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Deamidation enables pathogenic SMAD6 variants to activate the BMP signaling pathway

Science China(Life Sciences) 2024年第9期67卷 1915-1927页

作者： Ling Li Lei Lu Ziqi Xiao Jingyi Lv Hefeng Huang Bo Wu Tongjin Zhao Chengtao Li Weimin Wang Hongyan Wang Obstetrics and Gynecology Hospital State Key Laboratory of Genetic EngineeringInstitute of Reproduction and Developmentand Children’s HospitalFudan UniversityShanghai 200090China Shanghai Key Laboratory of Metabolic Remodeling and Health Institute of Metabolism and Integrative BiologyFudan UniversityShanghai 200438China Prenatal Diagnosis Center of Shenzhen Maternity&child Healthcare Hospital Shenzhen 518028China Shanghai Medical College Fudan UniversityShanghai 200032China Department of Pharmacy College of Life SciencesChina Jiliang UniversityHangzhou 310018China

The BMP signaling pathway plays a crucial role in regulating early embryonic development and tissue ***6 encodes a negative regulator of BMP,and rare variants of SMAD6 are recurrently found in individuals with birth ***,we observed that a subset of rare pathogenic variants of SMAD6 consistently exhibited positive regulatory effects instead of the initial negative effects on the BMP signaling *** sought to determine whether these SMAD6 variants have common pathogenic ***,we showed that pathogenic SMAD6 variants accompanying this functional reversal exhibit similar increases in ***,increased deamidation of SMAD6 variants promotes the accumulation of the BMP receptor BMPR1A and the formation of new complexes,both of which lead to BMP signaling pathway ***,two residues,N262 and N404,in SMAD6 were identified as the crucial sites of deamidation,which was catalyzed primarily by glutamine-fructose-6-phosphate transaminase 2(GFPT2).Additionally,treatment of cells harboring SMAD6 variants with a deamidase inhibitor restored the inhibitory effect of SMAD6 on the BMP signaling ***,when wild-type SMAD6 was manually simulated to mimic the deamidated state,the reversed function of activating BMP signaling was *** together,these findings show that deamidation of SMAD6 plays a crucial role in the functional reversal of BMP signaling activity,which can be induced by a subset of various SMAD6 *** study reveals a common pathogenic mechanism shared by these variants and provides a potential strategy for preventing birth defects through deamidation regulation,which might prevent the off-target effects of gene editing.

关键词： SMAD6 deamidation BMP signaling pathway GFPT2

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Deleterious variants in RNF111 impair female fertility and induce premature ovarian insufficiency in humans and mice

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Science China(Life Sciences) 2024年第7期67卷 1325-1337页

作者： Chengcheng Song Yingying Qin Yan Li Bingyi Yang Ting Guo Wenqing Ma Dian Xu Keyan Xu Fangfang Fu Li Jin Yanhua Wu Shuyan Tang Xiaojun Chen Feng Zhang Obstetrics and Gynecology Hospital State Key Laboratory of Genetic EngineeringInstitute of Medical Genetics and GenomicsFudan UniversityShanghai 200011China Human Phenome institute Zhangjiang Fudan International Innovation CenterFudan UniversityShanghai 201203China Center for Reproductive Medicine Cheeloo College of MedicineShandong UniversityJinan 250021China State Key Laboratory of Reproductive Medicine and Offspring Health Key Laboratory of Reproductive Endocrinology of Ministry of EducationNational Research Center for Assisted Reproductive Technology and Reproductive GeneticsShandong Key Laboratory of Reproductive MedicineShandong Provincial Clinical Research Center for Reproductive HealthShandong UniversityJinan 250021China Department of Obstetrics and Gynecology Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China National Demonstration Center for Experimental Biology Education School of Life SciencesFudan UniversityShanghai 200433China Department of Gynecology the Tenth People’s Hospital of Tongji UniversityShanghai 200072China Soong Ching Ling institute of Maternity and child Health International Peace Maternity and Child Health Hospital of China Welfare InstituteShanghai 200030China

Premature ovarian insufficiency(POI)is a heterogeneous female disorder characterized by the loss of ovarian function before the age of *** represents a significant detriment to female ***,the known POI-causative genes currently account for only a fraction of *** elucidate the genetic factors underlying POI,we conducted whole-exome sequencing on a family with three fertile POI patients and identified a deleterious missense variant in *** a subsequent replication study involving 1,030 POI patients,this variant was not only confirmed but also accompanied by the discovery of three additional predicted deleterious RNF111 *** variants collectively account for eight cases,representing 0.78%of the study cohort.A further study involving 500 patients with diminished ovarian reserve also identified two additional RNF111 ***,RNF111 encodes an E3 ubiquitin ligase with a regulatory role in the TGF-β/BMP signaling *** analysis revealed that RNF111/RNF111 is predominantly expressed in the oocytes of mice,monkeys,and *** further investigate the functional implications of RNF111 variants,we generated two mouse models:one with a heterozygous missense mutation(Rnf111+/M)and another with a heterozygous null mutation(Rnf111^(+/-)).Both mouse models exhibited impaired female fertility,characterized by reduced litter sizes and small ovarian ***,RNA-seq and quantitative proteomics analysis unveiled that Rnf111 haploinsufficiency led to dysregulation in female gonad development and negative regulation of the BMP signaling pathway within mouse *** conclusion,our findings strongly suggest that monoallelic deleterious variants in RNF111 can impair female fertility and induce POI in both humans and mice.

关键词： POI RNF111 female fertility ovarian reserve

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Combined Effect of Outdoor Time and Other Modifiable Factors on Myopia Incidence Among children and Adolescents—9 PLADs,China,2020

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China CDC weekly 2024年第9期6卷 151-156,I0001,I0002页

作者： Panliang Zhong Yunfei Liu Ning Ma Jiajia Dang Di Shi Shan Cai Ziyue Chen Yanhui Dong Peijin Hu Jun Ma Patrick W.C Lau Randall S.Stafford Yi Song institute of child and Adolescent Health School of Public HealthPeking UniversityNational Health Commission Key Laboratory of Reproductive HealthBeijingChina Department of Sport Physical Education&HealthHong Kong Baptist UniversityKowloon TongHong Kong Special Administrative RegionChina Department of Medicine Stanford Prevention Research CenterStanford University School of MedicineStanfordCAUnited States

Summary What is already known about this topic?Myopia has been identified as a significant emerging challenge and policy priority among children and adolescents in China by the Ministry of Education and seven other *** research has been conducted to investigate the collective impact of outdoor time and other modifiable factors on the incidence of myopia.

关键词： Incidence collective policy

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COX-2 blocking therapy in cisplatin chemosensitization of ovarian cancer:An allicin-based nanomedicine approach

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Chinese Chemical Letters 2024年第8期35卷 449-454页

作者： Huijiao Fu Peiqin Liang Qianwen Chen Yan Wang Guang Li Xuzi Cai Shengtao Wang Kun Chen Shengying Shi Zhiqiang Yu Xuefeng Wang Department of Obstetrics and Gynecology The Third Affiliated Hospital of Southern Medical UniversityGuangzhou 510630China Department of Obstetrics and Gynecology Huizhou Central People’s HospitalHuizhou 516001China Affiliated Foshan Maternity&child Healthcare Hospital Southern Medical University(Foshan Maternity&Child Healthcare Hospital)Foshan 528000China Guangdong Key Laboratory of New Drug Screening School of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou 510515China Department of Nursing Nanfang HospitalSouthern Medical UniversityGuangzhou 510515China Department of Laboratory Medicine Dongguan Institute of Clinical Cancer ResearchThe Tenth Affiliated Hospital of Southern Medical University(Dongguan People’s Hospital)Dongguan 523018China

Recently,the utilization of nonsteroidal anti-inflammatory drugs(NSAIDs)to sensitize cisplatin(CDDP)has gained substantial traction in the treatment of ovarian cancer(OC).However,even widely employed NSAIDs such as celecoxib and naproxen carry an elevated risk of cardiovascular events,notably ***,the diminished sensitivity to CDDP therapy in OC is multifactorial,rendering the ap-plication of NSAIDs only partially effective due to their cyclooxygenase-2(COX-2)inhibiting ***,in this study,reactive oxygen species(ROS)-responsive composite nano-hydrangeas loaded with the Chinese medicine small molecule allicin and platinum(IV)prodrug(DTP@AP NPs)were prepared to achieve comprehensive *** one front,allicin achieved COX-2 blocking therapy,en-compassing the inhibition of proliferation,angiogenesis and endothelial mesenchymal transition(EMT),thereby mitigating the adverse impacts of CDDP ***,synergistic chemosensi-tization was achieved from multifaceted mechanisms by decreasing CDDP inactivation,damaging mito-chondria and inhibiting DNA *** essence,these findings provided an optimized approach for syner-gizing CDDP with COX-2 inhibitors,offering a promising avenue for enhancing OC treatment outcomes.

关键词： COX-2 blocking therapy CDDP Chemosensitization Allicin Ovarian cancer

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Proficiency score as a predictor of early trifecta achievement during the learning curve of robot-assisted radical prostatectomy for high-risk prostate cancer:Results of a multicentric series

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Current Urology 2024年第2期18卷 110-114页

作者： Umberto Anceschi Rocco Simone Flammia Antonio Tufano Michele Morelli Antonio Galfano Lorenzo Giuseppe Luciani Leonardo Misuraca Paolo Dell’Oglio Gabriele Tuderti Aldo Brassetti Maria Consiglia Ferriero Alfredo Maria Bove Riccardo Mastroianni Francesco Prata Isabella Sperduti Giovanni Petralia SilviaSecco Ettore Di Trapani DanieleMattevi Tommaso Cai Aldo Massimo Bocciardi Giuseppe Simone Department of Urology IRCCS“Regina Elena”National Cancer InstituteRomeItaly Urologic Clinic Department of Maternal-Child and Urologic SciencesSapienza University of RomeItaly Ospedale Niguarda Ca’Granda Department of UrologyMilanItaly Department of Urology APSS Santa Chiara Regional HospitalTrentoItaly Department of Biostatistical Unit IRCCS Regina Elena National Cancer InstituteRomeItaly

Background:Recently,an innovative tool called“proficiency score”was introduced to assess the learning curve for robot-assisted radical prostatectomy(RARP).However,the initial study only focused on patients with low-risk prostate cancer forwhompelvic lymph node dissection(PLND)was not *** address this issue,we aimed to validate proficiency scores of a contemporarymulticenter cohort of patients with high-risk prostate cancer treated with RARP plus extended PLND by trainee *** andmethods:Between 2010 and 2020,4 Italian institutional prostate-cancer datasets weremerged and queried for“RARP”and“high-risk prostate cancer.”High-risk prostate cancer was defined according to the most recent European Association of Urology guidelines as follows:prostate-specific antigen>20 ng/mL,International Society ofUrological Pathology≥4,and/or clinical stage(cT)≥2c on preoperative *** selected cohort(n=144)included clinical cases performed by trainee surgeons(n=4)after completing their RARP learning curve(50 procedures for low-risk prostate cancer).The outcome of interest,the proficiency score,was defined as the coexistence of all the following criteria:a comparable operation time to the interquartile range of the mentor surgeon at each center,absence of any significant perioperative complications Clavien-Dindo Grade 3–5,no perioperative blood transfusions,and negative surgical margins.A logistic binary regression model was built to identify the predictors of 1-year trifecta achievement in the trainee *** all statistical analyses,a 2-sided p<0.05 was considered ***:A proficiency score was achieved in 42.3%*** univariable level,proficiency score was associated with 1-year trifecta achievement(odds ratio,8.77;95%confidence interval,2.42–31.7;p=0.001).After multivariable adjustments for age,nerve-sparing,and surgical technique,the proficiency score independently predicted 1-year trifecta achievement(odds ratio,9.58;95%confidence i

关键词： Trifecta Learning curve Robot-assisted radical prostatectomy High-risk prostate cancer

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Sleep Posture Classification Using RGB and Thermal Cameras Based on Deep Learning Model

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Computer Modeling in Engineering & Sciences 2024年第8期140卷 1729-1755页

作者： Awais Khan Chomyong Kim Jung-Yeon Kim Ahsan Aziz Yunyoung Nam Department of ICT Convergence Soonchunhyang UniversityAsan31538Korea ICT Convergence Research Center Soonchunhyang UniversityAsan31538Korea Emotional and Intelligent child Care Convergence Research Center Soonchunhyang UniversityAsan31538Korea

Sleep posture surveillance is crucial for patient comfort,yet current systems face difficulties in providing compre-hensive studies due to the obstruction caused by *** posture assessment remains challenging because of the complex nature of the human body and variations in sleep ***,this study introduces an innovative method utilizing RGB and thermal cameras for comprehensive posture classification,thereby enhancing the analysis of body position and *** method begins by capturing a dataset of sleep postures in the form of videos using RGB and thermal cameras,which depict six commonly adopted postures:supine,left log,right log,prone head,prone left,and prone *** study involves 10 participants under two conditions:with and without ***,the database is normalized into a video *** subsequent step entails training a fine-tuned,pretrained Visual Geometry Group(VGG16)and ResNet50 *** the third phase,the extracted features are utilized for *** fourth step of the proposed approach employs a serial fusion technique based on the normal distribution to merge the vectors derived from both the RGB and thermal ***,the fused vectors are passed to machine learning classifiers for final *** dataset,which includes human sleep postures used in this study’s experiments,achieved a 96.7%accuracy rate using the Quadratic Support Vector Machine(QSVM)without the ***,the Linear SVM,when utilized with a blanket,attained an accuracy of 96%.When normal distribution serial fusion was applied to the blanket features,it resulted in a remarkable average accuracy of 99%.

关键词： Human sleep posture VGG16 deep learning ResNet50 fusion machine learning

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Mitochondria-targeted carrier-free nanoparticles based on dihydroartemisinin against hepatocellular carcinoma

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Chinese Chemical Letters 2024年第10期35卷 355-359页

作者： Zhiyu Yu Xiang Luo Cheng Zhang Xin Lu Xiaohui Li Pan Liao Zhongqiu Liu Rong Zhang Shengtao Wang Zhiqiang Yu Guochao Liao Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China International Institute for Translational Chinese Medicine Guangzhou University of Chinese Medicine Guangzhou Yuemei Pharmaceutical Technology Co. Ltd. Affiliated Foshan Maternity & child Healthcare Hospital Southern Medical University School of Pharmaceutical Sciences Southern Medical University Department of Laboratory Medicine Dongguan Institute of Clinical Cancer Research Dongguan Key Laboratory of Precision Diagnosis and Treatment for Tumors The Tenth Affiliated Hospital of Southern Medical University (Dongguan People's Hospital)

Hepatocellular carcinoma is a common and fatal malignancy for which there is no effective systemic therapeutic strategy. Dihydroartemisinin(DHA), a derivative of artemisinin, has been shown to exert anti-tumor effects through the production of reactive oxygen species(ROS) and resultant mitochondrial damage. However, clinical translation is limited by several drawbacks, such as insolubility, instability and low bioavailability. Here, based on a nanomedicine-based delivery strategy, we fabricated mitochondria-targeted carrier-free nanoparticles coupling DHA and triphenylphosphonium(TPP), aiming to improve bioavailability and mitochondrial targeting. DHA-TPP nanoparticles can be passively delivered to the tumor site by enhanced penetration and retention and then internalized. Flow cytometry and Western blot analysis showed that DHA-TPP nanoparticles increased intracellular ROS, which increased mitochondrial stress and in turn upregulated the downstream Bcl-2 pathway, leading to apoptosis. In vivo experiments showed that DHA-TPP nanoparticles exhibited anti-tumor effects in a mouse model of hepatocellular carcinoma. These findings suggest carrier-free DHA-TPP nanoparticles as a potential therapeutic strategy for hepatocellular carcinoma.

关键词： Apoptosis Carrier-free nanoparticles Dihydroartemisinin Hepatocellular carcinoma Mitochondria targeting

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Interaction between ozone and paternal smoking on fetal congenital heart defects among pregnant women at high risk a multicenter maternal-fetal medicine study

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World Journal of Pediatrics 2024年第6期20卷 621-632页

作者： Huan Wang Yan-Ping Ruan Sheng Ma Ya-Qi Wang Xiao-Yu Wan Yi-Hua He Jing Li Zhi-Yong Zou institute of child and Adolescent Health School of Public HealthNational Health Commission Key Laboratory of Reproductive HealthPeking UniversityNo.38 Xueyuan RdHaidian DistrictBeijing 100191China Echocardiography Medical Center Beijing Anzhen Hospital.Capital Medical UniversityMaternal-Fetal Medicine center in Fetal Heart DiseaseBeijing Anzhen HospitalNo.2 Anzhen RdChaoyang DistrictBeijing 100029China

Background Evidence remains limited on the association between maternal ozone(O,)exposure and congenital heart defects(CHDs)in offspring,and few studies have investigated the interaction and modification of paternal smoking on this *** Using a sample including pregnant women at high risk of fetal CHD(with metabolic disease,first-trimester viral infection,family history of CHD,etc.)from a maternal-fetal medicine study covering 1313 referral hospitals in China during 2013-2021,we examined the associations between maternal O_(3)exposure during 3-8 weeks of gestational age and fetal CHD in offspring and investigated the interaction and modification of paternal smoking on this *** was diagnosed by fetal echocardiograms,maximum daily 8-hour average O,exposure data at a 10 km×10 km spatial resolution came from the Tracking Air Pollution in China dataset,and paternal smoking was collected using *** regression models were used to estimate adjusted odds ratios(ORs)and 95%confidence intervals(CIs).Results Among 27,834 pregnant women at high risk of fetal CHD,17.4%of fetuses were diagnosed with *** 10μg/m^(3)increase in maternal O_(3)exposure was associated with a 17%increased risk of CHD in offspring(OR=1.17,95%CI=1.14-1.20).Compared with paternal nonsmoking and maternal low O_(3)exposure,the ORs(95%CI)of CHD for smoking and low O_(3)exposure,nonsmoking and high O_(3)exposure,and smoking and high O_(3)exposure were 1.25(1.08-1.45),1.81(1.56-2.08),and 2.23(1.84-2.71),*** smoking cessation seemingly mitigated the increased risk of *** Maternal O_(3)exposure and paternal smoking were interactively associated with an increased risk of fetal CHD in offspring,which calls for effective measures to decrease maternal exposure to O_(3)pollution and secondhand smoke for CHDprevention.

关键词： Congenital heart defects Fetal heart development Ozone exposure Tobacco smoking

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The Uptake and Distribution Evidence of Nano-and Microplastics in vivo after a Single High Dose of Oral Exposure

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Biomedical and Environmental Sciences 2024年第1期37卷 31-41页

作者： HONG Tao SUN Wei DENG Yuan LYU Jian Da JIN Cui Hong BAI Ying Long NA Jun ZHANG Rui GAO Yuan PAN Guo Wei YANG Zuo Sen YAN Ling Jun Research Center for Universal Health School of Public HealthChina Medical UniversityShenyang 110122LiaoningChina Department of Pain Management Shengjing Hospital of China Medical UniversityShenyang 110004LiaoningChina Department of Toxicology School of Public HealthChina Medical UniversityShenyang 110122LiaoningChina Department of Maternal and child Health School of Public HealthChina Medical UniversityShenyang 110122LiaoningChina institute of Preventive Medicine China Medical UniversityShenyang 110122LiaoningChina institute of Chronic Diseases Liaoning Provincial Center for Disease Control and PreventionShenyang 110000LiaoningChina

Objective Tissue uptake and distribution of nano-/microplastics was studied at a single high dose by gavage in *** Fluorescent microspheres(100 nm,3μm,and 10μm)were given once at a dose of 200 mg/(kg∙body weight).The fluorescence intensity(FI)in observed organs was measured using the IVIS Spectrum at 0.5,1,2,and 4 h after *** was performed to corroborate these *** In the 100 nm group,the FI of the stomach and small intestine were highest at 0.5 h,and the FI of the large intestine,excrement,lung,kidney,liver,and skeletal muscles were highest at 4 h compared with the control group(P<0.05).In the 3μm group,the FI only increased in the lung at 2 h(P<0.05).In the 10μm group,the FI increased in the large intestine and excrement at 2 h,and in the kidney at 4 h(P<0.05).The presence of nano-/microplastics in tissues was further verified by *** peak time of nanoplastic absorption in blood was *** Nanoplastics translocated rapidly to observed organs/tissues through blood circulation;however,only small amounts of MPs could penetrate the organs.

关键词： Microplastics Nanoplastics IVIS Spectrum small-animal imaging system Tissue distribution Blood

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The Traf2 and NcK interacting kinase inhibitor NCB-0846 suppresses seizure activity involving the decrease of GRIA1

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Genes & Diseases 2024年第3期11卷 452-467页

作者： Min Wang Yixue Gu Qiubo Li Bangzhe Feng Xinke Lv Hao Zhang Qingxia Kong Zhifang Dong Xin Tian Yanke Zhang Department of Neurology Affiliated Hospital of Jining Medical UniversityJiningShandong 272000China Department of Neurology The First Affiliated Hospital of Chongqing Medical UniversityChongqing Key Laboratory of NeurologyChongqing 400016China Department of Pediatrics Affiliated Hospital of Jining Medical UniversityJiningShandong 272000China Department of Neurosurgery Affliated Hospital of Jining Medical UniversityJiningShandong 272000China Pediatric Research institute Ministry of Education Key Laboratory of Child Development and DisordersNational Clinical Research Center for Child Health and DisordersChongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory DisordersChildren's Hospital of Chongqing Medical UniversityChongqing 400014China Center for Excellence in Brain Science and Intelligence Technology Chinese Academy of SciencesShanghai 200031China

Epilepsy,one of the most common neurological disorders,is characterized by spon-taneous recurrent *** lobe epilepsy(TLE)is one of the most common medically intractable seizure ***2-and NcK-interacting kinase(TNIK)has recently attracted attention as a critical modulation target of many neurological and psychiatric disorders,but its role in epilepsy remains *** this study,we hypothesized the involvement of TNIK in epilepsy and investigated TNIK expression in patients with intractable TLE and in a pilocarpineinduced rat model of epilepsy by western blotting,immunofluorescence,and immunohistochemistry.A pentylenetetrazole(PTZ)-induced epilepsy rat model was used to determine the effect of the TNIK inhibitor NCB-0846 on behavioral manifestations of ***(Co-IP)/mass spectrometry(MS)was used to identify the potential *** Co-IP,we detected and confirmed the main potential TNIK *** fractionation was used to establish the effect of NCB-0846 on the expression of the main interactors in postsynaptic density(PSD)*** found that TNIK was primarily located in neurons and decreased significantly in epilepsy model rats and TLE patients compared with ***-0846 delayed kindling progression and decreased seizure ***-IP/MS identified 63 candidate TNIK interactors in rat hippocampi,notably ***-IP showed that TNIK might correlate with endogenous GRIA1,SYN2,PSD-95,CaMKIV,GABRG1,and *** addition,the significant decrease in GRIA1 in hippocampal total lysate and PSDs after NCB-0846 treatment might help modify the progression of PTZ *** results suggest that TNIK contributes to epileptic pathology and is a potential antiepileptic drug target.

关键词： Epilepsy NCB-0846 Rat TLE TNIK Traf2-and NcK-interacting kinase

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