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.
Electroreduction of CO2 to acetate provides a promising strategy to reduce CO2 emissions and store renewable energy, but acetate is usually a by‐product. Here, we show a stable and conductive ...two‐dimensional phthalocyanine‐based covalent‐organic framework (COF) as an electrocatalyst for reduction of CO2 to acetate with a single‐product Faradaic efficiency (FE) of 90.3(2)% at −0.8 V (vs. RHE) and a current density of 12.5 mA cm−2 in 0.1 M KHCO3 solution. No obvious degradation was observed over 80 hours of continuous operation. Combined with the comparison of the properties of other catalysts with isolated metal active sites, theoretical calculations and in situ infrared spectroscopy revealed that the isolated copper‐phthalocyanine active site with high electron density is conducive to the key step of C−C coupling of *CH3 with CO2 to produce acetate, and can avoid the coupling of *CO with *CO or *CHO to produce ethylene and ethanol.
Compared to multiple active sites, an isolated active site with high electron density may be more suitable for electroreduction of CO2 towards the C2 product acetate, and can avoid the coupling of *CO with *CO or *CHO to produce ethylene and ethanol.
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.
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.
Zika virus (ZIKV) has evolved into a global health threat because of its unexpected causal link to microcephaly. Phylogenetic analysis reveals that contemporary epidemic strains have accumulated ...multiple substitutions from their Asian ancestor. Here we show that a single serine-to-asparagine substitution Ser139→Asn139 (S139N) in the viral polyprotein substantially increased ZIKV infectivity in both human and mouse neural progenitor cells (NPCs) and led to more severe microcephaly in the mouse fetus, as well as higher mortality rates in neonatal mice. Evolutionary analysis indicates that the S139N substitution arose before the 2013 outbreak in French Polynesia and has been stably maintained during subsequent spread to the Americas. This functional adaption makes ZIKV more virulent to human NPCs, thus contributing to the increased incidence of microcephaly in recent ZIKV epidemics.
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in an unprecedented public health crisis. There are no approved ...vaccines or therapeutics for treating COVID-19. Here we report a humanized monoclonal antibody, H014, that efficiently neutralizes SARS-CoV-2 and SARS-CoV pseudoviruses as well as authentic SARS-CoV-2 at nanomolar concentrations by engaging the spike (S) receptor binding domain (RBD). H014 administration reduced SARS-CoV-2 titers in infected lungs and prevented pulmonary pathology in a human angiotensin-converting enzyme 2 mouse model. Cryo-electron microscopy characterization of the SARS-CoV-2 S trimer in complex with the H014 Fab fragment unveiled a previously uncharacterized conformational epitope, which was only accessible when the RBD was in an open conformation. Biochemical, cellular, virological, and structural studies demonstrated that H014 prevents attachment of SARS-CoV-2 to its host cell receptors. Epitope analysis of available neutralizing antibodies against SARS-CoV and SARS-CoV-2 uncovered broad cross-protective epitopes. Our results highlight a key role for antibody-based therapeutic interventions in the treatment of COVID-19.
Producing polyesters with high molecular weight (Mn) through ring‐opening copolymerization (ROCOP) of epoxides with cyclic anhydrides remains a major challenge. Herein, we communicate a metal‐free, ...highly active, and high thermoresistance system for the ROCOP of epoxides with cyclic anhydrides to prepare polyesters (13 examples). The organoboron catalysts can endure a reaction temperature as high as 180 °C for the ROCOP of cyclohexane oxide (CHO) with phthalic anhydride (PA) without the observation of any side reactions. The average Mn of the produced poly(CHO‐alt‐PA) climbed to 94.5 kDa with low polydispersity (Ð=1.19). Furthermore, an unprecedented turnover number of 9900, equivalent to an efficiency of 7.4 kg of polyester/g of catalyst, was achieved at a feed ratio of CHO/PA/catalyst=20000:10000:1 at 150 °C. Kinetic studies, crystal structure analysis, 11B NMR spectra, and DFT calculations provided mechanistic justification for the effectiveness of the catalyst system.
Ring‐opening copolymerization of epoxides and cyclic anhydrides by organoboron catalysts is presented. In view of their facile preparation and unprecedented performance (thermostability, reactivity, and productivity), the catalysts provided here hold promise in pushing ROCOP of epoxides with cyclic anhydrides to the industry line.
Zika virus (ZIKV) has become a global public health emergency due to its rapidly expanding range and its ability to cause severe congenital defects such as microcephaly. However, there are no ...FDA-approved therapies or vaccines against ZIKV infection. Through our screening of viral entry inhibitors, we found that chloroquine (CQ), a commonly used antimalarial and a FDA-approved drug that has also been repurposed against other pathogens, could significantly inhibit ZIKV infection in vitro, by blocking virus internalization. We also demonstrated that CQ attenuates ZIKV-associated morbidity and mortality in mice. Finally, we proved that CQ protects fetal mice from microcephaly caused by ZIKV infection. Our methodology of focusing on previously identified antivirals in screens for effectiveness against ZIKV proved to be a rapid and efficient means of discovering new ZIKV therapeutics. Selecting drugs that were previously FDA-approved, such as CQ, also improves the likelihood that they may more quickly reach stages of clinical testing and use by the public.
•5 out 16 tested Ebola virus entry inhibitors can inhibit ZIKV entry efficiently•Chloroquine can inhibit ZIKV internalization in vitro and reduce ZIKV-associated morbidity and mortality in mice•Chloroquine prevents ZIKV-associated congenital microcephaly in mice
Zika virus (ZIKV) is an emerging virus which can cause birth defects, however there are currently no effective treatments or vaccines. We tested the effects of 16 verified Ebola virus cell entry inhibitors on ZIKV infection, and found that chloroquine (CQ) could prevent ZIKV infection in cell cultures, consistent with results from a previous study. We then demonstrated that CQ can reduce ZIKV-associated morbidity and mortality in mice. Most importantly, it protects fetal mice from microcephaly caused by ZIKV infection. Therefore, CQ is a potential drug which would be used to treat ZIKV infection after clinical test.
Selective partial oxidation of methane to methanol suffers from low efficiency. Here, we report a heterogeneous catalyst system for enhanced methanol productivity in methane oxidation by in situ ...generated hydrogen peroxide at mild temperature (70°C). The catalyst was synthesized by fixation of AuPd alloy nanoparticles within aluminosilicate zeolite crystals, followed by modification of the external surface of the zeolite with organosilanes. The silanes appear to allow diffusion of hydrogen, oxygen, and methane to the catalyst active sites, while confining the generated peroxide there to enhance its reaction probability. At 17.3% conversion of methane, methanol selectivity reached 92%, corresponding to methanol productivity up to 91.6 millimoles per gram of AuPd per hour.
Owing to their outstanding comprehensive performance, polyimide (PI) composite films are widely used on the external surfaces of spacecraft to protect them from the adverse conditions of low Earth ...orbit (LEO). However, current PI composite films have inadequate mechanical properties and atomic oxygen (AO) resistance. Herein, this work fabricates a new PI‐based nanocomposite film with greatly enhanced mechanical properties and AO resistance by integrating mica nanosheets with PI into a unique double‐layer nacre‐inspired structure with a much higher density of mica nanosheets in the top layer. In addition, the unique microstructure and the intrinsic properties of mica also impart the nanocomposite film with favorable ultraviolet and high‐temperature resistance. The comprehensive performance of this material is superior to those of pure PI, single‐layer PI‐mica, and previously reported PI‐based composite films. Thus, the double‐layer nanocomposite film displays great potential as an aerospace material for use in LEO.
A polyimide‐mica (PI‐Mica) nanocomposite film with outstanding mechanical properties and atomic oxygen resistance is produced by integrating mica nanosheets with polyimide into a double‐layer nacre‐inspired structure with a much higher density of mica in the top layer. This unique microstructure and advantages of mica also impart the film with favorable resistance to ultraviolet, space debris, and high temperatures.
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