Huntington's disease(HD)is caused by the abnormal expansion of polyglutamine(poly Q)repeats encoded in exon 1 of the huntingtin(HTT)gene,with neurotoxicity typically emerging when the repeat length exceeds 36 glut...Huntington's disease(HD)is caused by the abnormal expansion of polyglutamine(poly Q)repeats encoded in exon 1 of the huntingtin(HTT)gene,with neurotoxicity typically emerging when the repeat length exceeds 36 glutamine residues.Increasing the poly Q length promotes hypercompact conformations;however,how such compact chains mechanically unfold under nanoconfinement remains insufficiently understood.In this study,all-atom molecular dynamics simulations were performed to investigate the nanopore transport and surface-induced unfolding of poly Q chains of different lengths(Q22,Q36,Q40,and Q46)through graphene nanopores under controlled pulling velocities.By quantitatively analyzing the transport dynamics,as characterized by the pulling force,radius of gyration,center-of-mass distance,interaction energies,number of transported residues,and pulling energy,we demonstrated that poly Q chains of all investigated lengths can successfully translocate through the nanopore and undergo progressive unfolding on the graphene surface over a wide range of pulling velocities.Longer poly Q chains exhibit a higher resistance to unfolding,characterized by enhanced force peaks and increased pulling energy,reflecting stronger intramolecular interactions.Moreover,slower pulling velocities reduce the force fluctuations and lower the overall pulling energy.These results provide molecular-level mechanistic insights into the length-dependent transport and surface-mediated unfolding of poly Q,offering a physical basis for understanding poly Q conformational regulation relevant to Huntington's disease.展开更多
In hybrid beamforming design using the conventional gradient projection(GP)algorithm,it is common to use a fixed step size,which results in a slow convergence rate and unsatisfactory achievable rate performance.This p...In hybrid beamforming design using the conventional gradient projection(GP)algorithm,it is common to use a fixed step size,which results in a slow convergence rate and unsatisfactory achievable rate performance.This paper employs a deep unfolding algorithm within a small fixed number of iterations to tackle the hybrid beamforming optimization problem.The optimal step size is obtained by combining the conventional GP algorithm with the deep learning technique,and every step in deep learning is explainable.Simulation results show that the proposed deep unfolding algorithm demonstrates a lower computational time and superior achievable rate performance than the conventional GP algorithm.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
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
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
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
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 this work,multiple molecular dynamics simulations of protein G and protein L unfolding trajectories provide a direct demonstration of the diversity of unfolding pathway and give a statistically utmost unfolding pat...In this work,multiple molecular dynamics simulations of protein G and protein L unfolding trajectories provide a direct demonstration of the diversity of unfolding pathway and give a statistically utmost unfolding pathway under the physical property space.展开更多
Within the cell, several mechanisms exist to maintain homeostasis of the endoplasmic reticulum （ER）. One of the primary mechanisms is the unfolded protein response （UPR）. In this review, we primarily focus on the ...Within the cell, several mechanisms exist to maintain homeostasis of the endoplasmic reticulum （ER）. One of the primary mechanisms is the unfolded protein response （UPR）. In this review, we primarily focus on the latest signal webs and regulation mechanisms of the UPR. The relationships among ER stress, apoptosis, and cancer are also discussed. Under the normal state, binding immunoglobulin protein （BiP） interacts with the three sensors （protein kinase RNA-like ER kinase （PERK）, activating transcription factor 6 （ATF6）, and inositol-requiring enzyme la （IREla）） Under ER stress, misfolded proteins interact with BiP, resulting in the release of BiP from the sensors. Subsequently, the three sensors dimerize and autophosphorylate to promote the signal cascades of ER stress. ER stress includes a series of positive and negative feedback signals, such as those regulating the stabilization of the sensors/BiP complex, activating and inactivating the sensors by autophosphorylation and dephosphorylation, activating specific transcription factors to enable selective transcription, and augmenting the ability to refold and export. Apart from the three basic pathways, vascular endothelial growth factor （VEGF）-VEGF receptor （VEGFR）-phospholipase C-~ （PLCy）-mammalian target of rapamycin complex 1 （mTORC1） pathway, induced only in solid tumors, can also activate ATF6 and PERK signal cascades, and IREla also can be activated by activated RAC-alpha serine/threonine-protein kinase （AKT）. A moderate UPR functions as a pro-survival signal to return the cell to its state of homeostasis. However, persistent ER stress will induce cells to undergo apoptosis in response to increasing reactive oxygen species （ROS）, Ca2＋ in the cytoplasmic matrix, and other apoptosis signal cascades, such as c-Jun N-terminal kinase （JNK）, signal transducer and activator of transcription 3 （STAT3）, and P38, when cellular damage exceeds the capacity of this adaptive response.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
Acute pancreatitis (AP) is an inflammatory disorder of pancreatic tissue initiated in injured acinar cells. Severe AP remains a significant challenge due to the lack of effective treatment. The widely-accepted autodig...Acute pancreatitis (AP) is an inflammatory disorder of pancreatic tissue initiated in injured acinar cells. Severe AP remains a significant challenge due to the lack of effective treatment. The widely-accepted autodigestion theory of AP is now facing challenges, since inhibiting protease activation has negligible effectiveness for AP treatment despite numerous efforts. Furthermore, accumulating evidence supports a new concept that malfunction of a self-protective mechanism, the unfolded protein response(UPR), is the driving force behind the pathogenesis of AP. The UPR is induced by endoplasmic reticulum(ER) stress, a disturbance frequently found in acinar cells, to prevent the aggravation of ER stress that can otherwise lead to cell injury. In addition, the UPR's signaling pathways control NFκB activation and autophagy flux, and these dysregulations cause acinar cell inflammatory injury in AP, but with poorly understood mechanisms. We therefore summarize the protective role of the UPR in AP, propose mechanistic models of how inadequate UPR could promote NFκB's pro-inflammatory activity and impair autophagy's protective function in acinar cells, and discuss its relevance to current AP treatment. We hope that insight provided in this review will help facilitate the research and management of AP.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
Porcine circovirus type 2（PCV2）has recently been reported to elicit the unfolded protein response（UPR）via activation of the PERK/e IF2α（RNA-activated protein kinase-like endoplasmic reticulum（ER）kinase/eukaryo...Porcine circovirus type 2（PCV2）has recently been reported to elicit the unfolded protein response（UPR）via activation of the PERK/e IF2α（RNA-activated protein kinase-like endoplasmic reticulum（ER）kinase/eukaryotic initiation factor 2α）pathway.This study attempted to examine which viral protein might be involved in inducing UPR and whether this cellular event would lead to apoptosis of the cells expressing the viral protein.By transient expression,we found that both replicase（Rep）and capsid（Cap）proteins of PCV2 could induce ER stress as shown by increased phosphorylation of PERK with subsequent activation of the eI F2α-ATF4（activating transcription factor 4）-CHOP（CCAAT/enhancer-binding protein homologous protein）axis.Cap expression,but not Rep,significantly reduced antiapoptotic B-cell lymphoma-2（Bcl-2）and increased caspase-3 cleavage,possibly due to increased expression of CHOP.Since knockdown of PERK by RNA interference clearly reduced Cap-induced CHOP expression,caspase-3cleavage,and apoptotic cell death possibly by partially rescuing Bcl-2 expression,we propose that there is connection between Cap-induced UPR and apoptosis via the PERK/eI F2α/ATF4/CHOP/Bcl-2 pathway.This study,together with our earlier studies,provides insight into the mechanisms underlying PCV2 pathogenesis.展开更多
A self-adaptive differential evolution neutron spectrum unfolding algorithm(SDENUA)is established in this study to unfold the neutron spectra obtained from a water-pumping-injection multilayered concentric sphere neut...A self-adaptive differential evolution neutron spectrum unfolding algorithm(SDENUA)is established in this study to unfold the neutron spectra obtained from a water-pumping-injection multilayered concentric sphere neutron spectrometer(WMNS).Specifically,the neutron fluence bounds are estimated to accelerate the algorithm convergence,and the minimum error between the optimal solution and input neutron counts with relative uncertainties is limited to 10^(-6)to avoid unnecessary calculations.Furthermore,the crossover probability and scaling factor are self-adaptively controlled.FLUKA Monte Carlo is used to simulate the readings of the WMNS under(1)a spectrum of Cf-252 and(2)its spectrum after being moderated,(3)a spectrum used for boron neutron capture therapy,and(4)a reactor spectrum.Subsequently,the measured neutron counts are unfolded using the SDENUA.The uncertainties of the measured neutron count and the response matrix are considered in the SDENUA,which does not require complex parameter tuning or an a priori default spectrum.The results indicate that the solutions of the SDENUA agree better with the IAEA spectra than those of MAXED and GRAVEL in UMG 3.1,and the errors of the final results calculated using the SDENUA are less than 12%.The established SDENUA can be used to unfold spectra from the WMNS.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 Foundation of China(Nos.12302408,20904047 and62375245)the Natural Science Foundation of Zhejiang Province(Nos.LY17A040001 and LY19F03004)+1 种基金the ZUST Postgraduate Course Development Fund(No.2025yjskj05)the ZUST Postgraduate Research and Innovation Fund(No.2025yjskc20)。
文摘Huntington's disease(HD)is caused by the abnormal expansion of polyglutamine(poly Q)repeats encoded in exon 1 of the huntingtin(HTT)gene,with neurotoxicity typically emerging when the repeat length exceeds 36 glutamine residues.Increasing the poly Q length promotes hypercompact conformations;however,how such compact chains mechanically unfold under nanoconfinement remains insufficiently understood.In this study,all-atom molecular dynamics simulations were performed to investigate the nanopore transport and surface-induced unfolding of poly Q chains of different lengths(Q22,Q36,Q40,and Q46)through graphene nanopores under controlled pulling velocities.By quantitatively analyzing the transport dynamics,as characterized by the pulling force,radius of gyration,center-of-mass distance,interaction energies,number of transported residues,and pulling energy,we demonstrated that poly Q chains of all investigated lengths can successfully translocate through the nanopore and undergo progressive unfolding on the graphene surface over a wide range of pulling velocities.Longer poly Q chains exhibit a higher resistance to unfolding,characterized by enhanced force peaks and increased pulling energy,reflecting stronger intramolecular interactions.Moreover,slower pulling velocities reduce the force fluctuations and lower the overall pulling energy.These results provide molecular-level mechanistic insights into the length-dependent transport and surface-mediated unfolding of poly Q,offering a physical basis for understanding poly Q conformational regulation relevant to Huntington's disease.
基金STU Scientific Research Foundation for Talents under Grants NTF21048。
文摘In hybrid beamforming design using the conventional gradient projection(GP)algorithm,it is common to use a fixed step size,which results in a slow convergence rate and unsatisfactory achievable rate performance.This paper employs a deep unfolding algorithm within a small fixed number of iterations to tackle the hybrid beamforming optimization problem.The optimal step size is obtained by combining the conventional GP algorithm with the deep learning technique,and every step in deep learning is explainable.Simulation results show that the proposed deep unfolding algorithm demonstrates a lower computational time and superior achievable rate performance than the conventional GP algorithm.
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 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 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.
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.
文摘In this work,multiple molecular dynamics simulations of protein G and protein L unfolding trajectories provide a direct demonstration of the diversity of unfolding pathway and give a statistically utmost unfolding pathway under the physical property space.
基金Project supported by the National Basic Research Program(973)of China(No.2012CB518900)the National Natural Science Foundation of China(Nos.31160240 and 31260621)+2 种基金the National Major Scientific and Technological Special Project during the Twelfth Five-year Plan Period of China(No.2012ZX10002006)the Hangzhou Normal University Supporting Project(No.PE13002004042)the Natural Science Foundation of Jiangxi Province(No.20114BAB204016),China
文摘Within the cell, several mechanisms exist to maintain homeostasis of the endoplasmic reticulum （ER）. One of the primary mechanisms is the unfolded protein response （UPR）. In this review, we primarily focus on the latest signal webs and regulation mechanisms of the UPR. The relationships among ER stress, apoptosis, and cancer are also discussed. Under the normal state, binding immunoglobulin protein （BiP） interacts with the three sensors （protein kinase RNA-like ER kinase （PERK）, activating transcription factor 6 （ATF6）, and inositol-requiring enzyme la （IREla）） Under ER stress, misfolded proteins interact with BiP, resulting in the release of BiP from the sensors. Subsequently, the three sensors dimerize and autophosphorylate to promote the signal cascades of ER stress. ER stress includes a series of positive and negative feedback signals, such as those regulating the stabilization of the sensors/BiP complex, activating and inactivating the sensors by autophosphorylation and dephosphorylation, activating specific transcription factors to enable selective transcription, and augmenting the ability to refold and export. Apart from the three basic pathways, vascular endothelial growth factor （VEGF）-VEGF receptor （VEGFR）-phospholipase C-~ （PLCy）-mammalian target of rapamycin complex 1 （mTORC1） pathway, induced only in solid tumors, can also activate ATF6 and PERK signal cascades, and IREla also can be activated by activated RAC-alpha serine/threonine-protein kinase （AKT）. A moderate UPR functions as a pro-survival signal to return the cell to its state of homeostasis. However, persistent ER stress will induce cells to undergo apoptosis in response to increasing reactive oxygen species （ROS）, Ca2＋ in the cytoplasmic matrix, and other apoptosis signal cascades, such as c-Jun N-terminal kinase （JNK）, signal transducer and activator of transcription 3 （STAT3）, and P38, when cellular damage exceeds the capacity of this adaptive response.
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.
文摘Acute pancreatitis (AP) is an inflammatory disorder of pancreatic tissue initiated in injured acinar cells. Severe AP remains a significant challenge due to the lack of effective treatment. The widely-accepted autodigestion theory of AP is now facing challenges, since inhibiting protease activation has negligible effectiveness for AP treatment despite numerous efforts. Furthermore, accumulating evidence supports a new concept that malfunction of a self-protective mechanism, the unfolded protein response(UPR), is the driving force behind the pathogenesis of AP. The UPR is induced by endoplasmic reticulum(ER) stress, a disturbance frequently found in acinar cells, to prevent the aggravation of ER stress that can otherwise lead to cell injury. In addition, the UPR's signaling pathways control NFκB activation and autophagy flux, and these dysregulations cause acinar cell inflammatory injury in AP, but with poorly understood mechanisms. We therefore summarize the protective role of the UPR in AP, propose mechanistic models of how inadequate UPR could promote NFκB's pro-inflammatory activity and impair autophagy's protective function in acinar cells, and discuss its relevance to current AP treatment. We hope that insight provided in this review will help facilitate the research and management of AP.
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(No.31272534)the Department of Education of Zhejiang Province(No.Y201635576),China
文摘Porcine circovirus type 2（PCV2）has recently been reported to elicit the unfolded protein response（UPR）via activation of the PERK/e IF2α（RNA-activated protein kinase-like endoplasmic reticulum（ER）kinase/eukaryotic initiation factor 2α）pathway.This study attempted to examine which viral protein might be involved in inducing UPR and whether this cellular event would lead to apoptosis of the cells expressing the viral protein.By transient expression,we found that both replicase（Rep）and capsid（Cap）proteins of PCV2 could induce ER stress as shown by increased phosphorylation of PERK with subsequent activation of the eI F2α-ATF4（activating transcription factor 4）-CHOP（CCAAT/enhancer-binding protein homologous protein）axis.Cap expression,but not Rep,significantly reduced antiapoptotic B-cell lymphoma-2（Bcl-2）and increased caspase-3 cleavage,possibly due to increased expression of CHOP.Since knockdown of PERK by RNA interference clearly reduced Cap-induced CHOP expression,caspase-3cleavage,and apoptotic cell death possibly by partially rescuing Bcl-2 expression,we propose that there is connection between Cap-induced UPR and apoptosis via the PERK/eI F2α/ATF4/CHOP/Bcl-2 pathway.This study,together with our earlier studies,provides insight into the mechanisms underlying PCV2 pathogenesis.
基金supported by the National Key R&D Program of the MOST of China(No.2016YFA0300204)the National Natural Science Foundation of China(Nos.11227902)as part of the Si PáME2beamline project+1 种基金supported by the National Natural Science Foundation of China(No.41774120)the Sichuan Science and Technology Program(No.2021YJ0329)。
文摘A self-adaptive differential evolution neutron spectrum unfolding algorithm(SDENUA)is established in this study to unfold the neutron spectra obtained from a water-pumping-injection multilayered concentric sphere neutron spectrometer(WMNS).Specifically,the neutron fluence bounds are estimated to accelerate the algorithm convergence,and the minimum error between the optimal solution and input neutron counts with relative uncertainties is limited to 10^(-6)to avoid unnecessary calculations.Furthermore,the crossover probability and scaling factor are self-adaptively controlled.FLUKA Monte Carlo is used to simulate the readings of the WMNS under(1)a spectrum of Cf-252 and(2)its spectrum after being moderated,(3)a spectrum used for boron neutron capture therapy,and(4)a reactor spectrum.Subsequently,the measured neutron counts are unfolded using the SDENUA.The uncertainties of the measured neutron count and the response matrix are considered in the SDENUA,which does not require complex parameter tuning or an a priori default spectrum.The results indicate that the solutions of the SDENUA agree better with the IAEA spectra than those of MAXED and GRAVEL in UMG 3.1,and the errors of the final results calculated using the SDENUA are less than 12%.The established SDENUA can be used to unfold spectra from the WMNS.
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.
