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The effective antiviral agents that treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are urgently needed around the world. The 3C-like protease (3CLpro) of SARS-CoV-2 plays a pivotal role in virus replication; it also has become an important therapeutic target for the infection of SARS-CoV-2. In this work, we have identified Darunavir derivatives that inhibit the 3CLpro through a high-throughput screening method based on a fluorescence resonance energy transfer (FRET) assay in vitro. We found that the compounds 29# and 50# containing polyphenol and caffeine derivatives as the P2 ligand, respectively, exhibited favorable anti-3CLpro potency with EC50 values of 6.3 μM and 3.5 μM and were shown to bind to SARS-CoV-2 3CLpro in vitro. Moreover, we analyzed the binding mode of the DRV in the 3CLpro through molecular docking. Importantly, 29# and 50# exhibited a similar activity against the protease in Omicron variants. The inhibitory effect of compounds 29# and 50# on the SARS-CoV-2 3CLpro warrants that they are worth being the template to design functionally improved inhibitors for the treatment of COVID-19. [ABSTRACT FROM AUTHOR]

ANO1, a calcium-activated chloride channel (CACC), is also known as transmembrane protein 16A (TMEM16A). It plays a vital role in the occurrence, development, metastasis, proliferation, and apoptosis of various malignant tumors. This article reviews the mechanism of ANO1 involved in the replication, proliferation, invasion and apoptosis of various malignant tumors. Various molecules and Stimuli control the expression of ANO1, and the regulatory mechanism of ANO1 is different in tumor cells. To explore the mechanism of ANO1 overexpression and activation of tumor cells by studying the different effects of ANO1. Current studies have shown that ANO1 expression is controlled by 11q13 gene amplification and may also exert cell-specific effects through its interconnected protein network, phosphorylation of different kinases, and signaling pathways. At the same time, ANO1 also resists tumor apoptosis and promotes tumor immune escape. ANO1 can be used as a promising biomarker for detecting certain malignant tumors. Further studies on the channels and the mechanism of protein activity of ANO1 are needed. Finally, the latest inhibitors of ANO1 are summarized, which provides the research direction for the tumor-promoting mechanism of ANO1. [ABSTRACT FROM AUTHOR]

Biochar has been widely applied for the remediation of petroleum-contaminated soil. However, the effect of biochar on the transport of petroleum degradation bacteria has not been studied. A typical Gram-positive petroleum degradation bacteria- Corynebacterium variabile HRJ4 was used to study the effect of different biochars on bacterial transport and retention. Results indicated that the addition of biochar in sand was effective for reducing the transport of bacteria and poplar sawdust biochar (PSBC) had a stronger hinder effect than corn straw biochar (CSBC). The hindrance was more evident with pyrolysis temperature of biochar raised from 300°C to 600°C, which was attributed to the increase of specific surface area (309 times). The hindrance effect also enhanced with higher application rate of biochar. Furthermore, the reduction of HRJ4 transport was more obvious in higher (25 mmol/L) concentration of NaCl solution owing to electrostatic attraction enhancement. The adsorption of biochar to HRJ4 was defined to contribute to the hindrance of HRJ4 transport mainly. Combining the influence of feedstocks and pyrolysis temperature on HRJ4 transport, it suggested that specific surface area had the greatest effect on HRJ4 transport, and pore-filling, electrostatic force also contributed to HRJ4 retained in quartz sand column. At last, phenol transportation experiment indicated that the restriction of biochar on HRJ4 enhanced the phenol removal rate in the column. This study provides a theoretical basis for the interaction of biochar and bacteria, which is vital for the remediation of oil-contaminated soil and groundwater in the field. Graphical Abstract Image, graphical abstract [ABSTRACT FROM AUTHOR]

This paper studies the returns to general labour market experience and firm-specific tenure, using data from China. Specifically, it focuses on explaining the gender wage difference from the perspective of general human capital and specific human capital. It applies the Heckman maximum likelihood estimator and Topel two-step estimation methodology to correct sample selection bias and individual heterogeneity. After correcting the errors, the authors find that returns to experience are higher for men than women, especially for married men and women. Furthermore, the return to tenure is higher than that to general experience. For men, the former is about 6% higher than the latter. But for women, tenure contributes 7–8% more to the wage growth than experience. The return of general experience mainly contributes to gender wage difference in China. Empirical results also show that the cross section analysis downward biases the returns to potential experience and a simple Topel-2S estimation in the panel study upward biases the returns. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is an incurable primary brain tumor that is highly resistant to current treatments. Glioma stem-like cells (GSCs) are an aggressive population of glioma cells that not only initiate malignant growth, but also promote therapeutic resistance. Thus, targeting GSCs is critical for improving GBM treatment and ensuring complete eradication of the tumor. Here, we show that NT5DC2 (5′-Nucleotidase Domain Containing 2), a functionally unknown protein, plays a crucial role in GSC tumor initiation via upregulating Fyn expression. NT5DC2 is preferentially expressed in GSCs relative to the non-stem tumor cells. Knockdown of NT5DC2 significantly inhibits the GSC tumorsphere formation and cell viability in vitro, and tumorigenesis in vivo, thus, prolonging animal survival. Moreover, disruption of NT5DC2 in GSCs markedly reduces the expression of Fyn, a Src family proto-oncogene that has been implicated in the regulation of GBM progression. Importantly, the expression of NT5DC2 strongly correlated with increased aggression of human gliomas, but not that of other brain tumors. Taken together, our results uncover the function of NT5DC2 in GSC maintenance and highlight NT5DC2 as a promising therapeutic target for GBM. • NT5DC2 is preferentially expressed in glioma stem-like cells. • NT5DC2 promotes glioma stem-like cells tumorigenesis. • NT5DC2 up-regulates Fyn expression in glioma stem-like cells. • NT5DC2 correlates with glioma malignant progression and patient survival. [ABSTRACT FROM AUTHOR]

Lung squamous cell carcinoma (LUSC) is the second major type of lung cancer globally. The majority of patients with LUSC are clinically diagnosed at the advanced stages, thus it is urgent to identify suitable prognostic markers for LUSC. B-cell lymphoma 2 (Bcl-2) has been widely studied in non-small cell lung cancer (NSCLC). However, the prognostic role of Bcl-2 in NSCLC remains conflicting and controversial, particularly for LUSC. Although certain studies have been performed to identify the prognostic value of Bcl-2, to the best of our knowledge, no study has investigated the prognostic role of Bcl-2 in LUSC specifically. The present study aimed to comprehensively evaluate the prognostic value of Bcl-2 in LUSC. Microarray data for LUSC were downloaded from public databases, including the Gene Expression Omnibus and The Cancer Genome Atlas. Microarray data of 901 patients with LUSC from 16 data sets were retrieved. The meta-z algorithm was applied and the combined z score was identified as -2.43, suggesting Bcl-2 is a favorable prognostic biomarker. Furthermore, immunohistochemical staining of Bcl-2 expression was performed in a tissue microarray of 72 patients with LUSC and survival analysis demonstrated that patients with high expression Bcl-2 exhibited significantly more improved overall survival rates compared with those with low Bcl-2 expression. Multivariate Cox regression revealed that high expression of Bcl-2 is an independent favorable prognostic factor (hazard ratio, 0.295; confidence interval, 0.097-0.904; P<0.05). Therefore, the results of the present study demonstrated that Bcl-2 is a favorable prognostic biomarker in LUSC. [ABSTRACT FROM AUTHOR]

Antibiotic resistance genes (ARGs) have caused widespread concern because of their potential harm to environmental safety and human health. As substitutes for conventional plastics, the toxic effects of short-term degradation products of biodegradable plastics (polylactic acid (PLA) and polyhydroxyalkanoates (PHA)) on bacteria and their impact on ARGs transfer were the focus of this study. After 60 days of degradation, more secondary nanoplastics were released from the biodegradable plastics PLA and PHA than that from the conventional plastics polystyrene (PS). All kinds of nanoplastics, no matter released from biodegradable plastics or conventional plastics, had no significant toxicity to bacteria. Nanoplastic particles from biodegradable plastics could significantly increase the transfer efficiency of ARGs. Although the amount of secondary nanoplastics produced by PHA microplastics was much higher than that of PLA, the transfer frequency after exposure to PLA was much higher, which may be due to the agglomeration of PHA nanoplastics caused by plastic instability in solution. After exposure to the 60 d PLA nanoplastics, the transfer frequency was the highest, which was approximately 28 times higher than that of control. The biodegradable nanoplastics significantly enhanced the expression of the outer membrane pore protein genes omp A and omp C, which could increase cell membrane permeability. The expression levels of trf Ap and trb Bp were increased by repressed major global regulatory genes kor A, kor B, and trb A, which eventually led to an increase in conjugative transfer frequency. This study provides important insights into the evaluation of the environmental and health risks caused by secondary nanoplastics released from biodegradable plastics. [Display omitted] • After 60 d degradation, secondary nanoplastics had no significant toxicity to bacteria. • Biodegradable nanoplastics could promote the transfer of ARGs between bacteria. • PS nanoplastics had no significant effect on the transfer of ARGs between bacteria. • The short-term biological effect of biodegradable plastics could not be neglected. [ABSTRACT FROM AUTHOR]

Highlights: [•] A novel apigenin-loaded mixed micelle was prepared and optimized. [•] The solubility of apigenin in the micelles was 148 times that of crude apigenin. [•] CMC of the mixed micelles was as low as 4.23×10−5 mol/L. [•] The cytotoxicity against HepG2 and MCF-7 cells shows enhanced inhibition rate. [ABSTRACT FROM AUTHOR]

Antiviral therapeutics is one effective avenue to control and end this devastating COVID-19 pandemic. The viral RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 has been recognized as a valuable target of antivirals. However, the cell-free SARS-CoV-2 RdRp biochemical assay requires the conversion of nucleotide prodrugs into the active triphosphate forms, which regularly occurs in cells yet is a complicated multiple-step chemical process in vitro , and thus hinders the utility of this cell-free assay in the rapid discovery of RdRp inhibitors. In addition, SARS-CoV-2 exoribonuclease provides the proof-reading capacity to viral RdRp, thus creates relatively high resistance threshold of viral RdRp to nucleotide analog inhibitors, which must be examined and evaluated in the development of this class of antivirals. Here, we report a cell-based assay to evaluate the efficacy of nucleotide analog compounds against SARS-CoV-2 RdRp and assess their tolerance to viral exoribonuclease-mediated proof-reading. By testing seven commonly used nucleotide analog viral polymerase inhibitors, Remdesivir, Molnupiravir, Ribavirin, Favipiravir, Penciclovir, Entecavir and Tenofovir, we found that both Molnupiravir and Remdesivir showed the strong inhibition of SARS-CoV-2 RdRp, with EC50 value of 0.22 μM and 0.67 μM, respectively. Moreover, our results suggested that exoribonuclease nsp14 increases resistance of SARS-CoV-2 RdRp to nucleotide analog inhibitors. We also determined that Remdesivir presented the highest resistance to viral exoribonuclease activity in cells. Therefore, we have developed a cell-based SARS-CoV-2 RdRp assay which can be deployed to discover SARS-CoV-2 RdRp inhibitors that are urgently needed to treat COVID-19 patients. • A cell-based assay was built to evaluate the inhibitors against SARS-CoV-2 RdRp and their tolerance to viral exoribonuclease. • This cell-based assay targeting SARS CoV-2 RdRp meets the criteria required for High-throughput screening (HTS) assays. • Molnupiravir and Remdesivir showed the strong inhibition of SARS-CoV-2 RdRp with EC50 of 0.22 μM and 0.67 μM, respectively. • The exonuclease activity of nsp14 boosts the RdRp resistance to NA inhibitors. [ABSTRACT FROM AUTHOR]

• C-1- S/Se and C-3- S/Se glycals was synthesized with Ferrier reaction. • Hf(OTf) 4 was used as catalyst for the preparation of C-1-S/Se and C-3-S/Se glycals. • A temperature-dependent profile of the yield of these two products is given. By using Hf(OTf) 4 as the catalyst, under certain conditions, reaction of tri- O -acetyl- d -glucal and ((2 R ,3 S)-3-acetoxy-2,3-dihydrofuran-2-yl)methyl acetate with alkyl(aryl) bisulfide/alkyl(aryl) biselenide as nucleophile precursor leads to temperature-dependent formation of C-1 -S/Se and C-3- S/Se product. A temperature-dependent profile of the yield of these two products is given. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • 2,3-Unsatureted seleno-glycosides was synthesized first time with Ferrier Reaction. • Hf(OTf) 4 was used as catalyst for the preparation of 2,3-unsatureted seleno-glycosides. • Promoted by Hf(OTf) 4 , (RSe) 2 could be used as nucleophile source under reductive condition. Abstract By using Hf(OTf) 4 as the catalyst, a series of 2,3-unsaturated- Se -glucosides have been synthesized for the first time from tri- O -acetyl- d -glucal, 2,4,6-tri- O -benzyl- d -glucal, 3,4-di- O -acetyl- l -rhamnal and ((2 R ,3 S)-3-acetoxy-2,3-dihydrofuran-2-yl) methyl acetate with PhSeH or alkyl(aryl) hydroselenides as the nucleophile in good yield and high anomeric selectivity. [ABSTRACT FROM AUTHOR]

The rapid emergence of highly transmissible SARS-CoV-2 variants poses serious threat to the efficacy of vaccines and neutralizing antibodies. Thus, there is an urgent need to develop new and effective inhibitors against SARS-CoV-2 and future outbreaks. Here, we have identified a series of glycopeptide antibiotics teicoplanin derivatives that bind to the SARS-CoV-2 spike (S) protein, interrupt its interaction with ACE2 receptor and selectively inhibit viral entry mediated by S protein. Computation modeling predicts that these compounds interact with the residues in the receptor binding domain. More importantly, these teicoplanin derivatives inhibit the entry of both pseudotyped SARS-CoV-2 Delta and Omicron variants. Our study demonstrates the feasibility of developing small molecule entry inhibitors by targeting the interaction of viral S protein and ACE2. Together, considering the proven safety and pharmacokinetics of teicoplanin as a glycopeptide antibiotic, the teicoplanin derivatives hold great promise of being repurposed as pan-SARS-CoV-2 inhibitors. [Display omitted] • Teicoplanin derivatives inhibit binding of SARS-CoV-2 RBD to ACE2 in vitro. • Teicoplanin derivatives bind to RBD with high affinity. • Teicoplanin derivatives inhibit the entry of both pseudotyped SARS-CoV-2 Delta and Omicron variants. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen that caused the global COVID-19 outbreak. The 3C-like protease (3CLpro) of SARS-CoV-2 plays a key role in virus replication and has become an ideal target for antiviral drug design. In this work, we have employed bioluminescence resonance energy transfer (BRET) technology to establish a cell-based assay for screening inhibitors against SARS-CoV-2 3CLpro, and then applied the assay to screen a collection of known HIV/HCV protease inhibitors. Our results showed that the assay is capable of quantification of the cleavage efficiency of 3CLpro with good reproducibility (Z′ factor is 0.59). Using the assay, we found that 9 of 26 protease inhibitors effectively inhibited the activity of SARS-CoV-2 3CLpro in a dose-dependent manner. Among them, four compounds exhibited the ability to bind to 3CLpro in vitro. HCV protease inhibitor simeprevir showed the most potency against 3CLpro with an EC 50 vale of 2.6 μM, bound to the active site pocket of 3CLpro in a predicted model, and importantly, exhibited a similar activity against the protease containing the mutations P132H in Omicron variants. Taken together, this work demonstrates the feasibility of using the cell-based BRET assay for screening 3CLpro inhibitors and supports the potential of simeprevir for the development of 3CLpro inhibitors. [ABSTRACT FROM AUTHOR]