Since it was first recognized in bacteria and archaea as a mechanism for innate viral immunity in the early 2010 s,clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated protein(Cas)has ra...Since it was first recognized in bacteria and archaea as a mechanism for innate viral immunity in the early 2010 s,clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated protein(Cas)has rapidly been developed into a robust,multifunctional genome editing tool with many uses.Following the discovery of the initial CRISPR/Cas-based system,the technology has been advanced to facilitate a multitude of different functions.These include development as a base editor,prime editor,epigenetic editor,and CRISPR interference(CRISPRi)and CRISPR activator(CRISPRa)gene regulators.It can also be used for chromatin and RNA targeting and imaging.Its applications have proved revolutionary across numerous biological fields,especially in biomedical and agricultural improvement.As a diagnostic tool,CRISPR has been developed to aid the detection and screening of both human and plant diseases,and has even been applied during the current coronavirus disease 2019(COVID-19)pandemic.CRISPR/Cas is also being trialed as a new form of gene therapy for treating various human diseases,including cancers,and has aided drug development.In terms of agricultural breeding,precise targeting of biological pathways via CRISPR/Cas has been key to regulating molecular biosynthesis and allowing modification of proteins,starch,oil,and other functional components for crop improvement.Adding to this,CRISPR/Cas has been shown capable of significantly enhancing both plant tolerance to environmental stresses and overall crop yield via the targeting of various agronomically important gene regulators.Looking to the future,increasing the efficiency and precision of CRISPR/Cas delivery systems and limiting off-target activity are two major challenges for wider application of the technology.This review provides an in-depth overview of current CRISPR development,including the advantages and disadvantages of the technology,recent applications,and future considerations.展开更多
本文采用汉语本族语者口语语料库(Corpus of Native Chinese Conversation)和英语本族语者口语语料库(Louvain Corpus of Native English Conversation),探讨了汉语和英语本族语者在自我修补的两种常用策略——重复和替换使用上的异同,...本文采用汉语本族语者口语语料库(Corpus of Native Chinese Conversation)和英语本族语者口语语料库(Louvain Corpus of Native English Conversation),探讨了汉语和英语本族语者在自我修补的两种常用策略——重复和替换使用上的异同,重点分析在功能词和实义词各词类上重复起始词和替换词的使用情况。结果显示:二者对策略的使用共性与差异并存。共性主要表现在:汉英本族语者均倾向于将限定词作为重复起始词;倾向于将名词和限定词作为替换词。差异性则主要体现在:英语本族语者比汉语本族语者使用更多的功能词(如主格人称代词)作为重复起始词;而汉语本族语者比英语本族语者使用更多的实义词(尤其是动词和副词)作为重复起始词和替换词。本文从语序松紧度、句法投射性以及词组内部结构复杂度等视角对研究发现进行了讨论。展开更多
Parkinson’s disease is a neurodegenerative condition characterized by motor impairments caused by the selective loss of dopaminergic neurons in the substantia nigra.Levodopa is an effective and well-tolerated dopamin...Parkinson’s disease is a neurodegenerative condition characterized by motor impairments caused by the selective loss of dopaminergic neurons in the substantia nigra.Levodopa is an effective and well-tolerated dopamine replacement agent.However,levodopa provides only symptomatic improvements,without affecting the underlying pathology,and is associated with side effects after long-term use.Cell-based replacement is a promising strategy that offers the possibility to replace lost neurons in Parkinson’s disease treatment.Clinical studies of transplantation of human fetal ventral mesencephalic tissue have provided evidence that the grafted dopaminergic neurons can reinnervate the striatum,release dopamine,integrate into the host neural circuits,and improve motor functions.One of the limiting factors for cell therapy in Parkinson’s disease is the low survival rate of grafted dopaminergic cells.Different factors could cause cell death of dopaminergic neurons after grafting such as mechanical trauma,growth factor deprivation,hypoxia,and neuroinflammation.Neurotrophic factors play an essential role in the survival of grafted cells.However,direct,timely,and controllable delivery of neurotrophic factors into the brain faces important limitations.Different types of cells secrete neurotrophic factors constitutively and co-transplantation of these cells with dopaminergic neurons represents a feasible strategy to increase neuronal survival.In this review,we provide a general overview of the pioneering studies on cell transplantation developed in patients and animal models of Parkinson’s disease,with a focus on neurotrophic factor-secreting cells,with a particular interest in mesenchymal stromal cells;that co-implanted with dopaminergic neurons would serve as a strategy to increase cell survival and improve graft outcomes.展开更多
In plants and mammals,non-homologous end-joining is the dominant pathway to repair DNA doublestrand breaks,making it challenging to generate knock-in events.In this study,we identified two groups of exonucleases from ...In plants and mammals,non-homologous end-joining is the dominant pathway to repair DNA doublestrand breaks,making it challenging to generate knock-in events.In this study,we identified two groups of exonucleases from the herpes virus and the bacteriophage T7 families that conferred an up to 38-fold increase in homology-directed repair frequencies when fused to Cas9/Cas12a in a tobacco mosaic virus-based transient assay in Nicotiana benthamiana.We achieved precise and scar-free insertion of several kilobases of DNA both in transient and stable transformation systems.In Arabidopsis thaliana,fusion of Cas9 to a herpes virus family exonuclease led to 10-fold higher frequencies of knock-ins in the first generation of transformants.In addition,we demonstrated stable and heritable knock-ins in wheat in 1%of the primary transformants.Taken together,our results open perspectives for the routine production of heritable knock-in and gene replacement events in plants.展开更多
Most of the spare ordering policies treated up to now have assumed that preventive and corrective replacement costs are equal, which implies in essential that there is no significant need for preventive replacement. T...Most of the spare ordering policies treated up to now have assumed that preventive and corrective replacement costs are equal, which implies in essential that there is no significant need for preventive replacement. This paper presents an ordering policy for preventive age replacement with minimal repair. Introducing the replacement, repair, inventory holding and shortage costs, the expected cost rate is derived. A procedure to determine jointly the ordering time for a spare and the preventive replacement time for the operating unit so as to minimize the expected cost rate is proposed. To explain the ordering policy and the optimization procedure, a numerical example is also included.展开更多
基金supported in part by Cotton Incorporated and the National Science Foundation(award 1658709)supported by the National Natural Science Foundation of China(No.31700316)+1 种基金the Fundamental Research Funds for the Central Nonprofit Scientific Institution(No.1610172018009)the Natural Science Foundation of Hubei Province(No.2018CFB543),China。
文摘Since it was first recognized in bacteria and archaea as a mechanism for innate viral immunity in the early 2010 s,clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated protein(Cas)has rapidly been developed into a robust,multifunctional genome editing tool with many uses.Following the discovery of the initial CRISPR/Cas-based system,the technology has been advanced to facilitate a multitude of different functions.These include development as a base editor,prime editor,epigenetic editor,and CRISPR interference(CRISPRi)and CRISPR activator(CRISPRa)gene regulators.It can also be used for chromatin and RNA targeting and imaging.Its applications have proved revolutionary across numerous biological fields,especially in biomedical and agricultural improvement.As a diagnostic tool,CRISPR has been developed to aid the detection and screening of both human and plant diseases,and has even been applied during the current coronavirus disease 2019(COVID-19)pandemic.CRISPR/Cas is also being trialed as a new form of gene therapy for treating various human diseases,including cancers,and has aided drug development.In terms of agricultural breeding,precise targeting of biological pathways via CRISPR/Cas has been key to regulating molecular biosynthesis and allowing modification of proteins,starch,oil,and other functional components for crop improvement.Adding to this,CRISPR/Cas has been shown capable of significantly enhancing both plant tolerance to environmental stresses and overall crop yield via the targeting of various agronomically important gene regulators.Looking to the future,increasing the efficiency and precision of CRISPR/Cas delivery systems and limiting off-target activity are two major challenges for wider application of the technology.This review provides an in-depth overview of current CRISPR development,including the advantages and disadvantages of the technology,recent applications,and future considerations.
文摘本文采用汉语本族语者口语语料库(Corpus of Native Chinese Conversation)和英语本族语者口语语料库(Louvain Corpus of Native English Conversation),探讨了汉语和英语本族语者在自我修补的两种常用策略——重复和替换使用上的异同,重点分析在功能词和实义词各词类上重复起始词和替换词的使用情况。结果显示:二者对策略的使用共性与差异并存。共性主要表现在:汉英本族语者均倾向于将限定词作为重复起始词;倾向于将名词和限定词作为替换词。差异性则主要体现在:英语本族语者比汉语本族语者使用更多的功能词(如主格人称代词)作为重复起始词;而汉语本族语者比英语本族语者使用更多的实义词(尤其是动词和副词)作为重复起始词和替换词。本文从语序松紧度、句法投射性以及词组内部结构复杂度等视角对研究发现进行了讨论。
基金supported by grants from Consellería de Cultura,Educación e Ordenación Universitaria,Xunta de Galicia(ED431G/05,ED431C 2018/10)European Regional Development Fund(FEDER),Instituto de Salud CarlosⅢ(RD16/011/0016,RD21/0017/0031)Secretaría de Estado de Investigación,Desarrollo e Innovación(Grant/Award,number RTI2018-098830-B-I00)(to JLLG)。
文摘Parkinson’s disease is a neurodegenerative condition characterized by motor impairments caused by the selective loss of dopaminergic neurons in the substantia nigra.Levodopa is an effective and well-tolerated dopamine replacement agent.However,levodopa provides only symptomatic improvements,without affecting the underlying pathology,and is associated with side effects after long-term use.Cell-based replacement is a promising strategy that offers the possibility to replace lost neurons in Parkinson’s disease treatment.Clinical studies of transplantation of human fetal ventral mesencephalic tissue have provided evidence that the grafted dopaminergic neurons can reinnervate the striatum,release dopamine,integrate into the host neural circuits,and improve motor functions.One of the limiting factors for cell therapy in Parkinson’s disease is the low survival rate of grafted dopaminergic cells.Different factors could cause cell death of dopaminergic neurons after grafting such as mechanical trauma,growth factor deprivation,hypoxia,and neuroinflammation.Neurotrophic factors play an essential role in the survival of grafted cells.However,direct,timely,and controllable delivery of neurotrophic factors into the brain faces important limitations.Different types of cells secrete neurotrophic factors constitutively and co-transplantation of these cells with dopaminergic neurons represents a feasible strategy to increase neuronal survival.In this review,we provide a general overview of the pioneering studies on cell transplantation developed in patients and animal models of Parkinson’s disease,with a focus on neurotrophic factor-secreting cells,with a particular interest in mesenchymal stromal cells;that co-implanted with dopaminergic neurons would serve as a strategy to increase cell survival and improve graft outcomes.
基金funded by grant no.031B0548 in the frame of the program"Crop plants of the future"from the Bundesministerium fur Bildung und Forschung to A.T.funded by the Investissement d’Avenir program of the French National Agency of Research for the project GENIUS(ANR-11-BTBR-0001_GENIUS).
文摘In plants and mammals,non-homologous end-joining is the dominant pathway to repair DNA doublestrand breaks,making it challenging to generate knock-in events.In this study,we identified two groups of exonucleases from the herpes virus and the bacteriophage T7 families that conferred an up to 38-fold increase in homology-directed repair frequencies when fused to Cas9/Cas12a in a tobacco mosaic virus-based transient assay in Nicotiana benthamiana.We achieved precise and scar-free insertion of several kilobases of DNA both in transient and stable transformation systems.In Arabidopsis thaliana,fusion of Cas9 to a herpes virus family exonuclease led to 10-fold higher frequencies of knock-ins in the first generation of transformants.In addition,we demonstrated stable and heritable knock-ins in wheat in 1%of the primary transformants.Taken together,our results open perspectives for the routine production of heritable knock-in and gene replacement events in plants.
文摘Most of the spare ordering policies treated up to now have assumed that preventive and corrective replacement costs are equal, which implies in essential that there is no significant need for preventive replacement. This paper presents an ordering policy for preventive age replacement with minimal repair. Introducing the replacement, repair, inventory holding and shortage costs, the expected cost rate is derived. A procedure to determine jointly the ordering time for a spare and the preventive replacement time for the operating unit so as to minimize the expected cost rate is proposed. To explain the ordering policy and the optimization procedure, a numerical example is also included.
