Cleavage of amyloid precursor protein (APP) by the intramembrane protease γ-secretase is linked to Alzheimer's disease (AD). We report an atomic structure of human γ-secretase in complex with a ...transmembrane (TM) APP fragment at 2.6-angstrom resolution. The TM helix of APP closely interacts with five surrounding TMs of PS1 (the catalytic subunit of γ-secretase). A hybrid β sheet, which is formed by a β strand from APP and two β strands from PS1, guides γ-secretase to the scissile peptide bond of APP between its TM and β strand. Residues at the interface between PS1 and APP are heavily targeted by recurring mutations from AD patients. This structure, together with that of γ-secretase bound to Notch, reveal contrasting features of substrate binding, which may be applied toward the design of substrate-specific inhibitors.
Abstract Viral infections pose significant public health challenges, exemplified by the global impact of COVID-19 caused by SARS-CoV-2. Understanding the intricate molecular mechanisms governing ...virus-host interactions is pivotal for effective intervention strategies. Despite the burgeoning multi-omics data on viral infections, a centralized database elucidating host responses to viruses remains lacking. In response, we have developed a comprehensive database named ‘MOI’ (available at http://www.fynn-guo.cn/ ), specifically designed to aggregate processed M ulti- O mics data related to viral I nfections. This meticulously curated database serves as a valuable resource for conducting detailed investigations into virus-host interactions. Leveraging high-throughput sequencing data and metadata from PubMed and Gene Expression Omnibus (GEO), MOI comprises over 3200 viral-infected samples, encompassing human and murine infections. Standardized processing pipelines ensure data integrity, including bulk RNA sequencing (RNA-seq), single-cell RNA-seq (scRNA-seq), Chromatin Immunoprecipitation sequencing (ChIP-seq), and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq). MOI offers user-friendly interfaces presenting comprehensive cell marker tables, gene expression data, and epigenetic landscape charts. Analytical tools for DNA sequence conversion, FPKM calculation, differential gene expression, and Gene Ontology (GO)/ Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment enhance data interpretation. Additionally, MOI provides 16 visualization plots for intuitive data exploration. In summary, MOI serves as a valuable repository for researchers investigating virus-host interactions. By centralizing and facilitating access to multi-omics data, MOI aims to advance our understanding of viral pathogenesis and expedite the development of therapeutic interventions.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic poses an unprecedented public health crisis. Evidence suggests that SARS-CoV-2 infection causes dysregulation of the immune ...system. However, the unique signature of early immune responses remains elusive. We characterized the transcriptome of rhesus macaques and mice infected with SARS-CoV-2. Alarmin S100A8 was robustly induced in SARS-CoV-2-infected animal models as well as in COVID-19 patients. Paquinimod, a specific inhibitor of S100A8/A9, could rescue the pneumonia with substantial reduction of viral loads in SARS-CoV-2-infected mice. Remarkably, Paquinimod treatment resulted in almost 100% survival in a lethal model of mouse coronavirus infection using the mouse hepatitis virus (MHV). A group of neutrophils that contributes to the uncontrolled pathological damage and onset of COVID-19 was dramatically induced by coronavirus infection. Paquinimod treatment could reduce these neutrophils and regain anti-viral responses, unveiling key roles of S100A8/A9 and aberrant neutrophils in the pathogenesis of COVID-19, highlighting new opportunities for therapeutic intervention.
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•S100A8 is dramatically upregulated in SARS-CoV-2-infected animal models and patients•A group of aberrant immature neutrophils is induced during SARS-CoV-2 infection•Immune disorder is mediated by the S100A8/A9-TLR4 pathway•S100A8/A9 inhibitor, Paquinimod, could prevent COVID-19-associated immune disorder
Guo et al. demonstrate that over-activation of S100A8/A9-TLR4 signaling results in immune imbalance and expansion of aberrant immature neutrophils during SARS-CoV-2 infection. Relevant therapeutic targets were validated in animal infection models.
Endogenous retroviruses (ERVs) derived from the long terminal repeat (LTR) family of transposons constitute a significant portion of the mammalian genome, with origins tracing back to ancient viral ...infections. Despite comprising approximately 8% of the human genome, the specific role of ERVs in the pathogenesis of COVID-19 remains unclear. In this study, we conducted a genome-wide identification of ERVs in human peripheral blood mononuclear cells (hPBMCs) and primary lung epithelial cells from monkeys and mice, both infected and uninfected with SARS-CoV-2. We identified 405, 283, and 206 significantly up-regulated transposable elements (TEs) in hPBMCs, monkeys, and mice, respectively. This included 254, 119, 68, and 28 ERVs found in hPBMCs from severe and mild COVID-19 patients, monkeys, and transgenic mice expressing the human ACE2 receptor (hACE2) and infected with SARS-CoV-2. Furthermore, analysis using the Genomic Regions Enrichment of Annotations Tool (GREAT) revealed certain parental genomic sequences of these up-regulated ERVs in COVID-19 patients may be involved in various biological processes, including histone modification and viral replication. Of particular interest, we identified 210 ERVs specifically up-regulated in the severe COVID-19 group. The genes associated with these differentially expressed ERVs were enriched in processes such as immune response activation and histone modification. HERV1_I-int: ERV1:LTR and LTR7Y: ERV1:LTR were highlighted as potential biomarkers for evaluating the severity of COVID-19. Additionally, validation of our findings using RT-qPCR in Bone Marrow-Derived Macrophages (BMDMs) from mice infected by HSV-1 and VSV provided further support to our results. This study offers insights into the expression patterns and potential roles of ERVs following viral infection, providing a valuable resource for future studies on ERVs and their interaction with SARS-CoV-2.
A label-free biosensor for Escherichia coli (E. coli) ORN 178 based on faradaic electrochemical impedance spectroscopy (EIS) was developed. α-Mannoside or β-galactoside was immobilized on a gold disk ...electrode using a self-assembled monolayer (SAM) via a spacer terminated in a thiol functionality. Impedance measurements (Nyquist plot) showed shifts due to the binding of E. coli ORN 178, which is specific for α-mannoside. No significant change in impedance was observed for E. coli ORN 208, which does not bind to α-mannoside. With increasing concentrations of E. coli ORN 178, electron-transfer resistance (R et) increases before the sensor is saturated. After the Nyquist plot of E. coli/mixed SAM/gold electrode was modeled, a linear relationship between normalized R et and the logarithmic value of E. coli concentrations was found in a range of bacterial concentration from 102 to 103 CFU/mL. The combination of robust carbohydrate ligands with EIS provides a label-free, sensitive, specific, user-friendly, robust, and portable biosensing system that could potentially be used in a point-of-care or continuous environmental monitoring setting.
Carbon coating of fine particles of Li4Ti5O12 synthesized under hydrothermal condition is carried out by amphiphilic carbonaceous material (ACM) in aqueous solution, followed by carbonization at ...800°C for 2h. The particles prepared are comprised of highly-crystalline spinel-type Li4Ti5O12 with the size in the range of 100–400nm without any agglomeration, of which surface is uniformly covered by a thin carbon layer. Their electrochemical performance as an anode in lithium-ion batteries is evaluated. The initial discharge capacity of carbon-coated Li4Ti5O12 at 20C rate is 137mAhg−1 and remains as high as 125mAhg−1 after 100 cycles (91% retention), exhibiting good rate and cyclic performance. Carbon coating by using ACM as carbon precursor gives the Li4Ti5O12 particles an enhanced performance as an anode in lithium-ion batteries, owing to the improvement in electrical conductivity, polarization and ability of dispersion. This non-organic coating process may present a new economic, facile, and green pathway for the preparation of carbon-coated Li4Ti5O12 as a high power anode material in lithium-ion batteries.
► Carbon-coated Li4Ti5Ol2 was prepared by using ACM as a carbon precursor. ► The obtained Li4Ti5Ol2 electrode presents high-rate capability and cyclic stability. ► This economic, facile, and green synthesis method enables the production on a large scale.
The CRISPR-Cas13 system is an RNA-guided RNA-targeting system and has been widely used in transcriptome engineering with potentially important clinical applications. However, it is still ...controversial whether Cas13 exhibits collateral activity in mammalian cells.
Here, we find that knocking down gene expression using RfxCas13d in the adult brain neurons caused death of mice, which may result from the collateral activity of RfxCas13d rather than the loss of target gene function or off-target effects. Mechanistically, we show that RfxCas13d exhibits collateral activity in mammalian cells, which is positively correlated with the abundance of target RNA. The collateral activity of RfxCas13d could cleave 28s rRNA into two fragments, leading to translation attenuation and activation of the ZAKα-JNK/p38-immediate early gene pathway.
These findings provide new mechanistic insights into the collateral activity of RfxCas13d in mammalian cells and warn that the biosafety of the CRISPR-Cas13 system needs further evaluation before application to clinical treatments.
This study gives the first-time evidence for China that the geographical heterogeneity of the acute effects of outdoor PM10 can be partially explained by differences in indoor exposure to PM10 of ...outdoor origin. We used data from the China Air Pollution and Health Effects Study (CAPES), which demonstrated a geographical heterogeneity of the acute effect of particulate air pollution (particulate matter with an aerodynamic diameter smaller than 10 μm, or PM10) on mortality in 16 Chinese cities. Given that a large fraction of the exposure to PM10 of outdoor origin occurs indoors, we made the hypothesis that this heterogeneity might be partially explained by inter-city differences in indoor exposure to PM10 of outdoor origin. In our analysis, we estimated PM10 exposure coefficients (the change in the estimated personal exposure to PM10 of outdoor origin per unit change in outdoor PM10 concentration) in these 16 Chinese cities and examined their correlation with PM10 mortality coefficients (the increase in mortality associated with a given increase in the concentrations of outdoor PM10). We showed that the PM10 mortality coefficients and the PM10 exposure coefficients were significantly correlated, with an R-squared (R2) value of 0.549 (95% confidence interval: 0.201, 0.771; p < 0.01) for the 16 cities. The correlation was robust with different values of the key input parameters, and close in value to estimations found in previous studies on similar subjects.
•We define PM10 exposure coefficient to examine how outdoor PM10 affects exposure.•Correlation between exposure and mortality coefficients in CAPES is explored.•A strong correlation is found indicating indoor exposure's influence on CAPES.•Sensitivity analysis shows good robustness of the results.•PM10 exposure coefficient can partially explain the city-to-city difference in CAPES.
The Xishan coal mine area in Beijing, China has a long history of mining. Many landslide hazards, in addition to collapses and ground fractures, have occurred in this area. This study used ...multi-temporal satellite images to extract this region’s deformation information, identify landslides and analyze the deformation evolution process of these landslides. Taking the Anzigou ditch as an example, we investigate the “Quarry–Landslide–Mudslide” disaster chain model. We found that the landslide evolution process is closely related to the geological conditions, and usually goes through four stages: initial deformation, slope front swelling and collapsing, rear part connecting and rupturing, and landslide creeping. The surface deformation can be identified and tracked by high-resolution optical images and InSAR monitoring. Under the combined effects of rainfall and topographic conditions, medium and large landslides may occur and trigger a “Quarry–Landslide–Mudflow” disaster chain. The identification and analysis of these landslide hazards and the disaster chain help with geological disaster prevention, and provide reference for early identification and research of similar disasters.
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