The endoplasmic reticulum,a key cellular organelle,regulates a wide variety of cellular activities.Endoplasmic reticulum autophagy,one of the quality control systems of the endoplasmic reticulum,plays a pivotal role i...The endoplasmic reticulum,a key cellular organelle,regulates a wide variety of cellular activities.Endoplasmic reticulum autophagy,one of the quality control systems of the endoplasmic reticulum,plays a pivotal role in maintaining endoplasmic reticulum homeostasis by controlling endoplasmic reticulum turnover,remodeling,and proteostasis.In this review,we briefly describe the endoplasmic reticulum quality control system,and subsequently focus on the role of endoplasmic reticulum autophagy,emphasizing the spatial and temporal mechanisms underlying the regulation of endoplasmic reticulum autophagy according to cellular requirements.We also summarize the evidence relating to how defective or abnormal endoplasmic reticulum autophagy contributes to the pathogenesis of neurodegenerative diseases.In summary,this review highlights the mechanisms associated with the regulation of endoplasmic reticulum autophagy and how they influence the pathophysiology of degenerative nerve disorders.This review would help researchers to understand the roles and regulatory mechanisms of endoplasmic reticulum-phagy in neurodegenerative disorders.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
Background and objectives:A long-term high-fat diet(HFD)exerts lipotoxic effects on multiple organs,particularly the liver,leading to metabolic diseases.This study aimed to delineate the dynamic effects of HFD on lipi...Background and objectives:A long-term high-fat diet(HFD)exerts lipotoxic effects on multiple organs,particularly the liver,leading to metabolic diseases.This study aimed to delineate the dynamic effects of HFD on lipid metabolism,elucidate the mechanisms underlying hepatic lipotoxicity,and investigate the protective effects of Ganoderma lucidum against lipotoxicity both in vitro and in vivo.Methods:C57BL/6 mice were fed either a 45%or 60%HFD,followed by measurements of body composition,serum lipid profile,and liver pathology at four,eight,twelve,and sixteen weeks.Inflammatory responses,the unfolded protein response(UPR),and endoplasmic reticulum(ER)-phagy were examined in the livers of mice at 16 weeks.Male C57BL/6 mice were randomly assigned to four groups(n=12 per group):normal diet,45%HFD,and two HFD+Ganoderma lucidum water extract(GLE)groups(1 g/kg/d and 2 g/kg/d of crude drug,orally administered by gavage for eight weeks following a four-week HFD induction).Results:Body weight,body fat,serum lipids,and hepatic steatosis increased progressively,accompanied by impaired glucose tolerance and liver injury,as indicated by elevated serum alanine aminotransferase(ALT)and aspartate aminotransferase(AST)levels.HFD also induced activation of the STING and NF-κB signaling pathways,as well as the PERK and IRE1 branches of the UPR.Similarly,ER-phagy selective receptors,particularly FAM134B,which is primarily expressed in hepatocytes as shown by single-cell sequencing,were upregulated after 16 weeks of HFD feeding.Furthermore,GLE mitigated palmitic acid-induced lipotoxicity in primary hepatocytes,as evidenced by improved cell viability,reduced ALT,AST,and lactate dehydrogenase levels in the culture supernatant,and decreased transferase dUTP nick-end labeling-positive cell counts.In 45%HFD-fed mice,GLE reduced serum total cholesterol,low-density lipoprotein,and hepatic triglyceride levels.Conclusions:HFD-induced lipotoxicity causes hepatic tissue injury and inflammatory responses,which may be alleviated by coordinated regulation of compensatory UPR and ER-phagy.Ganoderma lucidum shows promise as a dietary supplement for managing metabolic disorders.展开更多
Double-resonance Raman(DRR)scattering in two-di-mensional(2D)materials describes the intravalley or intervalley scattering of an electron or a hole excited by incident photons.Although the presence of defects can prov...Double-resonance Raman(DRR)scattering in two-di-mensional(2D)materials describes the intravalley or intervalley scattering of an electron or a hole excited by incident photons.Although the presence of defects can provide additional momentum and influence the scat-tering process involving one or two phonons,only the idealized defects without any structural details are considered in tra-ditional DRR theory.Here,the second-order DRR spectra of WSe_(2) monolayer with different types of defects are calculated involving the combinations of acoustic and optical phonons in the vicinity of K(K')and M points of the Brillouin zone.The electronic band structures are modified due to the presence of defects,and the band unfolding method is adopted to show the bending of valence and conduction bands for the defective WSe_(2) monolayers.The associ-ated phononic band structures also exhibit different changes in phonon dispersion curves,re-sulting in different DRR spectra corresponding to the different types of defects in the WSe_(2) monolayers.For example,the existence of W vacancy in the WSe_(2) monolayer would result in downshifts in vibrational frequencies and asymmetrical broadenings in linewidths for most combination modes due to the dramatic changes in contour shape of electronic valleys at K and K'.Moreover,the scattering from K to Q is found to be forbidden for the two Se vacan-cies because of the elevation of conduction band at the Q point.Our work highlights the role of defect structures in the intervalley scattering and may provide better understanding in the underlying physics of DRR process in 2D materials.展开更多
In Candida species,the endoplasmic reticulum(ER)stress response—regulated by the unfolded protein response(UPR)—serves as a critical adaptive mechanism affecting both pathogenicity and antifungal resistance.This rev...In Candida species,the endoplasmic reticulum(ER)stress response—regulated by the unfolded protein response(UPR)—serves as a critical adaptive mechanism affecting both pathogenicity and antifungal resistance.This review aims to synthesize current knowledge on ER stress pathways in Candida glabrata and Candida albicans,highlighting their species-specific adaptations and therapeutic implications.We systematically analyzed peer-reviewed literature on ER stress mechanisms in Candida,focusing on comparative studies of UPR signaling.Emphasis was placed on C.glabrata’s inositol-requiring enzyme 1(IRE1)-dependent Regulated IRE1-Dependent Decay(RIDD)pathway and C.albicans’IRE1/HAC1 and calcium-mediated pathways.Connections to virulence and drug resistance were evaluated through genetic,transcriptomic,and phenotypic evidence.Candida species employ divergent UPR strategies:C.glabrata mitigates ER stress primarily via RIDD-mediated mRNA decay to reduce protein load,while C.albicans enhances folding capacity through HAC1 splicing and calcium homeostasis.These adaptations promote survival in hostile host environments(e.g.,oxidative stress,immune attacks)and are linked to resistance against azoles and echinocandins.Pharmacological disruption of UPR components(e.g.,IRE1 inhibitors)sensitizes Candida to antifungals in experimental models.ER stress response pathways are promising targets for antifungal drug development.Understanding species-specific UPR mechanisms in Candida could guide novel therapies to overcome resistance and improve treatment outcomes.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
Eukaryotic cells contain the endoplasmic reticulum(ER),a prevalent and intricate membranous structural system.During the development of inflammatory bowel disease(IBD),the stress on the ER and the start of the unfolde...Eukaryotic cells contain the endoplasmic reticulum(ER),a prevalent and intricate membranous structural system.During the development of inflammatory bowel disease(IBD),the stress on the ER and the start of the unfolded protein response are very important.Some chemicals,including 4μ8C,small molecule agonists of X-box binding protein 1,and ISRIB,work on the inositol-requiring enzyme 1,turn on transcription factor 6,and activate protein kinase RNA-like ER kinase path-ways.This may help ease the symptoms of IBD.Researchers investigating the gut microbiota have discovered a correlation between ER stress and it.This suggests that changing the gut microbiota could help make new medicines for IBD.This study looks at how ER stress works and how it contributes to the emergence of IBD.It also talks about its possible clinical importance as a therapeutic target and looks into new ways to treat this condition.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
基金supported by the National Natural Science Foundation of China,Nos.92049120 and 81870897STI2030-Major Projects,No.2021ZD0204001+6 种基金Guangdong Key Project for Development of New Tools for the Diagnosis and Treatment of Autism,No.2018B030335001the Natural Science Foundation of Jiangsu Province,No.BK20181436the National Major Scientific and Technological Special Project for Significant New Drug Development,No.2019ZX09301102the Discipline Construction Program of the Second Affiliated Hospital of Soochow University,No.XKTJ-TD202003Sino-German Cooperation Mobility Programme,No.M-0679the Science and Technology Project of Suzhou,No.SKY2022161Research Project of Neurological Diseases of the Second Affiliated Hospital of Soochow University Medical Center,No.ND2023A01(all to QHM)。
文摘The endoplasmic reticulum,a key cellular organelle,regulates a wide variety of cellular activities.Endoplasmic reticulum autophagy,one of the quality control systems of the endoplasmic reticulum,plays a pivotal role in maintaining endoplasmic reticulum homeostasis by controlling endoplasmic reticulum turnover,remodeling,and proteostasis.In this review,we briefly describe the endoplasmic reticulum quality control system,and subsequently focus on the role of endoplasmic reticulum autophagy,emphasizing the spatial and temporal mechanisms underlying the regulation of endoplasmic reticulum autophagy according to cellular requirements.We also summarize the evidence relating to how defective or abnormal endoplasmic reticulum autophagy contributes to the pathogenesis of neurodegenerative diseases.In summary,this review highlights the mechanisms associated with the regulation of endoplasmic reticulum autophagy and how they influence the pathophysiology of degenerative nerve disorders.This review would help researchers to understand the roles and regulatory mechanisms of endoplasmic reticulum-phagy in neurodegenerative disorders.
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(82204739)the CAMS Innovation Fund for Medical Sciences(CIFMS,2021-I2M-1-048).
文摘Background and objectives:A long-term high-fat diet(HFD)exerts lipotoxic effects on multiple organs,particularly the liver,leading to metabolic diseases.This study aimed to delineate the dynamic effects of HFD on lipid metabolism,elucidate the mechanisms underlying hepatic lipotoxicity,and investigate the protective effects of Ganoderma lucidum against lipotoxicity both in vitro and in vivo.Methods:C57BL/6 mice were fed either a 45%or 60%HFD,followed by measurements of body composition,serum lipid profile,and liver pathology at four,eight,twelve,and sixteen weeks.Inflammatory responses,the unfolded protein response(UPR),and endoplasmic reticulum(ER)-phagy were examined in the livers of mice at 16 weeks.Male C57BL/6 mice were randomly assigned to four groups(n=12 per group):normal diet,45%HFD,and two HFD+Ganoderma lucidum water extract(GLE)groups(1 g/kg/d and 2 g/kg/d of crude drug,orally administered by gavage for eight weeks following a four-week HFD induction).Results:Body weight,body fat,serum lipids,and hepatic steatosis increased progressively,accompanied by impaired glucose tolerance and liver injury,as indicated by elevated serum alanine aminotransferase(ALT)and aspartate aminotransferase(AST)levels.HFD also induced activation of the STING and NF-κB signaling pathways,as well as the PERK and IRE1 branches of the UPR.Similarly,ER-phagy selective receptors,particularly FAM134B,which is primarily expressed in hepatocytes as shown by single-cell sequencing,were upregulated after 16 weeks of HFD feeding.Furthermore,GLE mitigated palmitic acid-induced lipotoxicity in primary hepatocytes,as evidenced by improved cell viability,reduced ALT,AST,and lactate dehydrogenase levels in the culture supernatant,and decreased transferase dUTP nick-end labeling-positive cell counts.In 45%HFD-fed mice,GLE reduced serum total cholesterol,low-density lipoprotein,and hepatic triglyceride levels.Conclusions:HFD-induced lipotoxicity causes hepatic tissue injury and inflammatory responses,which may be alleviated by coordinated regulation of compensatory UPR and ER-phagy.Ganoderma lucidum shows promise as a dietary supplement for managing metabolic disorders.
基金supported by the National Natural Sci-ence Foundation of China(No.22174135,No.21790352)the National Key R&D Program of China(No.2021YFA1500500,No.2016YFA0200600)+4 种基金the Strategic Priority Research Program of Chinese Academy of Sciences(No.XDB36000000)Anhui Initiative in Quantum Information Technologies(No.AHY090100)CAS Project for Young Scientists in Basic Research(No.YSBR-054)Innovation Program for Quantum Science and Technology(No.2021ZD0303301)the Fundamental Research Funds for the Central Universities.
文摘Double-resonance Raman(DRR)scattering in two-di-mensional(2D)materials describes the intravalley or intervalley scattering of an electron or a hole excited by incident photons.Although the presence of defects can provide additional momentum and influence the scat-tering process involving one or two phonons,only the idealized defects without any structural details are considered in tra-ditional DRR theory.Here,the second-order DRR spectra of WSe_(2) monolayer with different types of defects are calculated involving the combinations of acoustic and optical phonons in the vicinity of K(K')and M points of the Brillouin zone.The electronic band structures are modified due to the presence of defects,and the band unfolding method is adopted to show the bending of valence and conduction bands for the defective WSe_(2) monolayers.The associ-ated phononic band structures also exhibit different changes in phonon dispersion curves,re-sulting in different DRR spectra corresponding to the different types of defects in the WSe_(2) monolayers.For example,the existence of W vacancy in the WSe_(2) monolayer would result in downshifts in vibrational frequencies and asymmetrical broadenings in linewidths for most combination modes due to the dramatic changes in contour shape of electronic valleys at K and K'.Moreover,the scattering from K to Q is found to be forbidden for the two Se vacan-cies because of the elevation of conduction band at the Q point.Our work highlights the role of defect structures in the intervalley scattering and may provide better understanding in the underlying physics of DRR process in 2D materials.
文摘In Candida species,the endoplasmic reticulum(ER)stress response—regulated by the unfolded protein response(UPR)—serves as a critical adaptive mechanism affecting both pathogenicity and antifungal resistance.This review aims to synthesize current knowledge on ER stress pathways in Candida glabrata and Candida albicans,highlighting their species-specific adaptations and therapeutic implications.We systematically analyzed peer-reviewed literature on ER stress mechanisms in Candida,focusing on comparative studies of UPR signaling.Emphasis was placed on C.glabrata’s inositol-requiring enzyme 1(IRE1)-dependent Regulated IRE1-Dependent Decay(RIDD)pathway and C.albicans’IRE1/HAC1 and calcium-mediated pathways.Connections to virulence and drug resistance were evaluated through genetic,transcriptomic,and phenotypic evidence.Candida species employ divergent UPR strategies:C.glabrata mitigates ER stress primarily via RIDD-mediated mRNA decay to reduce protein load,while C.albicans enhances folding capacity through HAC1 splicing and calcium homeostasis.These adaptations promote survival in hostile host environments(e.g.,oxidative stress,immune attacks)and are linked to resistance against azoles and echinocandins.Pharmacological disruption of UPR components(e.g.,IRE1 inhibitors)sensitizes Candida to antifungals in experimental models.ER stress response pathways are promising targets for antifungal drug development.Understanding species-specific UPR mechanisms in Candida could guide novel therapies to overcome resistance and improve treatment outcomes.
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,No.81873297the Fundamental Research Funds for the Central Public Welfare Research Institutes,No.ZZ13-YQ-006+1 种基金China Academy of Chinese Medical Sciences Innovation Fund,No.CI2021A01003the Hospital Capability Enhancement Project of Xiyuan Hospital,China Academy of Chinese Medical Sciences,No.XYZX0303-07.
文摘Eukaryotic cells contain the endoplasmic reticulum(ER),a prevalent and intricate membranous structural system.During the development of inflammatory bowel disease(IBD),the stress on the ER and the start of the unfolded protein response are very important.Some chemicals,including 4μ8C,small molecule agonists of X-box binding protein 1,and ISRIB,work on the inositol-requiring enzyme 1,turn on transcription factor 6,and activate protein kinase RNA-like ER kinase path-ways.This may help ease the symptoms of IBD.Researchers investigating the gut microbiota have discovered a correlation between ER stress and it.This suggests that changing the gut microbiota could help make new medicines for IBD.This study looks at how ER stress works and how it contributes to the emergence of IBD.It also talks about its possible clinical importance as a therapeutic target and looks into new ways to treat this condition.
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.
