In light of the low yields and complex reaction routes of some well-known 5,5-fused and 5,6-fused bicyclic compounds,a series of 5,7-fused bicyclic imidazole-diazepine compounds were developed with high yields by only...In light of the low yields and complex reaction routes of some well-known 5,5-fused and 5,6-fused bicyclic compounds,a series of 5,7-fused bicyclic imidazole-diazepine compounds were developed with high yields by only two efficient steps.Significantly,the seven-membered heterocyclic ring has a stable energetic skeleton with multiple modifiable sites.However,the 5,7-fused bicyclic energetic compounds were rarely reported in the area of energetic materials.Three neutral compounds 1,2 and 4 were synthesized in this work.To improve the detonation performances of the 5,7-fused neutral compounds,corresponding perchlorate 1a and 2a were further developed.The physicochemical and energetic performances of all newly developed compounds were experimentally determined.All newly prepared energetic compounds exhibit high decomposition temperatures(Td:243.8-336℃)and low mechanical sensitivities(IS:>15 J,FS:>280 N).Among them,the velocities performances of 1a(Dv=7651 m/s)and 4(Dv=7600 m/s)are comparable to that of typical heat-resistant energetic material HNS(Dv=7612 m/s).Meanwhile,the high decomposition temperature and low mechanical sensitivities(Td=336℃;IS=32 J;FS>353 N)of 4 are superior to that of HNS(Td=318℃;IS=5 J;FS=250 N).Hence,the 5,7-fused bicyclic compounds with high thermostability,low sensitivities and adjustable detonation performance have a clear tendency to open up a new space for the development of heat-resistant energetic materials.展开更多
Ischemic cerebrovascular disease is a leading cause of death globally and is often exacerbated by cerebral ischemic/reperfusion injury(CIRI).The exact mechanisms underlying I/R injury are unclear.In this study,we aime...Ischemic cerebrovascular disease is a leading cause of death globally and is often exacerbated by cerebral ischemic/reperfusion injury(CIRI).The exact mechanisms underlying I/R injury are unclear.In this study,we aimed to determine the role of m6A-modified methylase complex methyltransferase-like 3(METTL3)in cerebral ischemiareperfusion(I/R)injury.We found that m6A and METTL3 levels increased in OGD/RX-induced mouse astrocytescerebellar(MA-C)and the brain of middle cerebral artery occlusion(MCAO)model mice.METTL3 siRNA treatment reduced OGD-RX-induced MAC cell viability and proliferation,which increased with METTL3 over-expression.Flow cytometry analysis showed that silencing METTL3 significantly enhanced OGD/RX-induced MAC apoptosis,which was significantly reduced with METTL3 up-regulation.In an MCAO model,METTL3 overexpression significantly reduced cerebral infarction area and decreased brain cell apoptosis,indicating that METTL3 OE treatment could ameliorate brain edema and injury.Thus,METTL3 could be used as a target to treat I/R injury.展开更多
Although sorafenib has been found to prolong the survival time of patients with hepatocellular carcinoma(HCC),sorafenib resistance remains an important challenge.Increasing studies have demonstrated that long noncodin...Although sorafenib has been found to prolong the survival time of patients with hepatocellular carcinoma(HCC),sorafenib resistance remains an important challenge.Increasing studies have demonstrated that long noncoding RNAs(lncRNAs)contribute to drug resistance in a wide number of cancers.Human periodontal ligament stem cell(PDLSC)osteogenesis impairment-related lncRNA(POIR)is a recently defined lncRNA for which little is known regarding its function.Our study aimed to reveal the role of POIR in the development of HCC cell sorafenib resistance.The level of POIR expression in patients and tumor cells was examined by Reverse transcription-quantitative polymerase chain reaction(RT-qPCR)assay.CCK-8,EdU,and flow cytometry assay were adopted to examine cell viability,proliferation,and apoptosis,respectively.The autophagy-associated protein expressions were determined by western blotting and autophagic flux analysis.The results of this study exhibited increased POIR in HCC tissues and cells and may be correlated with sorafenib resistance.Knockdown of POIR elevated sorafenib sensitivity by suppressing autophagy in HCC cells.Mechanically,POIR knockdown upregulated miR-182-5p,implying that miR-182-5p mediates POIR regulation.MiR-182-5p overexpression significantly enhanced chemosensitivity to sorafenib,whereas miR-182-5p inhibition had the opposite effect.The sensitization of POIR siRNA to sorafenib was abolished by co-transfection with miR-182-5p inhibitor.Our findings provide a potential target for further clinical treatment of sorafenib-resistant HCC patients.展开更多
Background:The involvement of specific basal ganglia-thalamocortical circuits in response inhibition has been extensively mapped in animal models.However,the pivotal nodes and directed causal regulation within this in...Background:The involvement of specific basal ganglia-thalamocortical circuits in response inhibition has been extensively mapped in animal models.However,the pivotal nodes and directed causal regulation within this inhibitory circuit in humans remains con-troversial.Objective:The main aim of the present study was to determine the causal information flow and critical nodes in the basal ganglia-thalamocortical inhibitory circuits and also to examine whether these are modulated by biological factors(i.e.sex)and behavioral performance.Methods:Here,we capitalize on the recent progress in robust and biologically plausible directed causal modeling(DCM-PEB)and a large response inhibition dataset(n=250)acquired with concomitant functional magnetic resonance imaging to determine key nodes,their causal regulation and modulation via biological variables(sex)and inhibitory performance in the inhibitory circuit encompassing the right inferior frontal gyrus(rIFG),caudate nucleus(rCau),globus pallidum(rGP),and thalamus(rThal).Results:The entire neural circuit exhibited high intrinsic connectivity and response inhibition critically increased causal projections from the rIFG to both rCau and rThal.Direct comparison further demonstrated that response inhibition induced an increasing rIFG inflow and increased the causal regulation of this region over the rCau and rThal.In addition,sex and performance influenced the functional architecture of the regulatory circuits such that women displayed increased rThal self-inhibition and decreased rThal to GP modulation,while better inhibitory performance was associated with stronger rThal to rIFG communication.Furthermore,control analyses did not reveal a similar key communication in a left lateralized model.Conclusions:Together,these findings indicate a pivotal role of the rIFG as input and causal regulator of subcortical response inhibition nodes.展开更多
In this paper,the idea of a combination of variable separation approach and the extended homoclinic test approach is proposed to seek non-travelling wave solutions of Calogero equation.The equation is reduced to some(...In this paper,the idea of a combination of variable separation approach and the extended homoclinic test approach is proposed to seek non-travelling wave solutions of Calogero equation.The equation is reduced to some(1+1)-dimensional nonlinear equations by applying the variable separation approach and solves reduced equations with the extended homoclinic test technique.Based on this idea and with the aid of symbolic computation,some new explicit solutions can be obtained.展开更多
基金support from the National Natural Science Foundation of China(Grant No.22075143,21875110)the Science Challenge Project(Grant No.TZ2018004)the Qing Lan Project for the grant。
文摘In light of the low yields and complex reaction routes of some well-known 5,5-fused and 5,6-fused bicyclic compounds,a series of 5,7-fused bicyclic imidazole-diazepine compounds were developed with high yields by only two efficient steps.Significantly,the seven-membered heterocyclic ring has a stable energetic skeleton with multiple modifiable sites.However,the 5,7-fused bicyclic energetic compounds were rarely reported in the area of energetic materials.Three neutral compounds 1,2 and 4 were synthesized in this work.To improve the detonation performances of the 5,7-fused neutral compounds,corresponding perchlorate 1a and 2a were further developed.The physicochemical and energetic performances of all newly developed compounds were experimentally determined.All newly prepared energetic compounds exhibit high decomposition temperatures(Td:243.8-336℃)and low mechanical sensitivities(IS:>15 J,FS:>280 N).Among them,the velocities performances of 1a(Dv=7651 m/s)and 4(Dv=7600 m/s)are comparable to that of typical heat-resistant energetic material HNS(Dv=7612 m/s).Meanwhile,the high decomposition temperature and low mechanical sensitivities(Td=336℃;IS=32 J;FS>353 N)of 4 are superior to that of HNS(Td=318℃;IS=5 J;FS=250 N).Hence,the 5,7-fused bicyclic compounds with high thermostability,low sensitivities and adjustable detonation performance have a clear tendency to open up a new space for the development of heat-resistant energetic materials.
基金supported by the Natural Science Foundation of Guangdong Province(Grant No.2020A151501287)the General Project of Science and Technology Innovation Commission of Shenzhen(Grant Nos.JCYJ20210324134800001,JCYJ20190808103401655)+1 种基金Basic Public Welfare Research Project of Zhejiang Province(Grant No.LGF21H090011)the National Natural Science Foundation of China(Grant No.82174132).
文摘Ischemic cerebrovascular disease is a leading cause of death globally and is often exacerbated by cerebral ischemic/reperfusion injury(CIRI).The exact mechanisms underlying I/R injury are unclear.In this study,we aimed to determine the role of m6A-modified methylase complex methyltransferase-like 3(METTL3)in cerebral ischemiareperfusion(I/R)injury.We found that m6A and METTL3 levels increased in OGD/RX-induced mouse astrocytescerebellar(MA-C)and the brain of middle cerebral artery occlusion(MCAO)model mice.METTL3 siRNA treatment reduced OGD-RX-induced MAC cell viability and proliferation,which increased with METTL3 over-expression.Flow cytometry analysis showed that silencing METTL3 significantly enhanced OGD/RX-induced MAC apoptosis,which was significantly reduced with METTL3 up-regulation.In an MCAO model,METTL3 overexpression significantly reduced cerebral infarction area and decreased brain cell apoptosis,indicating that METTL3 OE treatment could ameliorate brain edema and injury.Thus,METTL3 could be used as a target to treat I/R injury.
基金supported by the National Natural Science Foundation of China (21603034,21576051)the National High Technology Research and Development Program of China (863 Program,2015AA03A402)~~
基金The study was supported by Zhejiang Provincial Nature Science Foundation of China(LR20H160001)Key R&D projects of Zhejiang Province(2020C03G5263593)+3 种基金Zhejiang Provincial Ten Thousand Plan for Young Top Talents(2018)Training objects of health innovative talents of Zhejiang Health(2018)Key Project Co-constructed by Zhejiang Province and Ministry(WKJ-ZJ-1916),Natural Science Foundation of China(81972693,81802383,81972674,81673809 and 31900543)Zhejiang Provincial Traditional Chinese Medicine Science and Technology Project(2020ZZ004).
文摘Although sorafenib has been found to prolong the survival time of patients with hepatocellular carcinoma(HCC),sorafenib resistance remains an important challenge.Increasing studies have demonstrated that long noncoding RNAs(lncRNAs)contribute to drug resistance in a wide number of cancers.Human periodontal ligament stem cell(PDLSC)osteogenesis impairment-related lncRNA(POIR)is a recently defined lncRNA for which little is known regarding its function.Our study aimed to reveal the role of POIR in the development of HCC cell sorafenib resistance.The level of POIR expression in patients and tumor cells was examined by Reverse transcription-quantitative polymerase chain reaction(RT-qPCR)assay.CCK-8,EdU,and flow cytometry assay were adopted to examine cell viability,proliferation,and apoptosis,respectively.The autophagy-associated protein expressions were determined by western blotting and autophagic flux analysis.The results of this study exhibited increased POIR in HCC tissues and cells and may be correlated with sorafenib resistance.Knockdown of POIR elevated sorafenib sensitivity by suppressing autophagy in HCC cells.Mechanically,POIR knockdown upregulated miR-182-5p,implying that miR-182-5p mediates POIR regulation.MiR-182-5p overexpression significantly enhanced chemosensitivity to sorafenib,whereas miR-182-5p inhibition had the opposite effect.The sensitization of POIR siRNA to sorafenib was abolished by co-transfection with miR-182-5p inhibitor.Our findings provide a potential target for further clinical treatment of sorafenib-resistant HCC patients.
基金supported by the by the National Key Research and Development Program of China (grant number:2018YFA0701400-BB)National Natural Science Foundation of China (grant numbers 31530032-KMK,91632117-BB,32200904 Qian Zhuang)Key Technological Projects of Guangdong Province (grant number 2018B030335001-KMK).
文摘Background:The involvement of specific basal ganglia-thalamocortical circuits in response inhibition has been extensively mapped in animal models.However,the pivotal nodes and directed causal regulation within this inhibitory circuit in humans remains con-troversial.Objective:The main aim of the present study was to determine the causal information flow and critical nodes in the basal ganglia-thalamocortical inhibitory circuits and also to examine whether these are modulated by biological factors(i.e.sex)and behavioral performance.Methods:Here,we capitalize on the recent progress in robust and biologically plausible directed causal modeling(DCM-PEB)and a large response inhibition dataset(n=250)acquired with concomitant functional magnetic resonance imaging to determine key nodes,their causal regulation and modulation via biological variables(sex)and inhibitory performance in the inhibitory circuit encompassing the right inferior frontal gyrus(rIFG),caudate nucleus(rCau),globus pallidum(rGP),and thalamus(rThal).Results:The entire neural circuit exhibited high intrinsic connectivity and response inhibition critically increased causal projections from the rIFG to both rCau and rThal.Direct comparison further demonstrated that response inhibition induced an increasing rIFG inflow and increased the causal regulation of this region over the rCau and rThal.In addition,sex and performance influenced the functional architecture of the regulatory circuits such that women displayed increased rThal self-inhibition and decreased rThal to GP modulation,while better inhibitory performance was associated with stronger rThal to rIFG communication.Furthermore,control analyses did not reveal a similar key communication in a left lateralized model.Conclusions:Together,these findings indicate a pivotal role of the rIFG as input and causal regulator of subcortical response inhibition nodes.
文摘In this paper,the idea of a combination of variable separation approach and the extended homoclinic test approach is proposed to seek non-travelling wave solutions of Calogero equation.The equation is reduced to some(1+1)-dimensional nonlinear equations by applying the variable separation approach and solves reduced equations with the extended homoclinic test technique.Based on this idea and with the aid of symbolic computation,some new explicit solutions can be obtained.
