Osteosarcoma(OS)is the most common primary malignant pediatric bone tumor and is characterized by high heterogeneity.Studies have revealed a wide range of phenotypic differences among OS cell lines in terms of their i...Osteosarcoma(OS)is the most common primary malignant pediatric bone tumor and is characterized by high heterogeneity.Studies have revealed a wide range of phenotypic differences among OS cell lines in terms of their in vivo tumorigenicity and in vitro colony-forming abilities.However,the underlying molecular mechanism of these discrepancies remains unclear.The potential role of mechanotransduction in tumorigenicity is of particular interest.To this end,we tested the tumorigenicity and anoikis resistance of OS cell lines both in vitro and in vivo.We utilized a sphere culture model,a soft agar assay,and soft and rigid hydrogel surface culture models to investigate the function of rigidity sensing in the tumorigenicity of OS cells.Additionally,we quantified the expression of sensor proteins,including four kinases and seven cytoskeletal proteins,in OS cell lines.The upstream core transcription factors of rigidity-sensing proteins were further investigated.We detected anoikis resistance in transformed OS cells.The mechanosensing function of transformed OS cells was also impaired,with general downregulation of rigidity-sensing components.We identified toggling between normal and transformed growth based on the expression pattern of rigidity-sensing proteins in OS cells.We further uncovered a novel TP53 mutation(R156P)in transformed OS cells,which acquired gain of function to inhibit rigidity sensing,thus sustaining transformed growth.Our findings suggest a fundamental role of rigidity-sensing components in OS tumorigenicity as mechanotransduction elements through which cells can sense their physical microenvironment.In addition,the gain of function of mutant TP53 appears to serve as an executor for such malignant programs.展开更多
Background:Ischemic injury is a primary cause of distal flap necrosis.Previous studies have shown that Flufenamic acid(FFA)can reduce inflammation,decrease oxidative stress(OS),and promote angiogenesis,suggesting its ...Background:Ischemic injury is a primary cause of distal flap necrosis.Previous studies have shown that Flufenamic acid(FFA)can reduce inflammation,decrease oxidative stress(OS),and promote angiogenesis,suggesting its potential role in protecting flaps from ischemic damage.This study investigated the effects and mechanisms of FFA in enhancing the survival of ischemic flaps.Methods:The viability of ischemic flaps was evaluated using laser doppler blood flow(LDBF)and survival rates.We examined levels of pyroptosis,OS,transcription factor E3(TFE3)-induced autophagy,and elements of the AMPK-TRPML1-Calcineurin pathway through western blotting(WB),immunofluorescence,molecular docking,cellular thermal shift assay(CETSA)and surface plasmon resonance.Results:The findings suggest that FFA significantly enhances the viability of ischemic flaps.The improvement in flap survival associated with FFA can be attributed to increased autophagy,diminished OS,and the suppression of pyroptosis.Notably,the promotion of autophagy flux and an augmented resistance to OS are instrumental in curbing pyroptosis in these flaps.Activation of TFE3 by FFA promoted autophagy and diminished oxidative damage.The therapeutic effects of FFA were negated when TFE3 levels were decreased using adeno-associated virus(AAV)-TFE3shRNA.Additionally,FFA modified TFE3 activity through the AMPK-TRPML1-Calcineurin pathway.Conclusions:FFA promotes ischemic flap survival via induction of autophagy and suppression of OS by activation of the AMPK-TRPML1-Calcineurin-TFE3 signaling pathway.These findings could have therapeutic implications.展开更多
Exosomes are small intracellular membrane-based vesicles with different compositions that are involved in several biological and pathological processes. The exploitation of exosomes as drug delivery vehicles offers im...Exosomes are small intracellular membrane-based vesicles with different compositions that are involved in several biological and pathological processes. The exploitation of exosomes as drug delivery vehicles offers important advantages compared to other nanoparticulate drug delivery systems such as liposomes and polymeric nanoparticles; exosomes are non-immunogenic in nature due to similar composition as body's own cells. In this article, the origin and structure of exosomes as well as their biological functions are outlined. We will then focus on specific applications of exosomes as drug delivery systems in pharmaceutical drug development. An overview of the advantages and challenges faced when using exosomes as a pharmaceutical drug delivery vehicles will also be discussed.展开更多
Graphene resting on a silicon-on-insulator platform offers great potential for optoelectronic devices.In the paper,we demonstrate all-optical modulation on the graphene-silicon hybrid waveguides(GSHWs)with tens of mic...Graphene resting on a silicon-on-insulator platform offers great potential for optoelectronic devices.In the paper,we demonstrate all-optical modulation on the graphene-silicon hybrid waveguides(GSHWs)with tens of micrometers in length.Owing to strong interaction between graphene and silicon strip waveguides with compact light confinement,the modulation depth reaches 22.7%with a saturation threshold down to 1.38 pJ per pulse and a 30-μm-long graphene pad.A response time of 1.65 ps is verified by a pump-probe measurement with an energy consumption of 2.1 pJ.The complementary metal-oxide semiconductor compatible GSHWs with the strip configuration exhibit great potential for ultrafast and broadband all-optical modulation,indicating that employing two-dimensional materials has become a complementary technology to promote the silicon photonic platform.展开更多
Bloch oscillations(BOs)were initially predicted for electrons in a solid lattice to which a static electric field is applied.The observation of BOs in solids remains challenging due to the collision scattering and bar...Bloch oscillations(BOs)were initially predicted for electrons in a solid lattice to which a static electric field is applied.The observation of BOs in solids remains challenging due to the collision scattering and barrier tunnelling of electrons.Nevertheless,analogies of electron BOs for photons,acoustic phonons and cold atoms have been experimentally demonstrated in various lattice systems.Recently,BOs in the frequency dimension have been proposed and studied by using an optical micro-resonator,which provides a unique approach to controlling the light frequency.However,the finite resonator lifetime and intrinsic loss hinder the effect from being observed practically.Here,we experimentally demonstrate BOs in a synthetic frequency lattice by employing a fibre-loop circuit with detuned phase modulation.We show that a detuning between the modulation period and the fibre-loop roundtrip time acts as an effective vector potential and hence a constant effective force that can yield BOs in the modulation-induced frequency lattices.With a dispersive Fourier transformation,the pulse spectrum can be mapped into the time dimension,and its transient evolution can be precisely measured.This study offers a promising approach to realising BOs in synthetic dimensions and may find applications in frequency manipulations in optical fibre communication systems.展开更多
Some fungal accessory chromosomes(ACs)may contribute to virulence in plants.However,the mecha-nisms by which ACs determine specific traits associated with lifestyle transitions along a symbiotic contin-uum are not cle...Some fungal accessory chromosomes(ACs)may contribute to virulence in plants.However,the mecha-nisms by which ACs determine specific traits associated with lifestyle transitions along a symbiotic contin-uum are not clear.Here we delineated the genetic divergence in two sympatric but considerably variable isolates(16B and 16W)of the poplar-associated fungus Stagonosporopsis rhizophilae.We identified a-0.6-Mb horizontally acquired AC in 16W that resulted in a mildly parasitic lifestyle in plants.Complete deletion of the AC(D16W)significantly altered the fungal phenotype.Specifically,D16W was morphologically more similar to 16B,showed enhanced melanization,and established beneficial interactions with poplar plants,thereby acting as a dark septate endophyte.RNA sequencing(RNA-seq)analysis showed that AC loss induced the upregulation of genes related to root colonization and biosynthesis of indole acetic acid and melanin.We observed that the AC maintained a more open status of chromatin across the genome,indicating an impressive remodeling of cis-regulatory elements upon AC loss,which potentially enhanced symbiotic effectiveness.We demonstrated that the symbiotic capacities were non-host-specific through comparable experiments on Triticum–and Arabidopsis–fungus associations.Furthermore,the three isolates generated symbiotic interactions with a nonvascular liverwort.In summary,our study suggests that the AC is a suppressor of symbiosis and provides insights into the underlying mechanisms of mutualism with vascular plants in the absence of traits encoded by the AC.We speculate that AC-situ-ated effectors and other potential secreted molecules may have evolved to specifically target vascular plants and promote mild virulence.展开更多
Background:Ensuring the survival of the distal end of a random flap during hypoperfusion(ischaemia)is difficult in clinical practice.Effective prevention of programmed cell death is a potential strategy for inhibiting...Background:Ensuring the survival of the distal end of a random flap during hypoperfusion(ischaemia)is difficult in clinical practice.Effective prevention of programmed cell death is a potential strategy for inhibiting ischaemic flap necrosis.The activation of stimulator of interferon genes(STING)pathway promotes inflammation and leads to cell death.The epidermal growth factor family member neuregulin-1(NRG1)reduces cell death by activating the protein kinase B(AKT)signalling pathway.Moreover,AKT signalling negatively regulates STING activity.We aimed to verify the efficacy of NRG1 injection in protecting against flap necrosis.Additionally,we investigated whether NRG1 effectively enhances ischemic flap survival by inhibiting pyroptosis and necroptosis through STING suppression.Methods:A random-pattern skin flap model was generated on the backs of C57BL/6 mice.The skin flap survival area was determined.The blood supply and vascular network of the flap was assessed by laser Doppler blood flow analysis.Cluster of differentiation 34 immunohistochemistry(IHC)and haematoxylin and eosin(H&E)staining of the flap sections revealed microvessels.Transcriptome sequencing analysis revealed the mechanism by which NRG1 promotes the survival of ischaemic flaps.The levels of angiogenesis,oxidative stress,necroptosis,pyroptosis and indicators associated with signalling pathways in flaps were examined by IHC,immunofluorescence and Western blotting.Packaging adenoassociated virus(AAV)was used to activate STING in flaps.Results:NRG1 promoted the survival of ischaemic flaps.An increased subcutaneous vascular network and neovascularization were found in ischaemic flaps after the application of NRG1.Transcriptomic gene ontology enrichment analysis and protein level detection indicated that necroptosis,pyroptosis and STING activity were reduced in the NRG1 group.The phosphorylation of AKT and forkhead box O3a(FOXO3a)were increased after NRG1 treatment.The increased expression of STING in flaps induced by AAV reversed the therapeutic effect of NRG1.The ability of NRG1 to phosphorylate AKT-FOXO3a,inhibit STING and promote flap survival was abolished after the application of the AKT inhibitor MK2206.Conclusions:NRG1 inhibits pyroptosis and necroptosis by activating the AKT-FOXO3a signalling pathway to suppress STING activation and promote ischaemic flap survival.展开更多
On-chip ultrafast mode-locking lasers are basic building blocks for the realization of a chip-based optical frequency comb.In this paper,an ultrafast saturable absorber made up of a graphene pad on top of a silicon wa...On-chip ultrafast mode-locking lasers are basic building blocks for the realization of a chip-based optical frequency comb.In this paper,an ultrafast saturable absorber made up of a graphene pad on top of a silicon waveguide is applied to implement an ultrafast pulse laser.Benefiting from the small mode area of the graphene/silicon hybrid waveguide,the saturable pulse energy is reduced by two orders of magnitude compared with the fiber.A mode-locked pulse with a duration of 542 fs and a repetition rate of 54.37 MHz is realized.Pump–probe measurement shows that the carrier relaxation process of free carrier recombination with atomic-thin graphene/silicon junctions is three orders of magnitude faster than silicon,which plays a fundamental role in pulse narrowing.The chip-scale silicon ultrafast laser lays a foundation for a new class of nonlinear devices,in which a combination with multiple functional silicon photonic circuits enables efficient nonlinear interaction at the micrometer scale and less than 1 W of power consumption.展开更多
基金sponsored by the National Natural Science Foundation of China(82202767)。
文摘Osteosarcoma(OS)is the most common primary malignant pediatric bone tumor and is characterized by high heterogeneity.Studies have revealed a wide range of phenotypic differences among OS cell lines in terms of their in vivo tumorigenicity and in vitro colony-forming abilities.However,the underlying molecular mechanism of these discrepancies remains unclear.The potential role of mechanotransduction in tumorigenicity is of particular interest.To this end,we tested the tumorigenicity and anoikis resistance of OS cell lines both in vitro and in vivo.We utilized a sphere culture model,a soft agar assay,and soft and rigid hydrogel surface culture models to investigate the function of rigidity sensing in the tumorigenicity of OS cells.Additionally,we quantified the expression of sensor proteins,including four kinases and seven cytoskeletal proteins,in OS cell lines.The upstream core transcription factors of rigidity-sensing proteins were further investigated.We detected anoikis resistance in transformed OS cells.The mechanosensing function of transformed OS cells was also impaired,with general downregulation of rigidity-sensing components.We identified toggling between normal and transformed growth based on the expression pattern of rigidity-sensing proteins in OS cells.We further uncovered a novel TP53 mutation(R156P)in transformed OS cells,which acquired gain of function to inhibit rigidity sensing,thus sustaining transformed growth.Our findings suggest a fundamental role of rigidity-sensing components in OS tumorigenicity as mechanotransduction elements through which cells can sense their physical microenvironment.In addition,the gain of function of mutant TP53 appears to serve as an executor for such malignant programs.
基金Public Welfare Technology Research Project of Zhejiang Province(No.LY24H110002).
文摘Background:Ischemic injury is a primary cause of distal flap necrosis.Previous studies have shown that Flufenamic acid(FFA)can reduce inflammation,decrease oxidative stress(OS),and promote angiogenesis,suggesting its potential role in protecting flaps from ischemic damage.This study investigated the effects and mechanisms of FFA in enhancing the survival of ischemic flaps.Methods:The viability of ischemic flaps was evaluated using laser doppler blood flow(LDBF)and survival rates.We examined levels of pyroptosis,OS,transcription factor E3(TFE3)-induced autophagy,and elements of the AMPK-TRPML1-Calcineurin pathway through western blotting(WB),immunofluorescence,molecular docking,cellular thermal shift assay(CETSA)and surface plasmon resonance.Results:The findings suggest that FFA significantly enhances the viability of ischemic flaps.The improvement in flap survival associated with FFA can be attributed to increased autophagy,diminished OS,and the suppression of pyroptosis.Notably,the promotion of autophagy flux and an augmented resistance to OS are instrumental in curbing pyroptosis in these flaps.Activation of TFE3 by FFA promoted autophagy and diminished oxidative damage.The therapeutic effects of FFA were negated when TFE3 levels were decreased using adeno-associated virus(AAV)-TFE3shRNA.Additionally,FFA modified TFE3 activity through the AMPK-TRPML1-Calcineurin pathway.Conclusions:FFA promotes ischemic flap survival via induction of autophagy and suppression of OS by activation of the AMPK-TRPML1-Calcineurin-TFE3 signaling pathway.These findings could have therapeutic implications.
文摘Exosomes are small intracellular membrane-based vesicles with different compositions that are involved in several biological and pathological processes. The exploitation of exosomes as drug delivery vehicles offers important advantages compared to other nanoparticulate drug delivery systems such as liposomes and polymeric nanoparticles; exosomes are non-immunogenic in nature due to similar composition as body's own cells. In this article, the origin and structure of exosomes as well as their biological functions are outlined. We will then focus on specific applications of exosomes as drug delivery systems in pharmaceutical drug development. An overview of the advantages and challenges faced when using exosomes as a pharmaceutical drug delivery vehicles will also be discussed.
基金National Natural Science Foundation of China(61775075)State Key Laboratory of Advanced Optical Communication Systems and Networks,Shanghai Jiao Tong University,China(2019GZKF03005)。
文摘Graphene resting on a silicon-on-insulator platform offers great potential for optoelectronic devices.In the paper,we demonstrate all-optical modulation on the graphene-silicon hybrid waveguides(GSHWs)with tens of micrometers in length.Owing to strong interaction between graphene and silicon strip waveguides with compact light confinement,the modulation depth reaches 22.7%with a saturation threshold down to 1.38 pJ per pulse and a 30-μm-long graphene pad.A response time of 1.65 ps is verified by a pump-probe measurement with an energy consumption of 2.1 pJ.The complementary metal-oxide semiconductor compatible GSHWs with the strip configuration exhibit great potential for ultrafast and broadband all-optical modulation,indicating that employing two-dimensional materials has become a complementary technology to promote the silicon photonic platform.
基金This work was supported by the National Natural Science Foundation of China(11974124,11947209,12021004,11674117)National Postdoctoral Program for Innovative Talent(BX20190129)Chinese Postdoctoral Science Foundation General Program(Grant 2019M660180).
文摘Bloch oscillations(BOs)were initially predicted for electrons in a solid lattice to which a static electric field is applied.The observation of BOs in solids remains challenging due to the collision scattering and barrier tunnelling of electrons.Nevertheless,analogies of electron BOs for photons,acoustic phonons and cold atoms have been experimentally demonstrated in various lattice systems.Recently,BOs in the frequency dimension have been proposed and studied by using an optical micro-resonator,which provides a unique approach to controlling the light frequency.However,the finite resonator lifetime and intrinsic loss hinder the effect from being observed practically.Here,we experimentally demonstrate BOs in a synthetic frequency lattice by employing a fibre-loop circuit with detuned phase modulation.We show that a detuning between the modulation period and the fibre-loop roundtrip time acts as an effective vector potential and hence a constant effective force that can yield BOs in the modulation-induced frequency lattices.With a dispersive Fourier transformation,the pulse spectrum can be mapped into the time dimension,and its transient evolution can be precisely measured.This study offers a promising approach to realising BOs in synthetic dimensions and may find applications in frequency manipulations in optical fibre communication systems.
基金supported by the National Key Research and Development Program of China (2022YFD2201900)the National Natural Science Foundation of China (no.31722014).
文摘Some fungal accessory chromosomes(ACs)may contribute to virulence in plants.However,the mecha-nisms by which ACs determine specific traits associated with lifestyle transitions along a symbiotic contin-uum are not clear.Here we delineated the genetic divergence in two sympatric but considerably variable isolates(16B and 16W)of the poplar-associated fungus Stagonosporopsis rhizophilae.We identified a-0.6-Mb horizontally acquired AC in 16W that resulted in a mildly parasitic lifestyle in plants.Complete deletion of the AC(D16W)significantly altered the fungal phenotype.Specifically,D16W was morphologically more similar to 16B,showed enhanced melanization,and established beneficial interactions with poplar plants,thereby acting as a dark septate endophyte.RNA sequencing(RNA-seq)analysis showed that AC loss induced the upregulation of genes related to root colonization and biosynthesis of indole acetic acid and melanin.We observed that the AC maintained a more open status of chromatin across the genome,indicating an impressive remodeling of cis-regulatory elements upon AC loss,which potentially enhanced symbiotic effectiveness.We demonstrated that the symbiotic capacities were non-host-specific through comparable experiments on Triticum–and Arabidopsis–fungus associations.Furthermore,the three isolates generated symbiotic interactions with a nonvascular liverwort.In summary,our study suggests that the AC is a suppressor of symbiosis and provides insights into the underlying mechanisms of mutualism with vascular plants in the absence of traits encoded by the AC.We speculate that AC-situ-ated effectors and other potential secreted molecules may have evolved to specifically target vascular plants and promote mild virulence.
基金supported by the Natural Science Foundation of China[82372540,82072192,81801930,81873942]Wenzhou Science and Technology Bureau Foundation[Y20210438,Y2023475]+3 种基金Public Welfare Technology Research Project of Zhejiang Province[LGF20H150003LQ23H090006]Basic Public Welfare Research Project of Zhejiang Province[No.LY19H060003]Medical Health Science and Technology Project of Zhejiang Province[No.2020KY183].
文摘Background:Ensuring the survival of the distal end of a random flap during hypoperfusion(ischaemia)is difficult in clinical practice.Effective prevention of programmed cell death is a potential strategy for inhibiting ischaemic flap necrosis.The activation of stimulator of interferon genes(STING)pathway promotes inflammation and leads to cell death.The epidermal growth factor family member neuregulin-1(NRG1)reduces cell death by activating the protein kinase B(AKT)signalling pathway.Moreover,AKT signalling negatively regulates STING activity.We aimed to verify the efficacy of NRG1 injection in protecting against flap necrosis.Additionally,we investigated whether NRG1 effectively enhances ischemic flap survival by inhibiting pyroptosis and necroptosis through STING suppression.Methods:A random-pattern skin flap model was generated on the backs of C57BL/6 mice.The skin flap survival area was determined.The blood supply and vascular network of the flap was assessed by laser Doppler blood flow analysis.Cluster of differentiation 34 immunohistochemistry(IHC)and haematoxylin and eosin(H&E)staining of the flap sections revealed microvessels.Transcriptome sequencing analysis revealed the mechanism by which NRG1 promotes the survival of ischaemic flaps.The levels of angiogenesis,oxidative stress,necroptosis,pyroptosis and indicators associated with signalling pathways in flaps were examined by IHC,immunofluorescence and Western blotting.Packaging adenoassociated virus(AAV)was used to activate STING in flaps.Results:NRG1 promoted the survival of ischaemic flaps.An increased subcutaneous vascular network and neovascularization were found in ischaemic flaps after the application of NRG1.Transcriptomic gene ontology enrichment analysis and protein level detection indicated that necroptosis,pyroptosis and STING activity were reduced in the NRG1 group.The phosphorylation of AKT and forkhead box O3a(FOXO3a)were increased after NRG1 treatment.The increased expression of STING in flaps induced by AAV reversed the therapeutic effect of NRG1.The ability of NRG1 to phosphorylate AKT-FOXO3a,inhibit STING and promote flap survival was abolished after the application of the AKT inhibitor MK2206.Conclusions:NRG1 inhibits pyroptosis and necroptosis by activating the AKT-FOXO3a signalling pathway to suppress STING activation and promote ischaemic flap survival.
基金National Natural Science Foundation of China(61775075).
文摘On-chip ultrafast mode-locking lasers are basic building blocks for the realization of a chip-based optical frequency comb.In this paper,an ultrafast saturable absorber made up of a graphene pad on top of a silicon waveguide is applied to implement an ultrafast pulse laser.Benefiting from the small mode area of the graphene/silicon hybrid waveguide,the saturable pulse energy is reduced by two orders of magnitude compared with the fiber.A mode-locked pulse with a duration of 542 fs and a repetition rate of 54.37 MHz is realized.Pump–probe measurement shows that the carrier relaxation process of free carrier recombination with atomic-thin graphene/silicon junctions is three orders of magnitude faster than silicon,which plays a fundamental role in pulse narrowing.The chip-scale silicon ultrafast laser lays a foundation for a new class of nonlinear devices,in which a combination with multiple functional silicon photonic circuits enables efficient nonlinear interaction at the micrometer scale and less than 1 W of power consumption.
