During development and in the context of different morphogenetic events, epithelial cells undergo a process called epithelial to mesenchymal transition or transdifferentiation （EMT）. In this process, the cells lose ...During development and in the context of different morphogenetic events, epithelial cells undergo a process called epithelial to mesenchymal transition or transdifferentiation （EMT）. In this process, the cells lose their epithelial characteristics, including their polarity and specialized cell-cell contacts, and acquire a migratory behavior, allowing them to move away from their epithelial cell community and to integrate into surrounding tissue, even at remote locations. EMT illustrates the differentiation plasticity during development and is complemented by another process, called mesenchymal to epithelial transition （MET）. While being an integral process during development, EMT is also recapitulated under pathological conditions, prominently in fibrosis and in invasion and metastasis of carcinomas. Accordingly, EMT is considered as an important step in tumor progression. TGF-β signaling has been shown to play an important role in EMT. In fact, adding TGF-β to epithelial cells in culture is a convenient way to induce EMT in various epithelial cells. Although much less characterized, epithelial plasticity can also be regulated by TGF-β-related bone morphogenetic proteins （BMPs）, and BMPs have been shown to induce EMT or MET depending on the developmental context. In this review, we will discuss the induction of EMT in response to TGF-β, and focus on the under- lying signaling and transcription mechanisms.展开更多
MicroRNAs （miRNAs） are a class of naturally occurring small non-coding RNAs that target protein-coding mRNAs at the post-transcriptional level. Our previous studies suggest that mir-21 functions as an oncogene and h...MicroRNAs （miRNAs） are a class of naturally occurring small non-coding RNAs that target protein-coding mRNAs at the post-transcriptional level. Our previous studies suggest that mir-21 functions as an oncogene and has a role in tumorigenesis, in part through regulation of the tumor suppressor gene tropomyosin 1 （TPM1）. Given that TPM1 has been implicated in cell migration, in this study we further investigated the role of mir-21 in cell invasion and tumor metastasis. We found that suppression of mir-21 in metastatic breast cancer MDA-MB-231 cells significantly reduced invasion and lung metastasis. Consistent with this, ectopic expression of TPM1 remarkably reduced cell invasion. Furthermore, we identified two additional direct mir-21 targets, programmed cell death 4 （PDCD4） and maspin, both of which have been implicated in invasion and metastasis. Like TPM1, PDCD4 and maspin also reduced invasiveness of MDA-MB-231 cells. Finally, the expression of PDCD4 and maspin inversely correlated with mir-21 expression in human breast tumor specimens, indicating the potential regulation of PDCD4 and maspin by mir-21 in these tumors. Taken together, the results suggest that, as an oncogenic miRNA, mir-21 has a role not only in tumor growth but also in invasion and tumor metastasis by targeting multiple tumor/metastasis suppressor genes. Therefore, suppression of mir-21 may provide a novel approach for the treatment of advanced cancers.展开更多
Tea is the world＇s oldest and most popular caffeine-containing beverage with immense economic, medicinal, and cultural importance. Here, we present the first high-quality nucleotide sequence of the repeat-rich （80.9...Tea is the world＇s oldest and most popular caffeine-containing beverage with immense economic, medicinal, and cultural importance. Here, we present the first high-quality nucleotide sequence of the repeat-rich （80.9%）, 3.02-Gb genome of the cultivated tea tree Camellia sinensis. We show that an extraordinarily large genome size of tea tree is resulted from the slow, steady, and long-term amplification of a few LTR retrotransposon families. In addition to a recent whole-genome duplication event, lineage-specific expansions of genes associated with flavonoid metabolic biosynthesis were discovered, which enhance catechin production, terpene enzyme activation, and stress tolerance, important features for tea flavor and adaptation. We demonstrate an independent and rapid evolution of the tea caffeine synthesis pathway relative to cacao and coffee. A comparative study among 25 Camellia species revealed that higher expression levels of most flavonoid- and caffeinebut not theanine-related genes contribute to the increased production of catechins and caffeine and thus enhance tea-processing suitability and tea quality. These novel findings pave the way for further metabolomic and functional genomic refinement of characteristic biosynthesis pathways and will help develop a more diversified set of tea flavors that would eventually satisfy and attract more tea drinkers worldwide.展开更多
Liver fibrosis is a reversible wound-healing process aimed at maintaining organ integrity, and presents as the critical pre-stage of liver cirrhosis, which will eventually progress to hepatocellular carcinoma in the a...Liver fibrosis is a reversible wound-healing process aimed at maintaining organ integrity, and presents as the critical pre-stage of liver cirrhosis, which will eventually progress to hepatocellular carcinoma in the absence of liver transplantation. Fibrosis generally results from chronic hepatic injury caused by various factors, mainly viral infection, schistosomiasis, and alcoholism; however, the exact pathological mechanisms are still unknown. Although numerous drugs have been shown to have antifibrotic activity in vitro and in animal models, none of these drugs have been shown to be efficacious in the clinic. Importantly, hepatic stellate cells(HSCs) play a key role in the initiation, progression, and regression of liver fibrosis by secreting fibrogenic factors that encourage portal fibrocytes, fibroblasts, and bone marrow-derived myofibroblasts to produce collagen and thereby propagate fibrosis. These cells are subject to intricate cross-talk with adjacent cells, resulting in scarring and subsequent liver damage. Thus, an understanding of the molecular mechanisms of liver fibrosis and their relationships with HSCs is essential for the discovery of new therapeutic targets. This comprehensive review outlines the role of HSCs in liver fibrosis and details novel strategies to suppress HSC activity, thereby providing new insights into potential treatments for liver fibrosis.展开更多
Abiotic stresses and soil nutrient limitations are major environmental conditions that reduce plant growth,productivity and quality.Plants have evolved mechanisms to perceive these environmental challenges,transmit th...Abiotic stresses and soil nutrient limitations are major environmental conditions that reduce plant growth,productivity and quality.Plants have evolved mechanisms to perceive these environmental challenges,transmit the stress signals within cells as well as between cells and tissues,and make appropriate adjustments in their growth and development in order to survive and reproduce.In recent years,significant progress has been made on many fronts of the stress signaling research,particularly in understanding the downstream signaling events that culminate at the activation of stress-and nutrient limitation-responsive genes,cellular ion homeostasis,and growth adjustment.However,the revelation of the early events of stress signaling,particularly the identification of primary stress sensors,still lags behind.In this review,we summarize recent work on the genetic and molecular mechanisms of plant abiotic stress and nutrient limitation sensing and signaling and discuss new directions for future studies.展开更多
Background:Human infections with zoonotic coronaviruses(CoVs),including severe acute respiratory syndrome(SARS)-CoV and Middle East respiratory syndrome(MERS)-CoV,have raised great public health concern globally.Here,...Background:Human infections with zoonotic coronaviruses(CoVs),including severe acute respiratory syndrome(SARS)-CoV and Middle East respiratory syndrome(MERS)-CoV,have raised great public health concern globally.Here,we report a novel batorigin CoV causing severe and fatal pneumonia in humans.Methods:We collected clinical data and bronchoalveolar lavage(BAL)specimens from five patients with severe pneumonia from Wuhan Jinyintan Hospital,Hubei province,China.Nucleic acids of the BAL were extracted and subjected to next-generation sequencing.Virus isolation was carried out,and maximum-likelihood phylogenetic trees were constructed.Results:Five patients hospitalized from December 18 to December 29,2019 presented with fever,cough,and dyspnea accompanied by complications of acute respiratory distress syndrome.Chest radiography revealed diffuse opacities and consolidation.One of these patients died.Sequence results revealed the presence of a previously unknownβ-CoV strain in all five patients,with 99.8%to 99.9%nucleotide identities among the isolates.These isolates showed 79.0%nucleotide identity with the sequence of SARS-CoV(GenBank NC_004718)and 51.8%identity with the sequence of MERS-CoV(GenBank NC_019843).The virus is phylogenetically closest to a bat SARS-like CoV(SL-ZC45,GenBank MG772933)with 87.6%to 87.7%nucleotide identity,but is in a separate clade.Moreover,these viruses have a single intact open reading frame gene 8,as a further indicator of bat-origin CoVs.However,the amino acid sequence of the tentative receptor-binding domain resembles that of SARS-CoV,indicating that these viruses might use the same receptor.Conclusion:A novel bat-borne CoV was identified that is associated with severe and fatal respiratory disease in humans.展开更多
The highly conserved Wnt secreted proteins are critical mediators of cell-to-cell signaling during development of animals. Recent biochemical and genetic analyses have led to significant insight into understanding how...The highly conserved Wnt secreted proteins are critical mediators of cell-to-cell signaling during development of animals. Recent biochemical and genetic analyses have led to significant insight into understanding how Wnt signals work. The catalogue of Wnt signaling components has exploded. We now realize that multiple extracellular, cytoplasmic, and nuclear components modulate Wnt signaling. Moreover, receptor-ligand specificity and multiple feedback loops determine Wnt signaling outputs. It is also clear that Wnt signals are required for adult tissue maintenance. Perturbations in Wnt signaling cause human degenerative diseases as well as cancer.展开更多
The importance of cancer stem cells （CSCs） in tumor-initiation has been firmly established in leukemia and recently reported for a variety of solid tumors. However, the role of CSCs in multistage cancer progression,...The importance of cancer stem cells （CSCs） in tumor-initiation has been firmly established in leukemia and recently reported for a variety of solid tumors. However, the role of CSCs in multistage cancer progression, particularly with respect to metastasis, has not been well-defined. Cancer metastasis requires the seeding and successful colonization of specialized CSCs at distant organs. The biology of normal stem cells and CSCs share remarkable similarities and may have important implications when applied to the study of cancer metastasis. Furthermore, overlapping sets of molecules and pathways have recently been identified to regulate both stem cell migration and cancer metastasis. These molecules constitute a complex network of cellular interactions that facilitate both the initiation of the pre-metastasis niche by the primary tumor and the formation of a nurturing organ microenvironment for migrating CSCs. In this review, we surveyed the recent advances in this dynamic field and propose a unified model of cancer progression in which CSCs assume a central role in both tumorigenesis and metastasis. Better understanding of CSCs as a fundamental component of the metastatic cascade will lead to novel therapeutic strategies against metastatic cancer.展开更多
Fecal microbiota transplantation （FMT） has become a research focus of biomedicine and clinical medicine in recent years. The clinical response from FMT for different diseases provided evidence for microbiota-host in...Fecal microbiota transplantation （FMT） has become a research focus of biomedicine and clinical medicine in recent years. The clinical response from FMT for different diseases provided evidence for microbiota-host interactions associated with various disorders, including Clostridium difficile infection, inflammatory bowel disease, diabetes mellitus, cancer, liver cirrhosis, gut- brain disease and others. To discuss the experiences of using microbes to treat human diseases from ancient China to current era should be important in moving standardized FMT forward and achieving a better future. Here, we review the changing concept of microbiota transplantation from FMT to selective microbiota transplantation, methodology development of FMT and step- up FMT strategy based on literature and state experts＇ perspectives.展开更多
Atherosclerosis is a chronic inflammatory vascular disease driven by traditional and nontraditional risk factors.Genome-wide association combined with clonal lineage tracing and clinical trials have demonstrated that ...Atherosclerosis is a chronic inflammatory vascular disease driven by traditional and nontraditional risk factors.Genome-wide association combined with clonal lineage tracing and clinical trials have demonstrated that innate and adaptive immune responses can promote or quell atherosclerosis.Several signaling pathways,that are associated with the inflammatory response,have been implicated within atherosclerosis such as NLRP3 inflammasome,toll-like receptors,proprotein convertase subtilisin/kexin type 9.展开更多
Transforming growth factor-beta （TGF-β）/bone morphogenic protein （BMP） signaling is involved in the vast majority of cellular processes and is fundamentally important during the entire life of all metazoans. Dere...Transforming growth factor-beta （TGF-β）/bone morphogenic protein （BMP） signaling is involved in the vast majority of cellular processes and is fundamentally important during the entire life of all metazoans. Deregulation of TGF-β/ BMP activity almost invariably leads to developmental defects and/or diseases, including cancer. The proper functioning of the TGF-β/BMP pathway depends on its constitutive and extensive communication with other signaling pathways, leading to synergistic or antagonistic effects and eventually desirable biological outcomes. The nature of such signaling cross-talk is overwhelmingly complex and highly context-dependent. Here we review the different modes of cross-talk between TGF-β/BMP and the signaling pathways of Mitogen-activated protein kinase, phosphatidylinositol-3 kinase/ Akt, Wnt, Hedgehog, Notch, and the interleukin/interferon-gamma/tumor necrosis factor-alpha cytokines, with an emphasis on the underlying molecular mechanisms.展开更多
Dear Editor Salvia miltiorrhiza Bunge （Danshen） is a medicinal plant of the Lamiaceae family, and its dried roots have long been used in traditional Chinese medicine with hydrophilic phenolic acids and tanshinones a...Dear Editor Salvia miltiorrhiza Bunge （Danshen） is a medicinal plant of the Lamiaceae family, and its dried roots have long been used in traditional Chinese medicine with hydrophilic phenolic acids and tanshinones as pharmaceutically active components （Zhang et al., 2014; Xu et al., 2016）. The first step of tanshinone biosynthesis is bicyclization of the general diterpene precursor （E,E,E）-geranylgeranyl diphosphate （GGPP） to copalyl diphosphate （CPP） by CPP synthases （CPSs）, which is followed by a cyclization or rearrangement reaction catalyzed by kaurene synthase-like enzymes （KSL）. The resulting intermediate is usually an olefin, which requires the insertion of oxygen by cytochrome P450 mono-oxygenases （CYPs） for the final production of diterpenoids （Zi et al., 2014）. While the CPS, KSL, and several early acting CYPs （CYP76AH1, CYP76AH3, and CYP76AK1） for tanshinone biosynthesis have been identified in S. miltiorrhiza （Gao et al., 2009; Guo et al., 2013, 2016; Zi and Peters, 2013）, the majority of the overall biosynthetic pathway, as well as the relevant regulatory factors associated with tanshinone production, remains elusive （Figure 1B）.展开更多
Studies in the past few years have provided compelling evidence for the critical role of aberrant Signal Transducer and Activator of Transcription 3 （STAT3） in malignant transformation and tumorigenesis. Thus, it is...Studies in the past few years have provided compelling evidence for the critical role of aberrant Signal Transducer and Activator of Transcription 3 （STAT3） in malignant transformation and tumorigenesis. Thus, it is now generally accepted that STAT3 is one of the critical players in human cancer formation and represents a valid target for novel anticancer drug design. This review focuses on aberrant STAT3 and its role in promoting tumor cell survival and sup- porting the malignant phenotype. A brief evaluation of the current strategies targeting STAT3 for the development of novel anticancer agents against human tumors harboring constitutively active STAT3 will also be presented.展开更多
Human mesenchymal stem cells （hMSCs） can home to tumor sites and inhibit the growth of tumor cells. Little is known about the underlying molecular mechanisms that link hMSCs to the targeted inhibition of tumor cells...Human mesenchymal stem cells （hMSCs） can home to tumor sites and inhibit the growth of tumor cells. Little is known about the underlying molecular mechanisms that link hMSCs to the targeted inhibition of tumor cells. In this study, we investigated the effects of hMSCs on two human hepatoma cell lines （H7402 and HepG2） using an animal transplantation model, a co-culture system and conditioned media from hMSCs. Animal transplantation studies showed that the latent time for tumor formation was prolonged and that the tumor size was smaller when SCID mice were injected with H7402 cells and an equal number of Z3 hMSCs. When co-cultured with Z3 cells, H7402 cell proliferation decreased, apoptosis increased, and the expression of Bcl-2, c-Myc, proliferating cell nuclear antigen （PCNA） and survivin was downregulated. After treatment with conditioned media derived from Z3 hMSC cultures, H4702 cells showed decreased colony-forming ability and decreased proliferation. Immunoblot analysis showed that β-catenin, Bcl-2, c-Myc, PCNA and survivin expression was downregulated in H7402 and HepG2 cells. Taken together, our findings demonstrate that hMSCs inhibit the malignant phenotypes of the H7402 and HepG2 human liver cancer cell lines, which include proliferation, colony-forming ability and oncogene expression both in vitro and in vivo. Furthermore, our studies provide evidence that the Wnt signaling pathway may have a role in hMSC-mediated targeting and tumor cell inhibition.展开更多
The majority of plant disease resistance （R） genes encode proteins that share common structural features. However, the transcription activator-like effector （TALE）-associated executor type R genes show no consider...The majority of plant disease resistance （R） genes encode proteins that share common structural features. However, the transcription activator-like effector （TALE）-associated executor type R genes show no considerable sequence homology to any known R genes. We adopted a map-based cloning approach and TALE-based technology to isolate and characterize Xa23, a new executor R gene derived from wild rice （Oryza rufipogon） that confers an extremely broad spectrum of resistance to bacterial blight caused by Xanthomonas oryzae pv. oryzae （Xoo）. Xa23 encodes a 113 amino acid protein that shares 50% identity with the known executor R protein XA10. The predicted transmembrane helices in XA23 also overlap with those of XA10. Unlike XalO, however, Xa23 transcription is specifically activated by AvrXa23, a TALE present in all examined Xoo field isolates. Moreover, the susceptible xa23 allele has an identical open reading frame of Xa23 but differs in promoter region by lacking the TALE binding element （EBE） for AvrXa23. XA23 can trigger a strong hypersensitive response in rice, tobacco, and tomato. Our results provide the first evidence that plant genomes have an executor R gene family of which members execute their function and spectrum of disease resistance by recognizing the cognate TALEs in the pathogen.展开更多
Stomata, the pores formed by a pair of guard cells, are the main gateways for water transpiration and photosynthetic CO2 exchange, as well as pathogen invasion in land plants. Guard cell movement is regulated by a com...Stomata, the pores formed by a pair of guard cells, are the main gateways for water transpiration and photosynthetic CO2 exchange, as well as pathogen invasion in land plants. Guard cell movement is regulated by a combination of environmental factors, including water status, light, CO2 levels and pathogen attack, as well as endogenous signals, such as abscisic acid and apoplastic reactive oxygen species （ROS）. Under abiotic and biotic stress conditions, extracellular ROS are mainly produced by plasma membrane-localized NADPH oxidases, whereas intracellular ROS are produced in multiple organelles. These ROS form a sophisticated cellular signaling network, with the accumulation of apoplastic ROS an early hallmark of stomatal movement. Here, we review recent progress in understanding the molecular mechanisms of the ROS signaling network, primarily during drought stress and pathogen attack. We summarize the roles of apoplastic ROS in regulating stomatal movement, ABA and CO2 signaling, and immunity responses. Finally, we discuss ROS accumulation and communication between organelles and cells. This information provides a conceptual framework for understanding how ROS signaling is integrated with various signaling pathways during plant responses to abiotic and biotic stress stimuli.展开更多
Dear Editor Precise modification of eukaryotic genomes has been accom- plished mainly through homology-directed repair （HDR） of DNA double-strand breaks （DSBs） （Hess et al., 2017）. However, the inherent low effi...Dear Editor Precise modification of eukaryotic genomes has been accom- plished mainly through homology-directed repair （HDR） of DNA double-strand breaks （DSBs） （Hess et al., 2017）. However, the inherent low efficiency of homologous recombination and poor availability of exogenous donor DNA as repair templates strongly impede the use of HDR for precise genome editing in many species （Komor et al., 2017a）. To complement the HDR method and circumvent some of its limitations.展开更多
Human induced pluripotent stem （iPS） cells are similar to embryonic stem （ES） cells, and can proliferate intensively and differentiate into a variety of cell types. However, the hepatic differentiation of human iP...Human induced pluripotent stem （iPS） cells are similar to embryonic stem （ES） cells, and can proliferate intensively and differentiate into a variety of cell types. However, the hepatic differentiation of human iPS cells has not yet been reported. In this report, human iPS cells were induced to differentiate into hepatic cells by a stepwise protocol. The expression of liver cell markers and liver-related functions of the human iPS cell-derived cells were monitored and compared with that of differentiated human ES cells and primary human hepatocytes. Approximately 60% of the differentiated human iPS cells at day 7 expressed hepatic markers alpha fetoprotein and Alb. The differentiated cells at day 21 exhibited liver cell functions including albumin Asecretion, glycogen synthesis, urea production and inducible cytochrome P450 activity. The expression of hepatic markers and fiver-related functions of the iPS cellderived hepatic ceils were comparable to that of the human ES cell-derived hepatic cells. These results show that human iPS cells, which are similar to human ES cells, can be efficiently induced to differentiate into hepatocyte-like cells.展开更多
Currently there is no effective antiviral therapy for SARS-CoV-2 infection, which frequently leads to fatal inflammatory responses and acute lung injury. Here, we discuss the various mechanisms of SARS-CoV-mediated in...Currently there is no effective antiviral therapy for SARS-CoV-2 infection, which frequently leads to fatal inflammatory responses and acute lung injury. Here, we discuss the various mechanisms of SARS-CoV-mediated inflammation. We also assume that SARS-CoV-2 likely shares similar inflammatory responses. Potential therapeutic tools to reduce SARS-CoV-2-induced inflammatory responses include various methods to block FcR activation. In the absence of a proven clinical FcR blocker, the use of intravenous immunoglobulin to block FcR activation may be a viable option for the urgent treatment of pulmonary inflammation to prevent severe lung injury. Such treatment may also be combined with systemic anti-inflammatory drugs or corticosteroids. However, these strategies, as proposed here, remain to be clinically tested for effectiveness.展开更多
文摘During development and in the context of different morphogenetic events, epithelial cells undergo a process called epithelial to mesenchymal transition or transdifferentiation （EMT）. In this process, the cells lose their epithelial characteristics, including their polarity and specialized cell-cell contacts, and acquire a migratory behavior, allowing them to move away from their epithelial cell community and to integrate into surrounding tissue, even at remote locations. EMT illustrates the differentiation plasticity during development and is complemented by another process, called mesenchymal to epithelial transition （MET）. While being an integral process during development, EMT is also recapitulated under pathological conditions, prominently in fibrosis and in invasion and metastasis of carcinomas. Accordingly, EMT is considered as an important step in tumor progression. TGF-β signaling has been shown to play an important role in EMT. In fact, adding TGF-β to epithelial cells in culture is a convenient way to induce EMT in various epithelial cells. Although much less characterized, epithelial plasticity can also be regulated by TGF-β-related bone morphogenetic proteins （BMPs）, and BMPs have been shown to induce EMT or MET depending on the developmental context. In this review, we will discuss the induction of EMT in response to TGF-β, and focus on the under- lying signaling and transcription mechanisms.
文摘MicroRNAs （miRNAs） are a class of naturally occurring small non-coding RNAs that target protein-coding mRNAs at the post-transcriptional level. Our previous studies suggest that mir-21 functions as an oncogene and has a role in tumorigenesis, in part through regulation of the tumor suppressor gene tropomyosin 1 （TPM1）. Given that TPM1 has been implicated in cell migration, in this study we further investigated the role of mir-21 in cell invasion and tumor metastasis. We found that suppression of mir-21 in metastatic breast cancer MDA-MB-231 cells significantly reduced invasion and lung metastasis. Consistent with this, ectopic expression of TPM1 remarkably reduced cell invasion. Furthermore, we identified two additional direct mir-21 targets, programmed cell death 4 （PDCD4） and maspin, both of which have been implicated in invasion and metastasis. Like TPM1, PDCD4 and maspin also reduced invasiveness of MDA-MB-231 cells. Finally, the expression of PDCD4 and maspin inversely correlated with mir-21 expression in human breast tumor specimens, indicating the potential regulation of PDCD4 and maspin by mir-21 in these tumors. Taken together, the results suggest that, as an oncogenic miRNA, mir-21 has a role not only in tumor growth but also in invasion and tumor metastasis by targeting multiple tumor/metastasis suppressor genes. Therefore, suppression of mir-21 may provide a novel approach for the treatment of advanced cancers.
基金This work was supported by the project of Yunnan Innovation Team Project, the Hundreds Oversea Talents Program of Yunnan Province, the Top Talents Program of Yunnan Province （Grant 20080A009）, the Key Project of the Natural Science Foundation of Yunnan Province （201401 PC00397）, National Science Foundation of China （U0936603）, Key Project of Natural Science Foundation of Yunnan Province （2008CC016）, Frontier Grant of Kunming Institute of Botany, CAS （672705232515）, Top Talents Program of Yunnan Province （20080A009）, and Hundreds Talents Program of Chinese Academy of Sciences （CAS） （to L.G.）.
文摘Tea is the world＇s oldest and most popular caffeine-containing beverage with immense economic, medicinal, and cultural importance. Here, we present the first high-quality nucleotide sequence of the repeat-rich （80.9%）, 3.02-Gb genome of the cultivated tea tree Camellia sinensis. We show that an extraordinarily large genome size of tea tree is resulted from the slow, steady, and long-term amplification of a few LTR retrotransposon families. In addition to a recent whole-genome duplication event, lineage-specific expansions of genes associated with flavonoid metabolic biosynthesis were discovered, which enhance catechin production, terpene enzyme activation, and stress tolerance, important features for tea flavor and adaptation. We demonstrate an independent and rapid evolution of the tea caffeine synthesis pathway relative to cacao and coffee. A comparative study among 25 Camellia species revealed that higher expression levels of most flavonoid- and caffeinebut not theanine-related genes contribute to the increased production of catechins and caffeine and thus enhance tea-processing suitability and tea quality. These novel findings pave the way for further metabolomic and functional genomic refinement of characteristic biosynthesis pathways and will help develop a more diversified set of tea flavors that would eventually satisfy and attract more tea drinkers worldwide.
基金Supported by the National Natural Science Foundation of China,No.81300251
文摘Liver fibrosis is a reversible wound-healing process aimed at maintaining organ integrity, and presents as the critical pre-stage of liver cirrhosis, which will eventually progress to hepatocellular carcinoma in the absence of liver transplantation. Fibrosis generally results from chronic hepatic injury caused by various factors, mainly viral infection, schistosomiasis, and alcoholism; however, the exact pathological mechanisms are still unknown. Although numerous drugs have been shown to have antifibrotic activity in vitro and in animal models, none of these drugs have been shown to be efficacious in the clinic. Importantly, hepatic stellate cells(HSCs) play a key role in the initiation, progression, and regression of liver fibrosis by secreting fibrogenic factors that encourage portal fibrocytes, fibroblasts, and bone marrow-derived myofibroblasts to produce collagen and thereby propagate fibrosis. These cells are subject to intricate cross-talk with adjacent cells, resulting in scarring and subsequent liver damage. Thus, an understanding of the molecular mechanisms of liver fibrosis and their relationships with HSCs is essential for the discovery of new therapeutic targets. This comprehensive review outlines the role of HSCs in liver fibrosis and details novel strategies to suppress HSC activity, thereby providing new insights into potential treatments for liver fibrosis.
文摘Abiotic stresses and soil nutrient limitations are major environmental conditions that reduce plant growth,productivity and quality.Plants have evolved mechanisms to perceive these environmental challenges,transmit the stress signals within cells as well as between cells and tissues,and make appropriate adjustments in their growth and development in order to survive and reproduce.In recent years,significant progress has been made on many fronts of the stress signaling research,particularly in understanding the downstream signaling events that culminate at the activation of stress-and nutrient limitation-responsive genes,cellular ion homeostasis,and growth adjustment.However,the revelation of the early events of stress signaling,particularly the identification of primary stress sensors,still lags behind.In this review,we summarize recent work on the genetic and molecular mechanisms of plant abiotic stress and nutrient limitation sensing and signaling and discuss new directions for future studies.
基金This study was supported by grants from the Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(No.2016-I2M-1-014)the National Major Science&Technology Project for Control and Prevention of Major Infectious Diseases in China(Nos.2017ZX10103004,2018ZX10305409,2017ZX10204401)the National Natural Science Foundation(No.81930063)
文摘Background:Human infections with zoonotic coronaviruses(CoVs),including severe acute respiratory syndrome(SARS)-CoV and Middle East respiratory syndrome(MERS)-CoV,have raised great public health concern globally.Here,we report a novel batorigin CoV causing severe and fatal pneumonia in humans.Methods:We collected clinical data and bronchoalveolar lavage(BAL)specimens from five patients with severe pneumonia from Wuhan Jinyintan Hospital,Hubei province,China.Nucleic acids of the BAL were extracted and subjected to next-generation sequencing.Virus isolation was carried out,and maximum-likelihood phylogenetic trees were constructed.Results:Five patients hospitalized from December 18 to December 29,2019 presented with fever,cough,and dyspnea accompanied by complications of acute respiratory distress syndrome.Chest radiography revealed diffuse opacities and consolidation.One of these patients died.Sequence results revealed the presence of a previously unknownβ-CoV strain in all five patients,with 99.8%to 99.9%nucleotide identities among the isolates.These isolates showed 79.0%nucleotide identity with the sequence of SARS-CoV(GenBank NC_004718)and 51.8%identity with the sequence of MERS-CoV(GenBank NC_019843).The virus is phylogenetically closest to a bat SARS-like CoV(SL-ZC45,GenBank MG772933)with 87.6%to 87.7%nucleotide identity,but is in a separate clade.Moreover,these viruses have a single intact open reading frame gene 8,as a further indicator of bat-origin CoVs.However,the amino acid sequence of the tentative receptor-binding domain resembles that of SARS-CoV,indicating that these viruses might use the same receptor.Conclusion:A novel bat-borne CoV was identified that is associated with severe and fatal respiratory disease in humans.
文摘The highly conserved Wnt secreted proteins are critical mediators of cell-to-cell signaling during development of animals. Recent biochemical and genetic analyses have led to significant insight into understanding how Wnt signals work. The catalogue of Wnt signaling components has exploded. We now realize that multiple extracellular, cytoplasmic, and nuclear components modulate Wnt signaling. Moreover, receptor-ligand specificity and multiple feedback loops determine Wnt signaling outputs. It is also clear that Wnt signals are required for adult tissue maintenance. Perturbations in Wnt signaling cause human degenerative diseases as well as cancer.
文摘The importance of cancer stem cells （CSCs） in tumor-initiation has been firmly established in leukemia and recently reported for a variety of solid tumors. However, the role of CSCs in multistage cancer progression, particularly with respect to metastasis, has not been well-defined. Cancer metastasis requires the seeding and successful colonization of specialized CSCs at distant organs. The biology of normal stem cells and CSCs share remarkable similarities and may have important implications when applied to the study of cancer metastasis. Furthermore, overlapping sets of molecules and pathways have recently been identified to regulate both stem cell migration and cancer metastasis. These molecules constitute a complex network of cellular interactions that facilitate both the initiation of the pre-metastasis niche by the primary tumor and the formation of a nurturing organ microenvironment for migrating CSCs. In this review, we surveyed the recent advances in this dynamic field and propose a unified model of cancer progression in which CSCs assume a central role in both tumorigenesis and metastasis. Better understanding of CSCs as a fundamental component of the metastatic cascade will lead to novel therapeutic strategies against metastatic cancer.
基金This work was supported by publicaUy donated Intestine Initiative Jiangsu Province Medicine Creation Team and Leading Talents project （Faming Zhang） National Natural Science Foundation of China （Grant Nos. 81670495 and 81600417） and National Center for Clinical Research of Digestive System Diseases （2015BAI13B07）.
文摘Fecal microbiota transplantation （FMT） has become a research focus of biomedicine and clinical medicine in recent years. The clinical response from FMT for different diseases provided evidence for microbiota-host interactions associated with various disorders, including Clostridium difficile infection, inflammatory bowel disease, diabetes mellitus, cancer, liver cirrhosis, gut- brain disease and others. To discuss the experiences of using microbes to treat human diseases from ancient China to current era should be important in moving standardized FMT forward and achieving a better future. Here, we review the changing concept of microbiota transplantation from FMT to selective microbiota transplantation, methodology development of FMT and step- up FMT strategy based on literature and state experts＇ perspectives.
基金This work was supported by the National Natural Science Foundation of China(91739301,91849102)the Key Natural Science Foundation Projects of Hebei Province(H2019206028)+1 种基金Natural Science Foundation of Hebei Province(H2021206006)Natural Science Youth Fund of Hebei Province Education Department(QN2020167).
文摘Atherosclerosis is a chronic inflammatory vascular disease driven by traditional and nontraditional risk factors.Genome-wide association combined with clonal lineage tracing and clinical trials have demonstrated that innate and adaptive immune responses can promote or quell atherosclerosis.Several signaling pathways,that are associated with the inflammatory response,have been implicated within atherosclerosis such as NLRP3 inflammasome,toll-like receptors,proprotein convertase subtilisin/kexin type 9.
文摘Transforming growth factor-beta （TGF-β）/bone morphogenic protein （BMP） signaling is involved in the vast majority of cellular processes and is fundamentally important during the entire life of all metazoans. Deregulation of TGF-β/ BMP activity almost invariably leads to developmental defects and/or diseases, including cancer. The proper functioning of the TGF-β/BMP pathway depends on its constitutive and extensive communication with other signaling pathways, leading to synergistic or antagonistic effects and eventually desirable biological outcomes. The nature of such signaling cross-talk is overwhelmingly complex and highly context-dependent. Here we review the different modes of cross-talk between TGF-β/BMP and the signaling pathways of Mitogen-activated protein kinase, phosphatidylinositol-3 kinase/ Akt, Wnt, Hedgehog, Notch, and the interleukin/interferon-gamma/tumor necrosis factor-alpha cytokines, with an emphasis on the underlying molecular mechanisms.
文摘Dear Editor Salvia miltiorrhiza Bunge （Danshen） is a medicinal plant of the Lamiaceae family, and its dried roots have long been used in traditional Chinese medicine with hydrophilic phenolic acids and tanshinones as pharmaceutically active components （Zhang et al., 2014; Xu et al., 2016）. The first step of tanshinone biosynthesis is bicyclization of the general diterpene precursor （E,E,E）-geranylgeranyl diphosphate （GGPP） to copalyl diphosphate （CPP） by CPP synthases （CPSs）, which is followed by a cyclization or rearrangement reaction catalyzed by kaurene synthase-like enzymes （KSL）. The resulting intermediate is usually an olefin, which requires the insertion of oxygen by cytochrome P450 mono-oxygenases （CYPs） for the final production of diterpenoids （Zi et al., 2014）. While the CPS, KSL, and several early acting CYPs （CYP76AH1, CYP76AH3, and CYP76AK1） for tanshinone biosynthesis have been identified in S. miltiorrhiza （Gao et al., 2009; Guo et al., 2013, 2016; Zi and Peters, 2013）, the majority of the overall biosynthetic pathway, as well as the relevant regulatory factors associated with tanshinone production, remains elusive （Figure 1B）.
文摘Studies in the past few years have provided compelling evidence for the critical role of aberrant Signal Transducer and Activator of Transcription 3 （STAT3） in malignant transformation and tumorigenesis. Thus, it is now generally accepted that STAT3 is one of the critical players in human cancer formation and represents a valid target for novel anticancer drug design. This review focuses on aberrant STAT3 and its role in promoting tumor cell survival and sup- porting the malignant phenotype. A brief evaluation of the current strategies targeting STAT3 for the development of novel anticancer agents against human tumors harboring constitutively active STAT3 will also be presented.
基金This work was supported by grants from the National Basic Research Program of China （973 Program, No. 2007CB914800 to Xiaodong Zhang）, National Natural Science Foundation of China （No. 30570698 to Xiaodong Zhang） and Tianjin Natural Scientific Foundation （No. 033801211 to Xiaodong Zhang）.
文摘Human mesenchymal stem cells （hMSCs） can home to tumor sites and inhibit the growth of tumor cells. Little is known about the underlying molecular mechanisms that link hMSCs to the targeted inhibition of tumor cells. In this study, we investigated the effects of hMSCs on two human hepatoma cell lines （H7402 and HepG2） using an animal transplantation model, a co-culture system and conditioned media from hMSCs. Animal transplantation studies showed that the latent time for tumor formation was prolonged and that the tumor size was smaller when SCID mice were injected with H7402 cells and an equal number of Z3 hMSCs. When co-cultured with Z3 cells, H7402 cell proliferation decreased, apoptosis increased, and the expression of Bcl-2, c-Myc, proliferating cell nuclear antigen （PCNA） and survivin was downregulated. After treatment with conditioned media derived from Z3 hMSC cultures, H4702 cells showed decreased colony-forming ability and decreased proliferation. Immunoblot analysis showed that β-catenin, Bcl-2, c-Myc, PCNA and survivin expression was downregulated in H7402 and HepG2 cells. Taken together, our findings demonstrate that hMSCs inhibit the malignant phenotypes of the H7402 and HepG2 human liver cancer cell lines, which include proliferation, colony-forming ability and oncogene expression both in vitro and in vivo. Furthermore, our studies provide evidence that the Wnt signaling pathway may have a role in hMSC-mediated targeting and tumor cell inhibition.
文摘The majority of plant disease resistance （R） genes encode proteins that share common structural features. However, the transcription activator-like effector （TALE）-associated executor type R genes show no considerable sequence homology to any known R genes. We adopted a map-based cloning approach and TALE-based technology to isolate and characterize Xa23, a new executor R gene derived from wild rice （Oryza rufipogon） that confers an extremely broad spectrum of resistance to bacterial blight caused by Xanthomonas oryzae pv. oryzae （Xoo）. Xa23 encodes a 113 amino acid protein that shares 50% identity with the known executor R protein XA10. The predicted transmembrane helices in XA23 also overlap with those of XA10. Unlike XalO, however, Xa23 transcription is specifically activated by AvrXa23, a TALE present in all examined Xoo field isolates. Moreover, the susceptible xa23 allele has an identical open reading frame of Xa23 but differs in promoter region by lacking the TALE binding element （EBE） for AvrXa23. XA23 can trigger a strong hypersensitive response in rice, tobacco, and tomato. Our results provide the first evidence that plant genomes have an executor R gene family of which members execute their function and spectrum of disease resistance by recognizing the cognate TALEs in the pathogen.
基金supported by the National Key Scientific Research Project(2011CB915400)supported by the National Natural Science Foundation of China(31730007)
文摘Stomata, the pores formed by a pair of guard cells, are the main gateways for water transpiration and photosynthetic CO2 exchange, as well as pathogen invasion in land plants. Guard cell movement is regulated by a combination of environmental factors, including water status, light, CO2 levels and pathogen attack, as well as endogenous signals, such as abscisic acid and apoplastic reactive oxygen species （ROS）. Under abiotic and biotic stress conditions, extracellular ROS are mainly produced by plasma membrane-localized NADPH oxidases, whereas intracellular ROS are produced in multiple organelles. These ROS form a sophisticated cellular signaling network, with the accumulation of apoplastic ROS an early hallmark of stomatal movement. Here, we review recent progress in understanding the molecular mechanisms of the ROS signaling network, primarily during drought stress and pathogen attack. We summarize the roles of apoplastic ROS in regulating stomatal movement, ABA and CO2 signaling, and immunity responses. Finally, we discuss ROS accumulation and communication between organelles and cells. This information provides a conceptual framework for understanding how ROS signaling is integrated with various signaling pathways during plant responses to abiotic and biotic stress stimuli.
文摘Dear Editor Precise modification of eukaryotic genomes has been accom- plished mainly through homology-directed repair （HDR） of DNA double-strand breaks （DSBs） （Hess et al., 2017）. However, the inherent low efficiency of homologous recombination and poor availability of exogenous donor DNA as repair templates strongly impede the use of HDR for precise genome editing in many species （Komor et al., 2017a）. To complement the HDR method and circumvent some of its limitations.
基金We thank Dr Zicai Liang and Huang Huang （Institute of Molecular Medicine, Peking University） for their kind help with BioTek Multi-Detection Microplate Reader and Yizhe Zhang for technical support on real-time PCR. We also thank Chengyan Wang, Pengbo Zhang, Pingping Hou, Haisong Liu, Chun Liu and other colleagues in our laboratory for technical assistance and advice in carrying out these experiments. This study was supported by a Bill ＆ Melinda Gates Foundation Grant （37871）, a Ministry of Education grant （705001）, the National Basic Research Program of China （973 program, 2009CB522502, 2009CB941200 and 2007CB947901）, National Natural Science Foundation of China for Creative Research Groups （30421004）, the Chinese Science and Technology Key Project （2008zx10002-014, 2008zx10002- 011 and 2009ZX 10004-403） and a 111 Project to Deng H.
文摘Human induced pluripotent stem （iPS） cells are similar to embryonic stem （ES） cells, and can proliferate intensively and differentiate into a variety of cell types. However, the hepatic differentiation of human iPS cells has not yet been reported. In this report, human iPS cells were induced to differentiate into hepatic cells by a stepwise protocol. The expression of liver cell markers and liver-related functions of the human iPS cell-derived cells were monitored and compared with that of differentiated human ES cells and primary human hepatocytes. Approximately 60% of the differentiated human iPS cells at day 7 expressed hepatic markers alpha fetoprotein and Alb. The differentiated cells at day 21 exhibited liver cell functions including albumin Asecretion, glycogen synthesis, urea production and inducible cytochrome P450 activity. The expression of hepatic markers and fiver-related functions of the iPS cellderived hepatic ceils were comparable to that of the human ES cell-derived hepatic cells. These results show that human iPS cells, which are similar to human ES cells, can be efficiently induced to differentiate into hepatocyte-like cells.
文摘Currently there is no effective antiviral therapy for SARS-CoV-2 infection, which frequently leads to fatal inflammatory responses and acute lung injury. Here, we discuss the various mechanisms of SARS-CoV-mediated inflammation. We also assume that SARS-CoV-2 likely shares similar inflammatory responses. Potential therapeutic tools to reduce SARS-CoV-2-induced inflammatory responses include various methods to block FcR activation. In the absence of a proven clinical FcR blocker, the use of intravenous immunoglobulin to block FcR activation may be a viable option for the urgent treatment of pulmonary inflammation to prevent severe lung injury. Such treatment may also be combined with systemic anti-inflammatory drugs or corticosteroids. However, these strategies, as proposed here, remain to be clinically tested for effectiveness.
