Hydrogel Nanoparticles Enable Nucleation Barrier Regulation and Ion Anchoring as an Alternative Pathway for Monosodium Urate Monohydrate Crystallization Control.

Gout flare-up, commonly resulting from monosodium urate monohydrate (MSUM) crystallization, has led to painful inflammatory arthritis among hundreds of millions of people. Herein, a kind of hydrogel nanoparticles (HNPs) with specific properties was developed, aimed at providing a promising pathway for MSUM crystallization control. The experimental and molecular dynamics simulation results synchronously indicate that the fabricated HNPs achieve efficient inhibition of MSUM crystallization governed by the mechanism of "host-guest interaction" even under very low-dose administration. HNPs as the host dispersed in the hyperuricemic model effectively lift the relative heterogeneous nucleation barrier of the MSUM crystal and hinder solute aggregation with strong electronegativity and hydrophobicity. The initial appearance of MSUM crystals was then delayed from 94 to 334 h. HNPs as the guest on the surface of the formed crystal can decelerate the growth rate by anchoring ions and occupying the active sites on the surface, and the terminal yield of the MSUM crystal declined to less than 1% of the control group. The good biocompatibility of HNPs (cell viability > 94%) renders it possible for future clinical applications. This study can guide the rational design of inhibitory nanomaterials and the development of their application in the control of relevant pathological crystallization.

Lactobacillus rhamnosus GG powder supplementation alleviates intestinal injury in piglets challenged by porcine epidemic diarrhea virus.

Porcine epidemic diarrhea virus (PEDV) has become a challenging problem in pig industry worldwide, causing significant profit losses. Lactobacillus rhamnosus GG (LGG) has been regarded as a safe probiotic strain and has been shown to exert protective effects on the intestinal dysfunction caused by PEDV. This study evaluated the effect of LGG on the gut health of lactating piglets challenged with PEDV. Fifteen piglets at 7 days of age were equally assigned into 3 groups (5 piglets per group): 1) control group (basal diet); 2) PEDV group: (basal diet + PEDV challenged); 3) LGG + PEDV group (basal diet + 3×109 CFU/pig/day LGG + PEDV). The trial lasted 11 days including 3 days of adaptation. The treatment with LGG was from D4 to D10. PEDV challenge was carried out on D8. PEDV infection disrupted the cell structure, undermined the integrity of the intestinal tract, and induced oxidative stress, and intestinal damage of piglets. Supplementation of LGG improved intestinal morphology, enhanced intestinal antioxidant capacity, and alleviated jejunal mucosal inflammation and lipid metabolism disorders in PEDV-infected piglets, which may be regulated by LGG by altering the expression of TNF signaling pathway, PPAR signaling pathway, and fat digestion and absorption pathway.

Identification of two flavonoids antiviral inhibitors targeting 3C-like protease of porcine epidemic diarrhea virus.

Porcine epidemic diarrhea virus (PEDV) has caused severe damage to the global pig industry in the past 20 years, creating an urgent demand for the development of associated medications. Flavonoids have emerged as promising candidates for combating coronaviruses. It is believed that certain flavonoids can directly inhibit the 3C-like protease (3CLpro), thus displaying antiviral activity against coronaviruses. In this investigation, we applied a flavonoid library to screen for natural compounds against PEDV 3CLpro. Baicalein and baicalin were found to efficiently inhibit PEDV 3CLproin vitro, with the IC50 value of 9.50 ± 1.02 µM and 65.80 ± 6.57 µM, respectively. A docking analysis supported that baicalein and baicalin might bind to the active site and binding pocket of PEDV 3CLpro. Moreover, both baicalein and baicalin successfully suppressed PEDV replication in Vero and LLC-PK1 cells, as indicated by reductions in viral RNA, protein, and titer. Further investigation revealed that baicalein and baicalin mainly inhibited the early viral replication of the post-entry stage. Furthermore, baicalein showed potential effects on the attachment or invasion step of PEDV. Collectively, our findings provide experimental proof for the inhibitory effects of baicalein and baicalin on PEDV 3CLpro activity and PEDV infection. These discoveries may introduce novel therapeutic strategies for controlling porcine epidemic diarrhea (PED).

Effect of supplementation with yeast polysaccharides on intestinal function in piglets infected with porcine epidemic diarrhea virus.

Porcine epidemic diarrhea virus (PEDV) has caused huge economic losses to the pig industry. Yeast polysaccharides (YP) has been used as a feed additive in recent years and poses good anti-inflammatory and antiviral effects. The present study aimed to explore the protective effect of YP on intestinal damage in PEDV-infected piglets. Eighteen 7-day-old piglets with similar body weights were randomly divided into three groups: Control group (basal diet), PEDV group (basal diet), and PEDV+YP group (basal diet +20 mg/kg BW YP), six replicates per group and one pig per replicate. Piglets in PEDV group and PEDV+YP group were orally given PEDV (dose: 1 × 106 TCID50) at 19:30 PM on the 8th day of the experiment. The control group received the same volume of PBS solution. Weight was taken on an empty stomach in the morning of the 11th day, blood was collected and then anesthetic was administered with pentobarbital sodium (50 mg/kg·BW) by intramuscular injection, and samples were slaughtered after the anesthetic was complete. The results showed that YP could alleviate the destruction of intestinal villus morphology of piglets caused by PEDV. Meanwhile, PEDV infection can reduce the activity of glutathione peroxidase, superoxide dismutase and catalase, and increase the content of malondialdehyde. YP can improve the antioxidative capacity in the serum and small intestine of PEDV-infected piglets. In addition, YP inhibited the replication of PEDV in the jejunum ileum and colon. Moreover, YP can regulate the mRNA levels of inflammatory genes (IL-1ß and iNOS) and lipid metabolic genes (APOA4 and APOC3) in the small intestine. In summary, YP could inhibit virus replicates, improve intestinal morphology, enhance antioxidant capacity, relieve inflammation and regulate the metabolism of the intestine in PEDV-infected piglets.

Zinc as a potential regulator of the BCR-ABL oncogene in chronic myelocytic leukemia cells.

BACKGROUND: Generally, decreased zinc in the serum of tumor patients but increased zinc in tumor cells can be observed. However, the role of zinc homeostasis in myeloid leukemia remains elusive. BCR-ABL is essential for the initiation, maintenance, and progression of chronic myelocytic leukemia (CML). We are currently investigating the association between zinc homeostasis and CML. METHODS: Genes involved in zinc homeostasis were examined using three GEO datasets. Western blotting and qPCR were used to investigate the effects of zinc depletion on BCR-ABL expression. Furthermore, the effect of TPEN on BCR-ABL promoter activity was determined using the dual-luciferase reporter assay. MRNA stability and protein stability of BCR-ABL were assessed using actinomycin D and cycloheximide. RESULTS: Transcriptome data mining revealed that zinc homeostasis-related genes were associated with CML progression and drug resistance. Several zinc homeostasis genes were affected by TPEN. Additionally, we found that zinc depletion by TPEN decreased BCR-ABL mRNA stability and transcriptional activity in K562 CML cells. Zinc supplementation and sodium nitroprusside treatment reversed BCR-ABL downregulation by TPEN, suggesting zinc- and nitric oxide-dependent mechanisms. CONCLUSION: Our in vitro findings may help to understand the role of zinc homeostasis in BCR-ABL regulation and thus highlight the importance of zinc homeostasis in CML.

Exploring the anti-ferroptosis mechanism of Kai-Xin-San against Alzheimer's disease through integrating network pharmacology, bioinformatics, and experimental validation strategy in vivo and in vitro.

ETHNOPHARMACOLOGICAL RELEVANCE: Kai Xin San (KXS), first proposed by Sun Simiao during the Tang Dynasty, has been utilized to treat dementia by tonifying qi and dispersing phlegm. AIM OF THE STUDY: This study aimed to elucidate the mechanism by which KXS exerts its therapeutic effects on Alzheimer's disease (AD) by targeting ferroptosis, using a combination of network pharmacology, bioinformatics, and experimental validation strategies. MATERIALS AND METHODS: The active target sites and the further potential mechanisms of KXS in protecting against AD were investigated through molecular docking, molecular dynamics simulation, and network pharmacology, and combined with the validation of animal experiments. RESULTS: Computational and experimental findings provide the first indication that KXS significantly improves learning and memory defects and inhibits neuronal ferroptosis by repairing mitochondria damage and upregulating the protein expression of ferroptosis suppressor protein 1 (FSP1) in vivo APP/PS1 mice AD model. According to bioinformatics analysis, the mechanism by which KXS inhibits ferroptosis may involve SIRT1. KXS notably upregulated the mRNA and protein expression of SIRT1 in both vivo APP/PS1 mice and in vitro APP-overexpressed HT22 cells. Additionally, KXS inhibited ferroptosis induced by APP-overexpression in HT22 cells through activating the SIRT1-FSP1 signal pathway. CONCLUSIONS: Collectively, our findings suggest that KXS may inhibit neuronal ferroptosis through activating the SIRT1/FSP1 signaling pathway. This study reveals the scientific basis and underlying modern theory of replenishing qi and eliminating phlegm, which involves the inhibition of ferroptosis. Moreover, it highlights the potential application of SIRT1 or FSP1 activators in the treatment of AD and other ferroptosis-related diseases.

Aquaculture activities influencing the generation of geosmin and 2-methylisoborneol: a case study in the aquaculture regions of Hongze Lake, China.

Contamination by odor substances such as geosmin (GSM) and 2-methylisoborneol (2-MIB) was examined in the cultured water from aquaculture farming in the region of the Hongze Lake in 2022, and some factors influencing residual levels of them in the water were analyzed. Geographically, high concentrations of GSM were located mainly in the north and northeast culture areas of the lake, while those of 2-MIB were found in the northeast and southwest. Analysis of the water in the enclosure culture revealed significant differences in the concentrations of GSM and 2-MIB among the cultured species. The mean concentrations of GSM in culture water were ranked in the order: crab > the four major Chinese carps > silver and bighead carp, and silver and bighead carp > crab > the four major Chinese carps for 2-MIB. The concentration of GSM was significantly higher at 38.99 ± 18.93 ng/L in crab culture water compared to other fish culture water. Significant differences were observed in GSM concentrations between crab enclosure culture and pond culture, while 2-MIB levels were comparable. These findings suggest that cultural management practices significantly affect the generation of odor substances. The taste and odor (T&O) assessment revealed that the residual levels of GSM and 2-MIB in most samples were below the odor threshold concentrations (OTCs), although high levels of GSM and 2-MIB in all water bodies were at 30.9% and 27.5%, respectively. Compared with the corresponding data from other places and the regulation guidelines of Japan, USA, and China, the region in the Hongze Lake is generally classified as a slightly T&O area, capable of supporting the aquaculture production scale.

Oncogenic KRAS effector USP13 promotes metastasis in non-small cell lung cancer through deubiquitinating ß-catenin.

KRAS mutations are frequently detected in non-small cell lung cancers (NSCLCs). Although covalent KRASG12C inhibitors have been developed to treat KRASG12C-mutant cancers, effective treatments are still lacking for other KRAS-mutant NSCLCs. Thus, identifying a KRAS effector that confers poor prognosis would provide an alternative strategy for the treatment of KRAS-driven cancers. Here, we show that KRAS drives expression of deubiquitinase USP13 through Ras-responsive element-binding protein 1 (RREB1). Elevated USP13 promotes KRAS-mutant NSCLC metastasis, which is associated with poor prognosis in NSCLC patients. Mechanistically, USP13 interacts with and removes the K63-linked polyubiquitination of ß-catenin at lysine 508, which enhances the binding between ß-catenin and transcription factor TCF4. Importantly, we identify 2-methoxyestradiol as an effective inhibitor for USP13 from a natural compound library, and it could potently suppress the metastasis of KRAS-mutant NSCLC cells in vitro and in vivo. These findings identify USP13 as a therapeutic target for metastatic NSCLC with KRAS mutations.

A Dual GLP-1/GIP Receptor Agonist Is More Effective than Liraglutide in the A53T Mouse Model of Parkinson's Disease.

Parkinson's disease (PD) is a complex syndrome with many elements, such as chronic inflammation, oxidative stress, mitochondrial dysfunction, loss of dopaminergic neurons, build-up of alpha-synuclein (α-syn) in cells, and energy depletion in neurons, that drive the disease. We and others have shown that treatment with mimetics of the growth factor glucagon-like peptide 1 (GLP-1) can normalize energy utilization, neuronal survival, and dopamine levels and reduce inflammation. Liraglutide is a GLP-1 analogue that recently showed protective effects in phase 2 clinical trials in PD patients and in Alzheimer disease patients. We have developed a novel dual GLP-1/GIP receptor agonist that can cross the blood-brain barrier and showed good protective effects in animal models of PD. Here, we test liraglutide against the dual GLP-1/GIP agonist DA5-CH (KP405) in the A53T tg mouse model of PD which expresses a human-mutated gene of α-synuclein. Drug treatment reduced impairments in three different motor tests, reduced levels of α-syn in the substantia nigra, reduced the inflammation response and proinflammatory cytokine levels in the substantia nigra and striatum, and normalized biomarker levels of autophagy and mitochondrial activities in A53T mice. DA5-CH was superior in almost all parameters measured and therefore may be a better drug treatment for PD than liraglutide.

Global cluster analysis and network visualization in organoids in cancer research: a scientometric mapping from 1991 to 2021.

Objective: In the last three decades, there has been a surge in research on cancer organoids using 3D culture technologies, which has resulted in the development of physiological human cancer models. This study aims to provide an overview of the global trends and frontiers in research on cancer organoids. Methods: A total of 3189 publications on organoids in cancer research from 1991 to 2021 were collected from the Science Citation Index-Expanded (SCIE) of Web of Science (WoS). Bibliometric methods such as the R package "Bibliometrix," Citespace, and VOS viewer software were employed to investigate and visualize bibliographic coupling, co-citation, co-authorship, and co-occurrence trends, as well as publication trends in the field of organoids in cancer research. Results: From 1991 to 2021, there has been a significant increase in publications on cancer organoids, with most articles being from North America, Eastern Asia, and Western Europe. The USA had the highest number of publications, citations, prolific authors, and research funding globally. Cancers was the journal with the most publications, while Nature had the best total link strength. Harvard University were the most contributive institutions. The global research in this field could be classified into five clusters: chemotherapy study, organoids for drug screening, different models, molecular mechanism study, and organoid construction. These areas are expected to remain hotspots for future research. Conclusions: The number of publications on organoids in cancer research is expected to increase based on current global trends.

Honeycomb Column Thin-Walled Structure Design and Mechanical Properties of Ti Alloy Fabricated through Selective Laser Melting.

A honeycomb column thin-walled structure (HCTS) was designed and the relative density was calculated for numerical simulation. The HCTS samples were fabricated via selective laser melting (SLM). The numerical simulation and a three-point bending test were conducted to evaluate the mechanical properties of the HCTS made of Ti6Al4V. The findings of the numerical simulation demonstrated that the HCTS had a stronger resistance to deformation and a maximum loading force 30% higher than the equivalent solid thin-walled structure (ESTS). The mechanical performance of the HCTS as determined by the three-point bending test was mostly comparable with the numerical simulation. The maximum loading force of the experimental HCTS050-E thin-walled structure was 1200 N higher than that of HCTS050-S. The numerical simulation can provide theoretical guidance for the SLM processing of HCTSs.

Relation between red blood cell distribution width and 30-day in-hospital mortality of patients with ventilator-associated pneumonia.

BACKGROUND: Epidemiological studies have demonstrated an association between red blood cell distribution width (RDW) and the prognosis of pneumonia-associated diseases. However, prognostic value of RDW in patients with ventilator-associated pneumonia (VAP) has yet to be investigated. This study aimed to explore the association between RDW and in-hospital mortality in VAP patients and explore predictive value of RDW for VAP patients. METHODS: This retrospective cohort study included 1,543 VAP patients from the Medical Information Mart for Intensive Care IV database 2008-2019. The primary outcome was considered to 30-day in-hospital mortality of VAP patients in this study. Non-high RDW level group was defined as <15 %, and high RDW level group as ≥15%. The possible confounding factors were screened by least absolute shrinkage and selection operator regression. Univariate and multivariate COX regression analyses were used for the assessment on the association of RDW and 30-day in-hospital mortality in VAP patients. We also performed subgroup analyses. Furthermore, a comparative analysis of RDW and sequential organ failure assessment (SOFA) score and simplified acute physiology score II (SAPS II) were performed by receiver operating characteristic (ROC) curves. RESULTS: The 30-day in-hospital mortality of VAP patients was approximately 19.05%. After adjusting all confounding factors, high RDW was associated with 30-day in-hospital mortality among VAP patients by using non-high RDW as the reference [hazard ratio (HR) =1.29, 95% confidence interval (CI): 1.01-1.63]. Additionally, the relationship was also robust in several populations, such as patients were younger than 60 years, or had not a history of congestive heart failure, or had a history of sepsis, or had not received renal replacement therapy, or had a duration of mechanical ventilation for more than 7 days. The result of ROC indicated that RDW had a better prognostic value in predicting 30-day in-hospital mortality for VAP patients than SOFA score and SAPS II score. CONCLUSION: High RDW level is associated with an increased 30-day in-hospital mortality. The RDW is a promising biomarker in predicting 30-day in-hospital mortality for patients admitted to the ICU, regardless of VAP.

Mitochondrial-related genes markers that predict survival in patients with head and neck squamous cell carcinoma affect immunomodulation through hypoxia, glycolysis, and angiogenesis pathways.

Mitochondria play a crucial role in the occurrence and development of tumors. We used mitochondria-related genes for consistent clustering to identify three stable molecular subtypes of head and neck squamous cell carcinoma (HNSCC) with different prognoses, mutations, and immune characteristics. Significant differences were observed in clinical characteristics, immune microenvironment, immune cell infiltration, and immune cell scores. TP53 was the most significantly mutated; cell cycle-related pathways and tumorigenesis-related pathways were activated in different subtypes. Risk modeling was conducted using a multifactor stepwise regression method, and nine genes were identified as mitochondria-related genes affecting prognosis (DKK1, EFNB2, ITGA5, AREG, EPHX3, CHGB, P4HA1, CCND1, and JCHAIN). Risk score calculations revealed significant differences in prognosis, immune cell scores, immune cell infiltration, and responses to conventional chemotherapy drugs. Glycolysis, angiogenesis, hypoxia, and tumor-related pathways were positively correlated with the RiskScore. Clinical samples were subjected to qPCR to validate the results. In this work, we constructed a prognostic model based on the mitochondrial correlation score, which well reflects the risk and positive factors for the prognosis of patients with HNSCC. This model can be used to guide individualized adjuvant and immunotherapy in patients with HNSCC.

UV-Induced Synthesis of Hybrid HMDSO/SiO2 Thin Films with Compositional Gradients for High-Performance Atomic Oxygen Resistance.

A flexible, dense, defect-free, highly adhesive, and highly dissociation energy-rich protective coating is essential to enhance the atomic oxygen (AO) resistance of polymeric materials in a low Earth orbit (LEO). In this work, a dense, defect-free hybrid HMDSO/SiO2 thin film coating with compositional gradients on the surface of polyimide was synthesized using vacuum-ultraviolet (VUV) irradiation. The effects of VUV irradiation on the morphology, optical transmittance, and chemical components of plasma-polymerized HMDSO (pp-HMDSO) thin-film coatings deposited on the polyimide surface were investigated in depth. There were no defects such as cracks and holes in the surface morphology of pp-HMDSO films after VUV irradiation, but the surface roughness increased slightly, and the corresponding optical transmittance decreased slightly. The chemical components of pp-HMDSO films were changed in the depth direction starting from the top of the surface, forming hybrid HMDSO/SiO2 thin films with compositional gradients. The component gradient HMDSO/SiO2 composite coating further enhanced the atomic oxygen resistance of the polyimide due to the surface layer of the UV-modified coating enriched with high dissociation energy SiOx material. Therefore, this work provides a facile UV-induced synthesis method to prepare dense, defect-free, and highly dissociation energy-rich protective gradient coatings, which are promising not only for excellent AO protection in LEO but also for potential application in water-oxygen barrier films.

Axial Symptoms After Conventional and Modified Laminoplasty: A Meta-analysis.

PURPOSE: The study aims to evaluate the impact of procedural variations in single-door laminoplasty on axial symptoms (AS) and neurologic outcomes. METHODS: A comprehensive literature search was conducted across PubMed, EMBASE, and the Cochrane Library, adhering to specific inclusion criteria. We extracted data on the prevalence of AS in both the modified and conventional laminoplasty groups from the selected studies. Neurologic outcomes were assessed using the Japanese Orthopedic Association (JOA) recovery rate, which was subsequently converted to Hedge's g for analysis. Forest plots were generated to visualize the effect sizes, and publication bias was assessed using both funnel plots and Egger's test. RESULTS: Fourteen studies comprising 1201 patients were included in this meta-analysis focused on AS. The aggregated SMD was -0.891 with a 95% CI of -1.146 to -0.631 (P < 0.01), denoting a statistically significant reduction in AS in the modified laminoplasty group compared with the conventional approach. Of the 14 studies, 10, encompassing 898 patients, contributed data for JOA recovery rate analysis. The overall effect size was 0.089, with a 95% CI ranging from -0.090 to 0.267, and a P value of 0.2901, indicating no significant difference in neurologic outcomes between the 2 techniques. No evidence of publication bias was detected. CONCLUSIONS: This meta-analysis demonstrates that modified laminoplasty is associated with a significant reduction in the incidence and severity of axial symptoms, without compromising neurologic functionality.

Phosphogypsum/titanium gypsum coupling for enhanced biochar immobilization of lead: Mineralization reaction behavior and electron transfer effect.

The hazards caused by Pb pollution have received worldwide attention. Phosphogypsum (PG) and titanium gypsum (TG) have the disadvantage of limited adsorption capacity and poor dispersion when used as heavy metal adsorbents on their own. The excellent pore and electron transfer capacity of biochar makes it possible to combine with PG and TG to solidify/stabilize Pb2+. In this study, the mechanism of Pb2+ adsorption/immobilization by rice husk biochar (BC) combined with PG/TG was investigated in terms of both mineral formation and electron transfer rate. The removal rate of Pb2+ by BC composite PG (BC/PG-Pb) or TG (BC/TG-Pb) was as high as 97%-98%, an increase of 120.9% and 122.5% over BC. Adsorption kinetics and mineral precipitation results indicate that the main removal of Pb2+ from BC/PG-Pb and BC/TG-Pb is achieved by PG/TG induced Pb-sulfate and Pb-phosphate formation. The addition of PG/TG significantly enhances the formation of stable Pb-minerals on the biochar surface, with the proportion of non-bioaccessible forms exceeding 50%. The four-step extraction results confirm that P and F in PG/TG are key in facilitating the conversion of Pb minerals to pyromorphite. The rich pore structure of biochar not only disperses the easily agglomerated PG/TG onto the biochar surface, but also attracts Pb2+ for uniformly dispersed precipitation. Furthermore, the excellent electrical conductivity and smooth electron transfer channels of biochar facilitate the reaction rate of Pb2+ mineralization. Overall, the use of biochar in combination with PG/TG is a promising technology for the combination of solid waste resourceisation and Pb remediation.

Metastatic Adrenocortical Carcinoma With Chromothripsis: A Case Report and Literature Review.

Metastatic adrenocortical carcinoma (ACC) often has a poor outcome, with a five-year survival of less than 25%. We report a rare case of metastatic ACC with a myxoid variant with chromothripsis. We review the histologic variants of ACC, including myxoid type, molecular drivers, and current and investigational therapies for adrenocortical carcinoma. We also discuss the mechanism of chromothripsis, chromothripsis in ACC tumorigenesis, and propose potential therapies targeting chromothripsis.

Tailored hydrogel composite membrane for the regulated crystallization of monosodium urate monohydrate within coffee's metabolites system.

Herein, a facile bionic research platform with fabricated hydrogel composite membrane (HCM) is constructed to uncover the effects of the main components of coffee's metabolites on MSUM crystallization. Tailored and biosafety polyethylene glycol diacrylate/N-isopropyl acrylamide (PEGDA/NIPAM) HCM allows the proper mass transfer of coffee's metabolites and can well simulate the process of coffee's metabolites acting in the joint system. With the validations of this platform, it is shown that chlorogenic acid (CGA) can hinder the MSUM crystals formation from 45 h (control group) to 122 h (2 mM CGA), which is the most likely reason that reduces the risk of gout after long-term coffee consumption. Molecular dynamics simulation further indicates that the high interaction energy (Eint) between CGA and MSUM crystal surface and the high electronegativity of CGA both contribute to the restraint of MSUM crystal formation. In conclusion, the fabricated HCM, as the core functional materials of the research platform, presents the understanding of the interaction between coffee consumption and gout control.

Fe/Cu diatomic catalysts for electrochemical nitrate reduction to ammonia.

Electrochemical conversion of nitrate to ammonia offers an efficient approach to reducing nitrate pollutants and a potential technology for low-temperature and low-pressure ammonia synthesis. However, the process is limited by multiple competing reactions and NO3- adsorption on cathode surfaces. Here, we report a Fe/Cu diatomic catalyst on holey nitrogen-doped graphene which exhibits high catalytic activities and selectivity for ammonia production. The catalyst enables a maximum ammonia Faradaic efficiency of 92.51% (-0.3 V(RHE)) and a high NH3 yield rate of 1.08 mmol h-1 mg-1 (at - 0.5 V(RHE)). Computational and theoretical analysis reveals that a relatively strong interaction between NO3- and Fe/Cu promotes the adsorption and discharge of NO3- anions. Nitrogen-oxygen bonds are also shown to be weakened due to the existence of hetero-atomic dual sites which lowers the overall reaction barriers. The dual-site and hetero-atom strategy in this work provides a flexible design for further catalyst development and expands the electrocatalytic techniques for nitrate reduction and ammonia synthesis.