Under evolutionary pressure from chemotherapy, cancer cells develop resistance characteristics such as a low redox state, which eventually leads to treatment failures. An attractive option for combatting resistance is producing a high concentration of produced free radicals in situ. Here, we report the production and use of dispersible hollow carbon nanospheres (HCSs) as a novel platform for delivering the drug doxorubicine (DOX) and generating additional cellular reactive oxygen species using near-infrared laser irradiation. These irradiated HCSs catalyzed sufficiently persistent free radicals to produce a large number of heat shock factor-1 protein homotrimers, thereby suppressing the activation and function of resistance-related genes. Laser irradiation also promoted the release of DOX from lysosomal DOX@HCSs into the cytoplasm so that it could enter cell nuclei. As a result, DOX@HCSs reduced the resistance of human breast cancer cells (MCF-7/ADR) to DOX through the synergy among photothermal effects, increased generation of free radicals, and chemotherapy with the aid of laser irradiation. HCSs can provide a unique and versatile platform for combatting chemotherapy-resistant cancer cells. These findings provide new clinical strategies and insights for the treatment of resistant cancers.

As one member of 70 kDa heat shock proteins, glucose-regulated protein 78 (GRP78) participates in protein folding, transportation and degradation. This sort of capacity can be enhanced by stresses under which GRP78 is induced rapidly. Unlike its homologues, GRP78 presents multifaceted subcellular position: When ER retention, it serves as the switch of unfolded protein response; When mitochondrial binding, it directly interacts with apoptotic executors; When cell surface residing, it recognizes extracellular ligands, transducing proliferative signals, especially in certain tumors. The close correlation between GRP78 and neoplasm provides us further insight into the event of carcinogenesis and cancer cell chemoresistance, indicating its prognostic predicting significance and validating potential therapeutics for clinical usage, especially because its small molecular inhibitors are emerging quickly these years. What's more, GRP78-related signaling may be helpful for clearer understanding of its biological mechanisms.

The aryl hydrocarbon receptor (AhR) has become increasingly recognized for its role in the differentiation and activity of immune cell subsets; however, its role in regulating the activity of natural killer (NK) cells has not been described. Here, we show that AhR expression is induced in murine NK cells upon cytokine stimulation. We show that in the absence of AhR, NK cells have reduced cytolytic activity and reduced capacity to control RMA-S tumor formation in vivo, despite having normal development and maturation markers. Although AhR was first identified to bind the xenobiotic compound dioxin, AhR is now known to bind a variety of natural exogenous (e.g., dietary) and endogenous ligands. We show that activation of AhR with an endogenous tryptophan derivative, 6-formylindolo[3,2-b]carbazole, potentiates NK cell IFN-γ production and cytolytic activity. Further, administration of 6-formylindolo[3,2-b]carbazole in vivo enhances NK cell control of tumors in an NK cell-and AhR-dependent manner. Finally, similar effects on NK cell potency occur with AhR dietary ligands, potentially explaining the numerous associations that have been observed in the past between diet and NK cell function. Our studies introduce AhR as another regulator of NK cell activity in vivo.FICZ | kynurenine, 3,3′-diindolylmethane (DIM) | indole-3-carbinol (I3C)

The emergence and spread of mobilized colistin resistance (mcr) genes have triggered extensive concerns worldwide. Here, we characterized the global distribution of mcr-9, a newly-identified variant of mcr, by assembling the data set of mcr-9-positive isolates from GenBank database and the literature available. Genetic features of all the mcr-9-harboring plasmids were determined by bioinformatic analysis. We showed that mcr-9 is globally distributed in 21 countries across six continents, with a wide dissemination among various species of Enterobacteriaceae strains from human, animal, food and environment. IncHI2-ST1 plasmids were found to be the predominant replicon type carrying mcr-9. Comparative genomics highlighted that IncHI2-type plasmids may also serve as a critical reservoir of mcr-9, from which different types of circulating plasmids acquired the mcr-9. Results revealed that the rcnR-rcnA-pcoE-pcoS-IS903-mcr-9-wbuC structure was consistent in most mcr-9 cassettes, suggesting a relatively unitary model involved in the mobilization of mcr-9. It is most likely that the spread of mcr-9 was mainly attributed to the conjugation and recombination events of mcr-9-carrying plasmids. In summary, our results provide a comprehensive picture of the distribution and genetic environment of mcr-9, and demonstrate the central roles played by IncHI2 plasmids in the worldwide dissemination of mcr-9. Antibiotic resistance poses a great threat to global public health and carbapenem-resistant Enterobacteriaceae is triggering a health crisis worldwide 1,2. Colistin, a cationic cyclic-peptide, is one of the last-resort antibiotics to defend against severe infections caused by carbapenem-resistant Enterobacteriaceae 3. However, since the initial discovery of a plasmid-mediated mobilized colistin resistance gene (mcr-1) in China in late 2015 4 , a number of diversified bacterial strains carrying mcr-1 have been detected across over 50 countries covering six continents 5. The prevalent plasmid-borne MCR enzyme can catalyze chemical addition of phosphoethanolamine to lipid A moiety of bacterial lipopolysaccharides, the target of colistin, which consequently promotes colistin resistance 6. In recent years, a growing number of mcr-like genes (namely, from mcr-2 to mcr-10) have been identified 7-14. These ongoing discoveries indicate a rapid evolution of MCR family under selective pressures, which raise global health concerns. mcr-9 is a newly emerging variant of the mobilized colistin resistance determinants, which was first identified in a clinical Salmonella enterica isolate in the USA in May, 2019 13. Since its initial identification, mcr-9 has been reported in several other countries, such as China 15 , Sweden 16 , and France 17. Not only that, in silico analysis using the GenBank database indicated that mcr-9 had already been presented in a number of Enterobacteriaceae isolates recovered worldwide 13,17. The high prevalence of mcr-9 suggests one more threat to public health. However, little information is available about the glo...

Although carbon itself acts as a catalyst in various reactions, the classical carbon materials (e.g., activated carbons, carbon aerogels, carbon black, carbon fiber, etc.) usually show low activity, stability, and oxidation resistance. With the recent availability of nanocarbon catalysts, the application of carbon materials in catalysis has gained a renewed momentum. The research is concentrated on tailoring the surface chemistry of nanocarbon materials, since the pristine carbons in general are not active for heterogeneous catalysis. Surface functionalization, doping with heteroatoms, and creating defects are the most used strategies to make efficient catalysts. However, the nature of the catalytic active sites and their role in determining the activity and selectivity is still not well understood. Herein, the types of active sites reported for several mainstream nanocarbons, including carbon nanotubes, graphene‐based materials, and 3D porous nanocarbons, are summarized. Knowledge about the active sites will be beneficial for the design and synthesis of nanocarbon catalysts with improved activity, selectivity, and stability.

The four serotypes of dengue virus (DENV1-4) are causative agents of dengue fever and dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). Previous DENV infection is a risk factor for DHF/DSS during subsequent infection by a different serotype. Nonetheless, most primary and secondary DENV infections are asymptomatic. To investigate the possible mechanisms of immune protection in vivo, 129/Pas mice lacking IFN-α/β and -γ receptors (AG129) were used to model secondary infection using both DENV1-DENV2 and DENV2-DENV4 sequences. At intervals between sequential infections of 4 to 52 weeks, protection against secondary heterologous DENV infection was observed. Passive transfer of DENV-immune serum was protective against replication of heterologous challenge virus in all tissues tested, whereas adoptive transfer of DENV-immune cells significantly protected mice from replication of the challenge virus only when a lower inoculum was administered. These findings are relevant for understanding both natural and vaccine-induced immunity to DENV.

Carbon-based single-atom catalysts (SACs) with well-defined and homogeneously dispersed metal−N 4 moieties provide a great opportunity for CO 2 reduction. However, controlling the binding strength of various reactive intermediates on catalyst surface is necessary to enhance the selectivity to a desired product, and it is still a challenge.

We developed a tandem electrocatalyst for CO 2 -to-CO conversion comprising the single Cu site co-coordinated with N and S anchored carbon matrix (Cu-S 1 N 3 ) and atomically dispersed Cu clusters (Cu x ), denoted as Cu-S 1 N 3 /Cu x . The as-prepared Cu-S 1 N 3 /Cu x composite presents a 100 % Faradaic efficiency towards CO generation (FE CO ) at À0.65 V vs. RHE and high FE CO over 90 % from À0.55 to À0.75 V, outperforming the analogues with Cu-N 4 (FE CO only 54 % at À0.7 V) and Cu-S 1 N 3 (FE CO 70 % at À0.7 V) configurations. The unsymmetrical Cu-S 1 N 3 atomic interface in the carbon basal plane possesses an optimized binding energy for the key intermediate *COOH compared with Cu-N 4 site. At the same time, the adjacent Cu x effectively promotes the protonation of *CO 2 À by accelerating water dissociation and offering *H to the Cu-S 1 N 3 active sites. This work provides a tandem strategy for facilitating proton-coupled electron transfer over the atomic-level catalytic sites.Electrochemical reduction CO 2 to value-added fuels using renewable electricity is one of appealing CO 2 utilization strategies for management of the global carbon balance. [1] Recent technoeconomic analysis shows that the reduction of CO 2 to CO or formic acid through two-electron transfer processes is the most economical approach for CO 2 conversion, owing to their high added value per KJ of electrical energy input. [2] As a typical product, CO, especially with high purity, is very attractive, because it can be readily used as an important feed-stock for a couple of chemical engineering processes such as Fischer-Tropsch synthesis. [3] Thus, efficient CO 2 -to-CO conversion catalysts with adequate activity and selectivity are highly desired.