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PINK1 gene mutation by pair truncated sgRNA/Cas9-D10A in cynomolgus monkeys

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Zoological Research 2021年第4期42卷 469-477页

作者： Zhen-Zhen Chen Jian-Ying Wang yu Kang Qiao-Yan Yang Xue-Ying Gu Da-Long Zhi Li Yan Cheng-Zu Long Bin Shen yu-yu niu Faculty of Life Science and Technology Kunming University of Science and TechnologyKunmingYunnan 650500China State Key Laboratory of Primate Biomedical Research Institute of Primate Translational MedicineKunming University of Science and TechnologyKunmingYunnan 650500China State Key Laboratory of Reproductive Medicine Department of Prenatal DiagnosisWomen’s Hospital of Nanjing Medical UniversityNanjing Maternity and Child Health HospitalNanjing Medical UniversityNanjingJiangsu 211166China Leon H Charney Division of Cardiology New York University School of MedicineNew YorkNY 10016USA Department of Dermatology Xijing HospitalFourth Military Medicine UniversityXi’anShaanxi 710032China

Mutations of PTEN-induced kinase I(PINK1)cause early-onset Parkinson’s disease(PD)with selective neurodegeneration in humans.However,current PINK1 knockout mouse and pig models are unable to recapitulate the typical neurodegenerative phenotypes observed in PD patients.This suggests that generating PINK1 disease models in non-human primates(NHPs)that are close to humans is essential to investigate the unique function of PINK1 in primate brains.Paired single guide RNA(sgRNA)/Cas9-D10A nickases and truncated sgRNA/Cas9,both of which can reduce off-target effects without compromising on-target editing,are two optimized strategies in the CRISPR/Cas9 system for establishing disease animal models.Here,we combined the two strategies and injected Cas9-D10A mRNA and two truncated sgRNAs into one-cell-stage cynomolgus zygotes to target the PINK1 gene.We achieved precise and efficient gene editing of the target site in three newborn cynomolgus monkeys.The frame shift mutations of PINK1 in mutant fibroblasts led to a reduction in mRNA.However,western blotting and immunofluorescence staining confirmed the PINK1 protein levels were comparable to that in wild-type fibroblasts.We further reprogramed mutant fibroblasts into induced pluripotent stem cells(iPSCs),which showed similar ability to differentiate into dopamine(DA)neurons.Taken together,our results showed that co-injection of Cas9-D10A nickase mRNA and sgRNA into one-cell-stage cynomolgus embryos enabled the generation of human disease models in NHPs and target editing by pair truncated sgRNA/Cas9-D10A in PINK1 gene exon 2 did not impact protein expression.

关键词： Cas9-D10A Cynomolgus PINK1

Long-term in vivo chimeric cells tracking in non-human primate

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Protein & Cell 2024年第3期15卷 207-222页

作者： Junmo Wu yu Kang Xiang Luo Shaoxing Dai yuxi Shi Zhuoyao Li Zengli Tang Zhenzhen Chen Ran Zhu Pengpeng Yang Zifan Li Hong Wang Xinglong Chen Ziyi Zhao Weizhi ji yuyu niu State Key Laboratory of Primate Biomedical Research Institute of Primate Translational MedicineKunming University of Science and TechnologyKunming 650500China yunnan Key Laboratory of Primate Biomedical Research Kunming 650500China Faculty of Life Science and Technology Kunming University of Science and TechnologyKunming 650500China

Non-human primates(NHPs)are increasingly used in preclinical trials to test the safety and efficacy of biotech-nology therapies.Nonetheless,given the ethical issues and costs associated with this model,it would be highly advantageous to use NHP cellular models in clinical studies.However,developing and maintaining the naive state of primate pluripotent stem cells(PSCs)remains difficult as does in vivo detection of PSCs,thus limiting biotech-nology application in the cynomolgus monkey.Here,we report a chemically defined,xeno-free culture system for culturing and deriving monkey PSCs in vitro.The cells display global gene expression and genome-wide hypometh-ylation patterns distinct from monkey-primed cells.We also found expression of signaling pathways components that may increase the potential for chimera formation.Crucially for biomedical applications,we were also able to integrate bioluminescent reporter genes into monkey PsCs and track them in chimeric embryos in vivo and in vitro.The engineered cells retained embryonic and extra-embryonic developmental potential.Meanwhile,we generated a chimeric monkey carrying bioluminescent cells,which were able to track chimeric cells for more than 2 years in living animals.Our study could have broad utility in primate stem cell engineering and in utilizing chimeric monkey models forclinical studies.

关键词： pluripotent stem cells bioluminescence imaging non-human primates

An integrative mathematical model of microwave ion thruster for mHz-frequency thrust noise analysis

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Chinese Journal of Aeronautics 2024年第4期37卷 121-136页

作者： Xiang niu Hui LIU Daren yu Plasma Propulsion Laboratory Harbin Institute of TechnologyHarbin 150001China

Many high-precision space missions need thrusters to produce thrust with low noise to compensate for disturbances and ensure satellite platform stability. Microwave ion thruster is characterized with a wide thrust range and potential for these missions. A cost-effective and accurate mathematical model is crucial for mHz-frequency thrust noise analysis and feedback controller design. The Particle-In-Cell(PIC) and global models are two common simulation tools. The PIC model is characterized with high accuracy but huge computation cost, which is difficult to analyze long-time performance characteristics. Now, the global model is only used for the discharge chamber with low accuracy and cannot reflect ion extraction properties. In this paper, an integrative mathematical model is built for a 1-cm microwave ion thruster and can reflect ion beamlet divergence and impingement on the Accelerator Grid(AG). Simulation results show good agreement with experiments at 0.06 sccm. However, the model demonstrates worse consistency with experiments when the flux increases to 0.1 sccm, which may be because the influence of neutral gas on the Electron Cyclotron Resonance(ECR) is not considered in the model. A long-time(1000 s) simulation is conducted with this model under 35 μN. It takes 3 hrs, and the thrust noise reaches 1 μN/Hz^(0.5) at 1 mHz.

关键词： Electric propulsion Microwave ion thruster Integrative model Sheath property Ion beamlet divergence Thrust noise Plasma

Highly Thermoconductive,Strong Graphene‑Based Composite Films by Eliminating Nanosheets Wrinkles

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Nano-Micro Letters 2024年第1期16卷 328-340页

作者： Guang Xiao Hao Li Zhizhou yu Haoting niu Yagang Yao College of Engineering and Applied Sciences Jiangsu Key Laboratory of Artificial Functional Materialsand Collaborative Innovation Center of Advanced MicrostructuresNational Laboratory of Solid State MicrostructuresNanjing UniversityNanjing 210093People’s Republic of China Institute of Laser Manufacturing Henan Academy of SciencesZhengzhou 450052People’s Republic of China Center for Quantum Transport and Thermal Energy Science School of Physics and TechnologyNanjing Normal UniversityNanjing 210023People’s Republic of China

Graphene-based thermally conductive composites have been proposed as effective thermal management materials for cooling high-power electronic devices.However,when flexible graphene nanosheets are assembled into macroscopic thermally conductive composites,capillary forces induce shrinkage of graphene nanosheets to form wrinkles during solution-based spontaneous drying,which greatly reduces the thermal conductivity of the composites.Herein,graphene nanosheets/aramid nanofiber(GNS/ANF)composite films with high thermal conductivity were prepared by in-plane stretching of GNS/ANF composite hydrogel networks with hydrogen bonds andπ-πinteractions.The in-plane mechanical stretching eliminates graphene nanosheets wrinkles by suppressing inward shrinkage due to capillary forces during drying and achieves a high in-plane orientation of graphene nanosheets,thereby creating a fast in-plane heat transfer channel.The composite films(GNS/ANF-60 wt%)with eliminated graphene nanosheets wrinkles showed a significant increase in thermal conductivity(146 W m^(−1)K^(−1))and tensile strength(207 MPa).The combination of these excellent properties enables the GNS/ANF composite films to be effectively used for cooling flexible LED chips and smartphones,showing promising applications in the thermal management of high-power electronic devices.

关键词： Graphene Aramid nanofiber Wrinkles elimination In-plane stretching Thermal conductivity

Intraspecific floral colour variation in three Pedicularis species

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Plant Diversity 2024年第2期46卷 274-279页

作者： Qiu-yu Zhang Zhe Chen Hang Sun Yang niu State Key Laboratory of Plant Diversity and Specialty Crops Kunming Institute of BotanyChinese Academy of SciencesKunming 650201YunnanChina University of Chinese Academy of Sciences Beijing 100049China

Flower constancy describes the phenomenon that pollinators tend to successively visit flowers of a single species during foraging,reducing reproductive interference in natural communities.The extent of flower constancy is largely determined by the floral traits of co-flowering species.Both higher inter-specific and lower intraspecific differences of floral traits should contribute to a higher level of flower constancy.However,previous studies mainly focused on interspecific difference,and the intraspecific variation(consistency)of floral traits received much less attention.We hypothesise that selection may favour lower intraspecific floral trait variation in communities composed of multiple co-flowering congeners.We investigated the floral colour variation of three focal Pedicularis species that share pollinators in 19communities composed of either single or multiple Pedicularis species.Colour was quantified using image-based colour analysis as perceived by pollinators.We found that most of the intrapopulation floral colour variation was below the colour discrimination threshold of bumblebees,implying strongly constrained by the visual selection by pollinators.Contrary to the hypothesis,there is no significant difference in intraspecific floral colour variation between different community contexts.It may be due to the relatively large interspecific floral colour differences of most co-flowering species.The influence of community context on intraspecific variation may be reflected in floral traits other than colours.

关键词： Flower constancy Floral colour variation Plantepollinator interactions Pollinator vision

Fc receptor-like 5(FCRL5)-directed CAR-T cells exhibit antitumor activity against multiple myeloma

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Signal Transduction and Targeted Therapy 2024年第2期9卷 724-737页

作者： Zhengyu yu Hexian Li Qizhong Lu Zongliang Zhang Aiping Tong Ting niu Department of Hematology State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengdu 610041China

Multiple myeloma(MM)remains a challenging hematologic malignancy despite advancements in chimeric antigen receptor T-cell(CAR-T)therapy.Current targets of CAR-T cells used in MM immunotherapy have limitations,with a subset of patients experiencing antigen loss resulting in relapse.Therefore,novel targets for enhancing CAR-T cell therapy in MM remain needed.Fc receptor-like 5(FCRL5)is a protein marker with considerably upregulated expression in MM and has emerged as a promising target for CAR-T cell therapeutic interventions,offering an alternative treatment for MM.To further explore this option,we designed FCRL5-directed CAR-T cells and assessed their cytotoxicity in vitro using a co-culture system and in vivo using MM cell-derived xenograft models,specifically focusing on MM with gain of chromosome 1q21.Given the challenges in CAR-T therapies arising from limited T cell persistence,our approach incorporates interleukin-15(IL-15),which enhances the functionality of central memory T(TCM)cells,into the design of FCRL5-directed CAR-T cells,to improve cytotoxicity and reduce T-cell dysfunction,thereby promoting greater CAR-T cell survival and efficacy.Both in vitro and xenograft models displayed that FCRL5 CAR-T cells incorporating IL-15 exhibited potent antitumor efficacy,effectively inhibiting the proliferation of MM cells and leading to remarkable tumor suppression.Our results highlight the capacity of FCRL5-specific CAR-T cells with the integration of IL-15 to improve the therapeutic potency,suggesting a potential novel immunotherapeutic strategy for MM treatment.

关键词： directed thereby offering

The effect of Ti and Zr content on the structure,mechanics and energy-release characteristics of Ti—Zr—Ta alloys

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Defence Technology（防务技术） 2024年第1期31卷 343-350页

作者： Jia-yu Meng Jing-zhi He Bin Zhang Jin Chen Shun Li Dun niu yu Tang Xi’an Modern Chemistry Research Institute Xi'an710065China College of Aerospace Science and Engineering National University of Defense TechnologyChangsha410073China

Energetic structural materials(ESMs)are a new type of structural materials with bearing and damage characteristics.In this work the microstructure,mechanical properties and energy release characteristics of multi-element Ti-Zr-Ta alloys with good casting performance were studied.The microstructure of the Ti_(x)ZrTa alloys gradually change from BCC+HCP to single BCC structure with the increase of Ti.While the Ti_(2)Zr_(y)Ta alloys was still uniform and single BCC structure with the increase of Zr.The evolution of microstructure and composition then greatly affect the mechanical properties and energy-release characteristics of Ti-Zr-Ta alloys.The synergistic effect of dual phase structure increases the fracture strain of Ti_(x)ZrTa(x=0.2,0.5)with the Ti content decreases,while the fracture strain of Ti_(x)ZrTa(x=2.0,3.0,4.0)gradually increase with the Ti content increases caused by the annihilation of the obstacles for dislocation movement.And as Zr content increases,the fracture strain of Ti_(2)Zr_(y)Ta alloys decrease,then the oxidation reaction rate and fragmentation degree gradually increase.The higher oxidation rate and the lager exposed oxidation area jointly leads the higher releasing energy efficiency of Ti_(x)ZrTa alloys with low Ti content and Ti_(2)Zr_(y)Ta alloys with high Zr content.

关键词： Energetic structural materials Ti-Zr-Ta Multi-element alloy Energy release characteristics

Development of wet adhesion of honeybee arolium incorporated polygonal structure with three-phase composite interfaces

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Friction 2024年第2期12卷 215-230页

作者： Lulu LIANG Jieliang ZHAO Qun niu Li yu Xiangbing WU Wenzhong WANG Shaoze YAN Zhenglei yu School of Mechanical Engineering Beijing Institute of TechnologyBeijing 100081China Division of Intelligent and Biomechanical Systems State Key Laboratory of TribologyDepartment of Mechanical EngineeringTsinghua UniversityBeijing 100084China Key of Bionic Engineering Ministry of EducationJilin UniversityChangchun 130022China

Inspired by the dynamic wet adhesive systems in nature,various artificial adhesive surfaces have been developed but still face different challenges.Crucially,the theoretical mechanics of wet adhesives has never been sufficiently revealed.Here,we develop a novel adhesive mechanism for governing wet adhesion and investigate the biological models of honeybee arolium for reproducing the natural wet adhesive systems.Micro-nano structures of honeybee arolium and arolium-prints were observed by Cryogenic scanning electron microscopy(Cryo-SEM),and the air pockets were found in the contact interface notably.Subsequently,the adhesive models with a three-phase composite interface(including air pockets,liquid secretion,and hexagonal frames of arolium),were formed to analyze the wet adhesion of honeybee arolium.The results of theoretical calculations and experiments indicated an enhanced adhesive mechanism of the honeybee by liquid self-sucking effects and air-embolism effects.Under these effects,normal and shear adhesion can be adjusted by controlling the proportion of liquid secretion and air pockets in the contact zone.Notably,the air-embolism effects contribute to the optimal coupling of smaller normal adhesion with greater shear adhesion,which is beneficial for the high stride frequency of honeybees.These works can provide a fresh perspective on the development of bio-inspired wet adhesive surfaces.

关键词： honeybee arolium air pockets wet adhesion a three-phase interface self-sucking effects air-embolism effects

Influence of carbides and pores on the localized deformation of nickel-based single-crystal superalloys

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Progress in Natural Science:Materials International 2024年第3期34卷 562-568页

作者： Rengeng Li yu Zhang Haoyi niu Hao Wang Hao Wu Key Laboratory for Light-weight Materials Nanjing Tech University College of Materials Science and Engineering Chongqing University CRRC Qishuyan Institute Co.Ltd.

The carbides and pores play a critical role in the cracking tendencies of nickel-based single-crystal superalloys during deformation. In the present study, the deformation mechanism and local strain evolution behavior around carbides and pores were studied through in-situ tensile deformation experiments. The findings indicate that multiple slip systems are easily activated during tensile deformation in single-crystal alloys. Furthermore, the strain localization in carbides is influenced by their morphology, with rod-like and flake-like carbides demonstrating an increased likelihood of cracking during deformation. The strain localization adjacent to pores is markedly more intense, rendering these areas particularly susceptible to cracking. Our work therefore offers a theoretical foundation for enhancing the mechanical properties of nickel-based single-crystal superalloys by controlling carbide morphology and pore formation.

关键词： Carbides In-situ tensile Nickel-based single-crystal Pores Strain evolution