diagnostic markers of AMI, and can provide new insights for future studies on the occurrence and the molecular mechanisms of AMI.
Introduction： In the past several decades, declining incidences of nasopharyngeal carcinoma （NPC） have been observed in Chinese populations in Hong Kong, Taiwan, Los Angeles, and Singapore. A ...previous study indicated that the incidence of NPC in Sihui County, South China remained stable until 2002, but whether age, diagnosis period, and birth cohort affect the incidence of NPC remains unknown. Methods： Age-standardized rates （ASRs） of NPC incidence based on the world standard population were examined in both males and females in Sihui County from 1987 to 2011. Joinpoint regression analysis was conducted to quantify the changes in incidence trends. A Poisson regression age-period-cohort model was used to assess the effects of age, diagnosis period, and birth cohort on the risk of NPC. Results： The ASRs of NPC incidence during the study period were 30.29/100,000 for males and 13.09/100,000 for females. The incidence of NPC remained stable at a non-significant average annual percent change of 0.2% for males and -1.6% for females throughout the entire period, A significantly increased estimated annual percent change of 6.8% （95% confidence interval, 0.1%-14.0%） was observed from 2003 to 2009 for males. The relative risk of NPC increased with advancing age up to 50-59 and decreased at ages 〉60 years. The period effect curves on NPC were nearly fiat for males and females. The birth cohort effect curve for males showed an increase from the 1922 cohort to the 1957 cohort and a decrease thereafter. In females, there was an undulating increase in the relative risk from the 1922 cohort to the 1972 cohort. Conclusions： The incidence trends for NPC remained generally stable in Sihui from 1987 to 2011, with an increase from 2003 to 2009. The relative risks of NPC increased in younger females.
Spin-orbital interactions (SOI) in silicene results in the quantum-spin-Hall effect, while the Hubbard-induced Coulomb interaction in zigzag nanoribbons often generates a band gap with the ...anti-ferromagnetic (AF) spin orders on two edges. In this paper we systematically study these two joint contributions to the zigzag silicene-like nanoribbons (zSiNR). Some topological and magnetic phase transitions are investigated with different material parameters and external fields. We find when the ribbon width or the SOI value exceeds some critical value, the SOI may overcome the Coulomb interaction and the system transits from a band insulator to a topological insulator: the quantum-spin-Hall or the spin quantum-anomalous Hall state. We also find some magnetic phase transition exists in the Hubbard-dominated zSiNR systems when the exchange field or the electric field goes beyond some critical values. Lastly we observe a double topological/magnetic phase transition in a Hubbard-SOI-balanced zSiNR system before the magnetic and topological phases are destroyed by a strong electric field.
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