Current status of transcutaneous auricular vagus nerve stimulation for tinnitus: a narrative review of modern research.

Tinnitus, characterized by phantom sound perception, is a highly disruptive disorder lacking definitive and effective treatments. Its intricate neural mechanisms are not fully understood. Transcutaneous auricular vagus nerve stimulation (taVNS) has demonstrated potential as a substitute or supplementary treatment by activating central vagal pathways. However, standardized therapeutic protocols and objective tests to assess efficacy are lacking. Therefore, taVNS shows promise as a therapy for tinnitus, and treatment protocols should be optimized in future clinical trials.

TRANSPARENT TESTA GLABRA1 Regulates High-Intensity Blue Light-Induced Phototropism by Reducing CRYPTOCHROME1 Levels.

The asymmetrical distribution of auxin supports high intensity blue light (HBL)-mediated phototropism. Flavonoids, secondary metabolites induced by blue light and TRANSPARENT TESTA GLABRA1 (TTG1), alter auxin transport. However, the role of TTG1 in HBL-induced phototropism in Arabidopsis (Arabidopsis thaliana) remains unclear. We found that TTG1 regulates HBL-mediated phototropism. HBL-induced degradation of CRYPTOCHROME 1 (CRY1) was repressed in ttg1-1, and depletion of CRY1 rescued the phototropic defects of the ttg1-1 mutant. Moreover, overexpression of CRY1 in a cry1 mutant background led to phototropic defects in response to HBL. These results indicated that CRY1 is involved in the regulation of TTG1-mediated phototropism in response to HBL. Further investigation showed that TTG1 physically interacts with CRY1 via its N-terminus and that the added TTG1 promotes the dimerization of CRY1. The interaction between TTG1 and CRY1 may promote HBL-mediated degradation of CRY1. TTG1 also physically interacted with blue light inhibitor of cryptochrome 1 (BIC1) and Light-Response Bric-a-Brack/Tramtrack/Broad 2 (LRB2), and these interactions either inhibited or promoted their interaction with CRY1. Exogenous gibberellins (GA) and auxins, two key plant hormones that crosstalk with CRY1, may confer the recovery of phototropic defects in the ttg1-1 mutant and CRY1-overexpressing plants. Our results revealed that TTG1 participates in the regulation of HBL-induced phototropism by modulating CRY1 levels, which are coordinated with GA or IAA signaling.

Identification and Application of CLE Peptides for Drought Resistance in Solanaceae Crops.

The CLE (CLAVATA3/Embryo Surrounding Region-related) family, a group of peptides with hormone-like features, plays a pivotal role in plant growth, development, and adaptation to stress. Through homology-based blast analysis of 32 Arabidopsis thaliana CLE peptide sequences, we have identified 5, 14, and 10 CLE family members in Nicotiana tabacum, Capsicum annuum, and Solanum melongena, respectively. Chemical synthesis and functional assays of the peptides led to the discovery that NtCLE3 substantially enhances the drought resistance of these three Solanaceae crops. Our transcriptome, RT-qPCR, and antioxidant enzyme activity data showed that NtCLE3 increased antioxidant capacity and ABA synthesis in tobacco. Moreover, the recombinant protein RPNtCLE3, composed of 6*NtCLE3, preserved the capacity to foster drought resilience and proved to be a promising drought resistance regulator, which presents a more favorable alternative for field applications compared to ABA which degrades rapidly under sunlight exposure. This research unveils the prospective utility of NtCLE3 in enhancing drought tolerance in Solanaceae crops and provides new ideas for the development of novel bioregulators aimed at mitigating drought stress.

A Novel Recombinant Human Filaggrin Segment (rhFLA-10) Alleviated a Skin Lesion of Atopic Dermatitis.

Atopic dermatitis (AD), a prevalent chronic inflammatory skin disorder, is marked by impaired skin barrier function and persistent pruritus. It significantly deteriorates patients' quality of life, making it one of the most burdensome non-lethal skin disorders. Filaggrin plays a crucial role in the pathophysiology of barrier disruption in AD, interacting with inflammatory mediators. It is an integral part of the extracellular matrix architecture, serving to protect the skin barrier and attenuate the inflammatory cascade. In this study, we engineered a novel recombinant human filaggrin (rhFLA-10) expression vector, which was subsequently synthesized and purified. In vitro and ex vivo efficacy experiments were conducted for AD. rhFLA-10, at low concentrations (5 to 20 µg/mL), was non-toxic to HACaT cells, significantly inhibited the degranulation of P815 mast cells, and was readily absorbed by cells, thereby exerting a soothing therapeutic effect. Furthermore, rhFLA-10 demonstrated anti-inflammatory properties (p < 0.05). In vivo, efficacy experiments further substantiated that rhFLA-10 could effectively ameliorate AD in mice and facilitate the repair of damaged skin (p < 0.001). These findings underscore the considerable potential of rhFLA-10 in the treatment of AD.

Functional screening of the Arabidopsis 2C protein phosphatases family identifies PP2C15 as a negative regulator of plant immunity by targeting BRI1-associated receptor kinase 1.

Genetic engineering using negative regulators of plant immunity has the potential to provide a huge impetus in agricultural biotechnology to achieve a higher degree of disease resistance without reducing yield. Type 2C protein phosphatases (PP2Cs) represent the largest group of protein phosphatases in plants, with a high potential for negative regulatory functions by blocking the transmission of defence signals through dephosphorylation. Here, we established a PP2C functional protoplast screen using pFRK1::luciferase as a reporter and found that 14 of 56 PP2Cs significantly inhibited the immune response induced by flg22. To verify the reliability of the system, a previously reported MAPK3/4/6-interacting protein phosphatase, PP2C5, was used; it was confirmed to be a negative regulator of PAMP-triggered immunity (PTI). We further identified PP2C15 as an interacting partner of BRI1-associated receptor kinase 1 (BAK1), which is the most well-known co-receptor of plasma membrane-localized pattern recognition receptors (PRRs), and a central component of PTI. PP2C15 dephosphorylates BAK1 and negatively regulates BAK1-mediated PTI responses such as MAPK3/4/6 activation, defence gene expression, reactive oxygen species bursts, stomatal immunity, callose deposition, and pathogen resistance. Although plant growth and 1000-seed weight of pp2c15 mutants were reduced compared to those of wild-type plants, pp2c5 mutants did not show any adverse effects. Thus, our findings strengthen the understanding of the mechanism by which PP2C family members negatively regulate plant immunity at multiple levels and indicate a possible approach to enhance plant resistance by eliminating specific PP2Cs without affecting plant growth and yield.

The efficacy and safety of electroacupuncture for diabetic peripheral neuropathy: A protocol for a systematic review and meta-analysis.

BACKGROUND: Diabetic peripheral neuropathy (DPN) is a chronic complication of diabetes mellitus, which is the most common neuropathy worldwide. Owing to the inadequacies of existing treatment methods, managing DPN remains a significant challenge. Studies suggest that electroacupuncture (EA) could potentially serve as a beneficial alternative treatment for this condition. Nevertheless, there is still inadequate proof of its therapeutic effectiveness and safety. As a result, the goal of this protocol is to methodically compile the data pertaining to the effectiveness and security of EA in the management of DPN. METHODS: To find appropriate randomized controlled trials (RCTs), nine reliable databases in the English and Chinese languages will be examined. RevMan5.3 will be used to combine the retrieved data and perform meta-analyses. The methodological quality of the included RCTs will be evaluated using the Cochrane Risk of Bias Assessment 2.0 tool. The Grades of Recommendations, Assessment, Development, and Evaluation (GRADE) system will be utilized to evaluate the degree of strength and certainty of the evidence. We will also perform publication bias, sensitivity and subgroup analyses. DISCUSSION: This protocol describes the intended scope and approach for a forthcoming systematic review and meta-analysis that will inform therapeutic decision-making by offering current information on the efficacy and safety of EA in the treatment of DPN. The results of the study will help standardize strategies for EA in the treatment of DPN.

Metal-organic polymer enables efficient organic photoelectrochemical transistor biosensing.

The field of organic photoelectrochemical transistor (OPECT) is newly emerged, with increasing efforts attempting to utilize its properties in biological sensing. Advanced materials with new physicochemical properties have proven important to this end. Herein, we report a metal-organic polymers-gated OPECT biosensing exemplified by CuⅠ-arylacetylide polymers (CuAs)-modulated poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) channel. Both the photoelectrochemical properties and gating capability of CuAs are explored and optimized for high-efficacy photogating. Morever, based on its inherent structure, the specific reaction between CuAs and sulfur ions (S2-) is revealed and S2--mediated microRNA-21 detection is realized by linking with nucleic acid amplification and alkaline phosphatase catalytic chemistry. This work introduces metal-organic polymers as gating materials for OPECT biosensing.

Discovery of a novel flavonol O-methyltransferase possessing sequential 4'- and 7-O-methyltransferase activity from Camptotheca acuminata Decne.

The biosynthetic route for flavonol in Camptotheca acuminata has been recently elucidated from a chemical point of view. However, the genes involved in flavonol methylation remain unclear. It is a critical step for fully uncovering the flavonol metabolism in this ancient plant. In this study, the multi-omics resource of this plant was utilized to perform flavonol O-methyltransferase-oriented mining and screening. Two genes, CaFOMT1 and CaFOMT2 are identified, and their recombinant CaFOMT proteins are purified to homogeneity. CaFOMT1 exhibits strict substrate and catalytic position specificity for quercetin, and selectively methylates only the 4'-OH group. CaFOMT2 possesses sequential O-methyltransferase activity for the 4'-OH and 7-OH of quercetin. These CaFOMT genes are enriched in the leaf and root tissues. The catalytic dyad and critical substrate-binding sites of the CaFOMTs are determined by molecular docking and further verified through site-mutation experiments. PHE181 and MET185 are designated as the critical sites for flavonol substrate selectivity. Genomic environment analysis indicates that CaFOMTs evolved independently and that their ancestral genes are different from that of the known Ca10OMT. This study provides molecular insights into the substrate-binding pockets of two new CaFOMTs responsible for flavonol metabolism in C. acuminata.

Mechanism of zinc stress on magnesium deficiency in rice plants (Oryza sativa L.): Insights from magnesium isotopes.

Magnesium (Mg) and zinc (Zn) are essential nutrients for plants. Mg deficiency often occurs in rice plants grown in Zn-polluted soil. However, the mechanism for this correlation is unclear. Here, we performed culture experiments on rice plants (Oryza sativa L.) and used Mg isotopes to investigate mechanisms of Zn stress on plant Mg deficiency. Our results show that excess Zn can significantly reduce the uptake of Mg in rice tissues. The root displays positive Δ26Mgplant-nutrient values (δ26Mgplant-δ26Mgnutrient; 1.90 ‰ to 2.06 ‰), which suggests that Mg enters the root cells mainly via Mg-specific transporters rather than non-selective diffusion. The decreased Δ26Mgplant-nutrient values with increasing Zn supply can be explained by the competition between Zn and Mg, both of which combine with same transporters in roots. In contrast, the shoots (stem and leaf) display much lower δ26Mg values than roots, which suggests that the transport of Mg from roots to aerial biomass is mainly via free Mg ions, during which Zn cannot competitively inhibit the movement of Mg. Our study suggests that the Mg deficiency in rice plants can be caused by high Zn-levels in soils and highlights the necessity of soil Zn-remediation in solving Mg deficiency problems in rice plants.

Performance of trauma scoring systems in predicting mortality in geriatric trauma patients: comparison of the ISS, TRISS, and GTOS based on a systemic review and meta-analysis.

PURPOSE: This meta-analysis aimed to evaluate the performance of the Injury Severity Score (ISS), Trauma and Injury Severity Score (TRISS), and the Geriatric Trauma Outcome Score (GTOS) in predicting mortality in geriatric trauma patients. METHODS: The MEDLINE, Web of Science, and EMBASE databases were searched for studies published from January 2008 to October 2023. Studies assessing the performance of the ISS, TRISS, or GTOS in predicting mortality in geriatric trauma patients (over 60 years old) and reporting data for the analysis of the pooled area under the receiver operating characteristic curve (AUROC) and the hierarchical summary receiver operating characteristic curve (HSROC) were included. Studies that were not conducted in a group of geriatric patients, did not consider mortality as the outcome variable, or had incomplete data were excluded. The Critical Appraisal Skills Programme (CASP) Clinical Prediction Rule Checklist was utilized to assess the risk of bias in included studies. STATA 16.0. was used for the AUROC analysis and HSROC analysis. RESULTS: Nineteen studies involving 118,761 geriatric trauma patients were included. The pooled AUROC of the TRISS (AUC = 0.82, 95% CI: 0.77-0.87) was higher than ISS (AUC = 0.74, 95% CI: 0.71-0.79) and GTOS (AUC = 0.80, 95%CI: 0.77-0.83). The diagnostic odds ratio (DOR) calculated from HSROC curves also suggested that the TRISS (DOR = 21.5) had a better performance in predicting mortality in geriatric trauma patients than the ISS (DOR = 6.27) and GTOS (DOR = 4.76). CONCLUSION: This meta-analysis suggested that the TRISS showed better accuracy and performance in predicting mortality in geriatric trauma patients than the ISS and GTOS.

Preparation and Lithium-Ion Capacitance Performance of Nitrogen and Sulfur Co-Doped Carbon Nanosheets with Limited Space via the Vermiculite Template Method.

Nitrogen and sulfur co-doped graphene-like carbon nanosheets (CNSs) with a two-dimensional structure are prepared by using methylene blue as a carbon source and expanded vermiculite as a template. After static negative pressure adsorption, high-temperature calcination, and etching in a vacuum oven, they are embedded in the limited space of the vermiculite template. The addition of an appropriate number of mixed elements can improve the performance of a battery. Via scanning electron microscopy, it is found that the prepared nitrogen-sulfur-co-doped carbon nanosheets exhibit a thin yarn shape. The XPS results show that there are four elements of C, N, O, and S in the carbon materials (CNS-600, CNS-700, CNS-800, CNS-900) prepared at different temperatures, and the N atom content shows a gradually decreasing trend. It is mainly doped into a graphene-like network in four ways (graphite nitrogen, pyridine nitrogen, pyrrole nitrogen, and pyridine nitrogen oxide), while the S element shows an increasing trend, mainly in the form of thiophene S and sulfur, which is covalently linked to oxygen. The results show that CNS-700 has a discharge-specific capacity of 460 mAh/g at a current density of 0.1 A/g, and it can still maintain a specific capacity of 200 mAh/g at a current density of 2 A/g. The assembled lithium-ion capacitor has excellent energy density and power density, with a maximum power density of 20,000 W/kg.

Sliding-mode fault-tolerant control of the six-rotor UAV with dead-zone-input under event-triggered mechanism.

This paper investigates the problem of event-triggered mechanism(ETM)-based sliding-mode fault-tolerant control (FTC) for a six-rotor Unmanned Aerial Vehicle (UAV) with dead zone input (DZI) cases, considering potential actuator and sensor faults. Initially, a dynamic ETM is designed, followed by the development of a non-fragile observer utilizing this designed ETM. An integral sliding surface (SS) is then designed in the observation space, and the system is augmented and treated as a variable time delay system. Subsequently, sufficient conditions to ensure the stability of the augmented system with an H∞ performance index γ are obtained using the Lyapunov-Krasovskii function. Next, a sliding mode control (SMC) law is formulated to guide the sliding variables to the SS in finite time. Furthermore, sufficient conditions for ensuring system stability with an H∞ performance index γ are decoupled, and the calculation methods for the non-fragile observer gain matrix and the sliding mode gain matrix are obtained. Finally, to validate the effectiveness of the proposed method in this paper, simulation experiments are conducted.

Extraction, Isolation, and Component Analysis of Turmeric-Derived Exosome-like Nanoparticles.

As one kind of plant-derived extracellular vesicle, turmeric-derived exosome-like nanoparticles (TELNs) are composed of proteins, lipids, nucleic acids, and small-molecule compounds, which possess good biocompatibility and safety. They are especially rich in information from the "mother plant", which provides more applications in biological fields. In this study, we isolated and purified TELNs using differential centrifugation and ultracentrifugation and systematically detected their physicochemical properties using multi-omics. The TELNs possessed a typical teacup-like exosome morphology, and the extraction rate was approximately 1.71 ± 0.176 mg/g. The average particle size was 183.2 ± 10.9 nm, and the average zeta potential was -17.6 ± 1.19 mV. They were rich in lipids, mainly phosphatidylethanolamine (PE) (17.4%), triglyceride (TG) (12.3%), phosphatidylinositol (PI) (9.82%), and phosphatidylcholine (PC) (7.93%). All of them are the key lipids in the exosomes. The protein content was approximately 12% (M/M), mainly curcumin synthase and other proteins involved in secondary metabolite biosynthesis. In addition, there are critical essential genes for curcumin biosynthesis, such as curcumin synthase (CURS) and diketocoenzyme A synthase (DCS). More importantly, a greater variety of small-molecule compounds, primarily curcumin and curcumin analogs such as demethoxycurcumin and volatile oleoresins such as curcuminoids, have now been revealed. In conclusion, TELNs were successfully isolated, containing 0.17% (M/M) turmeric and a large amount of chemical information, the same as the parent-of-origin plant. This is the first time combining multi-omics to analyze the characteristics and nature of the TELNs, which laid a solid material foundation for the further development of turmeric.

A Bacterial Nanomedicine Combines Photodynamic-Immunotherapy and Chemotherapy for Enhanced Treatment of Oral Squamous Cell Carcinoma.

Bacterial therapy is an emerging hotspot in tumor immunotherapy, which can initiate antitumor immune activation through multiple mechanisms. Porphyromonas gingivalis (Pg), a pathogenic bacterium inhabiting the oral cavity, contains a great deal of pathogen associated molecular patterns that can activate various innate immune cells to promote antitumor immunity. Owing to the presence of protoporphyrin IX (PpIX), Pg is also an excellent photosensitizer for photodynamic therapy (PDT) via the in situ generation of reactive oxygen species. This study reports a bacterial nanomedicine (nmPg) fabricated from Pg through lysozyme degradation, ammonium chloride lysis, and nanoextrusion, which has potent PDT and immune activation performances for oral squamous cell carcinoma (OSCC) treatment. To further promote the tumoricidal efficacy, a commonly used chemotherapeutic drug doxorubicin (DOX) is efficiently encapsulated into nmPg through a simple incubation method. nmPg/DOX thus prepared exhibits significant synergistic effects on inhibiting the growth and metastasis of OSCC both in vitro and in vivo via photodynamic-immunotherapy and chemotherapy. In summary, this work develops a promising bacterial nanomedicine for enhanced treatment of OSCC.

Maize MITOGEN-ACTIVATED PROTEIN KINASE 20 mediates high-temperature-regulated stomatal movement.

High temperature induces stomatal opening; however, uncontrolled stomatal opening is dangerous for plants in response to high temperature. We identified a high-temperature sensitive (hts) mutant from the ethyl methane sulfonate (EMS)-induced maize (Zea mays) mutant library that is linked to a single base change in MITOGEN-ACTIVATED PROTEIN KINASE 20 (ZmMPK20). Our data demonstrated that hts mutants exhibit substantially increased stomatal opening and water loss rate, as well as decreased thermotolerance, compared to wild-type plants under high temperature. ZmMPK20-knockout mutants showed similar phenotypes as hts mutants. Overexpression of ZmMPK20 decreased stomatal apertures, water loss rate, and enhanced plant thermotolerance. Additional experiments showed that ZmMPK20 interacts with MAP KINASE KINASE 9 (ZmMKK9) and E3 ubiquitin ligase RPM1 INTERACTING PROTEIN 2 (ZmRIN2), a maize homolog of Arabidopsis (Arabidopsis thaliana) RIN2. ZmMPK20 prevented ZmRIN2 degradation by inhibiting ZmRIN2 self-ubiquitination. ZmMKK9 phosphorylated ZmMPK20 and enhanced the inhibitory effect of ZmMPK20 on ZmRIN2 degradation. Moreover, we employed virus-induced gene silencing (VIGS) to silence ZmMKK9 and ZmRIN2 in maize and heterologously overexpressed ZmMKK9 or ZmRIN2 in Arabidopsis. Our findings demonstrated that ZmMKK9 and ZmRIN2 play negative regulatory roles in high-temperature-induced stomatal opening. Accordingly, we propose that the ZmMKK9-ZmMPK20-ZmRIN2 cascade negatively regulates high-temperature-induced stomatal opening and balances water loss and leaf temperature, thus enhancing plant thermotolerance.

Integrated water security and coupling of social-ecological system to improve river basin sustainability.

The river basin sustainability depends on both the coordinated development of socio-ecological systems and resilience to water resources. However, the lack of integrating them on spatial and temporal scales compromises our capacity to develop precise interventions towards sustainable river basins. We developed an approach by integrating water security and social-ecological coupling to assess the river basin sustainability. We divided it into four categories including highly sustainable (secure and coordinated), insecure, uncoordinated, and low sustainable (insecure and uncoordinated). The middle reach of Heihe River (MHR) was taken as the study area with the sub-basin as the spatial analysis unit from 2000 to 2020. The results showed that there was heterogeneity and agglomeration in spatial distribution. 23.8 %, 38.8 %, and 11% of the sub-basins mainly clustered in the north and central areas were found in the state of water insecure and SES uncoordinated, or both respectively. The unsustainable areas (five sub-basins) and lose-lose areas (two sub-basins) should be the priority areas for management interventions. Our approach can provide an important reference for assessing and improving the river basin sustainability.

Discharge Against Medical Advice After Hospitalization for Sepsis: Predictors, 30-Day Readmissions, and Outcomes.

BACKGROUND: Sepsis is a leading cause of death worldwide. However, little has been known concerning the status of discharge against medical advice (DAMA) in sepsis patients. OBJECTIVE: To identify factors associated with DAMA, evaluate the association of DAMA with 30-day unplanned readmission and readmitted outcomes after sepsis hospitalization. METHODS: Using the National Readmission Database, we identified sepsis patients who discharged routinely or DAMA in 2017. Multivariable models were used to identify factors related to DAMA, evaluate the association between DAMA and readmission, and elucidate the relationship between DAMA and outcomes in patients readmitted within 30 days. RESULTS: Among 1,012,650 sepsis cases, patients with DAMA accounted for 3.88% (n = 39,308). The unplanned 30-day readmission rates in patients who discharged home and DAMA were 13.08% and 27.21%, respectively. Predictors of DAMA in sepsis included Medicaid, diabetes, smoking, drug abuse, alcohol abuse, and psychoses. DAMA was statistically significantly associated with 30-day (odds ratio [OR] 2.18, 95% confidence interval [CI] 2.09-2.28), 60-day (OR 1.98, 95% CI 1.90-2.06), and 90-day (OR 1.88, 95% CI 1.81-1.96) readmission. DAMA is also associated with higher mortality in patients readmitted within 30 days (OR 1.38, 95% CI 1.17-1.63), whereas there were no statistically significant differences in length of stay and costs between patients who discharged home or DAMA. CONCLUSIONS: DAMA occurs in nearly 3.88% of sepsis patients and is linked to higher readmission and mortality. Those at high risk of DAMA should be early identified to motivate intervention to avoid premature discharges and associated adverse outcomes.

Temperature-Controlled Expression of a Recombinant Human-like Collagen I Peptide in Escherichia coli.

Collagen is the functional protein of the skin, tendons, ligaments, cartilage, bone, and connective tissue. Due to its extraordinary properties, collagen has a wide range of applications in biomedicine, tissue engineering, food, and cosmetics. In this study, we designed a functional fragment of human type I collagen (rhLCOL-I) and expressed it in Escherichia coli (E. coli) BL21(DE3) PlysS containing a thermal-induced plasmid, pBV-rhLCOL-I. The results indicated that the optimal expression level of the rhLCOL-I reached 36.3% of the total protein at 42 °C, and expressed in soluble form. In a 7 L fermentation, the yield of purified rhLCOL-I was 1.88 g/L. Interestingly, the plasmid, pBV220-rhLCOL-I, was excellently stable during the fermentation process, even in the absence of antibiotics. Functional analyses indicated that rhLCOL-I had the capacity to promote skin cell migration and adhesion in vitro and in vivo. Taken together, we developed a high-level and low-cost approach to produce collagen fragments suitable for medical applications in E. coli.

Nanograin-Boundary-Abundant Cu2O-Cu Nanocubes with High C2+ Selectivity and Good Stability during Electrochemical CO2 Reduction at a Current Density of 500 mA/cm2.

Surface and interface engineering, especially the creation of abundant Cu0/Cu+ interfaces and nanograin boundaries, is known to facilitate C2+ production during electrochemical CO2 reductions over copper-based catalysts. However, precisely controlling the favorable nanograin boundaries with surface structures (e.g., Cu(100) facets and Cu[n(100)×(110)] step sites) and simultaneously stabilizing Cu0/Cu+ interfaces is challenging, since Cu+ species are highly susceptible to be reduced into bulk metallic Cu at high current densities. Thus, an in-depth understanding of the structure evolution of the Cu-based catalysts under realistic CO2RR conditions is imperative, including the formation and stabilization of nanograin boundaries and Cu0/Cu+ interfaces. Herein we demonstrate that the well-controlled thermal reduction of Cu2O nanocubes under a CO atmosphere yields a remarkably stable Cu2O-Cu nanocube hybrid catalyst (Cu2O(CO)) possessing a high density of Cu0/Cu+ interfaces, abundant nanograin boundaries with Cu(100) facets, and Cu[n(100)×(110)] step sites. The Cu2O(CO) electrocatalyst delivered a high C2+ Faradaic efficiency of 77.4% (56.6% for ethylene) during the CO2RR under an industrial current density of 500 mA/cm2. Spectroscopic characterizations and morphological evolution studies, together with in situ time-resolved attenuated total reflection-surface enhanced infrared absorption spectroscopy (ATR-SEIRAS) studies, established that the morphology and Cu0/Cu+ interfacial sites in the as-prepared Cu2O(CO) catalyst were preserved under high polarization and high current densities due to the nanograin-boundary-abundant structure. Furthermore, the abundant Cu0/Cu+ interfacial sites on the Cu2O(CO) catalyst acted to increase the *CO adsorption density, thereby increasing the opportunity for C-C coupling reactions, leading to a high C2+ selectivity.