Targeted metabolomics reveals the aberrant energy status in diabetic peripheral neuropathy and the neuroprotective mechanism of traditional Chinese medicine JinMaiTong

Diabetic peripheral neuropathy (DPN) is a common and devastating complication of diabetes, for which effective therapies are currently lacking. Disturbed energy status plays a crucial role in DPN pathogenesis. However, the integrated profile of energy metabolism, especially the central carbohydrate metabolism, remains unclear in DPN. Here, we developed a metabolomics approach by targeting 56 metabolites using high-performance ion chromatography-tandem mass spectrometry (HPIC-MS/MS) to illustrate the integrative characteristics of central carbohydrate metabolism in patients with DPN and streptozotocin-induced DPN rats. Furthermore, JinMaiTong (JMT), a traditional Chinese medicine (TCM) formula, was found to be effective for DPN, improving the peripheral neurological function and alleviating the neuropathology of DPN rats even after demyelination and axonal degeneration. JMT ameliorated DPN by regulating the aberrant energy balance and mitochondrial functions, including excessive glycolysis restoration, tricarboxylic acid cycle improvement, and increased adenosine triphosphate (ATP) generation. Bioenergetic profile was aberrant in cultured rat Schwann cells under high-glucose conditions, which was remarkably corrected by JMT treatment. In-vivo and in-vitro studies revealed that these effects of JMT were mainly attributed to the activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK) and downstream peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Our results expand the therapeutic framework for DPN and suggest the integrative modulation of energy metabolism using TCMs, such as JMT, as an effective strategy for its treatment.

Targeted regeneration and upcycling of spent graphite by defect‐driven tin nucleation

The recycling of spent batteries has become increasingly important owing to their wide applications,abundant raw material supply,and sustainable development.Compared with the degraded cathode,spent anode graphite often has a relatively intact structure with few defects after long cycling.Yet,most spent graphite is simply burned or discarded due to its limited value and inferior performance on using conventional recycling methods that are complex,have low efficiency,and fail in performance restoration.Herein,we propose a fast,efficient,and“intelligent”strategy to regenerate and upcycle spent graphite based on defect‐driven targeted remediation.Using Sn as a nanoscale healant,we used rapid heating(~50 ms)to enable dynamic Sn droplets to automatically nucleate around the surface defects on the graphite upon cooling owing to strong binding to the defects(~5.84 eV/atom),thus simultaneously achieving Sn dispersion and graphite remediation.As a result,the regenerated graphite showed enhanced capacity and cycle stability(458.9 mAh g^(−1) at 0.2 A g^(−1) after 100 cycles),superior to those of commercial graphite.Benefiting from the self‐adaption of Sn dispersion,spent graphite with different degrees of defects can be regenerated to similar structures and performance.EverBatt analysis indicates that targeted regeneration and upcycling have significantly lower energy consumption(~99%reduction)and near‐zero CO_(2) emission,and yield much higher profit than hydrometallurgy,which opens a new avenue for direct upcycling of spend graphite in an efficient,green,and profitable manner for sustainable battery manufacture.

Antibody-platinum(IV)prodrugs conjugates for targeted treatment of cutaneous squamous cell carcinoma

Antibody-drug conjugates(ADCs)are a new type of targeting antibodies that conjugate with highly toxic anticancer drugs via chemical linkers to exert high specificity and efficient killing of tumor cells,thereby attracting considerable attention in precise oncology therapy.Cetuximab(Cet)is a typical antibody that offers the benefits of good targeting and safety for individuals with advanced and inoperable cutaneous squamous cell carcinoma(cSCC);however,its anti-tumor activity is limited to a single use.Cisplatin(CisPt)shows good curative effects;however,its adverse effects and non-tumor-targeting ability are major drawbacks.In this study,we designed and developed a new ADC based on a new cytotoxic platinum(IV)prodrug(C8Pt(IV))and Cet.The so-called antibody-platinum(IV)prodrugs conjugates,named Cet-C8Pt(IV),showed excellent tumor targeting in cSCC.Specifically,it accurately delivered C8Pt(IV)into tumor cells to exert the combined anti-tumor effect of Cet and CisPt.Herein,metabolomic analysis showed that Cet-C8Pt(IV)promoted cellular apoptosis and increased DNA damage in cSCC cells by affecting the vitamin B6 metabolic pathway in tumor cells,thereby further enhancing the tumor-killing ability and providing a new strategy for clinical cancer treatment using antibody-platinum(IV)prodrugs conjugates.

A food-grade and senescent cell-targeted fisetin delivery system based on whey protein isolate-galactooligosaccharides Maillard conjugate

Cellular senescence is the results of aging and age-related diseases,and the development of anti-aging methods may improve health and extend longevity.The natural flavonol fisetin has been shown to antagonize senescence in vitro and increases longevity in vivo,but has poor water solubility and limited bioavailability.In this study,a food-grade and senescent cell-targeted delivery system for fisetin was developed based on whey protein isolate-galactooligosaccharides(WPI-GOS)Maillard conjugate,which could recognize senescence associatedβ-galactosidase in senescent cells.The fisetin nanoparticles possessed a high encapsulation efficiency,excellent dispersibility in water,good storage stability and well biocompatibility.Moreover,they could effectively accumulate and retain in senescent cells with excellent senescent cell-targeting efficacy,and inhibit the oxidative stress-induced cellular senescence in vitro.Thus,this novel nanoparticle system based on WPI-GOS Maillard conjugate showed promise to deliver hydrophobic bioactive ingredients like fisetin to senescent cells to improve their bioavailability and anti-senescence effect.

Targeted multi-agent communication algorithm based on state control

As an important mechanism in multi-agent interaction,communication can make agents form complex team relationships rather than constitute a simple set of multiple independent agents.However,the existing communication schemes can bring much timing redundancy and irrelevant messages,which seriously affects their practical application.To solve this problem,this paper proposes a targeted multiagent communication algorithm based on state control(SCTC).The SCTC uses a gating mechanism based on state control to reduce the timing redundancy of communication between agents and determines the interaction relationship between agents and the importance weight of a communication message through a series connection of hard-and self-attention mechanisms,realizing targeted communication message processing.In addition,by minimizing the difference between the fusion message generated from a real communication message of each agent and a fusion message generated from the buffered message,the correctness of the final action choice of the agent is ensured.Our evaluation using a challenging set of Star Craft II benchmarks indicates that the SCTC can significantly improve the learning performance and reduce the communication overhead between agents,thus ensuring better cooperation between agents.

Efficacy and safety of targeted therapy plus immunotherapy combined with hepatic artery infusion chemotherapy (FOLFOX) for unresectable hepatocarcinoma

BACKGROUND The advent of cutting-edge systemic therapies has driven advances in the treatment of hepatocellular carcinoma(HCC),and therapeutic strategies with multiple modes of delivery have been shown to be more efficacious than mono-therapy.However,the mechanisms underlying this innovative treatment modality have not been elucidated.AIM To evaluate the clinical efficacy of targeted therapy plus immunotherapy combined with hepatic arterial infusion chemotherapy(HAIC)of FOLFOX in patients with unresectable HCC.METHODS We enrolled 53 patients with unresectable HCC who received a combination of targeted therapy,immunotherapy,and HAIC of FOLFOX between December 2020 and June 2021 and assessed the efficacy and safety of the treatment regimen.RESULTS The objective response rate was 60.4%(32/53),complete response was 24.5%(13/53),partial response was 35.9%(19/53),and stable disease was 39.6%(21/53).The median duration of response and median progression-free survival were 9.1 and 13.9 months,respectively.The surgical conversion rate was 34.0%(18/53),and 1-year overall survival was 83.0%without critical complicating diseases or adverse events(AEs).CONCLUSION The regimen of HAIC of FOLFOX,targeted therapy,and immunotherapy was curative for patients with unresectable HCC,with no serious AEs and a high rate of surgical conversion.

Dual ligand-targeted Pluronic P123 polymeric micelles enhance the therapeutic effect of breast cancer with bone metastases

Bone metastasis secondary to breast cancer negatively impacts patient quality of life and survival.The treatment of bone metastases is challenging since many anticancer drugs are not effectively delivered to the bone to exert a therapeutic effect.To improve the treatment efficacy,we developed Pluronic P123(P123)-based polymeric micelles dually decorated with alendronate(ALN)and cancer-specific phage protein DMPGTVLP(DP-8)for targeted drug delivery to breast cancer bone metastases.Doxorubicin(DOX)was selected as the anticancer drug and was encapsulated into the hydrophobic core of the micelles with a high drug loading capacity(3.44%).The DOX-loaded polymeric micelles were spherical,123 nm in diameter on average,and exhibited a narrow size distribution.The in vitro experiments demonstrated that a pH decrease from 7.4 to 5.0 markedly accelerated DOX release.The micelles were well internalized by cultured breast cancer cells and the cell death rate of micelle-treated breast cancer cells was increased compared to that of free DOX-treated cells.Rapid binding of the micelles to hydroxyapatite(HA)microparticles indicated their high affinity for bone.P123-ALN/DP-8@DOX inhibited tumor growth and reduced bone resorption in a 3D cancer bone metastasis model.In vivo experiments using a breast cancer bone metastasis nude model demonstrated increased accumulation of the micelles in the tumor region and considerable antitumor activity with no organ-specific histological damage and minimal systemic toxicity.In conclusion,our study provided strong evidence that these pH-sensitive dual ligand-targeted polymeric micelles may be a successful treatment strategy for breast cancer bone metastasis.

Role of glioma stem cells in promoting tumor chemo- and radioresistance: A systematic review of potential targeted treatments

BACKGROUND Gliomas pose a significant challenge to effective treatment despite advancements in chemotherapy and radiotherapy.Glioma stem cells(GSCs),a subset within tumors,contribute to resistance,tumor heterogeneity,and plasticity.Recent studies reveal GSCs’role in therapeutic resistance,driven by DNA repair mechanisms and dynamic transitions between cellular states.Resistance mechanisms can involve different cellular pathways,most of which have been recently reported in the literature.Despite progress,targeted therapeutic approaches lack consensus due to GSCs’high plasticity.AIM To analyze targeted therapies against GSC-mediated resistance to radio-and chemotherapy in gliomas,focusing on underlying mechanisms.METHODS A systematic search was conducted across major medical databases(PubMed,Embase,and Cochrane Library)up to September 30,2023.The search strategy utilized relevant Medical Subject Heading terms and keywords related to including“glioma stem cells”,“radiotherapy”,“chemotherapy”,“resistance”,and“targeted therapies”.Studies included in this review were publications focusing on targeted therapies against the molecular mechanism of GSC-mediated re-sistance to radiotherapy resistance(RTR).RESULTS In a comprehensive review of 66 studies on stem cell therapies for SCI,452 papers were initially identified,with 203 chosen for full-text analysis.Among them,201 were deemed eligible after excluding 168 for various reasons.The temporal breakdown of studies illustrates this trend:2005-2010(33.3%),2011-2015(36.4%),and 2016-2022(30.3%).Key GSC models,particularly U87(33.3%),U251(15.2%),and T98G(15.2%),emerge as significant in research,reflecting their representativeness of glioma characteristics.Pathway analysis indicates a focus on phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin(mTOR)(27.3%)and Notch(12.1%)pathways,suggesting their crucial roles in resistance development.Targeted molecules with mTOR(18.2%),CHK1/2(15.2%),and ATP binding cassette G2(12.1%)as frequent targets underscore their importance in overcoming GSC-mediated resistance.Various therapeutic agents,notably RNA inhibitor/short hairpin RNA(27.3%),inhibitors(e.g.,LY294002,NVP-BEZ235)(24.2%),and monoclonal antibodies(e.g.,cetuximab)(9.1%),demonstrate versatility in targeted therapies.among 20 studies(60.6%),the most common effect on the chemotherapy resistance response is a reduction in temozolomide resistance(51.5%),followed by reductions in carmustine resistance(9.1%)and doxorubicin resistance(3.0%),while resistance to RTR is reduced in 42.4%of studies.CONCLUSION GSCs play a complex role in mediating radioresistance and chemoresistance,emphasizing the necessity for precision therapies that consider the heterogeneity within the GSC population and the dynamic tumor microenvironment to enhance outcomes for glioblastoma patients.

Targeted metabolomics study of fatty-acid metabolism in lean metabolic-associated fatty liver disease patients

BACKGROUND The annual incidence of metabolic-associated fatty liver disease(MAFLD)in China has been increasing and is often overlooked owing to its insidious charac-teristics.Approximately 50%of the patients have a normal weight or are not obese.They are said to have lean-type MAFLD,and few studies of such patients are available.Because MAFLD is associated with abnormal lipid metabolism,lipid-targeted metabolomics was used in this study to provide experimental evidence for early diagnosis and pathogenesis.MAFLD and analyze metabolic pathways.UPLC-Q-Orbitrap/MS content determination was used to determine serum palmitic acid(PA),oleic acid(OA),linoleic acid(LA),and arachidonic acid(AA)levels in lean-type MAFLD patients.RESULTS Urea nitrogen and uric acid levels were higher in lean-type MAFLD patients than in healthy individuals(P<0.05).Alanine transaminase and cholinesterase levels were higher in lean-type MAFLD patients than in healthy indi-viduals(P<0.01).The expression of high-density lipoprotein and apolipoprotein A-1 were lower in lean-type MAFLD patients than in healthy individuals(P<0.05)and the expression of triglycerides and fasting blood glucose were increased(P<0.01).A total of 65 biomarkers that affected the synthesis and metabolism of fatty acids were found with P<0.05 and variable importance in projection>1.The levels of PA,OA,LA,and AA were significantly increased compared with healthy individuals.CONCLUSION The metabolic profiles of lean-type MAFLD patients and healthy participants differed significantly,yielding 65 identified biomarkers.PA,OA,LA,and AA exhibited the most significant changes,offering valuable clinical guidance for prevention and treatment of lean-type MAFLD.

Advances in targeted therapy for human epidermal growth factor receptor 2 positive in advanced gastric cancer

Emerging therapeutic methods represented by targeted therapy are effective supplements to traditional first-line chemoradiotherapy resistance.Human epidermal growth factor receptor 2(HER2)is one of the most important targets in targeted therapy for gastric cancer.Trastuzumab combined with chemotherapy has been used as the first-line treatment for advanced gastric cancer.The safety and efficacy of pertuzumab and margetuximab in the treatment of gastric cancer have been verified.However,monoclonal antibodies,due to their large molecular weight,inability to penetrate the blood-brain barrier,and drug resistance,lead to decreased therapeutic efficacy,so it is necessary to explore the efficacy of other HER2-targeting therapies in gastric cancer.Small-molecule tyrosine kinase inhibitors,such as lapatinib and pyrrotinib,have the advantages of small molecular weight,penetrating the blood-brain barrier and high oral bioavailability,and are expected to become the drugs of choice for perioperative treatment and neoadjuvant therapy of gastric cancer after validation by large-scale clinical trials in the future.Antibo-drug conjugate,such as T-DM1 and T-DXd,can overcome the resistance of monoclonal antibodies despite their different mechanisms of tumor killing,and are a supplement for the treatment of patients who have failed the treatment of monoclonal antibodies such as trastuzumab.Therefore,after more detailed stratification of gastric cancer patients,various gastric cancer drugs targeting HER2 are expected to play a more significant role.

Value of combining targeted emergency nursing with psychological nursing in children with febrile convulsions

BACKGROUND Febrile convulsions are a common pediatric emergency that imposes significant psychological stress on children and their families.Targeted emergency care and psychological nursing are widely applied in clinical practice,but their value and impact on the management of pediatric febrile convulsions are unclear.AIM To determine the impact of targeted emergency nursing combined with psychological nursing on satisfaction in children with febrile convulsions.METHODS Data from 111 children with febrile convulsions who received treatment at Nantong Maternal and Child Health Care Hospital between June 2021 and October 2022 were analyzed.The control group consisted of 44 children who received conventional nursing care and the research group consisted of 67 children who received targeted emergency and psychological nursing.The time to fever resolution,time to resolution of convulsions,length of hospital stays,Pittsburgh Sleep Quality Index,patient compliance,nursing satisfaction of the parents,occurrence of complications during the nursing process,and parental anxiety and depression were compared between the control and research groups.Parental anxiety and depression were assessed using the Hamilton Rating Scale for Depression(HAMD)and the Hamilton Rating Scale for Anxiety(HAMA).RESULTS The fever resolution,convulsion disappearance,and hospitalization times were longer in the control group compared with the research group(P<0.0001).The time to falling asleep,sleep time,sleep quality,sleep disturbance,sleep efficiency,and daytime status scores were significantly better in the research group compared with the control group(P<0.0001).The HAMD and HAMA scores for parents of children in the research group were lower than the scores in the control group after nursing(P<0.05).Compliance with treatment of children in the research group was higher than in the control group(P<0.05).Parental satisfaction with nursing in the research group was higher than in the control group(P<0.05).The total complication rate of children in the control group was higher than in the research group(P<0.05).CONCLUSION Combining psychological nursing with targeted emergency nursing improved the satisfaction of children’s families and compliance with treatment and promoted early recovery of clinical symptoms and improvement of sleep quality.

Research Progress in Targeted Therapy for Esophageal Cancer

Esophageal cancer (EC) is a prevalent malignant tumor that affects the digestive system and is often linked to a poor prognosis. The absence of effective early screening methods results in the diagnosis of esophageal cancer (EC) patients at advanced or metastatic stages. While historically considered incurable, ongoing advancements in medical research have led to the integration of various treatment modalities as primary approaches for managing advanced endometrial cancer. These modalities include surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy. Notably, the introduction of targeted therapy and immunotherapy has significantly enhanced the survival rates of individuals with EC. Immunotherapy has appeared as the predominant treatment for advanced esophageal cancer, while targeted therapy faces certain obstacles. Consequently, this review primarily focuses on the advancements in targeted therapy for esophageal cancer (EC), evaluating the effectiveness and safety of relevant medications, and aiming to provide guidance for the comprehensive management of EC based on current research findings.

Strategies for Cultivating Public Funded Targeted Normal Students Based on Goal Management Theory : A Case Study of East, West and North Guangdong

Public funded targeted normal students are an important component of China's teacher team construction.Since its implementation in 2007,a large number of outstanding rural teachers who have been striving on the front line of education have been trained.Based on the theory of goal management,this paper explores the problems and countermeasures in the training of public funded targeted normal students.It strives to solve the problems of low willingness to teach and high default rates among public funded normal students,and hopes that the suggestions proposed in this paper can further promote the effective implementation of policies for public funded normal students.

Handwriting Analysis Based on Belief of Targeted Individual Supporting Insider Threat Detection

The Unintentional Insider Threat (UIT) concept highlights that insider threats might not always stem from malicious intent and can occur across various domains. This research examines how individuals with medical or psychological issues might unintentionally become insider threats due to their perception of being targeted. Insights from the survey A Survey of Unintentional Medical Insider Threat Category indicate that such perceptions can be linked to underlying health conditions. The study Emotion Analysis Based on Belief of Targeted Individual Supporting Insider Threat Detection reveals that anger is a common emotion among these individuals. The findings suggest that UITs are often linked to medical or psychological issues, with anger being prevalent. To mitigate these risks, it is recommended that Insider Threat programs integrate expertise from medicine, psychology, and cybersecurity. Additionally, handwriting analysis is proposed as a potential tool for detecting insider threats, reflecting the evolving nature of threat assessment methodologies.

Comparison of Cognitive Registration Transrectal Ultrasound-Guided Targeted Biopsy of Prostate to Systematic 12-Core Biopsy: A Retrospective, Multicentre Study

Introduction: Prostate cancer (PCa) is the third most prevalent cancer among Malaysian males, often diagnosed at advanced stages, leading to suboptimal outcomes. While transrectal ultrasound-guided systematic biopsy (TRUS-SB) is the primary diagnostic method, prebiopsy multiparametric magnetic resonance imaging (mpMRI) is gaining popularity in identifying suspicious lesions. This study addresses the lack of comprehensive investigations into the efficacy of cognitive registration TRUS targeted biopsy (COG-TB) compared to conventional TRUS-SB, considering the resource limitations of the Malaysian healthcare system. Materials and Methods: A retrospective cohort study was conducted in two Malaysian healthcare facilities. 116 adult patients with a prostate-specific antigen (PSA) level of more than 4 ng/mL who underwent both COG-TB and TRUS-SB between October 2020 and March 2022 were included. Primary outcomes were cancer detection rate and histopathological outcomes, including Gleason score. Results: COG-TB showed a higher overall cancer detection rate (50%) compared to TRUS-SB (44%). Clinically significant cancer detection rates were similar between COG-TB and TRUS-SB (37.1%). Further analysis revealed that both COG-TB and TRUS-SB detected clinically significant cancer in 30.2% of patients, did not detect it in 56.0%, and had conflicting findings in 16 patients (p Conclusion: COG-TB and TRUS-SB have comparable detection rates for clinically significant prostate cancer, with COG-TB showing a higher tendency to detect insignificant prostate cancer. Further studies comparing these methods are warranted.

Covalent targeted radioligands potentiate radionuclide therapy

Targeted radionuclide therapy,in which radiopharmaceuticals deliver potent radionuclides to tumours for localized irradiation,has addressed unmet clinical needs and improved outcomes for patients with cancer1-4.A therapeutic radiopharmaceutical must achieve both sustainable tumour targeting and fast clearance from healthy tissue,which remains a major challenge5,6.A targeted ligation strategy that selectively fixes the radiopharmaceutical to the target protein in the tumour would be an ideal solution.Here we installed a sulfur(VI)fluoride exchange(SuFEx)chemistry-based linker on radiopharmaceuticals to prevent excessively fast tumour clearance.When the engineered radiopharmaceutical binds to the tumour-specific protein,the system undergoes a binding-to-ligation transition and readily conjugates to the tyrosine residues through the'click'SuFEx reaction.

Analysis of the Effectiveness of Targeted Nursing in Children with Severe Viral Encephalitis Complicated with Respiratory Failure

Objective:To explore and analyze the effectiveness of targeted nursing in children with severe viral encephalitis complicated with respiratory failure.Methods:From April 2021 to April 2023,74 children with severe viral encephalitis complicated with respiratory failure admitted to the Department of Pediatrics of our hospital were selected as the research objects and divided into the target group(n=37)and the reference group(n=37).Targeted nursing was given to the target group,while general nursing was given to the reference group.Physical rehabilitation,motor scores,and lung function were compared between the groups.Results:The recovery time of limb abnormalities,convulsions,abnormal consciousness,and cranial nerve disorders in the target group was significantly better than that in the reference group(P<0.05).The motor function,joint activity and pain,sensory function,and total score of the target group were significantly lower than those of the reference group(P<0.05).After the intervention,lung function indicators including VC(vital capacity),FVC(forced vital capacity),and MVV(maximum voluntary ventilation)of the target group were better than those of the reference group(P<0.05).Conclusion:Targeted nursing can shorten the recovery period of severe viral encephalitis complicated with respiratory failure in children,speed up the recovery of motor function,and improve lung function.This nursing model has a significant application effect in children with severe viral encephalitis complicated with respiratory failure.

Research Progress on the Bone Metastasis Mechanism of Prostate Cancer and Bone-Targeted Drugs

Prostate cancer is a common male malignant tumor,and bone metastasis is one of the common complications in the late stage of prostate cancer.The mechanism of prostate cancer bone metastasis is a complex process involving multiple factors and steps.In recent years,with in-depth research on the mechanism of prostate cancer bone metastasis and the development of new drugs,important progress has been made in the treatment of prostate cancer bone metastasis.Based on this,this article introduces the mechanism of prostate cancer bone metastasis and the research progress of several bone-targeted drugs to provide reference and inspiration for future research.

Resistance to targeted therapy in metastatic colorectal cancer:Current status and new developments

Colorectal cancer(CRC)is one of the most lethal and common malignancies in the world.Chemotherapy has been the conventional treatment for metastatic CRC(mCRC)patients.However,the effects of chemotherapy have been unsatisfactory.With the advent of targeted therapy,the survival of patients with CRC have been prolonged.Over the past 20 years,targeted therapy for CRC has achieved substantial progress.However,targeted therapy has the same challenge of drug resistance as chemotherapy.Consequently,exploring the resistance mechanism and finding strategies to address the resistance to targeted therapy,along with searching for novel effective regimens,is a constant challenge in the mCRC treatment,and it is also a hot research topic.In this review,we focus on the current status on resistance to existing targeted therapies in mCRC and discuss future developments.

Effects of mixed fertilizers formed by the compounding of two targeted controlled-release nitrogen fertilizers on yield,nitrogen use efficiency,and ammonia volatilization in double-cropping rice

One-time application of mixed fertilizer formed by the compounding of two controlled-release nitrogen fertilizers(CRUs)with targeted N supply during the periods from transplantation(TS)to panicle initiation(PI)and from PI to heading(HS)is expected to synchronize the double-peak N demand of rice.However,its effects on the yield and N use efficiency(NUE)of labor-intensive double-cropping rice were unknown.Two targeted CRU(CRU_(A)and CRU_(B))were compounded in five ratios(CRU_(A):CRU_(B)=10:0,7:3,5:5,3:7,and 0:10)to form five mixed fertilizers(BBFs):BBF1-5.A field experiment was performed to investigate the characteristics of N supply in early and late seasons under different BBFs and their effects on N uptake,yield,and ammonia volatilization(AV)loss from paddy fields of double-cropping rice.Conventional high-yield fertilization(CK,three split applications of urea)and zero-N treatments were established as controls.The N supply dropped significantly with the increased compound ratio of CRU_(B)during the period from TS to PI,but increased during the period from PI to HS.With the exception of the period from TS to PI in the late rice season,the N uptake of early and late rice maintained close synchronicity with the N supply of BBFs during the double-peak periods.Excessive N supply(BBF1 and BBF2)in the late rice season during the period from TS to PI increased N loss by AV.The effect of BBF on grain yield increase varied widely between seasons,irrespective of year.Among the BBFs,the BBF2 treatment of early rice not only stabilized the spikelets per panicle but also ensured a high number of effective panicles by promoting N uptake during the period from TS to PI and a high grain-filling percentage by appropriately reducing the N supply at the later PI stage,resulting in the highest rice yield.While stabilizing the effective panicle number,the BBF4 treatment of late rice increased the number of spikelets per panicle by promoting N uptake during the period from PI to HS,resulting in the highest rice yield.The two-year average yield and apparent N recovery efficiency of the BBF2 treatment during the early rice season were 9.6 t ha 1 and 45.3%,while those of late rice in BBF4 were 9.6 t ha 1 and 43.0%,respectively.The yield and NUE indexes of BBF2 in early rice and BBF4 in late rice showed no significant difference from those of CK.The AVs of BBF2 during the early rice season and of BBF4 during the late rice season were 50.0%and 76.8%lower,respectively,than those of CK.BBF2 and BBF4 could effectively replace conventional urea split fertilization in early and late rice seasons,ensuring rice yield and NUE and reducing AV loss in paddy fields.