The potential of messenger RNA(m RNA)as a therapeutic tool for treating diseases has garnered considerable interest,especially in the wake of the successful creation of m RNA vaccines to counter corona virus disease 2...The potential of messenger RNA(m RNA)as a therapeutic tool for treating diseases has garnered considerable interest,especially in the wake of the successful creation of m RNA vaccines to counter corona virus disease 2019(COVID-19).Nucleic acid-based drug gene therapies have emerged as exceptionally promising avenues for combating disease.Furthermore,lipid nanoparticles(LNPs)are ideal carriers for nucleic acid delivery owing to their ionic nature,which enables nucleic acids to electrostatically interact with intracellular membranes,thereby promoting efficient intracellular nucleic acid release.Unfortunately,the effectiveness of LNPs in targeting organs beyond the liver is relatively poor.Thus,enhanced extrahepatic targeting is another important property that would lead to improved in vivo delivery by LNPs.This review focuses on the fundamental characteristics and functions of LNPs developed to facilitate cellular uptake and ensure effective intracellular release of m RNAs.Promising applications,possible advantages and potential challenges associated with use of LNPs in organ specific delivery and release of m RNAs are summarized.Furthermore,the need for future research to address limitations of currently developed LNPs for clinical applications of the m RNA technology is emphasized.展开更多
体外嵌合抗原受体T细胞(ex vivo CAR-T)在改善血液系统恶性肿瘤(尤其是B细胞恶性肿瘤)方面显示出卓越的治疗潜力,但其广泛应用面临巨大挑战,包括体外制造工艺复杂、生产成本高昂等因素。近年来,随着RNA药物、靶向递送系统等领域的快速发...体外嵌合抗原受体T细胞(ex vivo CAR-T)在改善血液系统恶性肿瘤(尤其是B细胞恶性肿瘤)方面显示出卓越的治疗潜力,但其广泛应用面临巨大挑战,包括体外制造工艺复杂、生产成本高昂等因素。近年来,随着RNA药物、靶向递送系统等领域的快速发展,体内嵌合抗原受体T细胞(in vivo CAR-T)作为一种创新策略应运而生。in vivo CAR-T通过病毒载体或脂质纳米颗粒(LNPs)等靶向递送系统,将编码CAR的遗传物质直接导入患者体内,实现体内T细胞工程化改造,这一策略从根本上省去了繁琐的体外细胞操作步骤和传统的化疗预处理环节。本研究系统梳理了in vivo CAR-T的技术进展与非临床研究考虑。in vivo CAR-T兼具基因治疗与细胞治疗的双重属性,涉及多种递送载体,类型多样,机制复杂,其非临床研究可遵循基于风险、个案处理的原则,在现有相关技术指导原则框架下,合理设计并开展非临床研究,以获取科学规范的试验数据来支持开展临床试验和批准上市。展开更多
The massive COVID-19 vaccination campaign is the first time that mRNA vaccines have been used on a global scale.The mRNA vaccines correspond exactly to the definition of gene therapy of the American and European regul...The massive COVID-19 vaccination campaign is the first time that mRNA vaccines have been used on a global scale.The mRNA vaccines correspond exactly to the definition of gene therapy of the American and European regulatory agencies.The regulations require excretion studies of these drugs and their products(the translated proteins).These studies have not been done for mRNA vaccines(nor for adenovirus vaccines).There are numerous reports of symptoms and pathologies identical to the adverse effects of mRNA vaccines in unvaccinated persons in contact with freshly vaccinated persons.It is therefore important to review the state of knowledge on the possible excretion of vaccine nanoparticles as well as mRNA and its product,the spike protein.Vaccine mRNA-carrying lipid nanoparticles spread after injection throughout the body according to available animal studies and vaccine mRNA(naked or in nanoparticles or in natural exosomes)is found in the bloodstream as well as vaccine spike in free form or encapsulated in exosomes(shown in human studies).Lipid nanoparticles(or their natural equivalent,exosomes or extracellular vesicles(EVs))have been shown to be able to be excreted through body fluids(sweat,sputum,breast milk)and to pass the transplacental barrier.These EVs are also able to penetrate by inhalation and through the skin(healthy or injured)as well as orally through breast milk(and why not during sexual intercourse through semen,as this has not been studied).It is urgent to enforce the legislation on gene therapy that applies to mRNA vaccines and to carry out studies on this subject while the generalization of mRNA vaccines is being considered.展开更多
高光谱图像数据体现为波段多、地物标签获取困难大、谱信息抗干扰能力弱等特征,容易引起维数灾难、光谱空间变异性等问题,从而影响分类器的分类精度。针对这些问题,本文将负相似信息引入到拉普拉斯支持向量机(Laplacian Support Vector ...高光谱图像数据体现为波段多、地物标签获取困难大、谱信息抗干扰能力弱等特征,容易引起维数灾难、光谱空间变异性等问题,从而影响分类器的分类精度。针对这些问题,本文将负相似信息引入到拉普拉斯支持向量机(Laplacian Support Vector Machine,Lap SVM)的流形正则化项中,提出了一种引入负相似的拉普拉斯支持向量机(Dissimilarity in Laplacian Support Vector Machine,Diss-Lap SVM)分类算法,抑制光谱空间变异对分类结果的影响。同时,本文提出利用线性近邻传播(Linear Neighborhood Propagation,LNP)算法构造图的拉普拉斯矩阵,更有效地引入无标签样本的信息。实验结果表明,本文算法的分类精度得到了提高,特别是对光谱特征相似的地物。展开更多
Lattice-matched In0.5 Ga0.47 As/In0.52 Al 0.48 As high electron mobility transistors （HEMTs） with a cutoff frequency （ft） as high as 218GHz are reported. This fT is the highest value ever reported for HEMTs in Chi...Lattice-matched In0.5 Ga0.47 As/In0.52 Al 0.48 As high electron mobility transistors （HEMTs） with a cutoff frequency （ft） as high as 218GHz are reported. This fT is the highest value ever reported for HEMTs in China. These devices also demonstrate excellent DC characteristics：the extrinsic transconductance is 980mS/mm and the maximum current density is 870mA/mm. The material structure and all the device fabrication technology in this work were developed by our group.展开更多
The interactions between lignin oligomers and solvents determine the behaviors of lignin oligomers self-assembling into uniform lignin nanoparticles(LNPs).Herein,several alcohol solvents,which readily interact with th...The interactions between lignin oligomers and solvents determine the behaviors of lignin oligomers self-assembling into uniform lignin nanoparticles(LNPs).Herein,several alcohol solvents,which readily interact with the lignin oligomers,were adopted to study their effects during solvent shifting process for LNPs’production.The lignin oligomers with widely distributed molecular weight and abundant guaiacyl units were extracted from wood waste(mainly consists of pine wood),exerting outstanding self-assembly capability.Uniform and spherical LNPs were generated in H_(2)O-n-propanol cosolvent,whereas irregular LNPs were obtained in H_(2)O-methanol cosolvent.The unsatisfactory self-assembly performance of the lignin oligomers in H_(2)O-methanol cosolvent could be attributed to two aspects.On one hand,for the initial dissolution state,the distinguishing Hansen solubility parameter and polarity between methanol solvent and lignin oligomers resulted in the poor dispersion of the lignin oligomers.On the other hand,strong hydrogen bonds between methanol solvent and lignin oligomers during solvent shifting process,hindered the interactions among the lignin oligomers for self-assembly.展开更多
目的 LNP(linear-nonlinear-Poisson)模型很好地解译了神经元的响应过程,其重要环节之一是线性滤波器的提取。针对传统i STAC(information-theoretic spike-triggered average and covariance)算法运用于LNP模型时的神经元特性表征不足...目的 LNP(linear-nonlinear-Poisson)模型很好地解译了神经元的响应过程,其重要环节之一是线性滤波器的提取。针对传统i STAC(information-theoretic spike-triggered average and covariance)算法运用于LNP模型时的神经元特性表征不足、运动特征提取效果不佳等问题,特别是在处理低维度刺激问题时,提出了一种改进的i STAC神经元滤波特征提取算法。方法引入非触发刺激的统计量,从而更加准确地构建神经元滤波特征子空间的目标函数,同时增强系统的抗噪能力;采用变尺度法最大化目标函数,从而优化解空间,提升算法的收敛速率。结果不同非线性条件下对线性滤波器的恢复实验结果表明,新算法相较于传统i STAC算法在高维度刺激时保持较好的表征特性,在刺激维度小于6 500时有明显改善,且总体上优于STA(spike-triggered average)和STC(spike-triggered covariance)算法。结论提出的新算法适用范围更广,鲁棒性更强,能够运用于建立完整的基于视觉特性的视频运动特征提取模型。展开更多
基金supported by Guang Dong Basic and Applied Basic Research Foundation(No.2023B1515120001)Shenzhen University 2035 Program for Excellent Research(Nos.00000208 and 00000225)。
文摘The potential of messenger RNA(m RNA)as a therapeutic tool for treating diseases has garnered considerable interest,especially in the wake of the successful creation of m RNA vaccines to counter corona virus disease 2019(COVID-19).Nucleic acid-based drug gene therapies have emerged as exceptionally promising avenues for combating disease.Furthermore,lipid nanoparticles(LNPs)are ideal carriers for nucleic acid delivery owing to their ionic nature,which enables nucleic acids to electrostatically interact with intracellular membranes,thereby promoting efficient intracellular nucleic acid release.Unfortunately,the effectiveness of LNPs in targeting organs beyond the liver is relatively poor.Thus,enhanced extrahepatic targeting is another important property that would lead to improved in vivo delivery by LNPs.This review focuses on the fundamental characteristics and functions of LNPs developed to facilitate cellular uptake and ensure effective intracellular release of m RNAs.Promising applications,possible advantages and potential challenges associated with use of LNPs in organ specific delivery and release of m RNAs are summarized.Furthermore,the need for future research to address limitations of currently developed LNPs for clinical applications of the m RNA technology is emphasized.
文摘体外嵌合抗原受体T细胞(ex vivo CAR-T)在改善血液系统恶性肿瘤(尤其是B细胞恶性肿瘤)方面显示出卓越的治疗潜力,但其广泛应用面临巨大挑战,包括体外制造工艺复杂、生产成本高昂等因素。近年来,随着RNA药物、靶向递送系统等领域的快速发展,体内嵌合抗原受体T细胞(in vivo CAR-T)作为一种创新策略应运而生。in vivo CAR-T通过病毒载体或脂质纳米颗粒(LNPs)等靶向递送系统,将编码CAR的遗传物质直接导入患者体内,实现体内T细胞工程化改造,这一策略从根本上省去了繁琐的体外细胞操作步骤和传统的化疗预处理环节。本研究系统梳理了in vivo CAR-T的技术进展与非临床研究考虑。in vivo CAR-T兼具基因治疗与细胞治疗的双重属性,涉及多种递送载体,类型多样,机制复杂,其非临床研究可遵循基于风险、个案处理的原则,在现有相关技术指导原则框架下,合理设计并开展非临床研究,以获取科学规范的试验数据来支持开展临床试验和批准上市。
文摘The massive COVID-19 vaccination campaign is the first time that mRNA vaccines have been used on a global scale.The mRNA vaccines correspond exactly to the definition of gene therapy of the American and European regulatory agencies.The regulations require excretion studies of these drugs and their products(the translated proteins).These studies have not been done for mRNA vaccines(nor for adenovirus vaccines).There are numerous reports of symptoms and pathologies identical to the adverse effects of mRNA vaccines in unvaccinated persons in contact with freshly vaccinated persons.It is therefore important to review the state of knowledge on the possible excretion of vaccine nanoparticles as well as mRNA and its product,the spike protein.Vaccine mRNA-carrying lipid nanoparticles spread after injection throughout the body according to available animal studies and vaccine mRNA(naked or in nanoparticles or in natural exosomes)is found in the bloodstream as well as vaccine spike in free form or encapsulated in exosomes(shown in human studies).Lipid nanoparticles(or their natural equivalent,exosomes or extracellular vesicles(EVs))have been shown to be able to be excreted through body fluids(sweat,sputum,breast milk)and to pass the transplacental barrier.These EVs are also able to penetrate by inhalation and through the skin(healthy or injured)as well as orally through breast milk(and why not during sexual intercourse through semen,as this has not been studied).It is urgent to enforce the legislation on gene therapy that applies to mRNA vaccines and to carry out studies on this subject while the generalization of mRNA vaccines is being considered.
文摘高光谱图像数据体现为波段多、地物标签获取困难大、谱信息抗干扰能力弱等特征,容易引起维数灾难、光谱空间变异性等问题,从而影响分类器的分类精度。针对这些问题,本文将负相似信息引入到拉普拉斯支持向量机(Laplacian Support Vector Machine,Lap SVM)的流形正则化项中,提出了一种引入负相似的拉普拉斯支持向量机(Dissimilarity in Laplacian Support Vector Machine,Diss-Lap SVM)分类算法,抑制光谱空间变异对分类结果的影响。同时,本文提出利用线性近邻传播(Linear Neighborhood Propagation,LNP)算法构造图的拉普拉斯矩阵,更有效地引入无标签样本的信息。实验结果表明,本文算法的分类精度得到了提高,特别是对光谱特征相似的地物。
文摘Lattice-matched In0.5 Ga0.47 As/In0.52 Al 0.48 As high electron mobility transistors （HEMTs） with a cutoff frequency （ft） as high as 218GHz are reported. This fT is the highest value ever reported for HEMTs in China. These devices also demonstrate excellent DC characteristics：the extrinsic transconductance is 980mS/mm and the maximum current density is 870mA/mm. The material structure and all the device fabrication technology in this work were developed by our group.
基金supported by the National Natural Science Foundation of China(22078211)the China Postdoctoral Science Foundation(2022M721115).
文摘The interactions between lignin oligomers and solvents determine the behaviors of lignin oligomers self-assembling into uniform lignin nanoparticles(LNPs).Herein,several alcohol solvents,which readily interact with the lignin oligomers,were adopted to study their effects during solvent shifting process for LNPs’production.The lignin oligomers with widely distributed molecular weight and abundant guaiacyl units were extracted from wood waste(mainly consists of pine wood),exerting outstanding self-assembly capability.Uniform and spherical LNPs were generated in H_(2)O-n-propanol cosolvent,whereas irregular LNPs were obtained in H_(2)O-methanol cosolvent.The unsatisfactory self-assembly performance of the lignin oligomers in H_(2)O-methanol cosolvent could be attributed to two aspects.On one hand,for the initial dissolution state,the distinguishing Hansen solubility parameter and polarity between methanol solvent and lignin oligomers resulted in the poor dispersion of the lignin oligomers.On the other hand,strong hydrogen bonds between methanol solvent and lignin oligomers during solvent shifting process,hindered the interactions among the lignin oligomers for self-assembly.
