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There are currently approximately 4000 mutations in the SARS-CoV-2 S protein gene and emerging SARS-CoV-2 variants continue to spread rapidly worldwide. Universal vaccines with high efficacy and safety urgently need to be developed to prevent SARS-CoV-2 variants pandemic. Here, we described a novel self-assembling universal mRNA vaccine containing a heterologous receptor-binding domain (HRBD)-based dodecamer (HRBDdodecamer) against SARS-CoV-2 variants, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (B.1.1.28.1), Delta (B.1.617.2) and Omicron (B.1.1.529). HRBD containing four heterologous RBD (Delta, Beta, Gamma, and Wild-type) can form a stable dodecameric conformation under T4 trimerization tag (Flodon, FD). The HRBDdodecamer -encoding mRNA was then encapsulated into the newly-constructed LNPs consisting of a novel ionizable lipid (4N4T). The obtained universal mRNA vaccine (4N4T-HRBDdodecamer) presented higher efficiency in mRNA transfection and expression than the approved ALC-0315 LNPs, initiating potent immune protection against the immune escape of SARS-CoV-2 caused by evolutionary mutation. These findings demonstrated the first evidence that structure-based antigen design and mRNA delivery carrier optimization may facilitate the development of effective universal mRNA vaccines to tackle SARS-CoV-2 variants pandemic. The HRBDdodecamer containing four heterologous RBD (Delta, Beta, Gamma, and Wild-type) was designed as a safe, effective, and universal mRNA vaccine. [Display omitted] [ABSTRACT FROM AUTHOR]

Most of the nanomedicines can reduce the side effects of anti-tumor chemical drugs but do not have good enough therapeutic efficacy, largely due to the sustained drug release profile. It might be a promising alternative strategy to develop a cascade-responsive nanoplatform against tumor with the burst release of chemotherapeutics based on the highly efficient tumor cell targeting delivery. In this work, we constructed innovative nanoparticles (PMP/WPH-NPs) consisting of two functional polymers. PMP contained the MMP-2 enzyme sensitive linker and disulfide bond, which could respond to the tumor-overexpressing enzyme MMP-2 and high-level glutathione. While WPH promoted tumor penetration and acid-responsive drug release by modifying cellular penetrating peptides and polymerizing L-histidine. PMP/WPH-NPs exhibited outstanding features including longer blood circulation time, promoted tumor-specific accumulation, enhanced tumor penetration and efficient escape from lysosomes. Subsequently, the model drug paclitaxel (PTX), widely used in the tumor chemotherapy, was encapsulated into PMP/WPH-NPs via an emulsion solvent evaporation method. Within a short period of time, PTX-PMP/WPH-NP in simulated tumor cellular microenvironment could release 8 times more PTX than that in the physiological environment, demonstrating a good potential in tumor cell-specific burst drug release. In addition, PTX-PMP/WPH-NPs exhibited stronger anti-tumor activity than PTX in vitro and in vivo , which also had good biocompatibility according to the hemolysis assay and H&E staining. In summary, our work has succeeded in designing an original polymeric nanoplatform for programmed burst drug release based on the tailored tumor targeting delivery system. This new approach would facilitate the clinical translation of more anti-tumor nanomedicines. Biomaterials responsive to the tumor-specific stimulus has conventionally used in the targeted-delivery of anti-tumor drugs. However, the levels of common stimulus are not uniformly distributed and not high enough to effectively trigger drug release. In an effort to achieve a better specific drug release and promote the chemotherapeutic efficacy, we constructed a cascade responsive nanoplatform with tumor cell-specific drug burst release profile. The tailored biomaterial could overcome the bio-barriers in vivo and succeeded in the programmed burst drug release based on the tumor cell-specific delivery of chemotherapeutics. [Display omitted] [ABSTRACT FROM AUTHOR]

Sulfoconjugation of small molecules or protein peptides is a key mechanism to ensure biochemical and functional homeostasis in mammals. The PAPS synthase 2 (PAPSS2) is the primary enzyme to synthesize the universal sulfonate donor 3′-phosphoadenosine 5′-phosphosulfate (PAPS). Acetaminophen (APAP) overdose is the leading cause of acute liver failure (ALF), in which oxidative stress is a key pathogenic event, whereas sulfation of APAP contributes to its detoxification. The goal of this study was to determine whether and how PAPSS2 plays a role in APAP-induced ALF. Gene expression was analyzed in APAP-induced ALF in patients and mice. Liver-specific Papss2 -knockout mice using Alb-Cre (Papss2 ΔHC) or AAV8-TBG-Cre (Papss2 iΔHC) were created and subjected to APAP-induced ALF. Primary human and mouse hepatocytes were used for in vitro mechanistic analysis. The hepatic expression of PAPSS2 was decreased in APAP-induced ALF in patients and mice. Surprisingly, Papss2 ΔHC mice were protected from APAP-induced hepatotoxicity despite having a decreased APAP sulfation, which was accompanied by increased hepatic antioxidative capacity through the activation of the p53-p2-Nrf2 axis. Treatment with a sulfation inhibitor also ameliorated APAP-induced hepatotoxicity. Gene knockdown experiments showed that the hepatoprotective effect of Papss2 ΔHC was Nrf2, p53, and p21 dependent. Mechanistically, we identified p53 as a novel substrate of sulfation. Papss2 ablation led to p53 protein accumulation by preventing p53 sulfation, which disrupts p53-MDM2 interaction and p53 ubiquitination and increases p53 protein stability. We have uncovered a previously unrecognized and p53-mediated role of PAPSS2 in controlling oxidative response. Inhibition of p53 sulfation may be explored for the clinical management of APAP overdose. [Display omitted] Inhibition of sulfation prevents oxidative liver injury and acute liver failure by activating the p53-p21-Nrf2 signaling axis. [ABSTRACT FROM AUTHOR]

Acidosis, regardless of hypoxia involvement, is recognized as a chronic and harsh tumor microenvironment (TME) that educates malignant cells to thrive and metastasize. Although overwhelming evidence supports an acidic environment as a driver or ubiquitous hallmark of cancer progression, the unrevealed core mechanisms underlying the direct effect of acidification on tumorigenesis have hindered the discovery of novel therapeutic targets and clinical therapy. Here, chemical-induced and transgenic mouse models for colon, liver and lung cancer were established, respectively. miR-7 and TGF- β 2 expressions were examined in clinical tissues (n = 184). RNA-seq, miRNA-seq, proteomics, biosynthesis analyses and functional studies were performed to validate the mechanisms involved in the acidic TME-induced lung cancer metastasis. Our data show that lung cancer is sensitive to the increased acidification of TME, and acidic TME-induced lung cancer metastasis via inhibition of miR-7-5p. TGF- β 2 is a direct target of miR-7-5p. The reduced expression of miR-7-5p subsequently increases the expression of TGF- β 2 which enhances the metastatic potential of the lung cancer. Indeed, overexpression of miR-7-5p reduces the acidic pH-enhanced lung cancer metastasis. Furthermore, the human lung tumor samples also show a reduced miR-7-5p expression but an elevated level of activated TGF- β 2; the expressions of both miR-7-5p and TGF- β 2 are correlated with patients' survival. We are the first to identify the role of the miR-7/TGF- β 2 axis in acidic pH-enhanced lung cancer metastasis. Our study not only delineates how acidification directly affects tumorigenesis, but also suggests miR-7 is a novel reliable biomarker for acidic TME and a novel therapeutic target for non-small cell lung cancer (NSCLC) treatment. Our study opens an avenue to explore the pH-sensitive subcellular components as novel therapeutic targets for cancer treatment. Extracellular acidosis, hallmark of tumor microenvironment, remarkably suppressed miR-7-5p generation to directly active TGF- β 2 expression, which specifically sustained metastasis in lung cancer cells while protect normal cells from death. [Display omitted] [ABSTRACT FROM AUTHOR]

Triptolide (TP) is an important active compound from Tripterygium wilfordii Hook F (Tw HF), however, it is greatly limited in clinical practice due to its severe toxicity, especially testicular injury. Melatonin is an endogenous hormone and has beneficial effects on the reproductive system. However, whether triptolide-induced testicular injury can be alleviated by melatonin and the underlying mechanism are not clear. In this study, we aimed to explore whether triptolide-induced testicular Sertoli cells toxicity can be mitigated by melatonin and the underlying mechanisms involved. Cell apoptosis was assessed by flow cytometry, western blot, immunofluorescence and immunohistochemistry. Fluorescent probe Mito-Tracker Red CMXRos was used to observe the mitochondria morphology. Mitochondrial membrane potential and Ca2+ levels were used to investigate mitochondrial function by confocal microscope and flow cytometry. The expression levels of SIRT1/Nrf2 pathway were detected by western blot, immunofluorescence and immunohistochemistry. Small interfering RNA of NRF2 and SIRT1 inhibitor EX527 was used to confirm the role of SIRT1/NRF2 pathway in the mitigation of triptolide-induced Sertoli cell damage by melatonin. Co-Immunoprecipitation assay was used to determine the interaction between SIRT1 and NRF2. Triptolide-induced dysfunction of testicular Sertoli cells was significantly improved by melatonin treatment. Specifically, triptolide-induced oxidative stress damage and changes of mitochondrial morphology, mitochondrial membrane potential, and BTB integrity were alleviated by melatonin. Mechanistically, triptolide inhibited SIRT1 and then reduced the activation of NRF2 pathway via regulating the interaction between SIRT1 and NRF2, thereby downregulating the downstream antioxidant genes, which was reversed by melatonin. Nevertheless, knockdown of NRF2 or inhibition of SIRT1 abolished the protective effect of melatonin. Triptolide-induced testicular Sertoli cell damage could be alleviated by melatonin via regulating the crosstalk between SIRT1 and NRF2, which is helpful for developing a new strategy to alleviate triptolide-induced toxicity. [Display omitted] [ABSTRACT FROM AUTHOR]

Highlights include four points of less than 85 characters each. The specific modifications are as follows:. • Provided a research framework for assessing the level of new urbanization. • The spatially heterogeneous nature of new urbanization and PM 2.5 concentration was analyzed. • Five dimensions of urbanization had both positive and negative effects on PM 2.5 concentration. • Different stages of new urbanization had divergent impacts on PM 2.5 concentration. • Providing basis for coordinated development of new urbanization and environmental governance. Air pollution has become an increasingly prominent problem during the development of urbanization. This study evaluates new urbanization levels across five dimensions: population, economic, social, spatial and ecological; discusses the spatial divergence patterns of new urbanization and PM 2.5 concentrations in 2012 and 2019; and analyses the spatial spillover effects of urbanization on PM 2.5 concentrations in each dimension using a spatial error model. The results are as follows: During the study period, the level of new urbanization in China is unevenly distributed, with higher levels in the eastern coastal region than in other regions. The average PM 2.5 concentration increased significantly, by 4.87 μg/m3, an increase of 14.47%. The spillover effect of new urbanization on PM 2.5 concentration changes significantly at different stages of development, with the coefficients of economic and ecological new urbanization shifting from 0.629 and 0.015 to -0.377 and -0.356 respectively, while spatial new urbanization shifts from -0.667 to 0.613. This study elucidates how the process of new urbanization subsystem development and the mechanism of urbanization influence PM 2.5 concentration in each dimension, thus providing a reference for coordinating the relationship between urbanization development and environmental protection. [ABSTRACT FROM AUTHOR]

Background: Tanshinone IIA (Tan), the main active component of Salvia miltiorrhiza, has been demonstrated to have antioxidant activity. Acetaminophen (APAP), a widely used antipyretic and analgesic, can cause severe hepatotoxicity and liver failure when taken overdose. Oxidative stress has been reported to be involved in APAP-induced liver failure.Purpose: This study aimed to investigate the effect of Tan on APAP-induced hepatotoxicity and the underlying mechanisms involved.Study Design: C57BL/6J mice were divided into six groups: (1) control, (2) APAP group, (3) APAP+Tan (30mg/kg) group, (4) Tan (30mg/kg) group, (5) APAP+Tan (10mg/kg) group, (6) Tan (10mg/kg) group. Mice in group 3 and 5 were pre-treated with specified dose of Tan by gavage and subsequently injected with an overdose of APAP intraperitoneally (i.p., 300mg/kg). The effect of Tan on Nrf2 pathway was investigated in HepG2 cells and mice.Methods: Plasma aspartate transaminase (ALT), aspartate transaminase (AST), lactate dehydrogenase (LDH), liver glutathione (GSH), glutathione transferase (GST), glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT) levels were determined after mice were sacrificed. Lipid peroxidation and histological examination were performed. The effect of Tan on the Nrf2 pathway was detected by western blotting and qRT-PCR.Results: Tan pretreatment reduced APAP-induced liver injury. Tan was able to activate Nrf2 and increase the expression levels of Nrf2 target genes, including glutamate-cysteine ligase catalytic subunit (GCLC), NAD(P)H:quinine oxidoreductase 1 (NQO1) and hemeoxygenase-1 (HO-1), in a dose-dependent manner in HepG2 cells. Consistent with our observations in HepG2 cells, Tan increased nuclear Nrf2 accumulation and upregulated mRNA and protein levels of the Nrf2 target genes GCLC, NQO1 and HO-1 in C57BL/6J mice compared with mice treated with APAP alone.Conclusions: Our results demonstrate that Tan pretreatment could protect the liver from APAP-induced hepatic injury by activating the Nrf2 pathway. Tan may provide a new strategy for the protection against APAP-induced liver injury. [ABSTRACT FROM AUTHOR]

Background Triptolide, an active ingredient extracted from the Chinese herb Tripterygium wilfordii Hook f., has multiple pharmacological properties, including anti-inflammatory, immune-modulatory, and anti-proliferative activities. However, the hepatotoxicity of triptolide always limits its clinical applications. Hypothesis/Purpose Farnesoid X receptor (FXR) is a ligand-activated transcription factor that plays a key role in hepatoprotection through the maintenance of liver metabolism homeostasis. This study explored the role of FXR in triptolide-induced cytotoxicity and investigated whether activation of FXR can protect against triptolide-induced liver injury. Study design The role of FXR in triptolide-induced cytotoxicity was investigated in HepG2 cells. In addition, the protective effect of the selective FXR agonist GW4064 on triptolide-induced hepatotoxicity was explored in BALB/c mice. Methods HepG2 cells were transient transfected with FXR expression plasmid or FXR-siRNA. The cytotoxicity was compared using the MTT assay. The extent of liver injury was assessed by histopathology and serum aminotransferases. The expression of FXR and its target genes were detected by Western blot and qRT-PCR. Results The transient overexpression of FXR protected against triptolide-induced cell death, whereas FXR knockdown with a specific small interfering RNA resulted in increased cytotoxicity. In BALB/c mice, treatment with the FXR agonist GW4064 attenuated triptolide-induced liver dysfunction, structural damage, glutathione depletion and lipid peroxidation. Moreover, the livers of GW4064-treated mice showed increased expression of FXR and several related target genes involved in phase II and phase III xenobiotic metabolism. Conclusion Taken together, these results indicate that activation of FXR attenuates triptolide-induced hepatotoxicity and provide direct implications for the development of novel therapeutic strategies against triptolide-induced hepatotoxicity. [ABSTRACT FROM AUTHOR]

Cisplatin is a potent anti-cancer agent for various types of tumors. However, the clinical use of cisplatin is often limited by its nephrotoxicity. This study reports that WZ tablet (WZ, a preparation of an ethanol extract of Schisandra sphenanthera ) mitigates cisplatin-induced toxicity in renal epithelial HK-2 cells and in mice. Pretreatment of HK-2 cells with WZ ameliorated cisplatin-induced cytotoxicity caused by oxidative stress, as was demonstrated by reductions in the levels of reactive oxygen species (ROS) and increased levels of glutathione (GSH). WZ facilitated the nuclear accumulation of the transcription factor NF-E2-related factor 2 (Nrf2) and the subsequent expression of its target genes such as NAD(P)H:quinine oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1) and glutamate cysteine ligase (GCL). Protective effects of WZ on cisplatin-induced nephrotoxicity were also observed in mice. WZ attenuated cisplatin-induced renal dysfunction, structural damage and oxidative stress. The nuclear accumulation of Nrf2 and its target genes were increased by WZ treatment. Taken together, these findings demonstrated WZ have a protective effect against cisplatin-induced nephrotoxicity by activation of the Nrf2 mediated defense response, which is of significant importance for therapeutic intervention in cisplatin induced renal injury. [ABSTRACT FROM AUTHOR]

With the rapid development of aerospace technology, super-large-scale space structures have become the preferred solution for major aerospace countries to carry out in-orbit missions. Therefore, a scalable self-attaching/assembling robotic cluster (S2A2RC) system which can realize the component-level in-orbit assembly task requirements of ultra-large-scale space truss structures is proposed in this paper. On this basis, a monitoring system with self-powered sensor based on the triboelectric nanogenerator (TENG) technology is proposed. The sensory system is used to monitor the crawling state of the robot, the grasping state of the manipulator, and the assembly state of the truss components during the in-orbit assembly process in real time. In conclusion, the S2A2RC system is proposed in this paper, with the noticeable advantages in terms of the multi-functionalities, the cost, the power consumption, the signal reliability, and the minimized data size. Meanwhile, the S2A2RC system shows great potential for many other large-scale spacecrafts. [Display omitted] • A robotic system is proposed for attaching and moving on the spacecraft, include a mobile system and an operating system. • The mobile system uses a six-legged moving mechanism, triboelectric robot leg sensors (TRLS) for detecting the slippage. • The operating system consists of a robotic manipulator, triboelectric robot manipulator sensors (TRMS) can detect the gripping. • Triboelectric space truss sensors (TSTS) are in charge of sensing the completed assembling of each truss. • The TENG sensors are evaluated under the extreme environment, including radiation, varied temperature, and vacuum. [ABSTRACT FROM AUTHOR]

Abstract: This paper presents an integrated study of urbanization trends in Shijiazhuang City, Hebei Province of China, by using Geographical Information Systems (GIS) and remote sensing. The study explores the temporal and spatial characteristics of urban expansion from 1934 to 2001, and land use/cover change from 1987 to 2001. Temporally, urban expansion shows fast and slow growth stages, with the high-speed growth districts shifting to the east or west side of the city. The spatial patterns of urban growth can be categorized into three types: special objectives oriented type, social-political intervention type, and normal urban growth type. The remotely detected land use/cover change from 1987 to 2001 shows that the land use/cover was largely changed. The land use/cover conversion relationship implies that these changes are governed by urban expansion, which produces a force to drive the land use changes in search of a higher return. Lastly, the major factors influencing urban expansion and land use/cover change are also discussed. In general, the population, traffic conditions, industrialization, and policy are the major factors that influenced the urban expansion. [Copyright &y& Elsevier]

Sulfation is a conjugation reaction essential for numerous biochemical and cellular functions in mammals. The 3'-phosphoadenosine 5'-phosphosulfate (PAPS) synthase 2 (PAPSS2) is the key enzyme to generate PAPS, which is the universal sulfonate donor for all sulfation reactions. The goal of this study was to determine whether and how PAPSS2 plays a role in colitis and colonic carcinogenesis. Tissue arrays of human colon cancer specimens, gene expression data, and clinical features of cancer patients were analyzed. Intestinal-specific Papss2 knockout mice (Papss2 ΔIE) were created and subjected to dextran sodium sulfate–induced colitis and colonic carcinogenesis induced by a combined treatment of azoxymethane and dextran sodium sulfate or azoxymethane alone. The expression of PAPSS2 is decreased in the colon cancers of mice and humans. The lower expression of PAPSS2 in colon cancer patients is correlated with worse survival. Papss2 ΔIE mice showed heightened sensitivity to colitis and colon cancer by damaging the intestinal mucosal barrier, increasing intestinal permeability and bacteria infiltration, and worsening the intestinal tumor microenvironment. Mechanistically, the Papss2 ΔIE mice exhibited reduced intestinal sulfomucin content. Metabolomic analyses revealed the accumulation of bile acids, including the Farnesoid X receptor antagonist bile acid tauro-β-muricholic acid, and deficiency in the formation of bile acid sulfates in the colon of Papss2 ΔIE mice. We have uncovered an important role of PAPSS2-mediated sulfation in colitis and colonic carcinogenesis. Intestinal sulfation may represent a potential diagnostic marker and PAPSS2 may serve as a potential therapeutic target for inflammatory bowel disease and colon cancer. [Display omitted] [ABSTRACT FROM AUTHOR]