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Rare loss-of-function variants in FLNB cause non-syndromic orofacial clefts

Journal of Genetics and Genomics 2024年第2期51卷 222-229页

作者： Wenbin Huang Shiying Zhang Jiuxiang Lin yi Ding Nan jiang Jieni Zhang Huaxiang Zhao Feng Chen Department of Orthodontics Peking University School and Hospital of StomatologyBeijing100081China Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research College of StomatologyXi’an Jiaotong UniversityXi’anShaanxi710004China Guangdong Provincial High-level Clinical Key Specialty Guangdong Province Engineering Research Center of Oral Disease Diagnosis and TreatmentDepartment of OrthodonticsStomatological CenterPeking University Shenzhen HospitalShenzhen Peking University-The Hong Kong University of Science and Technology Medical CenterShenzhenGuangdong 518036China Department of Physiology and Pathophysiology School of Basic Medical SciencesXi'an Jiaotong UniversityXi'anShaanxi710049China National Center for Stomatology National Clinical Research Center for Oral DiseasesNational Engineering Laboratory for Digital and Material Technology of StomatologyBeijing Key Laboratory for Digital StomatologyResearch Center of Engineering and Technology for Computerized Dentistry Ministry of HealthNMPA Key Laboratory for Dental MaterialsBeijing100101China Central Laboratory Peking University School and Hospital of StomatologyBeijing100081China

Orofacial clefts (OFCs) are the most common congenital craniofacial disorders, of which the etiology is closely related to rare coding variants. Filamin B (FLNB) is an actin-binding protein implicated in bone formation. FLNB mutations have been identified in several types of syndromic OFCs and previous studies suggest a role of FLNB in the onset of non-syndromic OFCs (NSOFCs). Here, we report two rare heterozygous variants (p.P441T and p.G565R) in FLNB in two unrelated hereditary families with NSOFCs. Bioinformatics analysis suggests that both variants may disrupt the function of FLNB. In mammalian cells, p.P441T and p.G565R variants are less potent to induce cell stretches than wild type FLNB, suggesting that they are loss-of-function mutations. Immunohistochemistry analysis demonstrates that FLNB is abundantly expressed during palatal development. Importantly, Flnb^(−/−) embryos display cleft palates and previously defined skeletal defects. Taken together, our findings reveal that FLNB is required for development of palates in mice and FLNB is a bona fide causal gene for NSOFCs in humans.

关键词： Or ofacial clefts FLNB Loss-of-function mutati on Cleft palate Filamin B Actin flannent Knockout mouse

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Repurposing lansoprazole to alleviate metabolic syndrome via PHOSPHO1 inhibition

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Acta Pharmaceutica Sinica B 2024年第4期14卷 1711-1725页

作者： yingting Wu Jiaqi Xin Xinyu Li Ting Yang yi Liu Yongsheng Zhao Wen Xie Mengxi jiang Department of Pharmacology School of Basic Medical SciencesCapital Medical UniversityBeijing 100069China Department of Traditional Chinese Medicine Capital Medical UniversityBeijing 100069China Center for Pharmacogenetics and Department of Pharmaceutical Sciences University of PittsburghPittsburghPA 15261USA Advanced Innovation Center for Human Brain Protection Capital Medical UniversityBeijing 100069China

Drug repurposing offers an efficient approach to therapeutic *** this study,our bioinformatic analysis first predicted an association between obesity and lansoprazole(LPZ),a commonly prescribed drug for gastrointestinal *** went on to show that LPZ treatment increased energy expenditure and alleviated the high-fat diet-induced obesity,insulin resistance,and hepatic stea-tosis in *** with LPZ elicited thermogenic gene expression and mitochondrial respiration in primary adipocytes,and induced cold tolerance in cold-exposed mice,suggesting the activity of LPZ in promoting adipose thermogenesis and energy ***,LPZ is an efficient inhibitor of adipose phosphocholine phosphatase 1(PHOSPHOI)and produces metabolic benefits in a PHOS-PHO1-dependent *** results suggested that LPZ may stimulate adipose thermogenesis by inhi-biting the conversion of 2-arachidonoylglycerol-lysophosphatidic acid(2-AG-LPA)to 2-arachidonoylglycerol(2-AG)and reduce the activity of the thermogenic-suppressive cannabinoid recep-tor *** summary,we have uncovered a novel therapeutic indication and mechanism of LPZ in managing obesity and its related metabolic syndrome,and identified a potential metabolic basis by which LPZ improves energy metabolism.

关键词： Lansoprazole Proton pump inhibitors Adipose thermogenesis Energy expenditure Metabolic syndrome PHOSPHO1 inhibitor Cannabinoid receptor signaling Drug repurposing

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Mechanisms underlying the role of endoplasmic reticulum stress in the placental injury and fetal growth restriction in an ovine gestation model

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Journal of Animal Science and Biotechnology 2024年第1期15卷 201-217页

作者： Hao Zhang Xia Zha yi Zheng Xiaoyun Liu Mabrouk Elsabagh Hongrong Wang Honghua jiang Mengzhi Wang Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition College of Animal Science and TechnologyYangzhou UniversityYangzhou 225009P.R.China Joint International Research Laboratory of Agriculture and Agri‑Product Safety Ministry of Education of ChinaYangzhou UniversityYangzhou 225009P.R.China Department of Animal Production and Technology Faculty of Agricultural Sciences and TechnologiesNiğde Omer Halisdemir UniversityNigde 51240Turkey Department of Nutrition and Clinical Nutrition Faculty of Veterinary MedicineKafrelsheikh UniversityKafrelSheikhEgypt Department of Pediatrics Northern Jiangsu People’s HospitalClinical Medical CollegeYangzhou UniversityYangzhou 225001China State Key Laboratory of Sheep Genetic Improvement and Healthy Production Xinjiang Academy of Agricultural Reclamation ScienceShihezi 832000China

Background Exposure to bisphenol A(BPA),an environmental pollutant known for its endocrine-disrupting properties,during gestation has been reported to increase the risk of fetal growth restriction(FGR)in an ovine model of *** hypothesized that the FGR results from the BPA-induced insufficiency and barrier dysfunction of the placenta,oxidative stress,inflammatory responses,autophagy and endoplasmic reticulum stress(ERS).However,precise mechanisms underlying the BPA-induced placental dysfunction,and subsequently,FGR,as well as the potential involvement of placental ERS in these complications,remain to be *** In vivo experiment,16 twin-pregnant(from d 40 to 130 of gestation)Hu ewes were randomly distributed into two groups(8 ewes each).One group served as a control and received corn oil once a day,whereas the other group received BPA(5 mg/kg/d as a subcutaneous injection).In vitro study,ovine trophoblast cells(OTCs)were exposed to 4 treatments,6 replicates *** OTCs were treated with 400μmol/L BPA,400μmol/L BPA+0.5μg/m L tunicamycin(Tm;ERS activator),400μmol/L BPA+1μmol/L 4-phenyl butyric acid(4-PBA;ERS antagonist)and DMEM/F12 complete medium(control),for 24 *** In vivo experiments,pregnant Hu ewes receiving the BPA from 40 to 130 days of pregnancy experienced a decrease in placental efficiency,progesterone(P4)level and fetal weight,and an increase in placental estrogen(E2)level,together with barrier dysfunctions,OS,inflammatory responses,autophagy and ERS in type A *** vitro experiment,the OTCs exposed to BPA for 24 h showed an increase in the E2 level and related protein and gene expressions of autophagy,ERS,pro-apoptosis and inflammatory response,and a decrease in the P4 level and the related protein and gene expressions of antioxidant,anti-apoptosis and barrier ***,treating the OTCs with Tm aggravated BPA-induced dysfunction of barrier and endocrine(the increased E2 level and decreased P4 level),OS,inflamm

关键词： Autophagy Bisphenol A Endoplasmic reticulum stress Fetal growth restriction Inflammatory responses Sheep

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Human-like adrenal features in Chinese tree shrews revealed by multi-omics analysis of adrenal cell populations and steroid synthesis

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Zoological Research 2024年第3期45卷 617-632页

作者： Jing-Hang jiang yi-Fu Wang Jie Zheng yi-Ming Lei Zhong-Yuan Chen yi Guo Ya-Jie Guo Bing-Qian Guo Yu-Fang Lv Hong-Hong Wang Juan-Juan Xie yi-Xuan Liu Ting-Wei Jin Bi-Qi Li Xiao-Shu Zhu Yong-Hua jiang Zeng-Nan Mo Center for Genomic and Personalized Medicine Guangxi Collaborative Innovation Center for Genomic and Personalized MedicineGuangxi Key Laboratory for Genomic and Personalized MedicineGuangxi Medical UniversityNanningGuangxi 530021China Department of Urology First Affiliated Hospital of Guangxi Medical UniversityNanningGuangxi 530021China Reproductive Medicine Center Jingmen People’s HospitalJingChu University of Technology Affiliated Central HospitalJingmenHubei 448000China School of Computer Science and Engineering Yulin Normal UniversityYulinGuangxi 537000China Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-constructed by the Province and Ministry Guangxi Medical UniversityNanningGuangxi 530021China Department of Pathology Second Affiliated Hospital of Guangxi Medical UniversityNanningGuangxi 530007China Department of Obstetrics and Gynecology Second Affiliated Hospital of Guangxi Medical UniversityNanningGuangxi 530007China

The Chinese tree shrew(Tupaia belangeri chinensis)has emerged as a promising model for investigating adrenal steroid synthesis,but it is unclear whether the same cells produce steroid hormones and whether their production is regulated in the same way as in ***,we comprehensively mapped the cell types and pathways of steroid metabolism in the adrenal gland of Chinese tree shrews using single-cell RNA sequencing,spatial transcriptome analysis,mass spectrometry,and *** compared the transcriptomes of various adrenal cell types across tree shrews,humans,macaques,and *** showed that tree shrew adrenal glands expressed many of the same key enzymes for steroid synthesis as humans,including CYP11B2,CYP11B1,CYB5A,and *** analysis confirmed the production of aldosterone,cortisol,and dehydroepiandrosterone but not dehydroepiandrosterone sulfate in the tree shrew adrenal ***,genes in adrenal cell types in tree shrews were correlated with genetic risk factors for polycystic ovary syndrome,primary aldosteronism,hypertension,and related disorders in humans based on genome-wide association ***,this study suggests that the adrenal glands of Chinese tree shrews may consist of closely related cell populations with functional similarity to those of the human adrenal *** comprehensive results(publicly available at http://***:16245/scAGMap/)should facilitate the advancement of this animal model for the investigation of adrenal gland disorders.

关键词： Tree shrew Adrenal gland Dehydroepiandrosterone Genome-wide association studies Disease model

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High Speed Sintering:Assessing the Influence of Energy Input on Microstructure and Mechanical Properties of Polyether Block Amide(PEBA)Parts

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Chinese Journal of Polymer Science 2024年第5期42卷 675-682,I0004,I0010页

作者： jiang-Tao Sun Zhi-Yong Fan yi-Wei Mao Wei Li Wei Zhu Dao-Sheng Cai Qing-Song Wei State Key Laboratory of Materials Processing and Die&Mould Technology Huazhong University of Science and TechnologyWuhan430074China State Key Laboratory of Refractories and Metallurgy Wuhan University of Science and TechnologyWuhan430074China National Engineering Research Centre for High Efficiency Grinding Hunan UniversityChangsha410082China Wuhan EasyMFG Technology CO. LTDWuhan430074China

High speed sintering,a new powder-bed fusion additive manufacturing technology,utilizes infrared lights(IR)to intensely heat and melt polymer *** presence of defects such as porosity,which is associated with particle coalescence,is highly dependdent on the level of energy *** study investigate the influcence of energy input on porosity and its subsequent effects on the mechanical properties and microstructures of PEBA *** parts were manufactured with a variety of lamp powers,resulting in a range of energy input levels spanning from low to ***,they underwent testing using Archimedes’method,followed by tensile *** porosity,mechanical characteristics,and energy input exhibit a strong correlation;inadequate energy input was the primary cause of pore *** the reduced IR light power resulted in the following outcomes:porosity,ultimate tensile strength,and elongation of 1.37%,7.6 MPa,and 194.2%,*** the energy input was further increased,the porosity was reduced to as low as 0.05%and the ultimate tensile strength and elongation were increased to their peak values of 233.8%and 9.1 MPa,respectively.

关键词： High speed sintering Additive manufacturing Energy input Powder bed fusion PEBA

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{1012}twin–twin intersection-induced lattice rotation and dynamic recrystallization in Mg–6Al–3Sn–2Zn alloy

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Journal of Magnesium and Alloys 2024年第4期12卷 1529-1539页

作者： Bin-jiang Lv Sen Wang Fu-Hao Gao Ning Cui yi-Nan Li Tie-Wei Xu Feng Guo School of Mechanical and Automotive Engineering Qingdao University of Technology266520China Key Lab of industrial Fluid Energy Conservation and Pollution Control Qingdao University of Technology266520China

This study investigated the formation mechanism of new grains due to twin–twin intersections in a coarse-grained Mg–6Al–3Sn–2Zn alloy during different strain rates of an isothermal *** results of electron backscattered diffraction investigations showed that the activated twins were primarily{1012}tension twins,and 60°boundaries formed due to twin–twin intersections under different strain *** twin variants with 60°boundaries transformed into new grains through lattice rotations at a low strain rate(0.01 s^(−1)).At a high strain rate(10 s^(−1)),the regions surrounded by subgrain boundaries through high-density dislocation arrangement and the 60°boundaries transformed into new grains via dynamic recrystallization.

关键词： Mg alloy Twin-twin intersection Lattice rotation Dynamic recrystallization

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Circadian disturbance induces erectile dysfunction by impairing endothelial function

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Asian Journal of Andrology 2024年第2期26卷 205-211页

作者： Tao Li yi-Ting jiang Xin-Zhu Qi Peng Chen Jun-Hao Zhang Fu Luo Jun Qiao jiang Gu Guang-Shi Du Qiang Wang Department of Urology Affiliated Hospital of Guizhou Medical UniversityGuiyang 550004China Department of Urology Guizhou Provincial People's HospitalGuiyang 550002China Department of Otorhinolaryngology Affiliated Hospital of Guizhou Medical UniversityGuiyang 550004China Guizhou Institute for Food and Drug Control Guiyang 550004China Department of Reproductive Center Guizhou Provincial People's HospitalGuiyang 550002China Translational Medicine Research Center of Guizhou Medical University Guiyang 550025China

In order to explore the impact of circadian disturbance on erectile function,we randomly divided 24 adult male rats into groups of control(light on at 8:00 *** off at 8:00 p.m.),dark/dark(DD;constant dark),light/light(LL;constant light),and shift dark/light(DL;light off at 8:00 *** on at 8:0o p.m.).Four weeks later,erectile function was measured and corpora cavernosa were harvested for *** maximum intracavernous pressure(mlcP)and mCP/mean arterial pressure(MAP)ratio in the DD,LL,and DL groups were significantly lower than that in the control *** LL and DL groups showed significantly attenuated endothelial nitric oxide synthase(eNOS),while DD,LL,and DL showed reduced neuronal nitric oxide synthase(nNOS)at both mRNA and protein *** production of nitric oxide(NO)and cyclic guanosinemonophosphate(cGMP)was inhibited by altered light/dark cycles to varying *** disturbance impaired endothelial function and contributed to erectile *** the core circadian elements,mRNA expression of circadian locomotor output cycles kaput(Clock)and brain/muscle aryl-hydrocarbon receptor nuclear translocator-like protein 1(Bmal1)was elevated in the DL group,but their protein expression was not significantly ***,LL,and DL increased period 1(Per1)and Per3 levels,while LL and DL increased PER1 *** significant difference was found for Per2levels,and PER2 and PER3 concentrations were not significantly ***,LL and DL significantly increased cryptochrome-1(CRY1)and CRY2 at both mRNA and protein *** altered light/dark rat model showed that circadian disturbance contributed to erectile dysfunction probably by impairing endothelial ***,the core circadian elements were detected in the corpora cavernosa,but these were ***,which circadian element regulates erectile function and how it works need further analysis.

关键词： circadian disturbance endothelial function erectile function light/dark cycle NO/cGMP

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Geant4 simulation of fast-electron bremsstrahlung imaging at the HL-3 tokamak

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Nuclear Science and Techniques 2024年第9期35卷 213-229页

作者： Shi-Kui Cheng yi-Po Zhang Yue-jiang Shi Jie Zhang Shuai Guan Hong-Bing Xu Qiu-Lei Yang College of Science Chongqing University of TechnologyChongqing 400054China Chongqing Key Laboratory of New Energy Storage Materials and Devices Chongqing 400054China Southwestern Institute of Physics Chengdu 610041China Hebei Key Laboratory of Compact Fusion Langfang 065001China ENN Science and Technology Development Co. Ltd.Langfang 065001China

To further research on high-parameter plasma,we plan to develop a two-dimensional hard X-ray(HXR)imaging system at the HL-3 tokamak to measure HXRs with energies ranging from 20 to 300 *** application of an array-structured detector ensures that this system can measure HXR-radiation spectra from the entire plasma cross ***,it is suitable for the study of fast-electron physics,such as radio-frequency wave current drives,fast electrons driving instabilities,and plasma disruptions in fusion *** this study,we develop a simulation for calculating fast-electron bremsstrahlung in the HL-3 tokamak based on the Monte Carlo simulation code Geant4,in which the plasma geometry and forward scattering of fast-electron bremsstrahlung are *** preliminary calculation results indicate that the HXR energy deposi-tion on the detector is symmetrically distributed,even though the plasma distribution is asymmetric owing to the toroidal *** simulation results are helpful in constructing the relationship between the energy deposition on the detector and parameter distribution on the plasma cross section during HL-3 *** is beneficial for the reconstruction of the fast-electron-distribution function and for optimizing the design of the HXR-imaging system.

关键词： Geant4 simulation HL-3 tokamak Fast-electron bremsstrahlung Hard X-ray imaging

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Clinical characteristics of peripapillary hyperreflective ovoid mass-like structures in myopic children

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International Journal of Ophthalmology(English edition) 2024年第7期17卷 1292-1299页

作者： Lu Zhang Zuo-Hui-Zi yi Xuan jiang Gong-Peng Sun Fang Zhao Li Zhang yi Xiang Chang-Zheng Chen Department of Ophthalmology the Central Hospital of WuhanTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430014Hubei ProvinceChina Eye Center Renmin Hospital of Wuhan UniversityWuhan 430060Hubei ProvinceChina

AIM:To describe the characteristics of peripapillary hyperreflective ovoid mass-like structure(PHOMS)in myopic children and to investigate factors associated with ***:This retrospective observational study included 101 eyes of 101 children(age≤17y)with *** included patients underwent comprehensive clinical *** nerve canal parameters,including disc diameter,optic nerve head(ONH)tilt angle,and border tissue angle were measured using serial enhanced-depth imaging spectral-domain optical coherence tomography(EDI-OCT).Based on the optic disc drusen consortium’s definition of PHOMS,eyes were classified as PHOMS group and non-PHOMS *** was categorized according to ***:Sixty-seven(66.3%)eyes were found with *** PHOMS could only be detected by optical coherence tomography(OCT).Medium PHOMS could be seen with blurred optic disc borders corresponding to *** most frequent location of PHOMS was at the nasosuperior(91%,61 of 67 eyes)to ONH *** axial length and spherical equivalent were more myopic in the PHOMS group than in the non-PHOMS group(both P<0.001).ONH tilt angle was also significantly greater in PHOMS group than in non-PHOMS group[8.90(7.16-10.54)vs 3.93(3.09-5.25),P<0.001].Border tissue angle was significantly smaller in PHOMS group than in non-PHOMS group[29.70(20.90-43.81)vs 45.62(35.18-60.45),P<0.001].In the multivariable analysis,spherical equivalent(OR=3.246,95%CI=1.209-8.718,P=0.019)and ONH tilt angle(OR=3.275,95%CI=1.422-7.542,P=0.005)were significantly correlated with *** was no disc diameter associated with *** the linear regression analysis,border tissue angle was negatively associated with PHOMS height(β=-2.227,P<0.001).CONCLUSION:PHOMS is associated with optic disc tilt and optic disc nasal shift in *** diameter is not a risk factor for *** changes in ONH caused by axial elongation facilitated an understanding of the mechanism of PHOMS.

关键词： peripapillary hyperreflective ovoid masslike structure myopia optic disc edema enhanced-depth imaging spectral-domain optical coherence tomography

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RARRES2 regulates lipid metabolic reprogramming to mediate the development of brain metastasis in triple negative breast cancer

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Military Medical Research 2024年第1期11卷 34-49页

作者： yi-qun Li Fang-Zhou Sun Chun-Xiao Li Hong-Nan Mo Yan-Tong Zhou Dan Lv Jing-Tong Zhai Hai-Li Qian Fei Ma Department of Medical Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China State Key Laboratory of Molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China

Background Triple negative breast cancer(TNBC),the most aggressive subtype of breast cancer,is characterized by a high incidence of brain metastasis(BrM)and a poor *** the most lethal form of breast cancer,BrM remains a major clinical challenge due to its rising incidence and lack of effective treatment *** evidence suggested a potential role of lipid metabolic reprogramming in breast cancer brain metastasis(BCBrM),but the underlying mechanisms are far from being fully *** Through analysis of BCBrM transcriptome data from mice and patients,and immunohistochemical validation on patient tissues,we identified and verified the specific down-regulation of retinoic acid receptor responder 2(RARRES2),a multifunctional adipokine and chemokine,in BrM of *** investigated the effect of aberrant RARRES2 expression of BrM in both in vitro and in vivo *** signaling pathway components were evaluated using multi-omics *** were performed to elucidate the regulation of lipid metabolic reprogramming of *** We found that downregulation of RARRES2 is specifically associated with BCBrM,and that RARRES2 deficiency promoted BCBrM through lipid metabolic ***,reduced expression of RARRES2 in brain metastatic potential TNBC cells resulted in increased levels of glycerophospholipid and decreased levels of triacylglycerols by regulating phosphatase and tensin homologue(PTEN)-mammalian target of rapamycin(mTOR)-sterol regulatory element-binding protein 1(SREBP1)signaling pathway to facilitate the survival of breast cancer cells in the unique brain *** Our work uncovers an essential role of RARRES2 in linking lipid metabolic reprogramming and the development of ***2-dependent metabolic functions may serve as potential biomarkers or therapeutic targets for BCBrM.

关键词： RARRES2 Lipid metabolic reprogramming Brain metastasis(BrM) Breast cancer

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