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Chemical conversion of human and mouse fibroblasts into motor neurons

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Science China(Life Sciences) 2018年第10期61卷 1151-1167页

作者： Hua Qin ANDong Zhao kui ma Xiaobing Fu Graduate School of Tianjin Medical University Tianjin 300070 China Cell Biology and Tissue Repair Laboratory Key Laboratory of Wound Repair and Regeneration of PLA First Affiliated Hospital of PLA General HospitalBeijing 100048 China College of Life Sciences PLA General Hospital PLA Medical College Beijing 100853 China

Transplantation of motor neurons can provide long-term functional benefits in animal models of neurodegenerative motor neuron diseases such as amyotrophic lateral sclerosis and traumatic spinal cord injury. Although embryonic stem cells can differentiate into motor neurons, alternative sources of motor neurons may be controllable for disease modeling and transplantation. Here, we show that human and mouse fibroblasts can be efficiently and directly converted into motor neurons by a cocktail of five small molecules, without the involvement of the neural progenitor stage. The chemically-induced motor neurons display the distinct neuronal morphology and express motor neuron markers. Interestingly, when the same chemical compounds were soaked in beads and implanted in the hypodermis of the back skins of mice, surrounding cells begin to express motor neuron markers,indicating in vivo motor neuron reprogramming. Taken together, we provide an efficient approach for chemically converting human and mouse fibroblasts into motor neurons suitable for cell replacement therapy and neurodegenerative disease modeling.

关键词： fibroblast motor neuron small molecule transdifferentiation reprogramming conversion regeneration neurodegenerative diseases

一种差动式位移传感器芯片的信号调理电路设计

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电子器件 2024年第2期47卷 326-332页

作者：杨朝辉马奎杨发顺贵州大学大数据与信息工程学院贵州贵阳550025 半导体功率器件可靠性教育部工程研究中心贵州贵阳550025 贵州省微纳电子与软件技术重点实验室贵州贵阳550025

设计了一种适用于线性可变差动式位移传感器(LVDT)的信号调理电路,该电路用于将LVDT的副边输出信号进行处理,并输出一个表征铁芯位移的直流电压;主要由解调电路、除法电路和运算放大器组成。LVDT副边输出为两个互补的正弦波信号,直接驱... 详细信息

设计了一种适用于线性可变差动式位移传感器(LVDT)的信号调理电路,该电路用于将LVDT的副边输出信号进行处理,并输出一个表征铁芯位移的直流电压;主要由解调电路、除法电路和运算放大器组成。LVDT副边输出为两个互补的正弦波信号,直接驱动信号调理电路;由于该信号调理电路采用了独特的比值架构,得到的是两个电压的差与和的比值,所以不要求LVDT初级激励使电压幅度保持稳定,同时,LVDT初级与次级线圈的相移以及干扰电压对该电路的功能不会产生影响,能有效地解决传统信号调理电路在测量精度和可靠性等方面的问题,具有更好的稳定性和性能优势,经过仿真验证及流片测试表明,该信号调理电路总误差≤1.49%/FS,线性度≤0.05%,满量程输出电压≥±10 V。各项功能指标均达到设计要求。

关键词： LVDT 信号调理同步解调除法器

一种3×10^(-6)/℃的超低温漂带隙基准源

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半导体技术 2024年第8期49卷 742-748页

作者：娄义淳杜承钢闵睿郑倩杨发顺马奎贵州大学大数据与信息工程学院贵阳550025 贵州辰矽电子科技有限公司贵阳550025 半导体功率器件可靠性教育部工程研究中心贵阳550025 贵州省微纳电子与软件技术重点实验室贵阳550025

基于40 V双极型工艺,利用Brokaw型带隙基准源模型,设计了一种宽输入电压范围、超低温漂的带隙基准源。在Brokaw模型的基础上改进核心带隙基准电路设计,使用不同温度系数电阻的补偿方法对基准源的温漂进行二阶补偿;偏置电路使用改进的基... 详细信息

基于40 V双极型工艺,利用Brokaw型带隙基准源模型,设计了一种宽输入电压范围、超低温漂的带隙基准源。在Brokaw模型的基础上改进核心带隙基准电路设计,使用不同温度系数电阻的补偿方法对基准源的温漂进行二阶补偿;偏置电路使用改进的基极-发射极电压作为电流源,利用电流镜为其他模块提供电流;在钳位运放中引入负反馈,以提高电路的输入电压范围。芯片实测数据表明,在4~36 V的工作电压范围内,2.5 V和3 V输出电压的温漂系数均小于3×10^(-6)/℃;2.5 V和3 V输出电压的线性调整率分别为7.3μV/V和2.5μV/V,实现了超低的温度漂移和线性调整率。

关键词：双极型带隙基准源超低温漂 Brokaw模型二阶补偿

Constant Barrier Strategies in a Two-state markov-modulated Dual Risk Model

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Acta mathematicae Applicatae Sinica 2011年第4期27卷 679-690页

作者： Xue-min ma kui LUO Guang-ming WANG Yi-jun HU School of mathematics and Statistics Wuhan University Wuhan 430072 China

In this paper, we consider the dividend problem in a two-state markov-modulated dual risk model, in which the gain arrivals, gain sizes and expenses are influenced by a markov process. A system of integro-differential equations for the expected value of the discounted dividends until ruin is derived. In the case of exponential gain sizes, the equations are solved and the best barrier is obtained via numerical example. Finally, using numerical example, we compare the best barrier and the expected discounted dividends in the two-state markov-modulated dual risk model with those in an associated averaged compound Poisson risk model. Numerical results suggest that one could use the results of the associated averaged compound Poisson risk model to approximate those for the two-state markov-modulated dual risk model.

关键词： Dual risk model markov-modulated risk model barrier strategy

Efficient and rapid conversion of human astrocytes and ALS mouse model spinal cord astrocytes into motor neuron-like cells by defined small molecules

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Military Medical Research 2021年第1期8卷 62-78页

作者： An-Dong Zhao Hua Qin Meng-Li Sun kui ma Xiao-Bing Fu Tianjin Medical University Tianjin 300070China Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and 4th Medical Center PLA General Hospital and PLA Medical College28 Fu Xing RoadHaidian DistrictBeijing 100853China PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury Repair and RegenerationBeijing 100048China Research Unit of Trauma Care Tissue Repair and RegenerationChinese Academy of Medical SciencesBeijing 100048China

Background: Motor neuron degeneration or loss in the spinal cord is the characteristic phenotype of motor neuron diseases or spinal cord injuries. Being proliferative and located near neurons, astrocytes are considered ideal cell sources for regenerating ***: We selected and tested different combinations of the small molecules for inducing the conversion of human and mouse astrocytes into neurons. Microscopic imaging and immunocytochemistry analyses were used to characterize the morphology and phenotype of the induced neurons while RT-q PCR was utilized to analyze changes in gene expression. In addition, whole-cell patch-clamp recordings were measured to examine the electrophysiological properties of induced ***: The results showed that human astrocytes could be rapidly and efficiently converted into motor neuronlike cells by treatment with defined small molecules, with a yield of over 85% motor neuron-like cells attained. The induced motor neuron-like cells expressed the pan-neuronal markers TUJ1, maP2, Neu N, and Synapsin 1 and motor neuron markers HB9, ISL1, CHAT, and VACh T. During the conversion process, the cells did not pass through a proliferative neural progenitor cell intermediate. The induced motor neurons were functional, showing the electrophysiological properties of neurons. The same chemical cocktail could induce spinal cord astrocytes from an amyotrophic lateral sclerosis mouse model carrying a SOD1 mutation to become motor neuron-like cells that exhibited a decrease in cell survival and an increase in oxidative stress compared to that observed in wild-type MNs derived from healthy mice. Moreover, the chemical induction reduced oxidative stress in the mutant ***: The results of the present study demonstrated the feasibility of chemically converting human and mouse astrocytes into motor neuron-like cells that are useful for neurodegenerative disease modeling and regenerative medicine.

关键词： Human astrocyte Motor neuron Reprogramming Transdifferentiation Conversion Regeneration Amyotrophic lateral sclerosis Neurodegenerative

Direct conversion of human fibroblasts into dopaminergic neuron-like cells using small molecules and protein factors

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Military Medical Research 2021年第2期8卷 162-173页

作者： Hua Qin An-Dong Zhao Meng-Li Sun kui ma Xiao-Bing Fu Research Center for Tissue Repair and Regeneration affiliated to the Medical Innovation Research Division and 4th Medical Center PLA General Hospital and PLA Medical College28 Fu Xing RoadHaidian DistrictBeijing 100853China Tianjin Medical University Tianjin 300070China PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury Repair and RegenerationBeijing 100048China Research Unit of Trauma Care Tissue Repair and RegenerationChinese Academy of Medical Sciences2019RU051Beijing 100048China

Background:Generation of neurons is essential in cell replacement therapy for neurodegenerative disorders like Parkinson’s *** studies have reported the generation of dopaminergic(DA)neurons from mouse and human fibroblasts by ectopic expression of transcription factors,in which genetic manipulation is associated with potential ***:The small molecules and protein factors were selected based on their function to directly induce human fetal lung IMR-90 fibroblasts into DA neuron-like ***,immunocytochemical,and RT-qPCR analyses were used to characterize the morphology,phenotype,and gene expression features of the induced *** wholecell patch-clamp recordings were exploited to measure the electrophysiological ***:Human IMR-90 fibroblasts were rapidly converted into DA neuron-like cells after the chemical induction using small molecules and protein factors,with a yield of approximately 95%positive TUJ1-positive *** induced DA neuron-like cells were immunopositive for pan-neuronal markers maP2,NEUN,and Synapsin 1 and DA markers TH,DDC,DAT,and *** chemical induction process did not involve a neural progenitor/stem cell intermediate *** induced neurons could fire single action potentials,which reflected partially the electrophysiological properties of ***:We developed a chemical cocktail of small molecules and protein factors to convert human fibroblasts into DA neuron-like cells without passing through a neural progenitor/stem cell intermediate *** induced DA neuron-like cells from human fibroblasts might provide a cellular source for cell-based therapy of Parkinson’s disease in the future.

关键词： Human fibroblasts Dopaminergic neurons Parkinson's disease Small molecules Reprogramming Transdifferentiation

四川盆地德阳—安岳凹槽形成机理及灯影组沉积新格局

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天然气工业 2024年第8期44卷 13-28页

作者：周刚罗冰张新徐少立张本健马奎梁艺苇严威钟原张自力兰才俊李堃宇中国石油西南油气田公司勘探开发研究院北京源烃泰克科技有限公司

四川盆地德阳—安岳凹槽两侧陡坎带震旦系灯影组天然气勘探不断取得新突破，是盆地内天然气增储上产的重要领域。为了明确该凹槽的形成机理、形成期次及沉积新格局，进一步指导灯影组气藏的深化勘探，采用最新大连片三维地震成果、结合... 详细信息

四川盆地德阳—安岳凹槽两侧陡坎带震旦系灯影组天然气勘探不断取得新突破，是盆地内天然气增储上产的重要领域。为了明确该凹槽的形成机理、形成期次及沉积新格局，进一步指导灯影组气藏的深化勘探，采用最新大连片三维地震成果、结合钻井等资料，分析了各期陡坎之间、陡坎与台缘带之间的空间展布关系，探索了陡坎的演化规律，进一步明确了天然气的勘探方向。研究结果表明：(1)德阳—安岳凹槽陡坎总体表现为侵蚀谷特征，同沉积小断层的作用不明显；(2)灯影组二段（以下简称灯二段）发育Ⅰ、Ⅱ两个陡坎，灯影组四段（以下简称灯四段）发育一个陡坎，分别在桐湾Ⅰ和Ⅱ、Ⅲ幕侵蚀作用形成，这些陡坎与灯二段、灯四段台缘带无关；(3)灯二段沉积时期，受控于基底垒堑格局，发育由南向北进积的4～5排台缘带，呈北东向展布，其中蓬莱地区发育两个大型台缘带，台缘带丘滩体被陡坎Ⅱ截断，叠加岩溶作用形成优质储层。结论认为：(1)高石梯—磨溪地区灯四段与灯二段的陡坎叠合区发育灯四段陡坎型台缘带，而在灯四段槽上带，丘滩体仍呈北东向发育，表明该地区受陡坎Ⅱ与北东向古地貌双重因素控制；(2)蓬莱地区陡坎Ⅱ坡度变小，对灯四段台缘带控制作用减弱直至消失，主要发育2排北东向展布的缓坡型台缘带，即蓬莱(1)、(2)台缘带，蓬莱地区可作为今后天然气勘探重点关注目标区。

关键词：四川盆地德阳—安岳凹槽震旦系灯影组台缘带侵蚀谷阶地沉积

四川盆地蓬莱气区震旦系灯影组二段储层特征及其控制因素

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特种油气藏 2024年第2期31卷 47-56页

作者：徐少立马奎杨强谢长琼张新严威武鲁亚王文之中国石油西南油气田分公司四川成都610041 中国核工业二四建设有限公司四川绵阳621000

蓬莱气区震旦系灯影组天然气勘探取得重大突破,单井产量屡创新高,显示了蓬莱气区灯二段良好的规模资源潜力。但目前该区沉积、储层特征及其主控因素仍未明确,优质储层预测存在极大困难,严重阻碍了下步勘探部署和储量升级。在此背景下,... 详细信息

蓬莱气区震旦系灯影组天然气勘探取得重大突破,单井产量屡创新高,显示了蓬莱气区灯二段良好的规模资源潜力。但目前该区沉积、储层特征及其主控因素仍未明确,优质储层预测存在极大困难,严重阻碍了下步勘探部署和储量升级。在此背景下,为进一步深化蓬莱气区沉积储层特征研究并揭示优质储层主控因素,利用最新的岩电、地震及分析测试资料,对蓬莱气区灯二段开展新一轮沉积储层研究。结果表明:灯二段储集岩性为丘滩相凝块、砂屑云岩,储集空间包括孔隙、溶洞及裂缝三大类,储层展布纵向上差异大,平面上连续性较强。优质储层发育受沉积相带、岩溶作用及成岩作用的共同控制,其中,沉积相带是灯二段优质储层形成的基础;岩溶作用决定了储层储集性能;后期成岩作用是影响灯二段优质储层形成的重要因素。灯二段整体含气性良好,发育多个大型岩性圈闭,研究认为岩溶改造下的丘滩相岩性圈闭体是下步勘探的有利目标区带,亦是盆地天然气万亿方资源增储上产新阵地。该研究为明确蓬莱气区灯二段沉积、储层特征及其主控因素提供了基础材料与研究实例,以期为后续勘探开发工作提供借鉴。

关键词：储层特征岩溶作用主控因素白云岩蓬莱气区四川盆地

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川中古隆起北斜坡灯四段天然气成藏特征

天然气地球科学 2024年第4期35卷 635-644页

作者：马奎张本健徐少立严威周刚张新武鲁亚蒋航王文之许翔中国石油西南油气田分公司勘探开发研究院四川成都610041

继四川盆地川中古隆起安岳万亿方大气田发现之后,在古隆起斜坡区海相多层系又获得了勘探发现。其中古隆起斜坡蓬莱气区灯影组四段(灯四段)成藏条件优越,可能是盆地下一个深层油气富集的重要领域。结合地震和测井资料分析,对蓬莱气区灯... 详细信息

继四川盆地川中古隆起安岳万亿方大气田发现之后,在古隆起斜坡区海相多层系又获得了勘探发现。其中古隆起斜坡蓬莱气区灯影组四段(灯四段)成藏条件优越,可能是盆地下一个深层油气富集的重要领域。结合地震和测井资料分析,对蓬莱气区灯四段成藏条件进行评价,指出勘探有利区,并展望其勘探潜力。研究表明:①灯四段大型台缘带发育厚层块状丘滩相孔隙性储层,储集岩性主要为藻凝块白云岩、藻砂屑白云岩,储层厚169 m,平均孔隙度为3.1%。②沉积微地貌和同沉积断裂共同控制了蓬莱气区灯四段台缘相带分异,灯四段上倾方向发育台内洼地相带,具备岩性封堵条件。且台缘带发育丘滩体和丘滩间洼地2种亚相,具备多个大型岩性圈闭发育地质条件,岩性圈闭总面积达2650 km^(2)。③蓬莱气区灯四段油气原位聚集,经历了古油藏形成、原油裂解成气和气藏调整定型3个阶段,形成了现今多个大型构造—岩性油气藏群。

关键词：蓬莱气区灯四段岩性圈闭构造—岩性气藏原位聚集