Background:The development of relevant and robust large animal models of hepatocellular carcinoma is needed to test new therapeutic strategies for this disease.Transgenic approaches hold promise in addressing this com...Background:The development of relevant and robust large animal models of hepatocellular carcinoma is needed to test new therapeutic strategies for this disease.Transgenic approaches hold promise in addressing this complex problem.One such model,the Oncopig,has been reported to develop tumors of up to 4 cm in diameter within 7-14 days at sites of in situ vector inoculation.However,the resulting lesions reportedly contained an extensive inflammatory component that has not been evaluated in detail.Methods:Herein,we describe our results from multiparametric characterization of the lesions generated using liver biopsy cores incubated in vector solution and re-placed in the tissue.The study consisted of 3 animals in 3 cohorts(total of 9 animals)that were evaluated at 14,21,and 28 days.CT imaging,immunohistochemistry,multiplex immunofluorescence,and comprehensive blood analyses were used to quantify composition of the hepatic masses that developed following AdCre inoculation.Results:The tumors were hypovascular on CT and predominantly composed of CD45+cells with a strong lymphohistiocytic component,with no carcinomas identified.Ki-67 staining showed proliferation of CD45+immune cells but no neoplastic component.To provide further insight,the results are evaluated in the context of tumor growth kinetics.Conclusion:While progress has been made in generating targetable lesions,achieving a robust large animal model of liver cancer that faithfully recapitulates the human disease remains a challenging goal.展开更多
FL-Online(http://fanlab.ac.cn) is an out-of-box modern web service featuring a user-friendly interface and simplified parameters, providing academic users with access to a series of online programs for biomolecular cr...FL-Online(http://fanlab.ac.cn) is an out-of-box modern web service featuring a user-friendly interface and simplified parameters, providing academic users with access to a series of online programs for biomolecular crystallography, including SAPI-online, OASIS-online, C-IPCAS-online and a series of upcoming software releases. Meanwhile, it is a highly scalable and maintainable web application framework that provides a powerful and flexible solution for academic web development needs. All the codes are open-source under MIT licenses in GitHub.展开更多
Background Atg9-containing vesicles are enriched in synapses and undergo cycles of exo-and endocytosis similarly to synaptic vesicles,thereby linking presynaptic autophagy to neuronal activity.Dysfunction of presynapt...Background Atg9-containing vesicles are enriched in synapses and undergo cycles of exo-and endocytosis similarly to synaptic vesicles,thereby linking presynaptic autophagy to neuronal activity.Dysfunction of presynaptic autophagy is a pathophysiological mechanism in motoneuron disease(MND),which leads to impaired synaptic integrity and function.Here,we asked whether boosting neuronal activity by physical exercise modulates the cellular and motor phenotypes of Plekhg5-deficient mice,an MND model with defective presynaptic autophagy.Methods To characterize the vesicle accumulations in Plekhg5-deficient mice,we performed immunohistochemical staining,electron microscopy,and super-resolution imaging.Following voluntary running wheel exercise,we quantified the histopathological changes within the spinal cord and at neuromuscular junctions using an unbiased machine-learning approach.Additionally,we analyzed the motor performance of the animals by measuring their grip strength.To assess changes in the autophagic flux upon physical exercise in vivo,we utilized mRFP-GFP-LC3 expressing mice.The presence of Atg9-containing vesicle clusters in SOD1G93A was analyzed to examine the relevance of this pathological feature in a second MND model.Results We found marked accumulations of Atg9-containing vesicles at presynaptic sites of Plekhg5-deficient mice,which could be cleared by four weeks of voluntary running wheel exercise in young but surprisingly not in aged Plekhg5-deficient mice.However,physical exercise in aged mice led to synaptic vesicle sorting into the Atg9-containing vesicle accumulations without their removal.In line with these findings,short-term voluntary exercise triggered motoneuron autophagy in young but not old mice.Pointing to a broader role of Atg9-containing vesicles in the pathophysiology of MND,we also found Atg9-containing vesicle accumulations in SOD1G93A mice,a well-established ALS model.Strikingly,physical exercise in presymptomatic SOD1G93A mice resulted in a reduction of the vesicle accumulations.Conclusions Our data highlight the essential role of Atg9 in presynaptic autophagy and suggest that boosting autophagy by physical exercise provides a tool to maintain presynaptic function at the early but not late stages of Plekhg5-associated MND and possibly amyotrophic lateral sclerosis.展开更多
Matrix metalloproteinases(MMPs),coupled with other proteinases and glycanases,can degrade proteoglycans,collagens,and other extracellular matrix(ECM)components in inflammatory and non-inflammatory arthritis,making the...Matrix metalloproteinases(MMPs),coupled with other proteinases and glycanases,can degrade proteoglycans,collagens,and other extracellular matrix(ECM)components in inflammatory and non-inflammatory arthritis,making them important pathogenic molecules and ideal disease indicators and pharmaceutical intervention triggers.For MMP responsiveness,MMP-sensitive peptides(MSPs)are among the most easily synthesized and cost-effective substrates,with free ter-minal amine and/or carboxyl groups extensively employed in multiple designs.We hereby provide a comprehensive review over the mechanisms and advances in MSP applications for the management of arthritis.These applications include early and precise diagnosis of MMP activity via fluorescence probe technologies;acting as nanodrug carriers to enable on-demand drug release triggered by pathological microenvironments;and facilitating cartilage engineering through MMP-mediated degradation,which promotes cell migration,matrix synthesis,and tissue integration.Specifically,the ultra-sensitive MSP diagnostic probes could significantly advance the early diagnosis and detection of osteoarthritis(OA),while MSP-based drug carriers for rheumatoid arthritis(RA)can intelligently release antiinflammatory drugs effectively during flare-ups,or even before symptoms manifest.The continuous progress in MSP development may acceleratedly lead to novel management regimens for arthropathy in the future.展开更多
Perovskite photovoltaics upholds the most prominent position in the field of tandem technology development.In this aspect,the creation of perovskite material with suitable bandgap(≥1.65 eV)is necessary.And in order t...Perovskite photovoltaics upholds the most prominent position in the field of tandem technology development.In this aspect,the creation of perovskite material with suitable bandgap(≥1.65 eV)is necessary.And in order to achieve the best device characteristics,the high-quality film formation is crucial.To get a high-quality film,the solvent engineering approach stays at the forefront.However,although the solvent engineering was well discussed for such conventional material as MAPbI_(3),the field of wide bandgap perovskite materials is still lacking in this area.This paper presents the solvent engineering approach to improve the efficiency and stability of the conventional wide bandgap perovskite material Cs_(0.17)FA_(0.83)PbI_(1.8)Br_(1.2).Here we utilize several solvents such as traditional N,N-dimethylformamide,dimethyl sulfoxide,N-methyl-2-pyrrolidone and acetonitrile.It was demonstrated that implication of any binary DMF-X solvent improves the solar cell efficiency compared to the pure DMF solution,but the ratio of the X solvent is unique for every X and the foundation for the X influence is also unique.The addition of 2.4 M of DMSO is considered the best to improve the stability and efficiency of laboratory devices,however implementation of AcN allowed to produce 25 cm^(2)mini-modules with the PCE reaching 10%.展开更多
Primary cilia are microtubule-based cell organelles important for cellular communication. Since they are involved in the regulation of numerous signalling pathways, defects in cilia development or function are associa...Primary cilia are microtubule-based cell organelles important for cellular communication. Since they are involved in the regulation of numerous signalling pathways, defects in cilia development or function are associated with genetic disorders, collectively called ciliopathies. Besides their ciliary functions, recent research has shown that several ciliary proteins are involved in the coordination of the actin cytoskeleton. Although ciliary and actin phenotypes are related, the exact nature of their interconnection remains incompletely understood. Here, we show that the protein BBS6, associated with the ciliopathy Bardet–Biedl syndrome, cooperates with the actin-bundling protein Fascin-1 in regulating filopodia and ciliary signalling. We found that loss of Bbs6 affects filopodia length potentially via attenuated interaction with Fascin-1. Conversely, loss of Fascin-1 leads to a ciliary phenotype, subsequently affecting ciliary Wnt signalling, possibly in collaboration with BBS6. Our data shed light on how ciliary proteins are involved in actin regulations and provide new insight into the involvement of the actin regulator Fascin-1 in ciliogenesis and cilia-associated signalling. Advancing our knowledge of the complex regulations between primary cilia and actin dynamics is important to understand the pathogenic consequences of ciliopathies.展开更多
A key challenge in bioelectronics is to establish and improve the interface between electronic devices and living tissues,enabling a direct assessment of biological systems.Sensors integrated with plant tissue can pro...A key challenge in bioelectronics is to establish and improve the interface between electronic devices and living tissues,enabling a direct assessment of biological systems.Sensors integrated with plant tissue can provide valuable information about the plant itself as well as the surrounding environment,including air and soil quality.An obstacle in developing interfaces to plant tissue is mitigating the formation of fibrotic tissues,which can hinder continuous and accurate sensor operation over extended timeframes.Electronic systems that utilize suitable biocompatible materials alongside appropriate fabrication techniques to establish plantelectronic interfaces could provide for enhanced environmental understanding and ecosystem management capabilities.To meet these demands,this study introduces an approach for integrating printed electronic materials with biocompatible cryogels,resulting in stable implantable hydrogel-based bioelectronic devices capable of long-term operation within plant tissue.These inkjet-printed cryogels can be customized to provide various electronic functionalities,including electrodes and organic electrochemical transistors(OECTs),that exhibit high electrical conductivity for embedded conducting polymer traces(up to 350 S/cm),transconductance for OECTs in the mS range,a capacitance of up to 4.2mF g−1 in suitable structures,high stretchability(up to 330%strain),and selfhealing properties.The biocompatible functionalized cryogel-based electrodes and transistors were successfully implanted in plant tissue,and ionic activity in tomato plant stems was collected for over two months with minimal scar tissue formation,making these cryogel-based printed electronic devices excellent candidates for continuous,in-situ monitoring of plant and environmental status and health.展开更多
In the replacement of genetic probes,there is increasing interest in labeling living cells with high-quality extrinsic labels,which avoid over-expression artifacts and are available in a wide spectral range.This calls...In the replacement of genetic probes,there is increasing interest in labeling living cells with high-quality extrinsic labels,which avoid over-expression artifacts and are available in a wide spectral range.This calls for a broadly applicable technology that can deliver such labels unambiguously to the cytosol of living cells.Here,we demonstrate that nanoparticle-sensitized photoporation can be used to this end as an emerging intracellular delivery technique.We replace the traditionally used gold nanoparticles with graphene nanoparticles as photothermal sensitizers to permeabilize the cell membrane upon laser irradiation.We demonstrate that the enhanced thermal stability of graphene quantum dots allows the formation of multiple vapor nanobubbles upon irradiation with short laser pulses,allowing the delivery of a variety of extrinsic cell labels efficiently and homogeneously into live cells.We demonstrate high-quality time-lapse imaging with confocal,total internal reflection fluorescence(TIRF),and Airyscan superresolution microscopy.As the entire procedure is readily compatible with fluorescence(super resolution)microscopy,photoporation with graphene quantum dots has the potential to become the long-awaited generic platform for controlled intracellular delivery of fluorescent labels for live-cell imaging.展开更多
基金Institutional Research Grant,MD Anderson Cancer CenterUPWARDS Training Program(Undergraduate Students Working Towards Research in Science),Grant/Award Number:1R25CA240137-01A1the CPRIT Research Training Award CPRIT Training Program,Grant/Award Number:RP210028。
文摘Background:The development of relevant and robust large animal models of hepatocellular carcinoma is needed to test new therapeutic strategies for this disease.Transgenic approaches hold promise in addressing this complex problem.One such model,the Oncopig,has been reported to develop tumors of up to 4 cm in diameter within 7-14 days at sites of in situ vector inoculation.However,the resulting lesions reportedly contained an extensive inflammatory component that has not been evaluated in detail.Methods:Herein,we describe our results from multiparametric characterization of the lesions generated using liver biopsy cores incubated in vector solution and re-placed in the tissue.The study consisted of 3 animals in 3 cohorts(total of 9 animals)that were evaluated at 14,21,and 28 days.CT imaging,immunohistochemistry,multiplex immunofluorescence,and comprehensive blood analyses were used to quantify composition of the hepatic masses that developed following AdCre inoculation.Results:The tumors were hypovascular on CT and predominantly composed of CD45+cells with a strong lymphohistiocytic component,with no carcinomas identified.Ki-67 staining showed proliferation of CD45+immune cells but no neoplastic component.To provide further insight,the results are evaluated in the context of tumor growth kinetics.Conclusion:While progress has been made in generating targetable lesions,achieving a robust large animal model of liver cancer that faithfully recapitulates the human disease remains a challenging goal.
基金Project supported by the National Natural Science Foundation of China(Grant Nos.32371280 and T2350011)。
文摘FL-Online(http://fanlab.ac.cn) is an out-of-box modern web service featuring a user-friendly interface and simplified parameters, providing academic users with access to a series of online programs for biomolecular crystallography, including SAPI-online, OASIS-online, C-IPCAS-online and a series of upcoming software releases. Meanwhile, it is a highly scalable and maintainable web application framework that provides a powerful and flexible solution for academic web development needs. All the codes are open-source under MIT licenses in GitHub.
基金supported by the DFG grant DFG LU 2347/3-1.The JEOL JEM-2100 transmission electron microscope is funded by the Deutsche Forschungsgemeinschaft(DFG,German Research Foundation)-218894163VC and KGH were supported by a grant of the Interdisciplinary Center of Clinical Research(IZKF)of the Medical Facility of Wurzburg(grant number F-N-439)Super-resolution microscopy was further supported by the IZKF(Grant No.Z-12 to KGH)and the Core Unit Fluorescence Imaging of the Medical Faculty of the JMU.
文摘Background Atg9-containing vesicles are enriched in synapses and undergo cycles of exo-and endocytosis similarly to synaptic vesicles,thereby linking presynaptic autophagy to neuronal activity.Dysfunction of presynaptic autophagy is a pathophysiological mechanism in motoneuron disease(MND),which leads to impaired synaptic integrity and function.Here,we asked whether boosting neuronal activity by physical exercise modulates the cellular and motor phenotypes of Plekhg5-deficient mice,an MND model with defective presynaptic autophagy.Methods To characterize the vesicle accumulations in Plekhg5-deficient mice,we performed immunohistochemical staining,electron microscopy,and super-resolution imaging.Following voluntary running wheel exercise,we quantified the histopathological changes within the spinal cord and at neuromuscular junctions using an unbiased machine-learning approach.Additionally,we analyzed the motor performance of the animals by measuring their grip strength.To assess changes in the autophagic flux upon physical exercise in vivo,we utilized mRFP-GFP-LC3 expressing mice.The presence of Atg9-containing vesicle clusters in SOD1G93A was analyzed to examine the relevance of this pathological feature in a second MND model.Results We found marked accumulations of Atg9-containing vesicles at presynaptic sites of Plekhg5-deficient mice,which could be cleared by four weeks of voluntary running wheel exercise in young but surprisingly not in aged Plekhg5-deficient mice.However,physical exercise in aged mice led to synaptic vesicle sorting into the Atg9-containing vesicle accumulations without their removal.In line with these findings,short-term voluntary exercise triggered motoneuron autophagy in young but not old mice.Pointing to a broader role of Atg9-containing vesicles in the pathophysiology of MND,we also found Atg9-containing vesicle accumulations in SOD1G93A mice,a well-established ALS model.Strikingly,physical exercise in presymptomatic SOD1G93A mice resulted in a reduction of the vesicle accumulations.Conclusions Our data highlight the essential role of Atg9 in presynaptic autophagy and suggest that boosting autophagy by physical exercise provides a tool to maintain presynaptic function at the early but not late stages of Plekhg5-associated MND and possibly amyotrophic lateral sclerosis.
基金jointly supported by National Key R&D Program of China(2023YFB4606700)the National Natural Science Foundation of China(82272561)+2 种基金Sichuan Science and Technology Program(2024NSFSC0002)“1.3.5”Project for Disciplines of Excellence,West China Hospital,Sichuan University(ZYGD23037)China Post-doctoral Science Foundation(2024M752242).
文摘Matrix metalloproteinases(MMPs),coupled with other proteinases and glycanases,can degrade proteoglycans,collagens,and other extracellular matrix(ECM)components in inflammatory and non-inflammatory arthritis,making them important pathogenic molecules and ideal disease indicators and pharmaceutical intervention triggers.For MMP responsiveness,MMP-sensitive peptides(MSPs)are among the most easily synthesized and cost-effective substrates,with free ter-minal amine and/or carboxyl groups extensively employed in multiple designs.We hereby provide a comprehensive review over the mechanisms and advances in MSP applications for the management of arthritis.These applications include early and precise diagnosis of MMP activity via fluorescence probe technologies;acting as nanodrug carriers to enable on-demand drug release triggered by pathological microenvironments;and facilitating cartilage engineering through MMP-mediated degradation,which promotes cell migration,matrix synthesis,and tissue integration.Specifically,the ultra-sensitive MSP diagnostic probes could significantly advance the early diagnosis and detection of osteoarthritis(OA),while MSP-based drug carriers for rheumatoid arthritis(RA)can intelligently release antiinflammatory drugs effectively during flare-ups,or even before symptoms manifest.The continuous progress in MSP development may acceleratedly lead to novel management regimens for arthropathy in the future.
基金supported by Russian Science Foundation(project No.23-72-01114)funded by the Ministry of Science and Higher Education of the Russian Federation(project 122111700041-8).
文摘Perovskite photovoltaics upholds the most prominent position in the field of tandem technology development.In this aspect,the creation of perovskite material with suitable bandgap(≥1.65 eV)is necessary.And in order to achieve the best device characteristics,the high-quality film formation is crucial.To get a high-quality film,the solvent engineering approach stays at the forefront.However,although the solvent engineering was well discussed for such conventional material as MAPbI_(3),the field of wide bandgap perovskite materials is still lacking in this area.This paper presents the solvent engineering approach to improve the efficiency and stability of the conventional wide bandgap perovskite material Cs_(0.17)FA_(0.83)PbI_(1.8)Br_(1.2).Here we utilize several solvents such as traditional N,N-dimethylformamide,dimethyl sulfoxide,N-methyl-2-pyrrolidone and acetonitrile.It was demonstrated that implication of any binary DMF-X solvent improves the solar cell efficiency compared to the pure DMF solution,but the ratio of the X solvent is unique for every X and the foundation for the X influence is also unique.The addition of 2.4 M of DMSO is considered the best to improve the stability and efficiency of laboratory devices,however implementation of AcN allowed to produce 25 cm^(2)mini-modules with the PCE reaching 10%.
基金supported by grants from Johannes Gutenberg University Mainz,Alexander von Humboldt Foundation(Sofja Kovalevskaja Award),Hanns Seidel Foundation,and Sibylle Kalkhof-Rose Foundation.This project was further funded by Deutsche Forschungsgemeinschaft(DFG,German Research Foundation,GRK2526/1-Projectnr.407023052).
文摘Primary cilia are microtubule-based cell organelles important for cellular communication. Since they are involved in the regulation of numerous signalling pathways, defects in cilia development or function are associated with genetic disorders, collectively called ciliopathies. Besides their ciliary functions, recent research has shown that several ciliary proteins are involved in the coordination of the actin cytoskeleton. Although ciliary and actin phenotypes are related, the exact nature of their interconnection remains incompletely understood. Here, we show that the protein BBS6, associated with the ciliopathy Bardet–Biedl syndrome, cooperates with the actin-bundling protein Fascin-1 in regulating filopodia and ciliary signalling. We found that loss of Bbs6 affects filopodia length potentially via attenuated interaction with Fascin-1. Conversely, loss of Fascin-1 leads to a ciliary phenotype, subsequently affecting ciliary Wnt signalling, possibly in collaboration with BBS6. Our data shed light on how ciliary proteins are involved in actin regulations and provide new insight into the involvement of the actin regulator Fascin-1 in ciliogenesis and cilia-associated signalling. Advancing our knowledge of the complex regulations between primary cilia and actin dynamics is important to understand the pathogenic consequences of ciliopathies.
基金supported by the National Science Foundation(NSF)Signals in the Soils(SitS)program(Award No.1935594)as well as an award from the Natural Environment Research Council(NERC)(reference NE/T012293/1)Microscopic analyses were performed at MIMIC,University of Colorado Boulder(RRID:SCR 019307).
文摘A key challenge in bioelectronics is to establish and improve the interface between electronic devices and living tissues,enabling a direct assessment of biological systems.Sensors integrated with plant tissue can provide valuable information about the plant itself as well as the surrounding environment,including air and soil quality.An obstacle in developing interfaces to plant tissue is mitigating the formation of fibrotic tissues,which can hinder continuous and accurate sensor operation over extended timeframes.Electronic systems that utilize suitable biocompatible materials alongside appropriate fabrication techniques to establish plantelectronic interfaces could provide for enhanced environmental understanding and ecosystem management capabilities.To meet these demands,this study introduces an approach for integrating printed electronic materials with biocompatible cryogels,resulting in stable implantable hydrogel-based bioelectronic devices capable of long-term operation within plant tissue.These inkjet-printed cryogels can be customized to provide various electronic functionalities,including electrodes and organic electrochemical transistors(OECTs),that exhibit high electrical conductivity for embedded conducting polymer traces(up to 350 S/cm),transconductance for OECTs in the mS range,a capacitance of up to 4.2mF g−1 in suitable structures,high stretchability(up to 330%strain),and selfhealing properties.The biocompatible functionalized cryogel-based electrodes and transistors were successfully implanted in plant tissue,and ionic activity in tomato plant stems was collected for over two months with minimal scar tissue formation,making these cryogel-based printed electronic devices excellent candidates for continuous,in-situ monitoring of plant and environmental status and health.
基金support from the European Research Council(ERC)under the European Union’s Horizon 2020 research and innovation program(grant agreement No 648124)from the Ghent University Special Research Fund(01B04912)with gratitude+8 种基金support from the China Scholarship Council(CSC)(201506750012)the Special Research Fund from Ghent University(01SC1416)support from the China Scholarship Council(CSC)(2010634103)from the Research Foundation Flanders(Fonds Wetenschappelijk Onderzoek,FWO)for a doctoral fellowship(11ZB115N)from the Agency for Innovation by Science and Technology(IWT)support from the Centre National de la Recherche Scientifique(CNRS),the University of Lille,the Hauts-de-France region,the CPER“Photonics for Society”the EU union through FLAG-ERA JTC 2015-Graphtivitythe Marie Sklodowska-Curie action(H2020-MSCA-RISE-2015,PANG-690836)support by the FWO Research Community“Scanning and Wide Field Microscopy of(Bio)-organic Systems”and the Province of Limburg(Belgium)for the financial support within the tUL IMPULS FASE II program。
文摘In the replacement of genetic probes,there is increasing interest in labeling living cells with high-quality extrinsic labels,which avoid over-expression artifacts and are available in a wide spectral range.This calls for a broadly applicable technology that can deliver such labels unambiguously to the cytosol of living cells.Here,we demonstrate that nanoparticle-sensitized photoporation can be used to this end as an emerging intracellular delivery technique.We replace the traditionally used gold nanoparticles with graphene nanoparticles as photothermal sensitizers to permeabilize the cell membrane upon laser irradiation.We demonstrate that the enhanced thermal stability of graphene quantum dots allows the formation of multiple vapor nanobubbles upon irradiation with short laser pulses,allowing the delivery of a variety of extrinsic cell labels efficiently and homogeneously into live cells.We demonstrate high-quality time-lapse imaging with confocal,total internal reflection fluorescence(TIRF),and Airyscan superresolution microscopy.As the entire procedure is readily compatible with fluorescence(super resolution)microscopy,photoporation with graphene quantum dots has the potential to become the long-awaited generic platform for controlled intracellular delivery of fluorescent labels for live-cell imaging.
基金supported by the National Natural Science Foundation of China(32270774,31671400,81971439,32070694,31571436,31872822,and 31301153)the National Key Research and Development Program of China(2017YFA0503502,2016YFA0500903,2021YFC2700200,2017YFA0504600,and 2019YFA0508700)funded by the National Institutes of Health Office of Research Infrastructure Programs(P40 OD010440)。
