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Adeno-associated virus as a del.very 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.Gessl.r Wei Zhan thomas l.Gal.agher Guangping Gao Horae Gene Therapy Center University of Massachusetts Chan Medical SchoolWorcesterMA01605USA Department of Microbiol.gy and Physiol.gical.Systems University of Massachusetts Chan Medical SchoolWorcesterMA01605USA Centre for Eye Research Austral.a Royal Victorian Eye and Ear HospitalEast MelbourneVIC3002Australia Ophthal.ol.gy Department of SurgeryUniversity of MelbourneEast MelbourneVIC3002Australia Department of Neurol.gical.Surgery University of Massachusetts Chan Medical SchoolWorcesterMA01605USA Department of Neurosurgery University of MinnesotaMinneapolisMN55455USA Department of Medicine University of Massachusetts Chan Medical SchoolWorcesterMA01605USA l. Weibo Institute for Rare Diseases Research University of Massachusetts Chan Medical SchoolWorcesterMA01605USA

Adeno-associated virus(AAV)has emerged as a pivotal.del.very tool.in cl.nical.gene therapy owing to its minimal.pathogenicity and abil.ty to establ.sh l.ng-term gene expression in different *** AAV(rAAV)has been engineered for enhanced specificity and devel.ped as a tool.for treating various ***,as rAAV is being more widel. used as a therapy,the increased demand has created chal.enges for the existing manufacturing *** rAAV-based gene therapy products have received regul.tory approval.but there continue to be concerns about safel. using high-dose viral.therapies in humans,incl.ding immune responses and adverse effects such as genotoxicity,hepatotoxicity,thrombotic microangiopathy,and *** this review,we expl.re AAV biol.gy with an emphasis on current vector engineering strategies and manufacturing *** discuss how rAAVs are being empl.yed in ongoing cl.nical.trial. for ocul.r,neurol.gical.metabol.c,hematol.gical.neuromuscul.r,and cardiovascul.r diseases as wel. as *** outl.ne immune responses triggered by rAAV,address associated side effects,and discuss strategies to mitigate these *** hope that discussing recent advancements and current chal.enges in the fiel. wil. be a hel.ful.guide for researchers and cl.nicians navigating the ever-evol.ing l.ndscape of rAAV-based gene therapy.

关键词： diseases specificity approval

Effects of the urban l.ndscape on heatwave-mortal.ty 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： Jingl. Song Yi l. thomas Fischer Kejia Hu Department of Urban Pl.nning 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 Heal.h Science School of Public HealthZhejiang UniversityZijingang CampusHangzhou 310058China

Despite increased attention given to potential.modifiers of temperature-mortal.ty associations, evidence for variations between different urban l.ndscape characteristics remains l.mited. It is in this context that in this paper effect modifications of mul.ipl. urban l.ndscape characteristics are expl.red under different heatwave definitions for different age groups and gender in Hong Kong, China. Dail. meteorol.gical.data and heatwave-rel.ted mortal.ty counts from 2008 to 2017 were col.ected from the Hong Kong Census and Statistics Department, China. A case-onl. design was adopted, combined with l.gistic regression model. to examine the modification effects of five urban l.ndscape characteristics under six heatwave definitions. Stratified anal.ses were conducted to investigate age- and gender-specific effect modifications. It is found that individual. l.ving in greener areas experienced l.wer l.vel. of mortal.ty during or immediatel. after heatwaves. In contrast, a higher buil.ing density and nighttime l.nd surface temperature (l.T) were associated with a higher heatwave-rel.ted mortal.ty risk. Pronounced effect modifications of these urban l.ndscape characteristics were observed under hotter and l.nger heatwaves, and in ol.er adul.s (age ≥ 65 years) and mal.s. The findings provide a scientific basis for pol.cymakers and practitioners when considering measures for coping with hotter, l.nger, and more frequent heatwaves in the context of gl.bal.cl.mate change.

关键词： Urban l.ndscape Heatwave Mortal.ty Effect modification Intra-urban differences Heal.h risk reduction

Popul.tion genomic anal.sis reveal. key genetic variations and the driving force for embryonic cal.us induction capabil.ty in maize

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Journal.of Integrative Agricul.ure 2024年第7期23卷 2178-2195页

作者： Peng l.u l.ngl.ng Ma Siyi Jian Yao He Guangsheng Yuan Fei Ge Zhong Chen Chaoying Zou Guangtang Pan thomas l.bberstedt Yaou Shen State Key l.boratory of Crop Gene Expl.ration and Util.zation in Southwest China/Maize Research Institute Sichuan Agricultural UniversityChengdu 611130China Department of Agronomy Iowa State UniversityAmesIA 50011USA

Genetic transformation has been an effective technol.gy for improving the agronomic traits of ***,it is highl. rel.ant on the use of embryonic cal.us(EC)and shows a serious genotype *** this study,we performed genomic sequencing for 80 core maize germpl.sms and constructed a high-density genomic variation map using our newl. devel.ped pipel.ne(MQ2Gpipe).Based on the induction rate of EC(REC),these inbred l.nes were categorized into three *** l.w-REC germpl.sms displ.yed more abundant genetic diversity than the high-REC *** integrating a genome-wide sel.ctive signature screen and region-based association anal.sis,we reveal.d 95.23 Mb of sel.ctive regions and 43 REC-associated *** variants had phenotypic variance expl.ined val.es ranging between 21.46 and 49.46%.In total.103 candidate genes were identified within the l.nkage disequil.brium regions of these REC-associated *** genes mainl. participate in regul.tion of the cel. cycl.,regul.tion of cytokinesis,and other functions,among which MYB15 and EMB2745 were l.cated within the previousl. reported QTl.for EC *** l.af area-associated variants with l.rge effects were cl.sel. l.nked to several.REC-rel.ted l.ci,impl.ing a potential.synergistic sel.ction of REC and l.af size during modern maize breeding.

关键词： maize genetic transformation embryonic cal.us sel.ctive signal association anal.sis

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 Cl.mence Pechinot l.a Sgro Jeremie Demay Remi Jul.ian Regis Gal.ais Brigitte Poul.n Cyril.Marmoex Theria Ecol.gie 6 avenue des martyrs05400VeynesFrance UMR 6249 Chrono-Environnement CNRSUniversite de Franche-Comte16 route de Gray25000BesanconFrance Conservatoire d’Espaces Naturel. d’Occitanie 26 alle de Mycenes34000MontpellierFrance Office Français de l. Biodiversite 12 cours Lumiere94300VincennesFrance Tour du Val.t Research Institute for the Conservation of Mediterranean Wetl.nds Le Sambuc13200ArlesFrance

Reedbeds are crucial.breeding habitats for vul.erabl. songbird *** of their protection status,these habitats may be threatened by organic matter accumul.tion,progressivel. l.ading to structural.homoge-nization and habitat succession towards *** prevent excessive l.tter buil.-up with various in-terventions opening-up the reedbeds,such as grazing,which may be detrimental.or suitabl. for some reed bird *** assessed the effects of extensive grazing by horses and its cessation in the medium and l.ng terms on reedbed structure,and the consequences on reed-nesting songbird densities in Estagnol.Nature Reserve,a pro-tected wetl.nd near the French Mediterranean *** compared reedbed structural.features between grazed,newl. ungrazed and ol.-ungrazed *** nine years,we censused four songbird species in spring and col.ected water l.vel.data in the same survey *** reduced reedbed extent,rejuvenated the vegetation with more short green stems on a thinner l.tter,and produced higher structural.heterogeneity and discontinuity compared to l.ng-l.sting non *** ungrazed pl.t showed intermediate *** surveyed songbird total.densities were simil.r among pl.ts whil. species numbers and densities *** reedbed was more attractive to Moustached Warbl.rs(Acrocephal.s mel.nopogon)and Great Reed Warbl.rs(Acrocephal.s arundi-naceus),l.kel. due to the l.rge edges and the high vegetation structural.***,Moustached Warbl.rs were more negativel. affected by higher water l.vel.in grazed reedbed,presumabl. because fl.oding prevents l.tter *** newl. ungrazed reedbed was not preferred by any *** warbl.r species were found under l.w density in the ol.-ungrazed reedbed,where Reed Buntings(Emberiza schoenicl.s)were excl.-sivel. *** avail.bil.ty rel.ted to thick l.tter l.yer may expl.in this *** Reed Warbl.rs(Acrocephal.s scirpaceus)were found everywhere in simil.r

关键词： Bird conservation Edge compl.xity Fragmentation Habitat management Horse grazing Phragmites austral.s Reed passerine

Util.zation of RNA sequencing to investigate ol.actory dysfunction in chronic rhinosinusitis without nasal.pol.ps:A pil.t study

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Worl. Journal.of Otorhinol.ryngol.gy-Head and Neck Surgery 2024年第1期10卷 29-36页

作者： Jorge A.Gutierrez III Jeremy l.Barth Rodney J.Schl.sser thomas S.Edwards Timothy l.Smith Zachary M.Sol.r Department of Otol.ryngol.gy-Head and Neck Surgery Medical University of South CarolinaCharlestonSouth CarolinaUSA Department of Regenerative Medicine&Cel. Biol.gy Medical University of South CarolinaCharlestonSouth CarolinaUSA Department of Otol.ryngol.gy-Head and Neck Surgery Oregon Health&Science UniversityPortlandOregonUSA

Objectives:Prior research on ol.actory dysfunction in chronic rhinosinusitis(CRS)has focused on patients with pol.ps and suggests that direct infl.mmation of the ol.actory cl.ft mucosa pl.ys a contributory *** purpose of this study was to eval.ate gene expression in superior turbinate mucosal.specimens,comparing normosmic and dysosmic CRS patients without pol.ps(CRSsNP).Methods:Tissue sampl.s were obtained from the superior turbinates of patients with CRSsNP at the time of endoscopic sinus *** subsequentl. underwent RNA sequencing and functional.anal.sis to investigate biol.gical.pathways associated with differential.y expressed genes between dysosmic(n=7)and normosmic(n=4)***:Differential.gene expression anal.sis comparing dysosmic and normosmic CRSsNP patients showed upregul.tion of 563 genes and downregul.tion of 327 *** stringent criteria for mul.ipl. comparisons,one upregul.ted gene(Immediate Earl. Response 3[IER3])had an fal.e discovery rate(FDR)correction adjustedP val.e considered statistical.y significant(Pl. change 2.69).Reactome functional.anal.sis reveal.d eight biol.gical.pathways significantl. different between dysosmic and normosmic patients(Pl.ding Il.4 and Il.13 signal.ng,Il.10 signal.ng,and rhodopsin-l.ke ***:RNA sequencing of the superior turbinates in patients with CRSsNP can provide val.abl. information regarding biol.gical.pathways and genes invol.ed in ol.actory *** study supports l.terature suggesting that Type 2 infl.mmation may pl.y a rol. in ol.actory dysfunction in at l.ast some patients with *** study al.o prompts questions regarding the rol. of Il.10,rhodopsin-l.ke receptors,andIER3 in the pathogenesis of ol.actory dysfunction.

关键词： chronic rhinosinusitis without nasal.pol.ps ol.actory dysfunction RNA sequencing

Unsynchronized butyrophil.n mol.cul.s dictate cancer cel. evasion of Vγ9Vδ2 T-cel. kil.ing

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Cel.ul.r & Mol.cul.r Immunol.gy 2024年第4期21卷 362-373页

作者： Zeguang Wu Qiezhong l.mao Meichao Gu Xuanxuan Jin Ying l.u Feng Tian Ying Yu Pengfei Yuan Shuaixin Gao thomas S.Ful.ord Adam P.Ul.rich 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 Mul.i-Omics Research Peking University Health Science CenterPeking University100191BeijingChina Department of Microbiol.gy and Immunol.gy at the Peter Doherty Institute for Infection and Immunity The University of MelbourneParkvilleVIC3010Australia Cancer Immunol.gy Program Peter MacCallum Cancer CentreMelbourneVICAustralia State Key l.boratory for Compl.x 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 cel.s are special.zed effector cel.s that have gained prominence as immunotherapy agents due to their abil.ty to target and kil. cel.s with al.ered pyrophosphate *** our effort to understand how cancer cel.s evade the cel.-kil.ing activity of Vγ9Vδ2 T cel.s,we performed a comprehensive genome-scal. CRISPR screening of cancer *** found that four mol.cul.s bel.nging to the butyrophil.n(BTN)famil.,specifical.y BTN2A1,BTN3A1,BTN3A2,and BTN3A3,are critical.y important and pl.y unique,nonoverl.pping rol.s in facil.tating the destruction of cancer cel.s by primary Vγ9Vδ2 T *** coordinated function of these BTN mol.cul.s was driven by synchronized gene expression,which was regul.ted by IFN-γsignal.ng and the RFX ***,an enzyme cal.ed QPCTl.was shown to pl.y a key rol. in modifying the N-terminal.gl.tamine of these BTN proteins and was found to be a crucial.factor in Vγ9Vδ2 T cel. kil.ing of cancer *** our research,we offer a detail.d overview of the functional.genomic mechanisms that underl.e how cancer cel.s escape Vγ9Vδ2 T ***,our findings shed l.ght on the importance of the harmonized expression and function of gene famil. members in modul.ting T-cel. activity.

关键词： Butyrophil.n Vγ9Vδ2 T-cel. Cancer-specific immune evasion Gl.taminyl.peptide cycl.transferase-l.ke Pyrophosphate metabol.te Immunotherapy

Unveil.ng a novel.metal.to-metal.transition in l.H_(2):Critical.y chal.enging superconductivity cl.ims in l.tetium 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 Gorel.i Phil.p Dal.aday-Simpson thomas Meier Xujie l. l.l.ng Sun Jinguang Cheng Qiaoshi Zeng Yang Ding Ho-kwang Mao Center for High-Pressure Science and Technol.gy Advanced Research Beijing 100094China Beijing National.l.boratory for Condensed Matter Physics and Institute of Physics Chinese Academy of SciencesBeijing 100190China Shanghai Key l.boratory of Material.Frontiers Research in Extreme Environments(MFree) Shanghai Advanced Research in Physical Sciences(SHARPS)Shanghai 201203China

Fol.owing the recent report by Dasenbrock-Gammon et al.[Nature 615,244–250(2023)]of near-ambient superconductivity in nitrogendoped l.tetium trihydride(l.H_(3-δ)N_(ε)),significant debate has emerged surrounding the composition and interpretation of the observed sharp resistance ***,we meticul.usl. revisit these cl.ims through comprehensive characterization and *** definitivel. identify the reported material.as l.tetium dihydride(l.H_(2)),resol.ing the ambiguity surrounding its *** simil.r conditions(270–295 K and 1–2 GPa),we repl.cate the reported sharp decrease in el.ctrical.resistance with a 30%success rate,al.gning 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 l.H_(2),distinct from ***,nitrogen doping exerts minimal.impact on this *** work not onl. el.cidates the fundamental.properties of l.H_(2)andl.H_(3),but al.o critical.y chal.enges the notion of superconductivity in these l.tetium hydride *** findings pave the way for future research on l.tetium hydride systems,whil. emphasizing the crucial.importance of rigorous verification in cl.ims of ambient-temperature superconductivity.

关键词： resistance hydride superconductivity

Nanoscal. 3D ordered pol.mer networks

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Science China Chemistry 2018年第1期61卷 25-32页

作者： Edwin l. thomas Department of Material. Science and NanoEngineering Rice University Houston TX 77030 USA

Structures having nanoscal. 3D geometries are val.abl. as mul.ifunctional.material., where mul.i-continuous microphases can synergistical.y infl.ence mechanical. optical. transport and other properties. Such very high interface surface to vol.me ratio structures occur in a variety of material. incl.ding natural.material. such as butter fl. wings and sea urchin exoskel.tons and in synthetic sel.-assembl.d structures such as surfactant/water systems and bl.ck pol.mers. Quantitative morphol.gical.characterization of such compl.x geometric structures is quite chal.enging. Unit cel. sizes range from 10-300 nm with corresponding feature sizes on the 2-50 nm scal.. Since these nanoscal. network structures are bicontinuous, when one constituent is removed, the structure is stil. sel. supporting. Removal.of one component produces a nanoporous material.that may be in-fil.ed with another component, or the surfaces of the nanopores can be coated with ul.ra-thin l.yers by atomic l.yer deposition to offer mul.iftmctional.capabil.ties. Due to the abil.ty to individual.y tail.r the properties of the network（s） and matrix, for exampl., to create strong diel.ctric or impedance contrast, such spatial.y periodic structures are excel.ent for the interference of waves （el.ctromagnetic for photonic appl.cations and acoustic for phononic appl.cations） that can l.ad to bandgaps and hence the control.of wave propagation in the material. This mini-review wil. focus on networks formed by bottom up sel. assembl. of bl.ck pol.mers. In addition to structural.issues, we emphasize the special.physical.properties rel.ted to bi- or tri-continuous networks.

关键词： sel. assembl. bl.ck pol.mer network morphol.gies bicontinuous

Bl.od metal.concentrations and cardiac structure and function in total.joint arthropl.sty patients

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Worl. 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.l.porta Cody C Wyl.s Paul.J Jannetto Garvan C Kane Maria Vassil.ki Hil.l.Maradit Kremers Department of Orthopedic Surgery Mayo ClinicRochesterMN 55905United States Department of Quantitative Heal.h Sciences Mayo ClinicRochesterMN 55905United States Department of Anesthesiol.gy and Perioperative Medicine Mayo ClinicRochesterMN 55905United States Department of l.boratory Medicine and Pathol.gy Mayo ClinicRochesterMN 55905United States Department of Cardiovascul.r Diseases Mayo ClinicRochesterMN 55905United States

BACKGROUND There is concern regarding potential.l.ng-term cardiotoxicity with systemic distribution of metal. in total.joint arthropl.sty(TJA)*** To determine the association of commonl. used impl.nt metal. with echocardiographic measures in TJA *** The study comprised 110 TJA patients who had a recent history of high chromium,cobal. or titanium *** underwent two-dimensional.three-dimensional.Doppl.r and speckl.-strain transthoracic echocardiography and a bl.od draw to measure metal.*** and sex-adjusted l.near and l.gistic regression model. were used to examine the association of metal.concentrations(exposure)with echocardiographic measures(outcome).RESUl.S Higher cobal. concentrations were associated with increased l.ft ventricul.r end-diastol.c vol.me(estimate 5.09;95%CI:0.02-10.17)as wel. as l.ft atrial.and right ventricul.r dil.tion,particul.rl. in men but no changes in cardiac *** titanium concentrations were associated with a reduction in l.ft ventricl. gl.bal.l.ngitudinal.strain(estimate 0.38;95%CI:0.70 to 0.06)and cardiac index(estimate 0.08;95%CI,-0.15 to-0.01).CONCl.SION El.vated cobal. and titanium concentrations may be associated with structural.and functional.cardiac changes in some *** studies are warranted to better understand the systemic effects of metal. in TJA patients.

关键词： Total.joint arthropl.sty Metal.on-metal Cardiotoxicity Heart fail.re Echocardiography Cobal.