To understand how the nervous system develops from a small pool of progenitors during early embryonic development,it is fundamentally important to identify the diversity of neuronal subtypes,decode the origin of neuro...To understand how the nervous system develops from a small pool of progenitors during early embryonic development,it is fundamentally important to identify the diversity of neuronal subtypes,decode the origin of neuronal diversity,and uncover the principles governing neuronal specification across different regions.Recent single-cell analyses have systematically identified neuronal diversity at unprecedented scale and speed,leaving the deconstruction of spatiotemporal mechanisms for generating neuronal diversity an imperative and paramount challenge.In this review,we highlight three distinct strategies deployed by neural progenitors to produce diverse neuronal subtypes,including predetermined,stochastic,and cascade diversifying models,and elaborate how these strategies are implemented in distinct regions such as the neocortex,spinal cord,retina,and hypothalamus.Importantly,the identity of neural progenitors is defined by their spatial position and temporal patterning factors,and each type of progenitor cell gives rise to distinguishable cohorts of neuronal subtypes.Microenvironmental cues,spontaneous activity,and connectional pattern further reshape and diversify the fate of unspecialized neurons in particular regions.The illumination of how neuronal diversity is generated will pave the way for producing specific brain organoids to model human disease and desired neuronal subtypes for cell therapy,as well as understanding the organization of functional neural circuits and the evolution of the nervous system.展开更多
With the rapid development of the Internet,the types of webpages are more abundant than in previous decades.However,it becomes severe that people are facing more and more significant network security risks and enormou...With the rapid development of the Internet,the types of webpages are more abundant than in previous decades.However,it becomes severe that people are facing more and more significant network security risks and enormous losses caused by phishing webpages,which imitate the interface of real webpages and deceive the victims.To better identify and distinguish phishing webpages,a visual feature extraction method and a visual similarity algorithm are proposed.First,the visual feature extraction method improves the Visionbased Page Segmentation(VIPS)algorithm to extract the visual block and calculate its signature by perceptual hash technology.Second,the visual similarity algorithm presents a one-to-one correspondence based on the visual blocks’coordinates and thresholds.Then the weights are assigned according to the tree structure,and the similarity of the visual blocks is calculated on the basis of the measurement of the visual features’Hamming distance.Further,the visual similarity of webpages is generated by integrating the similarity and weight of different visual blocks.Finally,multiple pairs of phishing webpages and legitimate webpages are evaluated to verify the feasibility of the algorithm.The experimental results achieve excellent performance and demonstrate that our method can achieve 94%accuracy.展开更多
The rapid development of Internet of Things(IoT)technology has made previously unavailable data available,and applications can take advantage of device data for people to visualize,explore,and build complex analyses.A...The rapid development of Internet of Things(IoT)technology has made previously unavailable data available,and applications can take advantage of device data for people to visualize,explore,and build complex analyses.As the size of the network and the number of network users continue to increase,network requests tend to aggregate on a small number of network resources,which results in uneven load on network requests.Real-time,highly reliable network file distribution technology is of great importance in the Internet of Things.This paper studies real-time and highly reliable file distribution technology for large-scale networks.In response to this topic,this paper studies the current file distribution technology,proposes a file distribution model,and proposes a corresponding load balancing method based on the file distribution model.Experiments show that the system has achieved real-time and high reliability of network transmission.展开更多
Esophageal squamous cell carcinoma(ESCC),a malignancy of the digestive system,is highly prevalent and the primary cause of cancer-related deaths worldwide due to the lack of early diagnostic biomarkers and effective t...Esophageal squamous cell carcinoma(ESCC),a malignancy of the digestive system,is highly prevalent and the primary cause of cancer-related deaths worldwide due to the lack of early diagnostic biomarkers and effective therapeutic targets.Dysregulated ribonucleotide reductase(RNR)expression has been confirmed to be causally linked to tumorigenesis.This study demonstrated that ribonucleotide reductase small subunit M2(RRM2)is significantly upregulated in ESCC tissue and that its expression is negatively correlated with clinical outcomes.Mechanistically,HuR promotes RRM2 mRNA stabilization by binding to the adenine/uridine(AU)-rich elements(AREs)within the 3′UTR,resulting in persistent overexpression of RRM2.Furthermore,bifonazole is identified as an inhibitor of HuR via computational screening and molecular docking analysis.Bifonazole disrupts HuR-ARE interactions by competitively binding to HuR at F65,R97,I103,and R153 residues,resulting in reduced RRM2 expression.Furthermore,bifonazole exhibited antitumor effects on ESCC patient-derived xenograft(PDX)models by decreasing RRM2 expression and the dNTP pool.In summary,this study reveals the interaction network among HuR,RRM2,and bifonazole and demonstrated that bifonazole is a potential therapeutic compound for ESCC through inhibition of the HuR/RRM2 axis.展开更多
Although different types of drugs are available for postmenopausal osteoporosis,the limitations of the current therapies including drug resistances and adverse effects require identification of novel anti-osteoporosis...Although different types of drugs are available for postmenopausal osteoporosis,the limitations of the current therapies including drug resistances and adverse effects require identification of novel anti-osteoporosis agents.Here,we defined that norlichexanthone(NOR),a natural product,is a ligand of estrogen receptor-alpha(ERα)and revealed its therapeutic potential for postmenopausal osteoporosis.We used mammalian-one hybrid assay to screen for ERαmodulators from crude extracts of several plant endophytes.As a result,NOR purified from the extract of endophyte ARL-13 was identified as a selective ERαmodulator.NOR directly bound to ERαwith an affinity in nanomolar range,revealing that it is a natural ligand of ERα.NOR induced osteoblast formation in MC3T3-E1 precursor cells.Conversely,NOR inhibited receptor activator of nuclear factor-kappa B ligand(RANKL)-induced osteoclast formation in both RAW264.7 macrophages and mouse primary monocytes.Mechanistically,NOR inhibited RANKL-induced association of ERαand TRAF6 to prevent ERα-mediated TRAF6 activation via Lys63-linked ubiquitination.Importantly,NOR exhibited potent anti-osteoporosis efficacy in an ovariectomized mouse model.Comparing to estrogen,NOR was of much less capability in stimulating endometrial hyperplasia and promoting mammalian cancer cell proliferation.Taken together,our study identified NOR as a natural and high affinity ligand of ERαwith substantial anti-osteoporosis but less estrogenic activity.展开更多
基金supported by the National Key R&D Program of China(2019YFA0801900 and 2018YFA0801104)the National Natural Science Foundation of China(81891002,32070972,31921002,and 31771131)+2 种基金the Strategic Priority Research Program of Chinese Academy of Sciences(XDB32020000)the Hundred-Talent Program(Chinese Academy of Sciences)the Beijing Municipal Science&Technology Commission(Z210010 and Z181100001518001).
文摘To understand how the nervous system develops from a small pool of progenitors during early embryonic development,it is fundamentally important to identify the diversity of neuronal subtypes,decode the origin of neuronal diversity,and uncover the principles governing neuronal specification across different regions.Recent single-cell analyses have systematically identified neuronal diversity at unprecedented scale and speed,leaving the deconstruction of spatiotemporal mechanisms for generating neuronal diversity an imperative and paramount challenge.In this review,we highlight three distinct strategies deployed by neural progenitors to produce diverse neuronal subtypes,including predetermined,stochastic,and cascade diversifying models,and elaborate how these strategies are implemented in distinct regions such as the neocortex,spinal cord,retina,and hypothalamus.Importantly,the identity of neural progenitors is defined by their spatial position and temporal patterning factors,and each type of progenitor cell gives rise to distinguishable cohorts of neuronal subtypes.Microenvironmental cues,spontaneous activity,and connectional pattern further reshape and diversify the fate of unspecialized neurons in particular regions.The illumination of how neuronal diversity is generated will pave the way for producing specific brain organoids to model human disease and desired neuronal subtypes for cell therapy,as well as understanding the organization of functional neural circuits and the evolution of the nervous system.
基金This work is supported by the National Key R&D Program of China(2016QY05X1000)the National Natural Science Foundation of China(201561402137).
文摘With the rapid development of the Internet,the types of webpages are more abundant than in previous decades.However,it becomes severe that people are facing more and more significant network security risks and enormous losses caused by phishing webpages,which imitate the interface of real webpages and deceive the victims.To better identify and distinguish phishing webpages,a visual feature extraction method and a visual similarity algorithm are proposed.First,the visual feature extraction method improves the Visionbased Page Segmentation(VIPS)algorithm to extract the visual block and calculate its signature by perceptual hash technology.Second,the visual similarity algorithm presents a one-to-one correspondence based on the visual blocks’coordinates and thresholds.Then the weights are assigned according to the tree structure,and the similarity of the visual blocks is calculated on the basis of the measurement of the visual features’Hamming distance.Further,the visual similarity of webpages is generated by integrating the similarity and weight of different visual blocks.Finally,multiple pairs of phishing webpages and legitimate webpages are evaluated to verify the feasibility of the algorithm.The experimental results achieve excellent performance and demonstrate that our method can achieve 94%accuracy.
基金This work was supported by National Key Research&Development Plan of China under Grant 2016QY05X1000National Natural Science Foundation of China under Grant No.61771166CERNET Innovation Project(NGII20170412).
文摘The rapid development of Internet of Things(IoT)technology has made previously unavailable data available,and applications can take advantage of device data for people to visualize,explore,and build complex analyses.As the size of the network and the number of network users continue to increase,network requests tend to aggregate on a small number of network resources,which results in uneven load on network requests.Real-time,highly reliable network file distribution technology is of great importance in the Internet of Things.This paper studies real-time and highly reliable file distribution technology for large-scale networks.In response to this topic,this paper studies the current file distribution technology,proposes a file distribution model,and proposes a corresponding load balancing method based on the file distribution model.Experiments show that the system has achieved real-time and high reliability of network transmission.
基金funded by National Natural Science Foundation of China(grant numbers:81872335,82303891 and 82303119)The Central Plains Science and Technology Innovation Leading Talents(No.224200510015,China)+1 种基金Key scientific research project plan of colleges and universities in Henan Province(grant number:24A310025,China)Science and Technology Project of Henan Province(No.242102310414,China).
文摘Esophageal squamous cell carcinoma(ESCC),a malignancy of the digestive system,is highly prevalent and the primary cause of cancer-related deaths worldwide due to the lack of early diagnostic biomarkers and effective therapeutic targets.Dysregulated ribonucleotide reductase(RNR)expression has been confirmed to be causally linked to tumorigenesis.This study demonstrated that ribonucleotide reductase small subunit M2(RRM2)is significantly upregulated in ESCC tissue and that its expression is negatively correlated with clinical outcomes.Mechanistically,HuR promotes RRM2 mRNA stabilization by binding to the adenine/uridine(AU)-rich elements(AREs)within the 3′UTR,resulting in persistent overexpression of RRM2.Furthermore,bifonazole is identified as an inhibitor of HuR via computational screening and molecular docking analysis.Bifonazole disrupts HuR-ARE interactions by competitively binding to HuR at F65,R97,I103,and R153 residues,resulting in reduced RRM2 expression.Furthermore,bifonazole exhibited antitumor effects on ESCC patient-derived xenograft(PDX)models by decreasing RRM2 expression and the dNTP pool.In summary,this study reveals the interaction network among HuR,RRM2,and bifonazole and demonstrated that bifonazole is a potential therapeutic compound for ESCC through inhibition of the HuR/RRM2 axis.
基金supported by the National Natural Science Foundation of China(Grant Nos.31770811,31471318 and 31271453)the Fundamental Research Funds for the Central Universities(Grant No.20720190082,China)+1 种基金the Regional Demonstration of Marine Economy Innovative Development Project(Grant No.16PYY007SF17,China)the Fujian Provincial Science&Technology Department(Grant No.2017YZ0002-1,China)
文摘Although different types of drugs are available for postmenopausal osteoporosis,the limitations of the current therapies including drug resistances and adverse effects require identification of novel anti-osteoporosis agents.Here,we defined that norlichexanthone(NOR),a natural product,is a ligand of estrogen receptor-alpha(ERα)and revealed its therapeutic potential for postmenopausal osteoporosis.We used mammalian-one hybrid assay to screen for ERαmodulators from crude extracts of several plant endophytes.As a result,NOR purified from the extract of endophyte ARL-13 was identified as a selective ERαmodulator.NOR directly bound to ERαwith an affinity in nanomolar range,revealing that it is a natural ligand of ERα.NOR induced osteoblast formation in MC3T3-E1 precursor cells.Conversely,NOR inhibited receptor activator of nuclear factor-kappa B ligand(RANKL)-induced osteoclast formation in both RAW264.7 macrophages and mouse primary monocytes.Mechanistically,NOR inhibited RANKL-induced association of ERαand TRAF6 to prevent ERα-mediated TRAF6 activation via Lys63-linked ubiquitination.Importantly,NOR exhibited potent anti-osteoporosis efficacy in an ovariectomized mouse model.Comparing to estrogen,NOR was of much less capability in stimulating endometrial hyperplasia and promoting mammalian cancer cell proliferation.Taken together,our study identified NOR as a natural and high affinity ligand of ERαwith substantial anti-osteoporosis but less estrogenic activity.
