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Fine-tuning the activation behaviors of ternary modular cabazitaxel prodrugs for efficient and on-target oral anti-cancer therapy

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Asian Journal of Pharmaceutical Sciences 2024年第2期19卷 188-203页

作者： Mingyang Zhang Yifan Miao Can Zhao Tong Liu Xiyan Wang Zixuan Wang Wenxin zhong zhonggui He Chutong tian Jin Sun Department of Pharmaceutics Wuya College of InnovationShenyang Pharmaceutical UniversityShenyang 110016China Key Laboratory of Advanced Drug Delivery Systems of Zhejiang Province Hangzhou 310058China Joint International Research Laboratory of Intelligent Drug Delivery Systems Ministry of EducationShenyang 110016China Liaoning Provincial Institute of Drug Inspection and Testing Shenyang 110036China

The disulfide bond plays a crucial role in the design of anti-tumor prodrugs due to its exceptional tumor-specific redox responsiveness. However, premature breaking of disulfide bonds is triggered by small amounts of reducing substances (e.g., ascorbic acid, glutathione, uric acid and tea polyphenols) in the systemic circulation. This may lead to toxicity, particularly in oral prodrugs that require more frequent and high-dose treatments. Fine-tuning the activation kinetics of these prodrugs is a promising prospect for more efficient on-target cancer therapies. In this study, disulfide, steric disulfide, and ester bonds were used to bridge cabazitaxel (CTX) to an intestinal lymph vessel-directed triglyceride (TG) module. Then, synthetic prodrugs were efficiently incorporated into self-nanoemulsifying drug delivery system (corn oil and Maisine CC were used as the oil phase and Cremophor EL as the surfactant). All three prodrugs had excellent gastric stability and intestinal permeability. The oral bioavailability of the disulfide bond-based prodrugs (CTX-(C)S-(C)S-TG and CTX-S-S-TG) was 11.5- and 19.1-fold higher than that of the CTX solution, respectively, demonstrating good oral delivery efficiency. However, the excessive reduction sensitivity of the disulfide bond resulted in lower plasma stability and safety of CTX-S-S-TG than that of CTX-(C)S-(C)S-TG. Moreover, introducing steric hindrance into disulfide bonds could also modulate drug release and cytotoxicity, significantly improving the anti-tumor activity even compared to that of intravenous CTX solution at half dosage while minimizing off-target adverse effects. Our findings provide insights into the design and fine-tuning of different disulfide bond-based linkers, which may help identify oral prodrugs with more potent therapeutic efficacy and safety for cancer therapy.

关键词： Steric disulfide bond Triglyceride-like pr odrugs Cabazitaxel Lymphatic transport Oral chemotherapy

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Structurally Flexible 2D Spacer for Suppressing the Electron-Phonon Coupling Induced Non-Radiative Decay in Perovskite Solar Cells

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Nano-Micro Letters 2024年第9期16卷 325-340页

作者： Ruikun Cao Kexuan Sun Chang Liu Yuhong Mao wei Guo Ping Ouyang Yuanyuan Meng Ruijia tian Lisha Xie Xujie Lü Ziyi Ge Zhejiang Provincial Engineering Research Center of Energy Optoelectronic Materials and Devices Ningbo Institute of Materials Technology and EngineeringChinese Academy of SciencesNingbo 315201People’s Republic of China School of Materials Science and Chemical Engineering Ningbo UniversityNingbo 315211People’s Republic of China Center of Materials Science and Optoelectronics Engineering University of Chinese Academy of SciencesBeijing 100049People’s Republic of China Center for High Pressure Science and Technology Advanced Research(HPSTAR) Shanghai 201203People’s Republic of China

This study presents experimental evidence of the dependence of non-radiative recombination processes on the electron-phonon coupling of perovskite in perovskite solar cells(PSCs).Via A-site cation engineering,a weaker electron-phonon coupling in perovskite has been achieved by introducing the structurally soft cyclohexane methylamine(CMA^(+))cation,which could serve as a damper to alleviate the mechanical stress caused by lattice oscillations,compared to the rigid phenethyl methylamine(PEA^(+))analog.It demonstrates a significantly lower non-radiative recombination rate,even though the two types of bulky cations have similar chemical passivation effects on perovskite,which might be explained by the suppressed carrier capture process and improved lattice geometry relaxation.The resulting PSCs achieve an exceptional power conversion efficiency(PCE)of 25.5%with a record-high opencircuit voltage(V_(OC))of 1.20 V for narrow bandgap perovskite(FAPbI_(3)).The established correlations between electron-phonon coupling and non-radiative decay provide design and screening criteria for more effective passivators for highly efficient PSCs approaching the Shockley-Queisser limit.

关键词： Electron-phonon coupling A-site cation engineering Non-radiative recombination

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N-acetylcysteine ameliorates erectile dysfunction in rats with hyperlipidemia by inhibiting oxidative stress and corpus cavernosum smooth muscle cells phenotypic modulation

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Asian Journal of Andrology 2024年第1期26卷 99-106页

作者： wei Ding Jun-Hong Fan Li-Ren zhong Nan-Xiong Wang Lu-Hao Liu Hai-Bo Zhang Li Wang Ming-Qiang Wang Bing-Lin He An-Yang wei Department of Urology The First Affiliated Hospital of Guizhou University of Traditional Chinese MedicineGuiyang 550002China Department of Urology Guangdong Provincial People's HospitalGuangdong Academy of Medical SciencesGuangzhou 510000China Department of Urology Nanfang HospitalSouthern Medical UniversityGuangzhou 510000China Department of Urology Shenzhen Immigration Inspection General Station HospitalShenzhen 518000China Department of Organ Transplantation The Second Affiliated Hospital of Guangzhou Medical UniversityGuangzhou 510000China Department of Endocrinology The First Affiliated Hospital of Guizhou University of Traditional Chinese MedicineGuiyang 550002China

Hyperlipidemia is a major risk factor for erectile dysfunction(ED).Oxidative stress and phenotypic modulation of corpus cavernosum smooth muscle cells(CcSMCs)are the key pathological factors of ED.N-acetylcysteine(NAC)can inhibit oxidative stress;however,whether NAc can alleviate pathological variations in the corpus cavernosum and promote erectile function recovery in hyperlipidemic rats remains unclear.A hyperlipidemia model was established using 27 eight-week-old male Sprague-Dawley(SD)rats fed a high-fat and high-cholesterol diet(hyperlipidemic rats,HR).In addition,9 male SD rats were fed a normal diet to serve as controls(NC).HR rats were divided into three groups:HR,HR+normal saline(NS),and HR+NAC(n=9 for each group;NS or NAc intraperitoneal injections were administered daily for 16 weeks).Subsequently,the lipid profiles,erectile function,oxidative stress,phenotypic modulation markers of ccsMCs,and tissue histology were analyzed.The experimental results revealed that erectile function was significantly impaired in the HR and HR+NS groups,but enhanced in the HR+NAC group.Abnormal lipid levels,over-activated oxidative stress,and multi-organ lesions observed in the HR and HR+NS groups were improved in the HR+NAC group.Moreover,the HR group showed significant phenotypic modulation of CCSMCs,which was also inhibited by NAC treatment.This report focuses on the therapeutic effect of NAc in restoring erectile function using a hyperlipidemic rat model by preventing CcSMC phenotypic modulationand attenuating oxidativestress.

关键词： erectile dysfunction hyperlipidemia N-acetylcysteine oxidative stress henotypic modulation

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Polycytosine RNA-binding protein 1 regulates osteoblast function via a ferroptosis pathway in type 2 diabetic osteoporosis

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World Journal of Diabetes 2024年第5期15卷 977-987页

作者： Hong-Dong Ma Lei Shi Hai-tian Li Xin-Dong Wang Mao-wei Yang Department of Orthopedics The Affiliated Hospital of Nantong UniversityNantong 226001Jiangsu ProvinceChina Department of Orthopedics The First Hospital of China Medical UniversityShenyang 110001Liaoning ProvinceChina

BACKGROUND Recently,type 2 diabetic osteoporosis(T2DOP)has become a research hotspot for the complications of diabetes,but the specific mechanism of its occurrence and development remains unknown.Ferroptosis caused by iron overload is con-sidered an important cause of T2DOP.Polycytosine RNA-binding protein 1(PCBP1),an iron ion chaperone,is considered a protector of ferroptosis.AIM To investigate the existence of ferroptosis and specific role of PCBP1 in the development of type 2 diabetes.METHODS A cell counting kit-8 assay was used to detect changes in osteoblast viability under high glucose(HG)and/or ferroptosis inhibitors at different concentrations and times.Transmission electron microscopy was used to examine the morpho-logical changes in the mitochondria of osteoblasts under HG,and western blotting was used to detect the expression levels of PCBP1,ferritin,and the ferroptosis-related protein glutathione peroxidase 4(GPX4).A lentivirus silenced and overex-pressed PCBP1.Western blotting was used to detect the expression levels of the osteoblast functional proteins osteoprotegerin(OPG)and osteocalcin(OCN),whereas flow cytometry was used to detect changes in reactive oxygen species(ROS)levels in each group.RESULTS Under HG,the viability of osteoblasts was considerably decreased,the number of mitochondria undergoing atrophy was considerably increased,PCBP1 and ferritin expression levels were increased,and GPX4 expression was decreased.Western blotting results demonstrated that infection with lentivirus overexpressing PCBP1,increased the expression levels of ferritin,GPX4,OPG,and OCN,compared with the HG group.Flow cytometry results showed a reduction in ROS,and an opposite result was obtained after silencing PCBP1.CONCLUSION PCBP1 may protect osteoblasts and reduce the harm caused by ferroptosis by promoting ferritin expression under a HG environment.Moreover,PCBP1 may be a potential therapeutic target for T2DOP.

关键词： Polycytosine RNA-binding protein 1 Ferroptosis Reactive oxygen species Ferritin Osteoblast Type 2 diabetic osteoporosis

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Paravertebral block's effect on analgesia and inflammation in advanced gastric cancer patients undergoing transarterial chemoembolization and microwave ablation

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World Journal of Gastrointestinal Surgery 2024年第1期16卷 196-204页

作者： Ying-Fen Xiong Ben-zhong wei Yu-Feng Wang Xiao-Feng Li Cong Liu Department of Anesthesiology The First Affiliated Hospital of Nanchang UniversityNanchang 330006Jiangxi ProvinceChina Department of Anesthesiology Nanjing Gulou Hospital Group Yizheng HospitalYangzhou 211400Jiangsu ProvinceChina Nuclear Medicine Department Xuzhou Cancer HospitalXuzhou 221000Jiangsu ProvinceChina Department of Radiology Xuzhou Cancer HospitalXuzhou 221000Jiangsu ProvinceChina Department of Minimally Invasive Oncology Xuzhou New Health Hospital(Xuzhou Hospital Affiliated to Jiangsu University)Xuzhou 221000Jiangsu ProvinceChina

BACKGROUND Transarterial chemoembolization(TACE)combined with microwave ablation(MWA)is an effective treatment strategy for patients with advanced gastric cancer and liver metastasis.However,it may cause severe postoperative pain and inflammatory responses.The paravertebral block(PVB)is a regional anesthetic technique that provides analgesia to the thoracic and abdominal regions.AIM To evaluate the effect of PVB on postoperative analgesia and inflammatory response in patients undergoing TACE combined with MWA for advanced gastric cancer and liver metastasis.METHODS Sixty patients were randomly divided into PVB and control groups.The PVB group received ultrasound-guided PVB with 0.375%ropivacaine preoperatively,whereas the control group received intravenous analgesia with sufentanil.The primary outcome was the visual analog scale(VAS)score for pain at 6 h,12 h,24 h,and 48 h after the procedure.Secondary outcomes were the dose of sufentanil used,incidence of adverse events,and levels of inflammatory markers(white blood cell count,neutrophil percentage,C-reactive protein,and procalcitonin)before and after the procedure.RESULTS The PVB group had significantly lower VAS scores at 6 h,12 h,24 h,and 48 h after the procedure compared with the control group(P<0.05).The PVB group also had a significantly lower consumption of sufentanil and a lower incidence of nausea,vomiting,and respiratory depression than did the control group(P<0.05).Compared with the control group,the PVB group had significantly lower levels of inflammatory markers 24 h and 48 h after the procedure(P<0.05).CONCLUSION PVB can effectively reduce postoperative pain and inflammatory responses and improve postoperative comfort and recovery in patients with advanced gastric cancer and liver metastasis treated with TACE combined with MWA.

关键词： Transarterial chemoembolization Microwave ablation Paravertebral block Visual analog scale Sufentanil Inflammatory markers

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A synthesis of the Cretaceous wildfire record related to atmospheric oxygen levels?

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Journal of Palaeogeography 2024年第1期13卷 149-164页

作者： Da-wei Lü Wen-Xu Du Zhi-Hui Zhang Yuan Gao tian-tian Wang Jin-Cheng Xu Ao-Cong Zhang Cheng-Shan Wang Shandong Provincial Key Laboratory of Depositional Mineralization and Sedimentary Minerals College of Earth Sciences and EngineeringShandong University of Science and TechnologyQingdao 266590Shandong ProvinceChina School of Earth Sciences and Resources China University of GeosciencesBejing 100083China Institute of Earth Sciences China University of Geosciences(Bejing)Beijing 100083China

The Cretaceous was a significant greenhouse period in Earth's history with higher atmospheric CO_(2) levels and temperatures than today. Although evidence of combustion has been widely described from the Cretaceous deposits, our understanding of the spatiotemporal diversification pattern and process of the Cretaceous wildfires is still limited. In this study, we comprehensively synthesize a total of 271 published Cretaceous wildfire occurrences based on the by-products of burning, including fossil charcoal, pyrogenic inertinite(fossil charcoal in coal), and pyrogenic polycyclic aromatic hydrocarbons(PAHs). Spatially, the dataset shows a distinctive distribution of reported wildfire evidence characterized by high concentration in the middle latitudinal areas of the Northern Hemisphere(30°N-60°N) over the Cretaceous. Temporally, an overall increasing trend of the reported wildfire data from the Early Cretaceous to the Late Cretaceous is coincident with higher atmospheric O_(2) levels. However, the spatial and temporal patterns may result from many types of factors, such as taphonomy, preservation, and researcher biases, instead of a real picture of the Cretaceous wildfire evolution. To better understand the spatiotemporal diversification of the Cretaceous wildfire, more investigations on the record of wildfire occurrences during this period would be necessary in the future.

关键词： Wildfire Cretaceous Atmospheric oxygen Taphonomy Charcoal

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Frequency and associated factors of accommodation and non-strabismic binocular vision dysfunction among medical university students

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International Journal of Ophthalmology(English edition) 2024年第2期17卷 374-379页

作者： Jie Cai Wen-Wen Fan Yun-Hui zhong Cai-Lan Wen Xiao-Dan wei Wan-Chen wei Wan-Yan Xiang Jin-Mao Chen Department of Ophthalmology First Affiliated Hospital of Guangxi Medical UniversityNanning 530021Guangxi Zhuang Autonomous RegionChina Digital and Intelligent Technology Transformation and Application Research Institute of Visual Function Tianjin 300000China Guangxi Medical University Nanning 530021Guangxi Zhuang Autonomous RegionChina

AIM:To investigate the frequency and associated factors of accommodation and non-strabismic binocular vision dysfunction among medical university students.METHODS:Totally 158 student volunteers underwent routine vision examination in the optometry clinic of Guangxi Medical University.Their data were used to identify the different types of accommodation and nonstrabismic binocular vision dysfunction and to determine their frequency.Correlation analysis and logistic regression were used to examine the factors associated with these abnormalities.RESULTS:The results showed that 36.71%of the subjects had accommodation and non-strabismic binocular vision issues,with 8.86%being attributed to accommodation dysfunction and 27.85%to binocular abnormalities.Convergence insufficiency(CI)was the most common abnormality,accounting for 13.29%.Those with these abnormalities experienced higher levels of eyestrain(χ2=69.518,P<0.001).The linear correlations were observed between the difference of binocular spherical equivalent(SE)and the index of horizontal esotropia at a distance(r=0.231,P=0.004)and the asthenopia survey scale(ASS)score(r=0.346,P<0.001).Furthermore,the right eye's SE was inversely correlated with the convergence of positive and negative fusion images at close range(r=-0.321,P<0.001),the convergence of negative fusion images at close range(r=-0.294,P<0.001),the vergence facility(VF;r=-0.234,P=0.003),and the set of negative fusion images at far range(r=-0.237,P=0.003).Logistic regression analysis indicated that gender,age,and the difference in right and binocular SE did not influence the emergence of these abnormalities.CONCLUSION:Binocular vision abnormalities are more prevalent than accommodation dysfunction,with CI being the most frequent type.Greater binocular refractive disparity leads to more severe eyestrain symptoms.

关键词： optometry clinic non-strabismic binocular vision dysfunction college students convergence insufficiency

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A novel profile modification HPF-Co gel satisfied with fractured low permeability reservoirs in high temperature and high salinity

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Petroleum Science 2024年第1期21卷 683-693页

作者： Ya-Kai Li Ji-Rui Hou wei-Peng Wu Ming Qu Tuo Liang wei-Xin zhong Yu-Chen Wen Hai-Tong Sun Yi-Nuo Pan China University of Petroleum Beijing Beijing102249China PetroChina Tarim Oilfield Company Korla 841000XinjiangChina Key Laboratory of Improving Oil and Gas Recovery of Ministry of Education Northeast Petroleum University Daqing 163318HeilongjiangChina Xi'an Shiyou University Xi'an 710065ShaanxiChina Northwest Oilfield Company SINOPECUrumqi 830011XinjiangChina

Conformance control and water plugging are a widely used EOR method in mature oilfields.However,majority of conformance control and water plugging agents are unavoidable dehydrated situation in high-temperature and high-salinity low permeability reservoirs.Consequently,a novel conformance control system HPF-Co gel,based on high-temperature stabilizer(CoCl_(2)·H_(2)O,CCH)is developed.The HPF-Co bulk gel has better performances with high temperature(120℃)and high salinity(1×10^(5)mg/L).According to Sydansk coding system,the gel strength of HPF-Co with CCH is increased to code G.The dehydration rate of HPF-Co gel is 32.0%after aging for 150 d at 120℃,showing excellent thermal stability.The rheological properties of HPF gel and HPF-Co gel are also studied.The results show that the storage modulus(G′)of HPF-Co gel is always greater than that of HPF gel.The effect of CCH on the microstructure of the gel is studied.The results show that the HPF-Co gel with CCH has a denser gel network,and the diameter of the three-dimensional network skeleton is 1.5-3.5μm.After 90 d of aging,HPF-Co gel still has a good three-dimensional structure.Infrared spectroscopy results show that CCH forms coordination bonds with N and O atoms in the gel amide group,which can suppress the vibration of cross-linked sites and improve the stability at high temperature.Fractured core plugging test determines the optimized polymer gel injection strategy and injection velocity with HPF-Co bulk gel system,plugging rate exceeding 98%.Moreover,the results of subsequent waterflooding recovery can be improved by 17%.

关键词： Low permeability reservoir High-temperature resistant gel Complexation reaction Polymer gel injection strategy Plugging rate Enhanced oil recovery

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Perinatal outcomes of frozen-thawed embryo transfer following blastocyst-stage embryo transfer compared to those of cleavage-stage embryo transfer: analysis of 9408 singleton newborns using propensity score analysis

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生殖与发育医学(英文) 2024年第2期8卷 67-74页

作者： zhong Hu-Cen Wan Qi Hu Yu-Ling Li tian Huang Li-Juan Wang Mao Hu Xin-Yue Wang Meng-Di zhong Zhao-Hui School of Public Health Joint International Research Laboratory of Reproduction and Development of the Ministry of Education of China Chongqing China Department of Obstetrics and Gynecology West China Second Hospital Sichuan University Chengdu China Sichuan Jinxin Xinan Women and Children’s Hospital Chengdu Sichuan China Department of Reproductive Medicine the First Affiliated Hospital of Chongqing Medical University Chongqing China School of Public Health Research Center for Medical and Social Development Chongqing Medical University Chongqing China

Objective: Regarding frozen-thawed embryo transfer (FET), there is limited consensus on whether extending embryo culture from the cleavage stage to the blastocyst stage affects perinatal outcomes. This study aimed to compare perinatal outcomes of singletons between blastocyst-stage embryo transfer (BT) and cleavage-stage embryo transfer (CT) in FET.Methods: A total of 9408 FET cycles that met the inclusion criteria were included in this retrospective cohort study between 2019 and 2022. Blastocyst-stage embryo transfers were performed in the BT group, and cleavage-stage embryo transfers were performed in the CT group. Multivariate logistic regression analyses were performed, as well as propensity score matching (PSM) to adjust for confounders.Results: After PSM, a higher risk of pre-term birth (PTB; odds ratio [OR]: 1.23, 95% confidence interval [CI]: 1.00-1.50,P = 0.048) and being large for gestational age (LGA;OR: 1.16, 95%CI: 1.00-1.35,P = 0.050) was observed in the BT group compared to that in the CT group. After stratified PSM, in the subgroup under 35 years of age, only an increased risk of LGA was observed in the BT group compared to the CT group. Perinatal outcomes in the double-embryo transfer subgroup were similar to those in the unstratified group. However, in the subgroup beyond 35 years of age and the single embryo transfer subgroup, perinatal outcomes were not statistically different between the BT and CT groups (P >0.05).Conclusions: In FET, prolonged embryo culture to the blastocyst stage increased the risk of PTB and LGA in single fetuses. However, stratified analysis based on age and the number of transferred embryos yielded different results, necessitating further mechanistic studies.

关键词： Frozen-thawed embryo transfer Blastocyst Cleavage stage Perinatal outcomes Pre-term birth Large for gestational age Small for gestational age

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Resource-saving scheduling scheme for centralized target tracking in multiple radar system under automatic blanket jamming

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Chinese Journal of Aeronautics 2024年第5期37卷 349-362页

作者： Zhengjie LI Yujie wei Junwei XIE Haowei ZHANG Yu tian Air and Missile Defense College Air Force Engineering UniversityXi’an 710051China Air Force Xi’an Flying College Xi’an 710300China Air and Missile Defense Institute Air Force Research InstituteBeijing 100085China School of Economics and Management Beihang UniversityBeijing 100191China

This paper investigates the problem of Joint Radar Node Selection and Power Allocation(JRNSPA)in the Multiple Radar System(MRS)in the blanket jamming environment.Each radar node independently tracks moving target and subsequently transmits the raw observation data to the fusion center,which formulates a centralized tracking network structure.In order to establish a practical blanket jamming environment,we suppose that each target carries the self-defense jammer which automatically implements blanket jamming to the radar nodes that exceed the preset interception probability.Subsequently,the Predicted Conditional Cramer-Rao Lower Bound(PC-CRLB)is derived and utilized as the tracking accuracy criterion.Aimed at ensuring both the tracking performance and the Low Probability of Intercept(LPI)performance,the resource-saving scheduling model is formulated to minimize the transmit power consumption while meeting the requirements of tracking accuracy.Finally,the Modified Zoutendijk Method Of Feasible Directions(MZMFD)-based two-stage solution technique is adopted to solve the formulated non-convex optimization model.Simulation results show the effectiveness of the proposed JRNSPA scheme.

关键词： Multiple Radar System(MRS) Centralized target tracking Resource scheduling Blanket jamming Low Probability of Intercept(LPI)

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