Yes‐associated protein (YAP) is a transcriptional coactivator that promotes cell proliferation, stem cell maintenance and tissue homeostasis. The YAP activity is primarily regulated through an ...inhibitory phosphorylation by the serine/threonine kinases of Hippo pathway. Here, we show that receptor tyrosine kinase (RTK) erythropoietin‐producing hepatocellular receptor A2 (EphA2) interacts with and phosphorylates YAP protein, leading to stabilization, nuclear translocation and activation of YAP in gastric cancer (GC) cells. EphA2 induces chemotherapy‐resistance by increasing YAP stability and nuclear YAP protein. Knockdown of YAP blocks EphA2‐induced tumor growth in GC xenograft mouse models. Importantly, the coactivation of EphA2 and YAP is manifested in clinical human GC, and is related to GC recurrence. Thus, our results establish a novel EphA2‐to‐YAP pathway that drives GC growth, progression and therapy‐resistance, targeting this pathway would be an efficient way for the treatment of GC, particularly chemotherapy‐resistant GC.
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The discovery of novel molecular targets is fundamental to the continued advance of therapeutic agents for gastric cancer (GC). In this study, the authors identify a pathway involving interaction between EphA2, a member of the erythropoietin‐producing hepatocellular receptor family, and yes‐associated protein (YAP) as a promising therapeutic target for GC. In GC cells, EphA2 phosphorylation of YAP protein resulted in YAP stabilization, translocation to the nucleus, and activation. Increased YAP stabilization and nuclear concentration in GC cells and mouse models was further associated with EphA2‐induced chemoresistance. In patients, EphA2 overexpression and nuclear YAP accumulation was related to GC relapse.
Aculenes are a unique class of norsequiterpenes (C14) that are produced by Aspergillus aculeatus. The nordaucane skeleton in aculenes A–D may be derived from an ent‐daucane precursor through ...demethylation, however, the enzymes involved remain unexplored. We identified the biosynthetic gene cluster and characterized the biosynthetic pathway based on gene inactivation, feeding experiments, and heterologous reconstitution in Saccharomyces cerevisiae and Aspergillus oryzae. We discovered that three cytochrome P450 monoxygenases are required to catalyze the stepwise demethylation process. AneF converts the 12‐methyl group into a carboxylic acid and AneD installs the 10‐hydroxy group for later tautomerization and stabilization. Finally, AneG installs an electron‐withdrawing carbonyl group at the C‐2 position, which triggers C‐12 decarboxylation to yield the nordaucane skeleton. Additionally, a terpene cyclase (AneC) was found that forms a new product (dauca‐4,7‐diene).
Long time no C: Aculenes are a class of norsesquiterpenes (C14) that are derived from daucane sesquiterpenes (C15), but the biosynthetic basis of the demethylation remained unknown. Three novel P450 monooxygenases were discovered to catalyze a stepwise demethylation process, and a new ent‐daucane cyclase was also discovered. This work sheds light on how nature performs enzymatic demethylation and reveals new tools to expand chemical diversity.
Hydrogen production from photoelectrochemical (PEC) water splitting using semiconductor photocatalysts has attracted great attention to realize clean and renewable energy from solar energy. The ...visible light response of WO
3
with a long hole diffusion length (∼150 nm) and good electron mobility (∼12 cm
2
V
−1
s
−1
) makes it suitable as the photoanode. However, WO
3
suffers from issues including rapid recombination of photoexcited electron-hole pairs, photo-corrosion during the photocatalytic process due to the formation of peroxo-species, sluggish kinetics of photogenerated holes, and slow charge transfer at the semiconductor/electrolyte interface. This work highlights the approaches to overcome these drawbacks of WO
3
photoanodes, including: (i) the manipulation of nanostructured WO
3
photoanodes to decrease the nanoparticle size to promote hole migration to the WO
3
/electrolyte interface which benefits the charge separation; (ii) doping or introducing oxygen vacancies to improve electrical conductivity; exposing high energy crystal surfaces to promote the consumption of photogenerated holes on the high-active crystal face, thereby suppressing the recombination of photogenerated electrons and holes; (iii) decorating with co-catalysts to reduce the overpotential which inhibits the formation of peroxo-species; (iv) other methods such as coupling with narrow band semiconductors to accelerate the charge separation and controlling the crystal phase
via
annealing to reduce defects. These approaches are reviewed with detailed examples.
This paper reviews nanostructural tungsten oxides and their nanocomposites to enhance the activity of photoelectrochemical water splitting.
Nonferrous metallurgy is causing significant concerns due to its emissions of heavy metals into environment, degrading environmental quality, and consequently posing high risks to human health. In ...this study, the concentration levels of Cadmium (Cd), Copper (Cu), Lead (Pb), and Arsenic (As) were investigated in soil, crop, well water, and fish samples collected around the Daye Copper Smelter in Hubei province, China, and the potential health risks were assessed for local children. The results showed that soils near the smelter were heavily polluted by Cd, Cu, Pb, and As, with the mean concentrations of 4.87, 195.26, 92.65, and 35.84 mg/kg, respectively, which were significantly higher than the values of soil Cd (0.18 mg/kg), Cu (32.84 mg/kg), Pb (28.46 mg/kg), and As (13.65 mg/kg) in the reference area (p < 0.001). The concentrations of Cd and As in vegetable samples collected from smelter-affected area exceeded the maximum permissible level (MPL) for food in China by 82% and 39%, respectively. The concentrations of Cd and Pb in rice grain harvested from smelter-affected area were 9.35 and 1.35 times higher than the corresponding MPL, respectively. The concentrations of Cd, As, and Cu in fish muscle from smelter-affected area exceeded the national MPL by 72%, 41%, and 24% of analyzed samples, respectively. The concentrations of Cd (p < 0.05) and As (p < 0.01) in well water were significantly higher in the smelter-affected area than those in the reference area, respectively. The health risks to local children in the smelter-affected area were 30.25 times higher than the acceptable level of 1, and most of the risks were resulted from Cd (46%), As (27%) and Pb (20%). The intake of crops was a major source (78%) to health risks for local children.
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•A comprehensive heavy metal pollution and health risk assessment of soil, crop, well water and fish was conducted.•Elevated concentrations of heavy metals were found in the soil, crop, well water and fish.•Health risk of heavy metal pollution was high for local children.•Consumption of crops was the major contribution to risk.•Most of the risks were due to Cd, As and Pb pollution.
Sodium metal batteries have potentially high energy densities, but severe sodium-dendrite growth and side reactions prevent their practical applications, especially at high temperatures. Herein, we ...design an inorganic ionic conductor/gel polymer electrolyte composite, where uniformly cross-linked beta alumina nanowires are compactly coated by a poly(vinylidene fluoride-co-hexafluoropropylene)-based gel polymer electrolyte through their strong molecular interactions. These beta alumina nanowires combined with the gel polymer layer create dense and homogeneous solid-liquid hybrid sodium-ion transportation channels through and along the nanowires, which promote uniform sodium deposition and formation of a stable and flat solid electrolyte interface on the sodium metal anode. Side reactions between the sodium metal and liquid electrolyte, as well as sodium dendrite formation, are successfully suppressed, especially at 60 °C. The sodium vanadium phosphate/sodium full cells with composite electrolyte exhibit 95.3% and 78.8% capacity retention after 1000 cycles at 1 C at 25 °C and 60 °C, respectively.
This paper investigates the coupled Patlak–Keller–Segel–Navier–Stokes (PKS–NS) system in two-dimensional bounded domains with a focus on global well-posedness and the formation of striking patterns, ...in which the boundary conditions are Neumann conditions for the cell density and the chemical concentration, and the Navier slip boundary condition with zero friction for the fluid velocity. We prove that the solution of the system exists globally in time in the case of subcritical mass. Concerning the critical mass case, we construct the boundary spot steady states rigorously via the inner-outer gluing method.
While studying the global existence and the concentration phenomenon of the chemotaxis–fluid model, we develop the global W2,p theory for the 2D stationary Stokes system subject to Navier boundary conditions with zero friction and further establish semigroup estimates of the nonstationary counterpart by analyzing the Stokes eigenvalue problem.
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•There were different content characteristics of heavy metals under different land use.•Ecological and human health risks from different sources were quantitatively ...calculated.•Industrial activities contributed the most to ecological risks.•Agricultural practices were the largest source of human health risks.
Heavy metals (HMs) in soil cause adverse effects on ecosystem and human health. Quantifying ecological risk and human health risk (HHR) from sources can determine priority sources and help to mitigate the risks. In this research, geostatistics and positive matrix factorization (PMF) were used to identify and quantify the sources of soil HMs; and then ecological risk and HHR from different sources under woodland, construction land and farmland were quantitatively calculated by combining the potential ecological risk index (RI) and HHR assessment models with PMF model. Taking Jiedong District as an example, four sources were quantitatively apportioned, which were agricultural practices (23.08%), industrial activities (29.10%), natural source (22.87%) and traffic emissions (24.95%). For ecological risk, industrial activities were the greatest contributor, accounting for about 49.71%, 48.11% and 47.15% under construction land, woodland and farmland, respectively. For non-carcinogenic risk, agricultural practices were the largest source under woodland and farmland, while industrial activities were the largest source under construction land. As for carcinogenic risk, no matter which kind of land use, agricultural practices were the largest source. In addition, the health risks of children, including non-carcinogenic and carcinogenic risks, were higher than those of adults, and the trends in health risks for children and adults were similar. The integrated approach was useful to evaluate ecological risk and HHR quantification from sources under different land use, thereby providing valuable suggestions for reducing pollution and protecting human health from the sources.
The okaramines are a class of complex indole alkaloids isolated from Penicillium and Aspergillus species. Their potent insecticidal activity arises from selectively activating glutamate‐gated ...chloride channels (GluCls) in invertebrates, not affecting human ligand‐gated anion channels. Okaramines B (1) and D (2) contain a polycyclic skeleton, including an azocine ring and an unprecedented 2‐dimethyl‐3‐methyl‐azetidine ring. Owing to their complex scaffold, okaramines have inspired many total synthesis efforts, but the enzymology of the okaramine biosynthetic pathway remains unexplored. Here, we identified and characterized the biosynthetic gene cluster (oka) of 1 and 2, then elucidated the pathway with target gene inactivation, heterologous reconstitution, and biochemical characterization. Notably, we characterized an α‐ketoglutarate‐dependent non‐heme FeII dioxygenase that forged the azetidine ring on the okaramine skeleton.
Okaramines are a class of complex indole alkaloids and potential insecticidal agents that activate glutamate‐gated chloride channels (GluCls) in invertebrates selectively over human ligand‐gated anion channels. The biosynthesis pathway was mapped with genetic inactivation, pathway enzyme reconstitution in a yeast heterologous system, and biochemical characterization.
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