Gastric cancer (GC) is one of the most malignant tumors with a poor prognosis. Alterations in metabolic pathways are inextricably linked to GC progression. However, the underlying molecular mechanisms remain elusive. We performed NMR-based metabolomic analysis of sera derived from a rat model of gastric carcinogenesis, revealed significantly altered metabolic pathways correlated with the progression of gastric carcinogenesis. Rats were histologically classified into four pathological groups (gastritis, GS; low-grade gastric dysplasia, LGD; high-grade gastric dysplasia, HGD; GC) and the normal control group (CON). The metabolic profiles of the five groups were clearly distinguished from each other. Furthermore, significant inter-metabolite correlations were extracted and used to reconstruct perturbed metabolic networks associated with the four pathological stages compared with the normal stage. Then, significantly altered metabolic pathways were identified by pathway analysis. Our results showed that oxidative stress-related metabolic pathways, choline phosphorylation and fatty acid degradation were continually disturbed during gastric carcinogenesis. Moreover, amino acid metabolism was perturbed dramatically in gastric dysplasia and GC. The GC stage showed more changed metabolite levels and more altered metabolic pathways. Two activated pathways (glycolysis; glycine, serine and threonine metabolism) substantially contributed to the metabolic alterations in GC. These results lay the basis for addressing the molecular mechanisms underlying gastric carcinogenesis and extend our understanding of GC progression.
Breast cancer (BC) remains the most common malignancy among women. Circular RNAs (circRNAs) have been demonstrated to play important roles in human cancers, including BC. In this study, we sought to identify the precise parts of circ_0061825 (circRNA trefoil factor 1, circ_TFF1) in BC pathogenesis.The expression levels of circ_0061825, miR-593-3p and fibroblast growth factor receptor 3 (FGFR3) were detected by quantitative real-time polymerase chain reaction (qRT-PCR) or Western blot. Circ_0061825 was characterized using ribonuclease (RNase) R digestion, actinomycin D and subcellular fractionation assays. Cell viability, colony formation, migration, invasion, cell cycle progression and apoptosis were evaluated using Cell Counting Kit-8 (CCK-8), colony formation, wound-healing, transwell and flow cytometry assays, respectively. Targeted relationships among circ_0061825, miR-593-3p and FGFR3 were determined by a dual-luciferase reporter assay. Animal studies were used to assess the impact of circ_0061825 in tumor growth in vivo.Our data indicated that circ_0061825 was overexpressed in BC tissues and cells, and it was mainly localized in the cytoplasm of BC cells. Circ_0061825 knockdown hampered BC cell viability, colony formation, migration, invasion, cell cycle progression and enhanced cell apoptosis in vitro and weakened tumor growth in vivo. Mechanistically, circ_0061825 functioned as a molecular sponge of miR-593-3p, and circ_0061825 knockdown repressed BC cell malignant progression in vitro by miR-593-3p. FGFR3 was a direct target of miR-593-3p, and circ_0061825 modulated FGFR3 expression through sponging miR-593-3p. Moreover, miR-593-3p overexpression hindered BC cell malignant progression in vitro by down-regulating FGFR3.Our current work provided evidence that circ_0061825, an up-regulated circRNA in BC, regulated BC malignant progression at least in part through targeting the miR-593-3p/FGFR3 axis, illuminating a novel therapeutic target for BC management.
HIV-1 integrase (HIV-1 IN) is an enzyme produced by the HIV-1 virus that integrates genetic material of the virus into the DNA of infected human cells. HIV-1 IN acts as a key component of the Retroviral Pre-Integration Complex (PIC). Protein dynamics could play an important role during the catalysis of HIV-1 IN; however, this process has not yet been fully elucidated. X-ray free electron laser (XFEL) together with nuclear magnetic resonance (NMR) could provide information regarding the dynamics during this catalysis reaction. Here, we report the non-cryogenic crystal structure of HIV-1 IN catalytic core domain at 2.5 Å using microcrystals in XFELs. Compared to the cryogenic structure at 2.1 Å using conventional synchrotron crystallography, there was a good agreement between the two structures, except for a catalytic triad formed by Asp64, Asp116, and Glu152 (DDE) and the lens epithelium-derived growth factor binding sites. The helix III region of the 140-153 residues near the active site and the DDE triad show a higher dynamic profile in the non-cryogenic structure, which is comparable to dynamics data obtained from NMR spectroscopy in solution state.
Modifying the geometric and electronic structures of metal–N–C single-atom catalysts to improve their catalytic activities is quite desirable and challenging. Here, theoretical analysis and experiment indicate the inherent synergistic effect of dual metal sites in N-doped carbon for bifunctional ORR and OER. Specifically, introducing Ru to generate RuFe–N–C or RuCo–N–C double-atom catalysts (DACs) can significantly enhance the bifunctional ORR/OER activities of Fe(Co) and Ru sites, exceeding the equivalent single metal Fe(Co)–N–C and Ru–N–C. Investigations of a series of RuM–N–C DACs reveal that the intriguing synergistic effect results from the modified charge density and d-band center by combining two optimized metal atoms, which affects adsorption energies of intermediates and catalytic activity. Based on these theoretical guidelines, RuFe–N–C is synthesized using a bimetal MOF as the precursor, and it exhibits exceptional ORR/OER activities in alkaline media with a small ΔE of 0.63 V, significantly outperforming Fe–N–C, Ru–N–C, and even commercial Pt/C-RuO2.
Significance Light-driven rhodopsin proteins pump ions across cell membranes. They have applications in optogenetics and can potentially be used to develop solar energy–harvesting devices. A detailed understanding of rhodopsin dynamics and functions may therefore assist research in medicine, health, and clean energy. This time-resolved crystallography study carried out with X-ray free-electron lasers reveals detailed dynamics of chloride ion–pumping rhodopsin (ClR) within 100 ps of light activation. It shows the dissociation of Cl − from the Schiff base binding site upon light-triggered retinal isomerization. This Cl − dissociation is followed by diffusion toward the intracellular direction. The results hint at a common ion-pumping mechanism across rhodopsin families.
Abstract Nitrogen (N) doping of graphene with a three‐dimensional (3D) porous structure, high flexibility, and low cost exhibits potential for developing metal–air batteries to power electric/electronic devices. The optimization of N‐doping into graphene and the design of interconnected and monolithic graphene‐based 3D porous structures are crucial for mass/ion diffusion and the final oxygen reduction reaction (ORR)/battery performance. Aqueous‐type and all‐solid‐state primary Mg–air batteries using N‐doped nanoporous graphene as air cathodes are assembled. N‐doped nanoporous graphene with 50–150 nm pores and ≈99% porosity is found to exhibit a Pt‐comparable ORR performance, along with satisfactory durability in both neutral and alkaline media. Remarkably, the all‐solid‐state battery exhibits a peak power density of 72.1 mW cm −2 ; this value is higher than that of a battery using Pt/carbon cathodes (54.3 mW cm −2 ) owing to the enhanced catalytic activity induced by N‐doping and rapid air breathing in the 3D porous structure. Additionally, the all‐solid‐state battery demonstrates better performances than the aqueous‐type battery owing to slow corrosion of the Mg anode by solid electrolytes. This study sheds light on the design of free‐standing and catalytically active 3D nanoporous graphene that enhances the performance of both Mg–air batteries and various carbon‐neutral‐technologies using neutral electrolytes.
Noble metal elements are the key to many high-performance heterogeneous catalytic processes; nevertheless, how to reduce the usage of such scarce and prohibitive materials while maintaining or even enhancing the desired catalytic performance has always been a grand challenge. In this work, we introduce a general dealloying procedure to synthesize a series of predesigned rugged high-entropy alloy (HEA) nanowires, including Al–Ni–Co–Ru–X, where X = Mo, Cu, V, Fe as the trifunctional electrocatalysts for the hydrogen evolution reaction (HER), oxygen evolution reaction (OER), and oxygen reduction reaction (ORR). These mechanically and chemically stable HEAs can not only significantly reduce the noble-metal contents but also effectively enhance the flexibility in their electronic structures suitable for broad catalytic functionalities. Specifically, our etched Al–Ni–Co–Ru–Mo nanowires exhibit a similarly high electrocatalytic activity as commercial Pt/C for HER. Its OER activity is much higher than the commercial RuO2 and among the highest ever-reported Ru-based OER catalysts. Its ORR catalytic activity is even higher than Pt/C, although Ru is not considered as a good ORR catalyst. Moreover, the oxidized surfaces of these HEAs are highly stable during continuous working conditions, which is crucial for overall water splitting and rechargeable Zn–air batteries.
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