Palladium diselenide (PdSe2), a thus far scarcely studied group‐10 transition metal dichalcogenide has exhibited promising potential in future optoelectronic and electronic devices due to unique ...structures and electrical properties. Here, the controllable synthesis of wafer‐scale and homogeneous 2D PdSe2 film is reported by a simple selenization approach. By choosing different thickness of precursor Pd layer, 2D PdSe2 with thickness of 1.2–20 nm can be readily synthesized. Interestingly, with the increase in thickness, obvious redshift in wavenumber is revealed by Raman spectroscopy. Moreover, in accordance with density functional theory (DFT) calculation, optical absorption and ultraviolet photoemission spectroscopy (UPS) analyses confirm that the PdSe2 exhibits an evolution from a semiconductor (monolayer) to semimetal (bulk). Further combination of the PdSe2 layer with Si leads to a highly sensitive, fast, and broadband photodetector with a high responsivity (300.2 mA W−1) and specific detectivity (≈1013 Jones). By decorating the device with black phosphorus quantum dots, the device performance can be further optimized. These results suggest the as‐selenized PdSe2 is a promising material for optoelectronic application.
This study reports on the wafer‐area synthesis of a high‐quality 2D palladium diselenide (PdSe2) layer through a simple selenization method. Both experimental analysis and theoretical simulation reveal that the PdSe2 film exhibits a gradual transition from a semiconductor (monolayer) to semimetal (bulk). Further combination of PdSe2 with Si leads to a fast and sensitive broadband photodiode, with a high responsivity and specific detectivity.
AMPK and mTOR play principal roles in governing metabolic programs; however, mechanisms underlying the coordination of the two inversely regulated kinases remain unclear. In this study we found, most ...surprisingly, that the late endosomal/lysosomal protein complex v-ATPase-Ragulator, essential for activation of mTORC1, is also required for AMPK activation. We also uncovered that AMPK is a residential protein of late endosome/lysosome. Under glucose starvation, the v-ATPase-Ragulator complex is accessible to AXIN/LKB1 for AMPK activation. Concurrently, the guanine nucleotide exchange factor (GEF) activity of Ragulator toward RAG is inhibited by AXIN, causing dissociation from endosome and inactivation of mTORC1. We have thus revealed that the v-ATPase-Ragulator complex is also an initiating sensor for energy stress and meanwhile serves as an endosomal docking site for LKB1-mediated AMPK activation by forming the v-ATPase-Ragulator-AXIN/LKB1-AMPK complex, thereby providing a switch between catabolism and anabolism. Our current study also emphasizes a general role of late endosome/lysosome in controlling metabolic programs.
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•Ragulator is essential for starvation-induced AMPK activation•LKB1-dependent activation of AMPK takes place on late endosome/lysosome•V-ATPase-Ragulator provides docking sites for AXIN/LKB1 endosomal translocation•V-ATPase-Ragulator is a switch between anabolism and catabolism
AMPK and mTOR regulate cellular balance between catabolism and anabolism. Zhang et al. show that the endosomal v-ATPase-Ragulator complex, required for mTORC1 activation when nutrients are abundant, is also essential in LKB1-mediated AMPK activation in response to energy stress, thus acting as a dual energy sensor.
Renal cell carcinoma (RCC) is a common kidney cancer worldwide. Even though current treatments show promising therapeutic effectiveness, metastatic RCC still has limited therapeutic options so that ...novel treatments were urgently needed. Here, we identified that MUC12 was overexpressed in RCC patients and served as poor prognostic factor for RCC progression. Overexpression of MUC12 increased RCC cell growth and cell invasion while deficiency of MUC12 exerted opposite effects on RCC cells. Mechanistic dissection demonstrated that MUC12‐mediated RCC cell growth and cell invasion were dependent of TGF‐β1 signalling because they could be blocked in the presence of TGF‐β1 inhibitor. Moreover, the regulation of TGF‐β1 by MUC12 relied on the transactivation of c‐Jun. MUC12 promoted the recruitment of c‐Jun on the promoter of TGF‐β1, leading to its transcription. Importantly, knockdown of c‐Jun also attenuated MUC12‐mediated TGF‐β1 induction and RCC cell invasion. In summary, our study defines the role of MUC12 in RCC progression and provides rational to develop novel targeted therapy to battle against RCC.
The major energy source for most cells is glucose, from which ATP is generated via glycolysis and/or oxidative metabolism. Glucose deprivation activates AMP-activated protein kinase (AMPK), but it is ...unclear whether this activation occurs solely via changes in AMP or ADP, the classical activators of AMPK. Here, we describe an AMP/ADP-independent mechanism that triggers AMPK activation by sensing the absence of fructose-1,6-bisphosphate (FBP), with AMPK being progressively activated as extracellular glucose and intracellular FBP decrease. When unoccupied by FBP, aldolases promote the formation of a lysosomal complex containing at least v-ATPase, ragulator, axin, liver kinase B1 (LKB1) and AMPK, which has previously been shown to be required for AMPK activation. Knockdown of aldolases activates AMPK even in cells with abundant glucose, whereas the catalysis-defective D34S aldolase mutant, which still binds FBP, blocks AMPK activation. Cell-free reconstitution assays show that addition of FBP disrupts the association of axin and LKB1 with v-ATPase and ragulator. Importantly, in some cell types AMP/ATP and ADP/ATP ratios remain unchanged during acute glucose starvation, and intact AMP-binding sites on AMPK are not required for AMPK activation. These results establish that aldolase, as well as being a glycolytic enzyme, is a sensor of glucose availability that regulates AMPK.
Metformin, the most prescribed antidiabetic medicine, has shown other benefits such as anti-ageing and anticancer effects
. For clinical doses of metformin, AMP-activated protein kinase (AMPK) has a ...major role in its mechanism of action
; however, the direct molecular target of metformin remains unknown. Here we show that clinically relevant concentrations of metformin inhibit the lysosomal proton pump v-ATPase, which is a central node for AMPK activation following glucose starvation
. We synthesize a photoactive metformin probe and identify PEN2, a subunit of γ-secretase
, as a binding partner of metformin with a dissociation constant at micromolar levels. Metformin-bound PEN2 forms a complex with ATP6AP1, a subunit of the v-ATPase
, which leads to the inhibition of v-ATPase and the activation of AMPK without effects on cellular AMP levels. Knockout of PEN2 or re-introduction of a PEN2 mutant that does not bind ATP6AP1 blunts AMPK activation. In vivo, liver-specific knockout of Pen2 abolishes metformin-mediated reduction of hepatic fat content, whereas intestine-specific knockout of Pen2 impairs its glucose-lowering effects. Furthermore, knockdown of pen-2 in Caenorhabditis elegans abrogates metformin-induced extension of lifespan. Together, these findings reveal that metformin binds PEN2 and initiates a signalling route that intersects, through ATP6AP1, the lysosomal glucose-sensing pathway for AMPK activation. This ensures that metformin exerts its therapeutic benefits in patients without substantial adverse effects.
•Kinetic properties associated with Zn2+ and H+ were systematically investigated.•Distinctive porous structures can be achieved by introducing Co2+ ions.•Co2+ preinserted V2O5 samples exhibit ...enhanced apparent ion diffusion coefficient.•Promoted proton storage in CoVO samples leads to superior battery performance.
Aqueous zinc−ion batteries have received increasing attention due to the merits of low cost and high safety. In addition to Zn2+, protons can also serve as charge carriers in aqueous electrolytes for realizing energy storage. This work utilizes three electrolyte components, including 3 M ZnSO4/H2O, 1.5 M H2SO4/H2O, and 3 M ZnSO4/ethylene glycol (EG), to investigate kinetic properties of layered vanadium cathodes. As studied by CV and EIS analyses, the ion diffusion coefficient associated with Zn2+/H+ in Co2+ preinserted V2O5 (CoVO) samples are higher than that in V2O5. Interestingly, H+ diffusivity in Co0.17V2O5•0.83H2O (CoVO−2) is greatly promoted by a factor of ∼26 times in comparison with V2O5 (1.19 × 10−12 vs. 4.49 × 10−14 cm2 s−1) in 1.5 M H2SO4/H2O, while Zn2+ diffusivities in these two cathodes are comparable in 3 M ZnSO4/EG (1.48 × 10−14 vs. 9.80 × 10−15 cm2 s−1). The boosted proton diffusion coefficient renders superior battery performance of CoVO−2. As a result, high discharge capacity (393 mAh g−1 at 0.5 A g−1), good rate performance (148 mAh g−1 at 8 A g−1), and stable cycle retention (89 % after 2,000 cycles at 4 A g−1) can be achieved. By contrast, V2O5 exhibits inferior battery performance (185 and 57 mAh g−1 at 0.5 and 8 A g−1, respectively) due to sluggish kinetics of H+ transport in the host.
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2D materials hold great potential for designing novel electronic and optoelectronic devices. However, 2D material can only absorb limited incident light. As a representative 2D semiconductor, ...monolayer MoS2 can only absorb up to 10% of the incident light in the visible, which is not sufficient to achieve a high optical‐to‐electrical conversion efficiency. To overcome this shortcoming, a “gap‐mode” plasmon‐enhanced monolayer MoS2 fluorescent emitter and photodetector is designed by squeezing the light‐field into Ag shell‐isolated nanoparticles–Au film gap, where the confined electromagnetic field can interact with monolayer MoS2. With this gap‐mode plasmon‐enhanced configuration, a 110‐fold enhancement of photoluminescence intensity is achieved, exceeding values reached by other plasmon‐enhanced MoS2 fluorescent emitters. In addition, a gap‐mode plasmon‐enhanced monolayer MoS2 photodetector with an 880% enhancement in photocurrent and a responsivity of 287.5 A W−1 is demonstrated, exceeding previously reported plasmon‐enhanced monolayer MoS2 photodetectors.
By dropping Ag shell‐isolated nanoparticles onto Al2O3‐covered Au film, the gap‐mode plasmonic structure with a gap thickness of 7 nm can form naturally. By integrating monolayer MoS2 into this plasmonic structure, 110‐fold photoluminescence and 880% photocurrent enhancement are achieved. This work shows that the gap‐mode plasmonic structures have huge potential for realizing high‐performance 2D‐material‐based optoelectronic devices.
AMPK, a master regulator of metabolic homeostasis, is activated by both AMP-dependent and AMP-independent mechanisms. The conditions under which these different mechanisms operate, and their ...biological implications are unclear. Here, we show that, depending on the degree of elevation of cellular AMP, distinct compartmentalized pools of AMPK are activated, phosphorylating different sets of targets. Low glucose activates AMPK exclusively through the AMP-independent, AXIN-based pathway in lysosomes to phosphorylate targets such as ACC1 and SREBP1c, exerting early anti-anabolic and pro-catabolic roles. Moderate increases in AMP expand this to activate cytosolic AMPK also in an AXIN-dependent manner. In contrast, high concentrations of AMP, arising from severe nutrient stress, activate all pools of AMPK independently of AXIN. Surprisingly, mitochondrion-localized AMPK is activated to phosphorylate ACC2 and mitochondrial fission factor (MFF) only during severe nutrient stress. Our findings reveal a spatiotemporal basis for hierarchical activation of different pools of AMPK during differing degrees of stress severity.
Type II topoisomerases (TOP2s) resolve the topological problems of DNA by transiently cleaving both strands of a DNA duplex to form a cleavage complex through which another DNA segment can be ...transported. Several widely prescribed anticancer drugs increase the population of TOP2 cleavage complex, which leads to TOP2-mediated chromosome DNA breakage and death of cancer cells. We present the crystal structure of a large fragment of human TOP2β complexed to DNA and to the anticancer drug etoposide to reveal structural details of drug-induced stabilization of a cleavage complex. The interplay between the protein, the DNA, and the drug explains the structure-activity relations of etoposide derivatives and the molecular basis of drug-resistant mutations. The analysis of protein-drug interactions provides information applicable for developing an isoform-specific TOP2-targeting strategy.
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