Enhanced redox kinetics of Prussian blue analogues for superior electrochemical deionization performance.

Prussian blue analogues (PBAs), representing the typical faradaic electrode materials for efficient capacitive deionization (CDI) due to their open architecture and high capacity, have been plagued by kinetics issues, leading to insufficient utilization of active sites and poor structure stability. Herein, to address the conflict issue between desalination capacity and stability due to mismatched ionic and electronic kinetics for the PBA-based electrodes, a rational design, including Mn substitution and polypyrrole (ppy) connection, has been proposed for the nickel hexacyanoferrate (Mn-NiHCF/ppy), serving as a model case. Particularly, the theoretical calculation manifests the reduced bandgap and energy barrier for ionic diffusion after Mn substitution, combined with the increased electronic conductivity and integrity through ppy connecting, resulting in enhanced redox kinetics and boosted desalination performance. Specifically, the optimized Mn-NiHCF/ppy demonstrates a remarkable desalination capacity of 51.8 mg g-1 at 1.2 V, accompanied by a high charge efficiency of 81%, and excellent cycling stability without obvious degradation up to 50 cycles, outperforming other related materials. Overall, our concept shown herein provides insights into the design of advanced faradaic electrode materials for high-performance CDI.

RAB27B controls palmitoylation-dependent NRAS trafficking and signaling in myeloid leukemia.

RAS mutations are among the most prevalent oncogenic drivers in cancers. RAS proteins propagate signals only when associated with cellular membranes as a consequence of lipid modifications that impact their trafficking. Here, we discovered that RAB27B, a RAB family small GTPase, controlled NRAS palmitoylation and trafficking to the plasma membrane, a localization required for activation. Our proteomic studies revealed RAB27B upregulation in CBL- or JAK2-mutated myeloid malignancies, and its expression correlated with poor prognosis in acute myeloid leukemias (AMLs). RAB27B depletion inhibited the growth of CBL-deficient or NRAS-mutant cell lines. Strikingly, Rab27b deficiency in mice abrogated mutant but not WT NRAS-mediated progenitor cell growth, ERK signaling, and NRAS palmitoylation. Further, Rab27b deficiency significantly reduced myelomonocytic leukemia development in vivo. Mechanistically, RAB27B interacted with ZDHHC9, a palmitoyl acyltransferase that modifies NRAS. By regulating palmitoylation, RAB27B controlled c-RAF/MEK/ERK signaling and affected leukemia development. Importantly, RAB27B depletion in primary human AMLs inhibited oncogenic NRAS signaling and leukemic growth. We further revealed a significant correlation between RAB27B expression and sensitivity to MEK inhibitors in AMLs. Thus, our studies presented a link between RAB proteins and fundamental aspects of RAS posttranslational modification and trafficking, highlighting future therapeutic strategies for RAS-driven cancers.

Metabolomic insights of macrophage responses to graphene nanoplatelets: Role of scavenger receptor CD36.

Graphene nanoplatelets (GNPs) are novel two-dimensional engineered nanomaterials consisting of planar stacks of graphene. Although human exposures are increasing, our knowledge is lacking regarding immune-specific responses to GNPs and mechanisms of interactions. Our current study utilizes a metabolite profiling approach to evaluate macrophage responses to GNPs. Furthermore, we assessed the role of the scavenger receptor CD36 in mediating these GNP-induced responses. GNPs were purchased with dimensions of 2 µm × 2 µm × 12 nm. Macrophages were exposed to GNPs at different concentrations of 0, 25, 50, or 100 µg/ml for 1, 3, or 6 h. Following exposure, no cytotoxicity was observed, while GNPs readily associated with macrophages in a concentration-dependent manner. After the 1h-pretreatment of either a CD36 competitive ligand sulfo-N-succinimidyl oleate (SSO) or a CD36 specific antibody, the cellular association of GNPs by macrophages was significantly reduced. GNP exposure was determined to alter mitochondrial membrane potential while the pretreatment with a CD36 antibody inhibited these changes. In a separate exposure, macrophages were exposed to GNPs at concentrations of 0, 50, or 100 µg/mL for 1 or 3h or 100 µM SSO (a CD36 specific ligand) for 1h and collected for metabolite profiling. Principal component analysis of identified compounds determined differential grouping based on exposure conditions. The number of compounds changed following exposure was determined to be both concentration- and time-dependent. Identified metabolites were determined to relate to several metabolism pathways such as glutathione metabolism, Pantothenate and CoA biosynthesis, Sphingolipid metabolism, Purine metabolism, arachidonic acid metabolism and others. Lastly, a number of metabolites were found in common between cells exposed to the CD36 receptor ligand, SSO, and GNPs suggesting both CD36-dependent and independent responses to GNP exposure. Together our data demonstrates GNP-macrophage interactions, the role of CD36 in the cellular response, and metabolic pathways disrupted due to exposure.

Enhanced Degradation of Misfolded Proteins Promotes Tumorigenesis.

An adequate cellular capacity to degrade misfolded proteins is critical for cell survival and organismal health. A diminished capacity is associated with aging and neurodegenerative diseases; however, the consequences of an enhanced capacity remain undefined. Here, we report that the ability to clear misfolded proteins is increased during oncogenic transformation and is reduced upon tumor cell differentiation. The augmented capacity mitigates oxidative stress associated with oncogenic growth and is required for both the initiation and maintenance of malignant phenotypes. We show that tripartite motif-containing (TRIM) proteins select misfolded proteins for proteasomal degradation. The higher degradation power in tumor cells is attributed to the upregulation of the proteasome and especially TRIM proteins, both mediated by the antioxidant transcription factor Nrf2. These findings establish a critical role of TRIMs in protein quality control, connect the clearance of misfolded proteins to antioxidant defense, and suggest an intrinsic characteristic of tumor cells.

Mouse embryonic stem cells are deficient in type I interferon expression in response to viral infections and double-stranded RNA.

Embryonic stem cells (ESCs) are considered to be a promising cell source for regenerative medicine because of their unlimited capacity for self-renewal and differentiation. However, little is known about the innate immunity in ESCs and ESC-derived cells. We investigated the responses of mouse (m)ESCs to three types of live viruses as follows: La Crosse virus, West Nile virus, and Sendai virus. Our results demonstrated mESCs were susceptible to viral infection, but they were unable to express type I interferons (IFNα and IFNß, IFNα/ß), which differ from fibroblasts (10T1/2 cells) that robustly express IFNα/ß upon viral infections. The failure of mESCs to express IFNα/ß was further demonstrated by treatment with polyIC, a synthetic viral dsRNA analog that strongly induced IFNα/ß in 10T1/2 cells. Although polyIC transiently inhibited the transcription of pluripotency markers, the stem cell morphology was not significantly affected. However, polyIC can induce dsRNA-activated protein kinase in mESCs, and this activation resulted in a strong inhibition of cell proliferation. We conclude that the cytosolic receptor dsRNA-activated protein kinase is functional, but the mechanisms that mediate type I IFN expression are deficient in mESCs. This conclusion is further supported by the findings that the major viral RNA receptors are either expressed at very low levels (TLR3 and MDA5) or may not be active (retinoic acid-inducible gene I) in mESCs.