ER-phagy is a form of autophagy that is mediated by ER-phagy receptors and selectively degrades endoplasmic reticulum (ER). Coronaviruses have been shown to use the ER as a membrane source to ...establish their double-membrane vesicles (DMVs). However, whether viruses modulate ER-phagy to drive viral DMV formation and its underlying molecular mechanisms remains largely unknown. Here, we demonstrate that coronavirus subverts ER-phagy by hijacking the ER-phagy receptors FAM134B and ATL3 into p62 condensates, resulting in increased viral replication. Mechanistically, we show that viral protein ORF8 binds to and undergoes condensation with p62. FAM134B and ATL3 interact with homodimer of ORF8 and are aggregated into ORF8/p62 liquid droplets, leading to ER-phagy inhibition. ORF8/p62 condensates disrupt ER-phagy to facilitate viral DMV formation and activate ER stress. Together, our data highlight how coronavirus modulates ER-phagy to drive viral replication by hijacking ER-phagy receptors.
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•Coronavirus protein ORF8 undergoes condensation with p62•FAM134B and ATL3 are hijacked into ORF8/p62 condensates•ORF8/p62 condensates facilitate viral DMV production by inhibiting ER-phagy•ORF8 homodimerization is required for receptor binding and ER-phagy inhibition
Tan et al. describe an important mechanism by which SARS-CoV-2 protein ORF8 inhibits ER-phagy by hijacking the receptors FAM134B and ATL3 into p62 condensates, facilitating the production of viral replication organelle double-membrane vesicles.
Tartary buckwheat shows health benefits with its high antioxidant activity and abundant flavonoid content. However, glycosylated flavonoid accumulation patterns and their molecular basis remain ...unidentified in Tartary buckwheat. Here, our metabolomics analysis revealed that F3′H branching was the major flavonoid metabolic flux in Tartary buckwheat. Interestingly, metabolome results also showed that the most abundant flavonoids were mainly in the glycosylated form, including flavonoid glycosides and flavonoid diglycosides in Tartary buckwheat. However, the flavonoid glycosides glycosyltransferase (GGT) gene catalyzing the second glycosylation step of flavonoid diglycoside has not been discovered yet in Tartary buckwheat. Thus, we explored GGT genes in the transcriptome-metabolome correlation network and confirmed that FtUGT79A15 showed the rhamnosyltransferase activity to catalyze quercetin 3-O-glucoside to rutin invitro and inplanta. Overall, FtUGT79A15 was identified to involve in the flavonoid diglycoside biosynthesis pathway in Tartary buckwheat.
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•F3′H branching was the major metabolic flux in Tartary buckwheat.•Most abundant flavonoids were mainly in the glycosylated form in Tartary buckwheat.•Rutinoside was the most abundant diglycoside in Tartary buckwheat.•FtUGT79A15 showed the 1 → 6 rhamnosyltransferase activity invitro and inplanta.
Cl-rich Li-argyrodites are promising solid electrolytes (SEs) used in all-solid-state Li batteries (ASSLBs) owing to the fast ion transport. However, they are unstable in the air and their ...compatibility to metallic Li still needs to be strengthened. Here, we improve these properties through O doping with a relatively high concentration. The high O solid solution in the argyrodite lattice is verified. The optimized Li5.7PS4.5O0.2Cl1.3 SE possesses an enhanced room temperature ionic conductivity. In parallel, in the sample with a relatively high oxygen dose, a Cl-O coexistence interface layer is revealed at the Li|SE interface region, associated with the formation of LiCl and Li3OCl interphases. The highest amount of Li3OCl appears also in the interface of Li5.7PS4.5O0.2Cl1.3 SE. Along with a more stable PS4-xOx unit, a proper O doing concentration is beneficial to mitigate the decomposition rate of SEs and to improve the compatibility of SE against Li metal. Moreover, Li5.7PS4.5O0.2Cl1.3 gains significantly enhanced air stability in contrast to the O-free sample. Consequently, the ASSLBs using both pristine and air-exposed Li5.7PS4.5O0.2Cl1.3 SE demonstrate decent electrochemical performance. In sharp contrast, the ASSLBs using the O-free argyrodite SE after air exposure cannot work for even one cycle. A high amount of O incorporation in Cl-rich Li-argyrodite SEs is thus a facile and effective route for achieving good overall performance including a high ionic conductivity, Li|SE interface stability, Li dendrite suppression capability, and notably, air stability.
•The Cl-rich argyrodite lattice can accommodate high O dose.•A Cl-O coexistence interface layer associated with LiCl and Li3OCl interphases is revealed.•O doping improves the interface stability of Li/SE and Li dendrite suppression capability.•O doping dramatically enhances the moisture resistance of Cl-rich argyrodites.•O-doped SEs enable a decent battery performance even air-exposed in high humidity.
Although effective vaccines have been developed against coronavirus disease 2019 (COVID-19), the level of neutralizing antibodies (NAbs) induced after vaccination in the real world is still unknown. ...The aim of this work was to evaluate the level and persistence of NAbs induced by two inactivated COVID-19 vaccines in China.
Serum samples were collected from 1,335 people aged 18 years and over who were vaccinated with an inactivated COVID-19 vaccine at Peking University People's Hospital from January 19 to June 23, 2021, for the detection of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies.
The positive rate for NAbs against SARS-CoV-2 was 79-91% from the first month to the second month after the second vaccine dose. The gradual decline in positivity rate for NAb response was observed from 78% at 3 months post-vaccination to 0% at 12 months post-vaccination. When there was a 21-day interval between the two doses of vaccine, the NAb positivity rate was 0% 6 months after the second dose. NAb levels were significantly higher when the interval between two doses were 3-8 weeks than when it was 0-3 weeks (χ2 = 14.04,
< 0.001). There was a linear correlation between NAbs and IgG antibodies in 1,335 vaccinated patients. NAb levels decreased in 31 patients (81.6%) and increased in 7 patients (18.4%) over time in the series of 38 patients after the second vaccination. The NAb positivity rate was significantly higher in 18- to 40-year-old subjects than in 41- to 60-year-old subjects (
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The NAb positivity rate was the highest at the first and second month after the second dose of vaccine, and gradually decreased over time. With a 21-day interval between two doses of vaccine, neutralizing antibody levels persisted for only 6 months after the second dose of vaccine. Therefore, a third vaccine dose is recommended. Our results suggest that in cases in which NAbs cannot be detected, IgM/IgG antibodies can be detected instead. The level of NAbs produced after vaccination was affected by age but not by sex. Our results suggest that an interval of 21 to 56 days between shots is suitable for vaccination.
Summary
Resistance to BRAF inhibitors (BRAFi) is one of the major challenges for targeted therapies for BRAF‐mutant melanomas. However, little is known about the role of microRNAs in conferring BRAFi ...resistance. Herein, we demonstrate that miR‐200c expression is significantly reduced whereas miR‐200c target genes including Bmi1, Zeb2, Tubb3, ABCG5, and MDR1 are significantly increased in melanomas that acquired BRAFi resistance compared to pretreatment tumor biopsies. Similar changes were observed in BRAFi‐resistant melanoma cell lines. Overexpression of miR‐200c or knock‐down of Bmi1 in resistant melanoma cells restores their sensitivities to BRAFi, leading to deactivation of the PI3K/AKT and MAPK signaling cascades, and acquisition of epithelial–mesenchymal transition‐like phenotypes, including upregulation of E‐cadherin, downregulation of N‐cadherin, and ABCG5 and MDR1 expression. Conversely, knock‐down of miR‐200c or overexpression of Bmi1 in BRAFi‐sensitive melanoma cells activates the PI3K/AKT and MAPK pathways, upregulates N‐cadherin, ABCG5, and MDR1 expression, and downregulates E‐cadherin expression, leading to BRAFi resistance. Together, our data identify miR‐200c as a critical signaling node in BRAFi‐resistant melanomas impacting the MAPK and PI3K/AKT pathways, suggesting miR‐200c as a potential therapeutic target for overcoming acquired BRAFi resistance.
Retinal ganglion cells (RGCs) are the brain’s gateway to the visual world. They can be classified into different types on the basis of their electrophysiological, transcriptomic, or morphological ...characteristics. Here, we characterize the transcriptomic, morphological, and functional features of 472 high-quality RGCs using Patch sequencing (Patch-seq), providing functional and morphological annotation of many transcriptomic-defined cell types of a previously established RGC atlas. We show a convergence of different modalities in defining the RGC identity and reveal the degree of correspondence for well-characterized cell types across multimodal data. Moreover, we complement some RGC types with detailed morphological and functional properties. We also identify differentially expressed genes among ON, OFF, and ON-OFF RGCs such as Vat1l, Slitrk6, and Lmo7, providing candidate marker genes for functional studies. Our research suggests that the molecularly distinct clusters may also differ in their roles of encoding visual information.
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•Linking transcriptomes with morphological and functional phenotypes in mammalian retinal ganglion cells•Patch-seq data collected from 472 retinal ganglion cells with 144 morphologies•Functional and morphological features of transcriptomic types•Multimodal RGC atlas showing the convergence of different modalities
Huang et al. collect multimodal data from individual mouse retinal ganglion cells using the Patch-seq technique. Mapping these Patch-seq RGCs to existing transcriptomic cell types provides a link between transcriptomes and morphological and functional phenotypes in mammalian RGCs.
The absorption saturation under optically thick conditions will bring difficulties to laser spectroscopy gas sensing. We report the spectrum two wings reconstruction method and the transmitted laser ...intensity fitting method for tunable diode laser absorption saturation spectroscopy gas absolute measurements under optically thick conditions, and used the modified Lambert Beer's law to calculate methane concentration based on the incomplete spectrum of absorption saturation. The maximum deviation between the experimental measurement results and the standard methane concentration is about 4.7%, which verifies the feasibility of these new methods and also show that they have great potential for expanding the gas sensing range of a single absorption line.
Due to the potential harmful risks caused by the excessive X-ray radiation dose, low dose has emerged as one of the major rules of computed tomography (CT) for clinical applications. However, ...reducing radiation dose severely leads to degraded reconstructed CT image quality with noises and artifacts, and it may seriously hamper clinical diagnosis. Currently, model-driven deep learning (DL)-based dual-domain learning with expert knowledge can reconstruct CT images from projections acquired in nonideal conditions, and they have been demonstrated with inspired performance in low-dose CT (LDCT) reconstruction. However, because of domain-progressive strategy, these dual-domain methods are prone to produce seriously secondary artifacts and suffer from subtle structural degeneration. In this article, we propose a novel deep dual-domain united guiding learning framework, i.e., DUGL-Net. First, we put forward a domain-guiding strategy. The projection-domain network plays the guiding role on image-domain network to effectively enhance overall network stability and powerfully avoid secondary artifacts. Second, we elaborately design a global-local transformer-convolution U-Net, i.e., GL-TCUNet, as the base network in both projection domain and image domain for reinforcing dual-domain model learning. This efficiently leverages the advantages of Swin transformer and convolutional neural network (CNN) to suppress noises and artifacts. Finally, the proposed DUGL-Net is evaluated on the 2016 NIH-AAPM-Mayo clinic LDCT Grand Challenge dataset and real data, and our results validate that the proposed method outperforms the state-of-the-art (SOTA) competing methods. This efficient, accurate, and reliable LDCT denoising technique has great potential for clinical applications.
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