BACKGROUND Pancreatic cancer(PC)is one of the deadliest cancers worldwide.PC metastasis involves a complex set of events,including epithelial-mesenchymal transition(EMT),that increase tumor cell invasiveness.Recent ev...BACKGROUND Pancreatic cancer(PC)is one of the deadliest cancers worldwide.PC metastasis involves a complex set of events,including epithelial-mesenchymal transition(EMT),that increase tumor cell invasiveness.Recent evidence has shown that hypoxia is a major EMT regulator in pancreatic cancer cells and facilitates metastasis;however,the mechanisms remain elusive.AIM To investigate the role of miR-301a in hypoxia-induced EMT in PC cells.METHODS Real-time PCR and Western blot analysis were used to detect the expression of miR-301a and EMT markers in PDAC cells cultured in hypoxic and normoxic conditions.Western blot analysis was used to detect the expression of EMT markers in PDAC cells with miR-301a overexpression.Wound healing assay and Transwell assay were used to detect the migration capabilities of PDAC cells with miR-301a overexpression and knockout.Luciferase assay was used to detect the miR-301a promoter and the 3’untranslated region activity of TP63.Orthotopic PC mouse models were used to study the role of miR-301a in metastasis of PDAC cells in vivo.In situ hybridization assay was used to detect the expression of miR-301a in PDAC patient samples(adjacent paratumor and paired tumor tissues).RESULTS Hypoxic environment could directly promote the EMT of PC cells.The expression level of miR-301a was increased in a HIF2αdependent manner in hypoxia-cultured CFPAC-1 and BxPC-3 cells.Overexpression of miR-301a enhanced the hypoxia-induced EMT of PC cells,while knocking out miR-301a result in the suppression of hypoxia-induced EMT.TP63 was a direct target of miR-301a and involved in the metastatic process of PC cells.Furthermore,miR-301a upregulation facilitated PDAC distant metastasis and lymph node metastasis in vivo.Additionally,miR-301a overexpression was indicative of aggressive clinicopathological behaviors and poor prognosis.CONCLUSION The newly identified HIF-2α-miR301a-TP63 signaling pathway may play a crucial role in hypoxia-induced EMT in PDAC cells.展开更多
Fear memories are critical for survival.Nevertheless,over-generalization of these memories,depicted by a failure to distinguish threats from safe stimuli,is typical in stress-related disorders.Previous studies have su...Fear memories are critical for survival.Nevertheless,over-generalization of these memories,depicted by a failure to distinguish threats from safe stimuli,is typical in stress-related disorders.Previous studies have supported a protective role of ketamine against stress-induced depressive behavior.However,the effect of ketamine on fear generalization remains unclear.In this study,we investigated the effects of ketamine on fear generalization in a fear-generalized mouse model.The mice were given a single sub-anesthetic dose of ketamine(30 mg/kg,i.p.)1 h before,1 week before,immediately after,or 22 h after fear conditioning.The behavioral measure of fear(indicated by freezing level)and synaptic protein expression in the basolateral amygdala(BLA)and inferior-limbic pre-frontal cortex(IL-PFC)of mice were examined.We found that only ketamine administered 22 h after fear conditioning significantly decreased the fear generalization,and the effect was dose-dependent and lasted for at least 2 weeks.The fear-generalized mice showed a lower level of brainderived neurotrophic factor(BDNF)and a higher level of GluN2B protein in the BLA and IL-PFC,and this was reversed by a single administration of ketamine.Moreover,the GluN2B antagonist ifenprodil decreased the fear generalization when infused into the IL-PFC,but had no effect when infused into the BLA.Infusion of ANA-12(an antagonist of the BDNF receptor TrkB)into the BLA or ILPFC blocked the effect of ketamine on fear generalization.These findings support the conclusion that a single dose of ketamine administered 22 h after fear conditioning alleviates the fear memory generalization in mice and the GluN2B-related BDNF signaling pathway plays an important role in the alleviation of fear generalization.展开更多
Giant flares(GFs)are unusual bursts from soft gamma-ray repeaters(SGRs)that release an enormous amount of energy in a fraction of a second.The afterglow emission of these SGR-GFs or GF candidates is a highly beneficia...Giant flares(GFs)are unusual bursts from soft gamma-ray repeaters(SGRs)that release an enormous amount of energy in a fraction of a second.The afterglow emission of these SGR-GFs or GF candidates is a highly beneficial means of discerning their composition,relativistic speed and emission mechanisms.GRB 200415A is a recent GF candidate observed in a direction coincident with the nearby Sculptor galaxy at 3.5 Mpc.In this work,we searched for transient gamma-ray emission in past observations by Fermi-LAT in the direction of GRB 200415A.These observations confirm that GRB 200415A is observed as a transient GeV source only once.A pure pair-plasma fireball cannot provide the required energy for the interpretation of GeV afterglow emission and a baryonic poor outflow is additionally needed to explain the afterglow emission.A baryonic rich outflow is also viable,as it can explain the variability and observed quasi-thermal spectrum of the prompt emission if dissipation is happening below the photosphere via internal shocks.Using the peak energy(Ep)of the time-resolved prompt emission spectra and their fluxes(Fp),we found a correlation between Ep and Fp or isotropic luminosity Liso for GRB 200415A.This supports the intrinsic nature of Ep-Liso correlation found in SGRs-GFs,hence favoring a baryonic poor outflow.Our results also indicate a different mechanism at work during the initial spike,and that the evolution of the prompt emission spectral properties in this outflow would be intrinsically due to the injection process.展开更多
BACKGROUND Pancreatic cancer(PC)is one of the most lethal malignancies worldwide.It is known that the proliferation of PC cells is a critical process in the disease.Previous studies have failed to identify the key gen...BACKGROUND Pancreatic cancer(PC)is one of the most lethal malignancies worldwide.It is known that the proliferation of PC cells is a critical process in the disease.Previous studies have failed to identify the key genes associated with PC cell proliferation,using bioinformatic analysis,genome-wide association studies,and candidate gene testing.AIM To investigate the function of the chromobox 8(CBX8)/receptor substrate 1(IRS1)/AKT axis in PC.METHODS A genome-wide CRISPR-Cas9 screening was performed to select genes that could facilitate PC cell proliferation.Quantitative reverse transcription-polymerase chain reaction was used to detect the expression of CBX8 in PC tissues and cells.The regulatory roles of CBX8 in cell proliferation,migration,and invasion were verified by in vivo and in vitro functional assays.RESULTS CBX8 was upregulated in PC tissues and shown to drive PC cell proliferation.Higher expression of CBX8 was correlated with worse outcomes of PC patients from two independent cohorts comprising a total of 116 cases.CBX8 was also proved to serve as a promising therapeutic target for a PC xenograft model.We demonstrated that hypoxia-inducible factor(HIF)-1a induced CBX8 transcription by binding to the promoter of CBX8.CBX8 efficiently activated the PI3K/AKT signaling by upregulating insulin IRS1.CONCLUSION CBX8 is a key gene regulated by HIF-1α,and activates the IRS1/AKT pathway,which suggests that targeting CBX8 may be a promising therapeutic strategy for PC.展开更多
Correction to“Genome-wide CRISPR-Cas9 screening identifies that hypoxiainducible factor-1a-induced CBX8 transcription promotes pancreatic cancer progression via IRS1/AKT axis”(PMID:34853645 PMCID:PMC8603463 DOI:10.4...Correction to“Genome-wide CRISPR-Cas9 screening identifies that hypoxiainducible factor-1a-induced CBX8 transcription promotes pancreatic cancer progression via IRS1/AKT axis”(PMID:34853645 PMCID:PMC8603463 DOI:10.4251/wjgo.v13.i11.1709).In this article,the picture of Figure 6C was misused due to our carelessness while typesetting.We corrected this mistake,and replaced the incorrect image with the correct one.展开更多
In this new era of time-domain and multi-messenger astronomy,various new transients and new phenomena are constantly being discovered thanks to the rapid advances in observations,which provide the excellent opportunit...In this new era of time-domain and multi-messenger astronomy,various new transients and new phenomena are constantly being discovered thanks to the rapid advances in observations,which provide the excellent opportunity to study the physics in the extreme environments.The enhanced X-ray Timing and Polarimetry mission(eXTP),planned to be launched in 2030,has several key advantages,including advanced polarimetry,high sensitivity&large effective area,and wide energy range coverage,which make it a groundbreaking project in high-energy astrophysics.In this article,we briefly introduce the potential time-domain and multi-messenger targets for eXTP,including gravitational-wave(GW)counterparts,gamma-ray bursts(GRBs),magnetars and fast radio bursts(FRBs),tidal disruption events(TDEs),supernovae,high energy neutrinos and TeV active galactic nucleus(AGNs),and so on.We discuss the advantages of future eXTP observations for detecting these sources,their detection capabilities,the abilities to distinguish theoretical models,and their applications in gravity and cosmology.展开更多
基金Supported by National Natural Science Foundation of China,No.81372640.
文摘BACKGROUND Pancreatic cancer(PC)is one of the deadliest cancers worldwide.PC metastasis involves a complex set of events,including epithelial-mesenchymal transition(EMT),that increase tumor cell invasiveness.Recent evidence has shown that hypoxia is a major EMT regulator in pancreatic cancer cells and facilitates metastasis;however,the mechanisms remain elusive.AIM To investigate the role of miR-301a in hypoxia-induced EMT in PC cells.METHODS Real-time PCR and Western blot analysis were used to detect the expression of miR-301a and EMT markers in PDAC cells cultured in hypoxic and normoxic conditions.Western blot analysis was used to detect the expression of EMT markers in PDAC cells with miR-301a overexpression.Wound healing assay and Transwell assay were used to detect the migration capabilities of PDAC cells with miR-301a overexpression and knockout.Luciferase assay was used to detect the miR-301a promoter and the 3’untranslated region activity of TP63.Orthotopic PC mouse models were used to study the role of miR-301a in metastasis of PDAC cells in vivo.In situ hybridization assay was used to detect the expression of miR-301a in PDAC patient samples(adjacent paratumor and paired tumor tissues).RESULTS Hypoxic environment could directly promote the EMT of PC cells.The expression level of miR-301a was increased in a HIF2αdependent manner in hypoxia-cultured CFPAC-1 and BxPC-3 cells.Overexpression of miR-301a enhanced the hypoxia-induced EMT of PC cells,while knocking out miR-301a result in the suppression of hypoxia-induced EMT.TP63 was a direct target of miR-301a and involved in the metastatic process of PC cells.Furthermore,miR-301a upregulation facilitated PDAC distant metastasis and lymph node metastasis in vivo.Additionally,miR-301a overexpression was indicative of aggressive clinicopathological behaviors and poor prognosis.CONCLUSION The newly identified HIF-2α-miR301a-TP63 signaling pathway may play a crucial role in hypoxia-induced EMT in PDAC cells.
基金supported by grants from the National Natural Science Foundation of China(81530061 and 81471829)the Pearl River Nova Program of Guangzhou(201610010154)the Natural Science Foundation of Guangdong Province China(2017A030313095).
文摘Fear memories are critical for survival.Nevertheless,over-generalization of these memories,depicted by a failure to distinguish threats from safe stimuli,is typical in stress-related disorders.Previous studies have supported a protective role of ketamine against stress-induced depressive behavior.However,the effect of ketamine on fear generalization remains unclear.In this study,we investigated the effects of ketamine on fear generalization in a fear-generalized mouse model.The mice were given a single sub-anesthetic dose of ketamine(30 mg/kg,i.p.)1 h before,1 week before,immediately after,or 22 h after fear conditioning.The behavioral measure of fear(indicated by freezing level)and synaptic protein expression in the basolateral amygdala(BLA)and inferior-limbic pre-frontal cortex(IL-PFC)of mice were examined.We found that only ketamine administered 22 h after fear conditioning significantly decreased the fear generalization,and the effect was dose-dependent and lasted for at least 2 weeks.The fear-generalized mice showed a lower level of brainderived neurotrophic factor(BDNF)and a higher level of GluN2B protein in the BLA and IL-PFC,and this was reversed by a single administration of ketamine.Moreover,the GluN2B antagonist ifenprodil decreased the fear generalization when infused into the IL-PFC,but had no effect when infused into the BLA.Infusion of ANA-12(an antagonist of the BDNF receptor TrkB)into the BLA or ILPFC blocked the effect of ketamine on fear generalization.These findings support the conclusion that a single dose of ketamine administered 22 h after fear conditioning alleviates the fear memory generalization in mice and the GluN2B-related BDNF signaling pathway plays an important role in the alleviation of fear generalization.
基金support by the Fundamental Research Funds for the Central Universities(14380035)supported by National Key Research and Development Programs of China(2018YFA0404204)+3 种基金the National Natural Science Foundation of China(Grant Nos.11833003,U1838105 and U1831135)the Program for Innovative Talents,Entrepreneur in Jiangsuthe Strategic Priority Research Program on Space Science,the Chinese Academy of Sciences(Grant No.XDB23040400)BRICS grant DST/IMRCD/BRICS/PilotCall1/ProFCheap/2017(G)for the financial support。
文摘Giant flares(GFs)are unusual bursts from soft gamma-ray repeaters(SGRs)that release an enormous amount of energy in a fraction of a second.The afterglow emission of these SGR-GFs or GF candidates is a highly beneficial means of discerning their composition,relativistic speed and emission mechanisms.GRB 200415A is a recent GF candidate observed in a direction coincident with the nearby Sculptor galaxy at 3.5 Mpc.In this work,we searched for transient gamma-ray emission in past observations by Fermi-LAT in the direction of GRB 200415A.These observations confirm that GRB 200415A is observed as a transient GeV source only once.A pure pair-plasma fireball cannot provide the required energy for the interpretation of GeV afterglow emission and a baryonic poor outflow is additionally needed to explain the afterglow emission.A baryonic rich outflow is also viable,as it can explain the variability and observed quasi-thermal spectrum of the prompt emission if dissipation is happening below the photosphere via internal shocks.Using the peak energy(Ep)of the time-resolved prompt emission spectra and their fluxes(Fp),we found a correlation between Ep and Fp or isotropic luminosity Liso for GRB 200415A.This supports the intrinsic nature of Ep-Liso correlation found in SGRs-GFs,hence favoring a baryonic poor outflow.Our results also indicate a different mechanism at work during the initial spike,and that the evolution of the prompt emission spectral properties in this outflow would be intrinsically due to the injection process.
基金Supported by National Natural Science Foundation of China(General Program),No.81974372(to Qiu ZJ).
文摘BACKGROUND Pancreatic cancer(PC)is one of the most lethal malignancies worldwide.It is known that the proliferation of PC cells is a critical process in the disease.Previous studies have failed to identify the key genes associated with PC cell proliferation,using bioinformatic analysis,genome-wide association studies,and candidate gene testing.AIM To investigate the function of the chromobox 8(CBX8)/receptor substrate 1(IRS1)/AKT axis in PC.METHODS A genome-wide CRISPR-Cas9 screening was performed to select genes that could facilitate PC cell proliferation.Quantitative reverse transcription-polymerase chain reaction was used to detect the expression of CBX8 in PC tissues and cells.The regulatory roles of CBX8 in cell proliferation,migration,and invasion were verified by in vivo and in vitro functional assays.RESULTS CBX8 was upregulated in PC tissues and shown to drive PC cell proliferation.Higher expression of CBX8 was correlated with worse outcomes of PC patients from two independent cohorts comprising a total of 116 cases.CBX8 was also proved to serve as a promising therapeutic target for a PC xenograft model.We demonstrated that hypoxia-inducible factor(HIF)-1a induced CBX8 transcription by binding to the promoter of CBX8.CBX8 efficiently activated the PI3K/AKT signaling by upregulating insulin IRS1.CONCLUSION CBX8 is a key gene regulated by HIF-1α,and activates the IRS1/AKT pathway,which suggests that targeting CBX8 may be a promising therapeutic strategy for PC.
文摘Correction to“Genome-wide CRISPR-Cas9 screening identifies that hypoxiainducible factor-1a-induced CBX8 transcription promotes pancreatic cancer progression via IRS1/AKT axis”(PMID:34853645 PMCID:PMC8603463 DOI:10.4251/wjgo.v13.i11.1709).In this article,the picture of Figure 6C was misused due to our carelessness while typesetting.We corrected this mistake,and replaced the incorrect image with the correct one.
基金supported by China’s Space Origins Exploration Programsupport from the Chinese Academy of Sciences (Grant No.E32983U810)+13 种基金supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (Grant No.XDB0550300)the National Natural Science Foundation of China (Grant No.12325301)supported by the National Natural Science Foundation of China (Grant Nos.12233002,and 12041306)the National SKA Program of China (Grant No.2020SKA0120300)the National Key R&D Program of China (Grant No.2021YFA0718500)the support from the Xinjiang Tianchi Programsupported by the National Natural Science Foundation of China (Grant No.12333007)the International Partnership Program of the Chinese Academy of Sciences (Grant No.113111KYSB20190020)the Strategic Priority Research Program of the Chinese Academy of Sciences (Grant No.XDA15020100)supported by the Beijing Municipal Natural Science Foundation (Grant No.1242032)the Youth Innovation Promotion Association of the Chinese Academy of Sciences (Grant No.2022056)supported by the National Key Research and Development Program of China (Grant Nos.2022YFC2205201,and 2020YFC2201400)funding by the European Union-Next Generation EU RFF M4C2 1.1 PRIN 2022 project “2022RJLWHN URKA”INAF 2023 Theory Grant Ob Fu 1.05.23.06.06 “Understanding R-process & Kilonovae Aspects (URKA)”.
文摘In this new era of time-domain and multi-messenger astronomy,various new transients and new phenomena are constantly being discovered thanks to the rapid advances in observations,which provide the excellent opportunity to study the physics in the extreme environments.The enhanced X-ray Timing and Polarimetry mission(eXTP),planned to be launched in 2030,has several key advantages,including advanced polarimetry,high sensitivity&large effective area,and wide energy range coverage,which make it a groundbreaking project in high-energy astrophysics.In this article,we briefly introduce the potential time-domain and multi-messenger targets for eXTP,including gravitational-wave(GW)counterparts,gamma-ray bursts(GRBs),magnetars and fast radio bursts(FRBs),tidal disruption events(TDEs),supernovae,high energy neutrinos and TeV active galactic nucleus(AGNs),and so on.We discuss the advantages of future eXTP observations for detecting these sources,their detection capabilities,the abilities to distinguish theoretical models,and their applications in gravity and cosmology.
