Highly efficient nitrogen fixation over S-scheme heterojunction photocatalysts with enhanced active hydrogen supply.

Photocatalytic N2 fixation is a promising strategy for ammonia (NH3) synthesis; however, it suffers from relatively low ammonia yield due to the difficulty in the design of photocatalysts with both high charge transfer efficiency and desirable N2 adsorption/activation capability. Herein, an S-scheme CoSx/ZnS heterojunction with dual active sites is designed as an efficient N2 fixation photocatalyst. The CoSx/ZnS heterojunction exhibits a unique pocket-like nanostructure with small ZnS nanocrystals adhered on a single-hole CoSx hollow dodecahedron. Within the heterojunction, the electronic interaction between ZnS and CoSx creates electron-deficient Zn sites with enhanced N2 chemisorption and electron-sufficient Co sites with active hydrogen supply for N2 hydrogenation, cooperatively reducing the energy barrier for N2 activation. In combination with the promoted photogenerated electron-hole separation of the S-scheme heterojunction and facilitated mass transfer by the pocket-like nanostructure, an excellent N2 fixation performance with a high NH3 yield of 1175.37 µmol g-1 h-1 is achieved. This study provides new insights into the design of heterojunction photocatalysts for N2 fixation.

Enabling Logistics Automation in Nanofactory: Cobalt Phosphide Embedded Metal-Organic Frameworks for Efficient Electrocatalytic Nitrate Reduction to Ammonia.

Electrocatalytic nitrate reduction reaction (NitRR) in neutral condition offers a promising strategy for green ammonia synthesis and wastewater treatment, the rational design of electrocatalysts is the cornerstone. Inspired by modern factory design where both machines and logistics matter for manufacturing, it is reported that cobalt phosphide (CoP) nanoparticles embedded in zinc-based zeolite imidazole frameworks (Zn-ZIF) function as a nanofactory with high performance. By selective phosphorization of ZnCo bimetallic zeolite imidazole framework (ZnCo-ZIF), the generated CoP nanoparticles act as "machines" (active sites) for molecular manufacturing (NO3 - to NH4 + conversion). The purposely retained framework (Zn-ZIFs) with positive charge promotes logistics automation, i.e., the automatic delivery of NO3 - reactants and timely discharge of NH4 + products in-and-out the nanofactory due to electrostatic interaction. Moreover, the interaction between Zn-ZIF and CoP modulates the Co sites into electron insufficient state with upshifted d-band center, facilitating the reduction/hydrogenation of NO3 - to ammonia and restricting the competitive hydrogen evolution. Consequently, the assembled CoP/Zn-ZIF nanofactory exhibits superior NitRR performances with a high Faraday efficiency of ≈97% and a high ammonia yield of 0.89 mmol cm-1 h-1 in neutral condition, among the best of reported electrocatalysts. The work provides new insights into the design principles of efficient NitRR electrocatalysts.

A unique circulating microRNA pairs signature serves as a superior tool for early diagnosis of pan-cancer.

Cancer remains a major burden globally and the critical role of early diagnosis is self-evident. Although various miRNA-based signatures have been developed in past decades, clinical utilization is limited due to a lack of precise cutoff value. Here, we innovatively developed a signature based on pairwise expression of miRNAs (miRPs) for pan-cancer diagnosis using machine learning approach. We analyzed miRNA spectrum of 15832 patients, who were divided into training, validation, test, and external test sets, with 13 different cancers from 10 cohorts. Five different machine-learning (ML) algorithms (XGBoost, SVM, RandomForest, LASSO, and Logistic) were adopted for signature construction. The best ML algorithm and the optimal number of miRPs included were identified using area under the curve (AUC) and youden index in validation set. The AUC of the best model was compared to previously published 25 signatures. Overall, Random Forest approach including 31 miRPs (31-miRP) was developed, proving highly efficient in cancer diagnosis across different datasets and cancer types (AUC range: 0.980-1.000). Regarding diagnosis of cancers at early stage, 31-miRP also exhibited high capacities, with AUC ranging from 0.961 to 0.998. Moreover, 31-miRP exhibited advantages in differentiating cancers from normal tissues (AUC range: 0.976-0.998) as well as differentiating cancers from corresponding benign lesions. Encouragingly, comparing to previously published 25 different signatures, 31-miRP also demonstrated clear advantages. In conclusion, 31-miRP acts as a powerful model for cancer diagnosis, characterized by high specificity and sensitivity as well as a clear cutoff value, thereby holding potential as a reliable tool for cancer diagnosis at early stage.

Hepatic glycogenesis antagonizes lipogenesis by blocking S1P via UDPG.

The identification of mechanisms to store glucose carbon in the form of glycogen rather than fat in hepatocytes has important implications for the prevention of nonalcoholic fatty liver disease (NAFLD) and other chronic metabolic diseases. In this work, we show that glycogenesis uses its intermediate metabolite uridine diphosphate glucose (UDPG) to antagonize lipogenesis, thus steering both mouse and human hepatocytes toward storing glucose carbon as glycogen. The underlying mechanism involves transport of UDPG to the Golgi apparatus, where it binds to site-1 protease (S1P) and inhibits S1P-mediated cleavage of sterol regulatory element-binding proteins (SREBPs), thereby inhibiting lipogenesis in hepatocytes. Consistent with this mechanism, UDPG administration is effective at treating NAFLD in a mouse model and human organoids. These findings indicate a potential opportunity to ameliorate disordered fat metabolism in the liver.

DNA of neutrophil extracellular traps binds TMCO6 to impair CD8+ T-cell immunity in hepatocellular carcinoma.

Neutrophil extracellular traps (NETs), formed by the extracellular release of decondensed chromatin and granules, have been shown to promote tumor progression and metastasis. Tumor-associated neutrophils in hepatocellular carcinoma (HCC) are prone to NET formation, highlighting the need for a more comprehensive understanding of the mechanisms of action of NETs in liver cancer. Here, we showed that DNA of NETs (NET-DNA) binds transmembrane and coiled-coil domains 6 (TMCO6) on CD8+ T cells to impair anti-tumor immunity and thereby promote HCC progression. TGF-ß1 induced NET formation, which recruited CD8+ T cells. Binding to NET-DNA inhibited CD8+ T cells function while increasing apoptosis and TGF-ß1 secretion, forming a positive feedback loop to further stimulate NET formation and immunosuppression. Mechanistically, the N-terminus of TMCO6 interacted with NET-DNA and suppressed T-cell receptor signaling and NF-κB p65 nuclear translocation. Blocking NET formation by inhibiting PAD4 induced potent antitumor effects in wild-type mice but not TMCO6-/- mice. In clinical samples, CD8+ T cells expressing TMCO6 had an exhausted phenotype. TGF-ß1-signaling inhibition or TMCO6 deficiency combined with anti-PD-1 abolished NET-driven HCC progression in vivo. Collectively, this study unveils the role of NET-DNA in impairing CD8+ T-cell immunity by binding TMCO6 and identifies targeting this axis as an immunotherapeutic strategy for blocking HCC progression.

Pan-cancer characterization of cell-free immune-related miRNA identified as a robust biomarker for cancer diagnosis.

Minimally invasive testing is essential for early cancer detection, impacting patient survival rates significantly. Our study aimed to establish a pioneering cell-free immune-related miRNAs (cf-IRmiRNAs) signature for early cancer detection. We analyzed circulating miRNA profiles from 15,832 participants, including individuals with 13 types of cancer and control. The data was randomly divided into training, validation, and test sets (7:2:1), with an additional external test set of 684 participants. In the discovery phase, we identified 100 differentially expressed cf-IRmiRNAs between the malignant and non-malignant, retaining 39 using the least absolute shrinkage and selection operator (LASSO) method. Five machine learning algorithms were adopted to construct cf-IRmiRNAs signature, and the diagnostic classifies based on XGBoost algorithm showed the excellent performance for cancer detection in the validation set (AUC: 0.984, CI: 0.980-0.989), determined through 5-fold cross-validation and grid search. Further evaluation in the test and external test sets confirmed the reliability and efficacy of the classifier (AUC: 0.980 to 1.000). The classifier successfully detected early-stage cancers, particularly lung, prostate, and gastric cancers. It also distinguished between benign and malignant tumors. This study represents the largest and most comprehensive pan-cancer analysis on cf-IRmiRNAs, offering a promising non-invasive diagnostic biomarker for early cancer detection and potential impact on clinical practice.

High-efficiency Electroreduction of O2 into H2 O2 over ZnCo Bimetallic Triazole Frameworks Promoted by Ligand Activation.

Co-based metal-organic frameworks (MOFs) as electrocatalysts for two-electron oxygen reduction reaction (2e- ORR) are highly promising for H2 O2 production, but suffer from the intrinsic activity-selectivity trade-off. Herein, we report a ZnCo bimetal-triazole framework (ZnCo-MTF) as high-efficiency 2e- ORR electrocatalysts. The experimental and theoretical results demonstrate that the coordination between 1,2,3-triazole and Co increases the antibonding-orbital occupancy on the Co-N bond, promoting the activation of Co center. Besides, the adjacent Zn-Co sites on 1,2,3-triazole enable an asymmetric "side-on" adsorption mode of O2 , favoring the reduction of O2 molecules and desorption of OOH* intermediate. By virtue of the unique ligand effect, the ZnCo-MTF exhibits a 2e- ORR selectivity of ≈100 %, onset potential of 0.614 V and H2 O2 production rate of 5.55 mol gcat -1 h-1 , superior to the state-of-the-art zeolite imidazole frameworks. Our work paves the way for the design of 2e- ORR electrocatalysts with desirable coordination and electronic structure.

Nanostructured Li2S Cathodes for Silicon-Sulfur Batteries.

Lithium-sulfur batteries are regarded as an advantageous option for meeting the growing demand for high-energy-density storage, but their commercialization relies on solving the current limitations of both sulfur cathodes and lithium metal anodes. In this scenario, the implementation of lithium sulfide (Li2S) cathodes compatible with alternative anode materials such as silicon has the potential to alleviate the safety concerns associated with lithium metal. In this direction, here, we report a sulfur cathode based on Li2S nanocrystals grown on a catalytic host consisting of CoFeP nanoparticles supported on tubular carbon nitride. Nanosized Li2S is incorporated into the host by a scalable liquid infiltration-evaporation method. Theoretical calculations and experimental results demonstrate that the CoFeP-CN composite can boost the polysulfide adsorption/conversion reaction kinetics and strongly reduce the initial overpotential activation barrier by stretching the Li-S bonds of Li2S. Besides, the ultrasmall size of the Li2S particles in the Li2S-CoFeP-CN composite cathode facilitates the initial activation. Overall, the Li2S-CoFeP-CN electrodes exhibit a low activation barrier of 2.56 V, a high initial capacity of 991 mA h gLi2S-1, and outstanding cyclability with a small fading rate of 0.029% per cycle over 800 cycles. Moreover, Si/Li2S full cells are assembled using the nanostructured Li2S-CoFeP-CN cathode and a prelithiated anode based on graphite-supported silicon nanowires. These Si/Li2S cells demonstrate high initial discharge capacities above 900 mA h gLi2S-1 and good cyclability with a capacity fading rate of 0.28% per cycle over 150 cycles.

Aryl hydrocarbon receptor sulfenylation promotes glycogenolysis and rescues cancer chemoresistance.

Elevation of reactive oxygen species (ROS) levels is a general consequence of tumor cells' response to treatment and may cause tumor cell death. Mechanisms by which tumor cells clear fatal ROS, thereby rescuing redox balance and entering a chemoresistant state, remain unclear. Here, we show that cysteine sulfenylation by ROS confers on aryl hydrocarbon receptor (AHR) the ability to dissociate from the heat shock protein 90 complex but to bind to the PPP1R3 family member PPP1R3C of the glycogen complex in drug-treated tumor cells, thus activating glycogen phosphorylase to initiate glycogenolysis and the subsequent pentose phosphate pathway, leading to NADPH production for ROS clearance and chemoresistance formation. We found that basic ROS levels were higher in chemoresistant cells than in chemosensitive cells, guaranteeing the rapid induction of AHR sulfenylation for the clearance of excess ROS. These findings reveal that AHR can act as an ROS sensor to mediate chemoresistance, thus providing a potential strategy to reverse chemoresistance in patients with cancer.

Epitaxial growth of metal-organic framework nanosheets into single-crystalline orthogonal arrays.

Construction of two-dimensional nanosheets into three-dimensional regular structures facilitates the mass transfer and exploits the maximum potential of two-dimensional building blocks in applications such as catalysis. Here, we report the synthesis of metal-organic frameworks with an orthogonal nanosheet array. The assembly involves the epitaxial growth of single crystalline metal-organic framework nanosheets with a naturally non-preferred facet exposure as the shell on a cubic metal-organic framework as the core. The nanosheets, despite of two typical shapes and crystallographic orientations, also form a single crystalline orthogonally arrayed framework. The density and size of nanosheets in the core-shell-structured composite metal-organic frameworks can be well adjusted. Moreover, metal-organic frameworks with a single composition and hollow orthogonal nanosheet array morphology can be obtained. Benefiting from the unusual facet exposure and macroporous structure, the designed structure exhibits improved electrocatalytic oxygen evolution activity compared to conventional nanosheets.

Identifying the Role of the Cationic Geometric Configuration in Spinel Catalysts for Polysulfide Conversion in Sodium-Sulfur Batteries.

An AB2X4 spinel structure, with tetrahedral A and octahedral B sites, is a paradigmatic class of catalysts with several possible geometric configurations and numerous applications, including polysulfide conversion in metal-sulfur batteries. Nonetheless, the influence of the geometric configuration and composition on the mechanisms of catalysis and the precise manner in which spinel catalysts facilitate the conversion of polysulfides remain unknown. To enable controlled exposure of single active configurations, herein, Cotd2+ and Cooh3+ in Co3O4 catalysts for sodium polysulfide conversion are in large part replaced by Fetd2+ and Feoh3+, respectively, generating FeCo2O4 and CoFe2O4. Through an examination of electrochemical activation energies, the characterization of symmetric cells, and theoretical calculations, we determine that Cooh3+ serves as the active site for the breaking of S-S bonds, while Cotd2+ functions as the active site for the formation of S-Na bonds. The current study underlines the subtle relationship between activity and geometric configurations of spinel catalysts, providing unique insights for the rational development of improved catalysts by optimizing their atomic geometric configuration.

Fabrication of a composite 3D-printed titanium alloy combined with controlled in situ drug release to prevent osteosarcoma recurrence.

Osteosarcoma is a malignant bone tumor occurring in adolescents. Surgery combined with adjuvant or neoadjuvant chemotherapy is the standard treatment. However, systemic chemotherapy is associated with serious side effects and a high risk of postoperative tumor recurrence, leading to a high amputation rate and mortality in cancer patients. Implant materials that can simultaneously repair large bone defects and prevent osteosarcoma recurrence are in urgent need. Herein, an intelligent system comprising 3D-printed titanium scaffold (TS) and pH-responsive PEGylated paclitaxel prodrugs was fabricated for bone defect reconstruction and recurrence prevention following osteosarcoma surgery. The drug-loaded implants exhibited excellent stability and biocompatibility for supporting the activity of bone stem cells under normal body fluid conditions and the rapid release of drugs in response to faintly acidic environments. An in vitro study demonstrated that five human osteosarcoma cell lines could be efficiently eradicated by paclitaxel released in an acidic microenvironment. Using mice models, we demonstrated that the drug-loaded TS can enable a pH-responsive treatment of postoperative tumors and effectively prevent osteosarcoma recurrence. Therefore, local implantation of this composite scaffold may be a promising topical therapeutic method to prevent osteosarcoma recurrence.

Spatial Specific Janus S-Scheme Photocatalyst with Enhanced H2 O2 Production Performance.

Photocatalytic oxygen reduction reaction (ORR) for H2 O2 production in the absence of sacrificing agents is a green approach and of great significance, where the design of photocatalysts with high performance is the central task. Herein, a spatial specific S-scheme heterojunction design by introducing a novel semiconducting pair with a S-scheme mechanism in a purpose-designed Janus core-shell-structured hollow morphology is reported. In this design, TiO2 nanocrystals are grown inside the inner wall of resorcinol-formaldehyde (RF) resin hollow nanocakes with a reverse bumpy ball morphology (TiO2 @RF). The S-scheme heterojunction preserves the high redox ability of the TiO2 and RF pair, the spatial specific Janus design enhances the charge separation, promotes active site exposure, and reduces the H2 O2 decomposition to a large extent. The TiO2 @RF photocatalyst shows a high H2 O2 yield of 66.6 mM g-1  h-1 and solar-to-chemical conversion efficiency of 1.11%, superior to another Janus structure (RF@TiO2 ) with the same heterojunction but a reversed Janus spatial arrangement, and most reported photocatalysts under similar reaction conditions. The work has paved the way toward the design of next-generation photocatalysts for green synthesis of H2 O2 production.

Humanized mouse models with endogenously developed human natural killer cells for in vivo immunogenicity testing of HLA class I-edited iPSC-derived cells.

Human induced pluripotent stem cells (hiPSCs) genetically depleted of human leucocyte antigen (HLA) class I expression can bypass T cell alloimmunity and thus serve as a one-for-all source for cell therapies. However, these same therapies may elicit rejection by natural killer (NK) cells, since HLA class I molecules serve as inhibitory ligands of NK cells. Here, we focused on testing the capacity of endogenously developed human NK cells in humanized mice (hu-mice) using MTSRG and NSG-SGM3 strains to assay the tolerance of HLA-edited iPSC-derived cells. High NK cell reconstitution was achieved with the engraftment of cord blood-derived human hematopoietic stem cells (hHSCs) followed by the administration of human interleukin-15 (hIL-15) and IL-15 receptor alpha (hIL-15Rα). Such "hu-NK mice" rejected HLA class I-null hiPSC-derived hematopoietic progenitor cells (HPCs), megakaryocytes and T cells, but not HLA-A/B-knockout, HLA-C expressing HPCs. To our knowledge, this study is the first to recapitulate the potent endogenous NK cell response to non-tumor HLA class I-downregulated cells in vivo. Our hu-NK mouse models are suitable for the non-clinical evaluation of HLA-edited cells and will contribute to the development of universal off-the-shelf regenerative medicine.

Patterns and prognostic values of programmed cell death-ligand 1 expression and CD8+ T-cell infiltration in small cell carcinoma of the esophagus: a retrospective analysis of 34 years of National Cancer Center data in China.

BACKGROUND: Small cell carcinoma of the esophagus (SCCE) is an extremely rare and highly aggressive neuroendocrine malignancy with a strikingly poor prognosis. Given the great clinical successes of checkpoint immunotherapies, we explored the expression profile and clinical significance of programmed cell death-ligand 1 (PD-L1) and CD8+ T cell in SCCE for the first time. MATERIALS AND METHODS: Tumor-infiltrating immune cells (TIICs) and tumor cells in postoperative, whole tumor sections from 147 SCCE patients were stained for PD-LI expression. We also evaluated each patient's Combined Positive Score (CPS). Multiplex immunofluorescence staining (CD3, CD20, CD68, and PD-L1) was introduced to clarify the location of PD-L1. CD8 density was analyzed by digital imaging and analysis of entire slides. Clinical outcomes were tested for correlations with both PD-L1 expression and CD8 density. RESULTS: No patients had PD-L1 expressed in their tumor cells. PD-L1+ expression in TIICs was detected in 65 patients (44.2%) and 42 (28.6%) exhibited CPS positivity. Multiplex immunofluorescence staining demonstrated that most of the PD-L1 was expressed on the CD68+ monocytes/macrophages. PD-L1 expression in the TIICs and CPS was found to be correlated with paraffin block age, tumor length, macroscopic type, T stage, and increased overall survival (OS). Expression of PD-L1 in TIICs showed significantly prolonged relapse-free survival (RFS). Increasing CD8 densities were associated with increased PD-L1 expression (Ptrend<0.0001). Multivariate regression confirmed that PD-L1 in TIICs and CD8 states were independent predictors of OS, and CD8 status were found to be independently predictive of RFS. A stratification based on PD-L1 and CD8 status was also significantly associated with both OS and RFS. CONCLUSION: Expression of PD-L1 was only detected in TIICs from approximately half of the patients with SCCEs. In SCCEs, PD-L1 and CD8 status are novel prognostic biomarkers and may inform the implementation of risk-related therapeutic strategies. SCCEs with higher CD8 infiltration also had higher expression of PD-L1, suggesting the development of resistance against adaptive immunity. These findings support the assertion that PD-L1/programmed cell death 1 inhibitors should be investigated in this rare malignancy.

Crystal Engineering Enables Cobalt-Based Metal-Organic Frameworks as High-Performance Electrocatalysts for H2O2 Production.

Metal-organic frameworks (MOFs) with highly adjustable structures are an emerging family of electrocatalysts in two-electron oxygen reduction reaction (2e-ORR) for H2O2 production. However, the development of MOF-based 2e-ORR catalysts with high H2O2 selectivity and production rate remains challenging. Herein, an elaborate design with fine control over MOFs at both atomic and nano-scale is demonstrated, enabling the well-known Zn/Co bimetallic zeolite imidazole frameworks (ZnCo-ZIFs) as excellent 2e-ORR electrocatalysts. Experimental results combined with density functional theory simulation have shown that the atomic level control can regulate the role of water molecules participating in the ORR process, and the morphology control over desired facet exposure adjusts the coordination unsaturation degree of active sites. The structural regulation at two length scales leads to synchronous control over both the kinetics and thermodynamics for ORR on bimetallic ZIF catalysts. The optimized ZnCo-ZIF with a Zn/Co molar ratio of 9/1 and predominant {001} facet exposure exhibits a high 2e- selectivity of ∼100% and a H2O2 yield of 4.35 mol gcat-1 h-1. The findings pave a new avenue toward the development of multivariate MOFs as advanced 2e-ORR electrocatalysts.

Costimulatory molecule expression profile as a biomarker to predict prognosis and chemotherapy response for patients with small cell lung cancer.

Owing to the paucity of specimens, progress in identifying prognostic and therapeutic biomarkers for small cell lung cancer (SCLC) has been stagnant for decades. Considering that the costimulatory molecules are essential elements in modulating immune responses and determining therapeutic response, we systematically revealed the expression landscape and identified a costimulatory molecule-based signature (CMS) to predict prognosis and chemotherapy response for SCLCs for the first time. We found T cell activation was restrained in SCLCs, and costimulatory molecules exhibited widespread abnormal genetic alterations and expression. Using a LASSO Cox regression model, the CMS was built with a training cohort of 77 cases, which successfully divided patients into high- or low-risk groups with significantly different prognosis and chemotherapy benefit (both P < 0.001). The CMS was well validated in an independent cohort containing 131 samples with qPCR data. ROC and C-index analysis confirmed the superior predictive performance of the CMS in comparison with other clinicopathological parameters from different cohorts. Importantly, the CMS was confirmed as a significantly independent prognosticator for clinical outcomes and chemotherapy response in SCLCs through multivariate Cox analysis. Further analysis revealed that low-risk patients were characteristic by an activated immune phenotype with distinct expression of immune checkpoints. In summary, we firstly uncovered the expression heterogeneity of costimulatory molecules in SCLC and successfully constructed a novel predictive CMS. The identified signature contributed to more accurate patient stratification and provided robust prognostic value in estimating survival and the clinical response to chemotherapy, allowing optimization of treatment and prognosis management for patients with SCLC.

Spin Effect to Promote Reaction Kinetics and Overall Performance of Lithium-Sulfur Batteries under External Magnetic Field.

Lithium-sulfur batteries (LSBs) are still limited by the shuttle of lithium polysulfides (LiPS) and the slow Li-S reaction. Herein, we demonstrate that when using cobalt sulfide as a catalytic additive, an external magnetic field generated by a permanent magnet can significantly improve the LiPS adsorption ability and the Li-S reaction kinetics. More specifically, the results show both experimentally and theoretically how an electron spin polarization of Co ions reduces electron repulsion and enhances the degree of orbital hybridization, thus resulting in LSBs with unprecedented performance and stability. Under an external magnetic field, LSBs with 0.0084 % per cycle decay rate at 2 C during 8150 cycles are produced. Overall, this work not only demonstrates an effective strategy to promote LiPS adsorption and electrochemical conversion in LSBs at no additional energy cost but also enriches the application of the spin effect in the electrocatalysis fields.