Alcoholic liver disease(ALD) is a major cause of acute and chronic liver injury. Extensive evidence has been accumulated on the pathological process of ALD during the past decades. However, effective treatment options...Alcoholic liver disease(ALD) is a major cause of acute and chronic liver injury. Extensive evidence has been accumulated on the pathological process of ALD during the past decades. However, effective treatment options for ALD are very limited due to the lack of suitable in vivo models that recapitulate the full spectrum of ALD. Experimental animal models of ALD, particularly rodents, have been used extensively to mimic human ALD. An ideal animal model should recapitulate all aspects of the ALD process, including significant steatosis, hepatic neutrophil infiltration, and liver injury. A better strategy against ALD depends on clear diagnostic biomarkers, accurate predictor(s) of its progression and new therapeutic approaches to modulate stop or even reverse the disease. Numerous models employing rodent animals have been established in the last decades to investigate the effects of acute and chronic alcohol exposure on the initiation and progression of ALD. Although significant progress has been made in gaining better knowledge on the mechanisms and pathology of ALD, many features of ALD are unknown, and require further investigation, ideally with improved animal models that more effectively mimic human ALD. Although differences in the degree and stages of alcoholic liver injury inevitably exist between animal models and human ALD, the acquisition and translational relevance will be greatly enhanced with the development of new and improved animal models of ALD.展开更多
Aging is characterized by a progressive deterioration of physiological integrity,leading to impaired functional ability and ultimately increased susceptibility to death.It is a major risk factor for chronic human dise...Aging is characterized by a progressive deterioration of physiological integrity,leading to impaired functional ability and ultimately increased susceptibility to death.It is a major risk factor for chronic human diseases,including cardiovascular disease,diabetes,neurological degeneration,and cancer.Therefore,the growing emphasis on “healthy aging” raises a series of important questions in life and social sciences.In recent years,there has been unprecedented progress in aging research,particularly the discovery that the rate of aging is at least partly controlled by evolutionarily conserved genetic pathways and biological processes.In an attempt to bring full-fledged understanding to both the aging process and age-associated diseases,we review the descriptive,conceptual,and interventive aspects of the landscape of aging composed of a number of layers at the cellular,tissue,organ,organ system,and organismal levels.展开更多
Pigs lack functional uncoupling protein 1 （UCP1） making them susceptible to cold. Nevertheless, several pig breeds are known to be cold resistant. The molecular mechanism（s） enabling such adaptation are currently ...Pigs lack functional uncoupling protein 1 （UCP1） making them susceptible to cold. Nevertheless, several pig breeds are known to be cold resistant. The molecular mechanism（s） enabling such adaptation are currently unknown. Here, we show that this resist- ance is not dependent on shivering, but rather depends on UCP3 and white adipose tissue （WAT） browning. In two cold-resistant breeds （Tibetan and Min）, but not a cold-sensitive breed （Bama）, WAT browning was induced after cold exposure. Beige adipo- cytes from Tibetan pigs exhibited greater oxidative capacity than those from Bama pigs. Notably, UCP3 expression was signifi- cantly increased only in cold-resistant breeds, and knockdown of UCP3 expression in Tibetan adipocytes phenocopied Bama adipocytes in culture. Moreover, the eight dominant pig breeds found across China can be classified into cold-sensitive and cold- resistant breeds based on the UCP3 cDNA sequence. This study indicates that UCP3 has contributed to the evolution of cold resistance in the pig and overturns the orthodoxy that UCP1 is the only thermogenic uncoupling protein.展开更多
Transforming growth factor-β （TGF-β） members are key cytokines that control embryogenesis and tissue homeostasis via transmembrane TGF-β type II （TβR II） and type I （TβRI） and serine/threonine kinases recep...Transforming growth factor-β （TGF-β） members are key cytokines that control embryogenesis and tissue homeostasis via transmembrane TGF-β type II （TβR II） and type I （TβRI） and serine/threonine kinases receptors. Aberrant activation of TGF-β signaling leads to diseases, including cancer. In advanced cancer, the TGF-β/SMAD pathway can act as an oncogenic factor driving tumor cell invasion and metastasis, and thus is considered to be a therapeutic target. The activity of TGF-β/SMAD pathway is known to be regulated by ubiquitination at multiple levels. As ubiquitination is reversible, emerging studies have uncovered key roles for ubiquitin-removals on TGF-β signaling components by deubiquitinating enzymes （DUBs）. In this paper, we summarize the latest findings on the DUBs that control the activity of the TGF-β signaling pathway. The regula- tory roles of these DUBs as a driving force for cancer progression as well as their underlying working mech- anisms are also discussed.展开更多
Aging biomarkers are a combination of biological parameters to(i)assess age-related changes,(ii)track the physiological aging process,and(iii)predict the transition into a pathological status.Although a broad spectrum...Aging biomarkers are a combination of biological parameters to(i)assess age-related changes,(ii)track the physiological aging process,and(iii)predict the transition into a pathological status.Although a broad spectrum of aging biomarkers has been developed,their potential uses and limitations remain poorly characterized.An immediate goal of biomarkers is to help us answer the following three fundamental questions in aging research:How old are we?Why do we get old?And how can we age slower?This review aims to address this need.Here,we summarize our current knowledge of biomarkers developed for cellular,organ,and organismal levels of aging,comprising six pillars:physiological characteristics,medical imaging,histological features,cellular alterations,molecular changes,and secretory factors.To fulfill all these requisites,we propose that aging biomarkers should qualify for being specific,systemic,and clinically relevant.展开更多
Bread wheat(Triticum aestivum L.)is a major crop that feeds 40%of the world’s population.Over the past several decades,advances in genomics have led to tremendous achievements in understanding the origin and domestic...Bread wheat(Triticum aestivum L.)is a major crop that feeds 40%of the world’s population.Over the past several decades,advances in genomics have led to tremendous achievements in understanding the origin and domestication of wheat,and the genetic basis of agronomically important traits,which promote the breeding of elite varieties.In this review,we focus on progress that has been made in genomic research and genetic improvement of traits such as grain yield,end-use traits,flowering regulation,nutrient use efficiency,and biotic and abiotic stress responses,and various breeding strategies that contributed mainly by Chinese scientists.Functional genomic research in wheat is entering a new era with the availability of multiple reference wheat genome assemblies and the development of cutting-edge technologies such as precise genome editing tools,highthroughput phenotyping platforms,sequencing-based cloning strategies,high-efficiency genetic transformation systems,and speed-breeding facilities.These insights will further extend our understanding of the molecular mechanisms and regulatory networks underlying agronomic traits and facilitate the breeding process,ultimately contributing to more sustainable agriculture in China and throughout the world.展开更多
Vernalization is a physiological process in which prolonged cold exposure establishes flowering competence in winter plants. In hexaploid wheat, TaVRN1 is a cold-induced key regulator that accelerates floral transitio...Vernalization is a physiological process in which prolonged cold exposure establishes flowering competence in winter plants. In hexaploid wheat, TaVRN1 is a cold-induced key regulator that accelerates floral transition. However, the molecular mechanism underlying the gradual activation of TaVRN1 during the vernalization process remains unknown. In this study, we identified the novel transcript VAS (TaVRN1 alternative splicing) as a non-coding RNA derived from the sense strand of the TaVRN1 gene only in winter wheat, which regulates TaVRN1 transcription for flowering. VAS was induced during the early period of vernalization, and its overexpression promoted TaVRN1 expression to accelerate flowering in winter wheat. VAS physically associates with TaRF2b and facilitates docking of the TaRF2b-TaRF2a complex at the TaVRN1 promoter during the middle period of vernalization. TaRF2b recognizes the Sp1 motif within the TaVRN1 proximal promoter region, which is gradually exposed along with the disruption of a loop structure at the TaVRN1 locus during vernalization, to activate the transcription of TaVRN1. The tarf2b mutants exhibited delayed flowering, whereas transgenic wheat lines overexpressing TaRF2b showed earlier flowering. Taken together, our data reveal a distinct regulatory mechanism by which a long non-coding RNA facilitates the transcription factor targeting to regulate wheat flowering, providing novel insights into the vernalization process and a potential target for wheat genetic improvement.展开更多
The use of optical tweezers to measure forces acting upon microscopic particles has revolutionised fields from material science to cell biology.However,despite optical control capabilities,this technology is highly co...The use of optical tweezers to measure forces acting upon microscopic particles has revolutionised fields from material science to cell biology.However,despite optical control capabilities,this technology is highly constrained by the material properties of the probe,and its use may be limited due to concerns about the effect on biological processes.Here we present a novel,optically controlled trapping method based on light-induced hydrodynamic flows.Specifically,we leverage optical control capabilities to convert a translationally invariant topological defect of a flow field into an attractor for colloids in an effectively one-dimensional harmonic,yet freely rotatable system.Circumventing the need to stabilise particle dynamics along an unstable axis,this novel trap closely resembles the isotropic dynamics of optical tweezers.Using magnetic beads,we explicitly show the existence of a linear force-extension relationship that can be used to detect femtoNewton-range forces with sensitivity close to the thermal limit.Our force measurements remove the need for laser-particle contact,while also lifting material constraints,which renders them a particu-larly interesting tool for the life sciences and engineering.展开更多
Oocyte quality has long been considered as a main limiting factor for in vitro fertilization （IVF）. In the past decade, extensive observations demonstrated that the mitochondrion plays a vital role in the oocyte cyt...Oocyte quality has long been considered as a main limiting factor for in vitro fertilization （IVF）. In the past decade, extensive observations demonstrated that the mitochondrion plays a vital role in the oocyte cytoplasm, for it can provide adenosine triphosphate （ATP） for fertilization and preimplantation embryo development and also act as stores of intracellular calcium and proapoptotic factors. During the oocyte maturation, mitochondria are characterized by distinct changes of their distribution pattern from being homogeneous to heterogeneous, which is correlated with the cumulus apoptosis. Oocyte quality decreases with the increasing maternal age. Recent studies have shown that low quality oocytes have some age-related dysfunctions, which include the decrease in mitochondrial membrane potential, increase of mitochondrial DNA （mtDNA） damages, chromosomal aneuploidies, the incidence of apoptosis, and changes in mitochoncLrial gene expression. All these dysfunctions may cause a high level of de- velopmental retardation and arrest of preimplantation embryos. It has been suggested that these mitochondrial changes may arise from excessive reactive oxygen species （ROS） that is closely associated with the oxidative energy production or calcium overload, which may trigger permeability transition pore opening and subsequent apoptosis. Therefore, mitochondria can be seen as signs for oocyte quality evaluation, and it is possible that the oocyte quality can be improved by enhancing the physical function of mitochondria. Here we reviewed recent advances in mitochondrial functions on oocytes.展开更多
Cockayne syndrome(CS)is a rare autosomal recessive inherited disorder characterized by a variety of clinical features,including increased sensitivity to sunlight,progressive neurological abnormalities,and the appearan...Cockayne syndrome(CS)is a rare autosomal recessive inherited disorder characterized by a variety of clinical features,including increased sensitivity to sunlight,progressive neurological abnormalities,and the appearance of premature aging.However,the pathogenesis of CS remains unclear due to the limitations of current disease models.Here,we generate integration-free induced pluripotent stem cells(iPSCs)from fibroblasts from a CS patient bearing mutations in CSB/ERCC6 gene and further derive isogenic genecorrected CS-iPSCs(GC-iPSCs)using the CRISPR/Cas9 system.CS-associated phenotypic defects are recapitulated in CS-iPSC-derived mesenchymal stem cells(MSCs)and neural stem cells(NSCs),both of which display increased susceptibility to DNA damage stress.Premature aging defects in CS-MSCs are rescued by the targeted correction of mutant ERCC6.We next map the transcriptomic landscapes in CS-iPSCs and GC-iPSCs and their somatic stem cell derivatives(MSCs and NSCs)in the absence or presence of ultraviolet(UV)and replicative stresses,revealing that defects in DNA repair account for CS pathologies.Moreover,we generate autologous GC-MSCs free of pathogenic mutation under a cGMP(Current Good Manufacturing Practice)-compliant condition,which hold potential for use as improved biomaterials for future stem cell replacement therapy for CS.Collectively,our models demonstrate novel disease features and molecular mechanisms and lay a foundation for the development of novel therapeutic strategies to treat CS.展开更多
Genetically modified pigs are valuable models of human disease and donors of xenotransplanted organs.Conventional gene targeting in pig somatic cells is extremely inefficient.Zinc-finger nuclease(ZFN)technology has be...Genetically modified pigs are valuable models of human disease and donors of xenotransplanted organs.Conventional gene targeting in pig somatic cells is extremely inefficient.Zinc-finger nuclease(ZFN)technology has been shown to be a powerful tool for efficiently inducing mutations in the genome.However,ZFN-mediated targeting in pigs has rarely been achieved.Here,we used ZFNs to knock out the porcineα-1,3-galactosyl-transferase(GGTA1)gene,which generates Gal epitopes that trigger hyperacute immune rejection in pig-to-human transplantation.Primary pig fibroblasts were transfected with ZFNs targeting the coding region of GGTA1.Eighteen mono-allelic and four biallelic knockout cell clones were obtained after drug selection with efficiencies of 23.4%and 5.2%,respectively.The biallelic cells were used to produce cloned pigs via somatic cell nuclear transfer(SCNT).Three GGTA1 null piglets were born,and one knockout primary fibroblast cell line was established from a cloned fetus.Gal epitopes on GGTA1 null pig cells were completely eliminated from the cell membrane.Functionally,GGTA1 knockout cells were protected from complement-mediated immune attacks when incubated with human serum.This study demonstrated that ZFN is an efficient tool in creating gene-modified pigs.GGTA1 null pigs and GGTA1 null fetal fibroblasts would benefit research and pig-to-human transplantation.展开更多
Hormones are important signaling molecules regulating developmental processes and responses to environmental stimuli in higher plants.Rice endosperm,the portion of the seed surrounding the embryo,is the main determina...Hormones are important signaling molecules regulating developmental processes and responses to environmental stimuli in higher plants.Rice endosperm,the portion of the seed surrounding the embryo,is the main determinant of rice grain shape and yield;how-ever,the dynamics and exact functions of phyto-hormones in developing endosperm remain elusive.Through a systemic study including transcriptome analysis,hormone measurement,and transgene-based endosperm-specific expression of phytohormone bio-synthetic enzymes,we demonstrated that dynamic phytohormone levels play crucial roles in the developing rice endosperm,particularly in regard to grain shape and quality.We detected diverse,differential,and dra-matically changing expression patterns of genes related to hormone biosynthesis and signaling during endosperm development,especially at early devel-opmental stages.Liquid chromatography measure-ments confirmed the dynamic accumulation of hor-mones in developing endosperm.Further transgenic analysis performed on plants expressing hormone bio-synthesis genes driven by an endosperm-specific pro-moter revealed differential effects of the hormones,especially auxin and brassinosteroids,in regulating grain shape and quality.Our studies help elucidate the dis-tinct roles of hormones in developing endosperm and provide novel and useful tools for influencing crop seed shape and yield.展开更多
Epithelial–mesenchymal transition(EMT) is a complex nonlinear biological process that plays essential roles in fundamental biological processes such as embryogenesis, wounding healing, tissue regeneration,and cancer ...Epithelial–mesenchymal transition(EMT) is a complex nonlinear biological process that plays essential roles in fundamental biological processes such as embryogenesis, wounding healing, tissue regeneration,and cancer metastasis. A hallmark of EMT is the switch-like behavior during state transition, which is characteristic of phase transitions. Hence, detecting the tipping point just before mesenchymal state transition is critical for understanding molecular mechanism of EMT. Through dynamic network biomarkers(DNB) model, a DNB group with 37 genes was identified which can provide the early-warning signals of EMT. Particularly, we found that two DNB genes, i.e., SMAD7 and SERPINE1 promoted EMT by switching their regulatory network which was further validated by biological experiments. Survival analyses revealed that SMAD7 and SERPINE1 as DNB genes further acted as prognostic biomarkers for lung adenocarcinoma.展开更多
Dear Editor,Type1diabetes(T1D)isa lifelong(chronic)disease and a major health problem throughout the world.This disease can be treatedby either insulin injection or islet transplantation.Islet transplantation is consi...Dear Editor,Type1diabetes(T1D)isa lifelong(chronic)disease and a major health problem throughout the world.This disease can be treatedby either insulin injection or islet transplantation.Islet transplantation is considered as a better treatment for T1D patients,because islets can produce and release insulin at the appropriate time,resulting in tight blood glucose control.展开更多
Chromatin accessibility remodeling driven by pioneer factors is critical for the development of early embryos.Current studies have illustrated several pioneer factors as being important for agricultural animals,but wh...Chromatin accessibility remodeling driven by pioneer factors is critical for the development of early embryos.Current studies have illustrated several pioneer factors as being important for agricultural animals,but what are the pioneer factors and how the pioneer factors remodel the chromatin accessibility in porcine early embryos is not clear.By employing low-input DNase-seq(liDNase-seq),we profiled the landscapes of chromatin accessibility in porcine early embryos and uncovered a unique chromatin accessibility reprogramming pattern during porcine preimplantation development.Our data revealed that KLF4 played critical roles in remodeling chromatin accessibility in porcine early embryos.Knocking down of KLF4 led to the reduction of chromatin accessibility in early embryos,whereas KLF4 overexpression promoted the chromatin openness in porcine blastocysts.Furthermore,KLF4 deficiency resulted in mitochondrial dysfunction and developmental failure of porcine embryos.In addition,we found that overexpression of KLF4 in blastocysts promoted lipid droplet accumulation,whereas knockdown of KLF4 disrupted this process.Taken together,our study revealed the chromatin accessibility dynamics and identified KLF4 as a key regulator in chromatin accessibility and cellular metabolism during porcine preimplantation embryo development.展开更多
The oxidative pentose phosphate(OPP)pathway provides metabolic intermediates for the shikimate pathway and directs carbon flow to the biosynthesis of aromatic amino acids(AAAs),which serve as basic protein building bl...The oxidative pentose phosphate(OPP)pathway provides metabolic intermediates for the shikimate pathway and directs carbon flow to the biosynthesis of aromatic amino acids(AAAs),which serve as basic protein building blocks and precursors of numerous metabolites essential for plant growth.However,genetic evidence linking the two pathways is largely unclear.In this study,we identified 6-phosphogluconate dehydrogenase 2(PGD2),the rate-limiting enzyme of the cytosolic OPP pathway,through suppressor screening of arogenate dehydrogenase 2(adh2)in Arabidopsis.Our data indicated that a single amino acid substitution at position 63(glutamic acid to lysine)of PGD2 enhanced its enzyme activity by facilitating the dissociation of products from the active site of PGD2,thus increasing the accumulation of AAAs and partially restoring the defective phenotype of adh2.Phylogenetic analysis indicated that the point mutation occurred in a well-conserved amino acid residue.Plants with different amino acids at this conserved site of PGDs confer diverse catalytic activities,thus exhibiting distinct AAAs producing capability.These findings uncover the genetic link between the OPP pathway and AAAs biosynthesis through PGD2.The gain-of-function point mutation of PGD2 identified here could be considered as a potential engineering target to alter the metabolic flux for the production of AAAs and downstream compounds.展开更多
The endoplasmic reticulum(ER),which is composed of a continuous network of tubules and sheets,forms the most widely distributed membrane system in eukaryotic cells.As a result,it engages a variety of organelles by est...The endoplasmic reticulum(ER),which is composed of a continuous network of tubules and sheets,forms the most widely distributed membrane system in eukaryotic cells.As a result,it engages a variety of organelles by establishing membrane contact sites(MCSs).These contacts regulate organelle positioning and remodeling,including fusion and fission,facilitate precise lipid exchange,and couple vital signaling events.Here,we systematically review recent advances and converging themes on ER-involved organellar contact.The molecular basis,cellular influence,and potential physiological functions for ER/nuclear envelope contacts with mitochondria,Golgi,endosomes,lysosomes,lipid droplets,autophagosomes,and plasma membrane are summarized.展开更多
Sequences of circular RNAs(circ RNAs)produced from back-splicing of exon(s)completely overlap with those from cognate linear RNAs transcribed from the same gene loci with the exception of their back-splicing junction(...Sequences of circular RNAs(circ RNAs)produced from back-splicing of exon(s)completely overlap with those from cognate linear RNAs transcribed from the same gene loci with the exception of their back-splicing junction(BSJ)sites.Therefore,examination of global circ RNA expression from RNA-seq datasets generally relies on the detection of RNA-seq fragments spanning BSJ sites,which is different from the quantification of linear RNA expression by normalized RNA-seq fragments mapped to whole gene bodies.Thus,direct comparison of circular and linear RNA expression from the same gene loci in a genome-wide manner has remained challenging.Here,we update the previously-reported CIRCexplorer pipeline to version 3 for circular and linear RNA expression analysis from ribosomal-RNA depleted RNA-seq(CIRCexplorer3-CLEAR).A new quantitation parameter,fragments per billion mapped bases(FPB),is applied to evaluate circular and linear RNA expression individually by fragments mapped to circ RNA-specific BSJ sites or to linear RNA-specific splicing junction(SJ)sites.Comparison of circular and linear RNA expression levels is directly achieved by dividing FPBcircby FPBlinearto generate a CIRCscore,which indicates the relative circ RNA expression level using linear RNA expression level as the background.Highlyexpressed circ RNAs with low cognate linear RNA expression background can be readily identified by CIRCexplorer3-CLEAR for further investigation.CIRCexplorer3-CLEAR is publically available at https://github.com/Yang Lab/CLEAR.展开更多
Hermansky-Pudlak syndrome（HPS） is a recessive disorder with bleeding diathesis, which has been linked to platelet granule defects. Both platelet granules and endothelial Weibel-Palade bodies（WPBs）are members of ly...Hermansky-Pudlak syndrome（HPS） is a recessive disorder with bleeding diathesis, which has been linked to platelet granule defects. Both platelet granules and endothelial Weibel-Palade bodies（WPBs）are members of lysosome-related organelles（LROs） whose formation is regulated by HPS protein associated complexes such as BLOC（biogenesis of lysosome-related organelles complex）-1,-2,-3, AP-3（adaptor protein complex-3） and HOPS（homotypic fusion and protein sorting complex）. Von Willebrand factor（VWF） is critical to hemostasis, which is stored in a highly-multimerized form as tubules in the WPBs. In this study, we found the defective, but varying, release of VWF into plasma after desmopressin（DDAVP） stimulation in HPS1（BLOC-3 subunit）, HPS6（BLOC-2 subunit）, and HPS9（BLOC-1 subunit）deficient mice. In particular, VWF tubulation, a critical step in VWF maturation, was impaired in HPS6 deficient WPBs. This likely reflects a defective endothelium, contributing to the bleeding tendency in HPS mice or patients. The differentially defective regulated release of VWF in these HPS mouse models suggests the need for precise HPS genotyping before DDAVP administration to HPS patients.展开更多
基金the MINECO Retos,No.SAF2016-78711 and SAF2017-87919REXOHEP-CM,No.S2017/BMD-3727+8 种基金the AMMF Cholangiocarcinoma Charity,No.2018/117the COST Action,No.CA17112Ramón y Cajal,No.RYC-2014-15242 and No.RYC-2015-17438grant of ERAB,No.EA 14/18Gilead Liver Research Scholar 2018,No.44/2018Ministerio de Sanidad,Servicios Sociales e Igualdad,No.2017I065the UCM group “Lymphocyte Immunobiology”,No.920631(imas12-associated,Ref.IBL-6)German Research Foundation(SFB/TRR57/P04 and DFG NE 2128/2-1)Interdisciplinary Center for Clinical Research from the Faculty of Medicine at RWTH Aachen University(IZKF/E8-2)
文摘Alcoholic liver disease(ALD) is a major cause of acute and chronic liver injury. Extensive evidence has been accumulated on the pathological process of ALD during the past decades. However, effective treatment options for ALD are very limited due to the lack of suitable in vivo models that recapitulate the full spectrum of ALD. Experimental animal models of ALD, particularly rodents, have been used extensively to mimic human ALD. An ideal animal model should recapitulate all aspects of the ALD process, including significant steatosis, hepatic neutrophil infiltration, and liver injury. A better strategy against ALD depends on clear diagnostic biomarkers, accurate predictor(s) of its progression and new therapeutic approaches to modulate stop or even reverse the disease. Numerous models employing rodent animals have been established in the last decades to investigate the effects of acute and chronic alcohol exposure on the initiation and progression of ALD. Although significant progress has been made in gaining better knowledge on the mechanisms and pathology of ALD, many features of ALD are unknown, and require further investigation, ideally with improved animal models that more effectively mimic human ALD. Although differences in the degree and stages of alcoholic liver injury inevitably exist between animal models and human ALD, the acquisition and translational relevance will be greatly enhanced with the development of new and improved animal models of ALD.
基金supported by the National Natural Science Foundation of China(31871380,32000500,32070730,32170756,32170804,81330008,81671377,81725010,81725010,81872874,81921006,81922027,81971312,81991512,82030041,82103167,82122024,82125009,82125011,82130044,91749126,91949101,91949207,92049302)the National Key Research and Development Program of China(2017YFA0506400,2018YFA0800200,2018YFA0800700,2018YFA0900200,2018YFC2000100,2018YFC2000400,2018YFE-0203700,20192ACB70002,2019YFA0802202,2020YFA0113400,2020YFA0803401,2020YFA0804000,2020YFC2002800,2020YFC-2002900,2021ZD0202401)+11 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16010100,XDA16010603,XDA16020400,XDB29020000,XDB39000000,XDB39000000,XDB39030300)the China Association for Science and Technology(2021QNRC001)the Beijing Municipal Science and Technology Commission(Z200022)the Natural Science Foundation of Shanghai(21JC1406400)the Key Programs of the Jiangxi ProvinceChina(20192ACB70002)the“Shu Guang”Project supported by the Shanghai Municipal Education Commission and Shanghai Education Development Foundation(19SG18)the Shanghai Sailing Program(22YF1434300)the Research Project of Joint Laboratory of University of Science and Technology of China and Anhui Mental Health Center(2019LH03)the Fundamental Research Funds for the Central Universities(WK2070210004)the Young Elite Scientists Sponsorship Program by China Association for Science and Technology(YESS20210002)the Youth Innovation Promotion Association of Chinese Academy of Sciences(2022083)。
文摘Aging is characterized by a progressive deterioration of physiological integrity,leading to impaired functional ability and ultimately increased susceptibility to death.It is a major risk factor for chronic human diseases,including cardiovascular disease,diabetes,neurological degeneration,and cancer.Therefore,the growing emphasis on “healthy aging” raises a series of important questions in life and social sciences.In recent years,there has been unprecedented progress in aging research,particularly the discovery that the rate of aging is at least partly controlled by evolutionarily conserved genetic pathways and biological processes.In an attempt to bring full-fledged understanding to both the aging process and age-associated diseases,we review the descriptive,conceptual,and interventive aspects of the landscape of aging composed of a number of layers at the cellular,tissue,organ,organ system,and organismal levels.
文摘Pigs lack functional uncoupling protein 1 （UCP1） making them susceptible to cold. Nevertheless, several pig breeds are known to be cold resistant. The molecular mechanism（s） enabling such adaptation are currently unknown. Here, we show that this resist- ance is not dependent on shivering, but rather depends on UCP3 and white adipose tissue （WAT） browning. In two cold-resistant breeds （Tibetan and Min）, but not a cold-sensitive breed （Bama）, WAT browning was induced after cold exposure. Beige adipo- cytes from Tibetan pigs exhibited greater oxidative capacity than those from Bama pigs. Notably, UCP3 expression was signifi- cantly increased only in cold-resistant breeds, and knockdown of UCP3 expression in Tibetan adipocytes phenocopied Bama adipocytes in culture. Moreover, the eight dominant pig breeds found across China can be classified into cold-sensitive and cold- resistant breeds based on the UCP3 cDNA sequence. This study indicates that UCP3 has contributed to the evolution of cold resistance in the pig and overturns the orthodoxy that UCP1 is the only thermogenic uncoupling protein.
文摘Transforming growth factor-β （TGF-β） members are key cytokines that control embryogenesis and tissue homeostasis via transmembrane TGF-β type II （TβR II） and type I （TβRI） and serine/threonine kinases receptors. Aberrant activation of TGF-β signaling leads to diseases, including cancer. In advanced cancer, the TGF-β/SMAD pathway can act as an oncogenic factor driving tumor cell invasion and metastasis, and thus is considered to be a therapeutic target. The activity of TGF-β/SMAD pathway is known to be regulated by ubiquitination at multiple levels. As ubiquitination is reversible, emerging studies have uncovered key roles for ubiquitin-removals on TGF-β signaling components by deubiquitinating enzymes （DUBs）. In this paper, we summarize the latest findings on the DUBs that control the activity of the TGF-β signaling pathway. The regula- tory roles of these DUBs as a driving force for cancer progression as well as their underlying working mech- anisms are also discussed.
基金supported by the National Natural Science Foundation of China(31730036,31871380,31871382,31930055,31930058,32000500,32022034,32030033,32070730,32130046,3217050247,32150005,32200595,32222024,81730019,81730022,81830014,81921006,81925005,81970426,81971301,81971312,82030041,82061160495,82070805,82071595,82090020,82100841,82120108009,82122024,82125002,82125011,82125012,82130045,82171284,82173061,82173398,82225007,82225015,82225017,82225018,82230047,82230088,82271600,91949106,91949201,92049116,92049302,92049304,92149303,92149306,92157202,92168201,92169102,92249301,92268201)the National Key Research and Development Program of China(2018YFA0800700,2018YFC2000100,2018YFC2000102,2018YFC2002003,2019YFA0110900,2019YFA0801703,2019YFA0801903,2019YFA0802202,2019YFA0904800,2020YFA0113400,2020YFA0803401,2020YFA0804000,2020YFC2002900,2020YFC2008000,2020YFE0202200,2021YFA0804900,2021YFA1100103,2021YFA1100900,2021YFE0114200,2021ZD0202400,2022YFA0806001,2022YFA0806002,2022YFA0806600,2022YFA1103200,2022YFA1103601,2022YFA1103701,2022YFA1103800,2022YFA1103801,2022YFA1104100,2022YFA1104904,2022YFA1303000,2022YFC2009900,2022YFC2502401,2022YFC3602400,2022YFE0118000,2022ZD0213200)+9 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16030302,XDB39000000,XDB39030600)the Youth Innovation Promotion Association of Chinese Academy of Sciences(2020085,2021080)CAS Project for Young Scientists in Basic Research(YSBR-076)the Program of the Beijing Natural Science Foundation(JQ20031)Clinical Research Operating Fund of Central High level hospitals(2022-PUMCHE-001)CAMS Innovation Fund for Medical Sciences(CIFMS)(2022-I2M1-004)Talent Program of the Chinese Academy of Medical Science(2022RC310-10)Research Funds from Health@Inno HK Program launched by Innovation Technology Commission of the Hong Kong Special Administrative Region,Guangdong Basic and Applied Basic Research Foundation(2020B1515020044)Guangzhou Planned Project of Science and Technology(202002020039)the Major Technology Innovation of Hubei Province(2019ACA14
文摘Aging biomarkers are a combination of biological parameters to(i)assess age-related changes,(ii)track the physiological aging process,and(iii)predict the transition into a pathological status.Although a broad spectrum of aging biomarkers has been developed,their potential uses and limitations remain poorly characterized.An immediate goal of biomarkers is to help us answer the following three fundamental questions in aging research:How old are we?Why do we get old?And how can we age slower?This review aims to address this need.Here,we summarize our current knowledge of biomarkers developed for cellular,organ,and organismal levels of aging,comprising six pillars:physiological characteristics,medical imaging,histological features,cellular alterations,molecular changes,and secretory factors.To fulfill all these requisites,we propose that aging biomarkers should qualify for being specific,systemic,and clinically relevant.
基金This work was supported by the National Natural Science Foundation of China(31788103,31970529,32125030,31921005,31961143013,32072660)the Key Research and Development Program of Ministry of Science and Technology of China(2021YFF1000200)the Strategic Priority Research Program of Chinese Academy of Sciences(XDA24010202).
文摘Bread wheat(Triticum aestivum L.)is a major crop that feeds 40%of the world’s population.Over the past several decades,advances in genomics have led to tremendous achievements in understanding the origin and domestication of wheat,and the genetic basis of agronomically important traits,which promote the breeding of elite varieties.In this review,we focus on progress that has been made in genomic research and genetic improvement of traits such as grain yield,end-use traits,flowering regulation,nutrient use efficiency,and biotic and abiotic stress responses,and various breeding strategies that contributed mainly by Chinese scientists.Functional genomic research in wheat is entering a new era with the availability of multiple reference wheat genome assemblies and the development of cutting-edge technologies such as precise genome editing tools,highthroughput phenotyping platforms,sequencing-based cloning strategies,high-efficiency genetic transformation systems,and speed-breeding facilities.These insights will further extend our understanding of the molecular mechanisms and regulatory networks underlying agronomic traits and facilitate the breeding process,ultimately contributing to more sustainable agriculture in China and throughout the world.
基金We gratefully ack no wledge funding from the NSFC for the Basic Scie nee Center Program(31788103)the National Natural Science Foundation of China(31970529)the China Postdoctoral Science Foundation(2019M650892).
文摘Vernalization is a physiological process in which prolonged cold exposure establishes flowering competence in winter plants. In hexaploid wheat, TaVRN1 is a cold-induced key regulator that accelerates floral transition. However, the molecular mechanism underlying the gradual activation of TaVRN1 during the vernalization process remains unknown. In this study, we identified the novel transcript VAS (TaVRN1 alternative splicing) as a non-coding RNA derived from the sense strand of the TaVRN1 gene only in winter wheat, which regulates TaVRN1 transcription for flowering. VAS was induced during the early period of vernalization, and its overexpression promoted TaVRN1 expression to accelerate flowering in winter wheat. VAS physically associates with TaRF2b and facilitates docking of the TaRF2b-TaRF2a complex at the TaVRN1 promoter during the middle period of vernalization. TaRF2b recognizes the Sp1 motif within the TaVRN1 proximal promoter region, which is gradually exposed along with the disruption of a loop structure at the TaVRN1 locus during vernalization, to activate the transcription of TaVRN1. The tarf2b mutants exhibited delayed flowering, whereas transgenic wheat lines overexpressing TaRF2b showed earlier flowering. Taken together, our data reveal a distinct regulatory mechanism by which a long non-coding RNA facilitates the transcription factor targeting to regulate wheat flowering, providing novel insights into the vernalization process and a potential target for wheat genetic improvement.
基金We thank Iain Patten for valuable discussions on the structure and layout of the manuscript.IDS kindly acknowledges funding from the Life grant by Volkswagen Foundation(Grant No.92772).
文摘The use of optical tweezers to measure forces acting upon microscopic particles has revolutionised fields from material science to cell biology.However,despite optical control capabilities,this technology is highly constrained by the material properties of the probe,and its use may be limited due to concerns about the effect on biological processes.Here we present a novel,optically controlled trapping method based on light-induced hydrodynamic flows.Specifically,we leverage optical control capabilities to convert a translationally invariant topological defect of a flow field into an attractor for colloids in an effectively one-dimensional harmonic,yet freely rotatable system.Circumventing the need to stabilise particle dynamics along an unstable axis,this novel trap closely resembles the isotropic dynamics of optical tweezers.Using magnetic beads,we explicitly show the existence of a linear force-extension relationship that can be used to detect femtoNewton-range forces with sensitivity close to the thermal limit.Our force measurements remove the need for laser-particle contact,while also lifting material constraints,which renders them a particu-larly interesting tool for the life sciences and engineering.
基金supported by the National Natural Science Foundation of China (No. 30772345)the Research Program of the Science and Technology Bureau of Zhejiang Province (No. 2006C33016)+1 种基金the Natural Science Foundation of Zhejiang Province (No. Y204202)the Chinese Medicine Research Program of Zhejiang Province (No. 2007CA071), China
文摘Oocyte quality has long been considered as a main limiting factor for in vitro fertilization （IVF）. In the past decade, extensive observations demonstrated that the mitochondrion plays a vital role in the oocyte cytoplasm, for it can provide adenosine triphosphate （ATP） for fertilization and preimplantation embryo development and also act as stores of intracellular calcium and proapoptotic factors. During the oocyte maturation, mitochondria are characterized by distinct changes of their distribution pattern from being homogeneous to heterogeneous, which is correlated with the cumulus apoptosis. Oocyte quality decreases with the increasing maternal age. Recent studies have shown that low quality oocytes have some age-related dysfunctions, which include the decrease in mitochondrial membrane potential, increase of mitochondrial DNA （mtDNA） damages, chromosomal aneuploidies, the incidence of apoptosis, and changes in mitochoncLrial gene expression. All these dysfunctions may cause a high level of de- velopmental retardation and arrest of preimplantation embryos. It has been suggested that these mitochondrial changes may arise from excessive reactive oxygen species （ROS） that is closely associated with the oxidative energy production or calcium overload, which may trigger permeability transition pore opening and subsequent apoptosis. Therefore, mitochondria can be seen as signs for oocyte quality evaluation, and it is possible that the oocyte quality can be improved by enhancing the physical function of mitochondria. Here we reviewed recent advances in mitochondrial functions on oocytes.
基金supported by the National Key Research and Development Program of China(2018YFC2000100)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16010100)+5 种基金the National Key Research and Development Program of China(2018YFA0107203,2017YFA0103304,2017YFA0102802,2016YFC1000601,2015CB 964800,2014CB910503,and 2018YFA0108500)the National Natural Science Foundation of China(Grant Nos.81625009,81330008,91749202,91749123,31671429,81671377,81771515,31601109,31601158,81701388,81601233,81822018,81801399,31801010,81801370,81861168034,81571400,and 81771580)the Program of the Beijing Municipal Science and TechnologyCommission(Z151100003915072)the Key Research Program of the Chinese Academy of Sciences(KJZDEWTZ-L05)the Beijing Municipal Commission of Health and Family Planning(PXM2018_026283_000002)the Advanced Innovation Center for Human Brain Protection(117212,3500-1192012).
文摘Cockayne syndrome(CS)is a rare autosomal recessive inherited disorder characterized by a variety of clinical features,including increased sensitivity to sunlight,progressive neurological abnormalities,and the appearance of premature aging.However,the pathogenesis of CS remains unclear due to the limitations of current disease models.Here,we generate integration-free induced pluripotent stem cells(iPSCs)from fibroblasts from a CS patient bearing mutations in CSB/ERCC6 gene and further derive isogenic genecorrected CS-iPSCs(GC-iPSCs)using the CRISPR/Cas9 system.CS-associated phenotypic defects are recapitulated in CS-iPSC-derived mesenchymal stem cells(MSCs)and neural stem cells(NSCs),both of which display increased susceptibility to DNA damage stress.Premature aging defects in CS-MSCs are rescued by the targeted correction of mutant ERCC6.We next map the transcriptomic landscapes in CS-iPSCs and GC-iPSCs and their somatic stem cell derivatives(MSCs and NSCs)in the absence or presence of ultraviolet(UV)and replicative stresses,revealing that defects in DNA repair account for CS pathologies.Moreover,we generate autologous GC-MSCs free of pathogenic mutation under a cGMP(Current Good Manufacturing Practice)-compliant condition,which hold potential for use as improved biomaterials for future stem cell replacement therapy for CS.Collectively,our models demonstrate novel disease features and molecular mechanisms and lay a foundation for the development of novel therapeutic strategies to treat CS.
基金supported by grants from Ministry of Science and Technology of China(2011CBA01001,2012AA020503)the National Science Fund for Distinguished Young Scholars(31025016)+4 种基金the National Natural Science Foundation of China(31271577)Novel Agricultural Variety Breeding Project of Zhejiang Province(2012C12906-8)the Fundamental Research Funds for the Central Universitiesthe Key Construction Pro-gram of the National"985"Project(118000+193411801/006)the Research Fund for the Doctoral Program of Higher Education of China(20120101110089)
文摘Genetically modified pigs are valuable models of human disease and donors of xenotransplanted organs.Conventional gene targeting in pig somatic cells is extremely inefficient.Zinc-finger nuclease(ZFN)technology has been shown to be a powerful tool for efficiently inducing mutations in the genome.However,ZFN-mediated targeting in pigs has rarely been achieved.Here,we used ZFNs to knock out the porcineα-1,3-galactosyl-transferase(GGTA1)gene,which generates Gal epitopes that trigger hyperacute immune rejection in pig-to-human transplantation.Primary pig fibroblasts were transfected with ZFNs targeting the coding region of GGTA1.Eighteen mono-allelic and four biallelic knockout cell clones were obtained after drug selection with efficiencies of 23.4%and 5.2%,respectively.The biallelic cells were used to produce cloned pigs via somatic cell nuclear transfer(SCNT).Three GGTA1 null piglets were born,and one knockout primary fibroblast cell line was established from a cloned fetus.Gal epitopes on GGTA1 null pig cells were completely eliminated from the cell membrane.Functionally,GGTA1 knockout cells were protected from complement-mediated immune attacks when incubated with human serum.This study demonstrated that ZFN is an efficient tool in creating gene-modified pigs.GGTA1 null pigs and GGTA1 null fetal fibroblasts would benefit research and pig-to-human transplantation.
基金Funding for this research is gratefully acknowledged fromthe National Key Research and Development Programof China(2016YFD0100501,2016YFD0100902)the National Transformation Science and Technology Pro-gram(2016ZX08001006-009).
文摘Hormones are important signaling molecules regulating developmental processes and responses to environmental stimuli in higher plants.Rice endosperm,the portion of the seed surrounding the embryo,is the main determinant of rice grain shape and yield;how-ever,the dynamics and exact functions of phyto-hormones in developing endosperm remain elusive.Through a systemic study including transcriptome analysis,hormone measurement,and transgene-based endosperm-specific expression of phytohormone bio-synthetic enzymes,we demonstrated that dynamic phytohormone levels play crucial roles in the developing rice endosperm,particularly in regard to grain shape and quality.We detected diverse,differential,and dra-matically changing expression patterns of genes related to hormone biosynthesis and signaling during endosperm development,especially at early devel-opmental stages.Liquid chromatography measure-ments confirmed the dynamic accumulation of hor-mones in developing endosperm.Further transgenic analysis performed on plants expressing hormone bio-synthesis genes driven by an endosperm-specific pro-moter revealed differential effects of the hormones,especially auxin and brassinosteroids,in regulating grain shape and quality.Our studies help elucidate the dis-tinct roles of hormones in developing endosperm and provide novel and useful tools for influencing crop seed shape and yield.
基金supported by the National Key Research and Development Program of China (2017YFA0505500)the National Natural Science Foundation of China (31930022, 31771476, 61773196)+5 种基金Shanghai Municipal Science and Technology Major Project (2017SHZDZX01)Key Project of Zhangjiang National Innovation Demonstration Zone Special Development Fund (ZJ2018ZD-013)Ministry of Science and Technology Project (2017YFC0907505)Guangdong Provincial Key Laboratory Funds (2017B030301018, 2019B030301001)Shenzhen Research Funds (JCYJ20170307104535585, ZDSYS20140509142721429)Shenzhen Peacock Plan (KQTD2016053117035204)
文摘Epithelial–mesenchymal transition(EMT) is a complex nonlinear biological process that plays essential roles in fundamental biological processes such as embryogenesis, wounding healing, tissue regeneration,and cancer metastasis. A hallmark of EMT is the switch-like behavior during state transition, which is characteristic of phase transitions. Hence, detecting the tipping point just before mesenchymal state transition is critical for understanding molecular mechanism of EMT. Through dynamic network biomarkers(DNB) model, a DNB group with 37 genes was identified which can provide the early-warning signals of EMT. Particularly, we found that two DNB genes, i.e., SMAD7 and SERPINE1 promoted EMT by switching their regulatory network which was further validated by biological experiments. Survival analyses revealed that SMAD7 and SERPINE1 as DNB genes further acted as prognostic biomarkers for lung adenocarcinoma.
基金supported by grants from the National Basic Research Program of China (973 programs) (2011CB944203,2011CB944204)the National High-Tech R&D Program of China (863 Programs) (2014AA021602)+3 种基金the National Natural Science Foundation of China (31401271)the Key Deployment Project of the Chinese Academy of Sciences (KSZD-EW-Z-005-003-002)the Science and Technology Planning Project of Guangdong Province,China (2014B030301058,2015A030310119)Bureau of Science and Technology of GuangzhouMunicipality (201505011111498).
文摘Dear Editor,Type1diabetes(T1D)isa lifelong(chronic)disease and a major health problem throughout the world.This disease can be treatedby either insulin injection or islet transplantation.Islet transplantation is considered as a better treatment for T1D patients,because islets can produce and release insulin at the appropriate time,resulting in tight blood glucose control.
基金This work was supported by the National Natural Science Foundation of China(31902161)the National Key Research and Development Program of China(2022YFD1302201,2018YFA0107001)+3 种基金Strategic Priority Research Program of Chinese Academy of Sciences(XDA24020203)Key Research and Development Program of Hubei Province(2021BBA221)Major Project of Hubei Hongshan Laboratory(2021hszd003)Foundation of Key Laboratory of Animal Genetics,Breeding and Reproduction in the Plateau Mountainous Region,Ministry of Education,Guizhou University(QJHKY[2022]373).
文摘Chromatin accessibility remodeling driven by pioneer factors is critical for the development of early embryos.Current studies have illustrated several pioneer factors as being important for agricultural animals,but what are the pioneer factors and how the pioneer factors remodel the chromatin accessibility in porcine early embryos is not clear.By employing low-input DNase-seq(liDNase-seq),we profiled the landscapes of chromatin accessibility in porcine early embryos and uncovered a unique chromatin accessibility reprogramming pattern during porcine preimplantation development.Our data revealed that KLF4 played critical roles in remodeling chromatin accessibility in porcine early embryos.Knocking down of KLF4 led to the reduction of chromatin accessibility in early embryos,whereas KLF4 overexpression promoted the chromatin openness in porcine blastocysts.Furthermore,KLF4 deficiency resulted in mitochondrial dysfunction and developmental failure of porcine embryos.In addition,we found that overexpression of KLF4 in blastocysts promoted lipid droplet accumulation,whereas knockdown of KLF4 disrupted this process.Taken together,our study revealed the chromatin accessibility dynamics and identified KLF4 as a key regulator in chromatin accessibility and cellular metabolism during porcine preimplantation embryo development.
基金supported by the National Key Research and Development Program of China(2019YFA0903900)the National Natural Science Foundation of China(32300233)+1 种基金Guangdong Provincial Key Laboratory of Synthetic Genomics(2023B1212060054)Shenzhen Key Laboratory of Synthetic Genomics(ZDSYS201802061806209).
文摘The oxidative pentose phosphate(OPP)pathway provides metabolic intermediates for the shikimate pathway and directs carbon flow to the biosynthesis of aromatic amino acids(AAAs),which serve as basic protein building blocks and precursors of numerous metabolites essential for plant growth.However,genetic evidence linking the two pathways is largely unclear.In this study,we identified 6-phosphogluconate dehydrogenase 2(PGD2),the rate-limiting enzyme of the cytosolic OPP pathway,through suppressor screening of arogenate dehydrogenase 2(adh2)in Arabidopsis.Our data indicated that a single amino acid substitution at position 63(glutamic acid to lysine)of PGD2 enhanced its enzyme activity by facilitating the dissociation of products from the active site of PGD2,thus increasing the accumulation of AAAs and partially restoring the defective phenotype of adh2.Phylogenetic analysis indicated that the point mutation occurred in a well-conserved amino acid residue.Plants with different amino acids at this conserved site of PGDs confer diverse catalytic activities,thus exhibiting distinct AAAs producing capability.These findings uncover the genetic link between the OPP pathway and AAAs biosynthesis through PGD2.The gain-of-function point mutation of PGD2 identified here could be considered as a potential engineering target to alter the metabolic flux for the production of AAAs and downstream compounds.
基金supported by the National Natural Science Foundation of China(92254305)supported by the National Natural Science Foundation of China(92254305,91854204,32130026)+20 种基金supported by National Natural Science Foundation of China(92254302,32225013,32130023)supported by the National Natural Science Foundation of China(91954201,31971289)supported by grants from the National Natural Science Foundation of China(91954207)supported by the National Natural Science Foundation of China(32170753)supported by the National Natural Science Foundation of China(32170692,92154001)supported by grants from the National Natural Science Foundation of China(92254303,32170701)supported by grants from the National Natural Science Foundation of China(32101000,32271273)the Strategic Priority Research Program(XDB39000000)Project for Young Scientists in Basic Research(YSBR-075)of the Chinese Academy of Sciencesthe National Key Research and Development Program of China(2021YFA1300800)National Key Research and Development Program of China(2021YFA0804802,2019YFA0508602)Beijing Natural Science Foundation(JQ20028)New Cornerstone Science Foundation(Xplorer Prize)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB37020304)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB37040402)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA24030205)the National Key Research and Development Program of China(2021YFA1300301)the National Key Research and Development Program of China(2018YFA0506902)the Fundamental Research Funds for the Central Universities(63213104,63223043)the Talent Training Project at Nankai University(035-BB042112)supported by the Beijing Municipal Science&Technology Commission(5202022)。
文摘The endoplasmic reticulum(ER),which is composed of a continuous network of tubules and sheets,forms the most widely distributed membrane system in eukaryotic cells.As a result,it engages a variety of organelles by establishing membrane contact sites(MCSs).These contacts regulate organelle positioning and remodeling,including fusion and fission,facilitate precise lipid exchange,and couple vital signaling events.Here,we systematically review recent advances and converging themes on ER-involved organellar contact.The molecular basis,cellular influence,and potential physiological functions for ER/nuclear envelope contacts with mitochondria,Golgi,endosomes,lysosomes,lipid droplets,autophagosomes,and plasma membrane are summarized.
基金the Strategic Priority Research Program of Chinese Academy of Sciences,China(Grant No.XDB19020104)the National Natural Science Foundation of China(Grant Nos.31730111,31925011,and 91940306)the Howard Hughes Medical Institute International Program,the United States(Grant No.55008728).
文摘Sequences of circular RNAs(circ RNAs)produced from back-splicing of exon(s)completely overlap with those from cognate linear RNAs transcribed from the same gene loci with the exception of their back-splicing junction(BSJ)sites.Therefore,examination of global circ RNA expression from RNA-seq datasets generally relies on the detection of RNA-seq fragments spanning BSJ sites,which is different from the quantification of linear RNA expression by normalized RNA-seq fragments mapped to whole gene bodies.Thus,direct comparison of circular and linear RNA expression from the same gene loci in a genome-wide manner has remained challenging.Here,we update the previously-reported CIRCexplorer pipeline to version 3 for circular and linear RNA expression analysis from ribosomal-RNA depleted RNA-seq(CIRCexplorer3-CLEAR).A new quantitation parameter,fragments per billion mapped bases(FPB),is applied to evaluate circular and linear RNA expression individually by fragments mapped to circ RNA-specific BSJ sites or to linear RNA-specific splicing junction(SJ)sites.Comparison of circular and linear RNA expression levels is directly achieved by dividing FPBcircby FPBlinearto generate a CIRCscore,which indicates the relative circ RNA expression level using linear RNA expression level as the background.Highlyexpressed circ RNAs with low cognate linear RNA expression background can be readily identified by CIRCexplorer3-CLEAR for further investigation.CIRCexplorer3-CLEAR is publically available at https://github.com/Yang Lab/CLEAR.
基金partially supported by the grants from the National Natural Science Foundation of China(Nos.91539204 and 31230046)the Ministry of Science and Technology of China(No.2013CB530605)(to W.L.)from MRC of UK(MC-UU-12018/2,to D.C.)
文摘Hermansky-Pudlak syndrome（HPS） is a recessive disorder with bleeding diathesis, which has been linked to platelet granule defects. Both platelet granules and endothelial Weibel-Palade bodies（WPBs）are members of lysosome-related organelles（LROs） whose formation is regulated by HPS protein associated complexes such as BLOC（biogenesis of lysosome-related organelles complex）-1,-2,-3, AP-3（adaptor protein complex-3） and HOPS（homotypic fusion and protein sorting complex）. Von Willebrand factor（VWF） is critical to hemostasis, which is stored in a highly-multimerized form as tubules in the WPBs. In this study, we found the defective, but varying, release of VWF into plasma after desmopressin（DDAVP） stimulation in HPS1（BLOC-3 subunit）, HPS6（BLOC-2 subunit）, and HPS9（BLOC-1 subunit）deficient mice. In particular, VWF tubulation, a critical step in VWF maturation, was impaired in HPS6 deficient WPBs. This likely reflects a defective endothelium, contributing to the bleeding tendency in HPS mice or patients. The differentially defective regulated release of VWF in these HPS mouse models suggests the need for precise HPS genotyping before DDAVP administration to HPS patients.
基金supported by the National Key R&D Program of China(2017YFA0505500)National Natural Science Foundation of China(11771152,12026608,11901203,31930022,and 31771476)+7 种基金Guangdong Basic and Applied Basic Research Foundation(2019B151502062,and 2021A1515012317)Strategic Priority Research Program of the Chinese Academy of Sciences(XDB38040400)Shanghai Municipal Science and Technology Major Project(2017SHZDZX01)Japan Society for the Promotion of Science KAKENHI(15H05707)Japan Science and Technology Agency Moonshot R&D(JPMJMS2021)Japan Agency for Medical Research and Development(JP20dm0307009)UTokyo Center for Integrative Science of Human Behavior(CiSHuB)the International Research Center for Neurointelligence(WPI-IRCN)at The University of Tokyo Institutes for Advanced Study(UTIAS).
