MRE11 liberates cGAS from nucleosome sequestration during tumorigenesis.

Oncogene-induced replication stress generates endogenous DNA damage that activates cGAS-STING-mediated signalling and tumour suppression1-3. However, the precise mechanism of cGAS activation by endogenous DNA damage remains enigmatic, particularly given that high-affinity histone acidic patch (AP) binding constitutively inhibits cGAS by sterically hindering its activation by double-stranded DNA (dsDNA)4-10. Here we report that the DNA double-strand break sensor MRE11 suppresses mammary tumorigenesis through a pivotal role in regulating cGAS activation. We demonstrate that binding of the MRE11-RAD50-NBN complex to nucleosome fragments is necessary to displace cGAS from acidic-patch-mediated sequestration, which enables its mobilization and activation by dsDNA. MRE11 is therefore essential for cGAS activation in response to oncogenic stress, cytosolic dsDNA and ionizing radiation. Furthermore, MRE11-dependent cGAS activation promotes ZBP1-RIPK3-MLKL-mediated necroptosis, which is essential to suppress oncogenic proliferation and breast tumorigenesis. Notably, downregulation of ZBP1 in human triple-negative breast cancer is associated with increased genome instability, immune suppression and poor patient prognosis. These findings establish MRE11 as a crucial mediator that links DNA damage and cGAS activation, resulting in tumour suppression through ZBP1-dependent necroptosis.

Dynamic Event-Triggered Safe Control for Nonlinear Game Systems With Asymmetric Input Saturation.

This article focuses on the Pareto optimal issues of nonlinear game systems with asymmetric input saturation under dynamic event-triggered mechanism (DETM). First, the safe control is guaranteed by transforming the system with safety constraints into the one without state constraints utilizing barrier function. The united cost function integrating nonquadratic utility function is constructed to provide the foundation to achieve the Pareto optimal solutions. Then, the adaptive dynamic programming method with concurrent learning is proposed to approximate the Pareto optimal strategies wherein both current and historical data are utilized. To further lessen the consumptions of computation/communication resources, the DETM is integrated into the adaptive algorithm framework which can avoid Zeno phenomena. All the signals of the closed-loop system are proved to be uniformly ultimately bounded. Finally, the simulation results are given to validate the effectiveness of the proposed method from several aspects.

Co-targeting JAK1/STAT6/GAS6/TAM signaling improves chemotherapy efficacy in Ewing sarcoma.

Ewing sarcoma is a pediatric bone and soft tissue tumor treated with chemotherapy, radiation, and surgery. Despite intensive multimodality therapy, ~50% patients eventually relapse and die of the disease due to chemoresistance. Here, using phospho-profiling, we find Ewing sarcoma cells treated with chemotherapeutic agents activate TAM (TYRO3, AXL, MERTK) kinases to augment Akt and ERK signaling facilitating chemoresistance. Mechanistically, chemotherapy-induced JAK1-SQ phosphorylation releases JAK1 pseudokinase domain inhibition allowing for JAK1 activation. This alternative JAK1 activation mechanism leads to STAT6 nuclear translocation triggering transcription and secretion of the TAM kinase ligand GAS6 with autocrine/paracrine consequences. Importantly, pharmacological inhibition of either JAK1 by filgotinib or TAM kinases by UNC2025 sensitizes Ewing sarcoma to chemotherapy in vitro and in vivo. Excitingly, the TAM kinase inhibitor MRX-2843 currently in human clinical trials to treat AML and advanced solid tumors, enhances chemotherapy efficacy to further suppress Ewing sarcoma tumor growth in vivo. Our findings reveal an Ewing sarcoma chemoresistance mechanism with an immediate translational value.

Introducing a Pyrazinoquinoxaline Derivative into a Metal-Organic Framework: Achieving Fluorescence-Enhanced Detection for Cs+ and Enhancing Photocatalytic Activity.

Conventional photoresponsive materials have low photon utilization due to irregular distribution of photoactive groups, which severely limits the related real applications. Metal-organic frameworks (MOFs) can modulate the regular arrangement of functional groups to improve the electron transport paths and enhance the photon utilization, which provides strong support for the development of photoactive materials with excellent performance. In this work, one effective strategy for constructing a photoactive MOF had been developed via the utilization of Cd2+ and pyrazinoquinoxaline tetracarboxylic acid. The structural advantages of the Cd-MOF, such as a porous structure, abundant subject-object interaction sites, and a stable framework, ensure the prerequisite for various applications, while the better synergistic effect of Cd3 clusters and the pyrazinoquinoxaline derivative ensures efficient electron transfer efficiency. Therefore, by virtue of these structural advantages, the Cd-MOF can achieve fluorescence quenching detection for a variety of substrates, such as Fe3+, Cr2O72-, MnO4-, nitrofuran antibiotics, and TNP explosives, while fluorescence enhancement detection can be achieved for halogen ions, Cs+, Pb2+, and NO2-. In addition, the Cd-MOF can be used as a photocatalyst to successfully achieve the photocatalytic conversion of benzylamine to N-benzylbenzimidate under mild conditions. Thus, the Cd-MOF as a whole shows the possibility of application as a diverse fluorescence detection and photocatalyst and also illustrates the feasibility of preparing high-performance photoactive materials using the pyrazinoquinoxaline derivative.