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Efficient scar-free knock-ins of several kilobases in plants by engineered CRISPR-Cas endonucleases

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Molecular Plant 2024年第5期17卷 824-837页

作者： Tom Schreiber Anja Prange Petra Schafer thomas Iwen Ramona Grutzner Sylvestre Marillonnet Aurelie Lepage Marie Javelle Wyatt paul Alain Tissier Department of Cell and Metabolic Biology Leibniz Institute of Plant BiochemistryWeinberg 306120 Halle(Saale)Germany Limagrain Centre de RechercheRoute d’EnnezatCS 9012663720 ChappesFrance

In plants and mammals,non-homologous end-joining is the dominant pathway to repair DNA doublestrand breaks,making it challenging to generate knock-in *** this study,we identified two groups of exonucleases from the herpes virus and the bacteriophage T7 families that conferred an up to 38-fold increase in homology-directed repair frequencies when fused to Cas9/Cas12a in a tobacco mosaic virus-based transient assay in Nicotiana *** achieved precise and scar-free insertion of several kilobases of DNA both in transient and stable transformation *** Arabidopsis thaliana,fusion of Cas9 to a herpes virus family exonuclease led to 10-fold higher frequencies of knock-ins in the first generation of *** addition,we demonstrated stable and heritable knock-ins in wheat in 1%of the primary *** together,our results open perspectives for the routine production of heritable knock-in and gene replacement events in plants.

关键词： homology-directed repair knockin gene replacement CRISPR-Cas 50 exonuclease plants

Attitudes,beliefs,behaviours and perspectives on barriers and enablers of Australian general practitioners towards non-drug interventions:a national survey

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Family Medicine and Community Health 2024年第1期12卷 1-8页

作者： Loai Albarqouni Hannah Greenwood Caroline Dowsett Tammy Hoffmann Rae thomas paul Glasziou Institute for Evidence-based Healthcare Faculty of Health Sciences&MedicineBond UniversityRobinaQueenslandAustralia Tropical Australian Academic Health Centre TownsvilleQueenslandAustralia

Background Many guidelines recommend non-drug interventions(NDIs)for managing common conditions in primary ***,compared with drug interventions,NDIs are less widely known,promoted and *** aim to(1)examine general practitioners’(GPs’)knowledge,attitudes and practices for NDIs,including their use of the Royal Australian College of General Practitioners(RACGP)Handbook of Non-Drug Interventions(HANDI),and(2)identify factors influencing their use of NDIs and *** We conducted a web-based cross-sectional survey of practicing GP members in Australia during October-November *** survey contained five sections:characteristics of GP;knowledge and use of NDIs;attitudes towards NDIs;barriers and enablers to using HANDI;and suggestions of NDIs and ideas to improve the uptake of NDIs in primary *** Of the 366 GPs who completed the survey,242(66%)were female,and 248(74%)were≥45 years *** in three GPs reported that they regularly(‘always’)recommend NDIs to their patients when appropriate(34%),whereas one-third of GPs were unaware of HANDI(39%).GPs identified several factors that improve the uptake of HANDI,including‘access and integration of HANDI in clinical practice’,‘content and support to use in practice’and‘awareness and training’.Conclusions While many GPs are aware of the effectiveness of NDIs and often endorse their use,obstacles still prevent widespread adoption in primary *** results of this survey can serve as a foundation for developing implementation strategies to improve the uptake of effective evidence-based NDIs in primary care.

关键词： enable survey sectional

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

Targeted therapy for capillary-venous malformations

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Signal Transduction and Targeted Therapy 2024年第7期9卷 3024-3039页

作者： Lola Zerbib Sophia Ladraa Antoine Fraissenon Charles Bayard Marina Firpion Quitterie Venot Sanela Protic Clément Hoguin Amandine thomas Sylvie Fraitag Jean-paul Duong Sophie Kaltenbach Estelle Balducci Coline Lefevre Patrick Villarese Vahid Asnafi Christine Broissand Nicolas Goudin Ivan Nemazanyy Gwennhael Autret Bertrand Tavitian Christophe Legendre Nadia Arzouk Veronique Minard-Colin Caroline Chopinet Michael Dussiot Denise MAdams Tristan Mirault Laurent Guibaud paul Isenring Guillaume Canaud UniversitéParis Cité ParisFrance INSERM U1151 Institut Necker-Enfants MaladesParisFrance Service d’Imagerie Pédiatrique Hôpital Femme-Mère-EnfantHCLBronFrance CREATIS UMR 5220 Villeurbanne 69100France Service de Radiologie Mère-Enfant Hôpital NordSaint EtienneFrance Service d’Anatomie pathologique Hôpital Necker-Enfants MaladesAP-HPParisFrance Laboratoire d’Oncohématologie Hôpital Necker-Enfants MaladesAP-HPParisFrance Pharmacie Hôpital Necker-Enfants MaladesAP-HPParisFrance Necker Bio-Image Analysis INSERM US24/CNRS UMS 3633ParisFrance Platform for Metabolic Analyses Structure Fédérative de Recherche NeckerINSERM US24/CNRS UMS 3633ParisFrance Plateforme Imageries du Vivant Universitéde ParisPARCCINSERMParisFrance Service de Néphrologie Transplantation AdultesHôpital Necker-Enfants MaladesAP-HPParisFrance Service de Transplantation Hôpital La PitiéSalpétrièreAP-HPParisFrance Department of Pediatric and Adolescent Oncology INSERM 1015Gustave RoussyUniversitéParis-SaclayVillejuifFrance Service de Physiologie&Explorations Fonctionnelles Cardiovasculaires CHU de LilleLille 59000France INSERM U1163 Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic ImplicationsLaboratoire d’Excellence GR-ExParisFrance Division of Oncology Comprehensive Vascular Anomalies ProgramChildren’s Hospital of PhiladelphiaPhiladelphiaPAUSA Service de Médecine Vasculaire hôpital Européen Georges-PompidouParisFrance Nephrology Research Group L’Hôtel-Dieu de Québec Research CenterDepartment of MedicineFaculty of MedicineLaval UniversityQuebecQC G1R2J6Canada Unitéde médecine translationnelle et thérapies ciblées Hôpital Necker-Enfants MaladesAP-HPParisFrance CNRS UMR8253 Institut Necker-Enfants MaladesParisFrance

Sporadic venous malformations are genetic conditions primarily caused by somatic gain-of-function mutation of PIK3CA or TEK,an endothelial transmembrane receptor signaling through *** malformations are associated with pain,bleedings,thrombosis,pulmonary embolism,esthetic deformities and,in severe cases,life-threatening *** authorized medical treatment exists for patients with venous ***,we created a genetic mouse model of PIK3CA-related capillary venous malformations that replicates patient *** showed that these malformations only partially signal through AKT *** compared the efficacy of different drugs,including rapamycin,a mTORC1 inhibitor,miransertib,an AKT inhibitor and alpelisib,a PI3Kαinhibitor at improving the lesions seen in the mouse *** demonstrated the effectiveness of alpelisib in preventing vascular malformations’occurrence,improving the already established ones,and prolonging *** these findings,we were authorized to treat 25 patients with alpelisib,including 7 children displaying PIK3CA(n=16)or TEK(n=9)-related capillary venous malformations resistant to usual therapies including sirolimus,debulking surgical procedures or percutaneous *** assessed the volume of vascular malformations using magnetic resonance imaging(MRI)for each *** demonstrated improvement in all 25 *** malformations previously considered intractable were reduced and clinical symptoms were *** showed a decrease of 33.4%and 27.8%in the median volume of PIK3CA and TEK malformations respectively,over 6 months on *** conclusion,this study supports PI3Kαinhibition as a promising therapeutic strategy in patients with PIK3CA or TEK-related capillary venous malformations.

关键词： PIK3CA malformations venous

A system-on-chip microwave photonic processor solves dynamic RF interference in real time with picosecond latency

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Light(Science & Applications) 2024年第1期13卷 91-102页

作者： Weipeng Zhang Joshua C.Lederman thomas Ferreira de Lima Jiawei Zhang Simon Bilodeau Leila Hudson Alexander Tait Bhavin J.Shastri paul R.Prucnal Department of Electrical and Computer Engineering Princeton UniversityPrinceton08544NJUSA NEC Laboratories America Princeton08540NJUSA Department of Electrical and Computer Engineering Queen’s UniversityKingstonK7L 3N6OntarioCanada Department of Physics Engineering Physics and AstronomyQueen’s UniversityKingstonK7L 3N6OntarioCanada

Radio-frequency interference is a growing concern as wireless technology advances,with potentially life-threatening consequences like interference between radar altimeters and 5 G cellular *** transceivers mix signals with varying ratios over time,posing challenges for conventional digital signal processing(DSP)due to its high *** challenges will worsen as future wireless technologies adopt higher carrier frequencies and data ***,conventional DSPs,already on the brink of their clock frequency limit,are expected to offer only marginal speed *** paper introduces a photonic processor to address dynamic interference through blind source separation(BSS).Our system-on-chip processor employs a fully integrated photonic signal pathway in the analogue domain,enabling rapid demixing of received mixtures and recovering the signal-of-interest in under 15 *** reduction in latency surpasses electronic counterparts by more than three orders of *** complement the photonic processor,electronic peripherals based on field-programmable gate array(FPGA)assess the effectiveness of demixing and continuously update demixing weights at a rate of up to 305 *** compact setup features precise dithering weight control,impedance-controlled circuit board and optical fibre packaging,suitable for handheld and mobile *** experimentally demonstrate the processor’s ability to suppress transmission errors and maintain signal-to-noise ratios in two scenarios,radar altimeters and mobile *** work pioneers the real-time adaptability of integrated silicon photonics,enabling online learning and weight adjustments,and showcasing practical operational applications for photonic processing.

关键词： processor mixing dynamic

Reduction of Transient Engine-Out NO_(x)-Emissions by Advanced Digital Combustion Rate Shaping

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Automotive Innovation 2020年第2期3卷 181-190页

作者： Daniel Neumann Lukas Schäfers paul Muthyala Jakob andert Stefan Pischinger Institute for Combustion Engines RWTH Aachen UniversityAachenGermany FEV Consulting GmbH Neuenhofstraße 18152078 AachenGermany

Modern diesel passenger cars already fulfill high demands regarding the reduction in NOx emissions through complex exhaust aftertreatment *** the consideration of real driving emissions,the reduction in NOx emissions in high transient engine operation becomes even more *** from increasing the complexity of exhaust aftertreatment systems,internal engine measures play a major *** approach to reducing NOx emissions described in this paper uses the precise control of the *** this purpose,the method of digital combustion rate shaping control is applied,which allows the realization of a predefined combustion by automatically adapting the injection profile during *** this work,this controller is extended in order to control the predefined combustion trace based on target NOx ***,the working principal of the state-of-the-art digital combusting rate shaping controller is *** the next step,the design and strategy of the extended control approach are explained and ***,its potential to reduce engine-out NOx emissions during transient driving situations is evaluated based on simulations of the *** is shown that the control concept fulfills the requirements and is able to effectively reduce high NOx peaks during transient operation.

关键词： Diesel engine Emission control Combustion rate shaping Closed loop combustion control NO_(x)Control

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

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CFO与供应链管理

新理财（公司理财） 2024年第1期 83-85页

作者： thomas G.Canace Ayaz Jaffer paul E.Juras 不详

CFO和财务团队完全有能力应对长期供应链扰动给现金流和盈利能力带来的挑战。在经历了新冠疫情带来的供应链扰动后,首席财务官(CFO)和企业都在猜测供应链问题引发的一系列影响何时才能过去。但供应链问题并未随疫情的结束而结束,仍在不... 详细信息

CFO和财务团队完全有能力应对长期供应链扰动给现金流和盈利能力带来的挑战。在经历了新冠疫情带来的供应链扰动后,首席财务官(CFO)和企业都在猜测供应链问题引发的一系列影响何时才能过去。但供应链问题并未随疫情的结束而结束,仍在不断加剧,导致企业无力满足新冠疫情期间被抑制的客户需求,也阻碍了企业的收入增长。

关键词：供应链管理现金流财务团队 CFO 供应链问题盈利能力客户需求疫情

Storylines of family medicine Ⅻ:family medicine and the healthcare system

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Family Medicine and Community Health 2024年第S3期12卷 109-118页

作者： William B Ventres Leslie A Stone Jeannette E South-paul Kendall M Campbell Aerial R Petty Hima Ekanadham Kurt C Stange Rebecca S Etz William L Miller Robert L Ferrer Marianna Kong thomas Bodenheimer Roger Strasser Sharon C M Reece Joshua Freeman John M Westfall Family and Preventive Medicine University of Arkansas for Medical Sciences College of MedicineLittle RockArkansasUSA Meharry Medical College NashvilleTennesseeUSA Family Medicine University of Texas Medical Branch at Galveston School of MedicineGalvestonTexasUSA Family Medicine Residency Program New York-Presbyterian Columbia University Medical CenterNew YorkNew YorkUSA Center for Family and Community Medicine Columbia University Vagelos College of Physicians and SurgeonsNew YorkNew YorkUSA Center for Community Health Integration Case Western Reserve University School of MedicineClevelandOhioUSA Family Medicine and Population Health Virginia Commonwealth University School of MedicineRichmondVirginiaUSA Family Medicine Lehigh Valley Health NetworkAllentownPennsylvaniaUSA University of South Florida Morsani College of Medicine TampaFloridaUSA Family and Community Medicine UT Health San Antonio Long School of MedicineSan AntonioTexasUSA Family and Community Medicine University of California San Francisco School of MedicineSan FranciscoCaliforniaUSA Northern Ontario School of Medicine University SudburyOntarioCanada Family Medicine Baylor Scott and White HealthTempleTexasUSA Family Medicine University of Kansas School of MedicineKansas CityKansasUSA DARTNet Insitute AuroraColoradoUSA

Storylines of Family Medicine is a 12-part series of thematically linked mini-essays with accompanying illustrations that explore the many dimensions of family medicine,as interpreted by individual family physicians and medical educators in the USA and elsewhere around the ***‘Ⅻ:Family medicine and the future of the healthcare system’,authors address the following themes:‘Leadership in family medicine’,‘Becoming an academic family physician’,‘Advocare—our call to act’,‘The paradox of primary care and three simple rules’,‘The quadruple aim—melding the patient and the health system’,‘Fit-for-purpose medical workforce’,‘Universal healthcare—coverage for all’,‘The futures of family medicine’and‘The 100th essay.’May readers of these essays feel empowered to be part of family medicine’s exciting future.

关键词： system illustration family