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Gene therapy for monogenic disorders: challenges, strategies, and perspectives

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Journal of Genetics and Genomics 2024年第2期51卷 133-143页

作者： Yi Zhang zhi-Ying wu Department of Medical Genetics and Center for Rare Diseases Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang 310009China Department of Neurology Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang 310009China Key Laboratory of Medical Neurobiology of Zhejiang Province HangzhouZhejiang 310009China

Monogenic disorders refer to a group of human diseases caused by mutations in single genes. While disease-modifying therapies have offered some relief from symptoms and delayed progression for some monogenic diseases, most of these diseases still lack effective treatments. In recent decades, gene therapy has emerged as a promising therapeutic strategy for genetic disorders. Researchers have developed various gene manipulation tools and gene delivery systems to treat monogenic diseases. Despite this progress, concerns about inefficient delivery, persistent expression, immunogenicity, toxicity, capacity limitation, genomic integration, and limited tissue specificity still need to be addressed. This review gives an overview of commonly used gene therapy and delivery tools, along with the challenges they face and potential strategies to counter them.

关键词： Gene therapy Monogenic diseases Geneediting Genedelivery Challenges

Ballistic performances of the hourglass lattice sandwich structures under high-velocity fragments

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Defence Technology（防务技术） 2024年第1期31卷 312-325页

作者： He-xiang wu Jia Qu Lin-zhi wu Key Laboratory of Advanced Ship Materials and Mechanics College of Aerospace and Civil EngineeringHarbin Engineering UniversityHarbin150001China School of Civil Engineering Northeast Forestry UniversityHarbin150040China

In this paper,the numerical simulation method is used to study the ballistic performances of hourglass lattice sandwich structures with the same mass under the vertical incidence of fragments.Attention is paid to elucidating the influences of rod cross-section dimensions,structure height,structure layer,and rod inclination angle on the deformation mode,ballistic performances,and ability to change the ballistic direction of fragments.The results show that the ballistic performances of hourglass lattice sandwich structures are mainly affected by their structural parameters.In this respect,structural parameters optimization of the hourglass lattice sandwich structures enable one to effectively improve their ballistic limit velocity and,consequently,ballistic performances.

关键词： Hourglass lattice sandwich structures Ballistic performances high-velocity Finite element analysis

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Effect of stress-relief annealing on thermal fatigue cracks for die-casting die steels

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Journal of Iron and Steel Research(International) 2024年第5期31卷 1164-1176页

作者： zhi-xiong Bai Xiao-chun wu School of Materials Science and Engineering Shanghai UniversityShanghai200444China

The effect of stress-relief annealing at different stages of thermal fatigue tests on crack growth was investigated using a self-built thermal cycle setup.The results showed that annealing could limit crack expansion effectively.It reduced dislocation density and released the accumulation of residual stress.In addition,the strain accumulation in carbides was reduced by this process.It was also found that double annealing was even more effective at inhibiting crack expansion compared to single stress-relief annealing.After 1000 cycles,the maximum crack length was reduced by 31.1%and 45.2%for the samples after using the optimal single and double annealing processes,respectively.For single stress-relief annealing,earlier annealing provides more benefit in delaying crack expansion.However,effective double stress-relief annealing requires a suitable time interval between the annealing steps.Besides,after 800 cycles,surface hardness decreased significantly accompanied by an increase in the size and number of carbides,and cracks expanded predominantly along grain boundaries.

关键词： Thermal fatigue Steel Carbide Stress-relief annealing Dislocation Residual stress

Comparison of biliary protein spectrum in gallstone patients with obesity and those with normal body weight

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Hepatobiliary & Pancreatic Diseases International 2024年第4期23卷 385-392页

作者： Min-zhi Chen Ping Xie Xiao-Chang wu Zhen-Hua Tan Hai Qian zhi-Hong Ma Xing Yao Department of Hepatopancreatobiliary Surgery Huzhou Central HospitalAffiliated Huzhou HospitalZhejiang University School of MedicineHuzhou 313000China Huzhou Key Laboratory of Molecular Medicine Huzhou Central HospitalAffiliated Huzhou HospitalZhejiang University School of MedicineHuzhou 313000China

Background:Obesity is a common public health issue and is currently deemed a disease.Research has shown that the risk of gallstones in individuals with obesity is elevated.This study aimed to explore the bile proteomics differences between cholelithiasis patients with obesity and normal body weight.Methods:Bile samples from 20 patients(10 with obesity and 10 with normal body weight)who underwent laparoscopic cholecystectomy at our center were subjected to tandem mass tag labeling(TMT)and liquid chromatography-tandem mass spectrometry(LC-MS/MS),followed by further bioinformatic analysis.Results:Among the differentially expressed proteins,23 were upregulated and 67 were downregulated.Bioinformatic analysis indicated that these differentially expressed proteins were mainly involved in cell development,inflammatory responses,glycerolipid metabolic processes,and protein activation cascades.In addition,the activity of the peroxisome proliferator-activated receptor(PPAR,a subfamily of nuclear receptors)signaling pathway was decreased in the Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis.Two downregulated proteins in the PPAR signaling pathway,APO A-I and APO A-II,were confirmed using enzyme-linked immunosorbent assay.Conclusions:The PPAR signaling pathway may play a crucial role in the development of cholelithiasis among patients with obesity.Furthermore,biliary proteomics profiling of gallstones patients with obesity is revealed,providing a reference for future research.

关键词： Proteome profiling Gallstones Obesity-associated gallstones Tandem mass tag labeling PPAR signaling

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A Hybrid Signal Processing Method Combining Mathematical Morphology and Walsh Theory for Power Quality Disturbance Detection and Classification

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CSEE Journal of Power and Energy Systems 2024年第2期10卷 584-592页

作者： zhi Ding Tianyao Ji Mengshi Li Q.H.wu School of Electric Power Engineering South China University of Technology(SCUT)Guangzhou 510641China

In this paper, a novel signal processing method combining mathematical morphology (MM) and Walsh theory is proposed, which uses Walsh functions to control the structuring element (SE) and MM operators. Based on the Walsh-MM method, a scheme for power quality disturbances detection and classification is developed, which involves three steps: denoising, feature extraction and morphological clustering. First, various evolution rules of Walsh function are used to generate groups of SEs for the multiscale Walsh-ordered morphological operation, so the original signal can be denoised. Next, the fundamental wave of the denoised signal is suppressed by Hadamard matrix;thus, disturbances can be extracted. Finally, the Walsh power spectrum of the waveform extracted in the previous step is calculated, and the parameters of which are taken by morphological clustering to classify the disturbances. Simulation results reveal the proposed scheme can effectively detect and classify disturbances, and the Walsh-MM method is less affected by noise and only involves simple calculation, which has a potential to be implemented in hardware and more suitable for real-time application.

关键词： Hadamard matrix mathematical morphology morphological clustering power quality disturbance Walsh theory

PACS gene family-related neurological diseases: limited genotypes and diverse phenotypes

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World Journal of Pediatrics 2024年第1期20卷 82-91页

作者： Han Zhang Kai Gao Shuang Wang Yue-Hua Zhang zhi-Xian Yang Ye wu Yu-wu Jiang Department of Pediatrics Peking University First Hospital.No.1 Xi'an Men StreetWest DistrictBeijing 100034China Bejing Key Laboratory of Molecular Diagnosis and Study on Pediatric Genetic Diseases BeijingChina Children Epilepsy Center Peking University First HospitalBeijingChina Key Laboratory for Neuroscience Ministry of Education/National Health and Family Planning CommissionPeking UniversityBeijingChina Center of Epilepsy Beijing Institute for Brain DisordersBeijingChina

Background The PACS gene family has been demonstrated to be related to intracellular vesicular trafficking.The phenotypic manifestations caused by the pathogenic variants of PACS include epilepsy,intellectual disability/developmental delay,and malformations,such as facial abnormalities.Methods We identified seven new cases with pathogenic or likely pathogenic PACS variants using next-generation sequencing.Detailed information obtained from these patients was analyzed along with that obtained from previously reported patients.Results With the inclusion of the newly diagnosed cases in this study,103 cases with PACS gene family-related neurological diseases were reported,of which 43 were PACS2-related cases and the remaining were PACSI-related cases.Most patients had seizures,which have been reported to be effectively controlled by several types of anti-seizure medications(ASMs).The most efficacious and frequently prescribed ASMs included sodium valproate(43.3%,13/30),oxcarbazepine/carbamazepine(26.7%,8/30),and levetiracetam(20%,6/30).Almost all patients had intellectual disability/developmental delay.The most common pathogenic missense variants were PACSI p.Arg203Trp and PACS2 p.Glu209Lys.In addition,we report a patient carrying a likely pathogenic copy number variation(CNV)(de novo heterozygous deletion of chr14:105821380-106107443,286 kilobase,destroyed part of the furin-binding region domain and the protein structure after it)with more severe and refractory late-onset epilepsy.Conclusions The clinical phenotypes of the different PACS heterozygous missense variants were similar.The pathogenic variant sites of PACSI and PACS2 were quite limited but located in different regions.A CNV destroying part of the PACS2 gene might also be pathogenic.These findings may provide an important clue for further functional studies on the pathogenic mechanism of neurological disorders related to the PACS gene family.

关键词： Developmental delay Epilepsy Intellectual disability PACSI PACS2

Synergistic Interdecadal Evolution of Precipitation over Eastern China and the Pacific Decadal Oscillation during 1951-2015

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Advances in Atmospheric Sciences 2024年第1期41卷 53-72页

作者： Minmin wu Rong-Hua ZHANG Junya HU Hai zhi Key Laboratory of Ocean Circulation and Waves Institute of OceanologyChinese Academy of SciencesQingdao 266071China School of Marine Sciences Nanjing University of Information Science and TechnologyNanjing 210044China Laosan Laboratory Qingdao 266237China School of Atmospheric Sciences Nanjing University of Information Science and TechnologyNanjing 210044China University of Chinese Academy of Sciences Beijing 100029China

By using the multi-taper method(MTM)of singular value decomposition(SVD),this study investigates the interdecadal evolution(10-to 30-year cycle)of precipitation over eastern China from 1951 to 2015 and its relationship with the North Pacific sea surface temperature(SST).Two significant interdecadal signals,one with an 11-year cycle and the other with a 23-year cycle,are identified in both the precipitation and SST fields.Results show that the North Pacific SST forcing modulates the precipitation distribution over China through the effects of the Pacific Decadal Oscillation(PDO)-related anomalous Aleutian low on the western Pacific subtropical high(WPSH)and Mongolia high(MH).During the development stage of the PDO cold phase associated with the 11-year cycle,a weakened WPSH and MH increased the precipitation over the Yangtze River Basin,whereas an intensified WPSH and MH caused the enhanced rain band to move northward to North China during the decay stage.During the development stage of the PDO cold phase associated with the 23-year cycle,a weakened WPSH and MH increased the precipitation over North China,whereas an intensified WPSH and the weakened MH increased the precipitation over South China during the decay stage.The 11-year and 23-year variabilities contribute differently to the precipitation variations in the different regions of China,as seen in the 1998flooding case.The 11-year cycle mainly accounts for precipitation increases over the Yangtze River Basin,while the 23-year cycle is responsible for the precipitation increase over Northeast China.These results have important implications for understanding how the PDO modulates the precipitation distribution over China,helping to improve interdecadal climate prediction.

关键词： MTM-SVD PDO SST anomalies interdecadal variability precipitation over China

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Wettability regulation from superhydrophilic to superhydrophobic via nanosecond laser ablation

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Science China Technological Sciences 2024年第6期67卷 1829-1841页

作者： CHEN zhi wu zhiCheng ZHANG GuoJun LI DongHui HAN FengLin State Key Laboratory of Precision Manufacturing for Extreme Service Performance College of Mechanical and Electrical EngineeringCentral South University Guangdong Provincial Key Laboratory of Manufacturing Equipment Digitization Guangdong HUST Industrial Technology Research Institute China Harzone Industry Corp. Ltd.

Metal surfaces play a crucial role in numerous applications, from self-cleaning and anti-icing to anti-fogging and oil-water separation. The regulation of their wettability is essential to enhance their performance in these areas. This paper proposes a multi-state regulation method for metal surface wettability, leveraging nanosecond laser ablation. By creating non-uniform microstructures on a metal surface, the contact area between the solid and liquid phases can be increased, resulting in the attainment of superhydrophilic properties(contact angle(CA), ranging from 4.6° to 8.5°). Conversely, the construction of uniform microstructures leads to a decreased solid-liquid contact area, thereby rendering the metal surface hydrophilic(CA=12.2°–53°). Furthermore, through heat treatment on a surface with uniform microstructures, organic matter adsorption can be promoted while simultaneously reducing surface energy. This process results in the metal surface acquiring hydrophobic properties(CA=92.1°–133.5°), facilitated by the “air cushion effect.” Building on the hydrophobic surface, stearic acid modification can further reduce surface energy, ultimately bestowing the metal surface with superhydrophobic properties(CA=150.1°–152.7°, and sliding angle=3.8°). Performance testing has validated the durability and self-cleaning effectiveness of the fabricated superhydrophobic surface while also highlighting the excellent anti-fog performance of the superhydrophilic surface.These findings strongly indicate the immense potential of these surfaces in various engineering applications.

关键词： nanosecond laser ablation surface wettability superhydrophobic superhydrophilic

Clinical Value of the Quantitative Flow Ratio to Predict Long-term Target Vessel Failure in Patients with In-stent Restenosis after Drug-coated Balloon Angioplasty

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Current Medical Science 2024年第3期44卷 561-567页

作者： Xiang-qi wu Long-bo LI Wei YOU zhi-ming wu Lei ZHAO zhi-hui WANG Pei-na MENG Bin LIU Fei YE Department of Cardiology Nanjing First HospitalNanjing Medical UniversityNanjing210006China Department of Cardiology The Second Hospital of Jilin UniversityJilin130000China

Objective The study sought to investigate the clinical predictive value of quantitative flow ratio(QFR)for the long-term target vessel failure(TVF)outcome in patients with in-stent restenosis(ISR)by using drug-coated balloon(DCB)treatment after a long-term follow-up.Methods This was a retrospective study.A total of 186 patients who underwent DCB angioplasty for ISR in two hospitals from March 2014 to September 2019 were enrolled.The QFR of the entire target vessel was measured offline.The primary endpoint was TVF,including target vessel-cardiac death(TV-CD),target vessel-myocardial infarction(TV-MI),and clinically driven-target vessel revascularization(CD-TVR).Results The follow-up time was 3.09±1.53 years,and 50 patients had TVF.The QFR immediately after percutaneous coronary intervention(PCI)was significantly lower in the TVF group than in the no-TVF group.Multivariable Cox regression analysis indicated that the QFR immediately after PCI was an excellent predictor for TVF after the long-term follow-up[hazard ratio(HR):5.15×10−5(6.13×10−8−0.043);P<0.01].Receiver-operating characteristic(ROC)curve analysis demonstrated that the optimal cut-off value of the QFR immediately after PCI for predicting the long-term TVF was 0.925(area under the curve:0.886,95%confidence interval:0.834–0.938;sensitivity:83.40%,specificity:88.00;P<0.01).In addition,QFR≤0.925 post-PCI was strongly correlated with the TVF,including TV-MI and CD-TVR(P<0.01).Conclusion The QFR immediately after PCI showed a high predictive value of TVF after a long-term follow-up in ISR patients who underwent DCB angioplasty.A lower QFR immediately after PCI was associated with a worse TVF outcome.

关键词： percutaneous coronary intervention in-stent restenosis target vessel failure quantitative flow ratio