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Minimizing the ratio of ionizable lipid in lipid nanoparticles for in vivo base editing

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National Science Review 2024年第6期11卷 285-293页

作者： Qiubing Chen Xuebin Wang Yizhou Zhang Ming Tian Junyi Duan ying Zhang hao Yin Departments of Urology and Laboratory Medicine Frontier Science Center for Immunology and Metabolism Medical Research InstituteZhongnan Hospital of Wuhan UniversityWuhan University State Key Laboratory of Virology Tai Kang Center for Life and Medical Sciences Tai Kang Medical SchoolWuhan University Department of Rheumatology and Immunology Zhongnan Hospital of Wuhan UniversityWuhan University Wuhan Research Center for Infectious Diseases and Cancer Chinese Academy of Medical Sciences RNA Institute Wuhan University

Lipid nanoparticles(LNPs) have gained clinical approval as carriers for both siRNA and mRNA. Among the crucial components of LNPs, ionizable lipids play a pivotal role in determining the efficiency of RNA delivery. In this study, we synthesized a series of ionizable lipids, denoted as HTO, with a higher count of hydroxyl groups compared to SM-102. Remarkably, LNPs based on HTO12 lipid demonstrated comparable mRNA delivery efficiency and biosafety to those based on SM-102. However, the former reduced the ratio of ionizable lipid/total lipids to mRNA in LNPs by 2.5 times compared to SM-102. The HTO12 LNP efficiently encapsulated adenine base editor mRNA and sgRNA targeting Pcsk9, leading to substantial gene editing within the liver of mice and effective reduction of the target protein. Our study underscores that ionizable lipids with multiple hydroxyl groups may facilitate an improved lipid-to-mRNA ratio to minimize the dosage of ionizable lipids for in vivo delivery.

关键词： ionizable lipid lipid nanoparticle mRNA delivery base editor delivery Pcsk9

DNA vaccine prime and replicating vaccinia vaccine boost induce robust humoral and cellular immune responses against MERS-CoV in mice

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Virologica Sinica 2024年第3期39卷 490-500页

作者： Xiuli shen Shuhui Wang Yanling hao Yuyu Fu Li Ren Dan Li Wenqi Tang Jing Li Ran Chen Meiling Zhu Shuo Wang ying Liu Yiming Shao National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases National Center for AIDS/STD Control and PreventionChinese Center for Disease Control and PreventionBeijing 102206China Changping Laboratory Yard 28Science Park RoadChangping DistrictBeijing 102206China State Key Laboratory for Diagnosis and Treatment of Infectious Diseases National Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhou 310003China

As of December 2022,2603 laboratory-identified Middle East respiratory syndrome coronavirus(MERS-CoV)infections and 935 associated deaths,with a mortality rate of 36%,had been reported to the World Health Organization(WHO).However,there are still no vaccines for MERS-CoV,which makes the prevention and control of MERS-CoV *** this study,we generated two DNA vaccine candidates by integrating MERS-CoV Spike(S)gene into a replicating Vaccinia Tian Tan(VTT)*** to homologous immunization with either vaccine,mice immunized with DNA vaccine prime and VTT vaccine boost exhibited much stronger and durable humoral and cellular immune *** immunized mice produced robust binding antibodies and broad neutralizing antibodies against the EMC2012,England1 and KNIH strains of ***-Boost immunization also induced strong MERS-S specific T cells responses,with high memory and poly-functional(CD107a-IFN-γ-TNF-α)effector CD8t T *** conclusion,the research demonstrated that DNA-Prime/VTT-Boost strategy could elicit robust and balanced humoral and cellular immune responses against *** study not only provides a promising set of MERS-CoV vaccine candidates,but also proposes a heterologous sequential immunization strategy worthy of further development.

关键词： MERS-CoV VTT vaccine DNA vaccine Humoral and cellular immune responses Prime/boost strategy

Combination of iron flocculation and qPCR for quantitative evaluation of virus-shedding intensity of goldfish Carassius auratus infected with cyprinid herpesvirus 2 in the water and the effect of sodium chlorite powder in blocking waterborne horizontal viral transmission

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Aquaculture and Fisheries 2024年第4期9卷 617-625页

作者： Yufei Zhai Fei shen hao Wang Liqun Lu National Pathogen Collection Center for Aquatic Animals Shanghai Ocean UniversityShanghai201306China Key Laboratory for Freshwater Aquatic Genetic Resources at Shanghai Ocean University Ministry of Agriculture and Rural AffairsShanghai201306China College of Fisheries and Life Science Shanghai Ocean UniversityShanghai201306China

Cyprinid herpesvirus 2(CyHV-2),a member of the Alloherpesviridae family belonging to the genus Cyprinivirus,was initially isolated from goldfish(Carassius auratus)and has been recently emerging as a virulent pathogen for cultured prussian carp(Carassius auratus gibelio)*** this study,a novel and effective method for concentration and quantification of live CyHV-2 virions from water was successfully established through coupling the iron flocculation with real time qPCR ***,the shedding intensity of CyHV-2 in fish-tank water from artificially-challenged goldfish(25 fish/20 L)was monitored continuously for 7 days on a daily basis through quantitating viral genomic copy numbers by qPCR,and the maximum shedding level was determined to be 105 copies/*** transmission research system was established by inoculating healthy goldfish in water spiked with serial dilution of CyHV-2 virions ranging from 107 to 103 copies/*** results indicated that water-borne CyHV-2 efficiently caused the infection of tested goldfish even in a concentration of 103 copies/L,and the overall transmission efficacy was not linearly correlated with the level of input virus in the fish *** disinfectant Composite Sodium Chlorite Powder(CSCP)has been widely applied in aquaculture to control microbial infection through direct spill in the water,and its effect in inactivating the CyHV-2 infectivity remains *** further determined that the EC50 of CSCP against 3.89 TCID50/mL CyHV-2 was close to 15.625μg/mL in vitro,and application of CSCP in a level as high as 60μg/mL(the safety concentration of CSCP for goldfish)couldn’t protect goldfish from CyHV-2 challenge through ***,the disinfectant CSCP was regarded as none-effective for blocking CyHV-2 transmission in water during ***,our data provided quantitative data to demonstrate the shedding intensity of CyHV-2 in water,and CSCP was shown to be not effective in blocking water-borne horizontal

关键词： Cyprinid herpesvirus 2 Iron flocculation Virus shedding Water-borne horizontal transmission Composite sodium chlorite powder

A 27 GHz,simple 2-bit 1×8 phased array

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Journal of Electronic Science and Technology 2024年第3期22卷 26-34页

作者： Jun-Xian Liu Yun-ying Man hao Yang Peng Yang School of Electronic Science and Engineering University of Electronic Science and Technology of ChinaChengdu611731China

This study demonstrates a simple 2-bit phased array operating at 27 GHz that supports one-dimensional beam scanning with left-handed circular polarization(LHCP).The antenna is constructed using a compact four-layer printed circuit board(PCB)structure,consisting of a 90°phase shifter layer with microstrip structures,a ground(GND)layer,a direct current(DC)control layer,and a circularly polarized annular radiation patch layer with 1-bit phase *** on the proposed unit structure,a 1×8 array with half-wavelength inter-element spacing was designed and *** results show that the array achieves a peak gain of 10.23 dBi and is capable of beam scanning within±50°.

关键词： 27 GHz 2-bit P-i-n diodes Phased array Reconfigurable antennas

Synthetic Studies toward Pseudolaric Acids:Radical Cyclization to Form Bridged Scaffold

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Chinese Journal of Chemistry 2024年第15期42卷 1699-1705页

作者： Yujie Niu Minggui Lin hao Cui Yanji Huang Yang shen Yandong Zhang State Key Laboratoryof Physical Chemistry of Solid Surfaces Key Laboratory of Chemical Biology of Fujian ProvinceicHEMCollege of Chemistryand Chemical EngineeringXiamen UniversityXiamenFujian 361005China

Pseudolaric acids are a family of diterpenoid natural products that exhibit a broad spectrum of biological *** main structural feature of their framework is a trans-fused perhydroazulene bearing a bridged lactone positioned at the junction of the ***,we have developed a radical cyclization strategy that allows flexible tuning of the cyclization process through diverse silicon substitutions on the *** strategy can assist in constructing a series of skeletons with structural resemblance to pseudolaric acids and expedites the construction of the bridged ***,it facilitates the synthesis of the entire skeletal structure of the pseudolaric acidfamily of natural products,excludingthe B-ringfunctionalization.

关键词： Terpenoids Total synthesis Radical cyclization Bridged cycles Regioselectivity

Non-contact and full-field online monitoring of curing temperature during the in-situ heating process based on deep learning

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Advances in Manufacturing 2024年第1期12卷 167-176页

作者： Qiang-Qiang Liu Shu-Ting Liu ying-Guang Li Xu Liu Xiao-Zhong hao College of Mechanical and Electrical Engineering Nanjing University of Aeronautics and AstronauticsNanjing210016People’s Republic of China School of Mechanical and Power Engineering Nanjing Tech UniversityNanjing211816People’s Republic of China

Online monitoring of the curing temperature field is essential to improving the quality and efficiency of the manufacturing process of composite *** embedded sensor-based technologies have difficulty monitoring the full temperature field or have to introduce heterogeneous items that could have an undesired impact on the *** this paper,a non-contact,full-field monitoring method based on deep learning that predicts the internal temperature field of composite parts in real time using surface temperature measurements of auxiliary materials is *** the proposed method,an average temperature monitoring accuracy of 97%is achieved in various heating *** addition,this method also demonstrates satisfying feasibility when a stronger thermal barrier covers the *** method was experimentally validated during the self-resistance electric heating process,in which the monitoring accuracy reached 93.1%.This method can potentially be applied to automated manufacturing and process control in the composites industry.

关键词： Online monitoring Curing temperature field Deep learning(DL) In-situ heating

Harnessing innate immune pathways for therapeutic advancement in cancer

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1506-1564页

作者： Ankang Hu Li Sun hao Lin Yuheng Liao Hui Yang ying Mao Department of Neurosurgery Huashan HospitalFudan UniversityShanghaiP.R.China Institute for Translational Brain Research Shanghai Medical CollegeFudan University ShanghaiPR.China National Center for Neurological Disorders Huashan HospitalShanghai Medical CollegeFudan UniversityShanghaiP.R.China Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration Shanghai Clinical Medical Center of NeurosurgeryNeurosurgical Institute of Fudan UniversityHuashan HospitalShanghai Medical CollegeFudan UniversityShanghaiP.R.China State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science and MOE Frontiers Center for Brain Science Institutes of Brain ScienceShanghai Medical CollegeFudan UniversityShanghaiP.R.China Shanghai Key Laboratory of Medical Epigenetics International Co-laboratory of Medical Epigenetics and Metabolism(Ministry of Science and Technology)and Key Laboratory of Metabolism and Molecular Medicine(Ministry of Education)and Molecular and Cell Biology LabInstitutes of Biomedical SciencesShanghai Medical College of Fudan UniversityShanghaiP.R.China

The innate immune pathway is receiving increasing attention in cancer *** pathway is ubiquitous across various cell types,not only in innate immune cells but also in adaptive immune cells,tumor cells,and stromal *** targeting the innate immune pathway have shown profound changes in the tumor microenvironment(TME)and improved tumor prognosis in preclinical ***,to date,the clinical success of drugs targeting the innate immune pathway remains ***,recent studies have shown that activation of the innate immune pathway can paradoxically promote tumor *** uncertainty surrounding the therapeutic effectiveness of targeted drugs for the innate immune pathway is a critical issue that needs immediate *** this review,we observe that the role of the innate immune pathway demonstrates heterogeneity,linked to the tumor development stage,pathway status,and specific cell *** propose that within the TME,the innate immune pathway exhibits multidimensional *** diversity is fundamentally rooted in cellular heterogeneity and is manifested as a variety of signaling *** pro-tumor effect of innate immune pathway activation essentially reflects the suppression of classical pathways and the activation of potential pro-tumor alternative *** our understanding of the tumor's innate immune pathway network and employing appropriate targeting strategies can enhance our ability to harness the anti-tumor potential of the innate immune pathway and ultimately bridge the gap from preclinical to clinicalapplication.

关键词： drugs therapeutic innate

A deoxidation thermodynamic model for 304 stainless steel considering multiple-components coupled reactions

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Journal of Iron and Steel Research International 2024年第1期31卷 74-91页

作者： Yan Yan Guang-hao Shang Li-ping Zhang Shao-ying Li Han-jie Guo School of Metallurgical and Ecological Engineering University of Science and Technology BeijingBeijing100083China Beijing Key Laboratory of Special Melting and Preparation of High-End Metal Materials Beijing100083China Henan Jinhui Stainless Steel Industry Group Co. Ltd.Xuchang461500HenanChina Changge Jinhui Recycling Metal R&D Co. Ltd.Xuchang461500HenanChina

A thermodynamic model for predicting the equilibrium oxygens of 304 stainless steel was developed based on the theory of slag-steel equilibrium,the law of mass conservation,and the ion and molecule coexistence *** the developed model,the Fe-Cr-Mn-Si-Al-S-O-melts reaction system and CaO-MgO-CaF_(2)-FeO-MnO-Al_(2)O_(3)-SiO_(2)-Cr2O_(3)slags were *** oxygen contents calculated by the model are in good agreement with experimental results and reference *** equilibrium oxygen contents in 304 stainless steel mainly decrease with increasing binary basicity(w(CaO)/w(SiO_(2)),where w(i)is the mass percentage of component i)and decreasing *** binary basicity at 2.0 while maintaining temperatures lower than 1823 K will keep the oxygen contents in the 304 stainless steel lower than 15×10^(-6).The equilibrium oxygen contents may also be decreased with increasing content of MgO in slags,which is more significant at lower binary ***,a small amount of FeO,MnO,and Al_(2)O_(3)(about 0-2.5 wt.%)in slags has little effect on equilibrium oxygen ***,it is found that the[C]-[O]reaction may occur during refining process but will not significantly affect the equilibrium oxygen contents.

关键词： Complex deoxidation Thermodynamic model Ion and molecule coexistence theory 304 stainless steel Slag-steel reaction

Vortex identification based on the Liutex method and its effect on fish passage upstream

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Journal of Hydrodynamics 2024年第1期36卷 130-141页

作者： Chun-ying shen Rui-guo Yang Xiao-tao Shi Ming-ming Wang Shi-hua He Faculty of Electrical Power Engineering Kunming University of Science and TechnologyKunming650500China Hubei International Science and Technology Cooperation Base of Fish Passage China Three Gorges UniversityYichang443002China Shanghai Investigation Design and Research Institute Co.LtShanghai200434China

Fishway research is important for mitigating the fragmentation of river habitats caused by hydraulic *** vertical slit fishway is a broadly used fishway type because of its high efficiency and adaptability to water ***,the resulting vortex current disrupts the fish passage hence directly affecting fish *** study aims to accurately capture the vortex structure in the fishway and analyze the effect of vortex elements(vortex structure,vortex intensity,etc.)on *** conducted an analysis of the 3-D current flow field in the fishway through the utilization of an experimental model and the large eddy simulation(LES)***,we captured the vortex information in the fishway at different flow rates using the Liutex vortex identification method and investigated the effect of the vortex on fish *** results revealed that the structures inside the fishway pool occupy most of the room,however,the areas with higher vortex strength were primarily located in the vortex near the vertical seam and the mainstream,the vortex strength inside the fishway gradually increases with increasing flow,suppressing fish *** experienced significantly increased resistance when encountering strong *** suggests that the vortex may act as a physical barrier to fish *** findings highlight the potential negative effects of vortex on fish movement and reiterate the importance of understanding vortex dynamics for aquatic environmental *** an effective tool for identifying vortices in fluid flow,the Liutex method demonstrates features of vortex within the fishway,thereby providing important insights into the interaction between fluid dynamics and aquatic organisms.

关键词： Vertical slit fishway vortex identification method Liutex large eddy simulation(LES) fish experiment computational fluid dynamics