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Assessment of pathogenicity and functional characterization of APPL1 gene mutations in diabetic patients

World Journal of Diabetes 2024年第2期15卷 275-286页

作者： Ping Shi Yang Tian Feng xu Lu-Na Liu Wan-Hong Wu ying-Zhou Shi An-Qi Dai Hang-Yu Fang Kun-Xia Li Chao xu Department of Endocrinology Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityJinan 250021Shandong ProvinceChina Department of Pediatric Yantai Yuhuangding Hospital Affiliated to Qingdao UniversityYantai 264099Shandong ProvinceChina

BACKGROUND Adaptor protein,phosphotyrosine interacting with PH domain and leucine zipper 1(APPL1)plays a crucial role in regulating insulin signaling and glucose *** in the APPL1 gene have been associated with the development of maturity-onset diabetes of the young type 14(MODY14).Currently,only two mutations[c.1655T>A(***552*)and c.281G>A p.(Asp94Asn)]have been identified in association with this *** the limited understanding of MODY14,it is imperative to identify additional cases and carry out comprehensive research on MODY14 and APPL1 *** To assess the pathogenicity of APPL1 gene mutations in diabetic patients and to characterize the functional role of the APPL1 *** Patients exhibiting clinical signs and a medical history suggestive of MODY were screened for the *** exome sequencing was performed on the patients as well as their family *** pathogenicity of the identified APPL1 variants was predicted on the basis of bioinformatics *** addition,the pathogenicity of the novel APPL1 variant was preliminarily evaluated through in vitro functional ***,the impact of these variants on APPL1 protein expression and the insulin pathway were assessed,and the potential mechanism underlying the interaction between the APPL1 protein and the insulin receptor was further *** A total of five novel mutations were identified,including four missense mutations(Asp632Tyr,Arg633His,Arg532Gln,and Ile642Met)and one intronic mutation(1153-16A>T).Pathogenicity prediction analysis revealed that the Arg532Gln was pathogenic across all *** Asp632Tyr and Arg633His variants also had pathogenicity based on *** addition,multiple alignment of amino acid sequences showed that the Arg532Gln,Asp632Tyr,and Arg633His variants were conserved across different ***,in in vitro functional experiments,both the c.1894G>T(at Asp632Tyr)and c.1595G>A(at Arg532Gln)mutations

关键词： Adaptor protein,phosphotyrosine interacting with PH domain and leucine zipper 1 Maturity-onset diabetes of the young Bioinformatics analysis Gene mutation Domain

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Unveiling quality of clinical trial in China:from concern to confirmation

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Cancer Communications 2024年第5期44卷 576-579页

作者： Huiyao Huang Yiru Hou Hong Fang Ling xu Yue Yu Huifang Zhang Jing Zhang Yu Tang Gongtao Lan Wenbao Zhang ning Li Clinical Trials Center National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingP.R.China School of Basic Medicine and Clinical Pharmacy China Pharmaceutical UniversityNanjingJiangsuP.R.China Department of Quality Medicine Boehringer Ingelheim(China)Investment Co LtdShanghaiP.R.China Department of Clinical Development Quality Pfizer Research and Development(China)BeijingP.R.China Department of Drug Registration National Medical Products AdministrationBeijingP.R.China Bureau of Medical Administration National Health CommissionBeijingP.R.China

The cornerstone of scientifically valid and ethically sound clinical trials is in compliance with established global quality *** China has made significant progress over the past 20 years in terms of the clinical trial quantity[1],quality and participation in multiregional trials[2],there still remain concerns regarding the trial quality,which could be associated with the self-inspection initiative in 2015[3].

关键词： clinical corners confirmation

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A Coordinated Two-stage Decentralized Flexibility Trading in Distribution Grids with MGs

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Protection and Control of Modern Power Systems 2024年第5期9卷 54-69页

作者： Tao xu Rujing Wang He Meng Mengchao Li Hongru Wang Yu Ji ying Zhang Qingrong Zheng Ping Song Jiani Xiang Key Laboratory of Smart Grid of Ministry of Education Tianjin UniversityTianjin 300072China State Grid Shanghai Energy Interconnection Research Institute Co. Ltd.Shanghai 200031China Key Laboratory of Smart Grid Demand Response Shanghai 200030China State Grid Shanghai Municipal Electric Power Company Shanghai 200122China

Renewable energy dominated future power grids require enhanced system flexibility,in particular,activating the participation from various distributed en-ergy resources(DERs).A coordinated two-stage flexibility trading framework for distribution system with mi-crogrids(MGs)is proposed in this *** day-ahead stage,a peer to peer(P2P)trading mechanism and the associate leasing strategy of shared energy storage system are performed to solve the power variations caused by the wide spread integration of renewable resources,where asymmetric Nash bargaining is used to realize the fair revenue allocation according to the contribution of each MG in P2P *** intra-day stage,given the power imbalances from unexpected uncertainties,MGs exploit the adjustability of the DERs in responding to rapid flexibility requirements issued by distribution system *** particular,the average consensus based de-centralized Newton method with super linear convergence is utilized to meet the requirements of flexibility while maintaining the information *** feasibility,effectiveness and equity of the proposed trading strategies are verified through various simulation *** Terms—Microgrids,decentralized Newton,flexi-bility trading,asymmetric Nash bargaining,peer-to-peer.

关键词： Microgrids decentralized Newton flexibility trading asymmetric Nash bargaining peer-to-peer

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TAX1BP1 and FIP200 orchestrate non-canonical autophagy of p62 aggregates for mouse neural stem cell maintenance

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Zoological Research 2024年第4期45卷 937-950页

作者： Yi-Fu Zhu Rong-Hua Yu Shuai Zhou Pei-Pei Tang Rui Zhang Yu-Xin Wu Ran xu Jia-Ming Wei ying-ying Wang Jia-Li Zhang Meng-Ke Li Xiao-Jing Shi Yu-Wei Zhang Guang-Zhi Liu Rick FThorne xu Dong Zhang Mian Wu Song Chen School of Life Sciences Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhui 230001China Translational Research Institute of Henan Provincial People’s Hospital and People'’s Hospital of Zhengzhou University Tianjian Laboratory of Advanced Biomedical SciencesAcademy of Medical SciencesZhengzhou UniversityZhengzhouHenan 450053China Institute of Medicinal Biotechnology Jiangsu College of NursingHuai’anJiangsu 223300China Laboratory Animal Center Academy of Medical ScienceZhengzhou UniversityZhengzhouHenan 450052China Henan Key Laboratory of Stem cell Differentiation and Modification Henan Provincial People’s HospitalHenan UniversityZhengzhouHenan 450053China School of Biomedical Sciences and Pharmacy The University of NewcastleNSW 2308Australia

Autophagy plays a pivotal role in diverse biological processes,including the maintenance and differentiation of neural stem cells(NSCs).Interestingly,while complete deletion of Fip200 severely impairs NSC maintenance and differentiation,inhibiting canonical autophagy via deletion of core genes,such as Atg5,Atg16l1,and Atg7,or blockade of canonical interactions between FIP200 and ATG13(designated as FIP200-4A mutant or FIP200 KI)does not produce comparable detrimental *** highlights the likely critical involvement of the non-canonical functions of FIP200,the mechanisms of which have remained ***,utilizing genetic mouse models,we demonstrated that FIP200 mediates non-canonical autophagic degradation of p62/sequestome1,primarily via TAX1BP1 in *** deletion of Tax1bp1 in fip200hGFAP conditional knock-in(cKI)mice led to NSC deficiency,resembling the fip200hGFAP conditional knockout(cKO)mouse ***,reintroducing wild-type TAX1BP1 not only restored the maintenance of NSCs derived from tax1bp1-knockout fip200hGFAP cKI mice but also led to a marked reduction in p62 aggregate ***,a TAX1BP1 mutant incapable of binding to FIP200 or NBR1/p62 failed to achieve this ***,conditional deletion of Tax1bp1 in fip200hGFAP cKO mice exacerbated NSC deficiency and p62 aggregate accumulation compared to fip200hGFAP cKO ***,these findings illustrate the essential role of the FIP200-TAX1BP1 axis in mediating the non-canonical autophagic degradation of p62 aggregates towards NSC maintenance and function,presenting novel therapeutic targets for neurodegenerative diseases.

关键词： Non-canonical autophagy TAX1BP1 FIP200 p62 Aggregates Neural stem cell

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Decellularised extracellular matrix-based injectable hydrogels for tissue engineering applications

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Biomaterials Translational 2024年第2期5卷 114-128页

作者： Wan-ying Guo Wei-Huang Wang Pei-Yao xu Ranjith Kumar Kankala Ai-Zheng Chen Institute of Biomaterials and Tissue Engineering Huaqiao UniversityXiamenFujian ProvinceChina Fujian Provincial Key Laboratory of Biochemical Technology(Huaqiao University) XiamenFujian ProvinceChina

Decellularised extracellular matrix(dECM)is a biomaterial derived from natural tissues that has attracted considerable attention from tissue engineering researchers due to its exceptional biocompatibility and malleability *** advantageous properties often facilitate natural cell infiltration and tissue reconstruction for regenerative *** to their excellent fluidity,the injectable hydrogels can be administered in a liquid state and subsequently formed into a gel state in vivo,stabilising the target area and serving in a variety of ways,such as support,repair,and drug release ***,dECM-based injectable hydrogels have broad prospects for application in complex organ structures and various tissue injury *** review focuses on exploring research advances in dECM-based injectable hydrogels,primarily focusing on the applications and prospects of dECM hydrogels in tissue ***,the recent developments of the dECM-based injectable hydrogels are explained,summarising the different preparation methods with the evaluation of injectable hydrogel ***,some specific examples of the applicability of dECM-based injectable hydrogels are ***,we summarise the article with interesting prospects and challenges of dECM-based injectable hydrogels,providing insights into the development of these composites in tissue engineering and regenerative medicine.

关键词： decellularisation methods decellularised extracellular matrix injectable hydrogels tissue engineering

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120日龄金华猪骨骼肌酵母双杂交cDNA文库的构建

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浙江农业学报 2011年第3期23卷 511-513页

作者：陈哲沈一飞王颖徐宁迎浙江大学动物科学学院浙江杭州310029

选用Clontech SMART技术,在酵母菌株中构建猪骨骼肌全长cDNA文库,文库容量约为1.6×10cfu,插入的双链cDNA片段的长度在500-2 250 bp,文库重组比率为93.75%。该文库可以用于进一步的酵母双杂交筛选。

关键词：金华猪骨骼肌酵母双杂交 cDNA文库

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Mass spectrometry analysis of intact protein N-glycosylation signatures of cells and sera in pancreatic adenocarcinomas

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2024年第1期25卷 51-64页

作者： Mingming xu Zhaoliang LIU Wenhua HU ying HAN Zhen WU Sufeng CHEN Peng XIA Jing DU xumin ZHANG Piliang HAO Jun XIA Shuang YANG Center for Clinical Mass Spectrometry College of Pharmaceutical SciencesSoochow UniversitySuzhou215123China School of Life Science and Technology ShanghaiTech UniversityShanghai201210China State Key Laboratory of Genetic Engineering Department of BiochemistrySchool of Life SciencesFudan UniversityShanghai200438China Department of Clinical Laboratory Center Zhejiang Provincial People’s HospitalPeople’s Hospital of Hangzhou Medical CollegeHangzhou310014China

Pancreatic cancer is among the most malignant cancers,and thus early intervention is the key to better survival ***,no methods have been derived that can reliably identify early precursors of development into ***,it is urgent to discover early molecular changes during pancreatic *** aberrant glycosylation is closely associated with cancer progression,numerous efforts have been made to mine glycosylation changes as biomarkers for diagnosis;however,detailed glycoproteomic information,especially site-specific N-glycosylation changes in pancreatic cancer with and without drug treatment,needs to be further ***,we used comprehensive solid-phase chemoenzymatic glycoproteomics to analyze glycans,glycosites,and intact glycopeptides in pancreatic cancer cells and patient *** profiling of N-glycans in cancer cells revealed an increase in the secreted glycoproteins from the primary tumor of MIA PaCa-2 cells,whereas human sera,which contain many secreted glycoproteins,had significant changes of glycans at their specific *** results indicated the potential role for tumor-specific glycosylation as disease *** also found that AMG-510,a small molecule inhibitor against Kirsten rat sarcoma viral oncogene homolog(KRAS)G12C mutation,profoundly reduced the glycosylation level in MIA PaCa-2 cells,suggesting that KRAS plays a role in the cellular glycosylation process,and thus glycosylation inhibition contributes to the anti-tumor effect of AMG-510.

关键词： Pancreatic cancer Glycosylation Biomarker Glycoproteomics Mass spectrometry

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猪不同生长阶段甲状腺结构的形态计量学研究

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畜牧兽医学报 2012年第4期43卷 521-526页

作者：王燕丽李艳玲郝柱王颖徐宁迎浙江大学动物科学学院杭州310058 金华职业技术学院金华321007

为观察猪不同生长发育阶段甲状腺的形态学变化,本研究选用大约克夏猪,分别于初生、体质量为20、40、80和100kg时屠宰,测定甲状腺质量、长度、宽度、增殖细胞数量以及血清中甲状腺素的表达,并对猪的甲状腺石蜡切片进行组织学观察,应用Nik... 详细信息

为观察猪不同生长发育阶段甲状腺的形态学变化,本研究选用大约克夏猪,分别于初生、体质量为20、40、80和100kg时屠宰,测定甲状腺质量、长度、宽度、增殖细胞数量以及血清中甲状腺素的表达,并对猪的甲状腺石蜡切片进行组织学观察,应用Nikon NIS-Elements Documentation图像分析系统对甲状腺滤泡腔以及滤泡上皮细胞进行形态计量学指标的测量,并在不同生长阶段进行比较分析。结果表明,随着猪的生长发育,甲状腺增殖细胞的数量、甲状腺素的表达以及滤泡腔数密度、上皮细胞高度均逐渐降低;滤泡腔截面积及其等效直径、滤泡腔截面积密度逐步升高;而上皮细胞核截面积及其等效直径、上皮细胞核数密度变化规律不明显。相关分析表明,血清中FT3的表达与甲状腺宽度存在显著的负相关、与上皮细胞高度呈显著正相关;FT4、TT4的表达与体质量、甲状腺质量、甲状腺长度、甲状腺宽度、滤泡腔截面积、滤泡腔截面积等效直径存在显著负相关,与上皮细胞高度以及上皮细胞核数密度存在显著正相关。上述形态学测量结果为深入研究猪甲状腺在不同生长发育阶段所发生的形态学变化提供了准确的定量资料。

关键词：猪甲状腺组织形态学

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Chiral transfer amidst one-dimensional linear polymers and twodimensional network covalent organic frameworks:Striking a fine balance between helicity and crystallinity

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Nano Research 2024年第6期17卷 5726-5734页

作者： Xinlin Zha Mengjuan Zuo Guilin xu Zhong Yan Haining You Yi Xiong ying Liu yingying Li Liyan Yang Ke Liu Mufang Li Tao Zhao Dong Wang College of Chemistry and Chemical Engineering Donghua UniversityShanghai 201620China Key Laboratory of Textile Fiber and Products Ministry of EducationWuhan Textile UniversityWuhan 430200China

The current landscape of chiral covalent organic frameworks(COFs)predominantly centered on constructing asymmetric molecular-scale chirality,often introducing an inherent contradiction to the COF symmetry and limiting ***,we overcome these challenges by achieving chiral transfer between one-dimensional(1D)imine linear polymers(LPs)and two-dimensional(2D)networkβ-ketoenamine COFs composed of achiral *** successfully synthesize several 1D imine LPs with mesoscopic helical chirality,comprising achiral C2-symmetric terephthalaldehyde and diamine linkers in a chiral supramolecular transcription *** the irreversible tautomerism mechanism within the linker replacement approach,terephthalaldehyde(TPA)units in these helical 1D LPs are substituted with C3-symmetric 1,3,5-triformylphloroglucinol(TP),yielding the corresponding 2D networkβ-ketoenamine *** and helicity of the resultantβ-ketoenamine COFs intimately hinge on reaction conditions,including the aldehyde stoichiometry of Tp and TPA,as well as the quantity and concentration of the catalyst *** optimized conditions,the nucleation and growth were precisely governed,achieving a harmonious equilibrium of crystallinity and helicity within the generated 2D networkβ-ketoenamine COFs,even with covalent bond rupture,recombination,and topological transition(from[C2+C2]to[C3+C2]).Impressively,the ground state chirality inherent to helical 1D LPs seamlessly transfers to helical 2D networkβ-ketoenamine *** study not only offers new perspectives on the development of chiral functional COFs,but also provides fresh insights into the precise control of COFs'microscopic morphology.

关键词： chiral covalent organic frameworks chiral transfer dimensional transformation helicity

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Association between Exposure of Rare Earth Elements and Outcomes of In Vitro Fertilization-Embryo Transfer in Beijing

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Biomedical and Environmental Sciences 2024年第8期37卷 876-886页

作者： Yutong Wang Jing Li Shirong xu Shengli Lin Zhenchen Hou Linlin Wang Yali Huang Yue Sun Wei Guo Lailai Yan ying Wang Chan Tian State Key Laboratory of Female Fertility Promotion Center for Reproductive MedicineDepartment of Obstetrics and Gynecology Peking University Third HospitalBeijing 100191China Department of Medical Genetics Peking UniversityBeijing 100191China National Clinical Research Center for Obstetrics and Gynecology Peking University Third HospitalBeijing 100191China Key Laboratory of Assisted Reproduction(Peking University) Ministry of EducationBeijing 100191China Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology Beijing 100191China Central Laboratory of School of Public Health Peking UniversityBeijing 100191China School of Basic Medical Sciences Peking UniversityBeijing 100191China

Objective The study aimed to investigate the impact of rare earth elements(REEs)exposure on pregnancy outcomes of in vitro fertilization-embryo transfer(IVF-ET)by analyzing samples from *** A total of 141 couples were *** and follicular fluid from the wives and semen plasma from the husbands,were analyzed for REEs using inductively coupled plasma mass spectrometry(ICP-MS).Spearman's correlation coefficients and the Mann–Whitney U test were used to assess correlations and compare REE concentrations among three types of samples,*** models were utilized to estimate the individual REE effect on IVF-ET outcomes,while BKMR and WQS models explored the mixture of REE interaction effects on IVF-ET *** Higher La concentration in semen(median 0.089 ng/mL,P=0.03)was associated with a lower fertilization ***,this effect was not observed after artificial selection intervention through intracytoplasmic sperm injection(ICSI)(P=0.27).In semen,the REEs mixture did not exhibit any significant association with clinical *** Our study revealed a potential association between high La exposure in semen and a decline in fertilization rate,but not clinical pregnancy *** is the first to report REEs concentrations in follicular fluid with La,Ce,Pr,and Nd found at significantly lower concentrations than in serum,suggesting that these four REEs may not accumulate in the female reproductive ***,at the current exposure levels,mixed REEs exposure did not exhibit reproductive toxicity.

关键词： Rare earth elements In vitro fertilization Pregnancy outcomes Mixture exposure analysis

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