The size of C‐nanodots can be electrochemically tuned by changing the applied potential during their preparation. The higher the applied potential, the smaller the resulting C‐nanodots. Moreover, the ...surface oxidation degree of the C‐nanodots can also be electrochemically tuned. The red‐shift of emission independent of the size provides an insight into the luminescence mechanism of C‐nanodots.
The accumulation of lipid peroxides is recognized as a determinant of the occurrence of ferroptosis. However, the sensors and amplifying process of lipid peroxidation linked to ferroptosis remain ...obscure. Here we identify PKCβII as a critical contributor of ferroptosis through independent genome-wide CRISPR-Cas9 and kinase inhibitor library screening. Our results show that PKCβII senses the initial lipid peroxides and amplifies lipid peroxidation linked to ferroptosis through phosphorylation and activation of ACSL4. Lipidomics analysis shows that activated ACSL4 catalyses polyunsaturated fatty acid-containing lipid biosynthesis and promotes the accumulation of lipid peroxidation products, leading to ferroptosis. Attenuation of the PKCβII-ACSL4 pathway effectively blocks ferroptosis in vitro and impairs ferroptosis-associated cancer immunotherapy in vivo. Our results identify PKCβII as a sensor of lipid peroxidation, and the lipid peroxidation-PKCβII-ACSL4 positive-feedback axis may provide potential targets for ferroptosis-associated disease treatment.
Abstract
Most triple-negative breast cancer (TNBC) patients fail to respond to T cell-mediated immunotherapies. Unfortunately, the molecular determinants are still poorly understood. Breast cancer is ...the disease genetically linked to a deficiency in autophagy. Here, we show that autophagy defects in TNBC cells inhibit T cell-mediated tumour killing in vitro and in vivo. Mechanistically, we identify Tenascin-C as a candidate for autophagy deficiency-mediated immunosuppression, in which Tenascin-C is Lys63-ubiquitinated by Skp2, particularly at Lys942 and Lys1882, thus promoting its recognition by p62 and leading to its selective autophagic degradation. High Tenascin-C expression is associated with poor prognosis and inversely correlated with LC3B expression and CD8
+
T cells in TNBC patients. More importantly, inhibition of Tenascin-C in autophagy-impaired TNBC cells sensitizes T cell-mediated tumour killing and improves antitumour effects of single anti-PD1/PDL1 therapy. Our results provide a potential strategy for targeting TNBC with the combination of Tenascin-C blockade and immune checkpoint inhibitors.
Electrical conductivity and dielectric parameters are general inherent features of materials. Controlling these characteristics through applied bias will add a new dimension to regulate the dynamic ...response of smart materials. Here, a fascinating electrical transport behavior is observed in topological insulator (TI) Bi2Te3 nanorods, which will play a vital role in intelligent materials or devices as a unit for information reception, processing or feedback. The Bi2Te3 nanorod aggregates exhibit a monotonic resistance response to voltage, with observed four‐fold change of electrical conductivity in a small range electric field of 1 V mm−1. The dielectric constant and dielectric loss of Bi2Te3 nanorod composites also show strong dependences on bias voltage due to the unique electrical transport characteristics. The unique voltage‐controlled electrical responses are attributed to the change of Fermi levels within the band structure of disordered TI nanorods, which are non‐parallel to the applied electric field. The excellent controllable inherent characteristics through electric field endows Bi2Te3 nanomaterials bright prospects for applications in smart devices and resistive random access memories.
Bi2Te3 nanorods exhibit monotonic resistance response to voltage and strong dependence of dielectric constant on voltage. Compared with other materials, the Bi2Te3 nanorod aggregates have the largest electrical conductivity variation range with smallest voltage scope. The fascinating electrical transport behavior endows the material with tremendous application potential in communication systems, smart devices, miniature generators, and intelligent storage.
Most patients with triple negative breast cancer (TNBC) do not respond to anti-PD1/PDL1 immunotherapy, indicating the necessity to explore immune checkpoint targets. B7H3 is a highly glycosylated ...protein. However, the mechanisms of B7H3 glycosylation regulation and whether the sugar moiety contributes to immunosuppression are unclear. Here, we identify aberrant B7H3 glycosylation and show that N-glycosylation of B7H3 at NXT motif sites is responsible for its protein stability and immunosuppression in TNBC tumors. The fucosyltransferase FUT8 catalyzes B7H3 core fucosylation at N-glycans to maintain its high expression. Knockdown of FUT8 rescues glycosylated B7H3-mediated immunosuppressive function in TNBC cells. Abnormal B7H3 glycosylation mediated by FUT8 overexpression can be physiologically important and clinically relevant in patients with TNBC. Notably, the combination of core fucosylation inhibitor 2F-Fuc and anti-PDL1 results in enhanced therapeutic efficacy in B7H3-positive TNBC tumors. These findings suggest that targeting the FUT8-B7H3 axis might be a promising strategy for improving anti-tumor immune responses in patients with TNBC.
Summary
Chemotherapy is one of the prevailing methods used to treat malignant tumours, but the outcome and prognosis of tumour patients are not optimistic. Cancer cells gradually generate resistance ...to almost all chemotherapeutic drugs via a variety of distinct mechanisms and pathways. Chemotherapeutic resistance, either intrinsic or acquired, is caused and sustained by reduced drug accumulation and increased drug export, alterations in drug targets and signalling transduction molecules, increased repair of drug‐induced DNA damage, and evasion of apoptosis. In order to better understand the mechanisms of chemoresistance, this review highlights our current knowledge of the role of altered drug metabolism and transport and deregulation of apoptosis and autophagy in the development of tumour chemoresistance. Reduced intracellular activation of prodrugs (e.g. thiotepa and tegafur) or enhanced drug inactivation by Phase I and II enzymes contributes to the development of chemoresistance. Both primary and acquired resistance can be caused by alterations in the transport of anticancer drugs which is mediated by a variety of drug transporters such as P‐glycoprotein (P‐gp), multidrug resistance associated proteins, and breast cancer resistance protein. Presently there is a line of evidence indicating that deregulation of programmed cell death including apoptosis and autophagy is also an important mechanism for tumour resistance to anticancer drugs. Reversal of chemoresistance is likely via pharmacological and biological approaches. Further studies are warranted to grasp the full picture of how each type of cancer cells develop resistance to anticancer drugs and to identify novel strategies to overcome it.
Microbial reductive dechlorination of chlorinated aromatics frequently suffers from the long dechlorination period and the generation of toxic metabolites. Biocathode bioelectrochemical systems were ...verified to be effective in the degradation of various refractory pollutants. However, the electrochemical and microbial related working mechanisms for bio-dechlorination by electro-stimulation remain poorly understood. In this study, we reported the significantly improved 2,4,6-trichlorophenol dechlorination activity through the weak electro-stimulation (cathode potential of −0.36 V vs. SHE), as evidenced by the 3.1 times higher dechlorination rate and the complete dechlorination ability with phenol as the end dechlorination product. The high reductive dechlorination rate (20.8 μM/d) could be maintained by utilizing electrode as an effective electron donor (coulombic efficiency of 82.3 ± 4.8%). Cyclic voltammetry analysis of the cathodic biofilm gave the direct evidences of the cathodic respiration with the improved and positive-shifted reduction peaks of 2,4,6-TCP, 2,4-DCP and 4-CP. The optimal 2,4,6-TCP reductive dechlorination rate (24.2 μM/d) was obtained when a small amount of lactate (2 mM) was added, and the generation of H2 and CH4 were accompanied due to the biological fermentation and methanogenesis. The electrical stimulation significantly altered the cathodic biofilm structure and composition with some potential dechlorinators (like Acetobacterium) predominated. The microbial interactions in the ecological network of cathodic biofilm were more simplified than the planktonic community. However, some potential dechlorinators (Acetobacterium, Desulfovibrio, etc.) shared more positive interactions. The co-existence and possible cooperative relationships between potential dechlorinators and fermenters (Sedimentibacter, etc.) were revealed. Meanwhile, the competitive interrelations between potential dechlorinators and methanogens (Methanomassiliicoccus) were found. In the network of plankton, the fermenters and methanogens possessed the more positive interrelations. Electro-stimulation at the cathodic potential of −0.36 V selectively enhanced the dechlorination function, while it showed little influence on either fermentation or methanogenesis process. The study gave suggestions for the enhanced bioremediation of chlorinated aromatics, in views of the electro-stimulation capacity, efficiency and microbial interrelations related microbial mechanism.
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•Electro-stimulation significantly improved 2,4,6-TCP reductive dechlorination.•Electrode served as an effective electron donor for highly-efficient dechlorination.•Electro-stimulation distinctly altered the microbial community structure.•Cooperative and competitive interrelations of functional population were revealed.•Electro-stimulation optimized microbial interrelations for enhanced dechlorination.
Primary liver cancer is a lethal cancer. The phosphatidylinositol 3-kinase (PI3K)–Akt–mammalian target of rapamycin (mTOR) pathway has been implicated in the pathogenesis of liver cancer. Gomisin N ...(GN), a lignan isolated from the dried fruits of Schisandra chinensis (Turca.) Baill., has been reported to reduce viability of, and induce apoptosis in, HepG2 liver cancer cells. In preadipocytes, GN was found to inhibit Akt activity. In the present study, Akt signaling-related anti-liver cancer mechanisms of GN were investigated. We confirmed that GN reduces cell viability of, and triggers apoptosis in, more liver cancer cell lines. Mechanistic studies revealed that GN lowers protein levels of phospho-PI3K (p85 tyrosine (Tyr)458), phospho-Akt (serine (Ser)473), and Akt downstream molecules Mcl-1 in HepG2 and HCCLM3 cells. Meanwhile, GN activates mTOR and inhibits ULK1 (a negative downstream effector of mTOR) activities. Activation of mTOR has been reported to suppress ULK1 activity and repress autophagy. Indeed, we observed that GN inhibits autophagy in liver cancer cells. In summary, we for the first time demonstrated that GN inhibits the PI3K–Akt pathway and regulates the mTOR–ULK1 pathway in liver cancer cells.
Virtual reality (VR) is the use of computer technology to create an interactive three-dimensional (3D) world, which gives users a sense of spatial presence. In nursing education, VR has been used to ...help optimize teaching and learning processes.
The purpose of this study was to evaluate the effectiveness of VR in nursing education in the areas of knowledge, skills, satisfaction, confidence, and performance time.
We conducted a meta-analysis of the effectiveness of VR in nursing education based on the Cochrane methodology. An electronic literature search using the Cochrane Library, Web of Science, PubMed, Embase, and CINAHL (Cumulative Index to Nursing and Allied Health Literature), up to December 2019 was conducted to identify studies that reported the effectiveness of VR on knowledge, skills, satisfaction, confidence, and performance time. The study selection and data extraction were carried out by two independent reviewers. The methodological quality of the selected studies was determined using the Cochrane criteria for risk-of-bias assessment.
A total of 12 studies, including 821 participants, were selected for the final analysis. We found that VR was more effective than the control conditions in improving knowledge (standard mean difference SMD=0.58, 95% CI 0.41-0.75, P<.001, I
=47%). However, there was no difference between VR and the control conditions in skills (SMD=0.01, 95% CI -0.24 to 0.26, P=.93, I
=37%), satisfaction (SMD=0.01, 95% CI -0.79 to 0.80, P=.99, I
=86%), confidence (SMD=0.00, 95% CI -0.28 to 0.27, P=.99, I
=0%), and performance time (SMD=-0.55, 95% CI -2.04 to 0.94, P=.47, I
=97%).
The results of this study suggest that VR can effectively improve knowledge in nursing education, but it was not more effective than other education methods in areas of skills, satisfaction, confidence, and performance time. Further rigorous studies with a larger sample size are warranted to confirm these results.
MicroRNAs (miRNAs) are endogenous, small noncoding RNAs that play important roles in various cellular functions and tumor development. Recent studies have indicated that miR-21 is one of the ...important miRNAs associated with tumor growth and metastasis, but the role and molecular mechanism of miR-21 in regulating tumor angiogenesis remain to be elucidated. In this study, miR-21 was overexpressed by transfecting pre-miR-21 into human prostate cancer cells and tumor angiogenesis was assayed using chicken chorioallantoic membrane (CAM). We found that overexpression of miR-21 in DU145 cells increased the expression of HIF-1α and VEGF, and induced tumor angiogenesis. AKT and extracellular regulated kinases (ERK) 1/2 are activated by miR-21. Inhibition of miR-21 by the antigomir blocked this process. Overexpression of the miR-21 target, PTEN, also inhibited tumor angiogenesis by partially inactivating AKT and ERK and decreasing the expression of HIF-1 and VEGF. The AKT and ERK inhibitors, LY294002 and U0126, suppressed HIF-1α and VEGF expression and angiogenesis. Moreover, inhibition of HIF-1α expression alone abolished miR-21-inducing tumor angiogenesis, indicating that HIF-1α is required for miR-21-upregulated angiogenesis. Therefore, we demonstrate that miR-21 induces tumor angiogenesis through targeting PTEN, leading to activate AKT and ERK1/2 signaling pathways, and thereby enhancing HIF-1α and VEGF expression; HIF-1α is a key downstream target of miR-21 in regulating tumor angiogenesis.
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