Sleep benefits the restoration of energy metabolism and thereby suppo rts neuronal plasticity and cognitive behaviors.Sirt6 is a NAD+-dependent protein deacetylase that has been recognized as an essential regulator of...Sleep benefits the restoration of energy metabolism and thereby suppo rts neuronal plasticity and cognitive behaviors.Sirt6 is a NAD+-dependent protein deacetylase that has been recognized as an essential regulator of energy metabolism because it modulates various transcriptional regulators and metabolic enzymes.The aim of this study was to investigate the influence of Sirt6 on cerebral function after chronic sleep deprivation(CSD).We assigned C57BL/6J mice to control or two CSD groups and subjected them to AAV2/9-CMV-EGFP or AAV2/9-CMV-Sirt6-EGFP infection in the prelimbic cortex(PrL).We then assessed cerebral functional connectivity(FC) using resting-state functional MRI,neuron/astrocyte metabolism using a metabolic kinetics analysis;dendritic spine densities using sparse-labeling;and miniature excitato ry postsynaptic currents(mEPSCs) and action potential(AP) firing rates using whole-cell patchclamp recordings.In addition,we evaluated cognition via a comprehensive set of behavioral tests.Compared with controls,Sirt6 was significantly decreased(P<0.05) in the PrL after CSD,accompanied by cognitive deficits and decreased FC between the PrL and accumbens nucleus,piriform cortex,motor co rtex,somatosensory co rtex,olfactory tubercle,insular cortex,and cerebellum.Sirt6 ove rexpression reve rsed CSD-induced cognitive impairment and reduced FC.Our analysis of metabolic kinetics using [1-13C] glucose and [2-13C] acetate showed that CSD reduced neuronal Glu4and GABA2synthesis,which could be fully restored via forced Sirt6 expression.Furthermore,Sirt6 ove rexpression reversed CSD-induced decreases in AP firing rates as well as the frequency and amplitude of mEPSCs in PrL pyramidal neurons.These data indicate that Sirt6 can improve cognitive impairment after CSD by regulating the PrL-associated FC network,neuronal glucose metabolism,and glutamatergic neurotransmission.Thus,Sirt6 activation may have potential as a novel strategy for treating sleep disorder-related diseases.展开更多
Although the GABAA receptor(GABAAR)has been proposed as the main action site for sevoflurane,isoflurane,halothane,enflurane,propofol,and benzodiazepines(BZDs),binding of these anesthetics with high-resolution structur...Although the GABAA receptor(GABAAR)has been proposed as the main action site for sevoflurane,isoflurane,halothane,enflurane,propofol,and benzodiazepines(BZDs),binding of these anesthetics with high-resolution structures of the GABAAR have been rarely examined by comparative docking analyses.Moreover,various combinations of ligands on more GABAARs with various subtypes need to be analyzed to understand the elaborate action mechanism of GABAARs better because some GABAA ligands showed specificity toward the distinct subtypes of the GABAAR.Methods:We performed in silico docking analysis to compare the binding modes of sevoflurane,isoflurane,halothane,enflurane,propofol,and BZDs to the GABAAR based on one of the most recently provided 3D structures.We performed the docking analysis and the affinity-based ranking of the binding sites.Results:Our docking studies revealed that isoflurane,halothane,and enflurane docked in an extracellular domain(ECD)on GABAARs,in contrast to sevoflurane.Conclusion:Our results supported a multi-site mechanism for the allosteric modulation of propofol.Propofol was bound to the pore or favored various subsites in the transmembrane domain(TMD).Our result confirmed that different chemically related BZD ligands interact via distinct binding modes rather than by using a common binding mode,as previously suggested.展开更多
User-interactive electronic skin(e-skin) that could convert mechanical stimuli into distinguishable outputs displays tremendous potential for wearable devices and health care applications. However, the existing device...User-interactive electronic skin(e-skin) that could convert mechanical stimuli into distinguishable outputs displays tremendous potential for wearable devices and health care applications. However, the existing devices have the disadvantages such as complex integration procedure and lack of the intuitive signal display function. Here, we present a bioinspired user-interactive e-skin, which is simple in structure and can synchronously achieve digital electrical response and optical visualization upon external mechanical stimulus. The e-skin comprises a conductive layer with a carbon nanotubes/cellulose nanofibers/MXene nanohybrid network featuring remarkable electromechanical behaviors, and a stretchable elastomer layer, which is composed of silicone rubber and thermochromic pigments. Furthermore, the conductive nanohybrid network with outstanding Joule heating performance can generate controllable thermal energy under voltage input and then achieve the dynamic coloration of silicone-based elastomer. Especially, such an innovative fusion strategy of digital data and visual images enables the e-skin to monitor human activities with evermore intuition and accuracy. The simple design philosophy and reliable operation of the demonstrated e-skin are expected to provide an ideal platform for next-generation flexible electronics.展开更多
Ageing is one of the greatest risk factors for neurodegenerative diseases.How the complex biological changes in ageing increase the brain’s susceptibility to neurodegeneration remains incompletely understood.Research...Ageing is one of the greatest risk factors for neurodegenerative diseases.How the complex biological changes in ageing increase the brain’s susceptibility to neurodegeneration remains incompletely understood.Research into neurodegenerative disorders has shifted from a neuron-centric approach,to the contributing roles of age-related neurovascular and glial cell dysfunction.展开更多
Mineralization has found widespread use in the fabrication of composite biomaterials for hard tissue regeneration.The current mineralization processes are mainly carried out in neutral aqueous solutions of biomineral ...Mineralization has found widespread use in the fabrication of composite biomaterials for hard tissue regeneration.The current mineralization processes are mainly carried out in neutral aqueous solutions of biomineral counter-ions(a pair of cation and anion that form the corresponding minerals at certain conditions),which are stable only at very low concentrations.This typically results in inefficient mineralization and weak control over biomineral formation.Here,we find that,in the organic solvent glycerol,a variety of biomineral counter-ions(e.g.,Ca/PO_(4),Ca/CO_(3),Ca/SO_(4),Mg/PO_(4),or Fe/OH)corresponding to distinct biominerals at significantly high concentrations(up to hundreds-fold greater than those of simulated body fluid(SBF))are able to form translucent and stable solutions(mineralizing solution of highly concentrated counter-ions(MSCIs)),and mineralization can be triggered upon them with external solvents(e.g.,water or ethanol).Furthermore,with pristine bacterial cellulose(BC)membrane as a model,we demonstrate an effective and controllable mineralization performance of MSCIs on organic substrates.This approach not only forms the homogeneous biominerals on the BC fibers and in the interspaces,but also provides regulations over mineralization rate,mineral content,phase,and dopants.The resulting mineralized BC membranes(MBCs)exhibit high cytocompatibility and favor the proliferation of rat bone marrow mesenchymal stem cells(rBMSC).Following this,we prepare a mineralized bone suture(MBS)from MBC for non-weight bearing bone fixation,which then is tested on a rabbit median sternotomy model.It shows firm fixation of the rabbit sternum without causing discernible toxicity or inflammatory response.This study,by extending the mineralization to the organic solution system of highly concentrated counter-ions,develops a promising strategy to design and build targeted mineral-based composites.展开更多
Epidural spinal cord stimulation (ESCS) markedly improves motor and sensory function after spinal cord injury (SCI), but the underlying mechanisms are unclear.Here, we investigated whether ESCS affects oligodendrocyte...Epidural spinal cord stimulation (ESCS) markedly improves motor and sensory function after spinal cord injury (SCI), but the underlying mechanisms are unclear.Here, we investigated whether ESCS affects oligodendrocyte differentiation and its cellular and molecular mechanisms in rats with SCI. ESCS improved hindlimb motor function at 7 days, 14 days, 21 days, and 28 days after SCI.ESCS also significantly increased the myelinated area at 28days, and reduced the number of apoptotic cells in the spinal white matter at 7 days. SCI decreased the expression of 20,30-cyclic-nucleotide 30-phosphodiesterase (CNPase,an oligodendrocyte marker) at 7 days and that of myelin basic protein at 28 days. ESCS significantly upregulated these markers and increased the percentage of Sox2/CNPase/DAPI-positive cells (newly differentiated oligodendrocytes) at 7 days. Recombinant human bone morphogenetic protein 4 (rh BMP4) markedly downregulated these factors after ESCS. Furthermore, ESCS significantly decreased BMP4 and p-Smad1/5/9 expression after SCI,and rh BMP4 reduced this effect of ESCS. These findings indicate that ESCS enhances the survival and differentiation of oligodendrocytes, protects myelin, and promotes motor functional recovery by inhibiting the BMP4-Smad1/5/9 signaling pathway after SCI.展开更多
The seek of bioactive materials for promoting bone regeneration is a challenging and longterm task.Functionalization with inorganic metal ions or drug molecules is considered effective strategies to improve the bioact...The seek of bioactive materials for promoting bone regeneration is a challenging and longterm task.Functionalization with inorganic metal ions or drug molecules is considered effective strategies to improve the bioactivity of various existing biomaterials.Herein,amorphous calcium magnesium phosphate(ACMP)nanoparticles and simvastatin(SIM)-loaded ACMP(ACMP/SIM)nanocomposites were developed via a simple co-precipitation strategy.The physiochemical property of ACMP/SIM was explored using transmission electron microscope(TEM),Fourier transform infrared spectroscopy(FTIR),powder X-ray diffraction(XRD)and highperformance liquid chromatograph(HPLC),and the role of Mg^(2+) in the formation of ACMP/SIM was revealed using X-ray absorption near-edge structure(XANES).After that,the transformation process of ACMP/SIM in simulated body fluid(SBF)was also tracked to simulate and explore the in vivo mineralization performance of materials.We find that ACMP/SIM releases ions of Ca^(2+),Mg^(2+)and PO_(4)^(3),when it is immersed in SBF at 37℃,and a phase transformation occurred during which the initially amorphous ACMP turns into self-assembled hydroxyapatite(HAP).Furthermore,ACMP/SIM displays high cytocompatibility and promotes the proliferation and osteogenic differentiation of MC3T3-E1 cells.For the in vivo studies,lamellar ACMP/SIM/Collagen scaffolds with aligned pore structures were prepared and used to repair a rat defect model in calvaria.ACMP/SIM/Collagen scaffolds show a positive effect in promoting the regeneration of calvaria defect after 12weeks.The bioactive ACMP/SIM nanocomposites are promising as bone repair materials.Considering the facile preparation process and superior in vitro/vivo bioactivity,the as-prepared ACMP/SIM would be a potential candidate for bone related biomedical applications.展开更多
基金The Expert Workshop(Liverpool,UK,October 2012),upon which the present manuscript was based,was supported by The Pain Relief Foundation,Liverpool The Great-Britain Sasakawa Foundation Awards ProgrammeBaxter+3 种基金BPLBiotestCSLBehringand Grifols
基金National Natural Science Foundation of China,Nos.81771160 (to ZZ),81671060 (to CC),31970973 (to JW),21921004 (to FX)Translational Medicine and In terdisciplinary Research Joint Fund of Zhongnan Hospital of Wuhan University,No.ZNJC201934 (to ZZ)。
文摘Sleep benefits the restoration of energy metabolism and thereby suppo rts neuronal plasticity and cognitive behaviors.Sirt6 is a NAD+-dependent protein deacetylase that has been recognized as an essential regulator of energy metabolism because it modulates various transcriptional regulators and metabolic enzymes.The aim of this study was to investigate the influence of Sirt6 on cerebral function after chronic sleep deprivation(CSD).We assigned C57BL/6J mice to control or two CSD groups and subjected them to AAV2/9-CMV-EGFP or AAV2/9-CMV-Sirt6-EGFP infection in the prelimbic cortex(PrL).We then assessed cerebral functional connectivity(FC) using resting-state functional MRI,neuron/astrocyte metabolism using a metabolic kinetics analysis;dendritic spine densities using sparse-labeling;and miniature excitato ry postsynaptic currents(mEPSCs) and action potential(AP) firing rates using whole-cell patchclamp recordings.In addition,we evaluated cognition via a comprehensive set of behavioral tests.Compared with controls,Sirt6 was significantly decreased(P<0.05) in the PrL after CSD,accompanied by cognitive deficits and decreased FC between the PrL and accumbens nucleus,piriform cortex,motor co rtex,somatosensory co rtex,olfactory tubercle,insular cortex,and cerebellum.Sirt6 ove rexpression reve rsed CSD-induced cognitive impairment and reduced FC.Our analysis of metabolic kinetics using [1-13C] glucose and [2-13C] acetate showed that CSD reduced neuronal Glu4and GABA2synthesis,which could be fully restored via forced Sirt6 expression.Furthermore,Sirt6 ove rexpression reversed CSD-induced decreases in AP firing rates as well as the frequency and amplitude of mEPSCs in PrL pyramidal neurons.These data indicate that Sirt6 can improve cognitive impairment after CSD by regulating the PrL-associated FC network,neuronal glucose metabolism,and glutamatergic neurotransmission.Thus,Sirt6 activation may have potential as a novel strategy for treating sleep disorder-related diseases.
文摘Although the GABAA receptor(GABAAR)has been proposed as the main action site for sevoflurane,isoflurane,halothane,enflurane,propofol,and benzodiazepines(BZDs),binding of these anesthetics with high-resolution structures of the GABAAR have been rarely examined by comparative docking analyses.Moreover,various combinations of ligands on more GABAARs with various subtypes need to be analyzed to understand the elaborate action mechanism of GABAARs better because some GABAA ligands showed specificity toward the distinct subtypes of the GABAAR.Methods:We performed in silico docking analysis to compare the binding modes of sevoflurane,isoflurane,halothane,enflurane,propofol,and BZDs to the GABAAR based on one of the most recently provided 3D structures.We performed the docking analysis and the affinity-based ranking of the binding sites.Results:Our docking studies revealed that isoflurane,halothane,and enflurane docked in an extracellular domain(ECD)on GABAARs,in contrast to sevoflurane.Conclusion:Our results supported a multi-site mechanism for the allosteric modulation of propofol.Propofol was bound to the pore or favored various subsites in the transmembrane domain(TMD).Our result confirmed that different chemically related BZD ligands interact via distinct binding modes rather than by using a common binding mode,as previously suggested.
基金supported by National Key Basic Research Program of China(No.2017YFA0205301)Natural Science Foundation of China(31771081,81921002,and 8202010801)+2 种基金S&T Innovation 2025 Major Special Program of Ningbo(2018B10040)the Fundamental Research Funds for the Central Universities(22120210582)China Postdoctoral Science Foundation(2021TQ0247)。
文摘User-interactive electronic skin(e-skin) that could convert mechanical stimuli into distinguishable outputs displays tremendous potential for wearable devices and health care applications. However, the existing devices have the disadvantages such as complex integration procedure and lack of the intuitive signal display function. Here, we present a bioinspired user-interactive e-skin, which is simple in structure and can synchronously achieve digital electrical response and optical visualization upon external mechanical stimulus. The e-skin comprises a conductive layer with a carbon nanotubes/cellulose nanofibers/MXene nanohybrid network featuring remarkable electromechanical behaviors, and a stretchable elastomer layer, which is composed of silicone rubber and thermochromic pigments. Furthermore, the conductive nanohybrid network with outstanding Joule heating performance can generate controllable thermal energy under voltage input and then achieve the dynamic coloration of silicone-based elastomer. Especially, such an innovative fusion strategy of digital data and visual images enables the e-skin to monitor human activities with evermore intuition and accuracy. The simple design philosophy and reliable operation of the demonstrated e-skin are expected to provide an ideal platform for next-generation flexible electronics.
基金The present work was supported by a Croucher Innovation Award from the Croucher Foundation(to HK)a Faculty Innovation Award(FIA2017/B/01)from the Faculty of Medicine,the Chinese University of Hong Kong(CUHK)(to HK)+1 种基金the Gerald Choa Neuroscience Centre,the Margaret K.L.Cheung Research Centre for Parkinsonism Management,Faculty of Medicine,CUHK(to VCTM and HK)the Collaborative Research Fund(C6027-19GF)and the Area of Excellence Scheme(AoE/M-604/16)of the University Grants Committee of Hong Kong(to HK).
文摘Ageing is one of the greatest risk factors for neurodegenerative diseases.How the complex biological changes in ageing increase the brain’s susceptibility to neurodegeneration remains incompletely understood.Research into neurodegenerative disorders has shifted from a neuron-centric approach,to the contributing roles of age-related neurovascular and glial cell dysfunction.
基金supported by the National Key R&D Program of China(No.2022YFE0123500)the National Natural Science Foundation of China(Nos.52272304 and 31771081)Science and Technology Commission of Shanghai Municipality(Nos.21ZR1449700,22S31903300,and 22S31900100).
文摘Mineralization has found widespread use in the fabrication of composite biomaterials for hard tissue regeneration.The current mineralization processes are mainly carried out in neutral aqueous solutions of biomineral counter-ions(a pair of cation and anion that form the corresponding minerals at certain conditions),which are stable only at very low concentrations.This typically results in inefficient mineralization and weak control over biomineral formation.Here,we find that,in the organic solvent glycerol,a variety of biomineral counter-ions(e.g.,Ca/PO_(4),Ca/CO_(3),Ca/SO_(4),Mg/PO_(4),or Fe/OH)corresponding to distinct biominerals at significantly high concentrations(up to hundreds-fold greater than those of simulated body fluid(SBF))are able to form translucent and stable solutions(mineralizing solution of highly concentrated counter-ions(MSCIs)),and mineralization can be triggered upon them with external solvents(e.g.,water or ethanol).Furthermore,with pristine bacterial cellulose(BC)membrane as a model,we demonstrate an effective and controllable mineralization performance of MSCIs on organic substrates.This approach not only forms the homogeneous biominerals on the BC fibers and in the interspaces,but also provides regulations over mineralization rate,mineral content,phase,and dopants.The resulting mineralized BC membranes(MBCs)exhibit high cytocompatibility and favor the proliferation of rat bone marrow mesenchymal stem cells(rBMSC).Following this,we prepare a mineralized bone suture(MBS)from MBC for non-weight bearing bone fixation,which then is tested on a rabbit median sternotomy model.It shows firm fixation of the rabbit sternum without causing discernible toxicity or inflammatory response.This study,by extending the mineralization to the organic solution system of highly concentrated counter-ions,develops a promising strategy to design and build targeted mineral-based composites.
基金supported by the Natural Science Foundation of Liaoning Province (201602277)the Science and Technology Planning Project of Liaoning Province (LJQ2014091).
文摘Epidural spinal cord stimulation (ESCS) markedly improves motor and sensory function after spinal cord injury (SCI), but the underlying mechanisms are unclear.Here, we investigated whether ESCS affects oligodendrocyte differentiation and its cellular and molecular mechanisms in rats with SCI. ESCS improved hindlimb motor function at 7 days, 14 days, 21 days, and 28 days after SCI.ESCS also significantly increased the myelinated area at 28days, and reduced the number of apoptotic cells in the spinal white matter at 7 days. SCI decreased the expression of 20,30-cyclic-nucleotide 30-phosphodiesterase (CNPase,an oligodendrocyte marker) at 7 days and that of myelin basic protein at 28 days. ESCS significantly upregulated these markers and increased the percentage of Sox2/CNPase/DAPI-positive cells (newly differentiated oligodendrocytes) at 7 days. Recombinant human bone morphogenetic protein 4 (rh BMP4) markedly downregulated these factors after ESCS. Furthermore, ESCS significantly decreased BMP4 and p-Smad1/5/9 expression after SCI,and rh BMP4 reduced this effect of ESCS. These findings indicate that ESCS enhances the survival and differentiation of oligodendrocytes, protects myelin, and promotes motor functional recovery by inhibiting the BMP4-Smad1/5/9 signaling pathway after SCI.
基金support from the National Natural Science Foundation of China(31771081)the Science and Technology Commission of Shanghai Municipality(19441901900,19ZR1439700,19JC1414300)and S&T Innovation 2025 Major Special Programme of Ningbo(2018B10040)are gratefully acknowledged+1 种基金sponsored by Shanghai Pujiang Program(2020PJD045)supported by China Postdoctoral Science Foundation(2019M661630).
文摘The seek of bioactive materials for promoting bone regeneration is a challenging and longterm task.Functionalization with inorganic metal ions or drug molecules is considered effective strategies to improve the bioactivity of various existing biomaterials.Herein,amorphous calcium magnesium phosphate(ACMP)nanoparticles and simvastatin(SIM)-loaded ACMP(ACMP/SIM)nanocomposites were developed via a simple co-precipitation strategy.The physiochemical property of ACMP/SIM was explored using transmission electron microscope(TEM),Fourier transform infrared spectroscopy(FTIR),powder X-ray diffraction(XRD)and highperformance liquid chromatograph(HPLC),and the role of Mg^(2+) in the formation of ACMP/SIM was revealed using X-ray absorption near-edge structure(XANES).After that,the transformation process of ACMP/SIM in simulated body fluid(SBF)was also tracked to simulate and explore the in vivo mineralization performance of materials.We find that ACMP/SIM releases ions of Ca^(2+),Mg^(2+)and PO_(4)^(3),when it is immersed in SBF at 37℃,and a phase transformation occurred during which the initially amorphous ACMP turns into self-assembled hydroxyapatite(HAP).Furthermore,ACMP/SIM displays high cytocompatibility and promotes the proliferation and osteogenic differentiation of MC3T3-E1 cells.For the in vivo studies,lamellar ACMP/SIM/Collagen scaffolds with aligned pore structures were prepared and used to repair a rat defect model in calvaria.ACMP/SIM/Collagen scaffolds show a positive effect in promoting the regeneration of calvaria defect after 12weeks.The bioactive ACMP/SIM nanocomposites are promising as bone repair materials.Considering the facile preparation process and superior in vitro/vivo bioactivity,the as-prepared ACMP/SIM would be a potential candidate for bone related biomedical applications.