A critical function of flow cytometry is to count the concentration of blood cells,which helps in the diagnosis of certain diseases.However,the bulky nature of commercial flow cytometers makes such tests only availabl...A critical function of flow cytometry is to count the concentration of blood cells,which helps in the diagnosis of certain diseases.However,the bulky nature of commercial flow cytometers makes such tests only available in hospitals or laboratories,hindering the spread of point-of-care testing(POCT),especially in underdeveloped areas.Here,we propose a smart Palm-size Optofluidic Hematology Analyzer based on a miniature fluorescence microscope and a microfluidic platform to lighten the device to improve its portability.This gadget has a dimension of 35×30×80 mm and a mass of 39 g,less than 5%of the weight of commercially available flow cytometers.Additionally,automatic leukocyte concentration detection has been realized through the integration of image processing and leukocyte counting algorithms.We compared the leukocyte concentration measurement between our approach and a hemocytometer using the Passing-Bablok analysis and achieved a correlation coefficient of 0.979.Through Bland-Altman analysis,we obtained the relationship between their differences and mean measurement values and established 95%limits of agreement,ranging from−0.93×10^(3)to 0.94×10^(3)cells/μL.We anticipate that this device can be used widely for monitoring and treating diseases such as HIV and tumors beyond hospitals.展开更多
Chirality,as the symmetric breaking of molecules,plays an essential role in physical,chemical and especially biological processes,which highlights the accurate distinction among heterochiralities as well as the precis...Chirality,as the symmetric breaking of molecules,plays an essential role in physical,chemical and especially biological processes,which highlights the accurate distinction among heterochiralities as well as the precise preparation for homochirality.To this end,the well-designed structure-specific recognizer and catalysis reactor are necessitated,respectively.However,each kind of target molecules requires a custom-made chiral partner and the dynamic disorder of spatial-orientation distribution of molecules at the ensemble level leads to an inefficient protocol.In this perspective article,we developed a universal strategy capable of realizing the chirality detection and control by the external symmetry breaking based on the alignment of the molecular frame to external stimuli.Specifically,in combination with the discussion about the relationship among the chirality(molecule),spin(electron)and polarization(photon),i.e.,the three natural symmetry breaking,single-molecule junctions were proposed to achieve a single-molecule/event-resolved detection and synthesis.The fixation of the molecular orientation and the CMOS-compatibility provide an efficient interface to achieve the external input of symmetry breaking.This perspective is believed to offer more efficient applications in accurate chirality detection and precise asymmetric synthesis via the close collaboration of chemists,physicists,materials scientists,and engineers.展开更多
As one of the most widely used languages in the world,Chinese language is distinct from most western languages in many properties,thus providing a unique opportunity for understanding the brain basis of human language...As one of the most widely used languages in the world,Chinese language is distinct from most western languages in many properties,thus providing a unique opportunity for understanding the brain basis of human language and cognition.In recent years,non-invasive neuroimaging techniques such as magnetic resonance imaging(MRI)blaze a new trail to comprehensively study specific neural correlates of Chinese language processing and Chinese speakers.We reviewed the application of functional MRI(fMRI)in such studies and some essential findings on brain systems in processing Chinese.Specifically,for example,the application of task fMRI and resting-state fMRI in observing the process of reading and writing the logographic characters and producing or listening to the tonal speech.Elementary cognitive neuroscience and several potential research directions around brain and Chinese language were discussed,which may be informative for future research.展开更多
Few single-molecule experiments have enabled the direct imaging of functional biomacromolecules in real-time in their native liquid environments,resolving their conformational adaptations,transient interactions,and in...Few single-molecule experiments have enabled the direct imaging of functional biomacromolecules in real-time in their native liquid environments,resolving their conformational adaptations,transient interactions,and intermediate states.Liquid phase electron microscopy(LP-EM),due to its unique combination of spatial and temporal resolution,has shown to be a promising tool.Recent experiments have enabled successful imaging of intact structures of organic molecules and biological systems with an ordinary electron microscope.Adapting image processing methods and quantitative data analysis from single particle experiments based on the optical microscope,quantifying motion and relaxation of these interacting molecules allows the experimental observations of pathways,to test theoretical predictions,and discovery of new mechanisms.Combining LP-EM with tomography,fluorescence,and mass spectroscopy allows for probing multi-dimensional structural and dynamic information.Challenges remain in obtaining high-quality data in large quantities,which can be improved by developing new liquid cell platforms and machine learning-based data analysis.展开更多
Optical ultrasonic probes,exemplified by Fabry–Perot cavities on optical fibers,have small sizes,high sensitivity,and pure optical characteristics,making them highly attractive in high-resolution ultrasonic/photoacou...Optical ultrasonic probes,exemplified by Fabry–Perot cavities on optical fibers,have small sizes,high sensitivity,and pure optical characteristics,making them highly attractive in high-resolution ultrasonic/photoacoustic imaging,especially in near-field or endoscopic scenarios.Taking a different approach,we demonstrate an ultrasensitive and broadband ultrasound microprobe formed by an optical whispering-gallery-mode polymer microcavity coupled to a U-shaped microfiber.With the h/√igh-quality(Q)factors(>10^(6)),the noise equivalent pressure of the ultrasound microprobe reaches 1.07 m Pa∕Hz with a record broadband response of 150 MHz and a large detection angle of 180°.Our results show that this optical microprobe can overcome the strong decay resulting from ultrasound diverging and medium absorption through short working distances.We further demonstrate high-quality in vivo whole-body photoacoustic imaging of a zebrafish larva.Our implementation provides a new strategy for developing miniature ultrasound detectors and holds great potential for broad applications.展开更多
Hypomyelination leukodystrophies constitute a group of heritable white matter disorders exhibiting defective myelin development.Initially identified as a lysosomal protein,the TMEM106B D252N mutant has recently been a...Hypomyelination leukodystrophies constitute a group of heritable white matter disorders exhibiting defective myelin development.Initially identified as a lysosomal protein,the TMEM106B D252N mutant has recently been associated with hypomyelination.However,how lysosomal TMEM106B facilitates myelination and how the D252N mutation disrupts that process are poorly understood.We used superresolution Hessian structured illumination microscopy(Hessian-SIM)and spinning discconfocal structured illumination microscopy(SD-SIM)to find that the wild-type TMEM106B protein is targeted to the plasma membrane,filopodia,and lysosomes in human oligodendrocytes.The D252N mutation reduces the size of lysosomes in oligodendrocytes and compromises lysosome changes upon starvation stress.Most importantly,we detected reductions in the length and number of filopodia in cells expressing the D252N mutant.PLP1 is the most abundant myelin protein that almost entirely colocalizes with TMEM106B,and coexpressing PLP1 with the D252N mutant readily rescues the lysosome and filopodia phenotypes of cells.Therefore,interactions between TMEM106B and PLP1 on the plasma membrane are essential for filopodia formation and myelination in oligodendrocytes,which may be sustained by the delivery of these proteins from lysosomes via exocytosis.展开更多
Increasing evidence suggests that intratumoral microbiota plays a pivotal role in tumor progression,immunosurveillance,metastasis,and chemosensitivity.Particularly,in pancreatic ductal adenocarcinoma,tumor-resident Ga...Increasing evidence suggests that intratumoral microbiota plays a pivotal role in tumor progression,immunosurveillance,metastasis,and chemosensitivity.Particularly,in pancreatic ductal adenocarcinoma,tumor-resident Gammaproteobacteria could transform the chemotherapeutic drug gemcitabine(Gem)into its inactive form,thus rendering chemotherapy ineffective.Herein,a strategy for selectively eradicating intratumoral bacteria was described for overcoming Gem resistance in a pancreatic cancer animal model.An antimicrobial peptide was linked with photosensitizer through a poly(ethylene glycol)chain,which can self-assemble into micelles with a diameter of∼20 nm.The micelles could efficiently kill bacteria under light irradiation by inducing membrane depolarization,thereby inhibiting Gem metabolism.In a bacteria-resident pancreatic cancer animal model,the selective photodynamic eradication of intratumoral bacteria was demonstrated to efficiently reverse Gem resistance.This research highlights antibacterial photodynamic therapy as a promising adjuvant strategy for cancer therapy by modulating intratumoral microbiota.展开更多
To the editor:Gene therapy is considered a promising treatment option for several diseases,including neuromuscular disease,cardiovascular diseases,immunodeficiencies,and cancer.However,the promise of gene therapy is l...To the editor:Gene therapy is considered a promising treatment option for several diseases,including neuromuscular disease,cardiovascular diseases,immunodeficiencies,and cancer.However,the promise of gene therapy is largely compromised by a lack of suitable gene delivery systems.[1,2]Gene delivery approaches using common gene vectors including viral and nonviral vectors typically rely on specific targeting moieties or tissue tropism of the vectors.However,not all tissues possess unique receptors suitable for targeted gene delivery.This issue can be potentially solved by introducing external physical stimuli,such as ultrasound,magnetic force,heat,and light,which can guide the transgene expression independent of the intrinsic properties of the cells of interest.31 In addition,such physical stimuli can be integrated with medical imaging,thus making imaging-guided gene delivery possible.In this scenario,physical stimuli are applied to the area of interest guided by medical imaging and can then trigger robust transgene expression in selected areas.展开更多
Functional brain imaging technology has developed rapidly in recent years.On the one hand,high-field 7-Tesla magnetic resonance imaging(MRI)has excelled the limited spatial resolution of 3-Tesla MRI,allowing us to ent...Functional brain imaging technology has developed rapidly in recent years.On the one hand,high-field 7-Tesla magnetic resonance imaging(MRI)has excelled the limited spatial resolution of 3-Tesla MRI,allowing us to enter a new world of mesoscopic imaging from the macroscopic imaging of human brain functions.On the other hand,novel optical pumping magnetometer-magnetoencephalography(OPM-MEG)has broken down the technical barriers of traditional superconducting MEG,which brings imaging of neuronal electromagnetic signals from cortical imaging to whole-brain imaging.This article aims to present a brief introduction regarding the development of conventional MRI and MEG technology,and,more importantly,to delineate that high-field MRI and OPM-MEG complement each other and together will lead us into a new era of functional brain imaging.展开更多
In fluorescence microscopy,computational algorithms have been developed to suppress noise,enhance contrast,and even enable super-resolution(SR).However,the local quality of the images may vary on multiple scales,and t...In fluorescence microscopy,computational algorithms have been developed to suppress noise,enhance contrast,and even enable super-resolution(SR).However,the local quality of the images may vary on multiple scales,and these differences can lead to misconceptions.Current mapping methods fail to finely estimate the local quality,challenging to associate the SR scale content.Here,we develop a rolling Fourier ring correlation(rFRC)method to evaluate the reconstruction uncertainties down to SR scale.To visually pinpoint regions with low reliability,a filtered rFRC is combined with a modified resolution-scaled error map(RSM),offering a comprehensive and concise map for further examination.We demonstrate their performances on various SR imaging modalities,and the resulting quantitative maps enable better SR images integrated from different reconstructions.Overall,we expect that our framework can become a routinely used tool for biologists in assessing their image datasets in general and inspire further advances in the rapidly developing field of computational imaging.展开更多
Monitoring the dynamics of a single molecule provides unique insights into the fundamental physical and chemical properties of individual molecules.Over the past few decades,various approaches have been developed to e...Monitoring the dynamics of a single molecule provides unique insights into the fundamental physical and chemical properties of individual molecules.Over the past few decades,various approaches have been developed to enable the real-time and high-resolution detection at the single-molecule level.Among them,electrical and optical methods are the most promising tools,for the reason that electrical detection offers high resolution while optical technology provides non-invasive,targeted measurement with the added benefit of visualization.In this review,we summarized the current state-of-the-art electrical and optical techniques for single-molecule measurement and discussed their applications in detecting dynamic events such as conformational isomerizations,intermolecular interactions,chemical reactions,and biomolecular activities.In addition,we discussed the challenges and opportunities in this area and proposed possible directions for future development.展开更多
Principal component analysis(PCA),a common dimensionality reduction method,is introduced into SIM to identify the frequency vectors and pattern phases of the illumination pattern with precise subpixel accuracy,fast sp...Principal component analysis(PCA),a common dimensionality reduction method,is introduced into SIM to identify the frequency vectors and pattern phases of the illumination pattern with precise subpixel accuracy,fast speed,and noise-robustness,which is promising for real-time and long-term live-cell imaging.展开更多
Simultaneous localization of light to extreme spatial and spectral scales is of high importance for testing fundamental physics and various applications.However,there is a longstanding trade-off between localizing a l...Simultaneous localization of light to extreme spatial and spectral scales is of high importance for testing fundamental physics and various applications.However,there is a longstanding trade-off between localizing a light field in space and in frequency.Here we discover a new class of twisted lattice nanocavities based on mode locking in momentum space.The twisted lattice nanocavity hosts a strongly localized light field in a 0.048𝜆3 mode volume with a quality factor exceeding 2.9×1011(∼250𝜇s photon lifetime),which presents a record high figure of merit of light localization among all reported optical cavities.Based on the discovery,we have demonstrated silicon-based twisted lattice nanocavities with quality factor over 1 million.Our result provides a powerful platform to study light-matter interaction in extreme conditions for tests of fundamental physics and applications in nanolasing,ultrasensing,nonlinear optics,optomechanics and quantum-optical devices.展开更多
The miniaturization of lasers has opened up a wide variety of new applications,including on-chip optical communications,laser displays,medical imaging,and sensing.A representative example is the cell laser that emerge...The miniaturization of lasers has opened up a wide variety of new applications,including on-chip optical communications,laser displays,medical imaging,and sensing.A representative example is the cell laser that emerged in 2011,in which a single biological cell expressing green fluorescent protein generated laser emission under optical pumping with nanojoule pulse inside a Fabry–Pérot microcavity.展开更多
Small GTPases including Ras,Rho,Rab,Arf,and Ran are omnipresent molecular switches in regulating key cellular functions.Their dysregulation is a therapeutic target for tumors,neurodegeneration,cardiomyopathies,and inf...Small GTPases including Ras,Rho,Rab,Arf,and Ran are omnipresent molecular switches in regulating key cellular functions.Their dysregulation is a therapeutic target for tumors,neurodegeneration,cardiomyopathies,and infection.However,small GTPases have been historically recognized as“undruggable”.Targeting KRAS,one of the most frequently mutated oncogenes,has only come into reality in the last decade due to the development of breakthrough strategies such as fragment-based screening,covalent ligands,macromolecule inhibitors,and PROTACs.Two KRAS^(G12C)covalent inhibitors have obtained accelerated approval for treating KRAS^(G12C)mutant lung cancer,and allele-specific hotspot mutations on G12D/S/R have been demonstrated as viable targets.New methods of targeting KRAS are quickly evolving,including transcription,immunogenic neoepitopes,and combinatory targeting with immunotherapy.Nevertheless,the vast majority of small GTPases and hotspot mutations remain elusive,and clinical resistance to G12C inhibitors poses new challenges.In this article,we summarize diversified biological functions,shared structural properties,and complex regulatory mechanisms of small GTPases and their relationships with human diseases.Furthermore,we review the status of drug discovery for targeting small GTPases and the most recent strategic progress focused on targeting KRAS.The discovery of new regulatory mechanisms and development of targeting approaches will together promote drug discovery for small GTPases.展开更多
Structured illumination microscopy(SIM)has become the standard for next-generation wide-field microscopy,offering ultrahigh imaging speed,superresolution,a large fiield-of-view,and long-term imaging.Over the past deca...Structured illumination microscopy(SIM)has become the standard for next-generation wide-field microscopy,offering ultrahigh imaging speed,superresolution,a large fiield-of-view,and long-term imaging.Over the past decade,SIM hardware and software have flourished,leading to successful applications in various biological questions.However,unlocking the full potential of SIM system hardware requires the development of advanced reconstruction algorithms.Here,we introduce the basic theory of two SIM algorithms,namely,optical sectioning SIM(OS-SIM)and superresolution SIM(SR-SIM),and summarize their implementation modalities.We then provide a brief overview of existing OS-SIM processing algorithms and review the development of SR-SIM reconstruction algorithms,focusing primarily on 2D-SIM,3D-SIM,and blind-SIM.To showcase the state-of-the-art development of SIM systems and assist users in selecting a commercial SIM system for a specific application,we compare the features of representative off-the-shelf SIM systems.Finally,we provide perspectives on the potential future developments of SIM.展开更多
We present a novel noncontact ultrasound(US)and photoacoustic imaging(PAI)system,overcoming the limitations of traditional coupling media.Using a long coherent length laser,we employ a homodyne free-space Mach-Zehnder...We present a novel noncontact ultrasound(US)and photoacoustic imaging(PAI)system,overcoming the limitations of traditional coupling media.Using a long coherent length laser,we employ a homodyne free-space Mach-Zehnder setup with zero-crossing triggering,achieving a noise equivalent pressure of 703 Pa at 5 MHz and a-6 dB bandwidth of 1 to8.54 MHz.We address the phase uncertainty inherent in the homodyne method.Scanning the noncontact US probe enables photoacoustic computed tomography(PACT).Phantom studies demonstrate imaging performance and system stability,underscoring the potential of our system for noncontact US sensing and PAI.展开更多
High dielectric constants in organic semiconductors have been identified as a central challenge for the improvement in not only piexoelectric,preolecric,and freeltric efcts but also photoclecric conversion eficiency i...High dielectric constants in organic semiconductors have been identified as a central challenge for the improvement in not only piexoelectric,preolecric,and freeltric efcts but also photoclecric conversion eficiency in OPVs,carrier mobility in OFETS,and charge density in charge-trapping memories.Herein,we report an ultralong persistence length(≈41 nm)efet of spiro-fused organic nanopolymers on dielectric properties,together with excitonic and charge carrier behaviors.The state-of-the-art nanopolymers,namely,nanopolyspirogrids(NPSGs),are synthesized via the simple crossscale Friedel-Crafts polygridlization of AjB-type nanomonomers.The high dielectric constant(k=8.43)of NPSG is firstly achieved by locking spiro-polygridization efect that results in the enhancement of dipole polarization.When doping into a polystyrene-based dielectric layer,such a high-k feature of NPSG increases the feld-ffct carrier mobility from 0.20 to 0.90cm^(2)Vl s'in pentacene OFET devices.Meanwhile,amorphous NPSG film exhibits an ultralow energy disorder(<50 meV)for an exellent zero-field hole mobility of 3.94×10^(-1)cm^(2)V^(-1)s^(-1).surpassing most of the amorphousπconjugated polymers Onganic nanopolymers with high dielectric constants open a new way to break through the bottleneck of eficiency and multifunctionality in the blueprint of the fourth generation semiconductors.展开更多
The orientation of fluorophores can reveal crucial information about the structure and dynamics of their associated subcellular organelles.Despite significant progress in super-resolution,fluorescence polarization mic...The orientation of fluorophores can reveal crucial information about the structure and dynamics of their associated subcellular organelles.Despite significant progress in super-resolution,fluorescence polarization microscopy remains limited to unique samples with relatively strong polarization modulation and not applicable to the weak polarization signals in samples due to the excessive background noise.Here we apply optical lock-in detection to amplify the weak polarization modulation with super-resolution.This novel technique,termed optical lock-in detection super-resolution dipole orientation mapping(OLID-SDOM),could achieve a maximum of 100 frames per second and rapid extraction of 2D orientation,and distinguish distance up to 50 nm,making it suitable for monitoring structural dynamics concerning orientation changes in vivo.OLID-SDOM was employed to explore the universal anisotropy of a large variety of GFP-tagged subcellular organelles,including mitochondria,lysosome,Golgi,endosome,etc.We found that OUF(Orientation Uniformity Factor)of OLID-SDOM can be specific for different subcellular organelles,indicating that the anisotropy was related to the function of the organelles,and OUF can potentially be an indicator to distinguish normal and abnormal cells(even cancer cells).Furthermore,dual-color super-resolution OLID-SDOM imaging of lysosomes and actins demonstrates its potential in studying dynamic molecular interactions.The subtle anisotropy changes of expanding and shrinking dendritic spines in live neurons were observed with real-time OLID-SDOM.Revealing previously unobservable fluorescence anisotropy in various samples and indicating their underlying dynamic molecular structural changes,OLID-SDOM expands the toolkit for live cell research.展开更多
Achieving localization with molecular precision has been of great interest for extending fluorescence microscopy to nanoscopy.MINFLUX pioneers this transition through point spread function(PSF)engineering,yet its perf...Achieving localization with molecular precision has been of great interest for extending fluorescence microscopy to nanoscopy.MINFLUX pioneers this transition through point spread function(PSF)engineering,yet its performance is primarily limited by the signal-to-background ratio.Here we demonstrate theoretically that two-photon MINFLUX(2p-MINFLUX)could double its localization precision through PSF engineering by nonlinear effect.Cramér-Rao Bound(CRB)is studied as the maximum localization precision,and CRB of two-photon MINFLUX is halved compared to single-photon MINFLUX(1p-MINFLUX)in all three dimensions.Meanwhile,in order to achieve same localization precision with 1p-MINFLUX,2p-MINFLUX requires only 1/4 of fluorescence photons.Exploiting simultaneous two-photon excitation of multiple fluorophore species,2p-MINFLUX may have the potential for registration-free nanoscopy and multicolor tracking.展开更多
基金supported by the National Natural Science Foundation of China (grant no.62305083 to W.Z.,grant no.T2222009 to H.L.,grant no.32227802 to H.L.)China Postdoctoral Science Foundation (grant no.2023T160163 to W.Z.grant no.2022M720971 to W.Z.)+2 种基金the Heilongjiang Provincial Postdoctoral Science Foundation (grant no.LBH-Z22027 to W.Z.)the National Key Research and Development Program of China (grant no.2022YFC3400600 to H.L.)the Natural Science Foundation of Heilongjiang Province (grant no.YQ2021F013 to H.L.).
文摘A critical function of flow cytometry is to count the concentration of blood cells,which helps in the diagnosis of certain diseases.However,the bulky nature of commercial flow cytometers makes such tests only available in hospitals or laboratories,hindering the spread of point-of-care testing(POCT),especially in underdeveloped areas.Here,we propose a smart Palm-size Optofluidic Hematology Analyzer based on a miniature fluorescence microscope and a microfluidic platform to lighten the device to improve its portability.This gadget has a dimension of 35×30×80 mm and a mass of 39 g,less than 5%of the weight of commercially available flow cytometers.Additionally,automatic leukocyte concentration detection has been realized through the integration of image processing and leukocyte counting algorithms.We compared the leukocyte concentration measurement between our approach and a hemocytometer using the Passing-Bablok analysis and achieved a correlation coefficient of 0.979.Through Bland-Altman analysis,we obtained the relationship between their differences and mean measurement values and established 95%limits of agreement,ranging from−0.93×10^(3)to 0.94×10^(3)cells/μL.We anticipate that this device can be used widely for monitoring and treating diseases such as HIV and tumors beyond hospitals.
基金supports from the National Key R&D Program of China(2021YFA1200101 and 2022YFE0128700)the National Natural Science Foundation of China(22150013 and 21933001)+2 种基金the New Cornerstone Science Foundation through the XPLORER PRIZEthe Natural Science Foundation of Beijing(2222009)“Frontiers Science Centre for New Organic Matter”at Nankai University(63181206).
文摘Chirality,as the symmetric breaking of molecules,plays an essential role in physical,chemical and especially biological processes,which highlights the accurate distinction among heterochiralities as well as the precise preparation for homochirality.To this end,the well-designed structure-specific recognizer and catalysis reactor are necessitated,respectively.However,each kind of target molecules requires a custom-made chiral partner and the dynamic disorder of spatial-orientation distribution of molecules at the ensemble level leads to an inefficient protocol.In this perspective article,we developed a universal strategy capable of realizing the chirality detection and control by the external symmetry breaking based on the alignment of the molecular frame to external stimuli.Specifically,in combination with the discussion about the relationship among the chirality(molecule),spin(electron)and polarization(photon),i.e.,the three natural symmetry breaking,single-molecule junctions were proposed to achieve a single-molecule/event-resolved detection and synthesis.The fixation of the molecular orientation and the CMOS-compatibility provide an efficient interface to achieve the external input of symmetry breaking.This perspective is believed to offer more efficient applications in accurate chirality detection and precise asymmetric synthesis via the close collaboration of chemists,physicists,materials scientists,and engineers.
基金the National Natural Scientific Foundation of China(Grants 81790650,81790651,81727808,81627901,and 31771253)the Beijing Municipal Science and Technology Commission(Grants Z171100000117012 and Z181100001518003)the Collaborative Research Fund of the Chinese Institute for Brain Research,Beijing(No.2020-NKXPT-02).
文摘As one of the most widely used languages in the world,Chinese language is distinct from most western languages in many properties,thus providing a unique opportunity for understanding the brain basis of human language and cognition.In recent years,non-invasive neuroimaging techniques such as magnetic resonance imaging(MRI)blaze a new trail to comprehensively study specific neural correlates of Chinese language processing and Chinese speakers.We reviewed the application of functional MRI(fMRI)in such studies and some essential findings on brain systems in processing Chinese.Specifically,for example,the application of task fMRI and resting-state fMRI in observing the process of reading and writing the logographic characters and producing or listening to the tonal speech.Elementary cognitive neuroscience and several potential research directions around brain and Chinese language were discussed,which may be informative for future research.
基金H.W.thanks to the general support of the National Natural Science Foundation of China through funding 22174006the support of Beijing National Laboratory for Molecular Sciences,Center for Spectroscopy at Peking University.
文摘Few single-molecule experiments have enabled the direct imaging of functional biomacromolecules in real-time in their native liquid environments,resolving their conformational adaptations,transient interactions,and intermediate states.Liquid phase electron microscopy(LP-EM),due to its unique combination of spatial and temporal resolution,has shown to be a promising tool.Recent experiments have enabled successful imaging of intact structures of organic molecules and biological systems with an ordinary electron microscope.Adapting image processing methods and quantitative data analysis from single particle experiments based on the optical microscope,quantifying motion and relaxation of these interacting molecules allows the experimental observations of pathways,to test theoretical predictions,and discovery of new mechanisms.Combining LP-EM with tomography,fluorescence,and mass spectroscopy allows for probing multi-dimensional structural and dynamic information.Challenges remain in obtaining high-quality data in large quantities,which can be improved by developing new liquid cell platforms and machine learning-based data analysis.
基金China Postdoctoral Science Foundation(2021T140023,2020M680187)National Natural Science Foundation of China(62105006,81421004)National Key Research and Development Program of China(2017YFE0104200)。
文摘Optical ultrasonic probes,exemplified by Fabry–Perot cavities on optical fibers,have small sizes,high sensitivity,and pure optical characteristics,making them highly attractive in high-resolution ultrasonic/photoacoustic imaging,especially in near-field or endoscopic scenarios.Taking a different approach,we demonstrate an ultrasensitive and broadband ultrasound microprobe formed by an optical whispering-gallery-mode polymer microcavity coupled to a U-shaped microfiber.With the h/√igh-quality(Q)factors(>10^(6)),the noise equivalent pressure of the ultrasound microprobe reaches 1.07 m Pa∕Hz with a record broadband response of 150 MHz and a large detection angle of 180°.Our results show that this optical microprobe can overcome the strong decay resulting from ultrasound diverging and medium absorption through short working distances.We further demonstrate high-quality in vivo whole-body photoacoustic imaging of a zebrafish larva.Our implementation provides a new strategy for developing miniature ultrasound detectors and holds great potential for broad applications.
基金supported by the National Natural Science Foundation of China(81925022,61827825,32227802,92054301)the Fundamental Research Center Project of the National Natural Science Foundation of China(T2288102)+4 种基金the National Science and Technology Major Project Program(2022YFC3400600)Beijing Natural Science Foundation Key Research Topics(Z20J00059)UMHS-PUHSC Joint Institute for Translational and Clinical Research(BMU2019JI009)Beijing Key Laboratory of Molecular Diagnosis and Study on Pediatric Genetic Diseases(BZ0317)China Postdoctoral Science Foundation(2021M690465)。
文摘Hypomyelination leukodystrophies constitute a group of heritable white matter disorders exhibiting defective myelin development.Initially identified as a lysosomal protein,the TMEM106B D252N mutant has recently been associated with hypomyelination.However,how lysosomal TMEM106B facilitates myelination and how the D252N mutation disrupts that process are poorly understood.We used superresolution Hessian structured illumination microscopy(Hessian-SIM)and spinning discconfocal structured illumination microscopy(SD-SIM)to find that the wild-type TMEM106B protein is targeted to the plasma membrane,filopodia,and lysosomes in human oligodendrocytes.The D252N mutation reduces the size of lysosomes in oligodendrocytes and compromises lysosome changes upon starvation stress.Most importantly,we detected reductions in the length and number of filopodia in cells expressing the D252N mutant.PLP1 is the most abundant myelin protein that almost entirely colocalizes with TMEM106B,and coexpressing PLP1 with the D252N mutant readily rescues the lysosome and filopodia phenotypes of cells.Therefore,interactions between TMEM106B and PLP1 on the plasma membrane are essential for filopodia formation and myelination in oligodendrocytes,which may be sustained by the delivery of these proteins from lysosomes via exocytosis.
基金National Natural Science Foundation of China,Grant/Award Numbers:52273300,82102062,81930047China Postdoctoral Science Foundation,Grant/Award Number:2020TQ0008。
文摘Increasing evidence suggests that intratumoral microbiota plays a pivotal role in tumor progression,immunosurveillance,metastasis,and chemosensitivity.Particularly,in pancreatic ductal adenocarcinoma,tumor-resident Gammaproteobacteria could transform the chemotherapeutic drug gemcitabine(Gem)into its inactive form,thus rendering chemotherapy ineffective.Herein,a strategy for selectively eradicating intratumoral bacteria was described for overcoming Gem resistance in a pancreatic cancer animal model.An antimicrobial peptide was linked with photosensitizer through a poly(ethylene glycol)chain,which can self-assemble into micelles with a diameter of∼20 nm.The micelles could efficiently kill bacteria under light irradiation by inducing membrane depolarization,thereby inhibiting Gem metabolism.In a bacteria-resident pancreatic cancer animal model,the selective photodynamic eradication of intratumoral bacteria was demonstrated to efficiently reverse Gem resistance.This research highlights antibacterial photodynamic therapy as a promising adjuvant strategy for cancer therapy by modulating intratumoral microbiota.
基金National Natural Science Foundation of China(No.81930047,to ZDNo.82102062 to RL)China Postdoctoral Science Foundation(No.2020TQ0008,to RL).
文摘To the editor:Gene therapy is considered a promising treatment option for several diseases,including neuromuscular disease,cardiovascular diseases,immunodeficiencies,and cancer.However,the promise of gene therapy is largely compromised by a lack of suitable gene delivery systems.[1,2]Gene delivery approaches using common gene vectors including viral and nonviral vectors typically rely on specific targeting moieties or tissue tropism of the vectors.However,not all tissues possess unique receptors suitable for targeted gene delivery.This issue can be potentially solved by introducing external physical stimuli,such as ultrasound,magnetic force,heat,and light,which can guide the transgene expression independent of the intrinsic properties of the cells of interest.31 In addition,such physical stimuli can be integrated with medical imaging,thus making imaging-guided gene delivery possible.In this scenario,physical stimuli are applied to the area of interest guided by medical imaging and can then trigger robust transgene expression in selected areas.
文摘Functional brain imaging technology has developed rapidly in recent years.On the one hand,high-field 7-Tesla magnetic resonance imaging(MRI)has excelled the limited spatial resolution of 3-Tesla MRI,allowing us to enter a new world of mesoscopic imaging from the macroscopic imaging of human brain functions.On the other hand,novel optical pumping magnetometer-magnetoencephalography(OPM-MEG)has broken down the technical barriers of traditional superconducting MEG,which brings imaging of neuronal electromagnetic signals from cortical imaging to whole-brain imaging.This article aims to present a brief introduction regarding the development of conventional MRI and MEG technology,and,more importantly,to delineate that high-field MRI and OPM-MEG complement each other and together will lead us into a new era of functional brain imaging.
基金supported by the National Natural Science Foundation of China(grant no.T2222009 to H.L.,grant no.32227802 to L.C.,grant no.81925022 to L.C.,grant no.92054301 to L.C.,grant no.62305083 to W.Z.,grant no.12174208 to P.L.,grant no.32301257 to S.Z.,grant no.32222022 to Y.J.,grant no.32071458 to H.M.)the National Key Research and Development Program of China(grant no.2022YFC3400600 to L.C.)+4 种基金the Natural Science Foundation of Heilongjiang Province(grant no.YQ2021F013 to H.L.)the Beijing Natural Science Foundation(grant no.Z20J00059 to L.C.)the Guangdong Major Project of Basic and Applied Basic Research(grant no.2020B0301030009 to P.L.)the China Postdoctoral Science Foundation(grant no.2023T160163 to W.Z.,grant no.2022M720971 to W.Z.)the Heilongjiang Provincial Postdoctoral Science Foundation(grant no.LBH-Z22027 to W.Z.).L.C.acknowledges support from the High-performance Computing Platform of Peking University。
文摘In fluorescence microscopy,computational algorithms have been developed to suppress noise,enhance contrast,and even enable super-resolution(SR).However,the local quality of the images may vary on multiple scales,and these differences can lead to misconceptions.Current mapping methods fail to finely estimate the local quality,challenging to associate the SR scale content.Here,we develop a rolling Fourier ring correlation(rFRC)method to evaluate the reconstruction uncertainties down to SR scale.To visually pinpoint regions with low reliability,a filtered rFRC is combined with a modified resolution-scaled error map(RSM),offering a comprehensive and concise map for further examination.We demonstrate their performances on various SR imaging modalities,and the resulting quantitative maps enable better SR images integrated from different reconstructions.Overall,we expect that our framework can become a routinely used tool for biologists in assessing their image datasets in general and inspire further advances in the rapidly developing field of computational imaging.
基金We acknowledge primary financial supports from the National Key R&D Program of China(2021YFA1200102,2021YFA1200101,and 2022YFE0128700)the National Natural Science Foundation of China(22173050,22150013,21727806,and 21933001)+3 种基金the Fundamental Research Funds for the Central Universities(63223056)the Tencent Foundation through the XPLORER PRIZE,"Frontiers Science Center for New Organic Matter"at Nankai University(63181206)the Natural Science Foundation of Beijing(2222009)Beijing National Laboratory for Molecular Sciences(BNLMS202105).
文摘Monitoring the dynamics of a single molecule provides unique insights into the fundamental physical and chemical properties of individual molecules.Over the past few decades,various approaches have been developed to enable the real-time and high-resolution detection at the single-molecule level.Among them,electrical and optical methods are the most promising tools,for the reason that electrical detection offers high resolution while optical technology provides non-invasive,targeted measurement with the added benefit of visualization.In this review,we summarized the current state-of-the-art electrical and optical techniques for single-molecule measurement and discussed their applications in detecting dynamic events such as conformational isomerizations,intermolecular interactions,chemical reactions,and biomolecular activities.In addition,we discussed the challenges and opportunities in this area and proposed possible directions for future development.
文摘Principal component analysis(PCA),a common dimensionality reduction method,is introduced into SIM to identify the frequency vectors and pattern phases of the illumination pattern with precise subpixel accuracy,fast speed,and noise-robustness,which is promising for real-time and long-term live-cell imaging.
基金This work is supported by the National Key R&D Program of China(2018YFA0704401)the Beijing Natural Science Foundation(Z180011)+1 种基金the National Natural Science Foundation of China(12225402,91950115,11774014,61521004 and 62175003)the Tencent Foundation.
文摘Simultaneous localization of light to extreme spatial and spectral scales is of high importance for testing fundamental physics and various applications.However,there is a longstanding trade-off between localizing a light field in space and in frequency.Here we discover a new class of twisted lattice nanocavities based on mode locking in momentum space.The twisted lattice nanocavity hosts a strongly localized light field in a 0.048𝜆3 mode volume with a quality factor exceeding 2.9×1011(∼250𝜇s photon lifetime),which presents a record high figure of merit of light localization among all reported optical cavities.Based on the discovery,we have demonstrated silicon-based twisted lattice nanocavities with quality factor over 1 million.Our result provides a powerful platform to study light-matter interaction in extreme conditions for tests of fundamental physics and applications in nanolasing,ultrasensing,nonlinear optics,optomechanics and quantum-optical devices.
文摘The miniaturization of lasers has opened up a wide variety of new applications,including on-chip optical communications,laser displays,medical imaging,and sensing.A representative example is the cell laser that emerged in 2011,in which a single biological cell expressing green fluorescent protein generated laser emission under optical pumping with nanojoule pulse inside a Fabry–Pérot microcavity.
基金supported by grants from National Key R&D Program of China(2022YFC2305400,2022YFC3400600)Shenzhen Fundamental Research Program(JCYJ20220530145011025)+1 种基金National Natural ScienceFoundation of China(82282717,82073311)Natural Science Foundation of Sichuan Province(2022JDTD0025)。
文摘Small GTPases including Ras,Rho,Rab,Arf,and Ran are omnipresent molecular switches in regulating key cellular functions.Their dysregulation is a therapeutic target for tumors,neurodegeneration,cardiomyopathies,and infection.However,small GTPases have been historically recognized as“undruggable”.Targeting KRAS,one of the most frequently mutated oncogenes,has only come into reality in the last decade due to the development of breakthrough strategies such as fragment-based screening,covalent ligands,macromolecule inhibitors,and PROTACs.Two KRAS^(G12C)covalent inhibitors have obtained accelerated approval for treating KRAS^(G12C)mutant lung cancer,and allele-specific hotspot mutations on G12D/S/R have been demonstrated as viable targets.New methods of targeting KRAS are quickly evolving,including transcription,immunogenic neoepitopes,and combinatory targeting with immunotherapy.Nevertheless,the vast majority of small GTPases and hotspot mutations remain elusive,and clinical resistance to G12C inhibitors poses new challenges.In this article,we summarize diversified biological functions,shared structural properties,and complex regulatory mechanisms of small GTPases and their relationships with human diseases.Furthermore,we review the status of drug discovery for targeting small GTPases and the most recent strategic progress focused on targeting KRAS.The discovery of new regulatory mechanisms and development of targeting approaches will together promote drug discovery for small GTPases.
基金This work was supported by the Ministry of Science and Technology(2022YFC3401100)the National Natural Science Foundation of China(62025501,31971376,and 92150301)the fellowship of China Postdoctoral ScienceFoundation(2021M700243).
文摘Structured illumination microscopy(SIM)has become the standard for next-generation wide-field microscopy,offering ultrahigh imaging speed,superresolution,a large fiield-of-view,and long-term imaging.Over the past decade,SIM hardware and software have flourished,leading to successful applications in various biological questions.However,unlocking the full potential of SIM system hardware requires the development of advanced reconstruction algorithms.Here,we introduce the basic theory of two SIM algorithms,namely,optical sectioning SIM(OS-SIM)and superresolution SIM(SR-SIM),and summarize their implementation modalities.We then provide a brief overview of existing OS-SIM processing algorithms and review the development of SR-SIM reconstruction algorithms,focusing primarily on 2D-SIM,3D-SIM,and blind-SIM.To showcase the state-of-the-art development of SIM systems and assist users in selecting a commercial SIM system for a specific application,we compare the features of representative off-the-shelf SIM systems.Finally,we provide perspectives on the potential future developments of SIM.
基金supported by the National Key Research and Development Program of China(No.2017YFE0104200)the Beijing Natural Science Foundation(No.JQ18023)+1 种基金the National Natural Science Foundation of China(Nos.81421004 and 61971447)the National Key Instrumentation Development Project of China(No.2013YQ030651)。
文摘We present a novel noncontact ultrasound(US)and photoacoustic imaging(PAI)system,overcoming the limitations of traditional coupling media.Using a long coherent length laser,we employ a homodyne free-space Mach-Zehnder setup with zero-crossing triggering,achieving a noise equivalent pressure of 703 Pa at 5 MHz and a-6 dB bandwidth of 1 to8.54 MHz.We address the phase uncertainty inherent in the homodyne method.Scanning the noncontact US probe enables photoacoustic computed tomography(PACT).Phantom studies demonstrate imaging performance and system stability,underscoring the potential of our system for noncontact US sensing and PAI.
基金supported by the National Natural Science Foundation of China(21774061,22071112,and 61935017)National Key Laboratory(2009DS690095)+2 种基金Natural Science Foundation Major Research Program Integration Project(Grant Number 91833306)Natural Science Fund for Colleges and Universities in Jiangsu Province(20KJB150038)and Open Project from State Key Laboratory of Supramolecular Structure and Materials at jilin University(No.sklssm202014 and sklssm202108).
文摘High dielectric constants in organic semiconductors have been identified as a central challenge for the improvement in not only piexoelectric,preolecric,and freeltric efcts but also photoclecric conversion eficiency in OPVs,carrier mobility in OFETS,and charge density in charge-trapping memories.Herein,we report an ultralong persistence length(≈41 nm)efet of spiro-fused organic nanopolymers on dielectric properties,together with excitonic and charge carrier behaviors.The state-of-the-art nanopolymers,namely,nanopolyspirogrids(NPSGs),are synthesized via the simple crossscale Friedel-Crafts polygridlization of AjB-type nanomonomers.The high dielectric constant(k=8.43)of NPSG is firstly achieved by locking spiro-polygridization efect that results in the enhancement of dipole polarization.When doping into a polystyrene-based dielectric layer,such a high-k feature of NPSG increases the feld-ffct carrier mobility from 0.20 to 0.90cm^(2)Vl s'in pentacene OFET devices.Meanwhile,amorphous NPSG film exhibits an ultralow energy disorder(<50 meV)for an exellent zero-field hole mobility of 3.94×10^(-1)cm^(2)V^(-1)s^(-1).surpassing most of the amorphousπconjugated polymers Onganic nanopolymers with high dielectric constants open a new way to break through the bottleneck of eficiency and multifunctionality in the blueprint of the fourth generation semiconductors.
基金the National Natural Science Foundation of China(81890991,61705252,62025501,61729501,31971376)the State Key Research Development Program of China(2021YFE0201100,2017YFA0505503,2017YFC0110202)+3 种基金the Beijing Natural Science Foundation(JQ18019)CAS Interdisciplinary Innovation Team(JCTD-2020-04)Beijing Municipal Natural Science Foundation(Z200021)Shenzhen Science and Technology Program(KQTD20170810110913065).
文摘The orientation of fluorophores can reveal crucial information about the structure and dynamics of their associated subcellular organelles.Despite significant progress in super-resolution,fluorescence polarization microscopy remains limited to unique samples with relatively strong polarization modulation and not applicable to the weak polarization signals in samples due to the excessive background noise.Here we apply optical lock-in detection to amplify the weak polarization modulation with super-resolution.This novel technique,termed optical lock-in detection super-resolution dipole orientation mapping(OLID-SDOM),could achieve a maximum of 100 frames per second and rapid extraction of 2D orientation,and distinguish distance up to 50 nm,making it suitable for monitoring structural dynamics concerning orientation changes in vivo.OLID-SDOM was employed to explore the universal anisotropy of a large variety of GFP-tagged subcellular organelles,including mitochondria,lysosome,Golgi,endosome,etc.We found that OUF(Orientation Uniformity Factor)of OLID-SDOM can be specific for different subcellular organelles,indicating that the anisotropy was related to the function of the organelles,and OUF can potentially be an indicator to distinguish normal and abnormal cells(even cancer cells).Furthermore,dual-color super-resolution OLID-SDOM imaging of lysosomes and actins demonstrates its potential in studying dynamic molecular interactions.The subtle anisotropy changes of expanding and shrinking dendritic spines in live neurons were observed with real-time OLID-SDOM.Revealing previously unobservable fluorescence anisotropy in various samples and indicating their underlying dynamic molecular structural changes,OLID-SDOM expands the toolkit for live cell research.
基金Beijing Natural Science Foundation(JQ18019)National Natural Science Foundation of China(62025501,31971376,61729501)+1 种基金State Key Research Development Program of China(2017YFC0110202)Shenzhen Science and Technology Program(KQTD20170810110913065)。
文摘Achieving localization with molecular precision has been of great interest for extending fluorescence microscopy to nanoscopy.MINFLUX pioneers this transition through point spread function(PSF)engineering,yet its performance is primarily limited by the signal-to-background ratio.Here we demonstrate theoretically that two-photon MINFLUX(2p-MINFLUX)could double its localization precision through PSF engineering by nonlinear effect.Cramér-Rao Bound(CRB)is studied as the maximum localization precision,and CRB of two-photon MINFLUX is halved compared to single-photon MINFLUX(1p-MINFLUX)in all three dimensions.Meanwhile,in order to achieve same localization precision with 1p-MINFLUX,2p-MINFLUX requires only 1/4 of fluorescence photons.Exploiting simultaneous two-photon excitation of multiple fluorophore species,2p-MINFLUX may have the potential for registration-free nanoscopy and multicolor tracking.
