Enormous studies have corroborated that long non-codig RNAs(LncRNAs)extensively participate in crucial physiological processes such as metabolism and immunity,and are closely related to the occurrence and development ...Enormous studies have corroborated that long non-codig RNAs(LncRNAs)extensively participate in crucial physiological processes such as metabolism and immunity,and are closely related to the occurrence and development of tumors,cardiovascular diseases,nervous system disorders,nephropathy,and other diseases.The application of lncRNAs as biomarkers or intervention targets can provide new insights into the diagnosis and treatment of diseases.This paper has focused on the emerging research into lncRNAs as pharmacological targets and has reviewed the transition of IncRNAs from the role of disease coding to acting as drug candidates,including the current status and progress in preclinical research.Cutting-edge strategies for lncRNA modulation have been summarized,including the sources of LncRNA-related drugs,such as genetic technology and small-molecule compounds,and related delivery methods.The current progress of clinical trials of lncRNA-targeting drugs is also discussed.This information will form a latest updated reference for research and development of lncRNA-based drugs.展开更多
Extensive studies in various plants show that the anthocyanin biosynthetic process is affected by environmental factors and regulated by many transcription factors through sophisticated regulatory networks. However, i...Extensive studies in various plants show that the anthocyanin biosynthetic process is affected by environmental factors and regulated by many transcription factors through sophisticated regulatory networks. However, it remains largely unclear about the roles of microRNA in this process. Here, we demonstrate that miR858a is a positive regulator of anthocyanin biosynthesis in Arabidopsis seedlings. Overexpression of miR858a enhances the accumulation of anthocyanins, whereas the reduced miR858a activity results in low levels of anthocyanins in STTM858 transgenic plants. We found that miR858a inhibits the expression of MYBL2, a key negative regulator of anthocyanin biosynthesis, by translational repression. In addition, ELONGATED HYPOCOTYL 5 （HYS） was shown to directly bind the MYBL2 promoter and represses its expression via specific histone modifications. Interestingly, we found that miR858a exhibits light- responsive expression in an HY5-dependent manner. Together, these results delineate the HY5- MIR858a-MYBL2 loop as a cellular mechanism for modulating anthocyanin biosynthesis, suggesting that integration of transcriptional and posttranscriptional regulation is critical for governing proper anthocyanin accumulation in response to light and other environmental factors.展开更多
Spinal cord injury(SCI) leads to loss of motor and sensory function below the injury level and imposes a considerable burden on patients, families, and society. Repair of the injured spinal cord has been recognized as...Spinal cord injury(SCI) leads to loss of motor and sensory function below the injury level and imposes a considerable burden on patients, families, and society. Repair of the injured spinal cord has been recognized as a global medical challenge for many years.Significant progress has been made in research on the pathological mechanism of spinal cord injury. In particular, with the development of gene regulation, cell sequencing, and cell tracing technologies, in-depth explorations of the SCI microenvironment have become more feasible. However, translational studies related to repair of the injured spinal cord have not yielded significant results. This review summarizes the latest research progress on two aspects of SCI pathology: intraneuronal microenvironment imbalance and regenerative microenvironment imbalance. We also review repair strategies for the injured spinal cord based on microenvironment imbalance, including medications, cell transplantation, exosomes, tissue engineering, cell reprogramming, and rehabilitation. The current state of translational research on SCI and future directions are also discussed. The development of a combined, precise, and multitemporal strategy for repairing the injured spinal cord is a potential future direction.展开更多
After three decades of the amazing progress made on molecular studies of plant-microbe interactions(MPMI),we have begun to ask ourselves"what are the major questions still remaining?"as if the puzzle has onl...After three decades of the amazing progress made on molecular studies of plant-microbe interactions(MPMI),we have begun to ask ourselves"what are the major questions still remaining?"as if the puzzle has only a few pieces missing.Such an exercise has ultimately led to the realization that we still have many more questions than answers.Therefore,it would be an impossible task for us to project a coherent"big picture"of the MPMI field in a single review.Instead,we provide our opinions on where we would like to go in our research as an invitation to the community to join us in this exploration of new MPMI frontiers.展开更多
Drug-induced liver injury is an important clinical problem and a challenge for drug development.Whereas progress in understanding rare and unpredictable (idiosyncratic) drug hepatotoxicity is severely hampered by the ...Drug-induced liver injury is an important clinical problem and a challenge for drug development.Whereas progress in understanding rare and unpredictable (idiosyncratic) drug hepatotoxicity is severely hampered by the lack of relevant animal models,enormous insight has been gained in the area of predictable hepatotoxins,in particular acetaminopheninduced liver injury,from a broad range of experimental models.Importantly,mechanisms of toxicity obtained with certain experimental systems,such as in vivo mouse models,primary mouse hepatocytes,and metabolically competent cell lines,are being confirmed in translational studies in patients and in primary human hepatocytes.Despite this progress,suboptimal models are still being used and experimental data can be confusing,leading to controversial conclusions.Therefore,this review attempts to discuss mechanisms of drug hepatotoxicity using the most studied drug acetaminophen as an example.We compare the various experimental models that are used to investigate mechanisms of acetaminophen hepatotoxicity,discuss controversial topics in the mechanisms,and assess how these experimental findings can be translated to the clinic.The success with acetaminophen in demonstrating the clinical relevance of experimental findings could serve as an example for the study of other drug toxicities.展开更多
Vγ9Vδ2 T cells are promising candidates for cellular tumor immunotherapy.Due to their HLA-independent mode of action,allogeneic Vγ9Vδ2 T cells can be considered for clinical application.To apply allogeneic Vγ9Vδ...Vγ9Vδ2 T cells are promising candidates for cellular tumor immunotherapy.Due to their HLA-independent mode of action,allogeneic Vγ9Vδ2 T cells can be considered for clinical application.To apply allogeneic Vγ9Vδ2 T cells in adoptive immunotherapy,the methodology used to obtain adequate cell numbers with optimal effector function in vitro needs to be optimized,and clinical safety and efficacy also need to be proven.Therefore,we developed a novel formula to improve the expansion of peripheralγδT cells from healthy donors.Then,we used a humanized mouse model to validate the therapeutic efficacy of expandedγδT cells in vivo;furthermore,the expandedγδT cells were adoptively transferred into late-stage liver and lung cancer patients.We found that the expanded cells possessed significantly improved immune effector functions,including proliferation,differentiation,and cancer cell killing,both in vitro and in the humanized mouse model.Furthermore,a phase I clinical trial in 132 late-stage cancer patients with a total of 414 cell infusions unequivocally validated the clinical safety of allogeneic Vγ9Vδ2 T cells.Among these 132 patients,8 liver cancer patients and 10 lung cancer patients who received≥5 cell infusions showed greatly prolonged survival,which preliminarily verified the efficacy of allogeneic Vγ9Vδ2 T-cell therapy.Our clinical studies underscore the safety and efficacy of allogeneic Vγ9Vδ2 T-cell immunotherapy,which will inspire further clinical investigations and eventually benefit cancer patients.展开更多
Bmi-1 is a member of the Polycomb repressor complex 1 that mediates gene silencing by regulating chromatin structure and is indispensable for self-renewal of both normal and cancer stem cells.Despite three decades of ...Bmi-1 is a member of the Polycomb repressor complex 1 that mediates gene silencing by regulating chromatin structure and is indispensable for self-renewal of both normal and cancer stem cells.Despite three decades of research that have elucidated the transcriptional regulation,post-translational modifications and functions of Bmi-1 in regulating the DNA damage response,cellular bioenergetics,and pathologies,the entire potential of a protein with such varied functions remains to be realized.This review attempts to synthesize the current knowledge on Bmi-1 with an emphasis on its role in both normal physiology and cancer.Additionally,since cancer stem cells are emerging as a new paradigm for therapy resistance,the role of Bmi-1 in this perspective is also highlighted.The wide spectrum of malignancies that implicate Bmi-1 as a signature for stemness and oncogenesis also make it a suitable candidate for therapy.Nonetheless,new approaches are vitally needed to further characterize physiological roles of Bmi-1 with the long-term goal of using Bmi-1 as a prognostic marker and a therapeutic target.展开更多
Translational medicine is a new concept presented in recent decades, the core of which is to build a bridge between basic medical research and clinical application. From the beginning of constitution of Chinese medici...Translational medicine is a new concept presented in recent decades, the core of which is to build a bridge between basic medical research and clinical application. From the beginning of constitution of Chinese medicine, clinical application has been given priority. Therefore, the idea of translational medicine is fully demonstrated in the research into the three key scientific problems of ＂classification of constitution of Chinese medicine＂, ＂relationship between constitution and disease＂ and ＂adjustment of constitution＂. Under its guidance, not only was the systematic theory of constitution of Chinese medicine established, but also the Constitution of Chinese Medicine Scale and the Standards of Classification and determination of Constitution of Chinese Medicine were developed, which translates methods of classifying the nine constitutional types into guidance for prevention of disease, management of health and clinical application. The research findings of constitution of Chinese medicine have been applied in clinical practice and public health, establishing the diagnosis and treatment model of constitution-disease-syndrome differentiation. The nationwide application of constitution differentiation has shown good effect. In the future, constitution of Chinese medicine should strengthen the evidence-based research and multi-disciplinary cooperation, and establish a research team on comprehensive constitution of Chinese medicine and translational medicine, to translate the findings into clinical practice and public health more accurately and quickly.展开更多
Performance analysis and kinematic design of the 3-PUU pure translational parallel mechanism with vertical guide-ways are investigated. Two novel performance indices, the critical slider stroke and the main section ar...Performance analysis and kinematic design of the 3-PUU pure translational parallel mechanism with vertical guide-ways are investigated. Two novel performance indices, the critical slider stroke and the main section area of workspace, are defined; The expressions of two other indices, i.e. the global dexterity and global force transfer ratio are revised based on the main section of workspace. Using these indices, performance changes versus the varieties of dimensional parameters of mechanism are investigated in detail and the graphic descriptions of change tendencies of the performance indices are illustrated. By means of these obtained graphic descriptions, kinematic parameters for the 3-PUU pure translational parallel mechanism with better characteristics can be directly acquired.展开更多
Following publication of NASCIS Ⅱ, methylprednisolone sodium succinate（MPSS） was hailed as a breakthrough for patients with acute spinal cord injury（SCI）. MPSS use for SCI has since become very controversial and ...Following publication of NASCIS Ⅱ, methylprednisolone sodium succinate（MPSS） was hailed as a breakthrough for patients with acute spinal cord injury（SCI）. MPSS use for SCI has since become very controversial and it is our opinion that additional evidence is unlikely to break the stalemate amongst clinicians. Patient opinion has the potential to break this stalemate and we review our recent findings which reported that spinal cord injured patients informed of the risks and benefits of MPSS reported a preference for MPSS administration. We discuss the implications of the current MPSS debate on translational research and seek to address some misconceptions which have evolved. As science has failed to resolve the MPSS debate we argue that the debate is an increasingly philosophical one. We question whether SCI might be viewed as a serious condition like cancer where serious side effects of therapeutics are tolerated even when benefits may be small. We also draw attention to the similarity between the side effects of MPSS and isotretinoin which is prescribed for the cosmetic disorder acne vulgaris. Ultimately we question how patient autonomy should be weighed in the context of current SCI guidelines and MPSS＇s status as a historical standard of care.展开更多
The unprecedented wheat yield increases during the Green Revolution were achieved through the introduc-tion of the Reduced height(Rht)-B1b and Rht-D1b semi-dwarfing alleles.These Rht-1 alleles encode growth-repressing...The unprecedented wheat yield increases during the Green Revolution were achieved through the introduc-tion of the Reduced height(Rht)-B1b and Rht-D1b semi-dwarfing alleles.These Rht-1 alleles encode growth-repressing DELLA genes containing a stop codon within their open reading frame that confers gibberellin(GA)-insensitive semi-dwarfism.In this study,we successfully took the hurdle of detecting wild-type RHT-1 proteins in different wheat organs and confirmed their degradation in response to GAs.We further demonstrated that Rht-B1b and Rht-D1b produce N-terminal truncated proteins through trans-lational reinitiation.Expression of these N-terminal truncated proteins in transgenic lines and in Rht-D1c,an allele containing multiple Rht-D1b copies,demonstrated their ability to cause strong dwarfism,resulting from their insensitivity to GA-mediated degradation.N-terminal truncated proteins were detected in spikes and nodes,but not in the aleurone layers.Since Rht-B 1b and Rht-D1b alleles cause dwarfism but have wild-type dormancy,this finding suggests that tissue-specific differences in translational reinitiation may explain why the Rht-1 alleles reduce plant height without affecting dormancy.Taken together,our findings not only reveal the molecular mechanism underlying the Green Revolution but also demonstrate that trans-lational reinitiation in the main open reading frame occurs in plants.展开更多
Almost every experimental treatment strategy using non-autologous cell, tissue or organ transplantation is tested in small and large animal models before clinical translation. Because these strategies require immunosu...Almost every experimental treatment strategy using non-autologous cell, tissue or organ transplantation is tested in small and large animal models before clinical translation. Because these strategies require immunosuppression in most cases, immunosuppressive protocols are a key element in transplantation experiments. However, standard immunosuppressive protocols are often applied without detailed knowledge regarding their efficacy within the particular experimental setting and in the chosen model species. Optimization of such protocols is pertinent to the translation of experimental results to human patients and thus warrants further investigation. This review summarizes current knowledge regarding immunosuppressive drug classes as well as their dosages and application regimens with consideration of species-specific drug metabolization and side effects. It also summarizes contemporary knowledge of novel immunomodulatory strategies, such as the use of mesenchymal stem cells or antibodies. Thus, this review is intended to serve as a state-of-the-art compendium for researchers to refine applied experimental immunosuppression and immunomodulation strategies to enhance the predictive value of preclinical transplantation studies.展开更多
Coupling is the significant characteristic of parallel mechanism,while it is just the coupling that brings about much difficulty for the configuration design,theoretical analysis and the development of the control sys...Coupling is the significant characteristic of parallel mechanism,while it is just the coupling that brings about much difficulty for the configuration design,theoretical analysis and the development of the control system of the parallel mechanism. And recently,the research on the decoupled parallel mechanism becomes one of the research hot points in the mechanism fields. In this paper,a type synthesis method for the translational decoupled parallel mechanism( TDPM) is proposed based on the screw theory. To achieve the decoupling characteristics of the translational parallel mechanism,the translational decoupled criterion for type synthesis of the branches are presented in this paper. According to this criterion and the realization conditions of rotational degree of freedom of the mechanism proposed former,a large number of branches for the TDPM are obtained. Taking the three degrees of freedom( DOFs) TDPM as an example,the process of type synthesis is discussed in detail. Using this proposed type synthesis method,a serial of translational decoupled parallel mechanisms, including but not limited to all the existing typical 3-DOF TDPMs, are obtained, which identifies the correctness and effective of the method. The contents of this paper provide a reference and possess significant theoretical meanings for the synthesis and development of the novel decoupled parallel mechanisms.展开更多
PIWI-clade proteins harness pi RNAs of 24–33 nt in length.Of great puzzles are how PIWI-clade proteins incorporate pi RNAs of different sizes and whether the size matters to PIWI/pi RNA function.Here we report that a...PIWI-clade proteins harness pi RNAs of 24–33 nt in length.Of great puzzles are how PIWI-clade proteins incorporate pi RNAs of different sizes and whether the size matters to PIWI/pi RNA function.Here we report that a PIWI-Ins module unique in PIWIclade proteins helps define the length of pi RNAs.Deletion of PIWI-Ins in Miwi shifts MIWI to load with shorter pi RNAs and causes spermiogenic failure in mice,demonstrating the functional importance of this regulatory module.Mechanistically,we show that longer pi RNAs provide additional complementarity to target m RNAs,thereby enhancing the assembly of the MIWI/e IF3f/Hu R super-complex for translational activation.Importantly,we identify a c.1108C>T(p.R370W)mutation of HIWI(human PIWIL1)in infertile men and demonstrate in Miwi knock-in mice that this genetic mutation impairs male fertility by altering the property of PIWI-Ins in selecting longer pi RNAs.These findings reveal a critical role of PIWI-Ins-ensured longer pi RNAs in fine-tuning MIWI/pi RNA targeting capacity,proven essential for spermatid development and male fertility.展开更多
With the emergence of the modified forms of acupuncture-moxibustion such as dry needle,the discipline acupuncture-moxibustion faces significant opportunities and challenges.The concept and treatment of acupuncture-mox...With the emergence of the modified forms of acupuncture-moxibustion such as dry needle,the discipline acupuncture-moxibustion faces significant opportunities and challenges.The concept and treatment of acupuncture-moxibustion need to combine with modern medicine to consolidate the effectiveness and apply the research results to guide clinical treatment.By reviewing the brief history of acupuncture-moxibustion in the Western countries and summarizing the definitions,this article was to propose the trend and development strategies of this discipline in the future.展开更多
Light plays a critical role in plant growth and development,but the mechanisms through which light regulates fruit ripening and nutritional quality in horticultural crops remain largely unknown.Here,we found that ELON...Light plays a critical role in plant growth and development,but the mechanisms through which light regulates fruit ripening and nutritional quality in horticultural crops remain largely unknown.Here,we found that ELONGATED HYPOCOTYL 5(HY5),a master regulator in the light signaling pathway,is required for normal fruit ripening in tomato(Solanum lycopersicum).Loss of function of tomato HY5(SlHY5)impairs pigment accumulation and ethylene biosynthesis.Transcriptome profiling identified 2948 differentially expressed genes,which included 1424 downregulated and 1524 upregulated genes,in the Slhy5 mutants.In addition,genes involved in carotenoid and anthocyanin biosynthesis and ethylene signaling were revealed as direct targets of SlHY5 by chromatin immunoprecipitation.Surprisingly,the expression of a large proportion of genes encoding ribosomal proteins was downregulated in the Slhy5 mutants,and this downregulation pattern was accompanied by a decrease in the abundance of ribosomal proteins.Further analysis demonstrated that SlHY5 affected the translation efficiency of numerous ripening-related genes.These data indicate that SlHY5 regulates fruit ripening both at the transcriptional level by targeting specific molecular pathways and at the translational level by affecting the protein translation machinery.Our findings unravel the regulatory mechanisms of SlHY5 in controlling fruit ripening and nutritional quality and uncover the multifaceted regulation of gene expression by transcription factors.展开更多
Circular RNA(circRNA)is a novel class of single-stranded RNAs with a closed loop structure.The majority of circRNAs are formed by a back-splicing process in pre-mRNA splicing.Their expression is dynamically regulated ...Circular RNA(circRNA)is a novel class of single-stranded RNAs with a closed loop structure.The majority of circRNAs are formed by a back-splicing process in pre-mRNA splicing.Their expression is dynamically regulated and shows spatiotemporal patterns among cell types,tissues and developmental stages.CircRNAs have important biological functions in many physiological processes,and their aberrant expression is implicated in many human diseases.Due to their high stability,circRNAs are becoming promising biomarkers in many human diseases,such as cardiovascular diseases,autoimmune diseases and human cancers.In this review,we focus on the translational potential of using human blood circRNAs as liquid biopsy biomarkers for human diseases.We highlight their abundant expression,essential biological functions and significant correlations to human diseases in various components of peripheral blood,including whole blood,blood cells and extracellular vesicles.In addition,we summarize the current knowledge of blood circRNA biomarkers for disease diagnosis or prognosis.展开更多
基金supported by the Drug Innovation Major Project of China(Grant No.2018ZX09711001-002-010)Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(Grant No.2016-I2M-3e011,China)Beijing Natural Science Foundation(Grant Nos.7202138 and 7181007,China)
文摘Enormous studies have corroborated that long non-codig RNAs(LncRNAs)extensively participate in crucial physiological processes such as metabolism and immunity,and are closely related to the occurrence and development of tumors,cardiovascular diseases,nervous system disorders,nephropathy,and other diseases.The application of lncRNAs as biomarkers or intervention targets can provide new insights into the diagnosis and treatment of diseases.This paper has focused on the emerging research into lncRNAs as pharmacological targets and has reviewed the transition of IncRNAs from the role of disease coding to acting as drug candidates,including the current status and progress in preclinical research.Cutting-edge strategies for lncRNA modulation have been summarized,including the sources of LncRNA-related drugs,such as genetic technology and small-molecule compounds,and related delivery methods.The current progress of clinical trials of lncRNA-targeting drugs is also discussed.This information will form a latest updated reference for research and development of lncRNA-based drugs.
文摘Extensive studies in various plants show that the anthocyanin biosynthetic process is affected by environmental factors and regulated by many transcription factors through sophisticated regulatory networks. However, it remains largely unclear about the roles of microRNA in this process. Here, we demonstrate that miR858a is a positive regulator of anthocyanin biosynthesis in Arabidopsis seedlings. Overexpression of miR858a enhances the accumulation of anthocyanins, whereas the reduced miR858a activity results in low levels of anthocyanins in STTM858 transgenic plants. We found that miR858a inhibits the expression of MYBL2, a key negative regulator of anthocyanin biosynthesis, by translational repression. In addition, ELONGATED HYPOCOTYL 5 （HYS） was shown to directly bind the MYBL2 promoter and represses its expression via specific histone modifications. Interestingly, we found that miR858a exhibits light- responsive expression in an HY5-dependent manner. Together, these results delineate the HY5- MIR858a-MYBL2 loop as a cellular mechanism for modulating anthocyanin biosynthesis, suggesting that integration of transcriptional and posttranscriptional regulation is critical for governing proper anthocyanin accumulation in response to light and other environmental factors.
基金the National Key Research and Development Project of Stem Cell and Transformation Research(2019YFA0112100).
文摘Spinal cord injury(SCI) leads to loss of motor and sensory function below the injury level and imposes a considerable burden on patients, families, and society. Repair of the injured spinal cord has been recognized as a global medical challenge for many years.Significant progress has been made in research on the pathological mechanism of spinal cord injury. In particular, with the development of gene regulation, cell sequencing, and cell tracing technologies, in-depth explorations of the SCI microenvironment have become more feasible. However, translational studies related to repair of the injured spinal cord have not yielded significant results. This review summarizes the latest research progress on two aspects of SCI pathology: intraneuronal microenvironment imbalance and regenerative microenvironment imbalance. We also review repair strategies for the injured spinal cord based on microenvironment imbalance, including medications, cell transplantation, exosomes, tissue engineering, cell reprogramming, and rehabilitation. The current state of translational research on SCI and future directions are also discussed. The development of a combined, precise, and multitemporal strategy for repairing the injured spinal cord is a potential future direction.
基金grants from the National Institutes of Health(NIH 1R35GM118036)National Science Foundation(IOS 1645589)+5 种基金Howard Hughes Medical Institute to X.D.,grants from the NIH(NIH 1R35GM136402)National Science Foundation(NSF 1937855-0)United States Department of Agriculture(USDA,2019-70016-2979)G.C.,a grant from National Natural Science Foundation of China(31830019)J.-M.Z.,and a grant from National Natural Science Foundation of China(31922075)Youth Innovation Promotion Association of the Chinese Academy of Sciences to J.Z.
文摘After three decades of the amazing progress made on molecular studies of plant-microbe interactions(MPMI),we have begun to ask ourselves"what are the major questions still remaining?"as if the puzzle has only a few pieces missing.Such an exercise has ultimately led to the realization that we still have many more questions than answers.Therefore,it would be an impossible task for us to project a coherent"big picture"of the MPMI field in a single review.Instead,we provide our opinions on where we would like to go in our research as an invitation to the community to join us in this exploration of new MPMI frontiers.
基金Work in the authors' laboratory was supported in part by grants from the National Institutes of Health(R01 DK070195 and R01 AA12916)the National Center for Research Resources(5P20RR021940-07)the National Institute of General Medical Sciences (8 P20 GM103549-07) of the National Institutes of Health.Additional support came from the "Training Program in Environmental Toxicology" T32ES007079-26A2 (to M.R.M.) from the National Institute of Environmental Health Sciences
文摘Drug-induced liver injury is an important clinical problem and a challenge for drug development.Whereas progress in understanding rare and unpredictable (idiosyncratic) drug hepatotoxicity is severely hampered by the lack of relevant animal models,enormous insight has been gained in the area of predictable hepatotoxins,in particular acetaminopheninduced liver injury,from a broad range of experimental models.Importantly,mechanisms of toxicity obtained with certain experimental systems,such as in vivo mouse models,primary mouse hepatocytes,and metabolically competent cell lines,are being confirmed in translational studies in patients and in primary human hepatocytes.Despite this progress,suboptimal models are still being used and experimental data can be confusing,leading to controversial conclusions.Therefore,this review attempts to discuss mechanisms of drug hepatotoxicity using the most studied drug acetaminophen as an example.We compare the various experimental models that are used to investigate mechanisms of acetaminophen hepatotoxicity,discuss controversial topics in the mechanisms,and assess how these experimental findings can be translated to the clinic.The success with acetaminophen in demonstrating the clinical relevance of experimental findings could serve as an example for the study of other drug toxicities.
基金This work was supported by the Key Program of the National Natural Science Foundation of China(31830021)Major International Joint Research Program of China(31420103901)+12 种基金“111 project”(B16021)Scientific and Technological Plan of Guangdong Province(201704KW010)(Z.Y.)Fundamental Research Funds for the Central Universities,Natural Science Foundation of Guangdong Province,China(2020A1515010132)(Y.W.)General Research Fund,Research Grants Council of Hong Kong(17122519,17121214,17115015,and 17126317)(W.T.)Hong Kong SAR,ChinaThis work was also partially supported by the National Natural Science Foundation of China(31570898)the Natural Science Foundation of Guangdong Province,China(2016A030313112)(Z.X.)grant Ka 502/19-1 from the German Research Council(Deutsche Forschungsgemeinschaft)the Cluster of Excellence ExC 306“Inflammation-at-Interfaces”(Deutsche Forschungsgemeinschaft)(D.K.)Y.H.was supported by the China Postdoctoral Science Foundation(2017M622898)Y.X.was supported by the Postdoctoral Fund of the First Affiliated Hospital of Jinan University(809008)L.K.was supported by a long-term fellowship from the German Academic Exchange Service(DAAD)C.P.is the recipient of a grant from the Erich und Gertrud Roggenbruck Foundation.
文摘Vγ9Vδ2 T cells are promising candidates for cellular tumor immunotherapy.Due to their HLA-independent mode of action,allogeneic Vγ9Vδ2 T cells can be considered for clinical application.To apply allogeneic Vγ9Vδ2 T cells in adoptive immunotherapy,the methodology used to obtain adequate cell numbers with optimal effector function in vitro needs to be optimized,and clinical safety and efficacy also need to be proven.Therefore,we developed a novel formula to improve the expansion of peripheralγδT cells from healthy donors.Then,we used a humanized mouse model to validate the therapeutic efficacy of expandedγδT cells in vivo;furthermore,the expandedγδT cells were adoptively transferred into late-stage liver and lung cancer patients.We found that the expanded cells possessed significantly improved immune effector functions,including proliferation,differentiation,and cancer cell killing,both in vitro and in the humanized mouse model.Furthermore,a phase I clinical trial in 132 late-stage cancer patients with a total of 414 cell infusions unequivocally validated the clinical safety of allogeneic Vγ9Vδ2 T cells.Among these 132 patients,8 liver cancer patients and 10 lung cancer patients who received≥5 cell infusions showed greatly prolonged survival,which preliminarily verified the efficacy of allogeneic Vγ9Vδ2 T-cell therapy.Our clinical studies underscore the safety and efficacy of allogeneic Vγ9Vδ2 T-cell immunotherapy,which will inspire further clinical investigations and eventually benefit cancer patients.
基金This study was supported by the National Institutes of Health(NIH)CA157481 awarded to RB.
文摘Bmi-1 is a member of the Polycomb repressor complex 1 that mediates gene silencing by regulating chromatin structure and is indispensable for self-renewal of both normal and cancer stem cells.Despite three decades of research that have elucidated the transcriptional regulation,post-translational modifications and functions of Bmi-1 in regulating the DNA damage response,cellular bioenergetics,and pathologies,the entire potential of a protein with such varied functions remains to be realized.This review attempts to synthesize the current knowledge on Bmi-1 with an emphasis on its role in both normal physiology and cancer.Additionally,since cancer stem cells are emerging as a new paradigm for therapy resistance,the role of Bmi-1 in this perspective is also highlighted.The wide spectrum of malignancies that implicate Bmi-1 as a signature for stemness and oncogenesis also make it a suitable candidate for therapy.Nonetheless,new approaches are vitally needed to further characterize physiological roles of Bmi-1 with the long-term goal of using Bmi-1 as a prognostic marker and a therapeutic target.
基金Supported by the National Basic Research Program of China(973 Program,No.2011CB505403)
文摘Translational medicine is a new concept presented in recent decades, the core of which is to build a bridge between basic medical research and clinical application. From the beginning of constitution of Chinese medicine, clinical application has been given priority. Therefore, the idea of translational medicine is fully demonstrated in the research into the three key scientific problems of ＂classification of constitution of Chinese medicine＂, ＂relationship between constitution and disease＂ and ＂adjustment of constitution＂. Under its guidance, not only was the systematic theory of constitution of Chinese medicine established, but also the Constitution of Chinese Medicine Scale and the Standards of Classification and determination of Constitution of Chinese Medicine were developed, which translates methods of classifying the nine constitutional types into guidance for prevention of disease, management of health and clinical application. The research findings of constitution of Chinese medicine have been applied in clinical practice and public health, establishing the diagnosis and treatment model of constitution-disease-syndrome differentiation. The nationwide application of constitution differentiation has shown good effect. In the future, constitution of Chinese medicine should strengthen the evidence-based research and multi-disciplinary cooperation, and establish a research team on comprehensive constitution of Chinese medicine and translational medicine, to translate the findings into clinical practice and public health more accurately and quickly.
基金This project is supported by National Natural Science Foundation of China (No.60275031)Municipal Key Lab Open Fund of Beijing, China (No.KP01-072200384).
文摘Performance analysis and kinematic design of the 3-PUU pure translational parallel mechanism with vertical guide-ways are investigated. Two novel performance indices, the critical slider stroke and the main section area of workspace, are defined; The expressions of two other indices, i.e. the global dexterity and global force transfer ratio are revised based on the main section of workspace. Using these indices, performance changes versus the varieties of dimensional parameters of mechanism are investigated in detail and the graphic descriptions of change tendencies of the performance indices are illustrated. By means of these obtained graphic descriptions, kinematic parameters for the 3-PUU pure translational parallel mechanism with better characteristics can be directly acquired.
文摘Following publication of NASCIS Ⅱ, methylprednisolone sodium succinate（MPSS） was hailed as a breakthrough for patients with acute spinal cord injury（SCI）. MPSS use for SCI has since become very controversial and it is our opinion that additional evidence is unlikely to break the stalemate amongst clinicians. Patient opinion has the potential to break this stalemate and we review our recent findings which reported that spinal cord injured patients informed of the risks and benefits of MPSS reported a preference for MPSS administration. We discuss the implications of the current MPSS debate on translational research and seek to address some misconceptions which have evolved. As science has failed to resolve the MPSS debate we argue that the debate is an increasingly philosophical one. We question whether SCI might be viewed as a serious condition like cancer where serious side effects of therapeutics are tolerated even when benefits may be small. We also draw attention to the similarity between the side effects of MPSS and isotretinoin which is prescribed for the cosmetic disorder acne vulgaris. Ultimately we question how patient autonomy should be weighed in the context of current SCI guidelines and MPSS＇s status as a historical standard of care.
基金D.V.D.S.acknowledges Ghent University for financial support.S.T.was supported by the Biotechnology and Biological Sciences Research Council Designing Future Wheat Cross Institute Strategic Programme(grant BB/P016855/1).
文摘The unprecedented wheat yield increases during the Green Revolution were achieved through the introduc-tion of the Reduced height(Rht)-B1b and Rht-D1b semi-dwarfing alleles.These Rht-1 alleles encode growth-repressing DELLA genes containing a stop codon within their open reading frame that confers gibberellin(GA)-insensitive semi-dwarfism.In this study,we successfully took the hurdle of detecting wild-type RHT-1 proteins in different wheat organs and confirmed their degradation in response to GAs.We further demonstrated that Rht-B1b and Rht-D1b produce N-terminal truncated proteins through trans-lational reinitiation.Expression of these N-terminal truncated proteins in transgenic lines and in Rht-D1c,an allele containing multiple Rht-D1b copies,demonstrated their ability to cause strong dwarfism,resulting from their insensitivity to GA-mediated degradation.N-terminal truncated proteins were detected in spikes and nodes,but not in the aleurone layers.Since Rht-B 1b and Rht-D1b alleles cause dwarfism but have wild-type dormancy,this finding suggests that tissue-specific differences in translational reinitiation may explain why the Rht-1 alleles reduce plant height without affecting dormancy.Taken together,our findings not only reveal the molecular mechanism underlying the Green Revolution but also demonstrate that trans-lational reinitiation in the main open reading frame occurs in plants.
文摘Almost every experimental treatment strategy using non-autologous cell, tissue or organ transplantation is tested in small and large animal models before clinical translation. Because these strategies require immunosuppression in most cases, immunosuppressive protocols are a key element in transplantation experiments. However, standard immunosuppressive protocols are often applied without detailed knowledge regarding their efficacy within the particular experimental setting and in the chosen model species. Optimization of such protocols is pertinent to the translation of experimental results to human patients and thus warrants further investigation. This review summarizes current knowledge regarding immunosuppressive drug classes as well as their dosages and application regimens with consideration of species-specific drug metabolization and side effects. It also summarizes contemporary knowledge of novel immunomodulatory strategies, such as the use of mesenchymal stem cells or antibodies. Thus, this review is intended to serve as a state-of-the-art compendium for researchers to refine applied experimental immunosuppression and immunomodulation strategies to enhance the predictive value of preclinical transplantation studies.
基金Sponsored by the National Natural Science Foundation of China(Grant No.51005195,51205339)
文摘Coupling is the significant characteristic of parallel mechanism,while it is just the coupling that brings about much difficulty for the configuration design,theoretical analysis and the development of the control system of the parallel mechanism. And recently,the research on the decoupled parallel mechanism becomes one of the research hot points in the mechanism fields. In this paper,a type synthesis method for the translational decoupled parallel mechanism( TDPM) is proposed based on the screw theory. To achieve the decoupling characteristics of the translational parallel mechanism,the translational decoupled criterion for type synthesis of the branches are presented in this paper. According to this criterion and the realization conditions of rotational degree of freedom of the mechanism proposed former,a large number of branches for the TDPM are obtained. Taking the three degrees of freedom( DOFs) TDPM as an example,the process of type synthesis is discussed in detail. Using this proposed type synthesis method,a serial of translational decoupled parallel mechanisms, including but not limited to all the existing typical 3-DOF TDPMs, are obtained, which identifies the correctness and effective of the method. The contents of this paper provide a reference and possess significant theoretical meanings for the synthesis and development of the novel decoupled parallel mechanisms.
基金supported by the National Key Research and Development Program of China(2022YFA1303300,2021YFC2700200,2017YFA0504400)Chinese Academy of Sciences(“Strategic Priority Research Program”grants XDB37000000)+3 种基金the National Natural Science Foundation of China(31830109,31821004,91940305,31961133022,32101037,32271347,21933010,22203089)Science and Technology Commission of Shanghai Municipality(17JC1420100,2017SHZDZX01,19JC1410200,21YF1452700,21ZR1470500)the Young Elite Scientist Sponsorship Program of the China Association for Science and Technology(2021QNRC001)the Foundation of Key Laboratory of Gene Engineering of the Ministry of Education。
文摘PIWI-clade proteins harness pi RNAs of 24–33 nt in length.Of great puzzles are how PIWI-clade proteins incorporate pi RNAs of different sizes and whether the size matters to PIWI/pi RNA function.Here we report that a PIWI-Ins module unique in PIWIclade proteins helps define the length of pi RNAs.Deletion of PIWI-Ins in Miwi shifts MIWI to load with shorter pi RNAs and causes spermiogenic failure in mice,demonstrating the functional importance of this regulatory module.Mechanistically,we show that longer pi RNAs provide additional complementarity to target m RNAs,thereby enhancing the assembly of the MIWI/e IF3f/Hu R super-complex for translational activation.Importantly,we identify a c.1108C>T(p.R370W)mutation of HIWI(human PIWIL1)in infertile men and demonstrate in Miwi knock-in mice that this genetic mutation impairs male fertility by altering the property of PIWI-Ins in selecting longer pi RNAs.These findings reveal a critical role of PIWI-Ins-ensured longer pi RNAs in fine-tuning MIWI/pi RNA targeting capacity,proven essential for spermatid development and male fertility.
基金National Natural Science Foundation of China(国家自然科学基金,81873373,81473760,81574058,81774429)Shanghai Talent Development Fund(上海市人才发展基金,201610)+1 种基金Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning(上海高校特聘教授(东方学者)岗位计划资助,JZ2016010)Construction Project of Collaborative Innovation of Shanghai(上海市协同创新建设项目,ZYJKFW201701005).
文摘With the emergence of the modified forms of acupuncture-moxibustion such as dry needle,the discipline acupuncture-moxibustion faces significant opportunities and challenges.The concept and treatment of acupuncture-moxibustion need to combine with modern medicine to consolidate the effectiveness and apply the research results to guide clinical treatment.By reviewing the brief history of acupuncture-moxibustion in the Western countries and summarizing the definitions,this article was to propose the trend and development strategies of this discipline in the future.
基金the National Natural Science Foundation of China(grant Nos.31801601,31925035,and 31871855)the China Postdoctoral Science Foundation(2018T110153)the Youth Innovation Promotion Association CAS(2019083).
文摘Light plays a critical role in plant growth and development,but the mechanisms through which light regulates fruit ripening and nutritional quality in horticultural crops remain largely unknown.Here,we found that ELONGATED HYPOCOTYL 5(HY5),a master regulator in the light signaling pathway,is required for normal fruit ripening in tomato(Solanum lycopersicum).Loss of function of tomato HY5(SlHY5)impairs pigment accumulation and ethylene biosynthesis.Transcriptome profiling identified 2948 differentially expressed genes,which included 1424 downregulated and 1524 upregulated genes,in the Slhy5 mutants.In addition,genes involved in carotenoid and anthocyanin biosynthesis and ethylene signaling were revealed as direct targets of SlHY5 by chromatin immunoprecipitation.Surprisingly,the expression of a large proportion of genes encoding ribosomal proteins was downregulated in the Slhy5 mutants,and this downregulation pattern was accompanied by a decrease in the abundance of ribosomal proteins.Further analysis demonstrated that SlHY5 affected the translation efficiency of numerous ripening-related genes.These data indicate that SlHY5 regulates fruit ripening both at the transcriptional level by targeting specific molecular pathways and at the translational level by affecting the protein translation machinery.Our findings unravel the regulatory mechanisms of SlHY5 in controlling fruit ripening and nutritional quality and uncover the multifaceted regulation of gene expression by transcription factors.
基金This work was funded by Grants from National Key R&D Program of China(2018YFC1314900,2018YFC1314902)National Natural Science Foundation of China(61571109)the Fundamental Research Funds for the Central Universities(2242017K3DN04).
文摘Circular RNA(circRNA)is a novel class of single-stranded RNAs with a closed loop structure.The majority of circRNAs are formed by a back-splicing process in pre-mRNA splicing.Their expression is dynamically regulated and shows spatiotemporal patterns among cell types,tissues and developmental stages.CircRNAs have important biological functions in many physiological processes,and their aberrant expression is implicated in many human diseases.Due to their high stability,circRNAs are becoming promising biomarkers in many human diseases,such as cardiovascular diseases,autoimmune diseases and human cancers.In this review,we focus on the translational potential of using human blood circRNAs as liquid biopsy biomarkers for human diseases.We highlight their abundant expression,essential biological functions and significant correlations to human diseases in various components of peripheral blood,including whole blood,blood cells and extracellular vesicles.In addition,we summarize the current knowledge of blood circRNA biomarkers for disease diagnosis or prognosis.
