Sandwich-like CuNPs@AgNPs@PSB SERS substrates for sensitive detection of R6G and Forchlorfenuron.

The development of a highly sensitive, synthetically simple and economical SERS substrate is technically very important. A fast, economical, sensitive and reproducible CuNPs@AgNPs@ Porous silicon Bragg reflector (PSB) SERS substrate was prepared by electrochemical etching and in situ reduction method. The developed CuNPs@AgNPs@PSB has a large specific surface area and abundant "hot spot" region, which makes the SERS performance excellent. Meanwhile, the successful synthesis of CuNPs@AgNPs can not only modulate the plasmon resonance properties of nanoparticles, but also effectively prolong the time stability of Cu nanoparticles. The basic performance of the substrate was evaluated using rhodamine 6G (R6G). (Detection limit reached 10-15 M, R2 = 0.9882, RSD = 5.3 %) The detection limit of Forchlorfenuron was 10 µg/L. The standard curve with a regression coefficient of 0.979 was established in the low concentration range of 10 µg/L -100 µg/L. This indicates that the prepared substrates can accomplish the detection of pesticide residues in the low concentration range. The prepared high-performance and high-sensitivity SERS substrate have a very promising application in detection technology.

Nardilysin-regulated scission mechanism activates polo-like kinase 3 to suppress the development of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) develops through step-wise genetic and molecular alterations including Kras mutation and inactivation of various apoptotic pathways. Here, we find that development of apoptotic resistance and metastasis of KrasG12D-driven PDAC in mice is accelerated by deleting Plk3, explaining the often-reduced Plk3 expression in human PDAC. Importantly, a 41-kDa Plk3 (p41Plk3) that contains the entire kinase domain at the N-terminus (1-353 aa) is activated by scission of the precursor p72Plk3 at Arg354 by metalloendopeptidase nardilysin (NRDC), and the resulting p32Plk3 C-terminal Polo-box domain (PBD) is removed by proteasome degradation, preventing the inhibition of p41Plk3 by PBD. We find that p41Plk3 is the activated form of Plk3 that regulates a feed-forward mechanism to promote apoptosis and suppress PDAC and metastasis. p41Plk3 phosphorylates c-Fos on Thr164, which in turn induces expression of Plk3 and pro-apoptotic genes. These findings uncover an NRDC-regulated post-translational mechanism that activates Plk3, establishing a prototypic regulation by scission mechanism.

Progress in the Elimination of Organic Contaminants in Wastewater by Activation Persulfate over Iron-Based Metal-Organic Frameworks.

The release of organic contaminants has grown to be a major environmental concern and a threat to the ecology of water bodies. Persulfate-based Advanced Oxidation Technology (PAOT) is effective at eliminating hazardous pollutants and has an extensive spectrum of applications. Iron-based metal-organic frameworks (Fe-MOFs) and their derivatives have exhibited great advantages in activating persulfate for wastewater treatment. In this article, we provide a comprehensive review of recent research progress on the significant potential of Fe-MOFs for removing antibiotics, organic dyes, phenols, and other contaminants from aqueous environments. Firstly, multiple approaches for preparing Fe-MOFs, including the MIL and ZIF series were introduced. Subsequently, removal performance of pollutants such as antibiotics of sulfonamides and tetracyclines (TC), organic dyes of rhodamine B (RhB) and acid orange 7 (AO7), phenols of phenol and bisphenol A (BPA) by various Fe-MOFs was compared. Finally, different degradation mechanisms, encompassing free radical degradation pathways and non-free radical degradation pathways were elucidated. This review explores the synthesis methods of Fe-MOFs and their application in removing organic pollutants from water bodies, providing insights for further refining the preparation of Fe-MOFs.

Gasdermin C sensitizes tumor cells to PARP inhibitor therapy in cancer models.

Several poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are approved by FDA to treat cancer with BRCA mutations. BRCA mutations are considered to fuel a PARPi killing effect by inducing apoptosis. However, resistance to PARPi is frequently observed in the clinic due to an incomplete understanding on the molecular basis of PARPi function and a lack of good markers, beyond BRCA mutations, to predict response. Here, we show that gasdermin C (GSDMC) sensitized tumor cells to PARPi in vitro and in immunocompetent mice and caused durable tumor regression in an immune-dependent manner. A high expression level of GSDMC predicted better response to PARPi treatment in patients with triple-negative breast cancer (TNBC). PARPi treatment triggered GSDMC/caspase-8-mediated cancer cell pyroptosis (CCP) that enhanced PARPi killing of tumor cells. GSDMC-mediated CCP increased memory CD8+ T cell population in lymph node (LN), spleen, and tumor and, thus, promoted cytotoxic CD8+ T cell infiltration in the tumor microenvironment. T cell-derived granzyme B (GZMB) activated caspase-6, which subsequently cleaved GSDMC to induce pyroptosis. Interestingly, IFN-γ induced GSDMC expression, which, in turn, enhanced the cytotoxicity of PARPi and T cells. Importantly, GSDMC promoted tumor clearance independent of BRCA deficiency in multiple cancer types with PARPi treatment. This study identifies a general marker and target for PARPi therapy and offers insights into the mechanism of PARPi function.

Novel SERS biosensor for rapid detection of breast cancer based on Ag2O-Ag-PSi nanochips.

Ag2O-Ag-PSi (porous silicon) surface-enhanced Raman scattering (SERS) chip was successfully synthesized by electrochemical corrosion, in situ reduction and heat treatment technology. The influence of different heat treatment temperature on SERS performance of the chip is studied. The results show that the chip treated at 300 °C has the best SERS performance. The chip was composed of Ag2O-Ag nano core shell with a diameter of 40-60 nm and porous silicon substrate. Then, the optimized chip was used to perform SERS test on serum samples from 30 healthy volunteers and 30 early breast cancer patients, and the baseline was corrected by LabSpec6 software. Finally, the data were analyzed by principal component analysis combined with t-distributed Stochastic Neighbor Embedding (PCA-t-SNE). The results showed that the accuracy of the improved substrate combined with multivariate statistical method was 98%. The shelf life of the chips exceeded six months due to the presence of the Ag2O shell. This study provides a basis for developing a low-cost rapid and sensitive early screening technology for breast cancer.

Gasdermins and cancers.

The identification of gasdermin as the executor of pyroptosis has opened new avenues for the study of this process. Although pyroptosis research has mainly focused on immune cells since it was discovered three decades ago, accumulating evidence suggests that pyroptosis plays crucial roles in many biological processes. One example is the discovery of gasdermin-mediated cancer cell pyroptosis (CCP) which has become an important and frontier field in oncology. Recent studies have shown that CCP induction can heat tumor microenvironment (TME) and thereby elicit the robust anti-tumor immunity to suppress tumor growth. As a newly discovered form of tumor cell death, CCP offers promising opportunities for improving tumor treatment and developing new drugs. Nevertheless, the research on CCP is still in its infancy, and the molecular mechanisms underlying the expression, regulation and activation of gasdermins are not yet fully understood. In this review, we summarize the recent progress of gasdermin research in cancer area, and propose that the anti-tumor effect of immune cell pyroptosis (ICP) and CCP depends on their duration, intensity, and the type of cells undergoing pyroptosis within TME.

Nuclear export signal mutation of epidermal growth factor receptor enhances malignant phenotypes of cancer cells.

Nuclear epidermal growth factor receptor (EGFR) has been shown to be correlated with drug resistance and a poor prognosis in patients with cancer. Previously, we have identified a tripartite nuclear localization signal (NLS) within EGFR. To comprehensively determine the functions and underlying mechanism of nuclear EGFR and its clinical implications, we aimed to explore the nuclear export signal (NES) sequence of EGFR that is responsible for interacting with the exportins. We combined in silico prediction with site-directed mutagenesis approaches and identified a putative NES motif of EGFR, which is located in amino acid residues 736-749. Mutation at leucine 747 (L747) in the EGFR NES led to increased nuclear accumulation of the protein via a less efficient release of the exportin CRM1. Interestingly, L747 with serine (L747S) and with proline (L747P) mutations were found in both tyrosine kinase inhibitor (TKI)-treated and -naïve patients with lung cancer who had acquired or de novo TKI resistance and a poor outcome. Reconstituted expression of the single NES mutant EGFRL747P or EGFRL747S, but not the dual mutant along with the internalization-defective or NLS mutation, in lung cancer cells promoted malignant phenotypes, including cell migration, invasiveness, TKI resistance, and tumor initiation, supporting an oncogenic role of nuclear EGFR. Intriguingly, cells with germline expression of the NES L747 mutant developed into B cell lymphoma. Mechanistically, nuclear EGFR signaling is required for sustaining nuclear activated STAT3, but not for Erk. These findings suggest that EGFR functions are compartmentalized and that nuclear EGFR signaling plays a crucial role in tumor malignant phenotypes, leading to tumorigenesis in human cancer.

Detection of Gasdermin C-Mediated Cancer Cell Pyroptosis.

Gasdermin proteins except DFNB59 are the executioners of pyroptotic cell death. Cleavage of a gasdermin by an active protease causes lytic cell death. Gasdermin C (GSDMC) is cleaved by caspase-8 in response to macrophage-secreted TNF-α. Upon cleavage, the GSDMC-N domain is liberated and oligomerized, followed by pore formation in the plasma membrane. GSDMC cleavage, LDH release, and plasma membrane translocation of GSDMC-N domain are the reliable markers for GSDMC-mediated cancer cell pyroptosis (CCP). Here, we describe the methods for examining GSDMC-mediated CCP.

Coupling annealed silver nanoparticles with a porous silicon Bragg mirror SERS substrate and machine learning for rapid non-invasive disease diagnosis.

Ag2O-Ag-porous silicon Bragg mirror (PSB) composite SERS substrates were successfully synthesized by using a combination of electrochemical and thermochemical methods. Test results showed that the SERS signal increased and decreased as the annealing temperature used for the substrate increased, where the most intense SERS signal was obtained using a substrate annealed at 300 °C. Stability test results showed substantial enhancement of the SERS signal intensity of the Ag2O-Ag-PSB composite one month after preparation compared with that of conventional Ag-PSB. We conclude that Ag2O nanoshells play an essential role in SERS signal enhancement. Ag2O prevents natural oxidation of Ag nanoparticles (AgNPs) and has a solid localized surface plasmon resonance (LSPR). SERS signal enhancement was tested using this substrate for serum from patients with Sjögren's syndrome (SS) and Diabetic nephropathy (DN), as well as from healthy controls (HC). SERS feature extraction was performed using principal component analysis (PCA). The extracted features were analyzed by a support vector machine (SVM) algorithm. Finally, a rapid screening model for SS and HC, as well as DN and HC, was developed and used to perform controlled experiments. The results showed that the diagnostic accuracy, sensitivity and selectivity for SERS technology combined with machine learning algorithms reached 90.7%, 93.4% and 86.7% for SS/HC and 89.3%, 95.6% and 80% for DN/HC, respectively. The results of this study show that the composite substrate has excellent potential to be developed into a commercially available SERS chip for medical testing.

Study on Wastewater Demulsification Technology of Crude Oil in Xinjiang Oilfield.

The Second Oil Production Plant of Xinjiang Oilfield produces a large amount of highly emulsified crude oil, which has a serious impact on the subsequent oil-water separation. At present, the concentration of demulsifier has increased to 2000 mg/L, but the demulsification effect is still poor. In this paper, the source and physical properties of highly emulsified crude oil are investigated firstly. The results show that highly emulsified crude oil is composed of three kinds of liquid: (1) conventional water flooding (WF); (2) chemical flooding (CF); (3) fracturing backflow fluid (FB). Among them, high zeta potential, low density difference, high viscosity, and small emulsion particles are responsible for the difficulty in the demulsification of the WF emulsion, while the high pH value is the reason why the CF emulsion is difficult to demulsify. Therefore, systematic experiments were implemented to investigate the optimal demulsification approach towards the three liquids above. As for the WF emulsion, it was necessary to raise the temperature to 70 °C and the concentration of the demulsifier to 200 mg/L. Moreover, it was only necessary to add 200 mg/L of demulsifier to break the CF emulsion after adjusting the pH value to 7, while no extra treatments were needed to break the FB emulsion. We hope this study can provide a new insight for the treatment of emulsions in the later stage of oilfield development.

Construction of Z-scheme CdS/Ag/TiO2 NTs photocatalysts for photocatalytic dye degradation and hydrogen evolution.

The ternary CdS/Ag/TiO2 NTs photocatalysts with indirect Z-scheme heterojunctions were synthesized by the photoreduction deposition of Ag and successive ionic layer adsorption and reaction (SILAR) of CdS on TiO2 nanotube arrays (TiO2 NTs). The elemental composition, microstructure, photoresponse and photoelectrochemical property of the photocatalyst were systematically characterized. The results proved that compared with binary heterojunction, the light absorption range of the ternary CdS/Ag/TiO2 NTs photocatalyst was significantly extended, and the photoelectron transportation efficiency was improved. Under sunlight irradiation, the photocatalytic capacity was verified by investigating the photodegradation of MB and RhB dyes. The CdS/Ag/TiO2 NTs exhibited the optimal photocatalytic performance with the degradation efficiency of 82.24% for RhB and 100% for MB. The synthesized CdS/Ag/TiO2 NTs had high photocatalytic hydrogen evolution capacity and stability, and the hydrogen production reached 806.33 µmol·cm-2. Based on the results of electron spin resonance spectroscopy (ESR) and free radical trapping, the photocatalytic reaction mechanism was explained. The synthesis of ternary CdS/Ag/TiO2 NTs provides a practical reference and guidance for designing high-efficient photocatalysts with Z-scheme heterojunctions toward solar energy development for H2 generation, pollutant remediation and photoelectric conversion.

Fabrication and Performance of Graphene Flexible Pressure Sensor with Micro/Nano Structure.

Laser-induced graphene (LIG) has been widely used in flexible sensors due to its excellent mechanical properties and high conductivity. In this paper, a flexible pressure sensor prepared by bionic micro/nanostructure design and LIG mass fraction regulation is reported. First, prepared LIG and conductive carbon paste (CCP) solutions were mixed to obtain a conductive polymer. After the taro leaf structure was etched on the surface of the aluminum alloy plate by Nd:YAG laser processing, the conductive polymer was evenly coated on the template. Pressure sensors were packaged with a stencil transfer printing combined with an Ecoflex flexible substrate. Finally, the effects of different laser flux and the proportion of LIG in the composite on the sensitivity of the sensor are discussed. The results show that when the laser flux is 71.66 J·cm-2 and the mass fraction of LIG is 5%, the sensor has the best response characteristics, with a response time and a recovery time of 86 ms and 101 ms, respectively, with a sensitivity of 1.2 kPa-1 over a pressure range of 0-6 kPa, and stability of 650 cycle tests. The LIG/CCP sensor with a bionic structure demonstrates its potential in wearable devices.

Molecular mechanisms and functions of pyroptosis in inflammation and antitumor immunity.

Canonically, gasdermin D (GSDMD) cleavage by caspase-1 through inflammasome signaling triggers immune cell pyroptosis (ICP) as a host defense against pathogen infection. However, cancer cell pyroptosis (CCP) was recently discovered to be activated by distinct molecular mechanisms in which GSDMB, GSDMC, and GSDME, rather than GSDMD, are the executioners. Moreover, instead of inflammatory caspases, apoptotic caspases and granzymes are required for gasdermin protein cleavage to induce CCP. Sufficient accumulation of protease-cleaved gasdermin proteins is the prerequisite for CCP. Inflammation induced by ICP or CCP results in diametrically opposite effects on antitumor immunity because of the differential duration and released cellular contents, leading to contrary effects on therapeutic outcomes. Here, we focus on the distinct mechanisms of ICP and CCP and discuss the roles of ICP and CCP in inflammation and antitumor immunity, representing actionable targets.

PRMT1 enhances oncogenic arginine methylation of NONO in colorectal cancer.

Arginine methylation is an important posttranslational modification catalyzed by protein arginine methyltransferases (PRMTs). However, the role of PRMTs in colorectal cancer (CRC) progression is not well understood. Here we report that non-POU domain-containing octamer-binding protein (NONO) is overexpressed in CRC tissue and is a potential marker for poor prognosis in CRC patients. NONO silencing resulted in decreased proliferation, migration, and invasion of CRC cells, whereas overexpression had the opposite effect. In a xenograft model, tumors derived from NONO-deficient CRC cells were smaller than those derived from wild-type (WT) cells, and PRMT1 inhibition blocked CRC xenograft progression. A mass spectrometry analysis indicated that NONO is a substrate of PRMT1. R251 of NONO was asymmetrically dimethylated by PRMT1 in vitro and in vivo. Compared to NONO WT cells, NONO R251K mutant-expressing CRC cells showed reduced proliferation, migration, and invasion, and PRMT1 knockdown or pharmacological inhibition abrogated the malignant phenotype associated with NONO asymmetric dimethylation in both KRAS WT and mutant CRC cells. Compared to adjacent normal tissue, PRMT1 was highly expressed in the CRC zone in clinical specimens, which was correlated with poor overall survival in patients with locally advanced CRC. These results demonstrate that PRMT1-mediated methylation of NONO at R251 promotes CRC growth and metastasis, and suggest that PRMT1 inhibition may be an effective therapeutic strategy for CRC treatment regardless of KRAS mutation status.

Solvothermal preparation of Ti3+ self-doped TiO2-x nanotube arrays for enhanced photoelectrochemical performance.

Ti3+ self-doped TiO2-x nanotube arrays (TiO2-x NTs) were prepared by solvothermal treatment in KBH4 ethanol solution followed by calcination, and were characterized by field-emission scanning electron microscopy (FE-SEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS) and UV-vis diffusion reflection spectroscopy (DRS). The photoelectrochemical properties of TiO2-x NTs prepared in different KBH4 concentrations were investigated. The TiO2-x NTs exhibited high visible light response, visible light photocurrent and photoelectrocatalytic activities. The active species and photocatalytic mechanism for the dye degradation were proposed, and the improved photoelectrochemical performance was attributed to the synergistic effect of the narrowed energy gap and enhanced electron transportation. The ability to improve the photoelectrochemical properties of TiO2-x electrode materials should open up new opportunities for high-performance solar cells and photocatalysts.

Author Correction: PD-L1-mediated gasdermin C expression switches apoptosis to pyroptosis in cancer cells and facilitates tumour necrosis.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

PD-L1-mediated gasdermin C expression switches apoptosis to pyroptosis in cancer cells and facilitates tumour necrosis.

Although pyroptosis is critical for macrophages against pathogen infection, its role and mechanism in cancer cells remains unclear. PD-L1 has been detected in the nucleus, with unknown function. Here we show that PD-L1 switches TNFα-induced apoptosis to pyroptosis in cancer cells, resulting in tumour necrosis. Under hypoxia, p-Stat3 physically interacts with PD-L1 and facilitates its nuclear translocation, enhancing the transcription of the gasdermin C (GSDMC) gene. GSDMC is specifically cleaved by caspase-8 with TNFα treatment, generating a GSDMC N-terminal domain that forms pores on the cell membrane and induces pyroptosis. Nuclear PD-L1, caspase-8 and GSDMC are required for macrophage-derived TNFα-induced tumour necrosis in vivo. Moreover, high expression of GSDMC correlates with poor survival. Antibiotic chemotherapy drugs induce pyroptosis in breast cancer. These findings identify a non-immune checkpoint function of PD-L1 and provide an unexpected concept that GSDMC/caspase-8 mediates a non-canonical pyroptosis pathway in cancer cells, causing tumour necrosis.

PD-L1 upregulation by IFN-α/γ-mediated Stat1 suppresses anti-HBV T cell response.

Programmed death ligand 1 (PD-L1) has been recently shown to be a major obstacle to antiviral immunity by binding to its receptor programmed death 1 (PD-1) on specific IFN-γ producing T cells in chronic hepatitis B. Currently, IFN-α is widely used to treat hepatitis B virus (HBV) infection, but its antiviral effect vary greatly and the mechanism is not totally clear. We found that IFN-α/γ induced a marked increase of PD-L1 expression in hepatocytes. Signal and activators of transcription (Stat1) was then identified as a major transcription factor involved in IFN-α/γ-mediated PD-L1 elevation both in vitro and in mice. Blockage of the PD-L1/PD-1 interaction by a specific mAb greatly enhanced HBV-specific T cell activity by the gp96 adjuvanted therapeutic vaccine, and promoted HBV clearance in HBV transgenic mice. Our results demonstrate the IFN-α/γ-Stat1-PD-L1 axis plays an important role in mediating T cell hyporesponsiveness and inactivating liver-infiltrating T cells in the hepatic microenvironment. These data raise further potential interest in enhancing the anti-HBV efficacy of IFN-α and therapeutic vaccines.

Microwave method synthesis of magnetic ionic liquid/gold nanoparticles as ultrasensitive SERS substrates for trace clopidol detection.

Clopidol is one of the most widely used anti-coccidiosis drugs. Its residues in poultry products and the environment pose a serious threat to human health. In this work, microwave-assisted synthesis of magnetic ionic liquid/gold nanoparticles (MIL-Au NPs) as the SERS substrates were first designed for sensitive and reliable determination of clopidol residue in egg samples. The experiment shows that MIL(1-methyl-3-hexyl imidazole ferric tetrachloride ([C6mim]FeCl4)) and microwave play a key role in the dispersion and morphology of Au NPs. Under the optimal conditions, the as-prepared MIL-Au NPs were applied to the SERS detection of clopidol in methanol and egg solution and its detection limits can be as low as to 0.5 µg/kg (equal to 0.5 ppb) in both solutions. The standard curves with regression coefficients of 0.9298 and 0.93496 were constructed in the linear range of 100-1000 ppb and 0.5-50 ppb for clopidol in egg solutions. Moreover, satisfactory recoveries (97.5-103.2%) were obtained for egg samples. The developed SERS method provides a way for quantitation of clopidol and can be applied for the convenient, reliable, and highly sensitive detection of antibiotic residues in food and environment, which has great potential in food safety and biological monitoring. Graphical abstract.

Author Correction: CDK2-mediated site-specific phosphorylation of EZH2 drives and maintains triple-negative breast cancer.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.