Hearing loss is one of the most prevalent sensory disorders affecting the human nervous system.Liquid–liquid phase separation(LLPS)is a physiological process that facilitates the reversible and dynamic assembly of bi...Hearing loss is one of the most prevalent sensory disorders affecting the human nervous system.Liquid–liquid phase separation(LLPS)is a physiological process that facilitates the reversible and dynamic assembly of biomolecular condensates.Increasing evidence suggests that LLPS plays a significant role in the pathogenesis of hereditary hearing loss.Nevertheless,there is a conspicuous lack of systematic investigations exploring the impact of LLPS abnormalities on the etiology of hereditary hearing loss.In this review,we examine the mechanisms by which dysfunctions in LLPS contribute to hereditary hearing loss,specifically focusing on its effects on mechanoelectrical transduction in hair bundles,transcriptional regulation,post-transcriptional modifications,the actin cytoskeleton,ion homeostasis within the inner ear,and energy and redox homeostasis.Furthermore,we evaluate the considerable potential of targeting LLPS as a therapeutic approach for hearing loss and propose innovative perspectives on LLPS that may guide future research initiatives in the field of auditory disorders.展开更多
Intracellular liquid-liquid phase separation(LLPS)represents a pivotal biological process for the formation of cellular compartments,which involves the formation of droplet-like condensates through the hydrophobic and...Intracellular liquid-liquid phase separation(LLPS)represents a pivotal biological process for the formation of cellular compartments,which involves the formation of droplet-like condensates through the hydrophobic and hydrophilic interactions of biomolecules.LLPS plays a crucial role in normal cellular physiological activities,and it is also intimately linked to the pathological mechanisms of various diseases.This review summarizes the significant role of LLPS in regulating transcriptional mechanisms within the nucleus,with a focus on the mechanisms by which LLPS modulates gene transcription.Additionally,we highlight the roles of key proteins involved in LLPS,such as FOXK1,BRD4,Tau protein,and HDAC6,in the context of disease.We delve into the relationships between LLPS and diseases such as chronic kidney disease,atherosclerosis,Alzheimer’s disease,and triple-negative breast cancer,revealing the regulatory mechanisms of LLPS in disease onset and progression.Furthermore,we discuss the potential of pharmacological interventions targeting LLPS as novel therapeutic approaches,encompassing strategies such as gene therapy,traditional Chinese medicine monomers,and small-molecule inhibitors.In the future,a deeper understanding of the LLPS mechanism will continue to propel its application in disease prevention and treatment,providing robust support for the development of novel therapeutic strategies.展开更多
Liquid-liquid phase separation(LLPS)or biomolecular condensation that leads to formation of membraneless organelles plays a critical role in many biochemical processes.Mechanism study of regulating LLPS is therefore c...Liquid-liquid phase separation(LLPS)or biomolecular condensation that leads to formation of membraneless organelles plays a critical role in many biochemical processes.Mechanism study of regulating LLPS is therefore central to the understanding of protein aggregation and disease-relevant process.We report a fused in sarcoma protein(FUS)-derived low complexity(LC)sequence that undergoes LLPS in the presence of metal ions.The LC protein was constructed by fusing a hexhistidine-tag to the N-terminal low complexity domain(the residues 1–165 in QGSY-rich segment)of FUS.Spontaneous condensation of the intrinsic disordered protein into coacervate droplets was observed in the presence of metal ions that chelate oligohistidine moieties to form protein matrix.We demonstrate the key role of metal ion-histidine coordination in governing LLPS behaviours and the fluidity of biomolecular condensates.By taking advantage of competitive binding using chelators,we show the possibility of regulating dynamic behaviors of disease-relevant protein droplets,and developing a potential approach towards controllable biological encapsulation/release.展开更多
The liquid-liquid phase separation(LLPS)widely exists in biology,synthetic chemistry,crystallization kinetics and other fields,and it is very important to realize the related functions.The research on the competition ...The liquid-liquid phase separation(LLPS)widely exists in biology,synthetic chemistry,crystallization kinetics and other fields,and it is very important to realize the related functions.The research on the competition between LLPS and micellization/vesiculation has made considerable progress.However,the way to effectively control the formation paths from homogeneous state to aggregates has not been completely solved,which is vital to determine its structure and properties and even its future functions.Here we describe the phenomenon of LLPS and its effect on the dynamic process of self-assembly of amphiphilic diblock copolymers(BCPs).Starting from the establishment of phase diagram,we explore the existence conditions of LLPS state,the internal morphology and external size of large droplets,and its significant implications to the dynamic path of vesicle formation.Vesicles formed via LLPS have larger sized outer dimensions and inner cavities,and contain more solvents during certain stages.The detailed research of LLPS and its self-assembly simulation has contributed to completing its theoretical basis and practical applications in the future in various fields.展开更多
A numerical model has been developed to describe the microstructural evolution of Al In immiscible alloys through the miscibility gap. The model considers the common action of nucleation, diffusible growth, Brownian c...A numerical model has been developed to describe the microstructural evolution of Al In immiscible alloys through the miscibility gap. The model considers the common action of nucleation, diffusible growth, Brownian collision and motion collision between the second phase droplets. The simulation results are dynamically visualized and show that the volume fraction, distribution and size of the second phase droplets satisfactorily agree with the experimental results. So the model can be used to predict the microstructural evolution of Al In immiscible alloys during the cooling process.展开更多
Liquid-liquid phase separation in the undercooled Ni-20%Pb(mole fraction, the same below if not mentioned) hypermonotectic melts was investigated by the observation of the water-quenched structure and DTA analysis. Th...Liquid-liquid phase separation in the undercooled Ni-20%Pb(mole fraction, the same below if not mentioned) hypermonotectic melts was investigated by the observation of the water-quenched structure and DTA analysis. The results indicate that the number of spherical cells in the water-quenched microstructure increases with dropping temperature, and the cells gather and grow up obviously. The spherical cell origins from L1 phase separated from homogeneous melt, and is the product of monotectic reaction. Both results of the water-quenched structures and DTA analysis prove that liquid phase separation still occurs in the highly undercooled Ni-Pb hypermonotectic alloy melts, and liquid phase separation in the immiscible gap can not be fully inhibited by high undercooling and rapid solidification.展开更多
Based on that the poly（acrylonitrile-co-maleic acid） （PANCMA）/DMSO/nonsolvent system agreed with the empirical linearized cloud point （LCP） relation, thermodynamics and kinetics of liquid-liquid phase separation...Based on that the poly（acrylonitrile-co-maleic acid） （PANCMA）/DMSO/nonsolvent system agreed with the empirical linearized cloud point （LCP） relation, thermodynamics and kinetics of liquid-liquid phase separation behavior of this system were investigated through coagulation value and phase diagram. It was found that adding solvent to the coagulation bath decreased the coagulation power and diffusion exchange rate of solvent and nonsolvent, and the system became more stable thermodynamically. On the other hand, the system with poly（vinyl alcohol） （PVA） as additive was thermodynamically less stable than that with poly （vinylpyrrolidone） （PVP） and/or not. In addition, the polymer solution system at higher temperature became thermodynamically more stable and had a higher nonsolvent tolerance. Moreover, higher temperature heightened the diffusion exchange rate of solvent and nonsolvent and accelerated phase separation. It is indicated that phase diagram and coagulation value offered some useful and necessary thermodynamic and kinetic information to establish optimal conditions and guide practical membrane fabrication in the results.展开更多
The quorum-sensing systems are sophisticated networks mediating intra-/inter-species bacterial communication[1].They have essential roles in bacterial community shaping,pathogenesis,infection,microbial-host interactio...The quorum-sensing systems are sophisticated networks mediating intra-/inter-species bacterial communication[1].They have essential roles in bacterial community shaping,pathogenesis,infection,microbial-host interaction,and natural product production,etc.They commonly employ auto-inducible transcriptional circuits,where the small molecule auto-inducers bind to receptor proteins and globally boost the gene expression responsible for the above biological processes[1,2].Thus,these systems are promising targets for transcriptional engineering for bacterial drug resistance[3]and cancer therapy[4].However,how the biological activities of transcriptional factors in quorum-sensing axes are regulated for the strict control of quorum sensing remains poorly understood.It has impeded the precise design of artificial quorum-sensing systems based on synthetic biology for more promising applications,such as drug design and gut commensal balance for human health[5].展开更多
Glioblastoma multiforme(GBM)remains the most aggressive and challenging central nervous system tumor due to the heterogeneity of the tumor microenvironment,prompting suboptimal effects to immune checkpoint blockade tr...Glioblastoma multiforme(GBM)remains the most aggressive and challenging central nervous system tumor due to the heterogeneity of the tumor microenvironment,prompting suboptimal effects to immune checkpoint blockade treatments.展开更多
To develop an efficient filter for removing white blood cells from whole blood,hydrophilic large-pore blended membranes of poly(vinylidene fluoride)(PVDF),polyvinyl pyrrolidone and polyethylene glycol,with good biocom...To develop an efficient filter for removing white blood cells from whole blood,hydrophilic large-pore blended membranes of poly(vinylidene fluoride)(PVDF),polyvinyl pyrrolidone and polyethylene glycol,with good biocompatibility,were prepared using the process of vapor-induced phase separation at various PVDF concentrations.The results demonstrated that at a PVDF mass concentration of 14%,the membrane had increased surface roughness,significantly enhanced hydrophilicity and wettability,and a wetting time of 8 s.The surface roughness of the membrane was also reduced to 31.637 nm.Furthermore,hemolysis rate and protein adsorption tests indicated that the blended membranes possessed excellent biocompatibility.They were reduced to 2.48%and 34.44μg·cm^(−2),respectively.The pore size of the fabricated membrane was relatively large,which reached approximately 8μm respectively,satisfying the filtration requirements.Lastly,the effects of different temperatures and multi-layered filters on leukocyte removal and the retention of red blood cells and platelets from whole blood were evaluated.The results revealed that the leukocyte removal rate was highest at 4℃ and with three membrane layers,the leukocyte removal rate was highest,reaching 98.36%,while the RBC and platelet content remained nearly unchanged compared with the original blood.This study provides a new approach for blood cell separation that is expected to play a significant role in medical fields such as blood transfusion demonstrating great potential for application and innovation.展开更多
Most cancers are currently incurable,partly due to abnormal post-translational modifications(PTMs).In this study,we initially used multiple myeloma(MM)as a working model and found that SUMOylation activating enzyme su...Most cancers are currently incurable,partly due to abnormal post-translational modifications(PTMs).In this study,we initially used multiple myeloma(MM)as a working model and found that SUMOylation activating enzyme subunit 1(SAE1)promotes the malignancy of MM.Through proteome microarray analysis,SAE1 was identified as a potential target for bioactive colcemid or its derivative colchicine.Elevated levels of SAE1 were associated with poor clinical survival and increased MM proliferation in vitro and in vivo.Additionally,SAE1 directly SUMOylated and upregulated the total protein expression of p27,leading to LLPS-mediated nuclear export of p27.Our study also demonstrated the involvement of SAE1 in other types of cancer cells,and provided the first monomer crystal structure of SAE1 and its key binding model with colchicine.Colchicine also showed promising results in the Patient-Derived Tumor Xenograft(PDX)model.Furthermore,a controlled clinical trial with 56 MM patients demonstrated the clinical efficacy of colchicine.Our findings reveal a novel mechanism by which tumor cells evade p27-induced cellular growth arrest through p27 SUMOylation-mediated nuclear export.SAE1 may serve as a promising therapeutic target,and colchicine may be a potential treatment option for multiple types of cancer in clinical settings.展开更多
Biomolecular self-assembly based on peptides and proteins is a general phenomenon encountered in natural and synthetic systems.Liquid–liquid phase separation(LLPS)is intimately involved in biomolecular self-assembly,...Biomolecular self-assembly based on peptides and proteins is a general phenomenon encountered in natural and synthetic systems.Liquid–liquid phase separation(LLPS)is intimately involved in biomolecular self-assembly,yet the key factors at a molecular scale activating or modulating such a process remain largely elusive.Herein,we discovered in our experiments that multistep desolvation is fundamental to the formation and evolution of peptide-rich droplets:The first step was partial desolvation of peptides to form peptide clusters,and the second step was selective desolvation of hydrophobic groups within clusters to trigger LLPS and the formation of peptiderich droplets,followed by complete desolvation of droplets,initiating the nucleation of peptide selfassembly.Manipulation of the degree of desolvation at different stages was an effective strategy to control the self-assembly pathways and polymorphisms.This study sheds light on the molecular origin of LLPS-mediated self-assembly distinct from classical one-step self-assembly and paves the way for the precise control of supramolecular self-assembly.展开更多
Identification of environmental stress sensors is one of the most important research topics in plant abiotic stress research.Traditional strategies to identify stress sensors or early signaling components based on the...Identification of environmental stress sensors is one of the most important research topics in plant abiotic stress research.Traditional strategies to identify stress sensors or early signaling components based on the cell membrane as a primary site of sensing and calcium signal as a second messenger have had only limited successes.Therefore,the current theoretical framework underlying stress sensing in plants should be reconsidered and additional mechanisms need to be introduced.Recently,accumulating evidence has emerged to suggest that liquid-liquid phase separation(LLPS)is a major mechanism for environmental stress sensing and response in plants.In this review,we briefly introduce LLPS regarding its concept,compositions,and dynamics,and then summarize recent progress of LLPS research in plants,emphasizing the contribution of LLPS to the sensing of various environmental stresses,such as dehydration,osmotic stress,and low and high temperatures.Finally,we propose strategies to identify key proteins that sense and respond to environmental stimuli on the basis of LLPS,and discuss the research directions of LLPS in plant abiotic stress responses and its potential application in enhancing stress tolerance in crops.展开更多
Biomolecular aggregation within cellular environments via liquid-liquid phase separation(LLPS)spontaneously forms droplet-like structures,which play pivotal roles in diverse biological processes.These structures are c...Biomolecular aggregation within cellular environments via liquid-liquid phase separation(LLPS)spontaneously forms droplet-like structures,which play pivotal roles in diverse biological processes.These structures are closely associated with a range of diseases,including neurodegenerative disorders,cancer and infectious diseases,highlighting the significance of understanding LLPS mechanisms for elucidating disease pathogenesis,and exploring potential therapeutic interventions.In this review,we delineate recent advancements in LLPS research,emphasizing its pathological relevance,therapeutic considerations,and the pivotal role of bioinformatic tools and databases in facilitating LLPS investigations.Additionally,we undertook a comprehensive analysis of bioinformatic resources dedicated to LLPS research in order to elucidate their functionality and applicability.By providing comprehensive insights into current LLPS-related bioinformatics resources,this review highlights its implications for human health and disease.展开更多
Bayan Obo rare earth mine is the largest light rare earth resource worldwide,primarily extracts rare earth elements(REEs)from mixed RE concentrates with bastnaesite and monazite.Nevertheless,the adoption of the concen...Bayan Obo rare earth mine is the largest light rare earth resource worldwide,primarily extracts rare earth elements(REEs)from mixed RE concentrates with bastnaesite and monazite.Nevertheless,the adoption of the concentrated sulfuric acid roasting metallurgical process has resulted in damage to the environment.Therefore,this paper adopted the method of selective mineral phase transformation(MPT)followed by enhanced micro-flotation.By determining the optimal MPT co nditions,the flotation recovery of bastnaesite-roasted products by the collector(phthalic acid,PA)is improved,and the enhanced separation of bastnaesite with monazite is realized.The results show that with the increase of roasting temperature and time,the bastnaesite decomposition product is CeOF and monazite does not change significantly.Subsequent micro-flotation exhibits a gradual decline in the PA consumption of bastnaesiteroasted products,while the flotation recovery of monazite-roasted products remains poor.The artificial mixed ore experiments result in a CeOF foam product with a content of 94.14%and a recovery of 85.80%,and a monazite tank product with a content of 73.53%and a recovery of 87.87%.Compared with the preroasting ore,the surface and interior of bastnaesite-roasted products develop numerous cracks and porosities,and no obvious structural damage is observed in monazite-roasted particles.As the roasting temperature increases,the mineral particles undergo recrystallization or closure,reducing the specific surface area of bastnaesite-roasted products and enhancing hydrophobicity,leading to diminished PA consumption.Fourier transform infrared and other flotation-relation tests show that PA is chemisorbed on the surface of CeOF.The MPT conditions are optimized in this study,which provides a reference for further advancing the efficient separation of bastnaesite and monazite.展开更多
Developing a chiral material as versatile and universal chiral stationary phase(CSP) for chiral separation in diverse chromatographic techniques simultaneously is of great significance.In this study,we demonstrated fo...Developing a chiral material as versatile and universal chiral stationary phase(CSP) for chiral separation in diverse chromatographic techniques simultaneously is of great significance.In this study,we demonstrated for the first time that a chiral metal-organic cage(MOC),[Zn_(6)M_(4)],as a universal chiral recognition material for both multi-mode high-performance liquid chromatography(HPLC) and capillary gas chromatography(GC) enantioseparation.Two novel HPLC CSPs with different bonding arms(CSP-A with a cationic imidazolium bonding arm and CSP-B with an alkyl chain bonding arm) were prepared by clicking of functionalized chiral MOC [Zn_(6)M_(4)] onto thiolated silica via thiol-ene click chemistry.Meanwhile,a capillary GC column statically coated with the chiral MOC [Zn_(6)M_(4)] was also fabricated.The results showed that the chiral MOC exhibits excellent enantioselectivity not only in normal phase HPLC(NP-HPLC) and reversed phase(RP-HPLC) but also in GC,and various racemates were well separated,including alcohols,diols,esters,ketones,ethers,amines,and epoxides.Importantly,CSP-A and CSP-B are complementary to commercially available Chiralcel OD-H and Chiralpak AD-H columns in enantioseparation,which can separate some racemates that could not be or could not well be separated by the two widely used commercial columns,suggesting the great potential of the two prepared CSPs in enantioseparation.This work reveals that the chiral MOC is potential versatile chiral recognition materials for both HPLC and GC,and also paves the way to expand the potential applications of MOCs.展开更多
Welding high-entropy alloy(HEA)to Mg alloy has gained increasing attention for multi-metal structure design,while intrinsic sluggish diffusion kinetics of HEA confines diffusion-controlled interfacial reactions and mak...Welding high-entropy alloy(HEA)to Mg alloy has gained increasing attention for multi-metal structure design,while intrinsic sluggish diffusion kinetics of HEA confines diffusion-controlled interfacial reactions and makes it challenging to establish robust metallurgical bonding.This study investigated welding of FeCoCrNiMn HEA to commercial AZ31 as a model combination to pioneer thisfield.Interfacial phase separation phenomenon was observed,with the diffusion accelerated by in-situ engineering a submicron-scale thick(∼400–500 nm)HEA nearby the interface into nanocrystalline-structure during friction stir welding.Abundant grain boundaries generated in this nanocrystalline-interlayer serve as diffusion short-circuits and energetically preferred nucleation-sites,which promoted Al in AZ31 to diffuse into HEA and triggered quick separation into body-centered cubic AlNi-type and tetragonal FeCr-type intermetallics.HEA and AZ31 were thus metallurgically bonded by these interfacial intermetallics.The joint shows exceptional strength in tensile lap-shear testing with fracture largely occurred within AZ31 rather than right along interface as commonly reported previously for dissimilar joints.展开更多
The research,fabrication and development of piezoelectric nanofibrous materials offer effective solutions to the challenges related to energy consumption and non-renewable resources.However,enhancing their electrical ...The research,fabrication and development of piezoelectric nanofibrous materials offer effective solutions to the challenges related to energy consumption and non-renewable resources.However,enhancing their electrical output still remains a significant challenge.Here,a strategy of inducing constrained phase separation on single nanofibers via shear force was proposed.Employing electrospinning technology,a polyacrylonitrile/polyvinylidene difluoride(PAN/PVDF)nanofibrous membrane was fabricated in one step,which enabled simultaneous piezoelectric and triboelectric conversion within a single-layer membrane.Each nanofiber contained independent components of PAN and PVDF and exhibited a rough surface.The abundant frictional contact points formed between these heterogeneous components contributed to an enhanced endogenous triboelectric output,showcasing an excellent synergistic effect of piezoelectric and triboelectric response in the nanofibrous membrane.Additionally,the component mass ratio influenced the microstructure,piezoelectric conformation and piezoelectric performance of the PAN/PVDF nanofibrous membranes.Through comprehensive performance comparison,the optimal mass ratio of PAN to PVDF was determined to be 9∶1.The piezoelectric devices made of the optimal PAN/PVDF nanofibrous membranes with rough nanofiber surfaces generated an output voltage of 20 V,which was about 1.8 times that of the smooth one at the same component mass ratio.The strategy of constrained phase separation on the surface of individual nanofibers provides a new approach to enhance the output performance of single-layer piezoelectric nanofibrous materials.展开更多
TiAl alloys with the(α2+γ)lamellar structure are highly valued for their excellent high-temperature strength and creep resistance.Understanding the formation mechanism of the lamellar structure is crucial for tuning...TiAl alloys with the(α2+γ)lamellar structure are highly valued for their excellent high-temperature strength and creep resistance.Understanding the formation mechanism of the lamellar structure is crucial for tuning the microstructure and properties.This work investigates the formation of lamellar structure in Ti-48AI-7Nb-2.5V-1Cr alloy,revealing the presence of hcp-based long-period superstructure(hcp-LPS)as a metastable phase during lamellar formation.The identification of hcp-LPS demonstrates that the necessary solute enrichment for the formation ofγlamellae occurs on the hexagonalαmatrix,implying that phase separation ofα→Al-richαlamellae+Al-depletedαlamellae is the first step of lamellar formation.Once phase separation is completed,all subsequent phase transitions occur within the Al-richαlamellae.Additionally,the formation of twin lamellae is further discussed.The formation of the twin lamellae occurs sequentially.Pre-existing lamella promotes the formation of later lamella by inducing so-lute enrichment in its surrounding region,and then the successive slip of Shockley partial dislocations with opposite Burgers vectors ensures special stacking of later lamellae.These findings not only con-tribute to the fundamental understanding of spinodal mechanisms in hexagonal crystals,but also provide novel insights into the formation of twin lamellae.展开更多
Cells are compartmentalized by numerous membrane-enclosed organelles and membraneless compartments to ensure that a wide variety of cellular activities occur in a spatially and temporally controlled manner. The molecu...Cells are compartmentalized by numerous membrane-enclosed organelles and membraneless compartments to ensure that a wide variety of cellular activities occur in a spatially and temporally controlled manner. The molecular mechanisms underlying the dynamics of membrane-bound organelles, such as their fusion and fission, vesicle-mediated trafficking and membrane contactmediated inter-organelle interactions, have been extensively characterized. However, the molecular details of the assembly and functions of membraneless compartments remain elusive. Mounting evidence has emerged recently that a large number of membraneless compartments, collectively called biomacromolecular condensates, are assembled via liquid-liquid phase separation(LLPS). Phase-separated condensates participate in various biological activities, including higher-order chromatin organization,gene expression, triage of misfolded or unwanted proteins for autophagic degradation, assembly of signaling clusters and actin-and microtubule-based cytoskeletal networks, asymmetric segregations of cell fate determinants and formation of pre-and post-synaptic density signaling assemblies. Biomacromolecular condensates can transition into different material states such as gel-like structures and solid aggregates. The material properties of condensates are crucial for fulfilment of their distinct functions, such as biochemical reaction centers, signaling hubs and supporting architectures. Cells have evolved multiple mechanisms to ensure that biomacromolecular condensates are assembled and disassembled in a tightly controlled manner. Aberrant phase separation and transition are causatively associated with a variety of human diseases such as neurodegenerative diseases and cancers. This review summarizes recent major progress in elucidating the roles of LLPS in various biological pathways and diseases.展开更多
基金supported by the National Natural Science Foundation of China(82430035)the Foundation for Innovative Research Groups of Hubei Province(2023AFA038)+1 种基金the National Key Research and Development Program of China(2021YFF0702303,2024YFC2511101,and 2023YFE0203200)the Fundamental Research Funds for the Central Universities(2024BRA019).
文摘Hearing loss is one of the most prevalent sensory disorders affecting the human nervous system.Liquid–liquid phase separation(LLPS)is a physiological process that facilitates the reversible and dynamic assembly of biomolecular condensates.Increasing evidence suggests that LLPS plays a significant role in the pathogenesis of hereditary hearing loss.Nevertheless,there is a conspicuous lack of systematic investigations exploring the impact of LLPS abnormalities on the etiology of hereditary hearing loss.In this review,we examine the mechanisms by which dysfunctions in LLPS contribute to hereditary hearing loss,specifically focusing on its effects on mechanoelectrical transduction in hair bundles,transcriptional regulation,post-transcriptional modifications,the actin cytoskeleton,ion homeostasis within the inner ear,and energy and redox homeostasis.Furthermore,we evaluate the considerable potential of targeting LLPS as a therapeutic approach for hearing loss and propose innovative perspectives on LLPS that may guide future research initiatives in the field of auditory disorders.
基金supported by the Hebei Natural Science Foundation(Grant No.H2022110019).Peer review。
文摘Intracellular liquid-liquid phase separation(LLPS)represents a pivotal biological process for the formation of cellular compartments,which involves the formation of droplet-like condensates through the hydrophobic and hydrophilic interactions of biomolecules.LLPS plays a crucial role in normal cellular physiological activities,and it is also intimately linked to the pathological mechanisms of various diseases.This review summarizes the significant role of LLPS in regulating transcriptional mechanisms within the nucleus,with a focus on the mechanisms by which LLPS modulates gene transcription.Additionally,we highlight the roles of key proteins involved in LLPS,such as FOXK1,BRD4,Tau protein,and HDAC6,in the context of disease.We delve into the relationships between LLPS and diseases such as chronic kidney disease,atherosclerosis,Alzheimer’s disease,and triple-negative breast cancer,revealing the regulatory mechanisms of LLPS in disease onset and progression.Furthermore,we discuss the potential of pharmacological interventions targeting LLPS as novel therapeutic approaches,encompassing strategies such as gene therapy,traditional Chinese medicine monomers,and small-molecule inhibitors.In the future,a deeper understanding of the LLPS mechanism will continue to propel its application in disease prevention and treatment,providing robust support for the development of novel therapeutic strategies.
基金financially supported by the National Natural Science Foundation of China (Nos. 22072159 and 22172007)the Fundamental Research Funds for the Central Universities(No. buctrc202015)
文摘Liquid-liquid phase separation(LLPS)or biomolecular condensation that leads to formation of membraneless organelles plays a critical role in many biochemical processes.Mechanism study of regulating LLPS is therefore central to the understanding of protein aggregation and disease-relevant process.We report a fused in sarcoma protein(FUS)-derived low complexity(LC)sequence that undergoes LLPS in the presence of metal ions.The LC protein was constructed by fusing a hexhistidine-tag to the N-terminal low complexity domain(the residues 1–165 in QGSY-rich segment)of FUS.Spontaneous condensation of the intrinsic disordered protein into coacervate droplets was observed in the presence of metal ions that chelate oligohistidine moieties to form protein matrix.We demonstrate the key role of metal ion-histidine coordination in governing LLPS behaviours and the fluidity of biomolecular condensates.By taking advantage of competitive binding using chelators,we show the possibility of regulating dynamic behaviors of disease-relevant protein droplets,and developing a potential approach towards controllable biological encapsulation/release.
基金This work was financially supported by the National Natural Science Foundation of China(Nos.21973041,21674047,21474051 and 21734005)the Program for Changjiang Scholars and Innovative Research Team in University(PCSIRT)the Fundamental Research Funds for the Central Universities.
文摘The liquid-liquid phase separation(LLPS)widely exists in biology,synthetic chemistry,crystallization kinetics and other fields,and it is very important to realize the related functions.The research on the competition between LLPS and micellization/vesiculation has made considerable progress.However,the way to effectively control the formation paths from homogeneous state to aggregates has not been completely solved,which is vital to determine its structure and properties and even its future functions.Here we describe the phenomenon of LLPS and its effect on the dynamic process of self-assembly of amphiphilic diblock copolymers(BCPs).Starting from the establishment of phase diagram,we explore the existence conditions of LLPS state,the internal morphology and external size of large droplets,and its significant implications to the dynamic path of vesicle formation.Vesicles formed via LLPS have larger sized outer dimensions and inner cavities,and contain more solvents during certain stages.The detailed research of LLPS and its self-assembly simulation has contributed to completing its theoretical basis and practical applications in the future in various fields.
文摘A numerical model has been developed to describe the microstructural evolution of Al In immiscible alloys through the miscibility gap. The model considers the common action of nucleation, diffusible growth, Brownian collision and motion collision between the second phase droplets. The simulation results are dynamically visualized and show that the volume fraction, distribution and size of the second phase droplets satisfactorily agree with the experimental results. So the model can be used to predict the microstructural evolution of Al In immiscible alloys during the cooling process.
基金Project(50171055) supported by the National Natural Science Foundation of China Project(2004E108) supported by Shaanxi Natural Science Foundation, China+1 种基金 Project(03JK132) supported by Shaanxi Education Bureau Foundation, China Project(200208) supported by the Doctorate Creation Foundation of Northwestern Polytechnical University
文摘Liquid-liquid phase separation in the undercooled Ni-20%Pb(mole fraction, the same below if not mentioned) hypermonotectic melts was investigated by the observation of the water-quenched structure and DTA analysis. The results indicate that the number of spherical cells in the water-quenched microstructure increases with dropping temperature, and the cells gather and grow up obviously. The spherical cell origins from L1 phase separated from homogeneous melt, and is the product of monotectic reaction. Both results of the water-quenched structures and DTA analysis prove that liquid phase separation still occurs in the highly undercooled Ni-Pb hypermonotectic alloy melts, and liquid phase separation in the immiscible gap can not be fully inhibited by high undercooling and rapid solidification.
基金Acknowledgements： The financial supports of the National Research Fund of Fundamental Key Projects （2007CB936403） and the National Natural Science Foundation of China （20571077） are gratefully acknowledged.
文摘Based on that the poly（acrylonitrile-co-maleic acid） （PANCMA）/DMSO/nonsolvent system agreed with the empirical linearized cloud point （LCP） relation, thermodynamics and kinetics of liquid-liquid phase separation behavior of this system were investigated through coagulation value and phase diagram. It was found that adding solvent to the coagulation bath decreased the coagulation power and diffusion exchange rate of solvent and nonsolvent, and the system became more stable thermodynamically. On the other hand, the system with poly（vinyl alcohol） （PVA） as additive was thermodynamically less stable than that with poly （vinylpyrrolidone） （PVP） and/or not. In addition, the polymer solution system at higher temperature became thermodynamically more stable and had a higher nonsolvent tolerance. Moreover, higher temperature heightened the diffusion exchange rate of solvent and nonsolvent and accelerated phase separation. It is indicated that phase diagram and coagulation value offered some useful and necessary thermodynamic and kinetic information to establish optimal conditions and guide practical membrane fabrication in the results.
基金supported by the National Key Research and Development Program of China(2021YFA0909900)the National Natural Science Foundation of China(32070039 and 32370022).
文摘The quorum-sensing systems are sophisticated networks mediating intra-/inter-species bacterial communication[1].They have essential roles in bacterial community shaping,pathogenesis,infection,microbial-host interaction,and natural product production,etc.They commonly employ auto-inducible transcriptional circuits,where the small molecule auto-inducers bind to receptor proteins and globally boost the gene expression responsible for the above biological processes[1,2].Thus,these systems are promising targets for transcriptional engineering for bacterial drug resistance[3]and cancer therapy[4].However,how the biological activities of transcriptional factors in quorum-sensing axes are regulated for the strict control of quorum sensing remains poorly understood.It has impeded the precise design of artificial quorum-sensing systems based on synthetic biology for more promising applications,such as drug design and gut commensal balance for human health[5].
文摘Glioblastoma multiforme(GBM)remains the most aggressive and challenging central nervous system tumor due to the heterogeneity of the tumor microenvironment,prompting suboptimal effects to immune checkpoint blockade treatments.
基金The National Key Research and Development Program of China(2020YFC0862903)Supported by Jiangsu Future Membrane Technology Innovation Center(BM2021804)National Foreign Expert Program(H20240294).
文摘To develop an efficient filter for removing white blood cells from whole blood,hydrophilic large-pore blended membranes of poly(vinylidene fluoride)(PVDF),polyvinyl pyrrolidone and polyethylene glycol,with good biocompatibility,were prepared using the process of vapor-induced phase separation at various PVDF concentrations.The results demonstrated that at a PVDF mass concentration of 14%,the membrane had increased surface roughness,significantly enhanced hydrophilicity and wettability,and a wetting time of 8 s.The surface roughness of the membrane was also reduced to 31.637 nm.Furthermore,hemolysis rate and protein adsorption tests indicated that the blended membranes possessed excellent biocompatibility.They were reduced to 2.48%and 34.44μg·cm^(−2),respectively.The pore size of the fabricated membrane was relatively large,which reached approximately 8μm respectively,satisfying the filtration requirements.Lastly,the effects of different temperatures and multi-layered filters on leukocyte removal and the retention of red blood cells and platelets from whole blood were evaluated.The results revealed that the leukocyte removal rate was highest at 4℃ and with three membrane layers,the leukocyte removal rate was highest,reaching 98.36%,while the RBC and platelet content remained nearly unchanged compared with the original blood.This study provides a new approach for blood cell separation that is expected to play a significant role in medical fields such as blood transfusion demonstrating great potential for application and innovation.
基金supported by National Natural Science Foundation of China(82341230 to Ye Yang)Basic Research Plan(Natural Science Foundation)in“Climbing”Program of Jiangsu Province(BK20240003 to Ye Yang,China)+1 种基金Science and Technology Development Plan Project of Jiangsu Provincial Administration of Traditional Chinese Medicine(ZD202203 to Chunyan Gu,China)a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions(Traditional Chinese Medicine,Integration of Chinese and Western Medicine)(China).
文摘Most cancers are currently incurable,partly due to abnormal post-translational modifications(PTMs).In this study,we initially used multiple myeloma(MM)as a working model and found that SUMOylation activating enzyme subunit 1(SAE1)promotes the malignancy of MM.Through proteome microarray analysis,SAE1 was identified as a potential target for bioactive colcemid or its derivative colchicine.Elevated levels of SAE1 were associated with poor clinical survival and increased MM proliferation in vitro and in vivo.Additionally,SAE1 directly SUMOylated and upregulated the total protein expression of p27,leading to LLPS-mediated nuclear export of p27.Our study also demonstrated the involvement of SAE1 in other types of cancer cells,and provided the first monomer crystal structure of SAE1 and its key binding model with colchicine.Colchicine also showed promising results in the Patient-Derived Tumor Xenograft(PDX)model.Furthermore,a controlled clinical trial with 56 MM patients demonstrated the clinical efficacy of colchicine.Our findings reveal a novel mechanism by which tumor cells evade p27-induced cellular growth arrest through p27 SUMOylation-mediated nuclear export.SAE1 may serve as a promising therapeutic target,and colchicine may be a potential treatment option for multiple types of cancer in clinical settings.
基金supported by the National Science Fund for Distinguished Young Scholars of China(grant no.22025207)National Natural Science Foundation of China(grant nos.22172172 and 22232006)+3 种基金Youth Innovation Promotion Association of CAS(grant no.2022049)China Scholarship Council(CSC,grant no.202104910187)IPE Project for Frontier Basic Research(grant no.QYJC-2022-011)Natural Science Foundation of Hebei Province(grant nos.B2020103036 and B2020103025).
文摘Biomolecular self-assembly based on peptides and proteins is a general phenomenon encountered in natural and synthetic systems.Liquid–liquid phase separation(LLPS)is intimately involved in biomolecular self-assembly,yet the key factors at a molecular scale activating or modulating such a process remain largely elusive.Herein,we discovered in our experiments that multistep desolvation is fundamental to the formation and evolution of peptide-rich droplets:The first step was partial desolvation of peptides to form peptide clusters,and the second step was selective desolvation of hydrophobic groups within clusters to trigger LLPS and the formation of peptiderich droplets,followed by complete desolvation of droplets,initiating the nucleation of peptide selfassembly.Manipulation of the degree of desolvation at different stages was an effective strategy to control the self-assembly pathways and polymorphisms.This study sheds light on the molecular origin of LLPS-mediated self-assembly distinct from classical one-step self-assembly and paves the way for the precise control of supramolecular self-assembly.
基金supported by the National Natural Science Foundation of China(Grant No.32270283 and 32070295)the Science and Technology Commission of Shanghai Municipality(Grant no.22ZR1469600).
文摘Identification of environmental stress sensors is one of the most important research topics in plant abiotic stress research.Traditional strategies to identify stress sensors or early signaling components based on the cell membrane as a primary site of sensing and calcium signal as a second messenger have had only limited successes.Therefore,the current theoretical framework underlying stress sensing in plants should be reconsidered and additional mechanisms need to be introduced.Recently,accumulating evidence has emerged to suggest that liquid-liquid phase separation(LLPS)is a major mechanism for environmental stress sensing and response in plants.In this review,we briefly introduce LLPS regarding its concept,compositions,and dynamics,and then summarize recent progress of LLPS research in plants,emphasizing the contribution of LLPS to the sensing of various environmental stresses,such as dehydration,osmotic stress,and low and high temperatures.Finally,we propose strategies to identify key proteins that sense and respond to environmental stimuli on the basis of LLPS,and discuss the research directions of LLPS in plant abiotic stress responses and its potential application in enhancing stress tolerance in crops.
基金funded by grants from the Natural Science Foundation of Guangdong Province,China(No.2023A1515010148)the Postdoctoral Fellowship Program of CPSF(No.GZC20241143)+2 种基金the China Postdoctoral Science Foundation(No.2024M752202)the National Natural Youth Science Foundation of China(No.32100927)the National Natural Science Foundation of China(No.81970481).
文摘Biomolecular aggregation within cellular environments via liquid-liquid phase separation(LLPS)spontaneously forms droplet-like structures,which play pivotal roles in diverse biological processes.These structures are closely associated with a range of diseases,including neurodegenerative disorders,cancer and infectious diseases,highlighting the significance of understanding LLPS mechanisms for elucidating disease pathogenesis,and exploring potential therapeutic interventions.In this review,we delineate recent advancements in LLPS research,emphasizing its pathological relevance,therapeutic considerations,and the pivotal role of bioinformatic tools and databases in facilitating LLPS investigations.Additionally,we undertook a comprehensive analysis of bioinformatic resources dedicated to LLPS research in order to elucidate their functionality and applicability.By providing comprehensive insights into current LLPS-related bioinformatics resources,this review highlights its implications for human health and disease.
基金Project supported by the National Key R&D Program of China(2022YFC2905800)the National Natural Science Foundation of China(52174242)the National Youth Talent Support Program(QNBJ-2023-03)。
文摘Bayan Obo rare earth mine is the largest light rare earth resource worldwide,primarily extracts rare earth elements(REEs)from mixed RE concentrates with bastnaesite and monazite.Nevertheless,the adoption of the concentrated sulfuric acid roasting metallurgical process has resulted in damage to the environment.Therefore,this paper adopted the method of selective mineral phase transformation(MPT)followed by enhanced micro-flotation.By determining the optimal MPT co nditions,the flotation recovery of bastnaesite-roasted products by the collector(phthalic acid,PA)is improved,and the enhanced separation of bastnaesite with monazite is realized.The results show that with the increase of roasting temperature and time,the bastnaesite decomposition product is CeOF and monazite does not change significantly.Subsequent micro-flotation exhibits a gradual decline in the PA consumption of bastnaesiteroasted products,while the flotation recovery of monazite-roasted products remains poor.The artificial mixed ore experiments result in a CeOF foam product with a content of 94.14%and a recovery of 85.80%,and a monazite tank product with a content of 73.53%and a recovery of 87.87%.Compared with the preroasting ore,the surface and interior of bastnaesite-roasted products develop numerous cracks and porosities,and no obvious structural damage is observed in monazite-roasted particles.As the roasting temperature increases,the mineral particles undergo recrystallization or closure,reducing the specific surface area of bastnaesite-roasted products and enhancing hydrophobicity,leading to diminished PA consumption.Fourier transform infrared and other flotation-relation tests show that PA is chemisorbed on the surface of CeOF.The MPT conditions are optimized in this study,which provides a reference for further advancing the efficient separation of bastnaesite and monazite.
基金supported by the National Natural Science Foundation of China (Nos.22064020,22364022,and 22174125)the Applied Basic Research Foundation of Yunnan Province (Nos.202101AT070101 and 202201AT070029)。
文摘Developing a chiral material as versatile and universal chiral stationary phase(CSP) for chiral separation in diverse chromatographic techniques simultaneously is of great significance.In this study,we demonstrated for the first time that a chiral metal-organic cage(MOC),[Zn_(6)M_(4)],as a universal chiral recognition material for both multi-mode high-performance liquid chromatography(HPLC) and capillary gas chromatography(GC) enantioseparation.Two novel HPLC CSPs with different bonding arms(CSP-A with a cationic imidazolium bonding arm and CSP-B with an alkyl chain bonding arm) were prepared by clicking of functionalized chiral MOC [Zn_(6)M_(4)] onto thiolated silica via thiol-ene click chemistry.Meanwhile,a capillary GC column statically coated with the chiral MOC [Zn_(6)M_(4)] was also fabricated.The results showed that the chiral MOC exhibits excellent enantioselectivity not only in normal phase HPLC(NP-HPLC) and reversed phase(RP-HPLC) but also in GC,and various racemates were well separated,including alcohols,diols,esters,ketones,ethers,amines,and epoxides.Importantly,CSP-A and CSP-B are complementary to commercially available Chiralcel OD-H and Chiralpak AD-H columns in enantioseparation,which can separate some racemates that could not be or could not well be separated by the two widely used commercial columns,suggesting the great potential of the two prepared CSPs in enantioseparation.This work reveals that the chiral MOC is potential versatile chiral recognition materials for both HPLC and GC,and also paves the way to expand the potential applications of MOCs.
基金supported by the National Natural Science Foundation of China[Grant numbers:52475385,52305392]the China Postdoctoral Science Foundation(Grant No.2022M722048).
文摘Welding high-entropy alloy(HEA)to Mg alloy has gained increasing attention for multi-metal structure design,while intrinsic sluggish diffusion kinetics of HEA confines diffusion-controlled interfacial reactions and makes it challenging to establish robust metallurgical bonding.This study investigated welding of FeCoCrNiMn HEA to commercial AZ31 as a model combination to pioneer thisfield.Interfacial phase separation phenomenon was observed,with the diffusion accelerated by in-situ engineering a submicron-scale thick(∼400–500 nm)HEA nearby the interface into nanocrystalline-structure during friction stir welding.Abundant grain boundaries generated in this nanocrystalline-interlayer serve as diffusion short-circuits and energetically preferred nucleation-sites,which promoted Al in AZ31 to diffuse into HEA and triggered quick separation into body-centered cubic AlNi-type and tetragonal FeCr-type intermetallics.HEA and AZ31 were thus metallurgically bonded by these interfacial intermetallics.The joint shows exceptional strength in tensile lap-shear testing with fracture largely occurred within AZ31 rather than right along interface as commonly reported previously for dissimilar joints.
基金National Natural Science Foundation of China(No.52373281)National Energy-Saving and Low-Carbon Materials Production and Application Demonstration Platform Program,China(No.TC220H06N)。
文摘The research,fabrication and development of piezoelectric nanofibrous materials offer effective solutions to the challenges related to energy consumption and non-renewable resources.However,enhancing their electrical output still remains a significant challenge.Here,a strategy of inducing constrained phase separation on single nanofibers via shear force was proposed.Employing electrospinning technology,a polyacrylonitrile/polyvinylidene difluoride(PAN/PVDF)nanofibrous membrane was fabricated in one step,which enabled simultaneous piezoelectric and triboelectric conversion within a single-layer membrane.Each nanofiber contained independent components of PAN and PVDF and exhibited a rough surface.The abundant frictional contact points formed between these heterogeneous components contributed to an enhanced endogenous triboelectric output,showcasing an excellent synergistic effect of piezoelectric and triboelectric response in the nanofibrous membrane.Additionally,the component mass ratio influenced the microstructure,piezoelectric conformation and piezoelectric performance of the PAN/PVDF nanofibrous membranes.Through comprehensive performance comparison,the optimal mass ratio of PAN to PVDF was determined to be 9∶1.The piezoelectric devices made of the optimal PAN/PVDF nanofibrous membranes with rough nanofiber surfaces generated an output voltage of 20 V,which was about 1.8 times that of the smooth one at the same component mass ratio.The strategy of constrained phase separation on the surface of individual nanofibers provides a new approach to enhance the output performance of single-layer piezoelectric nanofibrous materials.
基金supported by the National Science and Technology Major Project of China(No.J2019-VI-0011-0125)ND Basic Research Funds of China(No.G2022WD)Shaanxi Province Innovation Capability Support Program(No.2023-CX-TD-47).
文摘TiAl alloys with the(α2+γ)lamellar structure are highly valued for their excellent high-temperature strength and creep resistance.Understanding the formation mechanism of the lamellar structure is crucial for tuning the microstructure and properties.This work investigates the formation of lamellar structure in Ti-48AI-7Nb-2.5V-1Cr alloy,revealing the presence of hcp-based long-period superstructure(hcp-LPS)as a metastable phase during lamellar formation.The identification of hcp-LPS demonstrates that the necessary solute enrichment for the formation ofγlamellae occurs on the hexagonalαmatrix,implying that phase separation ofα→Al-richαlamellae+Al-depletedαlamellae is the first step of lamellar formation.Once phase separation is completed,all subsequent phase transitions occur within the Al-richαlamellae.Additionally,the formation of twin lamellae is further discussed.The formation of the twin lamellae occurs sequentially.Pre-existing lamella promotes the formation of later lamella by inducing so-lute enrichment in its surrounding region,and then the successive slip of Shockley partial dislocations with opposite Burgers vectors ensures special stacking of later lamellae.These findings not only con-tribute to the fundamental understanding of spinodal mechanisms in hexagonal crystals,but also provide novel insights into the formation of twin lamellae.
基金supported by grants from the Beijing Municipal Science and Technology Committee (Z181100001318003)the National Natural Science Foundation of China (31421002, 31561143001,31630048, and 31790403)+17 种基金the National Natural Science Foundation of China (91853113 and 31872716)the National Natural Science Foundation of China (11672317)the National Natural Science Foundation of China (31871394 and 31670730)supported by grants from the National Natural Science Foundation of China (31420103916 and 31991192)the Ministry of Science and Technology of China (2017YFA0503401)supported by grants from the Ministry of Science and Technology of China (2019YFA0707000)supported by grants from the Ministry of Science and Technology of China (2019YFA0508401)the Strategic Priority Research Program of the Chinese Academy of Sciences (CAS) (XDB19000000)the Key Research Program of Frontier Sciences, CAS (QYZDY-SSW-SMC006)supported by funds from the Ministry of Science and Technology of China and the National Natural Science Foundation of China (2017YFA0506600 and 31871309)supported by funds from the Ministry of Science and Technology of China and the National Natural Science Foundation of China (2019YFA0508403 and 31871443)supported by grants from the Ministry of Science and Technology of China (2016YFA0501902)the Science and Technology Commission of Shanghai Municipality (18JC1420500)the Shanghai Municipal Science and Technology Major Project (2019SHZDZX02)the Shanghai Municipal Science and Technology Major Project (2018SHZDZX01)CAS (XDB19020102)supported by grants from RGC of Hong Kong (AoE-M09-12 and C6004-17G)National Key R&D Program of China (2016YFA0501903 and 2019YFA0508402)。
文摘Cells are compartmentalized by numerous membrane-enclosed organelles and membraneless compartments to ensure that a wide variety of cellular activities occur in a spatially and temporally controlled manner. The molecular mechanisms underlying the dynamics of membrane-bound organelles, such as their fusion and fission, vesicle-mediated trafficking and membrane contactmediated inter-organelle interactions, have been extensively characterized. However, the molecular details of the assembly and functions of membraneless compartments remain elusive. Mounting evidence has emerged recently that a large number of membraneless compartments, collectively called biomacromolecular condensates, are assembled via liquid-liquid phase separation(LLPS). Phase-separated condensates participate in various biological activities, including higher-order chromatin organization,gene expression, triage of misfolded or unwanted proteins for autophagic degradation, assembly of signaling clusters and actin-and microtubule-based cytoskeletal networks, asymmetric segregations of cell fate determinants and formation of pre-and post-synaptic density signaling assemblies. Biomacromolecular condensates can transition into different material states such as gel-like structures and solid aggregates. The material properties of condensates are crucial for fulfilment of their distinct functions, such as biochemical reaction centers, signaling hubs and supporting architectures. Cells have evolved multiple mechanisms to ensure that biomacromolecular condensates are assembled and disassembled in a tightly controlled manner. Aberrant phase separation and transition are causatively associated with a variety of human diseases such as neurodegenerative diseases and cancers. This review summarizes recent major progress in elucidating the roles of LLPS in various biological pathways and diseases.
