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Abstract Viral infection in respiratory tract usually leads to cell death, impairing respiratory function to cause severe disease. However, the diversity of clinical manifestations of SARS-CoV-2 infection increases the complexity and difficulty of viral infection prevention, and especially the high-frequency asymptomatic infection increases the risk of virus transmission. Studying how SARS-CoV-2 affects apoptotic pathway may help to understand the pathological process of its infection. Here, we uncovered SARS-CoV-2 imployed a distinct anti-apoptotic mechanism via its N protein. We found SARS-CoV-2 virus-like particles (trVLP) suppressed cell apoptosis, but the trVLP lacking N protein didn’t. Further study verified that N protein repressed cell apoptosis in cultured cells, human lung organoids and mice. Mechanistically, N protein specifically interacted with anti-apoptotic protein MCL-1, and recruited a deubiquitinating enzyme USP15 to remove the K63-linked ubiquitination of MCL-1, which stabilized this protein and promoted it to hijack Bak in mitochondria. Importantly, N protein promoted the replications of IAV, DENV and ZIKV, and exacerbated death of IAV-infected mice, all of which could be blocked by a MCL-1 specific inhibitor, S63845. Altogether, we identifed a distinct anti-apoptotic function of the N protein, through which it promoted viral replication. These may explain how SARS-CoV-2 effectively replicates in asymptomatic individuals without cuasing respiratory dysfunction, and indicate a risk of enhanced coinfection with other viruses. We anticipate that abrogating the N/MCL-1-dominated apoptosis repression is conducive to the treatments of SARS-CoV-2 infection as well as coinfections with other viruses.

“Cytokine storm” is common in critically ill COVID-19 patients, however, mechanisms remain largely unknown. Here, we reported that overexpression of SARS-CoV-2 N protein in diabetic db/db mice significantly increased tubular death and the release of HMGB1, one of the damage-associated molecular patterns (DAMPs), to trigger M1 proinflammatory macrophage activation and production of IL-6, TNF-α, and MCP-1 via a Mincle-Syk/NF-κB-dependent mechanism. This was further confirmed in vitro that overexpression of SARS-CoV-2 N protein caused the release of HMGB1 from injured tubular cells under high AGE conditions, which resulted in M1 macrophage activation and production of proinflammatory cytokines via a Mincle-Syk/NF-κB-dependent mechanism. This was further evidenced by specifically silencing macrophage Mincle to block HMGB1-induced M1 macrophage activation and production of IL-6, TNF-α, and MCP-1 in vitro. Importantly, we also uncovered that treatment with quercetin largely improved SARS-CoV-2 N protein-induced AKI in db/db mice. Mechanistically, we found that quercetin treatment significantly inhibited the release of a DAMP molecule HMGB1 and inactivated M1 pro-inflammatory macrophage while promoting reparative M2 macrophage responses by suppressing Mincle-Syk/NF-κB signaling in vivo and in vitro. In conclusion, SARS-CoV-2 N protein-induced AKI in db/db mice is associated with Mincle-dependent M1 macrophage activation. Inhibition of this pathway may be a mechanism through which quercetin inhibits COVID-19-associated AKI.

Abstract Actuator plays a significant role in soft robotics. This paper proposed an ultralong stretchable soft actuator (US2A) with a variable and sizeable maximum elongation. The US2A is composed of a silicone rubber tube and a bellows woven sleeve. The maximal extension can be conveniently regulated by just adjusting the wrinkles’ initial angle of the bellows woven sleeve. The kinematics of US2A could be obtained by geometrically analyzing the structure of the bellows woven sleeve when the silicone rubber tube is inflated. Based on the principle of virtual work, the actuating models have been established: the pressure-elongation model and the pressure-force model. These models reflect the influence of the silicone tube’s shell thickness and material properties on the pneumatic muscle’s performance, which facilitates the optimal design of US2A for various working conditions. The experimental results showed that the maximum elongation of the US2A prototype is 257%, and the effective elongation could be variably regulated in the range of 0 and 257%. The proposed models were also verified by pressure-elongation and pressure-force experiments, with an average error of 5% and 2.5%, respectively. Finally, based on the US2A, we designed a pneumatic rehabilitation glove, soft arm robot, and rigid-soft coupling continuous robot, which further verified the feasibility of US2A as a soft driving component.

NLRP3 inflammasome mainly controls interleukin-1β (IL-1β) secretion, leading to cell death called pyroptosis constituting a major antiviral host defense and inflammatory diseases upon viral infection. The RAF-MEK1/2-ERK1/2 cascade and downstream c-Jun/Fos and Activator protein-1 (AP1) signaling pathway control the degree of inflammatory response. Influenza A virus (IAV) infection is known to stimulate NLRP3 inflammasome activation and inflammatory responses. Nevertheless, the detailed mechanism by which IAV induces NLRP3 inflammasome activation involved in transcription of pro-IL-1β mRNA remains elusive. In our study, we found that IAV infection promotes pro-IL-1β mRNA transcription and activates NLRP3 inflammasome. Detailed studies reveal that type I interferon (IFN-α/IFN-β) as well as U0126 (a selective inhibitor of MEK-1 and MEK-2) typically inhibit IAV-mediated NLRP3 inflammasome activation via downregulating pro-IL-1β mRNA. Moreover, knock-down of c-Jun decreases pro-IL-1β mRNA and inhibits NLRP3 inflammasome activation upon IAV infection. Overall, the findings uncover that AP-1 signaling pathway promotes NLRP3 inflammasome activation upon IAV infection, which provides a new idea for the therapy of NLRP3 inflammasome-associated inflammatory diseases.

Industrial system operations usually have dynamic characteristics. If these characteristics are ignored, the performance of fault detection degrades. Herein, the fault-detection algorithm of dynamic global–local preserving projection (DGLPP) is employed to solve the problem mentioned. First, time-delay data are added to the sample to form an augmentation matrix and characterize the system dynamics. Second, the dimensionality of the augmented matrix is reduced using global–local preserving projection. The dimensionality-reduction method can preserve the data’s global and local structures. Then, a DGLPP model is built using the dimensionality-reduced data. Moreover, Hotelling’s T2 and squared prediction error (SPE) statistics are used for fault detection. Finally, this method is used to detect the fault in the Tennessee Eastman (TE) process. The experimental results show that the DGLPP method has an enhanced fault detection rate. Moreover, the fault-detection effects of the DGLPP method are better than those of the principal component analysis (PCA), local preserving projection (LPP), and global–local preserving projection (GLPP) methods.

Soft materials enable soft robots to accommodate unstructured working environments robustly. However, they may be easily damaged and destroyed due to their weak mechanical properties. Moreover, most soft materials are not repairable or degradable after being broken or abandoned, resulting in new environmental burdens. Here, a self-healable, recyclable, and degradable soft material (SRDSM) with a network structure formed with gelatin and polyvinyl alcohol (PVA) is reported. The SRDSM exhibits a fracture strength of 3–4 MPa and a stretchability of up to 300 %-400 % by controlling the composition ratio and drying time. Results show that the SRDSM can recover 90 % of its original mechanical strength after healing and 95 % after recycling. An SRDSM-based soft gripper is demonstrated that can be self-healed under thermal cycling after minor damage. It can be recycled and remanufactured to restore its original functionality after severe damage. Furthermore, the soft gripper can decomposes and degrades entirely after contact with water. This research provides an enabling material to develop environmental-friendly and recyclable soft robots, reducing their negative environmental impact.

Carbon neutrality is an important target in China’s efforts to combat the climate crisis. The implementation of carbon neutrality requires high crop yields in farmland ecosystems of arid regions. However, the responses of farmland ecosystems to environmental changes and their effects on the conversion and intensity of carbon sources/sinks within farmlands in arid regions remain unclear, which limits carbon sequestration. In this study, we used a set of eddy covariance systems to observe carbon and water fluxes in cotton and spring maize, two typical crops in arid regions of Northern Xinjiang in China. The carbon and water exchange and water use efficiency (WUE) of cotton and spring maize were evaluated over the entire growth cycle with respect to changes in the environment. Our results show that the carbon sequestration capacity of farmland ecosystems in arid regions is undeniable and is strongly influenced by the growth and development of plants. Spring maize, as a representative of C4 plants, exhibited a 58.4% higher carbon sequestration efficiency than cotton, a C3 plant, and they both reached their carbon sequestration efficiency peak in July. Throughout the growth period, temperature, net surface radiation, and saturated vapor pressure differences (VPD) significantly affected the carbon sequestration capacity and WUE of both crops. Optimal temperatures can maximize the carbon sequestration efficiency of cotton and spring maize; for cotton, they are 20–25 °C, and for spring maize, they are 22–27 °C, respectively. In addition, it is recommended that spring maize be harvested at the end of July when it meets the harvesting standards for silage feed and achieves the maximum carbon sequestration. Afterward, winter crops should be planted to maximize the yield and improve the carbon sequestration capacity of farmlands.

Precise regional crop yield estimates based on the high-spatiotemporal-resolution remote sensing data are essential for directing agronomic practices and policies to increase food security. This study used the enhanced spatial and temporal adaptive reflectance fusion model (ESTARFM), the flexible spatiotemporal data fusion (FSADF), and the spatial and temporal non-local filter based fusion model (STNLFFM) to calculate the normalized differential vegetation index (NDVI) of the summer maize planting area in the Southeast Loess Plateau based on the Sentinel-2 and MODIS data. The spatiotemporal resolution was 10 m and 1 d, respectively. Then, we evaluated the adaptability of the ESTARFM, FSADF, and STNLFFM fusion models in the field from the perspectives of spatial and textural characteristics of the data, summer maize NDVI growing curves, and yield estimation accuracy through qualitative visual discrimination and quantitative statistical analysis. The results showed that the fusion of ESTARFM–NDVI, FSDAF–NDVI, and STNLFFM–NDVI could precisely represent the variation tendency and local mutation information of NDVI during the growth period of summer maize, compared with MODIS–NDVI. The correlation between STNLFFM–NDVI and Sentinel-2–NDVI was favorable, with large correlation coefficients and a small root mean square error (RMSE). In the NDVI growing curve simulation of summer maize, STNLFFM introduced overall weights based on non-local mean filtering, which could significantly improve the poor fusion results at seedling and maturity stages caused by the long gap period of the high-resolution data in ESTARFM. Moreover, the accuracy of yield estimation was as follows (from high to low): STNLFFM (R = 0.742, mean absolute percentage error (MAPE) = 6.22%), ESTARFM (R = 0.703, MAPE = 6.80%), and FSDAF (R = 0.644, MAPE = 10.52%). The FADSF fusion model was affected by the spatial heterogeneity in the semi-humid areas, and the yield simulation accuracy was low. In the semi-arid areas, the FADSF fusion model had the advantages of less input data and a faster response.

Toll-like receptors (TLRs) are essential for the protection of the host from pathogen infections by initiating the integration of contextual cues to regulate inflammation and immunity. However, without tightly controlled immune responses, the host will be subjected to detrimental outcomes. Therefore, it is important to balance the positive and negative regulations of TLRs to eliminate pathogen infection, yet avert harmful immunological consequences. This study revealed a distinct mechanism underlying the regulation of the TLR network. The expression of sex-determining region Y-box 4 (Sox4) is induced by virus infection in viral infected patients and cultured cells, which subsequently represses the TLR signaling network to facilitate viral replication at multiple levels by a distinct mechanism. Briefly, Sox4 inhibits the production of myeloid differentiation primary response gene 88 (MyD88) and most of the TLRs by binding to their promoters to attenuate gene transcription. In addition, Sox4 blocks the activities of the TLR/MyD88/IRAK4/TAK1 and TLR/TRIF/TRAF3/TBK1 pathways by repressing their key components. Moreover, Sox4 represses the activation of the nuclear factor kappa-B (NF-κB) through interacting with IKKα/α, and attenuates NF-kB and IFN regulatory factors 3/7 (IRF3/7) abundances by promoting protein degradation. All these contributed to the down-regulation of interferons (IFNs) and IFN-stimulated gene (ISG) expression, leading to facilitate the viral replications. Therefore, we reveal a distinct mechanism by which viral pathogens evade host innate immunity and discover a key regulator in host defense.

Zika virus (ZIKV) infection can cause severe neurological disorders, including Guillain–Barre syndrome and meningoencephalitis in adults and microcephaly in fetuses. Here, we reveal that laminin receptor 1 (LAMR1) is a novel host resistance factor against ZIKV infection. Mechanistically, we found that LAMR1 binds to ZIKV envelope (E) protein via its intracellular region and attenuates E protein ubiquitination through recruiting the deubiquitinase eukaryotic translation initiation factor 3 subunit 5 (EIF3S5). We further found that the conserved G282 residue of E protein is essential for its interaction with LAMR1. Moreover, a G282A substitution abolished the binding of E protein to LAMR1 and inhibited LAMR1-mediated E protein deubiquitination. Together, our results indicated that LAMR1 represses ZIKV infection through binding to E protein and attenuating its ubiquitination.

Land–atmosphere interactions are influenced by the earth’s complex underlying subsurface, which in turn indirectly affects atmospheric motion and climate change. Human activities are increasingly exerting an influence on desert ecosystems, and artificial green land with clear functional orientation has been established in many desert areas. Consequently, the previously dominant, shifting, sand-covered, underlying surface in these desert regions is gradually transforming. This transformation has significant implications for the characteristics of land–atmosphere interactions, causing them to deviate from their original state. At present, existing studies still have not presented a systematic understanding of this change and have ignored the impact of human activities on land–atmosphere interactions in artificial green land. To address these research gaps, this study specifically targets artificial green land in the Tazhong region of Taklamakan Desert. We carried out observation experiments on land–atmosphere interactions in three different functional units from outside to inside: natural shifting sands, the shelter forest, and the living area. We also analyzed the differences and attribution of land–atmosphere interactions characteristics of different functional units. Compared with the natural shifting sands, the daily average maximum values of wind speed in the shelter forest decreased by 78%, and the daily average maximum air temperature and soil (0 cm) temperature decreased by 2.6 °C and 7 °C, respectively. Additionally, the soil moisture level was significantly increased throughout the green land due to the shelter forest. The surface albedo experienced a decrease, with an annual average of 0.21. Furthermore, the aerodynamic roughness and bulk transport coefficient increased by two orders of magnitude. The daily average maximum values of sensible heat flux and soil heat flux (G05) decreased by 18.7% and 75%, respectively, and the daily average maximum value of latent heat flux increased by 70.3%. This effectively improved the microclimate environment of the green land. The living area was greatly reduced by the shelter forest coverage and influenced by the buildings. Consequently, the environmental improvement was not as large as it was inside the shelter forest. However, it still provided a good shelter for production and living in the desert area. Throughout the year, a total of 4.60 × 105 t water was consumed through evapotranspiration in the artificial green land. The findings of this study have the potential to enhance our comprehension of land–atmosphere interactions in desert regions, thereby offering valuable insights for the establishment and effective management of artificial desert green lands.

Abstract Cytokine storm induced by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a major pathological feature of Coronavirus Disease 2019 (COVID-19) and a crucial determinant in COVID-19 prognosis. Understanding the mechanism underlying the SARS-CoV-2-induced cytokine storm is critical for COVID-19 control. Here, we identify that SARS-CoV-2 ORF3a and host hypoxia-inducible factor-1α (HIF-1α) play key roles in the virus infection and pro-inflammatory responses. RNA sequencing shows that HIF-1α signaling, immune response, and metabolism pathways are dysregulated in COVID-19 patients. Clinical analyses indicate that HIF-1α production, inflammatory responses, and high mortalities occurr in elderly patients. HIF-1α and pro-inflammatory cytokines are elicited in patients and infected cells. Interestingly, SARS-CoV-2 ORF3a induces mitochondrial damage and Mito-ROS production to promote HIF-1α expression, which subsequently facilitates SARS-CoV-2 infection and cytokines production. Notably, HIF-1α also broadly promotes the infection of other viruses. Collectively, during SARS-CoV-2 infection, ORF3a induces HIF-1α, which in turn aggravates viral infection and inflammatory responses. Therefore, HIF-1α plays an important role in promoting SARS-CoV-2 infection and inducing pro-inflammatory responses to COVID-19.

SARS-CoV-2 infection has been shown to drive NLRP3 inflammasome activation and thereby cytokine storm, but how it does so is unclear. Here the authors show that the viral N protein can bind to NLRP3, resulting in enhanced interaction with ASC and thereby with the NLRP3 inflammasome.

The exchange of energy between the land surface and atmosphere is dependent upon crucial parameters, including surface roughness, emissivity, bulk transfer coefficients for momentum (CD) and heat (CH). These parameters are calculated through site observation data and remote sensing data. The following conclusions are drawn: (1) the aerodynamic roughness of the Gurbantunggut Desert measures 1.1 × 10−2 m, which is influenced by the varying conditions of the underlying surface. The roughness decreases as wind speed increases and is seen to be directly proportional to the growth of vegetation. From April to June, the aerodynamic roughness increases with increasing vegetation cover, but begins to gradually decrease after July. Spatially, the middle regions show higher roughness values than the eastern and western areas. In the central part of the desert, the roughness is between 2.37 × 10−2 m and 2.46 × 10−2 m from April to November. The northwest and northeast regions measure 1.41 × 10−2 m–2.04 × 10−2 m and 1.53 × 10−2 m–2.39 × 10−2 m, respectively. (2) The surface emissivity is 0.93, and it varies depending on the snow and vegetation present in the underlying area. (3) CD and CH exhibit an inverse relationship with wind speed. When wind speed falls below 6 m/s, the CD declines rapidly as wind speed increases. In contrast, once wind speed surpasses 6 m/s, the propensity for the CD to decrease with increasing wind speed slows down and approaches stability.

In current forestry investigation studies, the research hotspots have tended to concentrate on ascertaining the precision of certain tree parameters. This has resulted in an augmented intricacy of the technique in terms of algorithms and observation instruments. The complexity of the technology and the cost of the equipment make it impossible to use for large-scale forest surveys, for example, a national forest inventory (NFI). The aim of our study was to design a new type of low-cost measuring method that could be utilized in a NFI and in developing countries. Meanwhile, the newly designed method was expected to be able to output certain forest measurement factors without necessitating data processing by NFI field investigators. Based on these objectives, we developed a measuring method that included hardware comprised of two tools. The first tool was an electronic measuring tape that contained a microcontroller unit (MCU) and could automatically record and collaborate with other equipment via wireless protocols. The second tool was a tree stem position mapper that utilized our own designed mechanisms. The results showed that the tree DBH measurements exhibited a 0.05 cm (0.20%) bias and a 0.36 cm (1.45%) root mean square error (RMSE), and the biases on the x-axis and the y-axis of the tree position estimations were −15.92–9.92 cm and −25.90–10.88 cm, respectively, accompanied by corresponding RMSEs of 15.27–29.40 cm and 14.49–34.68 cm. Moreover, an efficiency test determined that the average measurement time per tree was 20.34 s, thus, demonstrating a marked improvement in speed by nearly one-fold compared to the conventional method. Meanwhile, this measurement kit costs less than 150 Euros and is economically suitable for large-scale applications. We posit that our method has the potential to serve as a standard tool in a Chinese NFI and in developing countries in the future.

Continuous monitoring of evapotranspiration (ET) at high spatio-temporal resolutions is vital for managing agricultural water resources in arid and semi-arid regions. This study used the enhanced spatial and temporal adaptive reflectance fusion model (ESTARFM) to calculate the ET of winter wheat between the green-up and milk stages in Linfen Basin, a typical, semi-arid area of the Loess Plateau, at temporal and spatial resolutions of 30 m and 8 d, respectively. We then analyzed the impact of meteorological factors on ET and its variation during the main growth period of winter wheat. The fused ET data displayed the spatial details of the OLI ET data better and could accurately reflect ET variation and local sudden variations during the main growth period of winter wheat. Moreover, winter wheat ET in rain-fed areas is more heavily influenced by meteorological factors, and the effect is more direct. Affected by the synergistic effect of wind velocity, precipitation, and temperature, the ET of winter wheat in rain-fed area was lower in the green-up stage. Then, ET gradually increased, reaching its maximum in the heading–grain filling stage. At the jointing stage, temperature had a significant effect on ET. A combination of precipitation and temperature had the greatest impact on the ET of winter wheat in the heading–filling stage. In the milk stage, meteorological factors had a minor impact on ET. This study serves as a reference for ET in winter wheat in semi-arid areas and its influencing meteorological factors, which can assist in drought mitigation and regional food security strategies.

Assessing and predicting forest fires has long been an arduous task. Nowadays, the rapid advancement of artificial intelligence and machine learning technologies have provided a novel solution to forest fire occurrence assessment and prediction. In this research, we developed a novel hybrid machine-learning-technique algorithm to improve forest fire prediction based on random forest (RF), gradient-boosting decision tree (GBDT), support vector machine (SVM), and other machine learning models. The dataset we employed was satellite fire point data from 2010 to 2018 from the Chinese Department of Fire Prevention. The efficacy and performance of our methods were examined by validating the model fit and predictive capability. The results showed that the ensemble model LR (logistic regression)-RF-SVM-GBDT outperformed the single RFSVMGBDT model and the LR-RF-GBDT integrated framework, displaying higher accuracy and greater robustness. We believe that our newly developed hybrid machine-learning algorithm has the potential to improve the accuracy of predicting forest fire occurrences, thus enabling more efficient firefighting efforts and saving time and resources.

Enterovirus 71 (EV71) infection causes hand, foot, and mouth disease (HFMD), and even fatal neurological complications. However, the mechanisms underlying EV71 neurological pathogeneses are largely unknown. This study reveals a distinct mechanism by which EV71 induces apoptosis and autophagy in neural cells. EV71 non-structure protein 3D (also known as RNA-dependent RNA polymerase, RdRp) interacts with the peroxisomal protein acyl-CoA oxidase 1 (ACOX1), and contributes to ACOX1 downregulation. Further studies demonstrate that EV71 reduces peroxisome numbers. Additionally, knockdown of ACOX1 or peroxin 19 (PEX19) induces apoptosis and autophagy in neural cells including human neuroblastoma (SK-N-SH) cells and human astrocytoma (U251) cells, and EV71 infection induces neural cell death through attenuating ACOX1 production. Moreover, EV71 infection and ACOX1 knockdown facilitate reactive oxygen species (ROS) production and attenuate the cytoprotective protein deglycase (DJ-1)/Nuclear factor erythroid 2-related factor 2 (NRF2)/Heme oxygenase 1 (HO-1) pathway (DJ-1/NRF2/HO-1), which collectively result in ROS accumulation in neural cells. In conclusion, EV71 downregulates ACOX1 protein expression, reduces peroxisome numbers, enhances ROS generation, and attenuates the DJ-1/NRF2/HO-1 pathway, thereby inducing apoptosis and autophagy in neural cells. These findings provide new insights into the mechanism underlying EV71-induced neural pathogenesis, and suggest potential treatments for EV71-associated diseases.

Abstract Background Extracellular adenosine triphosphate (ATP), a key danger-associated molecular pattern (DAMP) molecule, is released to the extracellular medium during inflammation by injured parenchymal cells, dying leukocytes, and activated platelets. ATP directly activates the plasma membrane channel P2X7 receptor (P2X7R), leading to an intracellular influx of K+, a key trigger inducing NLRP3 inflammasome activation. However, the mechanism underlying P2X7R-mediated activation of NLRP3 inflammasome is poorly understood, and additional molecular mediators have not been identified. Here, we demonstrate that Paxillin is the molecule connecting the P2X7 receptor and NLRP3 inflammasome through protein interactions. Results We show a distinct mechanism by which Paxillin promotes ATP-induced activation of the P2X7 receptor and NLRP3 inflammasome. Extracellular ATP induces Paxillin phosphorylation and then facilitates Paxillin-NLRP3 interaction. Interestingly, Paxillin enhances NLRP3 deubiquitination and activates NLRP3 inflammasome upon ATP treatment and K+ efflux. Moreover, we demonstrated that USP13 is a key enzyme for Paxillin-mediated NLRP3 deubiquitination upon ATP treatment. Notably, extracellular ATP promotes Paxillin and NLRP3 migration from the cytosol to the plasma membrane and facilitates P2X7R-Paxillin interaction and PaxillinNLRP3 association, resulting in the formation of the P2X7R-Paxillin-NLRP3 complex. Functionally, Paxillin is essential for ATP-induced NLRP3 inflammasome activation in mouse BMDMs and BMDCs as well as in human PBMCs and THP-1-differentiated macrophages. Conclusions We have identified paxillin as a mediator of NLRP3 inflammasome activation. Paxillin plays key roles in ATP-induced activation of the P2X7 receptor and NLRP3 inflammasome by facilitating the formation of the P2X7R-Paxillin-NLRP3 complex.

Abstract Mukonal is an active member of carbazole alkaloids isolated from Murraya koenigii. It has been shown to possess remarkable biological and pharmacological activities including anticancer activity. Therefore, the aim of current investigation was to explore anti-breast cancer activity of mukonal and to explore the underlying mechanism. Results indicate that mukonal has potential to induce antiproliferative effects against MDA-MB-231 and SK-BR-3 cells with an IC50 of 7.5 µM. No significant toxicity of mukonal was observed in case of normal breast cells. The antiproliferative effects of mukonal were found to proceed via apoptosis, which was further supported by increased cleavage of PARP and caspase-3 and reduced expression of Bcl-2. Mukonal induced autophagic cells death in breast cancer cells as was evidenced by formation of autophagosomes and enhanced expressions of Beclin-1, LC3B-I and LC3B-II proteins. In vivo examination of anti-breast cancer property of mukonal indicated that it could potentially reduce tumor weight and volume in xenografted mice models. In conclusion, mukonal has a remarkable potential of inhibiting breast cancer via induction of apoptosis and autophagy. Mukonal also inhibited xenografted tumors models in a dose-dependent manner. Therefore, mukonal may prove lead molecule in breast cancer drug discovery and treatment provided further investigations are recommended.

Abstract COVID‐19 is infected by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and can cause severe multiple organ injury and death. Kidney is one of major target organs of COVID‐19 and acute kidney injury (AKI) is common in critically ill COVID‐19 patients. However, mechanisms through which COVID‐19 causes AKI remain largely unknown and treatment remains unspecific and ineffective. Here, the authors report that normal kidney‐specifically overexpressing SARS‐CoV‐2 N develops AKI, which worsens in mice under ischemic condition. Mechanistically, it is uncovered that SARS‐CoV‐2 N‐induced AKI is Smad3‐dependent as SARS‐CoV‐2 N protein can interact with Smad3 and enhance TGF‐β/Smad3 signaling to cause tubular epithelial cell death and AKI via the G1 cell cycle arrest mechanism. This is further confirmed in Smad3 knockout mice and cells in which deletion of Smad3 protects against SARS‐CoV‐2 N protein‐induced cell death and AKI in vivo and in vitro. Most significantly, it is also found that targeting Smad3 with a Smad3 pharmacological inhibitor is able to inhibit SARS‐CoV‐2 N‐induced AKI. In conclusion, the authors identify that SARS‐CoV‐2 N protein is a key mediator for AKI and induces AKI via the Smad3‐dependent G1 cell cycle arrest mechanism. Targeting Smad3 may represent as a novel therapy for COVID‐19‐asscoaited AKI.

Huanglongbing (HLB) has turned into a devastating botanical pandemic of citrus crops, caused by Candidatus Liberibacter asiaticus (CLas). However, until now the disease has remained incurable with very limited control strategies available. Restoration of the affected microbiomes in the diseased host through the introduction of an indigenous endophyte Bacillus subtilis L1-21 isolated from healthy citrus may provide an innovative approach for disease management. A novel half-leaf method was developed in vitro to test the efficacy of the endophyte L1-21 against CLas. Application of B. subtilis L1-21 at 104 colony forming unit (cfu ml−1) resulted in a 1,000-fold reduction in the CLas copies per gram of leaf midrib (107 to 104) in 4 days. In HLB-affected citrus orchards over a period of 2 years, the CLas incidence was reduced to < 3%, and CLas copies declined from 109 to 104 g−1 of diseased leaf midribs in the endophyte L1-21 treated trees. Reduction in disease incidence may corroborate a direct or an indirect biocontrol effect of the endophytes as red fluorescent protein-labeled B. subtilis L1-21 colonized and shared niche (phloem) with CLas. This is the first large-scale study for establishing a sustainable HLB control strategy through citrus endophytic microbiome restructuring using an indigenous endophyte.

Understanding the vertical structures of cloud condensation nuclei (CCN) and ice-nucleating particle (INP) number concentrations in desert source regions is crucial for examining dust-cloud interactions and other related impacts. To explore the vertical profiles of the CCN and INP number concentrations and their possible atmospheric–dynamic influence factors at the center of the Taklimakan Desert, intensive observations were conducted by employing a ground-based polarization Raman lidar, sounding balloons, and a sun photometer in Tazhong (83.39° E, 38.58° N, 1103 m above sea level) during the summer of 2019. Based on the GRASP algorithm, the extinction-to-volume conversion factor of dust aerosols was 0.85 × 10−12 Mmm3 m−3, and the extinction-to-number conversion factor was predicted to be 0.20 Mm cm−3 on the basis of the sun photometer observations. Thus, the vertical CCN and INP number concentration profiles obtained with different parameterization schemes in the presence of various pollution levels were calculated by combining dust extinction coefficients retrieved by lidar and meteorological data observed by sounding balloon observations. The achieved results indicated that the CCN number concentration varied from 10−2 to 102 cm−3 and decreased from ground level to 12 km with an average value of 36.57 cm−3 at the 10–12 km height range, while the INP number concentration based on parameterization schemes D10 and D15 mainly varied from 10−1 to 102 L−1 and from 1 L−1 to 103 L−1, with average values of 3.50 L−1 and 7.80 L−1, respectively. Moreover, we observed a strong relationship between the INP number concentration of scheme D10 and the wind speed, with an R2 value of 0.72, but a weak relationship between the CCN number concentration and the relative humidity in the boundary layer, with a Spearman’s rank correlation coefficient R2 value of 0.38. The present study provides original and valuable information regarding the CCN and INP number concentrations and their related influencing factors at the center of the Taklimakan Desert and can improve our understanding of the vertical distributions of dust–cloud–atmosphere dynamic interactions, as well as of the roles of dust aerosols in the desert hydrological cycle.

Zika virus (ZIKV) is an RNA-enveloped virus that belongs to the Flavivirus genus, and ZIKV infections potentially induce severe neurodegenerative diseases and impair male fertility. Palmitoylation is an important post-translational modification of proteins that is mediated by a series of DHHC-palmitoyl transferases, which are implicated in various biological processes and viral infections. However, it remains to be investigated whether palmitoylation regulates ZIKV infections. In this study, we initially observed that the inhibition of palmitoylation by 2-bromopalmitate (2-BP) enhanced ZIKV infections, and determined that the envelope protein of ZIKV is palmitoylated at Cys308. ZDHHC11 was identified as the predominant enzyme that interacts with the ZIKV envelope protein and catalyzes its palmitoylation. Notably, ZDHHC11 suppressed ZIKV infections in an enzymatic activity-dependent manner and ZDHHC11 knockdown promoted ZIKV infection. In conclusion, we proposed that the envelope protein of ZIKV undergoes a novel post-translational modification and identified a distinct mechanism in which ZDHHC11 suppresses ZIKV infections via palmitoylation of the ZIKV envelope protein.

Dengue virus (DENV) is a mosquito-borne pathogen that causes a spectrum of diseases including life-threatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Vascular leakage is a common clinical crisis in DHF/DSS patients and highly associated with increased endothelial permeability. The presence of vascular leakage causes hypotension, circulatory failure, and disseminated intravascular coagulation as the disease progresses of DHF/DSS patients, which can lead to the death of patients. However, the mechanisms by which DENV infection caused the vascular leakage are not fully understood. This study reveals a distinct mechanism by which DENV induces endothelial permeability and vascular leakage in human endothelial cells and mice tissues. We initially show that DENV2 promotes the matrix metalloproteinase-9 (MMP-9) expression and secretion in DHF patients' sera, peripheral blood mononuclear cells (PBMCs), and macrophages. This study further reveals that DENV non-structural protein 1 (NS1) induces MMP-9 expression through activating the nuclear factor κB (NF-κB) signaling pathway. Additionally, NS1 facilitates the MMP-9 enzymatic activity, which alters the adhesion and tight junction and vascular leakage in human endothelial cells and mouse tissues. Moreover, NS1 recruits MMP-9 to interact with β-catenin and Zona occludens protein-1/2 (ZO-1 and ZO-2) and to degrade the important adhesion and tight junction proteins, thereby inducing endothelial hyperpermeability and vascular leakage in human endothelial cells and mouse tissues. Thus, we reveal that DENV NS1 and MMP-9 cooperatively induce vascular leakage by impairing endothelial cell adhesion and tight junction, and suggest that MMP-9 may serve as a potential target for the treatment of hypovolemia in DSS/DHF patients.

Summary: The immune system is not only required for preventing threats exerted by pathogens but also essential for developing immune tolerance to avoid tissue damage. This study identifies a distinct mechanism by which MYSM1 suppresses innate immunity and autoimmunity. The expression of MYSM1 is induced upon DNA virus infection and by intracellular DNA stimulation. MYSM1 subsequently interacts with STING and cleaves STING K63-linked ubiquitination to suppress cGAS-STING signaling. Notably, Mysm1-deficient mice exhibit a hyper-inflammatory response, acute tissue damage, and high mortality upon virus infection. Moreover, in the PBMCs of patients with systemic lupus erythematosus (SLE), MYSM1 production decreases, while type I interferons and pro-inflammatory cytokine expressions increase. Importantly, MYSM1 treatment represses the production of IFNs and pro-inflammatory cytokines in the PBMCs of SLE patients. Thus, MYSM1 is a critical repressor of innate immunity and autoimmunity and is thus a potential therapeutic agent for infectious, inflammatory, and autoimmune diseases.

One of the fundamental reactions of the innate immune responses to pathogen infection is the release of pro-inflammatory cytokines, including IL-1β, processed by the NLRP3 inflammasome. The stimulator of interferon genes (STING) has the essential roles in innate immune response against pathogen infections. Here we reveal a distinct mechanism by which STING regulates the NLRP3 inflammasome activation, IL-1β secretion, and inflammatory responses in human cell lines, mice primary cells, and mice. Interestingly, upon HSV-1 infection and cytosolic DNA stimulation, STING binds to NLRP3 and promotes the inflammasome activation through two approaches. First, STING recruits NLRP3 and facilitates NLRP3 localization in the endoplasmic reticulum, thereby facilitating the inflammasome formation. Second, STING interacts with NLRP3 and attenuates K48- and K63-linked polyubiquitination of NLRP3, thereby promoting the inflammasome activation. Collectively, we demonstrate that the cGAS-STING-NLRP3 signaling is essential for host defense against HSV-1 infection.

During host–virus co-evolution, cells develop innate immune systems to inhibit virus invasion, while viruses employ strategies to suppress immune responses and maintain infection. Here, we reveal that Zika virus (ZIKV), a re-emerging arbovirus causing public concerns and devastating complications, restricts host immune responses through a distinct mechanism. ZIKV nonstructural protein 5 (NS5) interacts with the host retinoic acid-inducible gene I (RIG-I), an essential signaling molecule for defending pathogen infections. NS5 subsequently represses K63-linked polyubiquitination of RIG-I, attenuates the phosphorylation and nuclear translocation of interferon regulatory factor 3 (IRF3), and inhibits the expression and production of interferon-β (IFN-β), thereby restricting the RIG-I signaling pathway. Interestingly, we demonstrate that the methyltransferase (MTase) domain of NS5 is required for the repression of RIG-I ubiquitination, IRF3 activation, and IFN-β production. Detailed studies further reveal that the conservative active site D146 of NS5 is critical for the suppression of the RIG-I signaling. Therefore, we uncover an essential role of NS5 conservative site D146 in ZIKV-mediated repression of innate immune system, illustrate a distinct mechanism by which ZIKV evades host immune responses, and discover a potential target for anti-viral infection.

The NLRP3 inflammasome plays an important role in antiviral host responses. Here, the authors reveal that the polymerase of Zika virus binds NLRP3 to facilitate inflammasome complex assembly and induce production of IL-1β in human macrophages, human PBMCs and mice, resulting in pathogenesis in mice.

Zika virus (ZIKV) is a mosquito-borne flavivirus, and its infection may cause severe neurodegenerative diseases. The outbreak of ZIKV in 2015 in South America has caused severe human congenital and neurologic disorders. Thus, it is vitally important to determine the inner mechanism of ZIKV infection. Here, our data suggested that the ubiquitin-specific peptidase 38 (USP38) played an important role in host resistance to ZIKV infection, during which ZIKV infection did not affect USP38 expression. Mechanistically, USP38 bound to the ZIKV envelope (E) protein through its C-terminal domain and attenuated its K48-linked and K63-linked polyubiquitination, thereby repressed the infection of ZIKV. In addition, we found that the deubiquitinase activity of USP38 was essential to inhibit ZIKV infection, and the mutant that lacked the deubiquitinase activity of USP38 lost the ability to inhibit infection. In conclusion, we found a novel host protein USP38 against ZIKV infection, and this may represent a potential therapeutic target for the treatment and prevention of ZIKV infection.

As a neurotropic virus, human Enterovirus 71 (EV71) infection causes hand-foot-and-mouth disease (HFMD) and may develop severe neurological disorders in infants. Toll-like receptor 7 (TLR7) acts as an innate immune receptor and is also a death receptor in the central nervous system (CNS). However, the mechanisms underlying the regulation of TLR7-mediated brain pathogenesis upon EV71 infection remain largely elusive. Here we reveal a novel mechanism by which EV71 infects astrocytes in the brain and induces neural pathogenesis via TLR7 and interleukin-6 (IL-6) in C57BL/6 mice and in human astroglioma U251 cells. Upon EV71 infection, wild-type (WT) mice displayed more significant body weight loss, higher clinical scores, and lower survival rates as compared with TLR7-/- mice. In the cerebral cortex of EV71-infected mice, neurofilament integrity was disrupted, and inflammatory cell infiltration and neurodegeneration were induced in WT mice, whereas these were largely absent in TLR7-/- mice. Similarly, IL-6 production, Caspase-3 cleavage, and cell apoptosis were significantly higher in EV71-infected WT mice as compared with TLR7-/- mice. Moreover, EV71 preferentially infected and induced IL-6 in astrocytes of mice brain. In U251 cells, EV71-induced IL-6 production and cell apoptosis were suppressed by shRNA-mediated knockdown of TLR7 (shTLR7). Moreover, in the cerebral cortex of EV71-infected mice, the blockade of IL-6 with anti-IL-6 antibody (IL-6-Ab) restored the body weight loss, attenuated clinical scores, improved survival rates, reduced the disruption of neurofilament integrity, decreased cell apoptotic induction, and lowered levels of Caspase-3 cleavage. Similarly, in EV71-infected U251 cells, IL-6-Ab blocked EV71-induced IL-6 production and cell apoptosis in response to viral infection. Collectively, it's exhibited TLR7 upregulation, IL-6 induction and astrocytic cell apoptosis in EV71-infected human brain. Taken together, we propose that EV71 infects astrocytes of the cerebral cortex in mice and human and triggers TLR7 signaling and IL-6 release, subsequently inducing neural pathogenesis in the brain.

Dengue virus (DENV) infection causes several diseases ranging from dengue fever to life-threatening dengue hemorrhagic fever and dengue shock syndrome characterized by endothelial dysfunction, vascular leakage, and shock. Here, we identify a potential mechanism by which DENV induces tissue injury and vascular leakage by promoting the activation of interleukin (IL)-1β. DENV facilitates IL-1β secretion in infected patients, mice, human peripheral blood mononuclear cells (PBMCs), mouse bone marrow-derived macrophages (BMDMs), and monocyte-differentiated macrophages (THP-1) via activating the NLRP3 inflammasome. The accumulated data suggest that IL-1β probably induces vascular leakage and tissue injury in interferon-alpha/beta receptor 1 deficient C57BL/6 mice (IFNAR–/– C57BL/6), whereas IL-1 receptor antagonist (IL-1RA) alleviates these effects of IL-1β. Finally, administration of recombinant IL-1β protein results in vascular leakage and tissue injury in C57BL/6 mice. Together, the accumulated results demonstrate that IL-1β contributes to DENV-associated pathology and suggest that IL-1RA acts as a potential agent for the treatment of DENV-associated diseases.

SARS-CoV-2 is highly pathogenic in humans and poses a great threat to public health worldwide. Clinical data shows a disturbed type I interferon (IFN) response during the virus infection. In this study, we discovered that the nucleocapsid (N) protein of SARS-CoV-2 plays an important role in the inhibition of interferon beta (IFN-β) production. N protein repressed IFN-β production induced by poly(I:C) or upon Sendai virus (SeV) infection. We noted that N protein also suppressed IFN-β production, induced by several signaling molecules downstream of the retinoic acid-inducible gene I (RIG-I) pathway, which is the crucial pattern recognition receptor (PRR) responsible for identifying RNA viruses. Moreover, our data demonstrated that N protein interacted with the RIG-I protein through the DExD/H domain, which has ATPase activity and plays an important role in the binding of immunostimulatory RNAs. These results suggested that SARS-CoV-2 N protein suppresses the IFN-β response through targeting the initial step, potentially the cellular PRR–RNA-recognition step in the innate immune pathway. Therefore, we propose that the SARS-CoV-2 N protein represses IFN-β production by interfering with RIG-I.

Enterovirus 71 (EV71) infection causes hand-foot-mouth disease (HFMD), meningoencephalitis, neonatal sepsis, and even fatal encephalitis in children, thereby presenting a serious risk to public health. It is important to determine the mechanisms underlying the regulation of EV71 infection. In this study, we initially show that the interleukin enhancer-binding factor 2 (ILF2) reduces EV71 50% tissue culture infective dose (TCID50) and attenuates EV71 plaque-formation unit (PFU), thereby repressing EV71 infection. Microarray data analyses show that ILF2 mRNA is reduced upon EV71 infection. Cellular studies indicate that EV71 infection represses ILF2 mRNA expression and protein production in human leukemic monocytes (THP-1) -differentiated macrophages and human rhabdomyosarcoma (RD) cells. In addition, EV71 nonstructural protein 2B interacts with ILF2 in human embryonic kidney (HEK293T) cells. Interestingly, in the presence of EV71 2B, ILF2 is translocated from the nucleus to the cytoplasm, and it colocalizes with 2B in the cytoplasm. Therefore, we present a distinct mechanism by which EV71 antagonizes ILF2-mediated antiviral effects by inhibiting ILF2 expression and promoting ILF2 translocation from the nucleus to the cytoplasm through its 2B protein.

[This corrects the article DOI: 10.1371/journal.ppat.1006123.].

Activation of NLRP3 inflammasome is important for effective host defense against invading pathogen. Together with apoptosis-associated speck-like protein containing CARD domain (ASC), NLRP3 induces the cleavage of caspase-1 to facilitate the maturation of interleukin-1beta (IL-1β), an important pro-inflammatory cytokine. IL-1β subsequently plays critical roles in inflammatory responses by activating immune cells and inducing many secondary pro-inflammatory cytokines. Although the role of NLRP3 inflammasome in immune response is well defined, the mechanism underlying its assembly modulated by pathogen infection remains largely unknown. Here, we identified a novel mechanism by which enterovirus 71 (EV71) facilitates the assembly of NLRP3 inflammasome. Our results show that EV71 induces production and secretion of IL-1β in macrophages and peripheral blood mononuclear cells (PBMCs) through activation of NLRP3 inflammasome. EV71 replication and protein synthesis are required for NLRP3-mediated activation of IL-1β. Interestingly, EV71 3D protein, a RNA-dependent RNA polymerase (RdRp) was found to stimulate the activation of NLRP3 inflammasome, the cleavage of pro-caspase-1, and the release of IL-1β through direct binding to NLRP3. More importantly, 3D interacts with NLRP3 to facilitate the assembly of inflammasome complex by forming a 3D-NLRP3-ASC ring-like structure, resulting in the activation of IL-1β. These findings demonstrate a new role of 3D as an important player in the activation of inflammatory response, and identify a novel mechanism underlying the modulation of inflammasome assembly and function induced by pathogen invasion.