Treating bone defects complicated by bacterial infections remains a significant clinical challenge.Drawing inspiration from the human body's bone repair mechanisms,the use of biomimetic methods to design tissue en...Treating bone defects complicated by bacterial infections remains a significant clinical challenge.Drawing inspiration from the human body's bone repair mechanisms,the use of biomimetic methods to design tissue engineering scaffolds is of great significance for bone repair.This study synthesized copper(Cu)-doped mesoporous silica nanoparticles(Cu@MSN)modified with hydroxyethyl methacrylate to obtain methacrylated Cu@MSN(Cu@MSNMA).Furtheremore,bio-mimetic nanocomposite hydrogels were prepared by adding Cu@MSNMA to a GelMA/gelatin solution.This hydrogel achieves multi-modal bone tissue biomimicry:(ⅰ)GelMA/gelatin mimics the matrix components in bone ECM,ensuring biocompatibility while promoting cellular behavior(such as adhesion,proliferation,and differentiation);(ⅱ)GelMA/gela-tin and the crosslinking sites introduced by Cu@MSNMA form a stable porous network structure,achieving structural and mechanical biomimicry to provide necessary support for bone defects;(ⅲ)The elemental biomimicry of Si and Cu in Cu@MSNMA achieves efficient osteogenic induction.The effect of different proportions of Cu@MSNMA on the physi-cal properties of the composite hydrogels was investigated to determine the optimal proportion.The results indicated that the mechanical properties of hydrogel were enhanced with the increasing Cu@MSNMA mass ratio.Notably,5%NPs/GelMA/gelatin hydrogel exhibited excellent mechanical property compared to the GelMA/gelatin hydrogel.In vitro and vivo cellular experiments demonstrated a significant enhancement in antibacterial and osteogenic induction with Cu@MSNMA addition.In conclusion,the proposed nanocomposite hydrogel with biomimetic components and ion-regulating properties can serve as a multifunctional scaffold,offering antimicrobial properties for infected bone regeneration,and guide for future research in bone regeneration and three-dimensional printing.展开更多
PiT2 is an inorganic phosphate(Pi)transporter whose mutations are linked to primary familial brain calcification(PFBC).PiT2 mainly consists of two ProDom(PD)domains and a large intracellular loop region(loop7).The PD ...PiT2 is an inorganic phosphate(Pi)transporter whose mutations are linked to primary familial brain calcification(PFBC).PiT2 mainly consists of two ProDom(PD)domains and a large intracellular loop region(loop7).The PD domains are crucial for the Pi transport,but the role of PiT2-loop7 remains unclear.In PFBC patients,mutations in PiT2-loop7 are mainly nonsense or frameshift mutations that probably cause PFBC due to C-PD1131 deletion.To date,six missense mutations have been identified in PiT2-loop7;however,the mechanisms by which these mutations cause PFBC are poorly understood.Here,we found that the p.T390A and p.S434W mutations in PiT2-loop7 decreased the Pi transport activity and cell surface levels of PiT2.Furthermore,we showed that these two mutations attenuated its membrane localization by affecting adenosine monophosphate-activated protein kinase(AMPK)-or protein kinase B(AKT)-mediated PiT2 phosphorylation.In contrast,the p.S121C and p.S601W mutations in the PD domains did not affect PiT2 phosphorylation but rather impaired its substrate-binding abilities.These results suggested that missense mutations in PiT2-loop7 can cause Pi dyshomeostasis by affecting the phosphorylation-regulated cell-surface localization of PiT2.This study helps understand the pathogenesis of PFBC caused by PiT2-loop7 missense mutations and indicates that increasing the phosphorylation levels of PiT2-loop7 could be a promising strategy for developing PFBC therapies.展开更多
Essential tremor(ET)is a common neurological disease that is characterized by 4–12 Hz kinetic tremors of the upper limbs and high genetic heterogeneity.Although numerous candidate genes and loci have been reported,th...Essential tremor(ET)is a common neurological disease that is characterized by 4–12 Hz kinetic tremors of the upper limbs and high genetic heterogeneity.Although numerous candidate genes and loci have been reported,the etiology of ET remains unclear.A novel ET-related gene was initially identified in a five-generation family via whole-exome sequencing,and other variants were identified in 772 familial ET probands and 640 sporadic individuals via whole-genome sequencing.Among 71(9.18%)Chinese families and 47(7.34%)sporadic individuals with ET,we identified 15 types of protein-altering variants in solute carrier family 38 member 6(SLC38A6),which encodes sodium-coupled neutral amino acid transporter 6(SNAT6)and is inherited in an autosomal dominant pattern.Over-expression of mutant SNAT6 for the three most common human mutations(p.Y108F,p.M281T and p.G318S)significantly impaired L-arginine(L-Arg)uptake in HeLa cells.The homozygous Slc38a6 deletion mice(Slc38a6-/-)exhibited reduced L-Arg uptake in their cerebellar neurons,tremor,and cerebellar pathology.Slice electrophysiology revealed reduced neuronal Purkinje cell(PC)excitability and elevated inhibitory synaptic transmission in Slc38a6^(-/-)mice,in line with elevated“hairy”basket coverage around the PC soma.Furthermore,heterozygous Slc38a6 deletion(Slc38a6^(+/-))and PC-specific Slc38a6 deletion(Slc38a6^(PC-/-))mice also displayed tremor and PC abnormalities similar to those found in Slc38a6^(-/-)mice.These PCs displayed mitochondrial abnormalities and elevated ferroptosis markers(ACSL4,TFRC and Fe ions).In conclusion,we identified variants in SLC38A6 that contribute~8.35%to ET,generated mouse models displaying tremor,and delineated cerebellar cellular abnormalities and potential mechanisms underlying ET etiology.展开更多
In this work,we quantitatively studied the intertube coupling of different(n,m)-sorted semiconducting single-wall carbon nanotubes(SWCNTs)on their photoluminescence(PL)efficiencies by precisely tuning the ratio of(9,4...In this work,we quantitatively studied the intertube coupling of different(n,m)-sorted semiconducting single-wall carbon nanotubes(SWCNTs)on their photoluminescence(PL)efficiencies by precisely tuning the ratio of(9,4)and(6,5)SWCNTs in the mixture.A significant decrease in the PL intensity of(9,4)SWCNTs was observed after mixing with(6,5)species when fixing the(9,4)concentration,which was confirmed to be caused by the absorption of incident photons and reabsorption of the emitted photons by the added(6,5)species.By contrast,a similar decrease in the PL intensity of(6,5)SWCNTs was also observed after mixing with the larger-diameter(9,4)species.Different from that of(9,4)SWCNTs,the PL decrease of(6,5)SWCNTs was found to originate not only from photon absorption and reabsorption by the(9,4)species but also from one-way exciton energy transfer(EET)from the(6,5)SWCNTs to the larger-diameter(9,4)SWCNTs.Both the experimental results and numerical simulations further demonstrated that increasing the concentration of mixed(9,4)SWCNTs would enhance the effects of photon absorption and reabsorption and EET on the PL intensity of(6,5)SWCNTs quantified by the decrease ratio of the(6,5)PL intensity.Meanwhile,the influence of EET was found to be always weaker than that of photon absorption and reabsorption.We proposed that the observed EET between isolated SWCNTs in a surfactant solution is derived from their proximity due to Brownian motion.展开更多
基金National Key R&D Program of China(grant number 2022YFA1207500)National Natural Science Foundation of China(grant number 82072412).
文摘Treating bone defects complicated by bacterial infections remains a significant clinical challenge.Drawing inspiration from the human body's bone repair mechanisms,the use of biomimetic methods to design tissue engineering scaffolds is of great significance for bone repair.This study synthesized copper(Cu)-doped mesoporous silica nanoparticles(Cu@MSN)modified with hydroxyethyl methacrylate to obtain methacrylated Cu@MSN(Cu@MSNMA).Furtheremore,bio-mimetic nanocomposite hydrogels were prepared by adding Cu@MSNMA to a GelMA/gelatin solution.This hydrogel achieves multi-modal bone tissue biomimicry:(ⅰ)GelMA/gelatin mimics the matrix components in bone ECM,ensuring biocompatibility while promoting cellular behavior(such as adhesion,proliferation,and differentiation);(ⅱ)GelMA/gela-tin and the crosslinking sites introduced by Cu@MSNMA form a stable porous network structure,achieving structural and mechanical biomimicry to provide necessary support for bone defects;(ⅲ)The elemental biomimicry of Si and Cu in Cu@MSNMA achieves efficient osteogenic induction.The effect of different proportions of Cu@MSNMA on the physi-cal properties of the composite hydrogels was investigated to determine the optimal proportion.The results indicated that the mechanical properties of hydrogel were enhanced with the increasing Cu@MSNMA mass ratio.Notably,5%NPs/GelMA/gelatin hydrogel exhibited excellent mechanical property compared to the GelMA/gelatin hydrogel.In vitro and vivo cellular experiments demonstrated a significant enhancement in antibacterial and osteogenic induction with Cu@MSNMA addition.In conclusion,the proposed nanocomposite hydrogel with biomimetic components and ion-regulating properties can serve as a multifunctional scaffold,offering antimicrobial properties for infected bone regeneration,and guide for future research in bone regeneration and three-dimensional printing.
基金supported by the National Natural Science Foundation of China(31871262)a Shanghai Municipal Science and Technology Major Project(2018SHZDZX05).
文摘PiT2 is an inorganic phosphate(Pi)transporter whose mutations are linked to primary familial brain calcification(PFBC).PiT2 mainly consists of two ProDom(PD)domains and a large intracellular loop region(loop7).The PD domains are crucial for the Pi transport,but the role of PiT2-loop7 remains unclear.In PFBC patients,mutations in PiT2-loop7 are mainly nonsense or frameshift mutations that probably cause PFBC due to C-PD1131 deletion.To date,six missense mutations have been identified in PiT2-loop7;however,the mechanisms by which these mutations cause PFBC are poorly understood.Here,we found that the p.T390A and p.S434W mutations in PiT2-loop7 decreased the Pi transport activity and cell surface levels of PiT2.Furthermore,we showed that these two mutations attenuated its membrane localization by affecting adenosine monophosphate-activated protein kinase(AMPK)-or protein kinase B(AKT)-mediated PiT2 phosphorylation.In contrast,the p.S121C and p.S601W mutations in the PD domains did not affect PiT2 phosphorylation but rather impaired its substrate-binding abilities.These results suggested that missense mutations in PiT2-loop7 can cause Pi dyshomeostasis by affecting the phosphorylation-regulated cell-surface localization of PiT2.This study helps understand the pathogenesis of PFBC caused by PiT2-loop7 missense mutations and indicates that increasing the phosphorylation levels of PiT2-loop7 could be a promising strategy for developing PFBC therapies.
基金supported by the Natural Science Foundation of China(Grants U20A20355 and 32270663)the China Postdoctoral Science Foundation(Grant 2024M762007 and Postdoctoral Fellowship Program Grade B GZB20240453)the Shanghai Municipal Science and Technology Major Project(2018SHZDZX05).
文摘Essential tremor(ET)is a common neurological disease that is characterized by 4–12 Hz kinetic tremors of the upper limbs and high genetic heterogeneity.Although numerous candidate genes and loci have been reported,the etiology of ET remains unclear.A novel ET-related gene was initially identified in a five-generation family via whole-exome sequencing,and other variants were identified in 772 familial ET probands and 640 sporadic individuals via whole-genome sequencing.Among 71(9.18%)Chinese families and 47(7.34%)sporadic individuals with ET,we identified 15 types of protein-altering variants in solute carrier family 38 member 6(SLC38A6),which encodes sodium-coupled neutral amino acid transporter 6(SNAT6)and is inherited in an autosomal dominant pattern.Over-expression of mutant SNAT6 for the three most common human mutations(p.Y108F,p.M281T and p.G318S)significantly impaired L-arginine(L-Arg)uptake in HeLa cells.The homozygous Slc38a6 deletion mice(Slc38a6-/-)exhibited reduced L-Arg uptake in their cerebellar neurons,tremor,and cerebellar pathology.Slice electrophysiology revealed reduced neuronal Purkinje cell(PC)excitability and elevated inhibitory synaptic transmission in Slc38a6^(-/-)mice,in line with elevated“hairy”basket coverage around the PC soma.Furthermore,heterozygous Slc38a6 deletion(Slc38a6^(+/-))and PC-specific Slc38a6 deletion(Slc38a6^(PC-/-))mice also displayed tremor and PC abnormalities similar to those found in Slc38a6^(-/-)mice.These PCs displayed mitochondrial abnormalities and elevated ferroptosis markers(ACSL4,TFRC and Fe ions).In conclusion,we identified variants in SLC38A6 that contribute~8.35%to ET,generated mouse models displaying tremor,and delineated cerebellar cellular abnormalities and potential mechanisms underlying ET etiology.
基金This work is financially supported by the National Key R&D Program of China(No.2018YFA0208402)the National Natural Science Foundation of China(Nos.51820105002,11634014,,51872320)+1 种基金the Youth Innovation Promotion Association of CAS(No.2020005)the Key Research Program of Frontier Sciences,CAS(No.QYZDBSSW-SYS028).
文摘In this work,we quantitatively studied the intertube coupling of different(n,m)-sorted semiconducting single-wall carbon nanotubes(SWCNTs)on their photoluminescence(PL)efficiencies by precisely tuning the ratio of(9,4)and(6,5)SWCNTs in the mixture.A significant decrease in the PL intensity of(9,4)SWCNTs was observed after mixing with(6,5)species when fixing the(9,4)concentration,which was confirmed to be caused by the absorption of incident photons and reabsorption of the emitted photons by the added(6,5)species.By contrast,a similar decrease in the PL intensity of(6,5)SWCNTs was also observed after mixing with the larger-diameter(9,4)species.Different from that of(9,4)SWCNTs,the PL decrease of(6,5)SWCNTs was found to originate not only from photon absorption and reabsorption by the(9,4)species but also from one-way exciton energy transfer(EET)from the(6,5)SWCNTs to the larger-diameter(9,4)SWCNTs.Both the experimental results and numerical simulations further demonstrated that increasing the concentration of mixed(9,4)SWCNTs would enhance the effects of photon absorption and reabsorption and EET on the PL intensity of(6,5)SWCNTs quantified by the decrease ratio of the(6,5)PL intensity.Meanwhile,the influence of EET was found to be always weaker than that of photon absorption and reabsorption.We proposed that the observed EET between isolated SWCNTs in a surfactant solution is derived from their proximity due to Brownian motion.
