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The oncogene RAS, extensively studied for decades, presents persistent gaps in understanding, hindering the development of effective therapeutic strategies due to a lack of precise details on how RAS initiates MAPK signaling with RAF effector proteins at the plasma membrane. Recent advances in X-ray crystallography, cryo-EM, and super-resolution fluorescence microscopy offer structural and spatial insights, yet the molecular mechanisms involving protein-protein and protein-lipid interactions in RAS-mediated signaling require further characterization. This study utilizes single-molecule experimental techniques, nuclear magnetic resonance spectroscopy, and the computational Machine-Learned Modeling Infrastructure (MuMMI) to examine KRAS4b and RAF1 on a biologically relevant lipid bilayer. MuMMI captures long-timescale events while preserving detailed atomic descriptions, providing testable models for experimental validation. Both in vitro and computational studies reveal that RBDCRD binding alters KRAS lateral diffusion on the lipid bilayer, increasing cluster size and decreasing diffusion. RAS and membrane binding cause hydrophobic residues in the CRD region to penetrate the bilayer, stabilizing complexes through β-strand elongation. These cooperative interactions among lipids, KRAS4b, and RAF1 are proposed as essential for forming nanoclusters, potentially a critical step in MAP kinase signal activation.RAS binding to RAF’s RBDCRD domain on lipid bilayers cooperatively induces nanoclustering, slowing complex diffusion—an essential mechanism in initial signal activation. [ABSTRACT FROM AUTHOR]

Oxidation of renewable polyol/sugar into formic acid using molecular O2 over heterogeneous catalysts is still challenging due to the insufficient activation of both O2 and organic substrates on coordination-saturated metal oxides. In this study, we develop a defective MnO2 catalyst through a coordination number reduction strategy to enhance the aerobic oxidation of various polyols/sugars to formic acid. Compared to common MnO2, the tri-coordinated Mn in the defective MnO2 catalyst displays the electronic reconstruction of surface oxygen charge state and rich surface oxygen vacancies. These oxygen vacancies create more Mnδ+ Lewis acid site together with nearby oxygen as Lewis base sites. This combined structure behaves much like Frustrated Lewis pairs, serving to facilitate the activation of O2, as well as C–C and C–H bonds. As a result, the defective MnO2 catalyst shows high catalytic activity (turnover frequency: 113.5 h−1) and formic acid yield (>80%) comparable to noble metal catalysts for glycerol oxidation. The catalytic system is further extended to the oxidation of other polyols/sugars to formic acid with excellent catalytic performance. This work develops defective MnO2 catalysts with Frustrated Lewis Pairs through a coordination number reduction strategy to enhance the aerobic oxidation of various polyols/sugars to formic acid. [ABSTRACT FROM AUTHOR]

N6-methyladenosine (m6A) modification plays important roles in bioprocesses and diseases. AlkB homolog 5 (ALKBH5) is one of two m6A demethylases. Here, we reveal that ALKBH5 is acetylated at lysine 235 (K235) by lysine acetyltransferase 8 and deacetylated by histone deacetylase 7. K235 acetylation strengthens the m6A demethylation activity of ALKBH5 by increasing its recognition of m6A on mRNA. RNA-binding protein paraspeckle component 1 (PSCP1) is a regulatory subunit of ALKBH5 and preferentially interacts with K235-acetylated ALKBH5 to recruit and facilitate the recognition of m6A mRNA by ALKBH5, thereby promoting m6A erasure. Mitogenic signals promote ALKBH5 K235 acetylation. K235 acetylation of ALKBH5 is upregulated in cancers and promotes tumorigenesis. Thus, our findings reveal that the m6A demethylation activity of ALKBH5 is orchestrated by its K235 acetylation and regulatory subunit PSPC1 and that K235 acetylation is necessary for the m6A demethylase activity and oncogenic roles of ALKBH5. Deregulation of N6-methyladenosine (m6A) modification can contribute to the pathogenesis of cancers. Here the authors show that m6A demethylase ALKBH5 is acetylated at K235 by acetyltransferase KAT8 and interacts with RNA-binding protein PSCP1 to enhance m6A demethylation and promote tumorigenesis. [ABSTRACT FROM AUTHOR]

Refractory high-entropy alloys are considered as potential structural materials for elevated temperature applications. To obtain refractory high-entropy alloys with high strength, different amounts of Si were added into the NbMoTiVW refractory high-entropy alloys. The effects of Si on the phase constitution, microstructure characteristics and mechanical properties of NbMoTiVWSix alloys were investigated. Results show that when the addition of Si is 0, 0.025 and 0.05 (molar ratio), the alloys are consisted of primary BCC and secondary BCC in the intergranular area. When the addition of Si is increased to 0.075 and 0.1, eutectic structure including silicide phase and secondary BCC phase is formed. The primary BCC phase shows dendritic morphology, and is refined by adding Si. The volume fraction of intergranular area is increased from 12.22% to 18.13% when the addition of Si increases from 0 to 0.1. The ultimate compressive strength of the NbMoTiVW alloy is improved from 2,242 MPa to 2,532 MPa. Its yield strength is also improved by the addition of Si, and the yield strength of NbMoTiVWSi0.1 reaches maximum of 2,298 MPa. However, the fracture strain of the alloy is decreased from 15.31% to 12.02%. The fracture mechanism of the alloys is changed from mixed fracture of ductile and quasi-cleavage to cleavage fracture with increasing of Si. The strengthening of alloys is attributed to the refinement of primary BCC phase, volume fraction increment of secondary BCC phase, and formation of eutectic structure by addition of Si. [ABSTRACT FROM AUTHOR]

Radiotherapy is an important therapeutic strategy for cancer treatment through direct damage to cancer cells and augmentation of antitumor immune responses. However, the efficacy of radiotherapy is limited by hypoxia-mediated radioresistance and immunosuppression in tumor microenvironment. Here, we construct a stabilized theranostic nanoprobe based on quantum dots emitting in the near-infrared IIb (NIR-IIb, 1,500–1,700 nm) window modified by catalase, arginine–glycine–aspartate peptides and poly(ethylene glycol). We demonstrate that the nanoprobes effectively aggregate in the tumor site to locate the tumor region, thereby realizing precision radiotherapy with few side-effects. In addition, nanoprobes relieve intratumoral hypoxia and reduce the tumor infiltration of immunosuppressive cells. Moreover, the nanoprobes promote the immunogenic cell death of cancer cells to trigger the activation of dendritic cells and enhance T cell-mediated antitumor immunity to inhibit tumor metastasis. Collectively, the nanoprobe-mediated immunogenic radiotherapy can boost the abscopal effect to inhibit tumor metastasis and prolong survival. Hypoxia and immunosuppression contribute to tumor resistance to radiotherapy (RT). Here the authors design a nanoprobe based on NIR-IIb emitting quantum dots for image-guided RT and modified with catalase to relieve hypoxia in the tumor microenvironment, enhancing the precision and efficacy of RT and promoting anti-tumor immune responses. [ABSTRACT FROM AUTHOR]

A molecular-level understanding of how the electronic structure of metal center tunes the catalytic behaviors remains a grand challenge in heterogeneous catalysis. Herein, we report an unconventional kinetics strategy for bridging the microscopic metal electronic structure and the macroscopic steady-state rate for CO oxidation over Pt catalysts. X-ray absorption and photoelectron spectroscopy as well as electron paramagnetic resonance investigations unambiguously reveal the tunable Pt electronic structures with well-designed carbon support surface chemistry. Diminishing the electron density of Pt consolidates the CO-assisted O2 dissociation pathway via the O*-O-C*-O intermediate directly observed by isotopic labeling studies and rationalized by density-functional theory calculations. A combined steady-state isotopic transient kinetic and in situ electronic analyses identifies Pt charge as the kinetics indicators by being closely related to the frequency factor, site coverage, and activation energy. Further incorporation of catalyst structural parameters yields a novel model for quantifying the electronic effects and predicting the catalytic performance. These could serve as a benchmark of catalyst design by a comprehensive kinetics study at the molecular level. A molecular-level understanding of the electronic effects remains a grand challenge in heterogeneous catalysis. Here, the authors report an unconventional kinetics strategy for bridging the upscaling gap between the microscopic fingerprints of active sites and the macroscopic catalytic performance. [ABSTRACT FROM AUTHOR]