BACKGROUND Acute lung injury(ALI)and its final severe stage,acute respiratory distress syndrome,are associated with high morbidity and mortality rates in patients due to the lack of effective specific treatments.Gut m...BACKGROUND Acute lung injury(ALI)and its final severe stage,acute respiratory distress syndrome,are associated with high morbidity and mortality rates in patients due to the lack of effective specific treatments.Gut microbiota homeostasis,including that in ALI,is important for human health.Evidence suggests that the gut microbiota improves lung injury through the lung-gut axis.Human umbilical cord mesenchymal cells(HUC-MSCs)have attractive prospects for ALI treatment.This study hypothesized that HUC-MSCs improve ALI via the lung-gut microflora.AIM To explore the effects of HUC-MSCs on lipopolysaccharide(LPS)-induced ALI in mice and the involvement of the lung-gut axis in this process.METHODS C57BL/6 mice were randomly divided into four groups(18 rats per group):Sham,sham+HUC-MSCs,LPS,and LPS+HUC-MSCs.ALI was induced in mice by intraperitoneal injections of LPS(10 mg/kg).After 6 h,mice were intervened with 0.5 mL phosphate buffered saline(PBS)containing 1×10^(6) HUC-MSCs by intraperitoneal injections.For the negative control,100 mL 0.9%NaCl and 0.5 mL PBS were used.Bronchoalveolar lavage fluid(BALF)was obtained from anesthetized mice,and their blood,lungs,ileum,and feces were obtained by an aseptic technique following CO_(2) euthanasia.Wright’s staining,enzyme-linked immunosorbent assay,hematoxylin-eosin staining,Evans blue dye leakage assay,immunohistochemistry,fluorescence in situ hybridization,western blot,16S rDNA sequencing,and non-targeted metabolomics were used to observe the effect of HUC-MSCs on ALI mice,and the involvement of the lung-gut axis in this process was explored.One-way analysis of variance with post-hoc Tukey’s test,independent-sample Student’s t-test,Wilcoxon rank-sum test,and Pearson correlation analysis were used for statistical analyses.RESULTS HUC-MSCs were observed to improve pulmonary edema and lung and ileal injury,and decrease mononuclear cell and neutrophil counts,protein concentrations in BALF and inflammatory cytokine levels in the serum,lung,and ileum of ALI mice.Especially,HUC-MSCs decreased Evans blue concentration and Toll-like receptor 4,myeloid differentiation factor 88,p-nuclear factor kappa-B(NF-κB)/NF-κB,and p-inhibitorαof NF-κB(p-IκBα)/IκBαexpression levels in the lung,and raised the pulmonary vascular endothelial-cadherin,zonula occludens-1(ZO-1),and occludin levels and ileal ZO-1,claudin-1,and occludin expression levels.HUC-MSCs improved gut and BALF microbial homeostases.The number of pathogenic bacteria decreased in the BALF of ALI mice treated with HUCMSCs.Concurrently,the abundances of Oscillospira and Coprococcus in the feces of HUS-MSC-treated ALI mice were significantly increased.In addition,Lactobacillus,Bacteroides,and unidentified_Rikenellaceae genera appeared in both feces and BALF.Moreover,this study performed metabolomic analysis on the lung tissue and identified five upregulated metabolites and 11 downregulated metabolites in the LPS+MSC group compared to the LPS group,which were related to the purine metabolism and the taste transduction signaling pathways.Therefore,an intrinsic link between lung metabolite levels and BALF flora homeostasis was established.CONCLUSION This study suggests that HUM-MSCs attenuate ALI by redefining the gut and lung microbiota.展开更多
The‘Two Oceans and One Sea’area(West Pacific,Indian Ocean,and South China Sea;15°S–60°N,39°–178°E)is a core strategic area for the‘21st Century Maritime Silk Road’project,as well as national ...The‘Two Oceans and One Sea’area(West Pacific,Indian Ocean,and South China Sea;15°S–60°N,39°–178°E)is a core strategic area for the‘21st Century Maritime Silk Road’project,as well as national defense.With the increasing demand for disaster prevention and mitigation,the importance of 10–30-day extended range prediction,between the conventional short-term(around seven days)and the climate scale(longer than one month),is apparent.However,marine extended range prediction is still a‘blank point’in China,making the early warning of marine disasters almost impossible.Here,the authors introduce a recently launched Chinese national project on a numerical forecasting system for extended range prediction in the‘Two Oceans and One Sea’area based on a regional ultra-high resolution multi-layer coupled model,including the scientific aims,technical scheme,innovation,and expected achievements.The completion of this prediction system is of considerable significance for the economic development and national security of China.展开更多
Alumina(Al_(2)O_(3))is widely used in the chemical industry as the catalyst and support due to its high specific surface area,abundant pore size distribution and chemical stability.However,the occurrence of hydration ...Alumina(Al_(2)O_(3))is widely used in the chemical industry as the catalyst and support due to its high specific surface area,abundant pore size distribution and chemical stability.However,the occurrence of hydration in water environment,result in outstanding decrease in specific surface area and collapse of pore structure.In this work,dodecyl phosphoric acid(PA)is used to modify the surface of Al_(2)O_(3)to obtain a series of hydrophobic material(Al_(2)O_(3)-PA).Based on XPS and NMR analysis,PA is chemically bonded on Al_(2)O_(3)to form PAOAAl bond.Furthermore,BET and WCA results display that Al_(2)O_(3)-1PA exhibits excellent the hydrophobicity and hydrothermal stability while maintains the pore structure.Take it as the substrate to support the Pd nanoparticles,the as-prepared Pd/Al_(2)O_(3)-PA shows the superior catalytic performance in the hydrogenation of phenol and anthraquinone relative to Pd/Al_(2)O_(3),indicating the accessibility of Pd sites after PA modification.Especially,the significantly enhanced stability is also obtained in four cycles for aqueous phenol hydrogenation.This can be ascribed that the PA modification inhibits the aggregation of Pd nanoparticles and the products adhesion in the reaction process.The extension of PA coatings to monolithic catalysts could expand their current capabilities in industrial applications and warrants ongoing investigation.展开更多
SsrA peptide tag from Mycoplasma fl orum has been developed as a versatile biotechnology tool to control orthogonal degradation of tagged proteins in Escherichia coli . Here, using the systematic deletion mutants of m...SsrA peptide tag from Mycoplasma fl orum has been developed as a versatile biotechnology tool to control orthogonal degradation of tagged proteins in Escherichia coli . Here, using the systematic deletion mutants of mf -ssrA tag, we demonstrated that the residues in two separate regions have diff erent functions in mf -Lon-mediated specifi c orthogonal target protein degradation in E. coli . The deletion of multiple residues, up to six amino acids, did not fatally abolish its specifi c degradation activity, instead of being able to improve the stability of the tagged protein in the presence of endogenous proteases before mf -Lon expression in E. coli . Except for previously identifi ed essential residues, the region adjacent to the C-terminal of the mf -ssrA tag was involved in mf -Lon and endogenous protease-mediated degradation. Moreover, the deletion of specifi c residues made the mf -ssrA tag more eff ective and compact. The mf -ssrA tag can be implemented in synthetic biology and bioengineering for development of synthetic circuits.展开更多
Chikungunya virus(CHIKV)is a re-emerging mosquito-transmitted RNA virus causing joint and muscle pain.To better understand how CHIKV rewires the host cell and usurps host cell functions,we generated a systematic CHIKV...Chikungunya virus(CHIKV)is a re-emerging mosquito-transmitted RNA virus causing joint and muscle pain.To better understand how CHIKV rewires the host cell and usurps host cell functions,we generated a systematic CHIKV-human protein-protein interaction map and revealed several novel connections that will inform further mechanistic studies.One of these novel interactions,between the viral protein E1 and STIP1 homology and U-box containing protein 1(STUB1),was found to mediate ubiquitination of E1 and degrade E1 through the proteasome.Capsid associated with G3BP1,G3BP2 and AAAþATPase valosin-containing protein(VCP).Furthermore,VCP inhibitors blocked CHIKV infection,suggesting VCP could serve as a therapeutic target.Further work is required to fully understand the functional consequences of these interactions.Given that CHIKV proteins are conserved across alphaviruses,many virus-host protein-protein interactions identified in this study might also exist in other alphaviruses.Construction of interactome of CHIKV provides the basis for further studying the function of alphavirus biology.展开更多
A combined approach of physicochemical extraction and sulfur K-edge X-ray absorption near-edge structure（XANES） spectroscopy was applied to characterize the extracellular polymeric substances（EPS） of typical bacte...A combined approach of physicochemical extraction and sulfur K-edge X-ray absorption near-edge structure（XANES） spectroscopy was applied to characterize the extracellular polymeric substances（EPS） of typical bacterial biofilms in this study. Physicochemical analysis showed variation of the contents of DNA,polysaccharide and protein in different fractions of EPS in different mediums. The sulfur K-edge XANES analysis yielded a variety of spectra.Spectral fitting of the XANES spectra utilizing a large set of model compounds showed that there was more reduced sulfur in both LB-EPS（loosely bound EPS） and TB-EPS（tightly bound EPS） of all the biofilms in LB medium than in R2 A medium. More oxidized sulfur was identified in LB-EPS than that in TB-EPS,suggesting different niches and physiological heterogeneity in the biofilms. Our results suggested that the sulfur K-edge XANES can be a useful tool to analyze the sulfur speciation in EPS of biofilms.展开更多
Protein O-GlcNAcylation is a monosaccharide post-translational modification maintained by two evolutionarily conserved enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Mutations in human OGT have recently be...Protein O-GlcNAcylation is a monosaccharide post-translational modification maintained by two evolutionarily conserved enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Mutations in human OGT have recently been associated with neurodevelopmental disorders, although the mechanisms linking O-GlcNAc homeostasis to neurodevelopment are not understood. Here, we investigate the effects of perturbing protein O-GlcNAcylation using transgenic Drosophila lines that overexpress a highly active OGA. We reveal that temporal reduction of protein O-GlcNAcylation in early embryos leads to reduced brain size and olfactory learning in adult Drosophila. Downregulation of O-GlcNAcylation induced by the exogenous OGA activity promotes nuclear foci formation of Polycomb-group protein Polyhomeotic and the accumulation of excess K27 trimethylation of histone H3 (H3K27me3) at the mid-blastula transition. These changes interfere with the zygotic expression of several neurodevelopmental genes, particularly short gastrulation (sog), a component of an evolutionarily conserved sog-Decapentaplegic (Dpp) signaling system required for neuroectoderm specification. Our findings highlight the importance of early embryonic O-GlcNAcylation homeostasis for the fidelity of facultative heterochromatin redeployment and initial cell fate commitment of neuronal lineages, suggesting a possible mechanism underpinning OGT-associated intellectual disability.展开更多
Lesions on the DNA template can impact transcription via distinct regulatory pathways.Ionizing radiation(IR)as the mainstay modality for many malignancies elicits most of the cytotoxicity by inducing a variety of DNA ...Lesions on the DNA template can impact transcription via distinct regulatory pathways.Ionizing radiation(IR)as the mainstay modality for many malignancies elicits most of the cytotoxicity by inducing a variety of DNA damages in the genome.How the IR treatment alters the transcription cycle and whether it contributes to the development of radioresistance remain poorly understood.Here,we report an increase in the paused RNA polymerase II(RNAPII),as indicated by the phosphorylation at serine 5 residue of its C-terminal domain,in recurrent nasopharyngeal carcinoma(NPC)patient samples after IR treatment and cultured NPC cells developing IR resistance.Reducing the pool of paused RNAPII by either inhibiting TFIIH-associated CDK7 or stimulating the positive transcription elongation factor b,a CDK9-CycT1 heterodimer,attenuates IR resistance of NPC cells.Interestingly,the poly(ADP-ribosyl)ation of CycT1,which disrupts its phase separation,is elevated in the IR-resistant cells.Mutation of the major poly(ADP-ribosyl)ation sites of CycT1 decreases RNAPII pausing and restores IR sensitivity.Genome-wide chromatin immunoprecipitation followed by sequencing analyses reveal that several genes involved in radiation response and cell cycle control are subject to the regulation imposed by the paused RNAPII.Particularly,we identify the NIMA-related kinase NEK7 under such regulation as a new radioresistancefactor,whose downregulation results in the increased chromosome instability,enabling the development of IR resistance.Overall,our results highlight a novel link between the alteration in the transcription cycle and the acquisition of IR resistance,opening up new opportunities to increase the efficacy of radiotherapy and thwart radioresistance in NpC.展开更多
We fabricated and characterized two hybrid adsorbents originated from hydrated ferric oxides （HFOs） using a polymeric anion exchanger D201 and calcite as host. The resultant adsorbents （denoted as HFO-201 and IOCCS...We fabricated and characterized two hybrid adsorbents originated from hydrated ferric oxides （HFOs） using a polymeric anion exchanger D201 and calcite as host. The resultant adsorbents （denoted as HFO-201 and IOCCS） were employed for Sb（V） removal from water. Increasing solution pH from 3 to 9 apparently weakened Sb（V） removal by both composites, while increasing temperature from 293 to 313 K only improved Sb（V） uptake by IOCCS. HFO-201 exhibited much higher capacity for Sb（V） than for IOCCS in the absence of other anions in solution. Increasing ionic strength from 0.01 to 0.1 mol/L NaNO3 would result in a significant drop of the capacity of HFO-201 in the studied pH ranges; however, negligible effect was observed for 1OCCS under similar conditions. Similarly, the competing chloride and sulfate pose more negative effect on Sb（V） adsorption by HFO-201 than by IOCCS, and the presence of silicate greatly decreased their adsorption simultaneously, while calcium ions were found to promote the adsorption of both adsorbents. XPS analysis further demonstrated that preferable Sb（V） adsorption by both hybrids was attributed to the inner sphere complexation of Sb（V） and HFO, and Ca（II） induced adsorption enhancement possibly resulted from the formation of HFO-Ca-Sb complexes. Column adsorption runs proved that Sb（V） in the synthetic water could be effectively removed from 30 μg/L to below 5μg/L （the drinking water standard regulated by China）, and the effective treatable volume of IOCCS was around 6 times as that of HFO-201, implying that HFO coatings onto calcite might be a more effective approach than immobilization inside D201.展开更多
Immobilization of hydrous ferric oxide(HFO) particles inside solid hosts of porous structure is an important approach to improve their applicability in advanced water treatment such as arsenic and heavy metal removal....Immobilization of hydrous ferric oxide(HFO) particles inside solid hosts of porous structure is an important approach to improve their applicability in advanced water treatment such as arsenic and heavy metal removal. Here, we fabricated three polystyrene(PS)-based nano-HFOs and explored the effect of host pore structure on the surface chemistry of the immobilized HFOs. Potentiometric titration of the hybrids and surface complexation modeling of their adsorption towards arsenite and arsenate were performed to evaluate the surface chemistry variation of the loaded HFOs. Polymer hosts of higher surface area and narrower pore size would result in smaller particle size of HFOs and lower the value of the point of zero charge. Also, the site density(normalized by Fe mass) and the deprotonation constants of the loaded HFOs increased with the decreasing host pore size. Arsenite adsorption did not change the surface charge of the loaded HFOs, whereas arsenate adsorption accompanied more of the negative surface charges. Adsorption affinity of both arsenic species with three HFO hybrids were compared in terms of the intrinsic surface complexation constants optimized based on the adsorption edges. HFO loaded in polystyrene host of smaller pore size exhibits stronger affinity with arsenic species.展开更多
Mouse embryonic stem cells(mESCs)cycle in and out of a transient 2-cell(2C)-like totipotent state,driven by a com-plex genetic circuit involves both the coding and repetitive sections of the genome.While a vast array ...Mouse embryonic stem cells(mESCs)cycle in and out of a transient 2-cell(2C)-like totipotent state,driven by a com-plex genetic circuit involves both the coding and repetitive sections of the genome.While a vast array of regulators,including the multi-functional protein Rif1,has been reported to influence the switch of fate potential,how they act in concert to achieve this cellular plasticity remains elusive.Here,by modularizing the known totipotency regulatory factors,we identify an unprecedented functional connection between Rif1 and the non-canonical polycomb repres-sive complex PRC1.6.Downregulation of the expression of either Rif1 or PRC1.6 subunits imposes similar impacts on the transcriptome of mESCs.The LacO-LacI induced ectopic colocalization assay detects a specific interaction between Rif1 and Pcgf6,bolstering the intactness of the PRC1.6 complex.Chromatin immunoprecipitation followed by sequencing(ChIP-seq)analysis further reveals that Rif1 is required for the accurate targeting of Pcgf6 to a group of genomic loci encompassing many genes involved in the regulation of the 2C-like state.Depletion of Rif1 or Pcgf6 not only activates 2C genes such as Zscan4 and Zfp352,but also derepresses a group of the endogenous retroviral element MERVL,a key marker for totipotency.Collectively,our findings discover that Rif1 can serve as a novel auxiliary component in the PRC1.6 complex to restrain the genetic circuit underlying totipotent fate potential,shedding new mechanistic insights into its function in regulating the cellular plasticity of embryonic stem cells.展开更多
Nonalcoholic fatty liver disease(NAFLD),including advancedstage nonalcoholic steatohepatitis(NASH),is currently the most common chronic liver disease worldwide and is projected to become the leading indication for liv...Nonalcoholic fatty liver disease(NAFLD),including advancedstage nonalcoholic steatohepatitis(NASH),is currently the most common chronic liver disease worldwide and is projected to become the leading indication for liver transplantation(LT).However,there are no effective pharmacological therapies for NAFLD.Endoscopic bariatric and metabolic therapies(EBMTs)are less invasive procedures for the treatment of obesity and its metabolic comorbidities.Several recent studies have demonstrated the beneficial effects of EBMTs on NAFLD/NASH.In this review,we summarize the major EBMTs and their mechanisms of action.We further discuss the current evidence on the efficacy and safety of EBMTs in people with NAFLD/NASH and obese cirrhotic LT candidates.The potential utility of EBMTs in reducing liver volume and perioperative complications in bariatric surgery candidates is also discussed.Moreover,we review the development of liver abscesses as a common serious adverse event in duodenaljejunal bypass liner implantation.展开更多
With sequence similarities to exogenous retroviruses,the proviral DNA elements named endogenous retroviruses(ERVs)make up∼8% of human genome,threatening genomic stability meanwhile nurturing regulatory innovations.Di...With sequence similarities to exogenous retroviruses,the proviral DNA elements named endogenous retroviruses(ERVs)make up∼8% of human genome,threatening genomic stability meanwhile nurturing regulatory innovations.Diverse host epigenetic mechanisms are enlisted to limit the ERVs’activity.However,in certain physiological and pathophysiological processes,distinct ERVs become abnormally activated,rewiring and perplexing the host regulons at different levels(Cosby et al.,2019).展开更多
基金the Key Research and Development Project of Science and Technology Department of Zhejiang Province,No.2019C03041.
文摘BACKGROUND Acute lung injury(ALI)and its final severe stage,acute respiratory distress syndrome,are associated with high morbidity and mortality rates in patients due to the lack of effective specific treatments.Gut microbiota homeostasis,including that in ALI,is important for human health.Evidence suggests that the gut microbiota improves lung injury through the lung-gut axis.Human umbilical cord mesenchymal cells(HUC-MSCs)have attractive prospects for ALI treatment.This study hypothesized that HUC-MSCs improve ALI via the lung-gut microflora.AIM To explore the effects of HUC-MSCs on lipopolysaccharide(LPS)-induced ALI in mice and the involvement of the lung-gut axis in this process.METHODS C57BL/6 mice were randomly divided into four groups(18 rats per group):Sham,sham+HUC-MSCs,LPS,and LPS+HUC-MSCs.ALI was induced in mice by intraperitoneal injections of LPS(10 mg/kg).After 6 h,mice were intervened with 0.5 mL phosphate buffered saline(PBS)containing 1×10^(6) HUC-MSCs by intraperitoneal injections.For the negative control,100 mL 0.9%NaCl and 0.5 mL PBS were used.Bronchoalveolar lavage fluid(BALF)was obtained from anesthetized mice,and their blood,lungs,ileum,and feces were obtained by an aseptic technique following CO_(2) euthanasia.Wright’s staining,enzyme-linked immunosorbent assay,hematoxylin-eosin staining,Evans blue dye leakage assay,immunohistochemistry,fluorescence in situ hybridization,western blot,16S rDNA sequencing,and non-targeted metabolomics were used to observe the effect of HUC-MSCs on ALI mice,and the involvement of the lung-gut axis in this process was explored.One-way analysis of variance with post-hoc Tukey’s test,independent-sample Student’s t-test,Wilcoxon rank-sum test,and Pearson correlation analysis were used for statistical analyses.RESULTS HUC-MSCs were observed to improve pulmonary edema and lung and ileal injury,and decrease mononuclear cell and neutrophil counts,protein concentrations in BALF and inflammatory cytokine levels in the serum,lung,and ileum of ALI mice.Especially,HUC-MSCs decreased Evans blue concentration and Toll-like receptor 4,myeloid differentiation factor 88,p-nuclear factor kappa-B(NF-κB)/NF-κB,and p-inhibitorαof NF-κB(p-IκBα)/IκBαexpression levels in the lung,and raised the pulmonary vascular endothelial-cadherin,zonula occludens-1(ZO-1),and occludin levels and ileal ZO-1,claudin-1,and occludin expression levels.HUC-MSCs improved gut and BALF microbial homeostases.The number of pathogenic bacteria decreased in the BALF of ALI mice treated with HUCMSCs.Concurrently,the abundances of Oscillospira and Coprococcus in the feces of HUS-MSC-treated ALI mice were significantly increased.In addition,Lactobacillus,Bacteroides,and unidentified_Rikenellaceae genera appeared in both feces and BALF.Moreover,this study performed metabolomic analysis on the lung tissue and identified five upregulated metabolites and 11 downregulated metabolites in the LPS+MSC group compared to the LPS group,which were related to the purine metabolism and the taste transduction signaling pathways.Therefore,an intrinsic link between lung metabolite levels and BALF flora homeostasis was established.CONCLUSION This study suggests that HUM-MSCs attenuate ALI by redefining the gut and lung microbiota.
基金supported by the National Key Research and Development Program of China(Grant Nos.2017YFC1404105,2017YFC1404100,2017YFC1404101,2017YFC1404102,2017YFC1404103 and 2017YFC1404104)
文摘The‘Two Oceans and One Sea’area(West Pacific,Indian Ocean,and South China Sea;15°S–60°N,39°–178°E)is a core strategic area for the‘21st Century Maritime Silk Road’project,as well as national defense.With the increasing demand for disaster prevention and mitigation,the importance of 10–30-day extended range prediction,between the conventional short-term(around seven days)and the climate scale(longer than one month),is apparent.However,marine extended range prediction is still a‘blank point’in China,making the early warning of marine disasters almost impossible.Here,the authors introduce a recently launched Chinese national project on a numerical forecasting system for extended range prediction in the‘Two Oceans and One Sea’area based on a regional ultra-high resolution multi-layer coupled model,including the scientific aims,technical scheme,innovation,and expected achievements.The completion of this prediction system is of considerable significance for the economic development and national security of China.
基金supported by National Key Research&Development Program of China(2021YFB3801600)Fundamental Research Funds for the Central University(buctrc201921,JD2223,12060093063)Innovative Achievement Commercialization Service-Platform of Industrial Catalysis(2019-00900-2-1).
文摘Alumina(Al_(2)O_(3))is widely used in the chemical industry as the catalyst and support due to its high specific surface area,abundant pore size distribution and chemical stability.However,the occurrence of hydration in water environment,result in outstanding decrease in specific surface area and collapse of pore structure.In this work,dodecyl phosphoric acid(PA)is used to modify the surface of Al_(2)O_(3)to obtain a series of hydrophobic material(Al_(2)O_(3)-PA).Based on XPS and NMR analysis,PA is chemically bonded on Al_(2)O_(3)to form PAOAAl bond.Furthermore,BET and WCA results display that Al_(2)O_(3)-1PA exhibits excellent the hydrophobicity and hydrothermal stability while maintains the pore structure.Take it as the substrate to support the Pd nanoparticles,the as-prepared Pd/Al_(2)O_(3)-PA shows the superior catalytic performance in the hydrogenation of phenol and anthraquinone relative to Pd/Al_(2)O_(3),indicating the accessibility of Pd sites after PA modification.Especially,the significantly enhanced stability is also obtained in four cycles for aqueous phenol hydrogenation.This can be ascribed that the PA modification inhibits the aggregation of Pd nanoparticles and the products adhesion in the reaction process.The extension of PA coatings to monolithic catalysts could expand their current capabilities in industrial applications and warrants ongoing investigation.
基金supported by the National Natural Science Foundation of China (No. 21476167 and No. 21778039)
文摘SsrA peptide tag from Mycoplasma fl orum has been developed as a versatile biotechnology tool to control orthogonal degradation of tagged proteins in Escherichia coli . Here, using the systematic deletion mutants of mf -ssrA tag, we demonstrated that the residues in two separate regions have diff erent functions in mf -Lon-mediated specifi c orthogonal target protein degradation in E. coli . The deletion of multiple residues, up to six amino acids, did not fatally abolish its specifi c degradation activity, instead of being able to improve the stability of the tagged protein in the presence of endogenous proteases before mf -Lon expression in E. coli . Except for previously identifi ed essential residues, the region adjacent to the C-terminal of the mf -ssrA tag was involved in mf -Lon and endogenous protease-mediated degradation. Moreover, the deletion of specifi c residues made the mf -ssrA tag more eff ective and compact. The mf -ssrA tag can be implemented in synthetic biology and bioengineering for development of synthetic circuits.
基金supported by National Natural Science Foundation of China (82072270 and 82272306)Taishan Scholars Program (tstp20221142)+1 种基金Shandong Provincial Natural Science Foundation (ZR2021QC095)Academic Promotion Programme of Shandong First Medical University (2019LJ001).
文摘Chikungunya virus(CHIKV)is a re-emerging mosquito-transmitted RNA virus causing joint and muscle pain.To better understand how CHIKV rewires the host cell and usurps host cell functions,we generated a systematic CHIKV-human protein-protein interaction map and revealed several novel connections that will inform further mechanistic studies.One of these novel interactions,between the viral protein E1 and STIP1 homology and U-box containing protein 1(STUB1),was found to mediate ubiquitination of E1 and degrade E1 through the proteasome.Capsid associated with G3BP1,G3BP2 and AAAþATPase valosin-containing protein(VCP).Furthermore,VCP inhibitors blocked CHIKV infection,suggesting VCP could serve as a therapeutic target.Further work is required to fully understand the functional consequences of these interactions.Given that CHIKV proteins are conserved across alphaviruses,many virus-host protein-protein interactions identified in this study might also exist in other alphaviruses.Construction of interactome of CHIKV provides the basis for further studying the function of alphavirus biology.
基金supported by the National Natural Science Foundation of China (No.51278482)the National High-Tech Research and Development (No.2012AA062607)+1 种基金the Fujian Provincial Natural Science Foundation (No.2013J05087)the Science and Technology Plan Projects of Xiamen (Nos.3502Z20110005,3502Z20132013)
文摘A combined approach of physicochemical extraction and sulfur K-edge X-ray absorption near-edge structure（XANES） spectroscopy was applied to characterize the extracellular polymeric substances（EPS） of typical bacterial biofilms in this study. Physicochemical analysis showed variation of the contents of DNA,polysaccharide and protein in different fractions of EPS in different mediums. The sulfur K-edge XANES analysis yielded a variety of spectra.Spectral fitting of the XANES spectra utilizing a large set of model compounds showed that there was more reduced sulfur in both LB-EPS（loosely bound EPS） and TB-EPS（tightly bound EPS） of all the biofilms in LB medium than in R2 A medium. More oxidized sulfur was identified in LB-EPS than that in TB-EPS,suggesting different niches and physiological heterogeneity in the biofilms. Our results suggested that the sulfur K-edge XANES can be a useful tool to analyze the sulfur speciation in EPS of biofilms.
基金This project has been supported by the National Natural Science Foundation of China(grants 91853108,92153301,31771589,and 32170821 to K.Y,32101034 to F.C)Department of Science and Technology of Hunan Province(grants 2017RS3013,2017XK2011,2018DK2015,2019SK1012,and 2021JJ10054 to K.Y,and the innovative team program 2019RS1010)+2 种基金Central South University(2018CX032 to K.Y,2019zzts046 to Y.Z,2019zzts339 to X.L,2021zzts497 to H.Y,and the innovation-driven team project 2020CX016)D.M.F.v.A.is supported by Wellcome Trust Investigator Award(110061)a Novo Nordisk Foundation Laureate award(NNF21OC0065969).
文摘Protein O-GlcNAcylation is a monosaccharide post-translational modification maintained by two evolutionarily conserved enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Mutations in human OGT have recently been associated with neurodevelopmental disorders, although the mechanisms linking O-GlcNAc homeostasis to neurodevelopment are not understood. Here, we investigate the effects of perturbing protein O-GlcNAcylation using transgenic Drosophila lines that overexpress a highly active OGA. We reveal that temporal reduction of protein O-GlcNAcylation in early embryos leads to reduced brain size and olfactory learning in adult Drosophila. Downregulation of O-GlcNAcylation induced by the exogenous OGA activity promotes nuclear foci formation of Polycomb-group protein Polyhomeotic and the accumulation of excess K27 trimethylation of histone H3 (H3K27me3) at the mid-blastula transition. These changes interfere with the zygotic expression of several neurodevelopmental genes, particularly short gastrulation (sog), a component of an evolutionarily conserved sog-Decapentaplegic (Dpp) signaling system required for neuroectoderm specification. Our findings highlight the importance of early embryonic O-GlcNAcylation homeostasis for the fidelity of facultative heterochromatin redeployment and initial cell fate commitment of neuronal lineages, suggesting a possible mechanism underpinning OGT-associated intellectual disability.
基金This project has been supported by grants from the National Natural ScienceFoundation of China(32170821 and 92153301 to K.Y.and 32101034 to F.C.)the Ministry of Science and Technologyyof the People's Republic of China(2021YFC2701202)+2 种基金Department of Science&Technology of Hunan Province(2021J10054 and 2019SK1012 to K.Y.,2021J41049 to C.Y.,and the Innovative Team Program 2019RS1010)Central South University(the Innovationdriven Team Project 2020CX016)K.Y.is supported by the National Thousand Talents Program for Young Outstanding Scientists.
文摘Lesions on the DNA template can impact transcription via distinct regulatory pathways.Ionizing radiation(IR)as the mainstay modality for many malignancies elicits most of the cytotoxicity by inducing a variety of DNA damages in the genome.How the IR treatment alters the transcription cycle and whether it contributes to the development of radioresistance remain poorly understood.Here,we report an increase in the paused RNA polymerase II(RNAPII),as indicated by the phosphorylation at serine 5 residue of its C-terminal domain,in recurrent nasopharyngeal carcinoma(NPC)patient samples after IR treatment and cultured NPC cells developing IR resistance.Reducing the pool of paused RNAPII by either inhibiting TFIIH-associated CDK7 or stimulating the positive transcription elongation factor b,a CDK9-CycT1 heterodimer,attenuates IR resistance of NPC cells.Interestingly,the poly(ADP-ribosyl)ation of CycT1,which disrupts its phase separation,is elevated in the IR-resistant cells.Mutation of the major poly(ADP-ribosyl)ation sites of CycT1 decreases RNAPII pausing and restores IR sensitivity.Genome-wide chromatin immunoprecipitation followed by sequencing analyses reveal that several genes involved in radiation response and cell cycle control are subject to the regulation imposed by the paused RNAPII.Particularly,we identify the NIMA-related kinase NEK7 under such regulation as a new radioresistancefactor,whose downregulation results in the increased chromosome instability,enabling the development of IR resistance.Overall,our results highlight a novel link between the alteration in the transcription cycle and the acquisition of IR resistance,opening up new opportunities to increase the efficacy of radiotherapy and thwart radioresistance in NpC.
基金supported by the National Natural Science Foundation of China(No.21177059)the Depart-ment of Science and Technology,Jiangsu Province(No.BK2012017/2011016,BE2012160)
文摘We fabricated and characterized two hybrid adsorbents originated from hydrated ferric oxides （HFOs） using a polymeric anion exchanger D201 and calcite as host. The resultant adsorbents （denoted as HFO-201 and IOCCS） were employed for Sb（V） removal from water. Increasing solution pH from 3 to 9 apparently weakened Sb（V） removal by both composites, while increasing temperature from 293 to 313 K only improved Sb（V） uptake by IOCCS. HFO-201 exhibited much higher capacity for Sb（V） than for IOCCS in the absence of other anions in solution. Increasing ionic strength from 0.01 to 0.1 mol/L NaNO3 would result in a significant drop of the capacity of HFO-201 in the studied pH ranges; however, negligible effect was observed for 1OCCS under similar conditions. Similarly, the competing chloride and sulfate pose more negative effect on Sb（V） adsorption by HFO-201 than by IOCCS, and the presence of silicate greatly decreased their adsorption simultaneously, while calcium ions were found to promote the adsorption of both adsorbents. XPS analysis further demonstrated that preferable Sb（V） adsorption by both hybrids was attributed to the inner sphere complexation of Sb（V） and HFO, and Ca（II） induced adsorption enhancement possibly resulted from the formation of HFO-Ca-Sb complexes. Column adsorption runs proved that Sb（V） in the synthetic water could be effectively removed from 30 μg/L to below 5μg/L （the drinking water standard regulated by China）, and the effective treatable volume of IOCCS was around 6 times as that of HFO-201, implying that HFO coatings onto calcite might be a more effective approach than immobilization inside D201.
基金supported by the National Natural Science Foundation of China(21177059/51378079)the Jiangsu Natural Science Foundation(BK2012017)
文摘Immobilization of hydrous ferric oxide(HFO) particles inside solid hosts of porous structure is an important approach to improve their applicability in advanced water treatment such as arsenic and heavy metal removal. Here, we fabricated three polystyrene(PS)-based nano-HFOs and explored the effect of host pore structure on the surface chemistry of the immobilized HFOs. Potentiometric titration of the hybrids and surface complexation modeling of their adsorption towards arsenite and arsenate were performed to evaluate the surface chemistry variation of the loaded HFOs. Polymer hosts of higher surface area and narrower pore size would result in smaller particle size of HFOs and lower the value of the point of zero charge. Also, the site density(normalized by Fe mass) and the deprotonation constants of the loaded HFOs increased with the decreasing host pore size. Arsenite adsorption did not change the surface charge of the loaded HFOs, whereas arsenate adsorption accompanied more of the negative surface charges. Adsorption affinity of both arsenic species with three HFO hybrids were compared in terms of the intrinsic surface complexation constants optimized based on the adsorption edges. HFO loaded in polystyrene host of smaller pore size exhibits stronger affinity with arsenic species.
基金This project has been supported by the National Natural Science Foundation of China(32170821,31771589 to K.Y)Ministry of Science and Technology of the People’s Republic of China(2021YFC2701202)+1 种基金Department of Science&Technology of Hunan Province(2021JJ10054,2019SK1012,2018DK2015,2017RS3013,2017XK2011 to K.Y,2019JJ40478 to P.L,and the innovative team program 2019RS1010)Central South University(2018CX032 to K.Y,and the innovation-driven team project 2020CX016)。
文摘Mouse embryonic stem cells(mESCs)cycle in and out of a transient 2-cell(2C)-like totipotent state,driven by a com-plex genetic circuit involves both the coding and repetitive sections of the genome.While a vast array of regulators,including the multi-functional protein Rif1,has been reported to influence the switch of fate potential,how they act in concert to achieve this cellular plasticity remains elusive.Here,by modularizing the known totipotency regulatory factors,we identify an unprecedented functional connection between Rif1 and the non-canonical polycomb repres-sive complex PRC1.6.Downregulation of the expression of either Rif1 or PRC1.6 subunits imposes similar impacts on the transcriptome of mESCs.The LacO-LacI induced ectopic colocalization assay detects a specific interaction between Rif1 and Pcgf6,bolstering the intactness of the PRC1.6 complex.Chromatin immunoprecipitation followed by sequencing(ChIP-seq)analysis further reveals that Rif1 is required for the accurate targeting of Pcgf6 to a group of genomic loci encompassing many genes involved in the regulation of the 2C-like state.Depletion of Rif1 or Pcgf6 not only activates 2C genes such as Zscan4 and Zfp352,but also derepresses a group of the endogenous retroviral element MERVL,a key marker for totipotency.Collectively,our findings discover that Rif1 can serve as a novel auxiliary component in the PRC1.6 complex to restrain the genetic circuit underlying totipotent fate potential,shedding new mechanistic insights into its function in regulating the cellular plasticity of embryonic stem cells.
基金supported in part by a grant from the Key Research and Development Program of Zhejiang Province(No.2019C03031).
文摘Nonalcoholic fatty liver disease(NAFLD),including advancedstage nonalcoholic steatohepatitis(NASH),is currently the most common chronic liver disease worldwide and is projected to become the leading indication for liver transplantation(LT).However,there are no effective pharmacological therapies for NAFLD.Endoscopic bariatric and metabolic therapies(EBMTs)are less invasive procedures for the treatment of obesity and its metabolic comorbidities.Several recent studies have demonstrated the beneficial effects of EBMTs on NAFLD/NASH.In this review,we summarize the major EBMTs and their mechanisms of action.We further discuss the current evidence on the efficacy and safety of EBMTs in people with NAFLD/NASH and obese cirrhotic LT candidates.The potential utility of EBMTs in reducing liver volume and perioperative complications in bariatric surgery candidates is also discussed.Moreover,we review the development of liver abscesses as a common serious adverse event in duodenaljejunal bypass liner implantation.
基金supported by grants from the National Natural Science Foundation of China(31771589,91853108,92153301,32170821,and 32101034)supported by the National Thousand Talents Program for Young Scientists.
文摘With sequence similarities to exogenous retroviruses,the proviral DNA elements named endogenous retroviruses(ERVs)make up∼8% of human genome,threatening genomic stability meanwhile nurturing regulatory innovations.Diverse host epigenetic mechanisms are enlisted to limit the ERVs’activity.However,in certain physiological and pathophysiological processes,distinct ERVs become abnormally activated,rewiring and perplexing the host regulons at different levels(Cosby et al.,2019).
