Lignified stone cells are a unique feature of pear fruit,significantly affecting fruit texture.Even though some research efforts have already been made,the stone cell formation mechanism is complex,with many aspects y...Lignified stone cells are a unique feature of pear fruit,significantly affecting fruit texture.Even though some research efforts have already been made,the stone cell formation mechanism is complex,with many aspects yet to be elucidated.Here,through a genome-wide association analysis of stone cell traits,we identified PbrMADS1,a member of the SEPALLATA3(SEP3)subfamily,as a candidate gene specifically expressed in stone cells during early fruit development.Functional studies confirmed that PbrMADS1 promotes stone cell formation;however,it does not directly activate lignin-related genes.Instead,Pbr MADS1 interacts with PbrMYB169,enhancing PbrMYB169's binding to AC elements and amplifying downstream gene activation.Notably,homologous MADS1 and MYB169 proteins from closely related species such as apple and loquat do not form a similar complex.Sequence analysis revealed that the protein sequence of PbrMADS1 contains methionine(M)at the 63rdamino acid position,while apple and loquat homologs carry threonine(T)at the same site.Substituting M with T(PbrMADS1^(M63T))weakened its interaction with Pbr MYB169 and impaired its function in regulating stone cell formation.This study offers new insights into MADS gene-mediated stone cell formation and highlights functional divergence within the SEP3 subfamily among apple tribe species of the Rosaceae family.展开更多
Objectives:The eukaryotic initiation factor 4F(eIF4F)translation initiation complex inhibitors(eIF4Fi)were recently found to hyperactivate extracellular signal-regulated kinases 1/2(ERK1/2)signals,which contribute to ...Objectives:The eukaryotic initiation factor 4F(eIF4F)translation initiation complex inhibitors(eIF4Fi)were recently found to hyperactivate extracellular signal-regulated kinases 1/2(ERK1/2)signals,which contribute to acquired resistance to BRAF(B-Raf proto-oncogene,serine/threonine kinase)inhibitors in melanoma.This present study aims to elucidate how to overcome the resistance of the eIF4Fi in BRAFV600E mutant melanoma cells and explore the underlying mechanisms.Methods:Melanoma A375(vemurafenib[VEM]-sensitive)and A375R(VEM-resistant)cells were exposed to eIF4Fi RocA at varying doses and durations in vitro.We investigated the impact of RocA on the activity of ERK1/2,AKT serine/threonine kinase 1(AKT1),eIF4E,and enhancer of zeste homolog 2(EZH2).We then examined the impact of RocA on pro-apoptotic BH3-only proteins and proliferative proteins.We subsequently determined the effect of combined eIF4Fi,AKT1 inhibitor,EZH2 inhibitor or VEM on tumor growth in vitro and in vivo.Results:RocA inhibited proliferation and induced apoptosis in A375 cells,but inhibited proliferation in A375R cells.RocA rapidly reactivated ERK1/2 at 3 h and returned to baseline levels at 48 h.However,eIF4E and AKT1 activation began at 12 h and peaked at 48 h.ERK1/2 positively regulated EZH2 and EZH2-dependent expression of c-Fos and EGR1,while AKT1 negatively regulated c-Myc,c-Jun,and BMF,but positively regulated eIF4E.RocA downregulated ERK1/2(or EZH2,AKT1,and eIF4E)independent bcl-2 and Mcl-1 expression.AKT1i enhanced RocA-induced cell apoptosis,while EZH2i reduced RocA-induced cell proliferation.Combined CR-1-31-B,EZH2i,and AKT1i effectively overcame resistance to RocA and VEM resistance both in vitro and in vivo.Conclusion:The eIF4F complex inhibitor reactivates ERK1/2-EZH2 and AKT1 signaling pathways,resulting in resistance to both eIF4Fi and VEM.Combined administration of an eIF4Fi with EZH2 and AKT1 inhibitors effectively enhances sensitivity to both eIF4F complex and BRAF inhibitors.展开更多
Objectives:Lung cancer represents a major global healthcare challenge,characterized by high annual incidence and mortality rates worldwide.Although targeted therapies for lung cancer have advanced,treatment outcomes f...Objectives:Lung cancer represents a major global healthcare challenge,characterized by high annual incidence and mortality rates worldwide.Although targeted therapies for lung cancer have advanced,treatment outcomes for advanced-stage patients remain suboptimal.This investigation examines the role of the translocase of the inner mitochondrial membrane(TIMM)8A-TIMM13 complex in lung cancer and evaluates its potential as a novel therapeutic target.Methods:A co-immunoprecipitation(Co-IP)assay was conducted to verify the interaction between TIMM8A and TIMM13.Differential gene expression analysis of TIMM8A or TIMM13 was executed using the TNMplot database,with survival estimates derived from the Kaplan-Meier plotter.Lung cancer cell proliferation was evaluated through Cell Counting Kit 8(CCK-8)and colony formation assays,while cell migration was assessed via Transwell assay.RNA sequencing identified the downstream effectors of TIMM13.RNAi technology facilitated the inhibition of TIMM8A or TIMM13 expression,which was measured through immunoblotting or qRT-PCR.Results:This investigation revealed that components of the TIMM8A-TIMM13 complex exhibited elevated expression in human lung cancer tissues,correlating with disease progression and poor overall survival rates among lung cancer patients.The suppression of either TIMM8A or TIMM13 inhibited cell proliferation and migration.Mechanistic studies through transcriptome analysis identified cell cycle-related pathways as potential key downstream effectors of the TIMM8A-TIMM13 complex.Subsequent experiments confirmed that the TIMM8A-TIMM13 complex significantly regulated the expression of cyclin D1(CCND1)and cyclin-dependent kinase 6(CDK6)complex.Conclusion:The elevated expression of TIMM8A-TIMM13 complex components plays a crucial role in lung cancer cell growth,suggesting its potential as a promising therapeutic target for lung cancer treatment.展开更多
Mosquito-borne flaviviruses,such as Zika virus(ZIKV)and dengue virus(DENV),cause diverse severe clinical manifestations including fever,rash,hepatitis,arthralgia,and congenital anomalies.Here,we identified a host fact...Mosquito-borne flaviviruses,such as Zika virus(ZIKV)and dengue virus(DENV),cause diverse severe clinical manifestations including fever,rash,hepatitis,arthralgia,and congenital anomalies.Here,we identified a host factor,the adaptor protein complex 1 gamma 1 subunit(AP1G1),which plays an important role in both ZIKV and dengue virus 2(DENV2)infections.We explored the role of AP1G1 in ZIKV and DENV2 infections using CRISPR/Cas9 gene editing technology and RNA interference(RNAi)techniques.Knockout or silencing of AP1G1 decreases the replication of ZIKV and DENV2 in multiple human cell lines.Intriguingly,depletion of AP1G1 results in a significant reduction in ZIKV at an early stage,but decreases DENV2 replication levels during the late stage,suggesting that AP1G1 plays distinct roles in the infection by ZIKV and DENV2.Furthermore,we determined that AP1G1 mediates ZIKV-endosomal membrane fusion through inhibitor experiments and fluorescence labeling assays.Mechanistically,we found that AP1G1 exerts its pro-viral effect through binding to the ZIKV envelope glycoprotein(E protein).This interaction promotes the fusion of viral and endosomal membranes,during which the ZIKV genomic RNAs are released from the endosome into the cytoplasm,a process that facilitates viral replication.However,for DENV2 infection,AP1G1 primarily affects its viral RNA replication stage,rather than the fusion of virus-endosomal membrane.Taken together,our work demonstrates that AP1G1 plays a pro-viral role in both ZIKV and DENV2 infections via distinct mechanisms,highlighting its potential as a therapeutic target for antiviral strategies.展开更多
BACKGROUND As a member of the chaperonin-containing tailless complex polypeptide 1(TCP1)complex,which plays a pivotal role in ensuring the accurate folding of numerous proteins,chaperonin-containing TCP1 subunit 6A(CC...BACKGROUND As a member of the chaperonin-containing tailless complex polypeptide 1(TCP1)complex,which plays a pivotal role in ensuring the accurate folding of numerous proteins,chaperonin-containing TCP1 subunit 6A(CCT6A)participates in various physiological and pathological processes.However,its effects on cell death and cancer therapy and the underlying mechanisms need further exploration in colorectal cancer(CRC)cells.AIM To explore the effects of CCT6A on cell death and cancer therapy and the underlying mechanisms in CRC.METHODS Cell proliferation was evaluated using the MTS assay,EdU staining,and colony growth assays.The expression of CCT6A was monitored by immunoblotting and quantitative PCR.CCT6A was knocked out by CRISPR-Cas9,and overexpressed by transfecting plasmids.Autophagy was examined by immunoblotting and the mCherry-GFP-LC3 assay.To monitor apoptosis and necroptosis,immunoblotting,co-immunoprecipitation,and flow cytometry were employed.RESULTS Cisplatin(DDP)exerted cytotoxic effects on CRC cells while simultaneously downregulating the expression of CCT6A.Depletion of CCT6A amplified the cytotoxic effects of DDP,whereas overexpression of CCT6A attenuated these adverse effects.CCT6A suppressed autophagy,apoptosis,and necroptosis under both basal and DDP-treated conditions.Autophagy inhibitors significantly enhanced the cytotoxic effects of DDP,whereas a necroptosis inhibitor partially reversed the cell viability loss induced by DDP.Furthermore,inhibiting autophagy enhanced both apoptosis and necroptosis induced by DDP.CONCLUSION CCT6A negatively modulates autophagy,apoptosis,and necroptosis,and CCT6A confers resistance to DDP therapy in CRC,suggesting its potential as a therapeutic target.展开更多
BACKGROUND Hepatocellular carcinoma(HCC)is a leading cause of cancer-related mortality worldwide,with hepatitis B virus(HBV)infection serving as a significant etiological factor in endemic regions.Alpha-fetoprotein(AF...BACKGROUND Hepatocellular carcinoma(HCC)is a leading cause of cancer-related mortality worldwide,with hepatitis B virus(HBV)infection serving as a significant etiological factor in endemic regions.Alpha-fetoprotein(AFP),the most commonly used biomarker,has limited sensitivity,particularly in AFP-negative HCC.Recent studies have identified origin recognition complex subunit 1(ORC1)and extra spindle pole bodies-like 1(ESPL1)as promising serum biomarkers,both linked to HBV DNA integration,a mechanism known to drive hepatocarcinogenesis.AIM To assess serum ORC1’s diagnostic value for HBV-HCC and its link to S gene integration.METHODS In this case-control study,479 HBV-infected patients were enrolled,including 20 hepatitis B,154 with HBV-related cirrhosis,and 96 with HBV-HCC.The control group comprised 73 individuals:29 with non-HBV-HCC and 44 healthy participants.Serum ORC1 and ESPL1 were measured by enzyme-linked immunosorbent assay.HBV integration sites were identified via whole-genome sequencing.Diagnostic performance was assessed using receiver operating characteristic analysis,including in AFP-negative patients.RESULTS HBV integration near the ORC1 locus(chromosome 1p32.3)was detected in 71.4%of HBV-HCC tissues.Serum ORC1 levels were significantly higher in HBV-infected patients than in non-HBV-infected controls(980.11 ng/L vs 746.82 ng/L,P<0.05)and in HBV-HCC compared with non-HBV-HCC(1077.07 ng/L vs 749.54 ng/L,P<0.05).Serum ORC1 and ESPL1 were elevated in HBV-HCC regardless of AFP status,and detected 64.8%and 73.2%of AFP-negative cases,respectively.The combined panel of ORC1[Area under receiver operating characteristic curve(AUC)=0.587],ESPL1(AUC=0.776),and AFP(AUC=0.844)achieved an AUC of 0.887,significantly higher than any single marker(P<0.05),with a sensitivity of 84.44%,specificity of 84.19%,and a negative predictive value of 94.91%.CONCLUSION Serum ORC1,driven by HBV integration,is a promising biomarker especially for AFP-negative HBV-HCC.Its combination with ESPL1 and AFP significantly improves early detection.展开更多
It is of great significance to evaluate the petrophysical properties in shale oil reservoir,which can contribute to geological storage CO_(2).Two-dimensional nuclear magnetic resonance(2D NMR)technology has been appli...It is of great significance to evaluate the petrophysical properties in shale oil reservoir,which can contribute to geological storage CO_(2).Two-dimensional nuclear magnetic resonance(2D NMR)technology has been applied to petrophysical characterization in shale oil reservoir.However,limitations of traditional 2D NMR(T_(1)-T_(2)or T_(2)-D)in detecting short-lived organic matter and the complexity of mineral compositions,pose NMR-based petrophysical challenges.The organic pores were assumed saturated oil and the inorganic pores were assumed saturated water,and the numerical algorithm and theory of T_(1)-T_(2)^(*)in shale oil reservoir were proposed,whose accuracy was validated through T_(2),T_(1)-T_(2)and T_(2)^(*)experiments.The effects of mineral types and contents on the T_(1)-T_(2)^(*)responses were firstly simulated by the random walk algorithm,revealing the NMR response mechanisms in shale oil reservoir with complex mineral compositions at different magnetic field frequency(f).The results indicate that when the pyrite content is 5.43%,dwell time is 4μs,the f is 200 MHz,and echo spacing is 0.4 ms,the T_(1)-T_(2)^(*)-based porosity is 2.39 times that of T_(1)-T_(2)-based porosity.The T_(2LM)^(*)is 0.015 ms,which is 0.015 times that of T_(2)LM.The T_(1LM)is 8.84 ms,which is 0.63 times that of T_(1LM).The T_(1)-T_(2)^(*)-based petrophysical conversion models were firstly created,and the foundation of petrophysical conversion was laid at different f.展开更多
Objective To explore the role of HIV-1 tat gene variations in AIDS dementia complex （ADC） pathogenesis. Methods HIV-1 tat genes derived from peripheral spleen and central basal ganglia of an AIDS patient with ADC an...Objective To explore the role of HIV-1 tat gene variations in AIDS dementia complex （ADC） pathogenesis. Methods HIV-1 tat genes derived from peripheral spleen and central basal ganglia of an AIDS patient with ADC and an AIDS patient without ADC were cloned for sequence analysis. HIV-1 tat gene sequence alignment was performed by using CLUSTAL W and the phylogentic analysis was conducted by using Neighbor-joining with MEGA4 software. All tat genes were used to construct recombinant retroviral expressing vector MSCV-IRES-GFP/tat. The MSCV-IRES-GFP/tat was cotransfected into 293T cells with pCMV-VSV-G and pUMVC vectors to assemble the recombinant retrovirus. After infection of gliomas U87 cells with equal amount of the recombinant retrovirus, TNF-α, and IL-1β concentrations in the supernatant of U87 cells were determined with ELISA. Results HIV-1 tat genes derived from peripheral spleen and central basal ganglia of the AIDS patient with ADC and the other one without ADC exhibited genetic variations. Tat variations and amino acid mutation sites existed mainly at Tat protein core functional area （38-47aa）. All Tat proteins could induce ug7 cells to produce TNF-α and IL-1β, but the level of IL-1β production was different among Tat proteins derived from the ADC patient＇s spleen, basal ganglia, and the non-ADC patient＇s spleen. The level of Tat proteins derived from the ADC patient＇s spleen, basal ganglia, and the non-ADC patient＇s spleen were obviously higher than that from the non-ADC patient＇s basal ganglia. Conclusion Tat protein core functional area （38-47aa） may serve as the key area of enhancing the secretion of IL-1β. This may be related with the neurotoxicity of HIV-1 Tat.展开更多
Metal (Me=Fe(III), Mo(VI), Mn(II), Co(II), Ni(II), Zn(II) and Cu(II)) 2-hydroxy-1-naphthaldehyde thiosemicarbazone complexes (MeHNT) were synthesized and used as mimic-enzyme catalysts to mimic the active group of hor...Metal (Me=Fe(III), Mo(VI), Mn(II), Co(II), Ni(II), Zn(II) and Cu(II)) 2-hydroxy-1-naphthaldehyde thiosemicarbazone complexes (MeHNT) were synthesized and used as mimic-enzyme catalysts to mimic the active group of horseradish peroxidase (HRP). The results showed that Fe-HNT, Mo-HNT are effective catalysts, which have similar catalytic activity as HRP. The sequence of catalytic activities of tested biomimic peroxidas is Mo-HNT > Fe-HNT > Zn-HNT > Ni-HNT > Mn-HNT. Among them, Fe-HNT is used as a mimic-enzyme catalyst in determination of ascorbic acid and glucose by coupling the catalytic reaction of glucose oxidase.展开更多
A novel cyclometalated iridium complex with 1, 3, 4-oxadiazole moiety was synthesizedand characterized. Its UV and photoluminescent properties were studied. The strong UVabsorption intensity around 462 nm attributed t...A novel cyclometalated iridium complex with 1, 3, 4-oxadiazole moiety was synthesizedand characterized. Its UV and photoluminescent properties were studied. The strong UVabsorption intensity around 462 nm attributed to spin-forbidden triplet metal–ligand charge transferband and photoluminescence at 518 nm were observed. This indicated that achieved iridiumcomplex could be used as an efficient electrophosphorescent material.展开更多
A novel heterometallic complex,[Zn4Ni（OH）2（btec）2（titb）2（H2O）2]·2H2O（1）（H4btec=1,2,4,5-benzenetetracarboxylic acid,titb=1,3,5-tris（imidazol-1-ylmethyl）-2,4,6-trime-thylbenzene）,has been hydrothermal...A novel heterometallic complex,[Zn4Ni（OH）2（btec）2（titb）2（H2O）2]·2H2O（1）（H4btec=1,2,4,5-benzenetetracarboxylic acid,titb=1,3,5-tris（imidazol-1-ylmethyl）-2,4,6-trime-thylbenzene）,has been hydrothermally prepared and characterized by IR spectroscopy,elemental analysis and single-crystal X-ray diffraction.The crystal is of triclinic system,space group P1 with a=10.817（10）,b=11.878（11）,c=14.569（14）,α=71.762（12）,β=76.122（13）,γ=71.493（13）°,V=1665（3）3,C62H62N12O22Zn4Ni,Mr=1647.43,Dc=1.643 g/cm3,F（000）=842,μ=1.784 mm-1 and Z=1.The final R=0.0531 and wR=0.0890 for 3545 observed reflections（Ⅰ 2σ（Ⅰ））.In the title complex,the btec ligand acts as a five-dentate bridging ligand to link up zinc and nickel atoms into a lamellar framework,which are further interlinked into a 3-D framework via the titb ligands.展开更多
基金funded by the National Science Foundation of China(U24A20415,32230097,32472689)the Earmarked Fund for China Agriculture Research System(CARS-28)+2 种基金the National Science Foundation of Shandong Province(ZR2024QC064)the Advanced Talents Research Foundation of Shandong Agricultural Universitythe“First Class Discipline”Construction Project of Shandong Agricultural University。
文摘Lignified stone cells are a unique feature of pear fruit,significantly affecting fruit texture.Even though some research efforts have already been made,the stone cell formation mechanism is complex,with many aspects yet to be elucidated.Here,through a genome-wide association analysis of stone cell traits,we identified PbrMADS1,a member of the SEPALLATA3(SEP3)subfamily,as a candidate gene specifically expressed in stone cells during early fruit development.Functional studies confirmed that PbrMADS1 promotes stone cell formation;however,it does not directly activate lignin-related genes.Instead,Pbr MADS1 interacts with PbrMYB169,enhancing PbrMYB169's binding to AC elements and amplifying downstream gene activation.Notably,homologous MADS1 and MYB169 proteins from closely related species such as apple and loquat do not form a similar complex.Sequence analysis revealed that the protein sequence of PbrMADS1 contains methionine(M)at the 63rdamino acid position,while apple and loquat homologs carry threonine(T)at the same site.Substituting M with T(PbrMADS1^(M63T))weakened its interaction with Pbr MYB169 and impaired its function in regulating stone cell formation.This study offers new insights into MADS gene-mediated stone cell formation and highlights functional divergence within the SEP3 subfamily among apple tribe species of the Rosaceae family.
文摘Objectives:The eukaryotic initiation factor 4F(eIF4F)translation initiation complex inhibitors(eIF4Fi)were recently found to hyperactivate extracellular signal-regulated kinases 1/2(ERK1/2)signals,which contribute to acquired resistance to BRAF(B-Raf proto-oncogene,serine/threonine kinase)inhibitors in melanoma.This present study aims to elucidate how to overcome the resistance of the eIF4Fi in BRAFV600E mutant melanoma cells and explore the underlying mechanisms.Methods:Melanoma A375(vemurafenib[VEM]-sensitive)and A375R(VEM-resistant)cells were exposed to eIF4Fi RocA at varying doses and durations in vitro.We investigated the impact of RocA on the activity of ERK1/2,AKT serine/threonine kinase 1(AKT1),eIF4E,and enhancer of zeste homolog 2(EZH2).We then examined the impact of RocA on pro-apoptotic BH3-only proteins and proliferative proteins.We subsequently determined the effect of combined eIF4Fi,AKT1 inhibitor,EZH2 inhibitor or VEM on tumor growth in vitro and in vivo.Results:RocA inhibited proliferation and induced apoptosis in A375 cells,but inhibited proliferation in A375R cells.RocA rapidly reactivated ERK1/2 at 3 h and returned to baseline levels at 48 h.However,eIF4E and AKT1 activation began at 12 h and peaked at 48 h.ERK1/2 positively regulated EZH2 and EZH2-dependent expression of c-Fos and EGR1,while AKT1 negatively regulated c-Myc,c-Jun,and BMF,but positively regulated eIF4E.RocA downregulated ERK1/2(or EZH2,AKT1,and eIF4E)independent bcl-2 and Mcl-1 expression.AKT1i enhanced RocA-induced cell apoptosis,while EZH2i reduced RocA-induced cell proliferation.Combined CR-1-31-B,EZH2i,and AKT1i effectively overcame resistance to RocA and VEM resistance both in vitro and in vivo.Conclusion:The eIF4F complex inhibitor reactivates ERK1/2-EZH2 and AKT1 signaling pathways,resulting in resistance to both eIF4Fi and VEM.Combined administration of an eIF4Fi with EZH2 and AKT1 inhibitors effectively enhances sensitivity to both eIF4F complex and BRAF inhibitors.
基金supported by Beijing Natural Science Foundation(7242268)Beijing Hospitals Authority Youth Programme(QML20230807)Training Fund for Open Projects at Clinical Institutes and Departments of Capital Medical University(CCMU2023ZKYXZ007).
文摘Objectives:Lung cancer represents a major global healthcare challenge,characterized by high annual incidence and mortality rates worldwide.Although targeted therapies for lung cancer have advanced,treatment outcomes for advanced-stage patients remain suboptimal.This investigation examines the role of the translocase of the inner mitochondrial membrane(TIMM)8A-TIMM13 complex in lung cancer and evaluates its potential as a novel therapeutic target.Methods:A co-immunoprecipitation(Co-IP)assay was conducted to verify the interaction between TIMM8A and TIMM13.Differential gene expression analysis of TIMM8A or TIMM13 was executed using the TNMplot database,with survival estimates derived from the Kaplan-Meier plotter.Lung cancer cell proliferation was evaluated through Cell Counting Kit 8(CCK-8)and colony formation assays,while cell migration was assessed via Transwell assay.RNA sequencing identified the downstream effectors of TIMM13.RNAi technology facilitated the inhibition of TIMM8A or TIMM13 expression,which was measured through immunoblotting or qRT-PCR.Results:This investigation revealed that components of the TIMM8A-TIMM13 complex exhibited elevated expression in human lung cancer tissues,correlating with disease progression and poor overall survival rates among lung cancer patients.The suppression of either TIMM8A or TIMM13 inhibited cell proliferation and migration.Mechanistic studies through transcriptome analysis identified cell cycle-related pathways as potential key downstream effectors of the TIMM8A-TIMM13 complex.Subsequent experiments confirmed that the TIMM8A-TIMM13 complex significantly regulated the expression of cyclin D1(CCND1)and cyclin-dependent kinase 6(CDK6)complex.Conclusion:The elevated expression of TIMM8A-TIMM13 complex components plays a crucial role in lung cancer cell growth,suggesting its potential as a promising therapeutic target for lung cancer treatment.
基金supported by the National Natural Science Foundation of China(No.82471389,No.32470986,No.82271385)Natural Science Foundation of Guangdong Province(No.2024A1515010471).
文摘Mosquito-borne flaviviruses,such as Zika virus(ZIKV)and dengue virus(DENV),cause diverse severe clinical manifestations including fever,rash,hepatitis,arthralgia,and congenital anomalies.Here,we identified a host factor,the adaptor protein complex 1 gamma 1 subunit(AP1G1),which plays an important role in both ZIKV and dengue virus 2(DENV2)infections.We explored the role of AP1G1 in ZIKV and DENV2 infections using CRISPR/Cas9 gene editing technology and RNA interference(RNAi)techniques.Knockout or silencing of AP1G1 decreases the replication of ZIKV and DENV2 in multiple human cell lines.Intriguingly,depletion of AP1G1 results in a significant reduction in ZIKV at an early stage,but decreases DENV2 replication levels during the late stage,suggesting that AP1G1 plays distinct roles in the infection by ZIKV and DENV2.Furthermore,we determined that AP1G1 mediates ZIKV-endosomal membrane fusion through inhibitor experiments and fluorescence labeling assays.Mechanistically,we found that AP1G1 exerts its pro-viral effect through binding to the ZIKV envelope glycoprotein(E protein).This interaction promotes the fusion of viral and endosomal membranes,during which the ZIKV genomic RNAs are released from the endosome into the cytoplasm,a process that facilitates viral replication.However,for DENV2 infection,AP1G1 primarily affects its viral RNA replication stage,rather than the fusion of virus-endosomal membrane.Taken together,our work demonstrates that AP1G1 plays a pro-viral role in both ZIKV and DENV2 infections via distinct mechanisms,highlighting its potential as a therapeutic target for antiviral strategies.
基金Supported by Shandong Provincial Natural Science Foundation,No.ZR2023MH329Project of Shandong Province Higher Educational Youth Innovation Science and Technology Program,No.2023KJ263and Natural Science Foundation of Gansu Province,China,No.22JR5RA953.
文摘BACKGROUND As a member of the chaperonin-containing tailless complex polypeptide 1(TCP1)complex,which plays a pivotal role in ensuring the accurate folding of numerous proteins,chaperonin-containing TCP1 subunit 6A(CCT6A)participates in various physiological and pathological processes.However,its effects on cell death and cancer therapy and the underlying mechanisms need further exploration in colorectal cancer(CRC)cells.AIM To explore the effects of CCT6A on cell death and cancer therapy and the underlying mechanisms in CRC.METHODS Cell proliferation was evaluated using the MTS assay,EdU staining,and colony growth assays.The expression of CCT6A was monitored by immunoblotting and quantitative PCR.CCT6A was knocked out by CRISPR-Cas9,and overexpressed by transfecting plasmids.Autophagy was examined by immunoblotting and the mCherry-GFP-LC3 assay.To monitor apoptosis and necroptosis,immunoblotting,co-immunoprecipitation,and flow cytometry were employed.RESULTS Cisplatin(DDP)exerted cytotoxic effects on CRC cells while simultaneously downregulating the expression of CCT6A.Depletion of CCT6A amplified the cytotoxic effects of DDP,whereas overexpression of CCT6A attenuated these adverse effects.CCT6A suppressed autophagy,apoptosis,and necroptosis under both basal and DDP-treated conditions.Autophagy inhibitors significantly enhanced the cytotoxic effects of DDP,whereas a necroptosis inhibitor partially reversed the cell viability loss induced by DDP.Furthermore,inhibiting autophagy enhanced both apoptosis and necroptosis induced by DDP.CONCLUSION CCT6A negatively modulates autophagy,apoptosis,and necroptosis,and CCT6A confers resistance to DDP therapy in CRC,suggesting its potential as a therapeutic target.
文摘BACKGROUND Hepatocellular carcinoma(HCC)is a leading cause of cancer-related mortality worldwide,with hepatitis B virus(HBV)infection serving as a significant etiological factor in endemic regions.Alpha-fetoprotein(AFP),the most commonly used biomarker,has limited sensitivity,particularly in AFP-negative HCC.Recent studies have identified origin recognition complex subunit 1(ORC1)and extra spindle pole bodies-like 1(ESPL1)as promising serum biomarkers,both linked to HBV DNA integration,a mechanism known to drive hepatocarcinogenesis.AIM To assess serum ORC1’s diagnostic value for HBV-HCC and its link to S gene integration.METHODS In this case-control study,479 HBV-infected patients were enrolled,including 20 hepatitis B,154 with HBV-related cirrhosis,and 96 with HBV-HCC.The control group comprised 73 individuals:29 with non-HBV-HCC and 44 healthy participants.Serum ORC1 and ESPL1 were measured by enzyme-linked immunosorbent assay.HBV integration sites were identified via whole-genome sequencing.Diagnostic performance was assessed using receiver operating characteristic analysis,including in AFP-negative patients.RESULTS HBV integration near the ORC1 locus(chromosome 1p32.3)was detected in 71.4%of HBV-HCC tissues.Serum ORC1 levels were significantly higher in HBV-infected patients than in non-HBV-infected controls(980.11 ng/L vs 746.82 ng/L,P<0.05)and in HBV-HCC compared with non-HBV-HCC(1077.07 ng/L vs 749.54 ng/L,P<0.05).Serum ORC1 and ESPL1 were elevated in HBV-HCC regardless of AFP status,and detected 64.8%and 73.2%of AFP-negative cases,respectively.The combined panel of ORC1[Area under receiver operating characteristic curve(AUC)=0.587],ESPL1(AUC=0.776),and AFP(AUC=0.844)achieved an AUC of 0.887,significantly higher than any single marker(P<0.05),with a sensitivity of 84.44%,specificity of 84.19%,and a negative predictive value of 94.91%.CONCLUSION Serum ORC1,driven by HBV integration,is a promising biomarker especially for AFP-negative HBV-HCC.Its combination with ESPL1 and AFP significantly improves early detection.
基金funded by the National Natural Science Foundation of China(42174131)。
文摘It is of great significance to evaluate the petrophysical properties in shale oil reservoir,which can contribute to geological storage CO_(2).Two-dimensional nuclear magnetic resonance(2D NMR)technology has been applied to petrophysical characterization in shale oil reservoir.However,limitations of traditional 2D NMR(T_(1)-T_(2)or T_(2)-D)in detecting short-lived organic matter and the complexity of mineral compositions,pose NMR-based petrophysical challenges.The organic pores were assumed saturated oil and the inorganic pores were assumed saturated water,and the numerical algorithm and theory of T_(1)-T_(2)^(*)in shale oil reservoir were proposed,whose accuracy was validated through T_(2),T_(1)-T_(2)and T_(2)^(*)experiments.The effects of mineral types and contents on the T_(1)-T_(2)^(*)responses were firstly simulated by the random walk algorithm,revealing the NMR response mechanisms in shale oil reservoir with complex mineral compositions at different magnetic field frequency(f).The results indicate that when the pyrite content is 5.43%,dwell time is 4μs,the f is 200 MHz,and echo spacing is 0.4 ms,the T_(1)-T_(2)^(*)-based porosity is 2.39 times that of T_(1)-T_(2)-based porosity.The T_(2LM)^(*)is 0.015 ms,which is 0.015 times that of T_(2)LM.The T_(1LM)is 8.84 ms,which is 0.63 times that of T_(1LM).The T_(1)-T_(2)^(*)-based petrophysical conversion models were firstly created,and the foundation of petrophysical conversion was laid at different f.
基金supported by the Science&Technology Development Program of Shandong Province(Grant No.2007GG30002003)
文摘Objective To explore the role of HIV-1 tat gene variations in AIDS dementia complex （ADC） pathogenesis. Methods HIV-1 tat genes derived from peripheral spleen and central basal ganglia of an AIDS patient with ADC and an AIDS patient without ADC were cloned for sequence analysis. HIV-1 tat gene sequence alignment was performed by using CLUSTAL W and the phylogentic analysis was conducted by using Neighbor-joining with MEGA4 software. All tat genes were used to construct recombinant retroviral expressing vector MSCV-IRES-GFP/tat. The MSCV-IRES-GFP/tat was cotransfected into 293T cells with pCMV-VSV-G and pUMVC vectors to assemble the recombinant retrovirus. After infection of gliomas U87 cells with equal amount of the recombinant retrovirus, TNF-α, and IL-1β concentrations in the supernatant of U87 cells were determined with ELISA. Results HIV-1 tat genes derived from peripheral spleen and central basal ganglia of the AIDS patient with ADC and the other one without ADC exhibited genetic variations. Tat variations and amino acid mutation sites existed mainly at Tat protein core functional area （38-47aa）. All Tat proteins could induce ug7 cells to produce TNF-α and IL-1β, but the level of IL-1β production was different among Tat proteins derived from the ADC patient＇s spleen, basal ganglia, and the non-ADC patient＇s spleen. The level of Tat proteins derived from the ADC patient＇s spleen, basal ganglia, and the non-ADC patient＇s spleen were obviously higher than that from the non-ADC patient＇s basal ganglia. Conclusion Tat protein core functional area （38-47aa） may serve as the key area of enhancing the secretion of IL-1β. This may be related with the neurotoxicity of HIV-1 Tat.
文摘Metal (Me=Fe(III), Mo(VI), Mn(II), Co(II), Ni(II), Zn(II) and Cu(II)) 2-hydroxy-1-naphthaldehyde thiosemicarbazone complexes (MeHNT) were synthesized and used as mimic-enzyme catalysts to mimic the active group of horseradish peroxidase (HRP). The results showed that Fe-HNT, Mo-HNT are effective catalysts, which have similar catalytic activity as HRP. The sequence of catalytic activities of tested biomimic peroxidas is Mo-HNT > Fe-HNT > Zn-HNT > Ni-HNT > Mn-HNT. Among them, Fe-HNT is used as a mimic-enzyme catalyst in determination of ascorbic acid and glucose by coupling the catalytic reaction of glucose oxidase.
基金This work was supported by the National Natural Science Foundation of China(No.20272014)the Project of National Education Ministry(Project No.204097)National 973 Project of China(Project No.2002CB613400-5).
文摘A novel cyclometalated iridium complex with 1, 3, 4-oxadiazole moiety was synthesizedand characterized. Its UV and photoluminescent properties were studied. The strong UVabsorption intensity around 462 nm attributed to spin-forbidden triplet metal–ligand charge transferband and photoluminescence at 518 nm were observed. This indicated that achieved iridiumcomplex could be used as an efficient electrophosphorescent material.
基金supported by the National Natural Science Foundation of China (No. 20971004)the Key Project of Chinese Ministry of Education (No. 210102)
文摘A novel heterometallic complex,[Zn4Ni（OH）2（btec）2（titb）2（H2O）2]·2H2O（1）（H4btec=1,2,4,5-benzenetetracarboxylic acid,titb=1,3,5-tris（imidazol-1-ylmethyl）-2,4,6-trime-thylbenzene）,has been hydrothermally prepared and characterized by IR spectroscopy,elemental analysis and single-crystal X-ray diffraction.The crystal is of triclinic system,space group P1 with a=10.817（10）,b=11.878（11）,c=14.569（14）,α=71.762（12）,β=76.122（13）,γ=71.493（13）°,V=1665（3）3,C62H62N12O22Zn4Ni,Mr=1647.43,Dc=1.643 g/cm3,F（000）=842,μ=1.784 mm-1 and Z=1.The final R=0.0531 and wR=0.0890 for 3545 observed reflections（Ⅰ 2σ（Ⅰ））.In the title complex,the btec ligand acts as a five-dentate bridging ligand to link up zinc and nickel atoms into a lamellar framework,which are further interlinked into a 3-D framework via the titb ligands.
