The necessity for new sources for greener and cleaner energy production to replace the existing ones has been increasingly growing in recent years. Of those new sources, the hydrogen evolution ...reaction has a large potential. In this work, for the first time, MoSe2/Mo core–shell 3D‐hierarchical nanostructures are created, which are derived from the Mo 3D‐hierarchical nanostructures through a low‐temperature plasma‐assisted selenization process with controlled shapes grown by a glancing angle deposition system.
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.
The exotic photophysical properties of organic–inorganic hybrid perovskite with long exciton lifetimes and small binding energy have appeared as promising front‐runners for next‐generation ...non‐volatile flash photomemory. However, the long photo‐programming time of photomemory limits its application on light‐fidelity (Li‐Fi), which requires high storage capacity and short programming times. Herein, the spatially addressable perovskite in polystyrene‐block‐poly(ethylene oxide) (PS‐b‐PEO)/perovskite composite film as an photoactive floating gate is demonstrated to elucidate the effect of morphology on the photo‐responsive characteristics of photomemory. The chelation between lead ion and PEO segment promotes the anti‐solvent functionalities of the perovskite/PS‐b‐PEO composite film, thus allowing the solution‐processable poly(3‐hexylthiophene‐2,5‐diyl) (P3HT) to act as the active channel. Through manipulating the interfacial area between perovskite and P3HT, fast photo‐induced charge transfer rate of 0.056 ns−1, high charge transfer efficiency of 89%, ON/OFF current ratio of 104, and extremely low programming time of 5 ms can be achieved. This solution‐processable and fast photo‐programmable non‐volatile flash photomemory can trigger the practical application on Li‐Fi.
The spatially addressable perovskite in a polystyrene‐block‐poly(ethylene oxide) (PS‐b‐PEO)/perovskite composite film as an photoactive floating gate is demonstrated. By manipulating the interfacial area between the perovskite and active channel, a fast photo‐induced charge transfer rate of 0.056 ns−1, high charge transfer efficiency of 89%, ON/OFF current ratio of 104, and extremely low programming time of 5 ms can be achieved.
An on-field colorimetric sensing strategy employing gold nanoparticles (AuNPs) and a paper-based analytical platform was investigated for mercury ion (Hg2+) detection at water sources. By utilizing ...thymine–Hg2+–thymine (T–Hg2+–T) coordination chemistry, label-free detection oligonucleotide sequences were attached to unmodified gold nanoparticles to provide rapid mercury ion sensing without complicated and time-consuming thiolated or other costly labeled probe preparation processes. Not only is this strategy’s sensing mechanism specific toward Hg2+, rather than other metal ions, but also the conformational change in the detection oligonucleotide sequences introduces different degrees of AuNP aggregation that causes the color of AuNPs to exhibit a mixture variance. To eliminate the use of sophisticated equipment and minimize the power requirement for data analysis and transmission, the color variance of multiple detection results were transferred and concentrated on cellulose-based paper analytical devices, and the data were subsequently transmitted for the readout and storage of results using cloud computing via a smartphone. As a result, a detection limit of 50 nM for Hg2+ spiked pond and river water could be achieved. Furthermore, multiple tests could be performed simultaneously with a 40 min turnaround time. These results suggest that the proposed platform possesses the capability for sensitive and high-throughput on-site mercury pollution monitoring in resource-constrained settings.
Macromolecularly crowded coacervate is useful in protein delivery for tissue engineering and regenerative medicine. However, coacervate tends to aggregate easily, which impedes their application. ...Here, this work presents a method to prepare coacervate with enhanced stability. This work assembles phospholipids on the surface of a coacervate to form lipocoacervate (LipCo). The resultant LipCo possesses a discrete spherical structure with a coacervate interior and phospholipid outer shell. The size of LipCo does not change over the four‐week observation window, whereas coacervate coalesced into one bulk phase within 30 min. This work uses vascular endothelial growth factor‐C (VEGF‐C) and fibroblast growth factor‐2 (FGF‐2) as examples to test LipCo's ability to maintain protein bioactivity. The in vitro lymphangiogenesis assay demonstrates that human dermal lymphatic endothelial cells (LECs) formed increased network of cord in VEGF‐C and FGF‐2 loaded LipCo group compared to free proteins and proteins loaded in coacervate. Overall, LipCo could serve as a protein delivery vehicle with improved colloidal stability.
A coacervate‐filled lipid vesicle (LipCo) for protein delivery: LipCo shows improved colloidal stability for long term storage (>4 weeks). Proteins released from LipCo are bioactive and induces more potent biological response than free proteins or proteins delivered by naked coacervate. LipCo is a promising delivery platform for therapeutic proteins.
The electrochemical CO2 reduction reaction (CO2RR) represents a viable alternative to help close the anthropogenic carbon cycle and convert intermittent electricity from renewable energy sources to ...chemical energy in the form of value-added chemicals. The development of economic catalysts possessing high faradaic efficiency (FE) and mass activity (MA) toward CO2RR is critical in accelerating CO2 utilization technology. Herein, an elaborate Au–Cu catalyst where an alloyed AuCu shell caps on a Cu core (Cu@AuCu) is developed and evaluated for CO2-to-CO electrochemical conversion. Specific roles of Cu and Au for CO2RR are revealed in the alloyed core–shell structure, respectively, and a compositional-dependent volcano-plot is disclosed for the Cu@AuCu catalysts toward selective CO production. As a result, the Au2–Cu8 alloyed core–shell catalyst (only 17% Au content) achieves an FECO value as high as 94% and an MACO of 439 mA/mgAu at −0.8 V (vs RHE), superior to the values for pure Au, reflecting its high noble metal utilization efficiency.
Metformin has been reported to possess antitumor activity and maintain high cytotoxic T lymphocyte (CTL) immune surveillance. However, the functions and detailed mechanisms of metformin’s role in ...cancer immunity are not fully understood. Here, we show that metformin increases CTL activity by reducing the stability and membrane localization of programmed death ligand-1 (PD-L1). Furthermore, we discover that AMP-activated protein kinase (AMPK) activated by metformin directly phosphorylates S195 of PD-L1. S195 phosphorylation induces abnormal PD-L1 glycosylation, resulting in its ER accumulation and ER-associated protein degradation (ERAD). Consistently, tumor tissues from metformin-treated breast cancer patients exhibit reduced PD-L1 levels with AMPK activation. Blocking the inhibitory signal of PD-L1 by metformin enhances CTL activity against cancer cells. Our findings identify a new regulatory mechanism of PD-L1 expression through the ERAD pathway and suggest that the metformin-CTLA4 blockade combination has the potential to increase the efficacy of immunotherapy.
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•Metformin enhances antitumor CTL immunity by blocking PD-L1/PD-1 axis•Metformin-activated AMPK directly binds to and phosphorylates PD-L1 at S195•Abnormal PD-L1 glycosylation induced by pS195 leads to PD-L1 degradation by ERAD•Combination therapy with metformin and anti-CTLA4 has a synergistic antitumor effect
Cha et al. elucidated a mechanism to show that metformin-activated AMPK phosphorylates PD-L1 at S195 to induce abnormal glycosylation and degrades PD-L1 through an ERAD pathway. This study suggests the potential to use metformin as an adjuvant with various non-PD-L1/PD-1-targeting immune therapies.
Glycosylation of immune receptors and ligands, such as T cell receptor and coinhibitory molecules, regulates immune signaling activation and immune surveillance. However, how oncogenic signaling ...initiates glycosylation of coinhibitory molecules to induce immunosuppression remains unclear. Here we show that IL-6-activated JAK1 phosphorylates programmed death-ligand 1 (PD-L1) Tyr112, which recruits the endoplasmic reticulum-associated N-glycosyltransferase STT3A to catalyze PD-L1 glycosylation and maintain PD-L1 stability. Targeting of IL-6 by IL-6 antibody induced synergistic T cell killing effects when combined with anti-T cell immunoglobulin mucin-3 (anti-Tim-3) therapy in animal models. A positive correlation between IL-6 and PD-L1 expression was also observed in hepatocellular carcinoma patient tumor tissues. These results identify a mechanism regulating PD-L1 glycosylation initiation and suggest the combination of anti-IL-6 and anti-Tim-3 as an effective marker-guided therapeutic strategy.
High invasiveness is a hallmark of human hepatocellular carcinoma (HCC). Large tumors predict invasion and metastasis. Epithelial‐mesenchymal transition (EMT) is crucial for cancer invasion and ...metastasis. However, the mechanisms whereby large tumors tend to undergo EMT remain unclear. We conducted a subgenome‐wide screen and identified KLHL23 as an HCC invasion suppressor by inhibiting EMT. KLHL23 binds to actin and suppresses actin polymerization. KLHL23 silencing induced filopodium and lamellipodium formation. Moreover, EMT was suppressed by KLHL23 through its action on actin dynamics. Traditionally, actin cytoskeleton remodeling is downstream of EMT reprogramming. It is therefore intriguing to ask why and how KLHL23 inversely regulates EMT. Activation of actin cytoskeleton remodeling by either KLHL23 silencing or treatment with actin cytoskeleton modulators augmented cellular hypoxic responses in a cell‐density–dependent manner, resulting in hypoxia‐inducible factor (HIF) and Notch signals and subsequent EMT. Environmental hypoxia did not induce EMT unless actin cytoskeleton remodeling was simultaneously activated and only when cells were at high density. The resulting EMT was reversed by either adenosine 5′‐triphosphate supplementation or actin polymerization inhibitors. Down‐regulation of KLHL23 was associated with invasion, metastasis, and poor prognosis of HCC and pancreatic cancer. Correlations of tumor size with EMT and inverse association of expression of KLHL23 with HIF/Notch signals were further validated in patient‐derived xenograft HCCs in mice. Conclusion: Simultaneously activation of actin cytoskeleton remodeling by intrinsic (such as KLHL23 down‐regulation) or microenvironment cues is crucial for cell‐density–dependent and hypoxia‐mediated EMT, providing a mechanistic link between large tumor size and invasion/metastasis. Our findings provide a means of developing the prevention and treatment strategies for tumor invasion and metastasis. (Hepatology 2018;67:2226‐2243).
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