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Adeno-associated virus as a delivery vector for gene therapy of human diseases

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Signal Transduction and Targeted Therapy 2024年第5期9卷 1808-1840页

作者： Jiang-Hui Wang Dominic J.Gessler Wei Zhan thomas l.Gallagher Guangping Gao Horae Gene Therapy Center University of Massachusetts Chan Medical SchoolWorcesterMA01605USA Department of Microbiology and Physiological Systems University of Massachusetts Chan Medical SchoolWorcesterMA01605USA Centre for Eye Research Australia Royal Victorian Eye and Ear HospitalEast MelbourneVIC3002Australia Ophthalmology Department of SurgeryUniversity of MelbourneEast MelbourneVIC3002Australia Department of Neurological Surgery University of Massachusetts Chan Medical SchoolWorcesterMA01605USA Department of Neurosurgery University of MinnesotaMinneapolisMN55455USA Department of Medicine University of Massachusetts Chan Medical SchoolWorcesterMA01605USA li Weibo Institute for Rare Diseases Research University of Massachusetts Chan Medical SchoolWorcesterMA01605USA

Adeno-associated virus(AAV)has emerged as a pivotal delivery tool in clinical gene therapy owing to its minimal pathogenicity and ability to establish long-term gene expression in different *** AAV(rAAV)has been engineered for enhanced specificity and developed as a tool for treating various ***,as rAAV is being more widely used as a therapy,the increased demand has created challenges for the existing manufacturing *** rAAV-based gene therapy products have received regulatory approval,but there continue to be concerns about safely using high-dose viral therapies in humans,including immune responses and adverse effects such as genotoxicity,hepatotoxicity,thrombotic microangiopathy,and *** this review,we explore AAV biology with an emphasis on current vector engineering strategies and manufacturing *** discuss how rAAVs are being employed in ongoing clinical trials for ocular,neurological,metabolic,hematological,neuromuscular,and cardiovascular diseases as well as *** outline immune responses triggered by rAAV,address associated side effects,and discuss strategies to mitigate these *** hope that discussing recent advancements and current challenges in the field will be a helpful guide for researchers and clinicians navigating the ever-evolving landscape of rAAV-based gene therapy.

关键词： diseases specificity approval

Decomposition of dynamic transcriptomic responses during effector-triggered immunity reveals conserved responses in two distinct plant cell populations

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Plant Communications 2024年第8期5卷 1-17页

作者： Xiaotong liu Daisuke Igarashi Rachel A.Hillmer thomas Stoddard You lu Kenichi Tsuda Chad l.Myers Fumiaki Katagiri Department of Plant and Microbial Biology University of Minnesota-Twin CitiesSt PaulMN 55108USA Department of Computer Science and Engineering University of Minnesota-Twin CitiesMinneapolisMN 55455USA Bioinformatics and Computational Biology Graduate Program University of Minnesota-Twin CitiesMinneapolisMN 55455USA Institute for Innovation Ajinomoto Co.Inc.KawasakiJapan State Key laboratory of Agricultural Microbiology Hubei Hongshan LaboratoryHubei Key Lab of Plant PathologyCollege of Plant Science and TechnologyHuazhong Agricultural UniversityWuhan 430070China Present address:225 S 6th St MinneapolisMN 55402USA Present address:Biotalys Inc.2520 Meridian Parkway Suite 480DurhamNC 27713USA Present address:life Sciences Institute and Department of Cell and Developmental Biology University of Michigan Medical SchoolAnn ArborMI 48109USA

Rapid plant immune responses in the appropriate cells are needed for effective defense against *** transcriptome analysis is often used to describe overall immune responses,collection of transcriptome data with sufficient resolution in both space and time is *** reanalyzed public Arabidopsis time-course transcriptome data obtained after low-dose inoculation with a Pseudomonas syringae strain expressing the effector AvrRpt2,which induces effector-triggered immunity in ***-peak time-course patterns are prevalent among thousands of upregulated *** implemented a multicompartment modeling approach to decompose the double-peak pattern into two single-peak patterns for each *** decomposed peaks reveal an“echoing”pattern:the peak times of the first and second peaks correlate well across most upregulated *** demonstrated that the two peaks likely represent responses of two distinct cell populations that respond either cell autonomously or indirectly to ***,the peak decomposition has extracted spatial information from the time-course *** echoing pattern also indicates a conserved transcriptome response with different initiation times between the two cell populations despite different elicitor types.A gene set highly overlapping with the conserved gene set is also upregulated with similar kinetics during pattern-triggered *** of a WRKY network via different entry-point WRKYs can explain the similar but not identical transcriptome responses elicited by different elicitor *** discuss potential benefits of the properties of the WRKY activation network as an immune signaling network in light of pressure from rapidly evolving pathogens.

关键词： Arabidopsis Pseudomonas syringae plant immune response multi-compartment model WRKY transcription factors resilient immune signaling network

Effects of the urban landscape on heatwave-mortality associations in Hong Kong: comparison of different heatwave definitions

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Frontiers of Environmental Science & Engineering 2024年第1期18卷 145-156页

作者： Jinglu Song Yi lu thomas Fischer Kejia Hu Department of Urban Planning and Design Xi’an Jiaotong-Liverpool UniversitySuzhou 215123China Department of Architecture and Civil Engineering City University of Hong KongKowloon TongHong Kong 999077China Environmental Assessment and Management Research Centre School of Environmental SciencesUniversity of LiverpoolLiverpool L35TRUK Research Unit for Environmental Sciences and Management Faculty of Natural and Agricultural SciencesNorth West UniversityPotchefstroom 31750South Africa Institute of Big Data in Health Science School of Public HealthZhejiang UniversityZijingang CampusHangzhou 310058China

Despite increased attention given to potential modifiers of temperature-mortality associations, evidence for variations between different urban landscape characteristics remains limited. It is in this context that in this paper effect modifications of multiple urban landscape characteristics are explored under different heatwave definitions for different age groups and gender in Hong Kong, China. Daily meteorological data and heatwave-related mortality counts from 2008 to 2017 were collected from the Hong Kong Census and Statistics Department, China. A case-only design was adopted, combined with logistic regression models to examine the modification effects of five urban landscape characteristics under six heatwave definitions. Stratified analyses were conducted to investigate age- and gender-specific effect modifications. It is found that individuals living in greener areas experienced lower levels of mortality during or immediately after heatwaves. In contrast, a higher building density and nighttime land surface temperature (lST) were associated with a higher heatwave-related mortality risk. Pronounced effect modifications of these urban landscape characteristics were observed under hotter and longer heatwaves, and in older adults (age ≥ 65 years) and males. The findings provide a scientific basis for policymakers and practitioners when considering measures for coping with hotter, longer, and more frequent heatwaves in the context of global climate change.

关键词： Urban landscape Heatwave Mortality Effect modification Intra-urban differences Health risk reduction

Population genomic analysis reveals key genetic variations and the driving force for embryonic callus induction capability in maize

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Journal of Integrative Agriculture 2024年第7期23卷 2178-2195页

作者： Peng liu langlang Ma Siyi Jian Yao He Guangsheng Yuan Fei Ge Zhong Chen Chaoying Zou Guangtang Pan thomas lübberstedt Yaou Shen State Key laboratory of Crop Gene Exploration and Utilization in Southwest China/Maize Research Institute Sichuan Agricultural UniversityChengdu 611130China Department of Agronomy Iowa State UniversityAmesIA 50011USA

Genetic transformation has been an effective technology for improving the agronomic traits of ***,it is highly reliant on the use of embryonic callus(EC)and shows a serious genotype *** this study,we performed genomic sequencing for 80 core maize germplasms and constructed a high-density genomic variation map using our newly developed pipeline(MQ2Gpipe).Based on the induction rate of EC(REC),these inbred lines were categorized into three *** low-REC germplasms displayed more abundant genetic diversity than the high-REC *** integrating a genome-wide selective signature screen and region-based association analysis,we revealed 95.23 Mb of selective regions and 43 REC-associated *** variants had phenotypic variance explained values ranging between 21.46 and 49.46%.In total,103 candidate genes were identified within the linkage disequilibrium regions of these REC-associated *** genes mainly participate in regulation of the cell cycle,regulation of cytokinesis,and other functions,among which MYB15 and EMB2745 were located within the previously reported QTl for EC *** leaf area-associated variants with large effects were closely linked to several REC-related loci,implying a potential synergistic selection of REC and leaf size during modern maize breeding.

关键词： maize genetic transformation embryonic callus selective signal association analysis

Effect of vaccinations and school restrictions on the spread of COVID-19 in different age groups in Germany

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Infectious Disease Modelling 2024年第4期9卷 1250-1264页

作者： Christiane Dings Dominik Selzer Nicola luigi Bragazzi Eva Mohler Markus Wenning thomas Gehrke Ulf Richter Alexandra Nonnenmacher Folke Brinkmann Tobias Rothoeft Michael Zemlin thomas lücke Thorsten lehr Department of Clinical Pharmacy Saarland University66123SaarbrückenGermany Department of Child and Adolescent Psychiatry Saarland University Hospital66421HomburgGermany Medical Association Westfalen-Lippe48151MünsterGermany School of Education and Psychology Siegen University57072SiegenGermany University Children's Hospital Ruhr University44791BochumGermany University Children's Hospital Airway Research Center North(ARCN)German Center for Lung Research(DZL)LübeckGermany Department of General Pediatrics and Neonatology Saarland University Hospital66421HomburgGermany

With the emergence of SARS-CoV-2,various non-pharmaceutical interventions were adopted to control virus transmission,including school ***,the introduction of vaccines mitigated not only disease severity but also the spread of *** study leveraged an adapted SIR model and non-linear mixed-effects modeling to quantify the impact of remote learning,school holidays,the emergence of Variants of Concern(VOCs),and the role of vaccinations in controlling SARS-CoV-2 spread across 16 German federal states with an age-stratified *** highlight a significant inverse correlation(Spearman's ρ=0.92,pll age ***-parameter estimation using the observed number of cases stratified by federal state and age allowed to assess the effects of school closure and holidays,considering adjustments for vaccinations and spread of VOCs over ***,modeling revealed significant(pl children(0-4),children(5-11),adolescents(12-17),adults(18-59),and the elderly(60+).The transition to remote learning emerged as a critical measure in significantly reducing infection rates among children and adolescents(plderly during these periods,suggesting a shift in infection networks due to altered caregiving ***,during school holiday periods,infection rates among adolescents mirrored those observed when schools were *** exercises based on the model provided evidence that COVID-19 vaccinations might serve a dual purpose:they protect the vaccinated individuals and contribute to the broader community's safety.

关键词： COVID-19 Vaccination Non-pharmaceutical interventions Age Mathematical modeling

Structural effects of reedbed grazing and its cessation on reed-nesting songbird densities

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Avian Research 2024年第2期15卷 238-248页

作者： thomas Pagnon Clemence Pechinot lea Sgro Jeremie Demay Remi Jullian Regis Gallais Brigitte Poulin Cyril Marmoex Theria Ecologie 6 avenue des martyrs05400VeynesFrance UMR 6249 Chrono-Environnement CNRSUniversite de Franche-Comte16 route de Gray25000BesanconFrance Conservatoire d’Espaces Naturels d’Occitanie 26 alle de Mycenes34000MontpellierFrance Office Français de la Biodiversite 12 cours Lumiere94300VincennesFrance Tour du Valat Research Institute for the Conservation of Mediterranean Wetlands Le Sambuc13200ArlesFrance

Reedbeds are crucial breeding habitats for vulnerable songbird *** of their protection status,these habitats may be threatened by organic matter accumulation,progressively leading to structural homoge-nization and habitat succession towards *** prevent excessive litter build-up with various in-terventions opening-up the reedbeds,such as grazing,which may be detrimental or suitable for some reed bird *** assessed the effects of extensive grazing by horses and its cessation in the medium and long terms on reedbed structure,and the consequences on reed-nesting songbird densities in Estagnol Nature Reserve,a pro-tected wetland near the French Mediterranean *** compared reedbed structural features between grazed,newly ungrazed and old-ungrazed *** nine years,we censused four songbird species in spring and collected water level data in the same survey *** reduced reedbed extent,rejuvenated the vegetation with more short green stems on a thinner litter,and produced higher structural heterogeneity and discontinuity compared to long-lasting non *** ungrazed plot showed intermediate *** surveyed songbird total densities were similar among plots while species numbers and densities *** reedbed was more attractive to Moustached Warblers(Acrocephalus melanopogon)and Great Reed Warblers(Acrocephalus arundi-naceus),likely due to the large edges and the high vegetation structural ***,Moustached Warblers were more negatively affected by higher water level in grazed reedbed,presumably because flooding prevents litter *** newly ungrazed reedbed was not preferred by any *** warbler species were found under low density in the old-ungrazed reedbed,where Reed Buntings(Emberiza schoeniclus)were exclu-sively *** availability related to thick litter layer may explain this *** Reed Warblers(Acrocephalus scirpaceus)were found everywhere in similar

关键词： Bird conservation Edge complexity Fragmentation Habitat management Horse grazing Phragmites australis Reed passerine

Unsynchronized butyrophilin molecules dictate cancer cell evasion of Vγ9Vδ2 T-cell killing

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Cellular & Molecular Immunology 2024年第4期21卷 362-373页

作者： Zeguang Wu Qiezhong lamao Meichao Gu Xuanxuan Jin Ying liu Feng Tian Ying Yu Pengfei Yuan Shuaixin Gao thomas S.Fulford Adam P.Uldrich Catherine C.l Wong Wensheng Wei Biomedical Pioneering Innovation Center Peking-Tsinghua Center for Life SciencesPeking University Genome Editing Research CenterState Key Laboratory of Protein and Plant Gene ResearchSchool of Life SciencesPeking University100871BeijingChina EdiGene Inc. Life Science ParkChangping District102206BeijingChina Center for Precision Medicine Multi-Omics Research Peking University Health Science CenterPeking University100191BeijingChina Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity The University of MelbourneParkvilleVIC3010Australia Cancer Immunology Program Peter MacCallum Cancer CentreMelbourneVICAustralia State Key laboratory for Complex Severe and Rare DiseasesClinical Research InstitutePeking Union Medical College HospitalChinese Academy of Medical Science&Peking Union Medical CollegePeking-Tsinghua Center for Life Sciences100871BeijingChina

Vγ9Vδ2 T cells are specialized effector cells that have gained prominence as immunotherapy agents due to their ability to target and kill cells with altered pyrophosphate *** our effort to understand how cancer cells evade the cell-killing activity of Vγ9Vδ2 T cells,we performed a comprehensive genome-scale CRISPR screening of cancer *** found that four molecules belonging to the butyrophilin(BTN)family,specifically BTN2A1,BTN3A1,BTN3A2,and BTN3A3,are critically important and play unique,nonoverlapping roles in facilitating the destruction of cancer cells by primary Vγ9Vδ2 T *** coordinated function of these BTN molecules was driven by synchronized gene expression,which was regulated by IFN-γsignaling and the RFX ***,an enzyme called QPCTl was shown to play a key role in modifying the N-terminal glutamine of these BTN proteins and was found to be a crucial factor in Vγ9Vδ2 T cell killing of cancer *** our research,we offer a detailed overview of the functional genomic mechanisms that underlie how cancer cells escape Vγ9Vδ2 T ***,our findings shed light on the importance of the harmonized expression and function of gene family members in modulating T-cell activity.

关键词： Butyrophilin Vγ9Vδ2 T-cell Cancer-specific immune evasion Glutaminyl-peptide cyclotransferase-like Pyrophosphate metabolite Immunotherapy

Unveiling a novel metal-to-metal transition in luH_(2):Critically challenging superconductivity claims in lutetium hydrides

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Matter and Radiation at Extremes 2024年第3期9卷 65-73页

作者： Dong Wang Ningning Wang Caoshun Zhang Chunsheng Xia Weicheng Guo Xia Yin Kejun Bu Takeshi Nakagawa Jianbo Zhang Federico Gorelli Philip Dalladay-Simpson thomas Meier Xujie lü liling Sun Jinguang Cheng Qiaoshi Zeng Yang Ding Ho-kwang Mao Center for High-Pressure Science and Technology Advanced Research Beijing 100094China Beijing National laboratory for Condensed Matter Physics and Institute of Physics Chinese Academy of SciencesBeijing 100190China Shanghai Key laboratory of Material Frontiers Research in Extreme Environments(MFree) Shanghai Advanced Research in Physical Sciences(SHARPS)Shanghai 201203China

Following the recent report by Dasenbrock-Gammon et al.[Nature 615,244–250(2023)]of near-ambient superconductivity in nitrogendoped lutetium trihydride(luH_(3-δ)N_(ε)),significant debate has emerged surrounding the composition and interpretation of the observed sharp resistance ***,we meticulously revisit these claims through comprehensive characterization and *** definitively identify the reported material as lutetium dihydride(luH_(2)),resolving the ambiguity surrounding its *** similar conditions(270–295 K and 1–2 GPa),we replicate the reported sharp decrease in electrical resistance with a 30%success rate,aligning with the observations by Dasenbrock-Gammon et ***,our extensive investigations reveal this phenomenon to be a novel pressure-induced metal-to-metal transition intrinsic to luH_(2),distinct from ***,nitrogen doping exerts minimal impact on this *** work not only elucidates the fundamental properties of luH_(2)andluH_(3),but also critically challenges the notion of superconductivity in these lutetium hydride *** findings pave the way for future research on lutetium hydride systems,while emphasizing the crucial importance of rigorous verification in claims of ambient-temperature superconductivity.

关键词： resistance hydride superconductivity

Blood metal concentrations and cardiac structure and function in total joint arthroplasty patients

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World Journal of Orthopedics 2024年第8期15卷 773-782页

作者： Peter C Brennan Stephanie M Peterson thomas J O'Byrne Mariana l laporta Cody C Wyles Paul J Jannetto Garvan C Kane Maria Vassilaki Hilal Maradit Kremers Department of Orthopedic Surgery Mayo ClinicRochesterMN 55905United States Department of Quantitative Health Sciences Mayo ClinicRochesterMN 55905United States Department of Anesthesiology and Perioperative Medicine Mayo ClinicRochesterMN 55905United States Department of laboratory Medicine and Pathology Mayo ClinicRochesterMN 55905United States Department of Cardiovascular Diseases Mayo ClinicRochesterMN 55905United States

BACKGROUND There is concern regarding potential long-term cardiotoxicity with systemic distribution of metals in total joint arthroplasty(TJA)*** To determine the association of commonly used implant metals with echocardiographic measures in TJA *** The study comprised 110 TJA patients who had a recent history of high chromium,cobalt or titanium *** underwent two-dimensional,three-dimensional,Doppler and speckle-strain transthoracic echocardiography and a blood draw to measure metal *** and sex-adjusted linear and logistic regression models were used to examine the association of metal concentrations(exposure)with echocardiographic measures(outcome).RESUlTS Higher cobalt concentrations were associated with increased left ventricular end-diastolic volume(estimate 5.09;95%CI:0.02-10.17)as well as left atrial and right ventricular dilation,particularly in men but no changes in cardiac *** titanium concentrations were associated with a reduction in left ventricle global longitudinal strain(estimate 0.38;95%CI:0.70 to 0.06)and cardiac index(estimate 0.08;95%CI,-0.15 to-0.01).CONClUSION Elevated cobalt and titanium concentrations may be associated with structural and functional cardiac changes in some *** studies are warranted to better understand the systemic effects of metals in TJA patients.

关键词： Total joint arthroplasty Metal-on-metal Cardiotoxicity Heart failure Echocardiography Cobalt