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Nanoporous poly(ionic liquid)s with both great porosities and high IL contents are prepared through a two-step synthetic strategy, serving as efficient heterogeneous catalysts for CO2 cycloaddition with epoxides under mild conditions.

A strategy for building ring-like deposit surface-enhanced Raman scattering (SERS) sensors with the coffee ring effect through the functional modification of the silica nanoparticle surface encapsulated by free-tagged Ag nanoparticles is addressed along with their applications in the SERS-based detection and degradation of target species, including paraquat, diquat, and their free radicals. The nanogap formed by two interparticles with SERS hotspots provides a gigantic amplification signal for the Raman scattering intensity of the analyte molecule located approximately at the hotspots. The enhanced Raman spectrum signals of these target analytes were achieved through the hotspot region of the surface plasmon resonance (SPR) located on the embankment formed by self-aggregation of SiO

Figure S1-GFI1 promotes GC cell proliferation and suppresses GKN2 expression.Figure S2-FBXW7 governs GFI1 stability.Figure S3-GSK3β destabilizes GFI1 and negatively regulates GFI1 expression. Figure S4-Spectrum of peptide containing GFI1 S94 phosphorylation.

Supplemental Figures for "FBW7 loss promotes chromosomal instability and tumorigenesis via Cyclin E1/CDK2-mediated phosphorylation of CENP-A"

Table S1: Antibodies used in this paper.

Gastric cancer is the third leading cause of cancer-related death worldwide. The regulatory mechanisms underlying gastric cancer cell proliferation are largely unclear. Here, we show that the transcription factor GFI1 is associated with advanced clinical gastric cancer progression and promoted gastric cancer cell proliferation partially through inhibition of gastrokine-2 (GKN2) transcription. GFI1 was a degrading substrate of FBXW7, whose loss was observed in gastric cancer. Mechanistically, GSK3β-mediated GFI1 S94/S98 phosphorylation triggered its interaction with FBXW7, resulting in SCFFBXW7-mediated ubiquitination and degradation. A nondegradable GFI1 S94A/S98A mutant was more potent in driving gastric cancer cell proliferation and tumorigenesis than wild-type GFI1. Overall, this study reveals the oncogenic role of GFI1 in gastric cancer and provides mechanistic insights into the tumor suppressor function of FBXW7.Significance:These findings demonstrate the oncogenic role of the transcription factor GFI1 and the tumor suppressive function of FBXW7 in gastric cancer.

The centromere regulates proper chromosome segregation, and its dysfunction is implicated in chromosomal instability (CIN). However, relatively little is known about how centromere dysfunction occurs in cancer. Here, we define the consequences of phosphorylation by cyclin E1/CDK2 on a conserved Ser18 residue of centromere-associated protein CENP-A, an essential histone H3 variant that specifies centromere identity. Ser18 hyperphosphorylation in cells occurred upon loss of FBW7, a tumor suppressor whose inactivation leads to CIN. This event on CENP-A reduced its centromeric localization, increased CIN, and promoted anchorage-independent growth and xenograft tumor formation. Overall, our results revealed a pathway that cyclin E1/CDK2 activation coupled with FBW7 loss promotes CIN and tumor progression via CENP-A–mediated centromere dysfunction. Cancer Res; 77(18); 4881–93. ©2017 AACR.

Herein, a strategy for a metal ion-imprinted artificial antibody with recognition sites tagged by fluorescein was carried out to construct the selective sites with a sensitive optical response signal to the specific metal ion. The synthesized silica nanoparticles were modified by the derivative residue group of 3-aminopropyltriethoxysilane conjugated with a 4-chloro-7-nitro-1,2,3-benzoxadiazole (NBD-Cl) molecule through the hydrolysis and condensation reactions. The as-prepared silica nanoparticles were encapsulated by metal ion (Cu2+, Cd2+, Hg2+, and Pb2+)-imprinted polymers with nanostructured layers through the copolymerization of ethyl glycol dimethyl methacrylate (EGDMA) as a cross-linker, AIBN as an initiator, metal ions as template molecules, AA as a functional monomer, and acetonitrile as a solvent. The layers of molecular imprinted polymers (MIPs) with a core-shell structure removed template molecules by EDTA-2Na to retain the cavities and spatial sizes to match the imprinted metal ions. The microsensor arrays were achieved by the self-assembly technique of SiO2@MIP nanoparticles on the etched silicon wafer with regular dot arrays. The nanostructured-shell layers with fluorescence-tagged recognition sites rebound metal ions by the driving force of concentration difference demonstrates the high selective recognition and sensitive detection to heavy metal ions through the decline of fluorescence intensity. The LOD concentration for four metal ions is down to 10-9 mol·L-1. The method will provide biomimetic synthesis, analyte screen, and detection of highly dangerous materials in the environment for theoretical foundation and technological support.

Wnt/β-catenin signaling is a conserved pathway crucially governing development, homeostasis and oncogenesis. Discovery of novel regulators holds great values in both basic and translational research. Through screening, we identified a deubiquitinase (DUB) USP10 as a novel and critical modulator of β-catenin. Mechanistically, USP10 binds to key scaffold Axin1 via conserved motifs and stabilizes Axin1 through K48-linked deubiquitination, and surprisingly, tethers Axin1 and β-catenin physically while promoting phase separation for β-catenin suppression regardless of its enzymatic activity. Functionally, USP10 prominently regulates embryonic development and intestinal homeostasis by antagonizing β-catenin via DUB activity. In colorectal cancer, USP10 substantially represses cancer growth mainly through physical binding compensation and phase separation promotion and correlates with Wnt/β-catenin magnitude clinically. Collectively, we discovered USP10 functioning in multiple biological processes against β-catenin and unearthed a novel enzyme-dependent and -independent “dual-regulating” mechanism by which USP10 utilizes parallelly and context-dependently. USP10 inhibitor was suggested in treating certain Wnt-related diseases.

Shouzhou kiln is located in the north of Anhui Province. Its porcelain was first fired in the Six Dynasties, peaked in the Sui and Tang Dynasties, but gradually declined in the late Tang Dynasty. Shouzhou kiln complied with the trend of the times and catered to the aesthetic taste of the public. In the Tang Dynasty, a new way was found, which laid a solid foundation for its great development and prosperity. In order to compare the differences between the Sui and Tang Dynasties and the modern Shouzhou kiln in the production process and composition, XRF and XRD were employed to analyze their compositions and structures. The results confirm that the main components are silica and alumina, which exist in the form of quartzite and mullite, indicating that the materials used for the body and glaze of Shouzhou kiln porcelain are relatively stable.

BackgroundImmune microenvironment is well recognized as a critical regulator across cancer types, despite its complex roles in different disease conditions. Intrahepatic cholangiocarcinoma (iCCA) is characterized by a tumor-reactive milieu, emphasizing a deep insight into its immunogenomic profile to provide prognostic and therapeutic implications.MethodsWe performed genomic, transcriptomic, and proteomic characterization of 255 paired iCCA and adjacent liver tissues. We validated our findings through H&E staining (n=177), multiplex immunostaining (n=188), single-cell RNA sequencing (scRNA-seq) (n=10), in vitro functional studies, and in vivo transposon-based mouse models.ResultsIntegrated multimodule data identified three immune subgroups with distinct clinical, genetic, and molecular features, designated as IG1 (immune-suppressive, 25.1%), IG2 (immune-exclusion, 42.7%), and IG3 (immune-activated, 32.2%). IG1 was characterized by excessive infiltration of neutrophils and immature dendritic cells (DCs). The hallmark of IG2 was the relatively higher tumor-proliferative activity and tumor purity. IG3 exhibited an enrichment of adaptive immune cells, natural killer cells, and activated DCs. These immune subgroups were significantly associated with prognosis and validated in two independent cohorts. Tumors with KRAS mutations were enriched in IG1 and associated with myeloid inflammation-dominated immunosuppression. Although tumor mutation burden was relatively higher in IG2, loss of heterozygosity in human leucocyte antigen and defects in antigen presentation undermined the recognition of neoantigens, contributing to immune-exclusion behavior. Pathological analysis confirmed that tumor-infiltrating lymphocytes and tertiary lymphoid structures were both predominant in IG3. Hepatitis B virus (HBV)-related samples tended to be under-represented in IG1, and scRNA-seq analyses implied that HBV infection indeed alleviated myeloid inflammation and reinvigorated antitumor immunity.ConclusionsOur study elucidates that the immunogenomic traits of iCCA are intrinsically heterogeneous among patients, posing great challenge and opportunity for the application of personalized immunotherapy.

Secreted isoform of endoplasmic reticulum membrane complex subunit 10 (scEMC10) is a poorly characterised secreted protein of largely unknown physiological function. Here we demonstrate that scEMC10 is upregulated in humans with obesity and is positively associated with insulin resistance. Consistent with a causal role for scEMC10 in obesity, Emc10-/- mice are resistant to diet-induced obesity due to an increase in energy expenditure. Furthermore, neutralization of circulating scEMC10 using a monoclonal antibody reduces body weight and enhances insulin sensitivity in obese mice. Mechanistically, we provide evidence that scEMC10 binds to the catalytic subunit of PKA and inhibits its stimulatory action on CREB while ablation of EMC10 promotes thermogenesis in adipocytes via activation of the PKA signalling pathway and its downstream targets. Taken together, our data identify scEMC10 as a novel circulating inhibitor of thermogenesis and a potential therapeutic target for obesity and its cardiometabolic complications.

Secreted isoform of endoplasmic reticulum membrane complex subunit 10 (scEMC10) is a poorly characterized secreted protein of largely unknown physiological function. Here we demonstrate that scEMC10 is upregulated in people with obesity and is positively associated with insulin resistance. Consistent with a causal role for scEMC10 in obesity, Emc10-/- mice are resistant to diet-induced obesity due to an increase in energy expenditure, while scEMC10 overexpression decreases energy expenditure, thus promoting obesity in mouse. Furthermore, neutralization of circulating scEMC10 using a monoclonal antibody reduces body weight and enhances insulin sensitivity in obese mice. Mechanistically, we provide evidence that scEMC10 can be transported into cells where it binds to the catalytic subunit of PKA and inhibits its stimulatory action on CREB while ablation of EMC10 promotes thermogenesis in adipocytes via activation of the PKA signalling pathway and its downstream targets. Taken together, our data identify scEMC10 as a circulating inhibitor of thermogenesis and a potential therapeutic target for obesity and its cardiometabolic complications.