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Background Natural killer (NK) cells play a major role in body’s fighting against various types of cancers. Their infiltration in the tumor microenvironment (TME) of gastric cancer (GC) are significantly decreased, which has been reported as a robust prognostic marker. However, the causes leading to NK cells loss in GC TME remains poorly understood. Methods We constructed a non-contact co-culturing system and humanized xenograft tumor mice model to detect the influence of GC microenvironment on NK-92 or primary human NK cells viability by flow cytometry. Then through using the specific inhibitors for different types of cell death and examining the surrogate markers, we confirmed ferroptosis in NK cells. Inspired by the accidental discoveries, we constructed a NK-92 cell strain with high expression of GPX4 and treated the humanized xenograft tumor mice model with the NK-92 cells. Results We found L-KYN, mainly generated through indoleamine 2, 3-dioxygenase (IDO) from GC cells, impaired NK cells viability in TME. Further analysis revealed L-KYN induced ferroptosis in NK cells via an AHR-independent way. Moreover, we found NK cells with higher GPX4 expression showed resistance to L-KYN induced ferroptosis. Based on this, we generated GPX4 over-expressed NK-92 cells, and found these cells showed therapeutic potential towards GC. Conclusions Our study revealed a novel mechanism to explain the decline of NK cell number in GC TME. Notably, we also developed a potential immunotherapy strategy, which might be beneficial in clinical treatment in the future.

Human serine palmitoyltransferase (SPT) complex catalyzes the initial and rate-limiting step in the de novo biosynthesis of all sphingolipids. ORMDLs regulate SPT function, with human ORMDL3 being related to asthma. Here we report three high-resolution cryo-EM structures: the human SPT complex, composed of SPTLC1, SPTLC2 and SPTssa; the SPT–ORMDL3 complex; and the SPT–ORMDL3 complex bound to two substrates, PLP- l -serine (PLS) and a non-reactive palmitoyl-CoA analogue. SPTLC1 and SPTLC2 form a dimer of heterodimers as the catalytic core. SPTssa participates in acyl-CoA coordination, thereby stimulating the SPT activity and regulating the substrate selectivity. ORMDL3 is located in the center of the complex, serving to stabilize the SPT assembly. Our structural and biochemical analyses provide a molecular basis for the assembly and substrate selectivity of the SPT and SPT–ORMDL3 complexes, and lay a foundation for mechanistic understanding of sphingolipid homeostasis and for related therapeutic drug development. Cryo-EM structures of serine palmitoyltransferase complexes mediating a key reaction of sphingolipid biosynthesis elucidate principles of its multimeric assembly, regulation and substrate selectivity

Optical networks that distribute entanglement among various quantum systems will form a powerful framework for quantum science but are yet to interface with leading quantum hardware such as superconducting qubits. Consequently, these systems remain isolated because microwave links at room temperature are noisy and lossy. Building long distance connectivity requires interfaces that map quantum information between microwave and optical fields. While preliminary microwave-to-optical transducers have been realized, developing efficient, low-noise devices that match superconducting qubit frequencies (gigahertz) and bandwidths (10 kilohertz – 1 megahertz) remains a challenge. Here we demonstrate a proof-of-concept on-chip transducer using trivalent ytterbium-171 ions in yttrium orthovanadate coupled to a nanophotonic waveguide and a microwave transmission line. The device′s miniaturization, material, and zero-magnetic-field operation are important advances for rare-earth ion magneto-optical devices. Further integration with high quality factor microwave and optical resonators will enable efficient transduction and create opportunities toward multi-platform quantum networks. Long distance interfaces between superconducting quantum information processing nodes would require coherent, efficient and low-noise microwave-to-optical conversion. Here, the authors use Yb ion ensembles in yttrium orthovanadate to demonstrate a transducer with the potential to fulfill these requirements.

Human ATP-binding cassette (ABC) subfamily A (ABCA) transporters mediate the transport of various lipid compounds across the membrane. Mutations in human ABCA transporters have been described to cause severe hereditary disorders associated with impaired lipid transport. However, little is known about the mechanistic details of substrate recognition and translocation by ABCA transporters. Here, we present three cryo-EM structures of human ABCA4, a retina-specific ABCA transporter, in distinct functional states at resolutions of 3.3–3.4 Å. In the nucleotide-free state, the two transmembrane domains (TMDs) exhibit a lateral-opening conformation, allowing the lateral entry of substrate from the lipid bilayer. The N-retinylidene-phosphatidylethanolamine (NRPE), the physiological lipid substrate of ABCA4, is sandwiched between the two TMDs in the luminal leaflet and is further stabilized by an extended loop from extracellular domain 1. In the ATP-bound state, the two TMDs display a closed conformation, which precludes the substrate binding. Our study provides a molecular basis to understand the mechanism of ABCA4-mediated NRPE recognition and translocation, and suggests a common ‘lateral access and extrusion’ mechanism for ABCA-mediated lipid transport. Here, cryo-EM structures of human retinal ABCA4 transporter, either in apo state, in complex with ATP or with the physiological lipid substrate N-retinylidene-phosphatidylethanolamine (NRPE), reveal lateral opening, substrate recognition and suggest ‘lateral access and extrusion’ mechanism for ABCA-mediated lipid transport.

Background Although the relationship between social media use and insomnia has been confirmed, few studies have explored the association between social media overload and insomnia, and the underlying mechanism is still unclear. The present research aims to propose a theoretical model in which information strain and depressive symptoms serve as mediating variables between social media overload and insomnia, providing new empirical evidence for the impact mechanism of insomnia. Methods 644 college students participated in the questionnaire survey, they all completed a self-report questionnaire with demographic information, social media overload, information strain, depressive symptoms, and insomnia. The data were processed using SPSS26 and the PROCESS4.0 tool. Results Social media overload, information strain, depressive symptoms, and insomnia were positively and significantly associated with each other. Information strain and depressive symptoms mediated the association between social media overload and insomnia. There also existed a chain-mediating effect between social media overload and insomnia. Conclusions This study highlights the potential negative effects of social media overload on sleep problems. The results of this article emphasize the importance of promoting good social media usage habits and healthy lifestyles during public health emergencies, which are important for improving health outcomes.

The design of functional materials with desired properties is essential in driving technological advances in areas such as energy storage, catalysis and carbon capture 1 , 2 – 3 . Generative models accelerate materials design by directly generating new materials given desired property constraints, but current methods have a low success rate in proposing stable crystals or can satisfy only a limited set of property constraints 4 , 5 , 6 , 7 , 8 , 9 , 10 – 11 . Here we present MatterGen, a model that generates stable, diverse inorganic materials across the periodic table and can further be fine-tuned to steer the generation towards a broad range of property constraints. Compared with previous generative models 4 , 12 , structures produced by MatterGen are more than twice as likely to be new and stable, and more than ten times closer to the local energy minimum. After fine-tuning, MatterGen successfully generates stable, new materials with desired chemistry, symmetry and mechanical, electronic and magnetic properties. As a proof of concept, we synthesize one of the generated structures and measure its property value to be within 20% of our target. We believe that the quality of generated materials and the breadth of abilities of MatterGen represent an important advancement towards creating a foundational generative model for materials design. MatterGen is a model that generates stable, diverse inorganic materials across the periodic table and can further be fine-tuned to steer the generation towards a broad range of property constraints.

The dense stroma of desmoplastic tumor limits nanotherapeutic penetration and hampers the antitumor immune response. Here, we report a denaturation-and-penetration strategy and the use of tin monosulfide nanoparticles (SnSNPs) as nano-sonosensitizers that can overcome the stromal barrier for the management of desmoplastic triple-negative breast cancer (TNBC). SnSNPs possess a narrow bandgap (1.18 eV), allowing for efficient electron (e − )-hole (h + ) pair separation to generate reactive oxygen species under US activation. More importantly, SnSNPs display mild photothermal properties that can in situ denature tumor collagen and facilitate deep penetration into the tumor mass upon near-infrared irradiation. This approach significantly enhances sonodynamic therapy (SDT) by SnSNPs and boosts antitumor immunity. In mouse models of malignant TNBC and hepatocellular carcinoma (HCC), the combination of robust SDT and enhanced cytotoxic T lymphocyte infiltration achieves remarkable anti-tumor efficacy. This study presents an innovative approach to enhance SDT and antitumor immunity using the denaturation-and-penetration strategy, offering a potential combined sono-immunotherapy approach for the cancer nanomedicine field. The dense stroma of desmoplastic tumor limits nanotherapeutic penetration and hampers the antitumor immune response. Here the authors use tin monosulfide nanoparticles as nano-sonosensitizers to overcome the stromal barrier in triple negative breast cancer and improve the efficacy of sonodynamic therapy and boost antitumor immunity.

Potassium (K) metal is a promising alkali metal anode for its high abundance. However, dendrite on K anode is a serious problem which is even worse than Li. Artificial SEI (ASEI) is one of effective routes for suppressing dendrite. However, there are still some issues of the ASEI made by the traditional methods, e.g. weak adhesion, insufficient/uneven reaction, which deeply affects the ionic diffusion kinetics and the effect of inhibiting dendrites. Herein, through a unique self-catalysis tribo-electrochemistry reaction, a continuous and compact protective layer is successfully constructed on K metal anode in seconds. Such a continuous and compact protective layer can not only improve the K + diffusion kinetics, but also strongly suppress K dendrite formation by its hard mechanical properties derived from rigid carbon system, as well as the improved K + conductivity and lowered electronic conductivity from the amorphous KF. As a result, the potassium symmetric cells exhibit stable cycles last more than 1000 h, which is almost 500 times that of pristine K. Potassium metal is a promising alkali metal anode but formation of dendrites limits its application. Here, the authors report construction of a continuous and compact protective layer on potassium metal anode through a self-catalysis tribo-electrochemistry reaction in seconds.

Natural products are important sources for drug discovery, especially anti-tumor drugs. β-Elemene, the prominent active ingredient extract from the rhizome of Curcuma wenyujin, is a representative natural product with broad anti-tumor activities. The main molecular mechanism of β-elemene is to inhibit tumor growth and proliferation, induce apoptosis, inhibit tumor cell invasion and metastasis, enhance the sensitivity of chemoradiotherapy, regulate the immune system, and reverse multidrug resistance (MDR). Elemene oral emulsion and elemene injection were approved by the China Food and Drug Administration (CFDA) for the treatment of various cancers and bone metastasis in 1994. However, the lipophilicity and low bioavailability limit its application. To discover better β-elemene-derived anti-tumor drugs with satisfying drug-like properties, researchers have modified its structure under the premise of not damaging the basic scaffold structure. In this review, we comprehensively discuss and summarize the potential anti-tumor mechanisms and the progress of structural modifications of β-elemene.

Diabetic retinopathy (DR) is a serious and relatively under-recognized complication of diabetes. Müller glial cells extend throughout the retina and play vital roles in maintaining retinal homeostasis. Previous studies have demonstrated that TGR5, a member of the bile acid-activated GPCR family, could ameliorate DR. However, the role of TGR5 in regulating Müller cell function and the underlying mechanism remains to be ascertained. To address this, high glucose (HG)-treated human Müller cells and streptozotocin-treated Sprague-Dawley rats were used in the study. The IP3R1-GRP75-VDAC1 axis and mitochondrial function were assessed after TGR5 ablation or agonism. Cytosolic mitochondrial DNA (mtDNA)-mediated cGAS-STING activation was performed. The key markers of retinal vascular leakage, apoptosis, and inflammation were examined. We found that mitochondrial Ca 2+ overload and mitochondrial dysfunction were alleviated by TGR5 agonist. Mechanically, TGR5 blocked the IP3R1-GRP75-VDAC1 axis mediated Ca 2+ efflux from the endoplasmic reticulum into mitochondria under diabetic condition. Mitochondrial Ca 2+ overload led to the opening of the mitochondrial permeability transition pore and the release of mitochondrial DNA (mtDNA) into the cytosol. Cytoplasmic mtDNA bound to cGAS and upregulated 2’3’ cyclic GMP-AMP. Consequently, STING-mediated inflammatory responses were activated. TGR5 agonist prevented retinal injury, whereas knockdown of TGR5 exacerbated retinal damage in DR rats, which was rescued by the STING inhibitor. Based on the above results, we propose that TGR5 might be a novel therapeutic target for the treatment of DR.