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

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

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Spatiotemporal dynamics of the social structure of Indo-Pacific humpback dolphins(Sousa chinensis)in Xiamen waters from 2007 to 2019

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Zoological Research 2024年第2期45卷 439-450页

作者： Yi Lu Xin-Rong Xu Bing-Yao Chen thomas A Jefferson Holly Fearnbach Guang Yang Jiangsu Key Laboratory for Biodiversity and Biotechnology College of Life SciencesNanjing Normal UniversityNanjingJiangsu 210023China Clymene Enterprises LakesideCalifornia 92040USA Marine Mammal Research SR3SeaLife ResponseRehabilitation and ResearchWA 98275USA Southern Marine Science and Engineering Guangdong Laboratory(Guangzhou) No.1119Haibin RoadNansha DistrictGuangzhouGuangdong 511458China

As highly social animals,Indo-Pacific humpback dolphins(Sousa chinensis)exhibit community ***,our understanding of the external and internal factors influencing these dynamics,as well as their spatiotemporal variations,is still *** the present study,variations in the social structure of an endangered Indo-Pacific humpback dolphin population in Xiamen Bay,China,were monitored over two distinct periods(2007–2010 and 2017–2019)to analyze the effects of habitat utilization and the composition of individuals within the *** both periods,the population demonstrated a strikingly similar pattern of social differentiation,characterized by the division of individuals into two main clusters and one small ***,the two primary clusters occupied the eastern and western waters,respectively,although the core distribution area of the eastern cluster shifted further eastward between the two *** this distribution shift,the temporal stability of the social structure and inter-associations within the eastern cluster remained unaffected.A subset of 16individuals observed in both periods,comprising 51.6%and 43.2%of the population in each respective period,emerged as a foundational element of the social structure and may be responsible for sustaining social structure stability,especially during the 2007–2010 *** observations suggest that the composition of dominant individuals,an internal factor,had a more substantial influence on the formation of the social network than changes in habitat use,an external ***,the study proposes distinct conservation measures tailored to each of the two main clusters.

关键词： Social differentiation Social structure Sousa chinensis Dynamics Conservation

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Explainability and Interpretability in Electric Load Forecasting Using Machine Learning Techniques–A Review

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Energy and AI 2024年第2期16卷 483-496页

作者： Lukas Baur Konstantin Ditschuneit Maximilian Schambach Can Kaymakci thomas Wollmann Alexander Sauer Fraunhofer Institute for Manufacturing Engineering and Automation IPA Nobelstraße 12Stuttgart70569Germany Institute for Energy Efficiency in Production(EEP) University of StuttgartNobelstraße 12Stuttgart70569Germany Merantix Momentum GmbH Max-Urich-Straße 3Berlin13355Germany

Electric Load Forecasting(ELF)is the central instrument for planning and controlling demand response programs,electricity trading,and consumption *** to the increasing automation of these processes,meaningful and transparent forecasts become more and more ***,at the same time,the complexity of the used machine learning models and architectures *** there is an increasing interest in interpretable and explainable load forecasting methods,this work conducts a literature review to present already applied approaches regarding explainability and interpretability for load forecasts using Machine *** on extensive literature research covering eight publication portals,recurring modeling approaches,trends,and modeling techniques are identified and clustered by properties to achieve more interpretable and explainable load *** results on interpretability show an increase in the use of probabilistic models,methods for time series decomposition and the use of fuzzy logic in addition to classically interpretable *** explainable approaches are Feature Importance and Attention *** discussion shows that a lot of knowledge from the related field of time series forecasting still needs to be adapted to the problems in *** to other applications of explainable and interpretable methods such as clustering,there are currently relatively few research results,but with an increasing trend.

关键词： Electric load forecasting Explainability InterpretabilityStructured review

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Comparing four machine learning algorithms for household non-intrusive load monitoring

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Energy and AI 2024年第3期17卷 206-219页

作者： thomas Lee Young James Gopsill Maria Valero Sindre Eikevåg Ben Hicks University of Bristol UK

The combination of Machine Learning (ML), smart energy meters, and availability of household appliance energy profile data has opened new opportunities for Non-Intrusive Load Monitoring (NILM). However, the number of options makes it challenging in selecting optimal combinations for different energy applications, which requires studies to examine their *** paper contributes one such study that investigated four established ML approaches – K Nearest Neighbour (KNN), Support Vector Machine (SVM), eXtreme Gradient Boosting (XGBoost) and Convolutional Neural Network (CNN) – and their performance in classifying appliance events from Alternating Current (AC) and Root Mean Square (RMS) energy data where the sampling frequency and training dataset set size was varied (10 Hz–1 kHz and 50–2000 examples per class, respectively). The computational expense during training, testing and storage was also assessed and evaluated with reference to real-world *** CNN classifier trained on AC data at 500 Hz and 11,000 examples gave the best F1-score (0.989) followed by the KNN classifier (0.940). The storage size required by the CNN models was 3̃MB, which is very close to fitting on cost-effective embedded system microcontrollers. This would prevent high-rate data needing to be sent to the cloud as analysis could be performed on edge computing Internet-of-Things (IoT) devices.

关键词： NILM ML Edge computing Signal processing Smart meters

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Examining the“revisability”benefit of hip resurfacing arthroplasty

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World Journal of Orthopedics 2024年第6期15卷 554-559页

作者： Jose George Adam J Taylor thomas P Schmalzried Department of Orthopedics Harbor UCLA Medical CenterTorranceCA 90509United States

BACKGROUND Hip resurfacing arthroplasty(HRA)is an alternative to total hip arthroplasty(THA)that is typically reserved for young active patients because it preserves ***,the benefits of HRA only hold true if conversion THA after failed HRA provides acceptable *** To compare patient reported outcomes for conversion THA after HRA failure to primary *** A retrospective review of 36 patients(37 hips)that underwent conversion THA for failed HRA between October 2006 and May 2019 by a single surgeon was *** reported outcomes[modified Harris Hip Score(mHHS),University of California Los Angeles(UCLA)activity score]were obtained via an email-based responder-anonymous *** were compared to normative data of a primary THA cohort with similar *** analysis was performed comparing outcomes of conversion THA for adverse local tissue reaction(ALTR)vs all other causes for *** The study group had a lower mHHS than the control group(81.7±13.8 vs 90.2±11.6,P<0.01);however,both groups had similar UCLA activity levels(7.5±2.3 vs 7.2±1.6,P=0.51).Patients that underwent conversion for non-ATLR causes had similar mHHS(85.2±11.5 vs 90.2±11.6,P=0.11)and higher UCLA activity levels(8.5±1.8 vs 7.2±1.6,P<0.01)compared to the control *** that underwent conversion for ATLR had worse mHHS(77.1±14.5 vs 90.2±11.6,P<0.01)and UCLA activity levels(6.1±2.3 vs 7.2±1.6,P=0.05)when compared to the control *** Patient outcomes equivalent to primary THA can be achieved following HRA conversion to ***,inferior outcomes were demonstrated for ALTR-related HRA *** selection and perhaps further studies examining alternative HRA bearing surfaces should be considered.

关键词： Total hip arthroplasty Hip resurfacing arthroplasty Conversion total hip arthroplasty Adverse local tissue reaction Patient reported outcome measures

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Enhanced diagnostic workup increases pathological findings in patients with acute ischaemic stroke:results of the prospective HEBRAS study

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Stroke & Vascular Neurology 2024年第2期9卷 145-152,I0414-I0425页

作者： Simon Hellwig thomas Krause Jan F Scheitz Juliane Herm Ulrike Grittner Nadja Jauert Jochen B Fiebach Mario Kasner Wolfram Doehner Matthias Endres Rolf Wachter thomas Elgeti Christian H Nolte Karl Georg Haeusler Department of Neurology with Experimental Neurology Charité-Universitätsmedizin Berlincorporate member of Freie Universität Berlin and Humboldt-Universität zu BerlinBerlinGermany Center for Stroke Research Berlin BerlinGermany Berlin Institute of Health at Charité–Universitätsmedizin Berlin BIH Biomedical Innovation AcademyBerlinGermany Department of Neurology Jüdisches Krankenhaus BerlinBerlinGermany German Center for Cardiovascular Diseases(DZHK) Partner Site BerlinBerlinGermany Institute of Biometry and Clinical Epidemiology Charité-Universitätsmedizin BerlinBerlinGermany BIH Center for Regenerative Therapies(BCRT) Berlin Institute of Health at Charité–Universitätsmedizin BerlinBerlinGermany Department of Cardiology Charité-Universitätsmedizin BerlinBerlinGermany Department of Cardiology Campus Benjamin FranklinCharité-Universitätsmedizin BerlinBerlinGermany German Center for Neurodegenerative Diseases(DZNE) Partner Site BerlinBerlinGermany Department of Cardiology University Hospital LeipzigLeipzigGermany Department of Radiology Charité-Universitätsmedizin BerlinBerlinGermany Department of Neurology University Hospital WürzburgWürzburgGermany

Background Stroke aetiology remains cryptogenic in a relevant proportion of patients with acute ischaemic stroke(AIS).We assessed whether enhanced diagnostic workup after AIS yields a higher rate of prespecified pathological findings compared with routine diagnostic care *** Hospitalised patients with AIS were prospectively enrolled in the investigator-initiated observational HEart and BRain Interfaces in Acute Ischaemic Stroke(HEBRAS)study at the Charité,Berlin,*** with AIS without known atrial fibrillation(AF)underwent cardiovascular MR imaging(CMR),MR-angiography of the aortic arch and prolonged Holter-ECG monitoring on top of routine diagnostic *** Among 356 patients with AIS(mean age 66 years,37.6%female),enhanced workup yielded a higher rate of prespecified pathological findings compared with routine care(17.7%vs 5.3%;p<0.001).Consequently,fewer patients were classified as cryptogenic after enhanced diagnostic workup(38.5%vs 45.5%,p<0.001).Routine care included echocardiography in 228(64.0%)*** was successfully performed in 292(82.0%)patients and revealed more often a prespecified pathological finding compared with routine echocardiography(16.1%vs 5.3%).Furthermore,study-related ECG monitoring(median duration 162 hours(IQR 98–210))detected AF in 16(4.5%)patients,while routine monitoring(median duration 51 hours(IQR 34–74))detected AF in seven(2.0%)*** Enhanced diagnostic workup revealed a higher rate of prespecified pathological findings in patients with AIS compared with routine diagnostic care and significantly reduced the proportion of patients with cryptogenic *** registration number NCT02142413.

关键词： routine patients prospective

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Tuning beneficial calcineurin phosphatase activation to counterα-synuclein toxicity in a yeast model of Parkinson’s disease

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Neural Regeneration Research 2025年第1期20卷 199-200页

作者： Srishti Chawla Mikael Molin thomas Nystrom Institute for Biomedicine Sahlgrenska AcademyCentre for Ageing and Health-AgeCapUniversity of GothenburgGothenburgSweden Department of Life Sciences Chalmers University of TechnologyGothenburgSweden

Calcineurin(CN)is a calcium-and calmodulindependent serine/threonine that has been studied in many model organisms including yeast,filamentous fungi,plants,and *** biological functions range from ion homeostasis and virulence in lower eukaryotes to T-cell activation in humans by human nuclear factors of activated *** is a heterodimeric protein consisting of a catalytic subunit,calcineurin A(Cna1p),which contains an active site with a dinuclear metal center,and a regulatory Ca^(2+) binding subunit called calcineurin B(Cnb1p)required to activate *** calcineurin B subunit has been highly conserved through evolution:For example,the mammalian calcineurin B shows 54%identity with calcineurin B from Saccharomyces cerevisiae.

关键词： activation dinuclear conserved

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A simulation study for a cost-effective PET-like detector system intended to track particles in granular assemblies

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Particuology 2024年第1期84卷 117-125页

作者： Josephine Oppotsch Antonios Athanassiadis Miriam Fritsch Fritz-Herbert Heinsius thomas Held Nikoline Hilse Viktor Scherer Matthias Steinke Ulrich Wiedner Ruhr-Universität Bochum Institut für Experimentalphysik I44801 BochumGermany Ruhr-Universität Bochum Lehrstuhl für Energieanlagen und Energieprozesstechnik44801 BochumGermany

Since many industrial applications rely on the processing of densely packed and moving granular ma-terial,obtaining bulk internal information on the particle movement inside the reactors is of great *** information can be delivered by Positron Emission Particle Tracking(PEPT).By marking pellets with a positron-emitting radioisotope,the position of these tracer particles can be determined via the time-of-flight differences of the emitted gamma-ray *** current paper proposes a PET-like detector system based on cost-effective organic plastic scintillators instead of the more common but expensive inorganic *** system is currently under construction and was tested for its resolution and efficiency in this simulation *** Monte Carlo simulations and the software toolkit Geant4,three different geometries(an empty glass box,a generic grate system,and a cubic box of 1 m3 completely filled with pellets)were investigated,leading to a spatial resolution in the millimeter range and an efficiency,defined as the ratio of reconstructed decay locations to simulated decays,of 2.7%,1.4%,and 0.3%.

关键词： Positron emission particle tracking Geant4 Monte Carlo method Time-of-flight Plastic scintillators Silicon photomultipliers(SiPMs)

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Wheat zinc finger protein TaZF interacts with both the powdery mildew AvrPm2 protein and the corresponding wheat Pm2a immune receptor

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Plant Communications 2024年第5期5卷 25-41页

作者： Beatrice Manser Helen Zbinden Gerhard Herren Joel Steger Jonatan Isaksson Stephanie Braunlich thomas Wicker Beat Keller Department of Plant and Microbial Biology University of ZurichZollikerstrasse 1078008 ZurichSwitzerland Agroscope Route de Duillier 501260 NyonSwitzerland BIOREBA AG Christoph Merian-Ring 74153 ReinachSwitzerland

Plant defense responses to pathogens are induced after direct or indirect perception of effector proteins or their activity on host *** fungal–plant interactions,relatively little is known about whether,in addi-tion to avirulence effectors and immune receptors,other proteins contribute to specific *** nucleotide-binding leucine-rich repeat(NLR)immune receptor Pm2a in wheat recognizes the fungal pow-dery mildew effector *** found that the predicted wheat zincfinger TaZF interacts with both the fungal avirulence protein AvrPm2 and the wheat NLR *** further demonstrated that the virulent AvrPm2-H2 variant does not interact with *** silencing in wheat resulted in a reduction but not a loss of Pm2a-mediated powdery mildew *** studies showed that the leucine-rich repeat domain of Pm2a is the mediator of the interaction with *** recruits both Pm2a and AvrPm2 from the cytosol to the nucleus,resulting in nuclear localization of Pm2a,TaZF,and AvrPm2 in *** propose that TaZF acts as a facilitator of Pm2a-dependent AvrPm2 effector *** highlight the importance of identifying effector host targets for characterization of NLR-mediated effector recognition.

关键词： plant immunity plant-fungal interactions pathogen effectors nucleotide-binding leucine-rich repeat immune receptor NLR wheat powdery mildew

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Bacterial plant pathogens affect the locomotor behavior of the insect vector:a case study of Citrus volkameriana-Triozae erytreae-Candidatus Liberibacter asiaticus system

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Insect Science 2024年第3期31卷 901-910页

作者： Arnaud Ameline Alain Karkach thomas Denoirjean Martial Grondin Florencia Molinari Patrick Turpin Helene Delatte Bernard Reynaud UMR CNRS 7058 EDYSAN(Ecologie et Dynamique des Systemes Anthropises) Universite de Picardie Jules VerneAmiensCedexFrance UMR PVBMT(Peuplements végétaux et bioagresseurs en milieu tropical) Universitéde la RéunionSaint PierreLa RéunionFrance

Plant pathogens can alter the behavior of their insect vectors as well as their survival and *** African psyllid,Trioza erytreae,is one of the vectors of Huanglongbing,a citrus disease caused mainly by"Candidatus Liberibacter asiaticus"(CLas).The purpose of this study was to characterize the effects of CLas on the psyllid,*** using Citrus volkamerina plants as the study *** study focused more specifically on the CLas effects prior to and after its acquisition by the psyllid *** results did not support the hypothesis that CLas effects psyllid probing behavior prior to acquisition;few differences were observed between uninfected *** feeding on CLas-infected versus control *** the other hand,compared to psyllids that had completed their development on control plants,the ones that had completed their development on a CLas-infected plant exhibited changes in their behavior(greater velocity),physiology(smaller mass)and biochemistry(lower water and lipid content).Altogether,our results confirm the existence of a marked postacquisition effect on the vector locomotor behavior and a minor preacquisition effect of CLas on the vector behavior,which can be partially explained by physiological and biochemical changes.

关键词： electrical penetration graph Huanglongbing locomotory behavior lipid biomass probing behavior vector manipulation

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