Spectrin domains,characterized by a distinctive triple helix structure,are crucial in physiological processes,particularly in maintaining membrane shape and crosslinking cytoskeletons.Previous research on the 16th dom...Spectrin domains,characterized by a distinctive triple helix structure,are crucial in physiological processes,particularly in maintaining membrane shape and crosslinking cytoskeletons.Previous research on the 16th domain of a-spectrin repeats(R16)has yielded conflicting results:bulk experiments showed an unfolding rate approximately two orders of magnitude faster than the zero-force result extrapolated from single-molecule force spectroscopy experiments using atomic force microscopy(AFM).To address this discrepancy,we investigated the folding and unfolding rates of R16 across a broader range of forces using magnetic tweezers(MT).Our findings reveal that AFM results at higher forces cannot be directly extrapolated to the low-force regime due to a nonlinear relationship between force and the logarithm of the unfolding rate.We demonstrated that two-dimensional model,structural-elastic model,and two-pathway model can all effectively explain the experimental data when they capture the core physics of the short unfolding distance at low forces.Our study provides a more comprehensive understanding of the unfolding dynamics of the spectrin domain,resolves previous contradictory experimental results,and highlights the common basis of different theoretical models.展开更多
Despite the expansive applications of gas-phase unfolding techniques,the molecular mechanism for the solvent-free forced unfolding pathway which substrate multidomain proteins usually adopt remains elusive at the seco...Despite the expansive applications of gas-phase unfolding techniques,the molecular mechanism for the solvent-free forced unfolding pathway which substrate multidomain proteins usually adopt remains elusive at the secondary structure level.Herein,upon carefully selecting CRM_(197) as a therapeutically-relevant model system containing multiple secondary structure-separated domains,we systematically examine its solvent-free unfolding pathway.Further-more,utilizing the hybrid of noncovalent chemical probing with niacinamide and ion mobility-mass spectrometry-guided all-atom molecular dynamics simulations,we map a nearly complete unfolding atlas for the conjugate vaccine carrier protein CRM_(197) in a domain-and secondary structure-resolved manner.The totality of our data supports the preferential unfolding of the sheet-rich domain,indicating the dynamic transition from β-sheet toα-helix,and demonstrating that helix exhibit comparatively higher stability thanβ-sheets.We propose that this sheet-to-helix dynamic transition may be central to the gas-phase unfolding pathways of multidomain proteins,suggesting the need for systematic studies on additional multidomain protein systems.展开更多
In this study,circular dichroism(CD)and molecular dynamics(MD)simulation were used to investigate the thermal unfolding pathway of staphylococcal enterotoxin B(SEB)at temperatures of 298–371 and 298–500 K,and the re...In this study,circular dichroism(CD)and molecular dynamics(MD)simulation were used to investigate the thermal unfolding pathway of staphylococcal enterotoxin B(SEB)at temperatures of 298–371 and 298–500 K,and the relationship between the experimental and simulation results were explored.Our computational findings on the secondary structure of SEB showed that at room temperature,the CD spectroscopic results were highly consistent with the MD results.Moreover,under heating conditions,the changing trends of helix,sheet and random coil obtained by CD spectral fitting were highly consistent with those obtained by MD.In order to gain a deeper understanding of the thermal stability mechanism of SEB,the MD trajectories were analyzed in terms of root mean square deviation(RMSD),secondary structure assignment(SSA),radius of gyration(R_(g)),free energy surfaces(FES),solvent-accessible surface area(SASA),hydrogen bonds and salt bridges.The results showed that at low heating temperature,domain Ⅰ without loops(omitting the mobile loop region)mainly relied on hydrophobic interaction to maintain its thermal stability,whereas the thermal stability of domain Ⅱ was mainly controlled by salt bridges and hydrogen bonds.Under high heating temperature conditions,the hydrophobic interactions in domain Ⅰ without loops were destroyed and the secondary structure was almost completely lost,while domain Ⅱ could still rely on salt bridges as molecular staples to barely maintain the stability of the secondary structure.These results help us to understand the thermodynamic and kinetic mechanisms that maintain the thermal stability of SEB at the molecular level,and provide a direction for establishing safer and more effective food sterilization processes.展开更多
Spectral compressive imaging has emerged as a powerful technique to collect the 3D spectral information as 2D measurements.The algorithm for restoring the original 3D hyperspectral images(HSIs)from compressive measure...Spectral compressive imaging has emerged as a powerful technique to collect the 3D spectral information as 2D measurements.The algorithm for restoring the original 3D hyperspectral images(HSIs)from compressive measurements is pivotal in the imaging process.Early approaches painstakingly designed networks to directly map compressive measurements to HSIs,resulting in the lack of interpretability without exploiting the imaging priors.While some recent works have introduced the deep unfolding framework for explainable reconstruction,the performance of these methods is still limited by the weak information transmission between iterative stages.In this paper,we propose a Memory-Augmented deep Unfolding Network,termed MAUN,for explainable and accurate HSI reconstruction.Specifically,MAUN implements a novel CNN scheme to facilitate a better extrapolation step of the fast iterative shrinkage-thresholding algorithm,introducing an extra momentum incorporation step for each iteration to alleviate the information loss.Moreover,to exploit the high correlation of intermediate images from neighboring iterations,we customize a cross-stage transformer(CSFormer)as the deep denoiser to simultaneously capture self-similarity from both in-stage and cross-stage features,which is the first attempt to model the long-distance dependencies between iteration stages.Extensive experiments demonstrate that the proposed MAUN is superior to other state-of-the-art methods both visually and metrically.Our code is publicly available at https://github.com/HuQ1an/MAUN.展开更多
Single-molecule magnetic tweezers(MTs) have revealed multiple transition barriers along the unfolding pathway of several two-state proteins, such as GB1 and Csp. In this study, we utilized MTs to measure the force-dep...Single-molecule magnetic tweezers(MTs) have revealed multiple transition barriers along the unfolding pathway of several two-state proteins, such as GB1 and Csp. In this study, we utilized MTs to measure the force-dependent folding and unfolding rates of both protein L(PLWT) and its Y47W mutant(PLY47W) where the mutation point is not at the force-bearing β-strands. The measurements were conducted within a force range of 3–120 pN. Notably, the unfolding rates of both PLWT and PWY47W exhibit distinct force sensitivities below 50 pN and above 60 pN, implying a two-barrier free energy landscape. Both PLWT and PLY47W share the same force-dependent folding rate and the same transition barriers,but the unfolding rate of PLY47W is faster than that of PLWT. Our finding demonstrates that the residue outside of the force-bearing region will also affect the force-induced unfolding dynamics.展开更多
We have performed molecular dynamics simulations on the reversible folding/unfolding of small α-helix(short Ala based peptide Ala5) in explicit water solvent in terms of ABEEMσπ/MM.A dynamics analysis shows that t...We have performed molecular dynamics simulations on the reversible folding/unfolding of small α-helix(short Ala based peptide Ala5) in explicit water solvent in terms of ABEEMσπ/MM.A dynamics analysis shows that the α-helical turn can be preserved up to a period of about 2 ns at 300 K,which supports the conclusions of Margulis et al.The time trajectory of the root mean square deviation between the heavy atoms of the backbone and the helical reference structure indicate that "helix melting and formation occurs rapidly on a time scale of 0.1 ns at 300 K" is not a felicitous conclusion.We first quantificationally concluded that the helix nucleation can maintain 2 ns,1―1.5 ns and 0.8 ns for Ala5 at 300 K,400 K and 500 K,respectively.Furthermore,increasing temperature dose not alter the pathway of folding/unfolding,but change the rate.An analysis of structures in a "transition-state ensemble" shows that helix-to-coil transitions occurs predominantly through breaking of hydrogen bonds at the helix ends(92%),particularly at the C-terminus(50%).Hydrogen bonds' breaking and formation occurs on a time scale of 0.1 ns.展开更多
An understanding of protein folding/unfolding processes has important implications for all biological processes, in- eluding protein degradation, protein translocation, aging, and diseases. All-atom molecular dynamics...An understanding of protein folding/unfolding processes has important implications for all biological processes, in- eluding protein degradation, protein translocation, aging, and diseases. All-atom molecular dynamics （MD） simulations are uniquely suitable for it because of their atomic level resolution and accuracy. However, limited by computational ca- pabilities, nowadays even for small and fast-folding proteins, all-atom MD simulations of protein folding still presents a great challenge. An alternative way is to study unfolding process using MD simulations at high temperature. High temper- ature provides more energy to overcome energetic barriers to unfolding, and information obtained from studying unfolding can shed light on the mechanism of folding. In the present study, a 1000-ns MD simulation at high temperature （500 K） was performed to investigate the unfolding process of a small protein, chicken villin headpiece （HP-35）. To infer the folding mechanism, a Markov state model was also built from our simulation, which maps out six macrostates during the folding/unfolding process as well as critical transitions between them, revealing the folding mechanism unambiguously.展开更多
Chondrocyte senescence is a critical pathological hallmark of osteoarthritis(OA).Aberrant mechanical stress is considered a pivotal determinant in chondrocyte aging;however,the precise underlying mechanism remains elu...Chondrocyte senescence is a critical pathological hallmark of osteoarthritis(OA).Aberrant mechanical stress is considered a pivotal determinant in chondrocyte aging;however,the precise underlying mechanism remains elusive.Our findings demonstrate that SPI1 plays a significant role in counteracting chondrocyte senescence and inhibiting OA progression.SPI1 binds to the PERK promoter,thereby promoting its transcriptional activity.Importantly,PERK,rather than GCN2,facilitates eIF2αphosphorylation,activating the mitochondrial unfolded protein response(UPRmt)and impeding chondrocyte senescence.Deficiency of SPI1 in mechanical overload-induced mice leads to diminished UPRmt activation and accelerated OA progression.Intra-articular injection of adenovirus vectors overexpressing SPI1 and PERK effectively mitigates cartilage degeneration.In summary,our study elucidates the crucial regulatory role of SPI1 in the pathogenesis of chondrocyte senescence by activating UPRmt signaling through PERK,which may present a novel therapeutic target for treating OA.展开更多
The unfolded protein response pathway is an evolutionarily conserved cytoprotective signaling cascade,essential for cell function and survival.Unfolded protein response signaling is tightly integrated with bone cell d...The unfolded protein response pathway is an evolutionarily conserved cytoprotective signaling cascade,essential for cell function and survival.Unfolded protein response signaling is tightly integrated with bone cell differentiation and function,and chronic unfolded protein response activation has been identified in bone disease.The unfolded protein response has been found to promote oncogenesis and drug resistance,raising the possibility that unfolded protein response modulators may have activity as anti-cancer agents.Cancer-associated bone disease remains a major cause of morbidity for patients with multiple myeloma or bone-metastatic disease.Understanding the critical role of unfolded protein response signaling in cancer development and metastasis,as well as its role in bone homeostasis,may lead to novel mechanisms by which to target cancer-associated bone disease.In this review,we summarize the current research delineating the roles of the unfolded protein response in bone biology and pathophysiology,and furthermore,review unfolded protein response modulating agents in the contexts of cancer and cancer-associated bone disease.展开更多
Morphing aircraft are designed to adaptively adjust their shape for changing flight missions,which enables them to improve their flight performance significantly for future applications.The folding wingtips represent ...Morphing aircraft are designed to adaptively adjust their shape for changing flight missions,which enables them to improve their flight performance significantly for future applications.The folding wingtips represent a key research aspect for morphing aircraft,since they can lead to potential improvements in flight range,maneuverability,load alleviation and airport compatibility.This paper proposes a hinge mechanism design for folding wingtips based on the shape memory alloy torsion tube,aiming to achieve successful folding using the actuation effect of the shape memory alloy.The proposed design employs a shape memory alloy torsion tube as the actuator for the active folding of the wingtip,which is motivated by the characteristics of the tube,enabling a simplified structure for the integration with high energy density.Through numerical simulation and testing of the folding wingtip structure,the concept is verified,which shows its potential as an actuator for folding wingtips.展开更多
Zishen Huoxue decoction(ZSHX)enhances cardiomyocyte viability following hypoxic stress;however,its upstream therapeutic targets remain unclear.Network pharmacology and RNA sequencing analyses revealed that ZSHX target...Zishen Huoxue decoction(ZSHX)enhances cardiomyocyte viability following hypoxic stress;however,its upstream therapeutic targets remain unclear.Network pharmacology and RNA sequencing analyses revealed that ZSHX target genes were closely associated with mitophagy and apoptosis in the mitochondrial pathway.In vitro,ZSHX inhibited pathological mitochondrial fission following hypoxic stress,regulated FUN14 domain-containing protein 1(FUNDC1)-related mitophagy,and increased the levels of mitophagy lysosomes and microtubule-associated protein 1 light chain 3 beta II(LC3II)/translocase of outer mitochondrial membrane 20(TOM20)expression while inhibiting the over-activated mitochondrial unfolded protein response.Additionally,ZSHX regulated the stability of beta-tubulin through Sirtuin 5(SIRT5)and could modulate FUNDC1-related synergistic mechanisms of mitophagy and unfolded protein response in the mitochondria(UPR^(mt))via the SIRT5 and-β-tubulin axis.This targeting pathway may be crucial for cardiomyocytes to resist hypoxia.Collectively,these findings suggest that ZSHX can protect against cardiomyocyte injury via the SIRT5-β-tubulin axis,which may be associated with the synergistic protective mechanism of SIRT5-β-tubulin axis-related mitophagy and UPR^(mt) on cardiomyocytes.展开更多
Two types of bound states in continuum(BICs),symmetry-protected and Brillouin zone folding driven,are identified in hollow Si nanorod arrays.By modulating the direction and distance of the air holes from the center of...Two types of bound states in continuum(BICs),symmetry-protected and Brillouin zone folding driven,are identified in hollow Si nanorod arrays.By modulating the direction and distance of the air holes from the center of the nanorods,it is possible to achieve either a single quasi-BIC or three quasi-BICs.The transmission spectra exhibit ultra-narrow lines,and the quasi-BICs demonstrate ultra-high Q factors.Additionally,efficient third-harmonic generation occurs at low pump intensities.The results indicate that the proposed nanostructures of two types of BICs with a flexible modulation hold great potential applications for nonlinear photonic devices.展开更多
To tackle the challenges of intractable parameter tun-ing,significant computational expenditure and imprecise model-driven sparse-based direction of arrival(DOA)estimation with array error(AE),this paper proposes a de...To tackle the challenges of intractable parameter tun-ing,significant computational expenditure and imprecise model-driven sparse-based direction of arrival(DOA)estimation with array error(AE),this paper proposes a deep unfolded amplitude-phase error self-calibration network.Firstly,a sparse-based DOA model with an array convex error restriction is established,which gets resolved via an alternating iterative minimization(AIM)algo-rithm.The algorithm is then unrolled to a deep network known as AE-AIM Network(AE-AIM-Net),where all parameters are opti-mized through multi-task learning using the constructed com-plete dataset.The results of the simulation and theoretical analy-sis suggest that the proposed unfolded network achieves lower computational costs compared to typical sparse recovery meth-ods.Furthermore,it maintains excellent estimation performance even in the presence of array magnitude-phase errors.展开更多
In an attempt to realize a flapping wing micro-air vehicle with morphing wings, we report on improvements to our previousfoldable artificial hind wing.Multiple hinges, which were implemented to mimic the bending zone ...In an attempt to realize a flapping wing micro-air vehicle with morphing wings, we report on improvements to our previousfoldable artificial hind wing.Multiple hinges, which were implemented to mimic the bending zone of a beetle hind wing, weremade of small composite hinge plates and tiny aluminum rivets.The buck-tails of rivets were flared after the hinge plates wereassembled with the rivets so that the folding/unfolding motions could be completed in less time, and the straight shape of theartificial hind wing could be maintained after fabrication.Folding and unfolding actions were triggered by electrically-activatedShape Memory Alloy (SMA) wires.For wing folding, the actuation characteristics of the SMA wire actuator were modifiedthrough heat treatment.Through a series of flapping tests, we confirmed that the artificial wings did not fold back and arbitrarilyfluctuate during the flapping motion.展开更多
Determining the similarity degree between process models was very important for their management,reuse,and analysis.Current approaches either focused on process model's structural aspect,or had inefficiency or imp...Determining the similarity degree between process models was very important for their management,reuse,and analysis.Current approaches either focused on process model's structural aspect,or had inefficiency or imprecision in behavioral similarity.Aiming at these problems,a novel similarity measure which extended an existing method named Transition Adjacent Relation(TAR) with improved precision and efficiency named TAR * was proposed.The ability of measuring similarity was extended by eliminating the duplicate tasks without impacting the behaviors.For precision,TARs was classified into repeatable and unrepeatable ones to identify whether a TAR was involved in a loop.Two new kinds of TARs were added,one related to the invisible tasks after the source place and before sink place,and the other representing implicit dependencies.For efficiency,all TARs based on unfolding instead of its reach ability graph of a labeled Petri net were calculated to avoid state space explosion.Experiments on artificial and real-world process models showed the effectiveness and efficiency of the proposed method.展开更多
An accurate energy calibration of a 5＂× 2＂ BC501A liquid scintillator-based neutron detector by means of photon sources and the unfolding of pulse height spectra are described. The photon responses were measure...An accurate energy calibration of a 5＂× 2＂ BC501A liquid scintillator-based neutron detector by means of photon sources and the unfolding of pulse height spectra are described. The photon responses were measured with 22Na, 137Cs and 54Mn photon sources and simulated using the GRESP code, which was developed at the Physiknlisch Technische Bundesanstalt in Germany. Pulse height spectra produced by three different photon sources were employed to investigate the effects of the unfolding techniques. It was found that the four unfolding codes of the HEPRO and UMG3.3 packages, including GRAVEL, UNFANA, MIEKE and MAXED, performed well with the test spectra and produced generally consistent results. They could therefore be used to obtain neutron energy spectra in toknmak experiments.展开更多
Many biological functions of RNA molecules are re- lated to their pseudoknot structures. It is significant for predicting the structure and function of RNA that learning about the stability and the process of RNA pseu...Many biological functions of RNA molecules are re- lated to their pseudoknot structures. It is significant for predicting the structure and function of RNA that learning about the stability and the process of RNA pseudoknot folding and unfolding. The structural features of mouse mammary tumor virus （MMTV） RNA pseudoknot in different ion concentration, the unfolding process of the RNA pseudoknot, and the two hairpin helices that constitute the RNA pseudoknot were studied with all atom molecule dynam- ics simulation method in this paper. We found that the higher cation concentration can cause structure of the RNA molecules more stable, and ions played an indispensable role in keeping the structure of RNA molecules stable; the unfolding process of hair- pin structure was corresponding to the antiprocess of its folding process. The main pathway of pseudoknot unfolding was that the inner base pair opened first, and then, the two helices, which formed the RNA pseudoknot opened decussately, while the folding pathway of the RNA pseudoknot was a helix folding after forma- tion of the other helix. Therefore, the unfolding process of RNA pseudoknot is different from the antiprocess of its folding process, and the unfolding process of each helix in the RNA pseudoknot is similar to the hairpin structure＇s unfolding process, which means that both are the unzipping process.展开更多
基金supported by the National Natural Science Foun-dation of China(Grant Nos.12174322,12474200,32271367,and 12204389)111 Project(B16029)Research Grant from Wenzhou Institute.
文摘Spectrin domains,characterized by a distinctive triple helix structure,are crucial in physiological processes,particularly in maintaining membrane shape and crosslinking cytoskeletons.Previous research on the 16th domain of a-spectrin repeats(R16)has yielded conflicting results:bulk experiments showed an unfolding rate approximately two orders of magnitude faster than the zero-force result extrapolated from single-molecule force spectroscopy experiments using atomic force microscopy(AFM).To address this discrepancy,we investigated the folding and unfolding rates of R16 across a broader range of forces using magnetic tweezers(MT).Our findings reveal that AFM results at higher forces cannot be directly extrapolated to the low-force regime due to a nonlinear relationship between force and the logarithm of the unfolding rate.We demonstrated that two-dimensional model,structural-elastic model,and two-pathway model can all effectively explain the experimental data when they capture the core physics of the short unfolding distance at low forces.Our study provides a more comprehensive understanding of the unfolding dynamics of the spectrin domain,resolves previous contradictory experimental results,and highlights the common basis of different theoretical models.
基金support by the National Key R&D Program of China(No.2022YFA1305200,to GL)National Natural Science Foundation of China(No.22104064 to GL,No.22173020 to JL)the US National Institute of Mental Health(No.R01MH122742,to CJW)for financial and instrumental support.
文摘Despite the expansive applications of gas-phase unfolding techniques,the molecular mechanism for the solvent-free forced unfolding pathway which substrate multidomain proteins usually adopt remains elusive at the secondary structure level.Herein,upon carefully selecting CRM_(197) as a therapeutically-relevant model system containing multiple secondary structure-separated domains,we systematically examine its solvent-free unfolding pathway.Further-more,utilizing the hybrid of noncovalent chemical probing with niacinamide and ion mobility-mass spectrometry-guided all-atom molecular dynamics simulations,we map a nearly complete unfolding atlas for the conjugate vaccine carrier protein CRM_(197) in a domain-and secondary structure-resolved manner.The totality of our data supports the preferential unfolding of the sheet-rich domain,indicating the dynamic transition from β-sheet toα-helix,and demonstrating that helix exhibit comparatively higher stability thanβ-sheets.We propose that this sheet-to-helix dynamic transition may be central to the gas-phase unfolding pathways of multidomain proteins,suggesting the need for systematic studies on additional multidomain protein systems.
文摘In this study,circular dichroism(CD)and molecular dynamics(MD)simulation were used to investigate the thermal unfolding pathway of staphylococcal enterotoxin B(SEB)at temperatures of 298–371 and 298–500 K,and the relationship between the experimental and simulation results were explored.Our computational findings on the secondary structure of SEB showed that at room temperature,the CD spectroscopic results were highly consistent with the MD results.Moreover,under heating conditions,the changing trends of helix,sheet and random coil obtained by CD spectral fitting were highly consistent with those obtained by MD.In order to gain a deeper understanding of the thermal stability mechanism of SEB,the MD trajectories were analyzed in terms of root mean square deviation(RMSD),secondary structure assignment(SSA),radius of gyration(R_(g)),free energy surfaces(FES),solvent-accessible surface area(SASA),hydrogen bonds and salt bridges.The results showed that at low heating temperature,domain Ⅰ without loops(omitting the mobile loop region)mainly relied on hydrophobic interaction to maintain its thermal stability,whereas the thermal stability of domain Ⅱ was mainly controlled by salt bridges and hydrogen bonds.Under high heating temperature conditions,the hydrophobic interactions in domain Ⅰ without loops were destroyed and the secondary structure was almost completely lost,while domain Ⅱ could still rely on salt bridges as molecular staples to barely maintain the stability of the secondary structure.These results help us to understand the thermodynamic and kinetic mechanisms that maintain the thermal stability of SEB at the molecular level,and provide a direction for establishing safer and more effective food sterilization processes.
基金supported by the National Natural Science Foundation of China(62276192)。
文摘Spectral compressive imaging has emerged as a powerful technique to collect the 3D spectral information as 2D measurements.The algorithm for restoring the original 3D hyperspectral images(HSIs)from compressive measurements is pivotal in the imaging process.Early approaches painstakingly designed networks to directly map compressive measurements to HSIs,resulting in the lack of interpretability without exploiting the imaging priors.While some recent works have introduced the deep unfolding framework for explainable reconstruction,the performance of these methods is still limited by the weak information transmission between iterative stages.In this paper,we propose a Memory-Augmented deep Unfolding Network,termed MAUN,for explainable and accurate HSI reconstruction.Specifically,MAUN implements a novel CNN scheme to facilitate a better extrapolation step of the fast iterative shrinkage-thresholding algorithm,introducing an extra momentum incorporation step for each iteration to alleviate the information loss.Moreover,to exploit the high correlation of intermediate images from neighboring iterations,we customize a cross-stage transformer(CSFormer)as the deep denoiser to simultaneously capture self-similarity from both in-stage and cross-stage features,which is the first attempt to model the long-distance dependencies between iteration stages.Extensive experiments demonstrate that the proposed MAUN is superior to other state-of-the-art methods both visually and metrically.Our code is publicly available at https://github.com/HuQ1an/MAUN.
基金supported by the National Natural Science Foundation of China(Grant Nos.12174322 to HC and 12204124 to ZG)111 Project(Grant No.B16029)+1 种基金the Graduate Scientific Research Foundation of Wenzhou University(Grant No.3162023003034 to JH)research grant from Wenzhou Institute。
文摘Single-molecule magnetic tweezers(MTs) have revealed multiple transition barriers along the unfolding pathway of several two-state proteins, such as GB1 and Csp. In this study, we utilized MTs to measure the force-dependent folding and unfolding rates of both protein L(PLWT) and its Y47W mutant(PLY47W) where the mutation point is not at the force-bearing β-strands. The measurements were conducted within a force range of 3–120 pN. Notably, the unfolding rates of both PLWT and PWY47W exhibit distinct force sensitivities below 50 pN and above 60 pN, implying a two-barrier free energy landscape. Both PLWT and PLY47W share the same force-dependent folding rate and the same transition barriers,but the unfolding rate of PLY47W is faster than that of PLWT. Our finding demonstrates that the residue outside of the force-bearing region will also affect the force-induced unfolding dynamics.
文摘We have performed molecular dynamics simulations on the reversible folding/unfolding of small α-helix(short Ala based peptide Ala5) in explicit water solvent in terms of ABEEMσπ/MM.A dynamics analysis shows that the α-helical turn can be preserved up to a period of about 2 ns at 300 K,which supports the conclusions of Margulis et al.The time trajectory of the root mean square deviation between the heavy atoms of the backbone and the helical reference structure indicate that "helix melting and formation occurs rapidly on a time scale of 0.1 ns at 300 K" is not a felicitous conclusion.We first quantificationally concluded that the helix nucleation can maintain 2 ns,1―1.5 ns and 0.8 ns for Ala5 at 300 K,400 K and 500 K,respectively.Furthermore,increasing temperature dose not alter the pathway of folding/unfolding,but change the rate.An analysis of structures in a "transition-state ensemble" shows that helix-to-coil transitions occurs predominantly through breaking of hydrogen bonds at the helix ends(92%),particularly at the C-terminus(50%).Hydrogen bonds' breaking and formation occurs on a time scale of 0.1 ns.
基金Project supported by the National Natural Science Foundation of China(Grant Nos.11175068 and 11474117)the Self-determined Research Funds of CCNU from the Colleges Basic Research and Operation of MOE,China(Grant No.230-20205170054)
文摘An understanding of protein folding/unfolding processes has important implications for all biological processes, in- eluding protein degradation, protein translocation, aging, and diseases. All-atom molecular dynamics （MD） simulations are uniquely suitable for it because of their atomic level resolution and accuracy. However, limited by computational ca- pabilities, nowadays even for small and fast-folding proteins, all-atom MD simulations of protein folding still presents a great challenge. An alternative way is to study unfolding process using MD simulations at high temperature. High temper- ature provides more energy to overcome energetic barriers to unfolding, and information obtained from studying unfolding can shed light on the mechanism of folding. In the present study, a 1000-ns MD simulation at high temperature （500 K） was performed to investigate the unfolding process of a small protein, chicken villin headpiece （HP-35）. To infer the folding mechanism, a Markov state model was also built from our simulation, which maps out six macrostates during the folding/unfolding process as well as critical transitions between them, revealing the folding mechanism unambiguously.
基金supported by the Anhui Provincial Natural Science Foundation(Grant No.2308085MH250)the Natural Science Research Project of Anhui Educational Committee(Grant No.2023AH053327)the Scientific Research Fund Project of Anhui Medical University(2020xkj039).
文摘Chondrocyte senescence is a critical pathological hallmark of osteoarthritis(OA).Aberrant mechanical stress is considered a pivotal determinant in chondrocyte aging;however,the precise underlying mechanism remains elusive.Our findings demonstrate that SPI1 plays a significant role in counteracting chondrocyte senescence and inhibiting OA progression.SPI1 binds to the PERK promoter,thereby promoting its transcriptional activity.Importantly,PERK,rather than GCN2,facilitates eIF2αphosphorylation,activating the mitochondrial unfolded protein response(UPRmt)and impeding chondrocyte senescence.Deficiency of SPI1 in mechanical overload-induced mice leads to diminished UPRmt activation and accelerated OA progression.Intra-articular injection of adenovirus vectors overexpressing SPI1 and PERK effectively mitigates cartilage degeneration.In summary,our study elucidates the crucial regulatory role of SPI1 in the pathogenesis of chondrocyte senescence by activating UPRmt signaling through PERK,which may present a novel therapeutic target for treating OA.
基金supported by the National Institutes of Health(Grants P30 CA036727 and R01 CA258621)and funding from the University of Nebraska Medical Center Graduate Studies Assistantship.
文摘The unfolded protein response pathway is an evolutionarily conserved cytoprotective signaling cascade,essential for cell function and survival.Unfolded protein response signaling is tightly integrated with bone cell differentiation and function,and chronic unfolded protein response activation has been identified in bone disease.The unfolded protein response has been found to promote oncogenesis and drug resistance,raising the possibility that unfolded protein response modulators may have activity as anti-cancer agents.Cancer-associated bone disease remains a major cause of morbidity for patients with multiple myeloma or bone-metastatic disease.Understanding the critical role of unfolded protein response signaling in cancer development and metastasis,as well as its role in bone homeostasis,may lead to novel mechanisms by which to target cancer-associated bone disease.In this review,we summarize the current research delineating the roles of the unfolded protein response in bone biology and pathophysiology,and furthermore,review unfolded protein response modulating agents in the contexts of cancer and cancer-associated bone disease.
基金supported by the National Natural Science Foundation of China(No.52305262)the Aeronautical Science Foundation of China(No.20230015052002)the Fundamental Research Funds for the Central Universities(No.NT2024001)。
文摘Morphing aircraft are designed to adaptively adjust their shape for changing flight missions,which enables them to improve their flight performance significantly for future applications.The folding wingtips represent a key research aspect for morphing aircraft,since they can lead to potential improvements in flight range,maneuverability,load alleviation and airport compatibility.This paper proposes a hinge mechanism design for folding wingtips based on the shape memory alloy torsion tube,aiming to achieve successful folding using the actuation effect of the shape memory alloy.The proposed design employs a shape memory alloy torsion tube as the actuator for the active folding of the wingtip,which is motivated by the characteristics of the tube,enabling a simplified structure for the integration with high energy density.Through numerical simulation and testing of the folding wingtip structure,the concept is verified,which shows its potential as an actuator for folding wingtips.
基金supported by the National Natural Science Foundation of China(No.82305204),the Special Project on Academic Inheritance and Communication,China Academy of Chinese Medical Sciences(No.CI2022E012XB)Chinese Academy of Chinese Medical Sciences Doctoral Talents Training Fund(No.2021)+1 种基金the Special Program for Training Outstanding Young Talents of Chinese Academy of Traditional Chinese Medicine(No.ZZ16-YQ-021)the Innovative Cultivation Project of Guang'anmen Hospital,Chinese Academy of Chinese Medical Sciences(No.2022s481).
文摘Zishen Huoxue decoction(ZSHX)enhances cardiomyocyte viability following hypoxic stress;however,its upstream therapeutic targets remain unclear.Network pharmacology and RNA sequencing analyses revealed that ZSHX target genes were closely associated with mitophagy and apoptosis in the mitochondrial pathway.In vitro,ZSHX inhibited pathological mitochondrial fission following hypoxic stress,regulated FUN14 domain-containing protein 1(FUNDC1)-related mitophagy,and increased the levels of mitophagy lysosomes and microtubule-associated protein 1 light chain 3 beta II(LC3II)/translocase of outer mitochondrial membrane 20(TOM20)expression while inhibiting the over-activated mitochondrial unfolded protein response.Additionally,ZSHX regulated the stability of beta-tubulin through Sirtuin 5(SIRT5)and could modulate FUNDC1-related synergistic mechanisms of mitophagy and unfolded protein response in the mitochondria(UPR^(mt))via the SIRT5 and-β-tubulin axis.This targeting pathway may be crucial for cardiomyocytes to resist hypoxia.Collectively,these findings suggest that ZSHX can protect against cardiomyocyte injury via the SIRT5-β-tubulin axis,which may be associated with the synergistic protective mechanism of SIRT5-β-tubulin axis-related mitophagy and UPR^(mt) on cardiomyocytes.
基金Project supported by the National Natural Science Foundation of China(Grant Nos.12174228 and 12274271)。
文摘Two types of bound states in continuum(BICs),symmetry-protected and Brillouin zone folding driven,are identified in hollow Si nanorod arrays.By modulating the direction and distance of the air holes from the center of the nanorods,it is possible to achieve either a single quasi-BIC or three quasi-BICs.The transmission spectra exhibit ultra-narrow lines,and the quasi-BICs demonstrate ultra-high Q factors.Additionally,efficient third-harmonic generation occurs at low pump intensities.The results indicate that the proposed nanostructures of two types of BICs with a flexible modulation hold great potential applications for nonlinear photonic devices.
基金supported by the National Natural Science Foundation of China(62301598).
文摘To tackle the challenges of intractable parameter tun-ing,significant computational expenditure and imprecise model-driven sparse-based direction of arrival(DOA)estimation with array error(AE),this paper proposes a deep unfolded amplitude-phase error self-calibration network.Firstly,a sparse-based DOA model with an array convex error restriction is established,which gets resolved via an alternating iterative minimization(AIM)algo-rithm.The algorithm is then unrolled to a deep network known as AE-AIM Network(AE-AIM-Net),where all parameters are opti-mized through multi-task learning using the constructed com-plete dataset.The results of the simulation and theoretical analy-sis suggest that the proposed unfolded network achieves lower computational costs compared to typical sparse recovery meth-ods.Furthermore,it maintains excellent estimation performance even in the presence of array magnitude-phase errors.
基金supported by the Korea Science and Engineering Foundation Grant(National Research Laboratory Program,R0A-2007-000-200012-0)the Korea Research Foundation(KRF-006-005-J03301)partially supported by the 2009 KU Brain Pool of Konkuk University
文摘In an attempt to realize a flapping wing micro-air vehicle with morphing wings, we report on improvements to our previousfoldable artificial hind wing.Multiple hinges, which were implemented to mimic the bending zone of a beetle hind wing, weremade of small composite hinge plates and tiny aluminum rivets.The buck-tails of rivets were flared after the hinge plates wereassembled with the rivets so that the folding/unfolding motions could be completed in less time, and the straight shape of theartificial hind wing could be maintained after fabrication.Folding and unfolding actions were triggered by electrically-activatedShape Memory Alloy (SMA) wires.For wing folding, the actuation characteristics of the SMA wire actuator were modifiedthrough heat treatment.Through a series of flapping tests, we confirmed that the artificial wings did not fold back and arbitrarilyfluctuate during the flapping motion.
基金Project supported by the National Science Foundation,China(No.61003099)the National Basic Research Program,China(No.2009CB320700)
文摘Determining the similarity degree between process models was very important for their management,reuse,and analysis.Current approaches either focused on process model's structural aspect,or had inefficiency or imprecision in behavioral similarity.Aiming at these problems,a novel similarity measure which extended an existing method named Transition Adjacent Relation(TAR) with improved precision and efficiency named TAR * was proposed.The ability of measuring similarity was extended by eliminating the duplicate tasks without impacting the behaviors.For precision,TARs was classified into repeatable and unrepeatable ones to identify whether a TAR was involved in a loop.Two new kinds of TARs were added,one related to the invisible tasks after the source place and before sink place,and the other representing implicit dependencies.For efficiency,all TARs based on unfolding instead of its reach ability graph of a labeled Petri net were calculated to avoid state space explosion.Experiments on artificial and real-world process models showed the effectiveness and efficiency of the proposed method.
基金supported by the State Key Development Program for Basic Research of China (Nos. 2008CB717803, 2009GB107001,2007CB209903)the Research Fund for the Doctoral Program of Higher Education of China (No. 200610011023)National Natural Science Foundation of China (No. 10875002)
文摘An accurate energy calibration of a 5＂× 2＂ BC501A liquid scintillator-based neutron detector by means of photon sources and the unfolding of pulse height spectra are described. The photon responses were measured with 22Na, 137Cs and 54Mn photon sources and simulated using the GRESP code, which was developed at the Physiknlisch Technische Bundesanstalt in Germany. Pulse height spectra produced by three different photon sources were employed to investigate the effects of the unfolding techniques. It was found that the four unfolding codes of the HEPRO and UMG3.3 packages, including GRAVEL, UNFANA, MIEKE and MAXED, performed well with the test spectra and produced generally consistent results. They could therefore be used to obtain neutron energy spectra in toknmak experiments.
基金Supported by the National Natural Science Foundation of China(10774115)the Doctoral Fund of Ministry of Education of China(20110141110009)
文摘Many biological functions of RNA molecules are re- lated to their pseudoknot structures. It is significant for predicting the structure and function of RNA that learning about the stability and the process of RNA pseudoknot folding and unfolding. The structural features of mouse mammary tumor virus （MMTV） RNA pseudoknot in different ion concentration, the unfolding process of the RNA pseudoknot, and the two hairpin helices that constitute the RNA pseudoknot were studied with all atom molecule dynam- ics simulation method in this paper. We found that the higher cation concentration can cause structure of the RNA molecules more stable, and ions played an indispensable role in keeping the structure of RNA molecules stable; the unfolding process of hair- pin structure was corresponding to the antiprocess of its folding process. The main pathway of pseudoknot unfolding was that the inner base pair opened first, and then, the two helices, which formed the RNA pseudoknot opened decussately, while the folding pathway of the RNA pseudoknot was a helix folding after forma- tion of the other helix. Therefore, the unfolding process of RNA pseudoknot is different from the antiprocess of its folding process, and the unfolding process of each helix in the RNA pseudoknot is similar to the hairpin structure＇s unfolding process, which means that both are the unzipping process.
