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Engineered human pluripotent stem cell-derived natural killer cells with PD-L1 responsive immunological memory for enhanced immunotherapeutic efficacy

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Bioactive Materials 2023年第9期27卷 168-180页

作者： Yun Chang Gyuhyung Jin Weichuan Luo Qian Luo Juhyung Jung Sydney N.Hummel Sandra Torregrosa-Allen Bennett D.Elzey Philip S.Low Xiaojun Lance Lian Xiaoping Bao Davidson School of Chemical Engineering Purdue UniversityWest LafayetteIN47907USA Purdue university Institute for Cancer Research West LafayetteIN47907USA Department of Comparative Pathobiology Purdue UniversityWest LafayetteIN 47907USA Department of Chemistry Purdue UniversityWest LafayetteIN47907USA Department of Biomedical Engineering The Huck Institutes of the Life SciencesDepartment of BiologyThe Pennsylvania State UniversityUniversity ParkPA16802USA

Adoptive chimeric antigen receptor(CAR)-engineered natural killer(NK)cells have shown promise in treating various ***,limited immunological memory and access to sufficient numbers of allogenic donor cells have hindered their broader preclinical and clinical ***,we first assess eight different CAR constructs that use an anti-PD-L1 nanobody and/or universal anti-fluorescein(FITC)single-chain variable fragment(scFv)to enhance antigen-specific proliferation and anti-tumor cytotoxicity of NK-92 cells against heterogenous solid *** next genetically engineer human pluripotent stem cells(hPSCs)with optimized CARs and differentiate them into functional dual CAR-NK *** tumor microenvironment responsive anti-PD-L1 CAR effectively promoted hPSC-NK cell proliferation and cytotoxicity through antigen-dependent activation of phosphorylated STAT3(pSTAT3)and pSTAT5 signaling pathways via an intracellular truncated IL-2 receptorβ-chain(ΔIL-2Rβ)and STAT3-binding tyrosine-X-X-glutamine(YXXQ)***-tumor activities of PD-L1-induced memory-like hPSC-NK cells were further boosted by administering a FITC-folate bi-specific adapter that bridges between a programmable anti-FITC CAR and folate receptor alpha-expressing breast tumor ***,our hPSC CAR-NK engineering platform is modular and could constitute a realistic strategy to manufacture off-the-shelf CAR-NK cells with immunological memory-like phenotype for targeted immunotherapy.

关键词： Natural killer cells Human pluripotent stem cells Immunological memory Immunotherapy Chimeric antigen receptor

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New Record Ocean Temperatures and Related Climate Indicators in 2023

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Advances in Atmospheric Sciences 2024年第6期41卷 1068-1082页

作者： Lijing CHENG John ABRAHAM Kevin E.TRENBERTH Tim BOYER Michael EMANN Jiang ZHU Fan WANG Fujiang YU Ricardo LOCARNINI John FASULLO Fei ZHENG Yuanlong LI Bin ZHANG Liying WAN Xingrong CHEN Dakui WANG Licheng FENG Xiangzhou SONG Yulong LIU Franco RESEGHETTI Simona SIMONCELLI Viktor GOURETSKI Gengxin CHEN Alexey MISHONOV Jim REAGAN Karina VON SCHUCKMANN Yuying PAN Zhetao TAN Yujing ZHU Wangxu WEI Guancheng LI Qiuping REN Lijuan CAO Yayang LU International Center for Climate and Environment Sciences Institute of Atmospheric PhysicsChinese Academy of SciencesBeijing 100029China university of St.Thomas School of EngineeringMinnesota 55105USA NSF National Center for Atmospheric Research BoulderColorado 80307USA university of Auckland Auckland 1010New Zealand National Oceanic and Atmospheric Administration National Centers for Environmental InformationSilver SpringMaryland 20910USA Department of Earth and Environmental Science University of PennsylvaniaPhiladelphiaPennsylvania 19104USA Institute of Oceanology Chinese Academy of SciencesQingdao 266071China National Marine Environmental Forecasting Center Ministry of Natural Resources of ChinaBeijing 100081China Oceanographic Data Center Chinese Academy of SciencesQingdao 266071China College of Oceanography Hohai UniversityNanjing 210098China National Marine Data and Information Service Tianjin 300171China Italian National Agency for New Technologies Energy and Sustainable Economic DevelopmentS.Teresa Research CenterLerici 19032Italy Istituto Nazionale di Geofisica e Vulcanologia Sede di BolognaBologna 40128Italy South China Sea Institute of Oceanology Chinese Academy of SciencesGuangzhou 510301China ESSIC/CISESS-MD University of MarylandCollege ParkMD20740USA Mercator Ocean International Toulouse 31400France Eco-Environmental Monitoring and Research Center Pearl River Valley and South China Sea Ecology and Environment AdministrationMinistry of Ecology and EnvironmentPRCGuangzhou 510611China National Meteorological Information Center China Meteorological AdministrationBeijing 100081China International Research Center of Big Data for Sustainable Development Goals Beijing 100094China

The global physical and biogeochemical environment has been substantially altered in response to increased atmospheric greenhouse gases from human *** 2023,the sea surface temperature(SST)and upper 2000 m ocean heat content(OHC)reached record *** 0–2000 m OHC in 2023 exceeded that of 2022 by 15±10 ZJ(1 Zetta Joules=1021 Joules)(updated IAP/CAS data);9±5 ZJ(NCEI/NOAA data).The Tropical Atlantic Ocean,the Mediterranean Sea,and southern oceans recorded their highest OHC observed since the *** with the onset of a strong El Niño,the global SST reached its record high in 2023 with an annual mean of~0.23℃ higher than 2022 and an astounding>0.3℃ above 2022 values for the second half of *** density stratification and spatial temperature inhomogeneity indexes reached their highest values in 2023.

关键词： ocean heat content salinity stratification global warming climate

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Plant physiological changes along an encroachment gradient: an assessment of US Mid-Atlantic serpentine barrens

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Journal of Plant Ecology 2018年第6期11卷 853-865页

作者： Nicole A.Havrilchak Jessica L.Schedlbauer Department of Biology West Chester University750 S.Church StreetWest ChesterPA 19383USA

Aims Serpentine barrens of the Mid-Atlantic United States are globally rare,grass-dominated ecosystems thought to exclude C3 spe-cies and characterized by unique soil ***,like many grassland ecosystems globally,these sites are presently facing encroachment by surrounding *** this ecosystem,the tendril climbing vine,Smilax rotundifolia,forms dense thickets around bar-rens that typically precede forest *** numerous factors speculatively initiate and promote encroachment in these systems,few studies have examined photosynthetic responses of serpentine grasses to changes in resource availability initiated by encroachers or physiological ability of encroaching *** to colonize high-light barren *** sought to under-stand both environmental and physiological dynamics of encroach-ment along an irradiance gradient in these *** At three serpentine barren sites in southeastern pennsylvania,physiological responses of the native grasses Sorghastrum nutans and Schizachyrium scoparium to increased shading by ***-folia were ***,the physiological performance of *** in the forest understory was compared to that in sunlit barrens ***-saturated photosynthesis(A_(sat)),stomatal conductance(g_(s)),instantaneous transpiration efficiency(ITE),maximum efficiency of photosystem II(F_(v)/F_(m)),midday leaf water potential(ψ_(leaf))and specific leaf area(SLA)were measured for all species over the course of the 2014 growing ***-way analyses of variance were used to assess changes in these param-eters across growing environments,as well as seasonally for each *** regression analyses were also performed to inves-tigate the influence of vapor pressure deficit(D)and leaf tempera-ture(T_(leaf))on A_(sat) and *** Findings Light-saturated photosynthesis was significantly greater in ***-difolia growing in sun than in the shade(P<0.001)and early in th

关键词： encroachment photosynthesis serpentine barren Schizachyrium scoparium Smilax rotundifolia Sorghastrum nutans

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A Task Allocation Method for Stream Processing with Recovery Latency Constraint

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Journal of Computer Science & Technology 2018年第6期33卷 1125-1139页

作者： Hong-Liang Li Jie Wu Zhen Jiang Xiang Li Xiao-Hui Wei College of Computer Science and Technology Jilin University Changchun 130012 China Key Laboratory of Symbolic Computation and Knowledge Engineering of the Ministry of Education Changchun 130012 China Department of Computer and Information Sciences Temple University Philadelphia PA 19122 U.S.A. Department of Computer Science West Chester University of Pennsylvania West Chester PA 19383 U.S.A.

Stream processing applications continuously process large amounts of online streaming data in real time or nearreal time. They have strict latency constraints. However, the continuous processing makes them vulnerable to any failures,and the recoveries may slow down the entire processing pipeline and break latency constraints. The upstream backupscheme is one of the most widely applied fault-tolerant schemes for stream processing systems. It introduces complexbackup dependencies to tasks, which increases the difficulty of controlling recovery latencies. Moreover, when dependenttasks are located on the same processor, they fail at the same time in processor-level failures, bringing extra recovery latencies that increase the impacts of failures. This paper studies the relationship between the task allocation and therecovery latency of a stream processing application. We present a correlated failure effect model to describe the recoverylatency of a stream topology in processor-level failures under a task allocation plan. We introduce a recovery-latency awaretask allocation problem （RTAP） that seeks task allocation plans for stream topologies that will achieve guaranteed recoverylatencies. We discuss the difference between RTAP and classic task allocation problems and present a heuristic algorithmwith a computational complexity of O（n log2 n） to solve the problem. Extensive experiments were conducted to verify thecorrectness and effectiveness of our approach. It improves the resource usage by 15%-20% on average.

关键词： stream processing task allocation fault-tolerance upstream backup, recovery latency

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A comprehensive review and characterization of nasopharyngeal carcinoma clinical trials

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World Journal of Otorhinolaryngology-Head and Neck Surgery 2023年第2期9卷 174-182页

作者： Katherine Xu Emma De Ravin Neeraj Suresh Robert M.Brody Karthik Rajasekaran Department of Otorhinolaryngology-Head&Neck Surgery University of PennsylvaniaPhiladelphiaPennsylvaniaUSA Perelman School of Medicine at the university of pennsylvania PhiladelphiaPennsylvaniaUSA Leonard Davis Institute of Health Economics University of PennsylvaniaPhiladelphiaPennsylvaniaUSA

Objective:Although standard of care for primary nasopharyngeal carcinoma(NPC)is chemoradiotherapy,there remains no consensus on management of recurrent or metastatic *** characterized recent clinical trials on NPC to assess trends in NPC treatment and establish promising areas for future *** Design:Retrospective database ***:*** ***:Retrospective review of all NPC trials from November 1999 to June *** each study,the following variables were extracted:study characteristics,intervention,outcome measures,and inclusion *** searches via PubMed and Google scholar determined trial publication ***:A total of 448 clinical trials were identified:72(16%)observational and 376(84%)interventional,of which there were 30(8%)Phase I,183(49%)Phase II,86 Phase III(23%),and 5(1%)Phase IV ***-four percent of trials included only primary NPC while 111(25%)exclusively studied recurrent *** most common interventions were cisplatin(n=64)and intensity modulated radiation therapy(n=54);there were 38 trials involving PD-1 monoclonal ***-four studies examined quality of life measures,including xerostomia and *** the completed studies,53.2%have published *** patient accrual was the most common reason for premature study ***:Novel immunotherapies have been increasingly incorporated into NPC studies in recent years,however,chemotherapy and radiation,despite their numerous side effects,are still widely used due to their clinical *** trials are warranted to determine the optimal therapeutic regimens to decrease relapse rates and side effects.

关键词： chemoradiotherapy clinical trial immunotherapy nasopharyngeal carcinoma nasopharyngeal neoplasms

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Analytical and numerical modeling of optical second harmonic generation in anisotropic crystals using #SHAARP package

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npj Computational Materials 2022年第1期8卷 2343-2354页

作者： Rui Zu Bo Wang Jingyang He Jian-Jun Wang Lincoln Weber Long-Qing Chen Venkatraman Gopalan Department of Materials Science and Engineering The Pennsylvania State UniversityUniversity ParkPA16802USA Materials Science Division Lawrence Livermore National LaboratoryLivermoreUSA Department of Engineering Science and Mechanics The Pennsylvania State UniversityUniversity ParkPA16802USA Department of Mathematics The Pennsylvania State UniversityUniversity ParkPA16802USA Department of Physics Pennsylvania State UniversityUniversity ParkPA16802USA

Electric-dipole optical second harmonic generation(SHG)is a second-order nonlinear process that is widely used as a sensitive probe to detect broken inversion symmetry and local polar *** modeling of the SHG polarimetry of a nonlinear optical material is essential to extract its point group symmetry and the absolute nonlinear *** literature on SHG analysis involves numerous approximations and a wide range of(in)*** have developed an open-source package called the Second Harmonic Analysis of Anisotropic Rotational Polarimetry(♯***)which derives analytical and numerical solutions of reflection SHG polarimetry from a single interface(.si)for bulk homogeneous crystals with arbitrary symmetry group,arbitrary crystal orientation,complex and anisotropic linear dielectric tensor with frequency dispersion,a general SHG tensor and arbitrary light polarization.♯*** enables accurate modeling of polarimetry measurements in reflection geometry from highly absorbing crystals or wedge-shaped transparent *** package is extendable to multiple interfaces.

关键词： arbitrary symmetry harmonic

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A quiet place:The impact of the word"quiet"on clinical workload

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World Journal of Otorhinolaryngology-Head and Neck Surgery 2023年第1期9卷 91-96页

作者： Beatrice C.Go Kevin Chorath Amy Schettino Vincent Anagnos Ivy Maina Laura Henry Lukas Dumberger Neel Sangal Vasiliki Triantafillou Solomon Husain Chad Sudoko Evan Cretney Karthik Rajasekaran Department of Otorhinolaryngology University of PennsylvaniaPhiladelphiaPennsylvaniaUSA Department of Otorhinolaryngology Leonard Davis Institute of Health EconomicsUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA

Purpose:This study aimed to determine the impact of uttering the word"quiet"on clinical workload during the overnight otolaryngology call shift and understand the factors contributing to resident *** and Methods:A multicenter,single-blind,randomized-controlled trial was conducted.A total of 80 overnight call shifts covered by a pool of 10 residents were randomized to the quiet or to the control *** the start of shift,residents were asked to state aloud,"Today will be a quiet night"(quiet group)or"Today will be a good night"(control group).Clinical workload,as measured by number of consults,was the primary *** measures included number of sign-out tasks,unplanned inpatient and operating room visits,number of phone calls and hours of sleep,and self-perceived ***:There was no difference in the number of total(P=0.23),nonurgent(P=0.18),and urgent(P=0.18)*** at signout,total phone calls,unplanned inpatient visits,and unplanned operating room visits did not differ between the control and quiet *** there were more unplanned operating room visits in the quiet group(29,80.6%)compared to the control group(34,94.4%),this was not found to be significant(P=0.07).The majority of residents reported feeling"not busy"during control nights(18,50.0%)compared to feeling"somewhat busy"during quiet nights(17,47.2%;P=0.42).Conclusion:Contrary to popular belief,there is no clear evidence that uttering the word"quiet"significantly increases clinical workload.

关键词： burnout call schedule quiet resident workload wellness

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A Temporal Convolutional Network Based Hybrid Model for Short-term Electricity Price Forecasting

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CSEE Journal of Power and Energy Systems 2024年第3期10卷 1119-1130页

作者： Haoran Zhang Weihao Hu Di Cao Qi Huang Zhe Chen Frede Blaabjerg School of Mechanical and Electrical Engineering University of Electronic Science and Technology of ChinaChengduChina Department of Energy Technology Aalborg UniversityAalborgDenmark IEEE

Electricity prices have complex features,such as high frequency,multiple seasonality,and *** factors will make the prediction of electricity prices ***,accurate electricity price prediction is important for energy producers and consumers to develop bidding *** improve the accuracy of prediction by using each algorithms’advantages,this paper proposes a hybrid model that uses the Empirical Mode Decomposition(EMD),Autoregressive Integrated Moving Average(ARIMA),and Temporal Convolutional Network(TCN).EMD is used to decompose the electricity prices into low and high frequency *** frequency components are forecasted by the ARIMA model and the high frequency series are predicted by the TCN *** results using the realistic electricity price data from pennsylvania-New Jersey-Maryland(PJM)electricity markets show that the proposed method has a higher prediction accuracy than other single methods and hybrid methods.

关键词： Autoregressive integrated moving average model electricity price forecasting empirical mode decomposition temporal convolutional network

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Robust genome and RNA editing via CRISPR nucleases in PiggyBac systems

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Bioactive Materials 2022年第8期7卷 313-320页

作者： Yuqian Jiang Rachel Catherine Hoenisch Yun Chang Xiaoping Bao Craig E.Cameron Xiaojun Lance Lian Department of Biomedical Engineering Pennsylvania State UniversityUniversity ParkPA16802USA Huck Institutes of the Life Sciences Pennsylvania State UniversityUniversity ParkPA16802USA Department of Biology Pennsylvania State UniversityUniversity ParkPA16802USA Davidson School of Chemical Engineering Purdue UniversityWest LafayetteIN47907USA Department of Microbiology and Immunology University of North Carolina School of MedicineChapel HillNC27599USA

CRISPR/Cas-mediated genome editing in human pluripotent stem cells(hPSCs)offers unprecedented opportunities for developing in vitro disease modeling,drug screening and cell-based *** efficiently deliver the CRISPR components,here we developed two all-in-one vectors containing Cas9/gRNA and inducible Cas13d/gRNA cassettes for robust genome editing and RNA interference *** vectors utilized the PiggyBac transposon system,which allows stable expression of CRISPR components in *** Cas9 vector PB-CRISPR exhibited high efficiency(up to 99%)of inducing gene knockout in both protein-coding genes and long non-coding *** other inducible Cas13d vector achieved extremely high efficiency in RNA knockdown(98%knockdown for CD90)with optimized gRNA *** together,our PiggyBac CRISPR vectors can serve as powerful toolkits for studying gene functions in hPSCs.

关键词： CRISPR-Cas9 Genome editing Cas13d RNA editing PiggyBac transposon Human pluripotent stem cells

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α-Synuclein arginylation in the human brain

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Translational Neurodegeneration 2022年第1期11卷 654-666页

作者： Jun Zhao Buyan Pan Marie Fina Yun Huang Marie Shimogawa Kelvin C.Luk Elizabeth Rhoades EJames Petersson Dawei W.Dong Anna Kashina Department of Biomedical Sciences University of Pennsylvania School of Veterinary MedicinePhiladelphiaPennsylvania 19104USA Department of Chemistry University of Pennsylvania School of Arts and SciencesPhiladelphiaPennsylvania 19104USA Center for Neurodegenerative Disease Research Department of Pathology and Laboratory MedicineUniversity of Pennsylvania Perelman School of MedicinePhiladelphiaPennsylvania 19104USA.

Background: Alpha-synuclein (α-syn) exhibits pathological misfolding in many human neurodegenerative disorders. We previously showed that α-syn is arginylated in the mouse brain and that lack of arginylation leads to neurodegen-eration in mice. Methods: Here, we tested α-syn arginylation in human brain pathology using newly derived antibodies in combina-tion with western blotting, biochemical assays, and experiments in live neurons. Results: We found that α-syn was arginylated in the human brain on E46 and E83, two sites previously implicated in α-syn pathology and familial cases of Parkinson’s disease. The levels of arginylation in different brain samples ranged between ~ 3% and ~ 50% of the total α-syn pool, and this arginylation nearly exclusively concentrated in the subcellu-lar α-syn fraction that sedimented at low centrifugation speeds and appeared to be simultaneously targeted by multi-ple posttranslational modifications. Arginylated α-syn was less susceptible to S129 phosphorylation and pathological aggregation in neurons. The arginylation level inversely correlated with the overall α-syn levels and with patient age, suggesting a possible causal relationship between arginylation decline and α-syn-dependent neuropathology. Conclusion: We propose that α-syn arginylation constitutes a potential neuroprotective mechanism that prevents its abnormal accumulation during neurodegeneration and aging in the human brain.

关键词： Arginylation Neurodegeneration Aging α-Synuclein

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