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Isocitrate dehydrogenase 1 (IDH1) is important for reductive carboxylation in cancer cells, and the IDH1 R132H mutation plays a pathogenic role in cancers including acute myeloid leukemia (AML). However, the regulatory mechanisms modulating mutant and/or wild-type (WT) IDH1 function remain unknown. Here, we show that two groups of tyrosine kinases (TK) enhance the activation of mutant and WT IDH1 through preferential Y42 or Y391 phosphorylation. Mechanistically, Y42 phosphorylation occurs in IDH1 monomers, which promotes dimer formation with enhanced substrate (isocitrate or α-ketoglutarate) binding, whereas Y42-phosphorylated dimers show attenuated disruption to monomers. Y391 phosphorylation occurs in both monomeric and dimeric IDH1, which enhances cofactor (NADP+ or NADPH) binding. Diverse oncogenic TKs phosphorylate IDH1 WT at Y42 and activate Src to phosphorylate IDH1 at Y391, which contributes to reductive carboxylation and tumor growth, whereas FLT3 or the FLT3-ITD mutation activates JAK2 to enhance mutant IDH1 activity through phosphorylation of Y391 and Y42, respectively, in AML cells. SIGNIFICANCE: We demonstrated an intrinsic connection between oncogenic TKs and activation of WT and mutant IDH1, which involves distinct TK cascades in related cancers. In particular, these results provide an additional rationale supporting the combination of FLT3 and mutant IDH1 inhibitors as a promising clinical treatment of mutant IDH1-positive AML.See related commentary by Horton and Huntly, p. 699.This article is highlighted in the In This Issue feature, p. 681.

To investigate the pollution characteristics of Pb and Cd in mining soil, dynamic leaching tests was conducted to explore the leaching characteristics. Pollution was evaluated using the Risk Index (RI) and Assessment Code (RAC). The results showed that under simulated acid rain, the soil had a certain buffer capacity, the pH value of leaching solution varied between 5.0 and 8.5. Heavy metals release also varied, with the highest amount of Pb dissolved being 2.27 mgꞏL-1, while that of Cd was relatively low, the highest is 0.93 mgꞏL−1. Moreover, heavy metals with larger particle sizes showed a greater propensity for dissolution when subjected to acid rain. BCR extraction revealed that the initial heavy metal status was mostly residual. After leaching, heavy metal morphology changed drastically, with the residual state of reducing significantly. RAC and RI indicated a moderate risk of Pb and Cd pollution under different treatment conditions.

Supernumerary robotic limbs (SRLs) are a new type of wearable robot that add artificial limbs to the human body to perform collaborative tasks. In contrast with exoskeletons, SRLs are kinematically independent of human limbs, allowing the wearer to overcome the limitations of human physiological ability, such as realizing the expansion of space in the human body, rather than enhancing existing limbs. In this study, a lightweight and compact hexagonal reconfigurable lower‐limb SRL system is proposed to assist human locomotion in daily activities, including walking, crouching, and stair climbing. To adapt to multiple scenarios, the hexagonal mechanism can be adjusted to different configurations including convex hexagonal configuration, pentagonal configuration, and concave hexagonal configuration. To achieve more optimized performance of different configurations, the optimization for identifying the optimal dimensions of each link was carried out. Subsequently, the detailed design methodology and specifics are presented. Finally, the load and wearing performance experiments were evaluated. The experiment results demonstrated that the tested maximum load in different configurations exceeded 90% of the simulated value and the entire equipment has a good wearing adaptability. This study may inspire the design of other lower‐limb SRLs and provide efficient solutions for stable support assistance in various scenarios. [ABSTRACT FROM AUTHOR]

To solve the problem that advanced persistent threat (APT) in the Internet of things (IoT) environment had the characteristics of strong concealment, long duration, and fast update iterations, it was difficult for traditional passive detection models to quickly search, a hypergraph Transformer threat-hunting network (HTTN) was proposed. The HTTN model had the function of quickly locating and discovering APT attack traces in IoT systems with long time spans and complicated information concealment. The input cyber threat intelligence (CTI) log graph and IoT system kernel audit log graph were encoded into hypergraphs by the model, and the global information and node features of the log graph were calculated through the hypergraph neural network (HGNN) layer, and then they were extracted for hyperedge position features by the Transformer encoder, and finally the similarity score was calculated by the hyperedge, thus the threat-hunting of APT was realized in the network environment of the Internet of things system. It is shown by the experimental results in the simulation environment of the Internet of things that the mean square error is reduced by about 20% compared to mainstream graph matching neural networks, the Spearman level correlation coefficient is improved by about 0.8%, and improved precision@10 is improved by about 1.2% by the proposed HTTN model. [ABSTRACT FROM AUTHOR]

How altered metabolism contributes to chemotherapy resistance in cancer cells remains unclear. Through a metabolism-related kinome RNAi screen, we identified inositol-trisphosphate 3-kinase B (ITPKB) as a critical enzyme that contributes to cisplatin-resistant tumor growth. We demonstrated that inositol 1,3,4,5- tetrakisphosphate (IP4), the product of ITPKB, plays a critical role in redox homeostasis upon cisplatin exposure by reducing cisplatin-induced ROS through inhibition of a ROS-generating enzyme, NADPH oxidase 4 (NOX4), which promotes cisplatin- resistant tumor growth. Mechanistically, we identified that IP4 competes with the NOX4 cofactor NADPH for binding and consequently inhibits NOX4. Targeting ITPKB with shRNA or its small-molecule inhibitor resulted in attenuation of NOX4 activity, imbalanced redox status, and sensitized cancer cells to cisplatin treatment in patient-derived xenografts. Our findings provide insight into the crosstalk between kinase-mediated metabolic regulation and platinum-based chemotherapy resistance in human cancers. Our study also suggests a distinctive signaling function of IP4 that regulates NOX4. Furthermore, pharmaceutical inhibition of ITPKB displayed synergistic attenuation of tumor growth with cisplatin, suggesting ITPKB as a promising synthetic lethal target for cancer therapeutic intervention to overcome cisplatin resistance., Introduction Cisplatin kills rapidly dividing cells by damaging their DNA and plays a crucial role in the chemotherapy of human cancers (1-3). Nevertheless, cisplatin is often accompanied by side effects, [...]

Diet-derived nutrients are inextricably linked to human physiology by providing energy and biosynthetic building blocks and by functioning as regulatory molecules. However, the mechanisms by which circulating nutrients in the human body influence specific physiological processes remain largely unknown. Here we use a blood nutrient compound library-based screening approach to demonstrate that dietary trans-vaccenic acid (TVA) directly promotes effector CD8+ T cell function and anti-tumour immunity in vivo. TVA is the predominant form of trans-fatty acids enriched in human milk, but the human body cannot produce TVA endogenously1. Circulating TVA in humans is mainly from ruminant-derived foods including beef, lamb and dairy products such as milk and butter2,3, but only around 19% or 12% of dietary TVA is converted to rumenic acid by humans or mice, respectively4,5. Mechanistically, TVA inactivates the cell-surface receptor GPR43, an immunomodulatory G protein-coupled receptor activated by its short-chain fatty acid ligands6–8. TVA thus antagonizes the short-chain fatty acid agonists of GPR43, leading to activation of the cAMP–PKA–CREB axis for enhanced CD8+ T cell function. These findings reveal that diet-derived TVA represents a mechanism for host-extrinsic reprogramming of CD8+ T cells as opposed to the intrahost gut microbiota-derived short-chain fatty acids. TVA thus has translational potential for the treatment of tumours.A screen of nutrient-derived compounds identified trans-vaccenic acid as a promoter of effector T cell function, and functional assays demonstrate that this occurs via inactivation of GPR43 on T cells. [ABSTRACT FROM AUTHOR]