The equivalent source(ES)method in the spherical coordinate system has been widely applied to processing,reduction,field modeling,and geophysical and geological interpretation of satellite magnetic anomaly data.Howeve...The equivalent source(ES)method in the spherical coordinate system has been widely applied to processing,reduction,field modeling,and geophysical and geological interpretation of satellite magnetic anomaly data.However,the inversion for the ES model suffers from nonuniqueness and instability,which remain unresolved.To mitigate these issues,we introduce both the minimum and flattest models into the model objective function as an alternative regularization approach in the spherical ES method.We first present the methods,then analyze the accuracy of forward calculation and test the proposed ES method in this study by using synthetic data.The experimental results from simulation data indicate that our proposed regularization effectively suppresses the Backus effect and mitigates inversion instability in the low-latitude region.Finally,we apply the proposed method to magnetic anomaly data from China Seismo-Electromagnetic Satellite-1(CSES-1)and Macao Science Satellite-1(MSS-1)magnetic measurements over Africa by constructing an ES model of the large-scale lithospheric magnetic field.Compared with existing global lithospheric magnetic field models,our ES model demonstrates good consistency at high altitudes and predicts more stable fields at low altitudes.Furthermore,we derive the reduction to the pole(RTP)magnetic anomaly fields and the apparent susceptibility contrast distribution based on the ES model.The latter correlates well with the regional tectonic framework in Africa and surroundings.展开更多
As a means of quantitative interpretation,forward calculations of the global lithospheric magnetic field in the Spherical Harmonic(SH)domain have been widely used to reveal geophysical,lithological,and geothermal vari...As a means of quantitative interpretation,forward calculations of the global lithospheric magnetic field in the Spherical Harmonic(SH)domain have been widely used to reveal geophysical,lithological,and geothermal variations in the lithosphere.Traditional approaches either do not consider the non-axial dipolar terms of the inducing field and its radial variation or do so by means of complicated formulae.Moreover,existing methods treat the magnetic lithosphere either as an infinitesimally thin layer or as a radially uniform spherical shell of constant thickness.Here,we present alternative forward formulae that account for an arbitrarily high maximum degree of the inducing field and for a magnetic lithosphere of variable thickness.Our simulations based on these formulae suggest that the satellite magnetic anomaly field is sensitive to the non-axial dipolar terms of the inducing field but not to its radial variation.Therefore,in forward and inverse calculations of satellite magnetic anomaly data,the non-axial dipolar terms of the inducing field should not be ignored.Furthermore,our results show that the satellite magnetic anomaly field is sensitive to variability in the lateral thickness of the magnetized shell.In particular,we show that for a given vertically integrated susceptibility distribution,underestimating the thickness of the magnetic layer overestimates the induced magnetic field.This discovery bridges the greatest part of the alleged gap between the susceptibility values measured from rock samples and the susceptibility values required to match the observed magnetic field signal.We expect the formulae and conclusions of this study to be a valuable tool for the quantitative interpretation of the Earth's global lithospheric magnetic field,through an inverse or forward modelling approach.展开更多
The persistence of covalently closed circular DNA(cccDNA)in hepatitis B virus(HBV)-infected hepatocytes remains a major obstacle to effective antiviral treatment.Understanding the molecular mechanisms regulating HBV c...The persistence of covalently closed circular DNA(cccDNA)in hepatitis B virus(HBV)-infected hepatocytes remains a major obstacle to effective antiviral treatment.Understanding the molecular mechanisms regulating HBV cccDNA transcription is essential for developing novel therapeutic strategies.In this study,we investigated the role of RNA binding motif protein 25(RBM25)in HBV replication,focusing on its interaction with cccDNA and its regulation of host transcription factors.The results demonstrated that RBM25 knockdown markedly inhibited HBV replication,reducing levels of HBV DNA,hepatitis B e antigen(HBeAg),hepatitis B surface antigen(HBsAg),HBV RNA,and L-HBs in HBV-replicating and infected cell models.Consistent results were observed in a mouse model hydrodynamically injected with 1.2HBV plasmid.Conversely,RBM25 overexpression significantly enhanced HBV replication.Mechanistically,RBM25 promoted HBV promoter activities by binding to cccDNA through its RE/RD and PWI domains.This effect was mediated by increased Yin Yang 1(YY1)expression,which enhanced acetylation of cccDNA-bound histones,promoting HBV transcription.Furthermore,RBM25 expression was upregulated and translocated to the nucleus following core protein expression and accumulation,while overexpression of RBM25 promoted core protein degradation.In conclusion,this study demonstrates that RBM25 is a novel host factor that enhances HBV replication by upregulating YY1-dependent transcriptional activation of cccDNA.It also reveales a reciprocal regulatory mechanism between the HBV core protein and RBM25,which helps sustain HBV replication.展开更多
Traditional pyrometallurgy and hydrometallurgy processes primarily focus on the recovery of valuable metals(Co,Ni,etc.)from spent lithium-ion batteries.However,these methods are not economical for recycling cheap LiFe...Traditional pyrometallurgy and hydrometallurgy processes primarily focus on the recovery of valuable metals(Co,Ni,etc.)from spent lithium-ion batteries.However,these methods are not economical for recycling cheap LiFePO_(4).Herein,a synergistic thermal-decomposition and electric-drive strategy is proposed to recover the whole spent LiFePO_(4)electrode by in-situ recovering the inactive lithium(dead lithium and trapped interlayer lithium).Firstly,the organic components in the dense solid electrolyte interface(SEI)are effectively decomposed through thermal-decomposition processing,exposing the dead lithium encapsulated within the SEI and recovering the electron channels between the dead lithium and graphite.Leveraging the difference between the Gibbs free energy of the dead lithium and graphite as the driving force facilitates the dead lithium inserting into the anode.Then,fully utilizing the remaining discharge capacity of the spent LiFePO_(4)cell,the inactive lithium is reinserted into LiFePO_(4)lattice during the electric-drive process.Consequently,the reactivated lithium content increases by more than 16%,reaching a capacity of 134.2 mA h g^(-1)compared to 115.2 mA h g^(-1)from degraded LiFePO_(4),allowing for effective participation in the subsequent cycling.This work provides new perspectives on highly profitable cycles with low energy and material consumption and a low carbon footprint.展开更多
The cell cycle is a tightly coupled series of events that enable cells to grow and proliferate.Cyclin-dependent kinases(CDKs)play crucial roles in the cell cycle by enabling cells to transition between different phase...The cell cycle is a tightly coupled series of events that enable cells to grow and proliferate.Cyclin-dependent kinases(CDKs)play crucial roles in the cell cycle by enabling cells to transition between different phases when they are activated.Cell cycle proteins enhance the activity of CDKs,while natural CDK inhibitors(CDKIs)suppress them.The cell cycle continues in cycles under normal conditions,but when conditions change,cells halt or terminate the cell cycle.Tumors are tissues that grow out of control,and the mechanisms of various types of tumors are different;however,almost all tumor cells share several common characteristics,including proliferation,prevention of apoptosis and genomic instability.Cellular division is essential in the progression of cancer.A key characteristic of cancer is the uncontrolled growth of tumor cells,which is due to the erratic behavior of several proteins during the cell cycle.Therefore,cell cycle regulators are considered attractive targets for the treatment of cancer.The present analysis highlights proteins that play a direct role in controlling the tumor cell cycle,such as CDKs,and provides a brief overview of checkpoint kinases.The present review also discusses how cell cycle proteins contribute to cancer and describes some of the antitumor drugs that are being researched.展开更多
Revealing the development of microstructural inhomogeneity in the multi-pass flow forming of titanium alloy components is of great significance to the microstructure control and property tailoring.To this end,the micr...Revealing the development of microstructural inhomogeneity in the multi-pass flow forming of titanium alloy components is of great significance to the microstructure control and property tailoring.To this end,the microstructural inhomogeneity of TA15 alloy spun cylindrical parts was analyzed based on the deformation history.The results indicate that the material underwent significant compressive strain in the normal direction(ND),tension strain in the rolling and circumferential directions(RD and CD),while tension strain in the CD is slightly small due to the limited material flow in this direction.These strain characteristics make the microstructure,especially the primary a(ap),present different morphologies in the different planes of the part.Meanwhile,the combined effects of inhomogeneous deformation and temperature distribution in the ND also cause the inhomogeneity of microstructure morphology and parameters in this direction.Quantitative analyses show that with the forming pass increasing,the aspect ratio of apincreases most in the normal-rolling plane,then in the normal-circumferential plane and least in the circumferential-rolling plane,whereas apcontent decreases in an opposite trend.Along the ND,the aspect ratio and content of apis relatively high in the outer and inner surface areas but lowest in the central area,and these inhomogeneous characteristics can be gradually diminished with the forming pass increasing.Furthermore,the variation of hardness inhomogeneity factor indicates that a four-pass forming with the total reduction ratio of 63%could obtain a homogenous microstructure along the ND of the TA15 alloy spun cylindrical part.展开更多
Corrigendum Text:On page 2 of this letter,there is a misprint in the unit.The unit of the geometrical dimension of the spherical hohlraums on this page should always be“mm”rather than“mm”,i.e.in the second paragra...Corrigendum Text:On page 2 of this letter,there is a misprint in the unit.The unit of the geometrical dimension of the spherical hohlraums on this page should always be“mm”rather than“mm”,i.e.in the second paragraph,“…with 800 J per beam at 0.35 mm…”should be“…with 800 J per beam at 0.35 mm…”,“The slit of 400 mm width is parallel…”should be“The slit of 400 mm width is parallel…”,“The laser focal diameter is about 500 mm…”should be“The laser focal diameter is about 500 mm…”;in the third paragraph,“…we take 850 mm as the radius…”should be“…we take 850 mm as the radius…”,“The LEH radius R_(L) is 400 mm…”should be“The LEH radius R_(L) is 400 mm…”,“…the radius of the cylindrical LEH outer ring is taken as 1.5 R_(L)=600 mm”should be“…the radius of the cylindrical LEH outer ring is taken as 1.5 R_(L)=600 mm”.This mistake does not affect any of the main results of the original letter.展开更多
We present our recent laser-plasmas instability(LPI)comparison experiment at the SGIII laser facility between the spherical and cylindrical hohlraums.Three kinds of filling are considered:vacuum,gas-filling with or wi...We present our recent laser-plasmas instability(LPI)comparison experiment at the SGIII laser facility between the spherical and cylindrical hohlraums.Three kinds of filling are considered:vacuum,gas-filling with or without a capsule inside.A spherical hohlraum of 3.6 mm in diameter,and a cylindrical hohlraum of 2.4 mm?4.3 mm are used.The capsule diameter is 0.96 mm.A flat-top laser pulse with 3 ns duration and up to 92.73 kJ energy is used.The experiment has shown that the LPI level in the spherical hohlraum is close to that of the outer beam in the cylindrical hohlraum,while much lower than that of the inner beam.The experiment is further simulated by using our 2-dimensional radiation hydrodynamic code LARED-Integration,and the laser back-scattering fraction and the stimulated Raman scatter(SRS)spectrum are post-processed by the high efficiency code of laser interaction with plasmas HLIP.According to the simulation,the plasma waves are strongly damped and the SRS is mainly developed at the plasma conditions of electron density from 0.08 n_(c) to 0.1 n_(c) and electron temperature from 1.5 keV to 2.0 keV inside the hohlraums.However,obvious differences between the simulation and experiment are found,such as that the SRS back-scattering is underestimated,and the numerical SRS spectrum peaks at a larger wavelength and at a later time than the data.These dif-ferences indicate that the development of a 3D radiation hydrodynamic code,with more accurate physics models,is mandatory for spherical hohlraum study.展开更多
This paper presents a 220-GHz-band 7-m wireless link with a 45-Gbps transmission data rate by using 16 quadrature amplitude modulation(16-QAM).Super-heterodyne transceiver modules are developed for transmission and re...This paper presents a 220-GHz-band 7-m wireless link with a 45-Gbps transmission data rate by using 16 quadrature amplitude modulation(16-QAM).Super-heterodyne transceiver modules are developed for transmission and reception of the modulated signals,which consist of a Schottky barrier diodes(SBD)based sub-harmonic mixer(SHM),an InP HEMT low noise amplifier(LNA),a waveguide band-pass filter(BPF),and a 108-GHz local oscillator(LO)multiplier chain.The transmitter features a peak transmit power of 1.41 dBm,and the IF frequency varies from 5 GHz to 20 GHz.Besides,the receiver features a conversion gain of 9.3 dB in average and a noise temperature of 3052.8 K.The measured results indicate that the transceiver modules enable data transmission of a 45-Gbps 16-QAM signal with Signal-Noise-Ratio(SNR)from 11.59 dB to 15.36 dB in a 7-m line-of-sight channel.展开更多
The octahedral spherical hohlraums have natural superiority in maintaining high radiation symmetry during the entire capsule implosion process in indirect drive inertial confinement fusion.While,in contrast to the cyl...The octahedral spherical hohlraums have natural superiority in maintaining high radiation symmetry during the entire capsule implosion process in indirect drive inertial confinement fusion.While,in contrast to the cylindrical hohlraums,the narrow space between the laser beams and the spherical hohlraum wall is usually commented.In this Letter,we address this crucial issue and report our experimental work conducted on the SGIII-prototype laser facility which unambiguously demonstrates that a simple design of cylindrical laser entrance hole(LEH)can dramatically improve the laser propagation inside the spherical hohlraums.In addition,the laser beam deflection in the hohlraum is observed for the first time in the experiments.Our 2-dimensional simulation results also verify qualitatively the advantages of the spherical hohlraums with cylindrical LEHs.Our results imply the prospect of adopting the cylindrical LEHs in future spherical ignition hohlraum design.展开更多
Zika virus(ZIKV)evolves non-structural proteins to evade immune response and ensure efficient replication in the host cells.Cholesterol metabolic enzyme 7-dehydrocholesterol reductase(DHCR7)was recently reported to im...Zika virus(ZIKV)evolves non-structural proteins to evade immune response and ensure efficient replication in the host cells.Cholesterol metabolic enzyme 7-dehydrocholesterol reductase(DHCR7)was recently reported to impact innate immune responses in ZIKV infection.However,the vital non-structural protein and mechanisms involved in DHCR7-mediated viral evasion are not well elucidated.In this study,we demonstrated that ZIKV infection facilitated DHCR7 expression.Notably,the upregulated DHCR7 in turn facilitated ZIKV infection and blocking DHCR7 suppressed ZIKV infection.Mechanically,ZIKV non-structural protein 4B(NS4B)interacted with DHCR7 to induce DHCR7 expression.Moreover,DHCR7 inhibited TANK-binding kinase 1(TBK1)and interferon regulatory factor 3(IRF3)phosphorylation,which resulted in the reduction of interferon-beta(IFN-β)and interferon-stimulated genes(ISGs)productions.Therefore,we propose that ZIKV NS4B binds to DHCR7 to repress TBK1 and IRF3 activation,which in turn inhibits IFN-βand ISGs,and thereby facilitating ZIKV evasion.This study broadens the insights on how viral non-structural proteins antagonize innate immunity to facilitate viral infection via cholesterol metabolic enzymes and intermediates.展开更多
Recycling graphite anode from spent lithium-ion batteries(SLIBs)is regarded as a crucial approach to promoting sustainable energy storage industry.However,the recycled graphite(RG)generally presents degraded structure...Recycling graphite anode from spent lithium-ion batteries(SLIBs)is regarded as a crucial approach to promoting sustainable energy storage industry.However,the recycled graphite(RG)generally presents degraded structure and performance.Herein,the residual fluoride self-activated effect is proposed for the upgraded utilization of RG.Simple and low-energy water immersion treatment not only widens the interlayer spacing,but also retains appropriate fluoride on the surface of RG.Theoretical analysis and experiments demonstrate that the residual fluoride can optimize Li~+migration and deposition kinetics,resulting in better Li~+intercalation/deintercalation in the interlayer and more stable Li metal plating/stripping on the surface of RG,As a result,the designed LFP||RG full cells achieve ultrahigh reversibility(~100%Coulombic efficiency),high capacity retention(67%after 200 cycles,0.85 N/P ratio),and commendable adaptability(stable cycling without short-circuiting,0.15 N/P ratio).The energy density is improved from 334 Wh kg^(-1)of 1.1 N/P ratio to 367 Wh kg^(-1)of 0.85 N/P ratio(total mass based on cathode and anode).The exploration of RG by residual fluoride self-activated effect achieves upgraded utilization beyond fresh commercial graphite and highlights a new strategy for efficient reuse of SLIBs.展开更多
This article presents the design and performance of a terahertz on-chip coupled-grounded coplanar waveguide(GCPW)power combiner using a 50μm-thick InP process.The proposed topology uses two coupled-GCPW lines at the ...This article presents the design and performance of a terahertz on-chip coupled-grounded coplanar waveguide(GCPW)power combiner using a 50μm-thick InP process.The proposed topology uses two coupled-GCPW lines at the end of the input port to substitute two quarter-wavelength GCPW lines,which is different from the conventional Wilkinson power combiner and can availably minimize the coverage area.According to the results obtained,for the frequency range of 210-250 GHz,the insertion losses for each two-way combiner and four-way combiner were lower than 1.05 dB and1.35 dB,respectively,and the in-band return losses were better than 11 dB.Moreover,the proposed on-chip GCPW-based combiners achieved a compromise in low-loss,broadband,and small-size,which can find wide applications in terahertz bands,such as power amplifiers and signal distribution networks.展开更多
Tyrosine kinase inhibitors(TKIs)are a novel category of antitumor agents with remarkable efficacy in extending pa-tient survival.However,clinical use of TKIs has been hindered by the major adverse effect of atrial fib...Tyrosine kinase inhibitors(TKIs)are a novel category of antitumor agents with remarkable efficacy in extending pa-tient survival.However,clinical use of TKIs has been hindered by the major adverse effect of atrial fibrillation(AF).Recent studies have revealed that TKIs induce metabolic alterations and remodeling in cardiomyocytes,thus perturb-ing energy metabolism.Specifically,mitochondrial dysfunction and shifts in cardiac substrate utilization have been implicated in the mechanisms underlying TKI-induced AF.In light of these findings,this article reviews the energy metabolism-associated pathways involved in TKI-induced AF,identifies precise therapeutic targets for managing this condition,and discusses evidence that may contribute to the development of novel TKIs without cardiac adverse ef-fects.展开更多
Atrial fibrillation ablation procedures have become a focus of research among electrophysiologists,with the aim of increasing success rates while minimizing complications.One major concern is phrenic nerve injury(PNI)...Atrial fibrillation ablation procedures have become a focus of research among electrophysiologists,with the aim of increasing success rates while minimizing complications.One major concern is phrenic nerve injury(PNI).Despite advancements in ablation strategies,equipment,and monitoring methods,the incidence of PNI during these procedures remains substantial,particularly during cryoballoon ablation,which has a reported PNI incidence of 3.5%.This review examines recent studies,to provide a comprehensive overview of PNI mechanisms,clinical features,prognosis,and methods for prevention during ablation.展开更多
Skeletal interoception regulates bone homeostasis through the prostaglandin E2(PGE2)concentration in bone.Vertebral endplates undergo ossification and become highly porous during intervertebral disc degeneration and a...Skeletal interoception regulates bone homeostasis through the prostaglandin E2(PGE2)concentration in bone.Vertebral endplates undergo ossification and become highly porous during intervertebral disc degeneration and aging.We found that the PGE2 concentration was elevated in porous endplates to generate spinal pain.Importantly,treatment with a high-dose cyclooxygenase 2 inhibitor(celecoxib,80 mg·kg−1 per day)decreased the prostaglandin E2 concentration and attenuated spinal pain in mice with lumbar spine instability.However,this treatment impaired bone formation in porous endplates,and spinal pain recurred after discontinuing the treatment.Interestingly,low-dose celecoxib(20 mg·kg−1 per day,which is equivalent to one-quarter of the clinical maximum dosage)induced a latent inhibition of spinal pain at 3 weeks post-treatment,which persisted even after discontinuing treatment.Furthermore,when the prostaglandin E2 concentration was maintained at the physiological level with low-dose celecoxib,endplate porosity was reduced significantly,which was associated with decreased sensory nerve innervation and spinal pain.These findings suggest that low-dose celecoxib may help to maintain skeletal interoception and decrease vertebral endplate porosity,thereby reducing sensory innervation and spinal pain in mice.展开更多
In this paper,we give a review of our theoretical and experimental progress in octahedral spherical hohlraum study.From our theoretical study,the octahedral spherical hohlraums with 6 Laser Entrance Holes(LEHs)of octa...In this paper,we give a review of our theoretical and experimental progress in octahedral spherical hohlraum study.From our theoretical study,the octahedral spherical hohlraums with 6 Laser Entrance Holes(LEHs)of octahedral symmetry have robust high symmetry during the capsule implosion at hohlraum-to-capsule radius ratio larger than 3.7.In addition,the octahedral spherical hohlraums also have potential superiority on low backscattering without supplementary technology.We studied the laser arrangement and constraints of the octahedral spherical hohlraums,and gave a design on the laser arrangement for ignition octahedral hohlraums.As a result,the injection angle of laser beams of 50°-60°was proposed as the optimum candidate range for the octahedral spherical hohlraums.We proposed a novel octahedral spherical hohlraum with cylindrical LEHs and LEH shields,in order to increase the laser coupling efficiency and improve the capsule symmetry and to mitigate the influence of the wall blowoff on laser transport.We studied on the sensitivity of the octahedral spherical hohlraums to random errors and compared the sensitivity among the octahedral spherical hohlraums,the rugby hohlraums and the cylindrical hohlraums,and the results show that the octahedral spherical hohlraums are robust to these random errors while the cylindrical hohlraums are the most sensitive.Up till to now,we have carried out three experiments on the spherical hohlraum with 2 LEHs on Shenguang(SG)laser facilities,including demonstration of improving laser transport by using the cylindrical LEHs in the spherical hohlraums,spherical hohlraum energetics on the SGIII prototype laser facility,and comparisons of laser plasma instabilities between the spherical hohlraums and the cylindrical hohlraums on the SGIII laser facility.展开更多
Photocatalytic solar fuel generation is currently a hot topic because of its potential for solving the energy crisis owing to its low cost and zero-carbon emissions.However,the rapid bulk recombination of photoexcited...Photocatalytic solar fuel generation is currently a hot topic because of its potential for solving the energy crisis owing to its low cost and zero-carbon emissions.However,the rapid bulk recombination of photoexcited carrier pairs is a fundamental disadvantage.To resolve this problem,we synthesized a dual cocatalysts system of cobalt phosphide(Co P)and molybdenum carbide(Mo_(2)C)embedded on strontium titanate(Sr TiO_(3))nanofibers.Compared with those of pristine SrTiO_(3) and binary samples,the dual cocatalysts system(denoted SCM)showed a significant improvement in the hydrogen evolution and CO_(2) reduction performance.Further,the structure of SCM effectively promoted spatial charge separation and enhanced the photocatalytic performance.In addition,the Schottky junction formed between the SrTiO_(3) and cocatalysts enabled the rapid transfer of photoexcited electrons from SrTiO_(3) to the cocatalysts,resulting in effective separation and prolonged photoexcited electron lifetimes.The electron migration route between SrTiO_(3) and the cocatalysts was determined by in situ irradiation X-ray spectroscopy,and band structures of Sr TiO_(3) and the cocatalysts are proposed based on results obtained from UV-vis diffraction reflection spectroscopy and ultraviolet photoelectron spectroscopy measurements.On the basis of our results,the dual cocatalysts unambiguously boosts charge separation and enhances photocatalytic performance.In summary,we have investigated the flux of photoexcited electrons in a dual cocatalysts system and provided a theoretical basis and ideas for subsequent research.展开更多
Background:Ibrutinib,a potent Bruton’s tyrosine kinase inhibitor with marked efficacy against hematological malignancies,is associated with the heightened risk of atrial fibrillation(AF).Although ibrutinib-induced AF...Background:Ibrutinib,a potent Bruton’s tyrosine kinase inhibitor with marked efficacy against hematological malignancies,is associated with the heightened risk of atrial fibrillation(AF).Although ibrutinib-induced AF is linked to enhanced oxidative stress,the underlying mechanisms remain unclear.Objective:This research aimed to explore the molecular mechanism and regulatory target in ibrutinib-induced AF.Methods:We performed in vivo electrophysiology studies using ibrutinib-treated mice,and then employed proteomic and single-cell transcriptomic analyses to identify the underlying targets and mechanisms.The effects of A-kinase anchoring protein 1(AKAP1)depletion on mitochondrial quality surveillance(MQS)were evaluated using both in vivo and ex vivo AKAP1 overexpression models.Results:Atrial AKAP1 expression was significantly reduced in ibrutinib-treated mice,leading to inducible AF,atrial fibrosis,and mitochondrial fragmentation.These pathological changes were effectively mitigated in an overexpression model of ibrutinib-treated mice injected with an adeno-associated virus carrying Akap1.In ibrutinib-treated atrial myocytes,AKAP1 down-regulation promoted dynamin-related protein 1(DRP1)translocation into mitochondria by facilitating DRP1 dephosphorylation at Ser637,thereby mediating excessive mitochondrial fission.Impaired MQS was also suggested by defective mitochondrial respiration,mitochondrial metabolic reprogramming,and suppressed mitochondrial biogenesis,accompanied by excessive oxidative stress and inflammatory activation.The ibrutinib-mediated MQS disturbance can be markedly improved with the inducible expression of the AKAP1 lentiviral system.Conclusions:Our findings emphasize the key role of AKAP1-mediated MQS disruption in ibrutinib-induced AF,which explains the previously observed reactive oxygen species overproduction.Hence,AKAP1 activation can be employed to prevent and treat ibrutinib-induced AF.展开更多
基金supported by the National Natural Science Foundation of China(Grant Nos.42250103 and 42174090)the Opening Fund of Key Laboratory of Geological Survey and Evaluation of Ministry of Education(Grant No.GLAB2023ZR02)the MOST Special Fund from the State Key Laboratory of Geological Processes and Mineral Resources(Grant No.MSFGPMR2022-4).
文摘The equivalent source(ES)method in the spherical coordinate system has been widely applied to processing,reduction,field modeling,and geophysical and geological interpretation of satellite magnetic anomaly data.However,the inversion for the ES model suffers from nonuniqueness and instability,which remain unresolved.To mitigate these issues,we introduce both the minimum and flattest models into the model objective function as an alternative regularization approach in the spherical ES method.We first present the methods,then analyze the accuracy of forward calculation and test the proposed ES method in this study by using synthetic data.The experimental results from simulation data indicate that our proposed regularization effectively suppresses the Backus effect and mitigates inversion instability in the low-latitude region.Finally,we apply the proposed method to magnetic anomaly data from China Seismo-Electromagnetic Satellite-1(CSES-1)and Macao Science Satellite-1(MSS-1)magnetic measurements over Africa by constructing an ES model of the large-scale lithospheric magnetic field.Compared with existing global lithospheric magnetic field models,our ES model demonstrates good consistency at high altitudes and predicts more stable fields at low altitudes.Furthermore,we derive the reduction to the pole(RTP)magnetic anomaly fields and the apparent susceptibility contrast distribution based on the ES model.The latter correlates well with the regional tectonic framework in Africa and surroundings.
基金supported by the National Natural Science Foundation of China(Grant Nos.42250103 and 42174090)the Opening Fund of Key Laboratory of Geological Survey and Evaluation of Ministry of Education(Grant No.GLAB2023ZR02)the Ministry of Science and Technology(MOST)Special Fund from the State Key Laboratory of Geological Processes and Mineral Resources(Grant No.MSFGPMR2022-4)。
文摘As a means of quantitative interpretation,forward calculations of the global lithospheric magnetic field in the Spherical Harmonic(SH)domain have been widely used to reveal geophysical,lithological,and geothermal variations in the lithosphere.Traditional approaches either do not consider the non-axial dipolar terms of the inducing field and its radial variation or do so by means of complicated formulae.Moreover,existing methods treat the magnetic lithosphere either as an infinitesimally thin layer or as a radially uniform spherical shell of constant thickness.Here,we present alternative forward formulae that account for an arbitrarily high maximum degree of the inducing field and for a magnetic lithosphere of variable thickness.Our simulations based on these formulae suggest that the satellite magnetic anomaly field is sensitive to the non-axial dipolar terms of the inducing field but not to its radial variation.Therefore,in forward and inverse calculations of satellite magnetic anomaly data,the non-axial dipolar terms of the inducing field should not be ignored.Furthermore,our results show that the satellite magnetic anomaly field is sensitive to variability in the lateral thickness of the magnetized shell.In particular,we show that for a given vertically integrated susceptibility distribution,underestimating the thickness of the magnetic layer overestimates the induced magnetic field.This discovery bridges the greatest part of the alleged gap between the susceptibility values measured from rock samples and the susceptibility values required to match the observed magnetic field signal.We expect the formulae and conclusions of this study to be a valuable tool for the quantitative interpretation of the Earth's global lithospheric magnetic field,through an inverse or forward modelling approach.
基金supported by the National Key R&D Program of China(No.2022YFA1303600 and No.2023YFC2306800)the National Natural Science Foundation of China(No.82372235 and No.82272315)the Sanming Project of Medicine in Shenzhen(No.SZSM202311032).
文摘The persistence of covalently closed circular DNA(cccDNA)in hepatitis B virus(HBV)-infected hepatocytes remains a major obstacle to effective antiviral treatment.Understanding the molecular mechanisms regulating HBV cccDNA transcription is essential for developing novel therapeutic strategies.In this study,we investigated the role of RNA binding motif protein 25(RBM25)in HBV replication,focusing on its interaction with cccDNA and its regulation of host transcription factors.The results demonstrated that RBM25 knockdown markedly inhibited HBV replication,reducing levels of HBV DNA,hepatitis B e antigen(HBeAg),hepatitis B surface antigen(HBsAg),HBV RNA,and L-HBs in HBV-replicating and infected cell models.Consistent results were observed in a mouse model hydrodynamically injected with 1.2HBV plasmid.Conversely,RBM25 overexpression significantly enhanced HBV replication.Mechanistically,RBM25 promoted HBV promoter activities by binding to cccDNA through its RE/RD and PWI domains.This effect was mediated by increased Yin Yang 1(YY1)expression,which enhanced acetylation of cccDNA-bound histones,promoting HBV transcription.Furthermore,RBM25 expression was upregulated and translocated to the nucleus following core protein expression and accumulation,while overexpression of RBM25 promoted core protein degradation.In conclusion,this study demonstrates that RBM25 is a novel host factor that enhances HBV replication by upregulating YY1-dependent transcriptional activation of cccDNA.It also reveales a reciprocal regulatory mechanism between the HBV core protein and RBM25,which helps sustain HBV replication.
基金supported by the Key Technologies R&D Program of Xiamen(No.3502Z20231057)the Natural Science Foundation of Fujian Province,China(No.2024J011210,No.2021J011214,No.2021J01685)+5 种基金the High-Level Talent Start-Up Foundation of Xiamen Institute of Technology for financial support(No.YKJ23017R)the Industry Leading Key Projects of Fujian Province(No.2022H0057)the Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang(2020R01002)the Fujian Young and Middle-aged Teachers Teacher Education Research Project(Science and Technology)(No.JAT200461)2023 Xiamen Overseas Students Scientific Research Project(Start-up)the National Natural Science Foundation of China(No.21975212,No.22101242,No.52002352,No.52071295)。
文摘Traditional pyrometallurgy and hydrometallurgy processes primarily focus on the recovery of valuable metals(Co,Ni,etc.)from spent lithium-ion batteries.However,these methods are not economical for recycling cheap LiFePO_(4).Herein,a synergistic thermal-decomposition and electric-drive strategy is proposed to recover the whole spent LiFePO_(4)electrode by in-situ recovering the inactive lithium(dead lithium and trapped interlayer lithium).Firstly,the organic components in the dense solid electrolyte interface(SEI)are effectively decomposed through thermal-decomposition processing,exposing the dead lithium encapsulated within the SEI and recovering the electron channels between the dead lithium and graphite.Leveraging the difference between the Gibbs free energy of the dead lithium and graphite as the driving force facilitates the dead lithium inserting into the anode.Then,fully utilizing the remaining discharge capacity of the spent LiFePO_(4)cell,the inactive lithium is reinserted into LiFePO_(4)lattice during the electric-drive process.Consequently,the reactivated lithium content increases by more than 16%,reaching a capacity of 134.2 mA h g^(-1)compared to 115.2 mA h g^(-1)from degraded LiFePO_(4),allowing for effective participation in the subsequent cycling.This work provides new perspectives on highly profitable cycles with low energy and material consumption and a low carbon footprint.
文摘The cell cycle is a tightly coupled series of events that enable cells to grow and proliferate.Cyclin-dependent kinases(CDKs)play crucial roles in the cell cycle by enabling cells to transition between different phases when they are activated.Cell cycle proteins enhance the activity of CDKs,while natural CDK inhibitors(CDKIs)suppress them.The cell cycle continues in cycles under normal conditions,but when conditions change,cells halt or terminate the cell cycle.Tumors are tissues that grow out of control,and the mechanisms of various types of tumors are different;however,almost all tumor cells share several common characteristics,including proliferation,prevention of apoptosis and genomic instability.Cellular division is essential in the progression of cancer.A key characteristic of cancer is the uncontrolled growth of tumor cells,which is due to the erratic behavior of several proteins during the cell cycle.Therefore,cell cycle regulators are considered attractive targets for the treatment of cancer.The present analysis highlights proteins that play a direct role in controlling the tumor cell cycle,such as CDKs,and provides a brief overview of checkpoint kinases.The present review also discusses how cell cycle proteins contribute to cancer and describes some of the antitumor drugs that are being researched.
基金the financial support from the National Science Fund for Distinguished Young Scholars of China(No.51625505)the Key Program Project of the Joint Fund of Astronomy and National Natural Science Foundation of China(No.U1537203)+1 种基金National Natural Science Foundation of China(No.51875467)the support of Young Elite Scientists Sponsorship Program by CAST of China(No.2018QNRC001)。
文摘Revealing the development of microstructural inhomogeneity in the multi-pass flow forming of titanium alloy components is of great significance to the microstructure control and property tailoring.To this end,the microstructural inhomogeneity of TA15 alloy spun cylindrical parts was analyzed based on the deformation history.The results indicate that the material underwent significant compressive strain in the normal direction(ND),tension strain in the rolling and circumferential directions(RD and CD),while tension strain in the CD is slightly small due to the limited material flow in this direction.These strain characteristics make the microstructure,especially the primary a(ap),present different morphologies in the different planes of the part.Meanwhile,the combined effects of inhomogeneous deformation and temperature distribution in the ND also cause the inhomogeneity of microstructure morphology and parameters in this direction.Quantitative analyses show that with the forming pass increasing,the aspect ratio of apincreases most in the normal-rolling plane,then in the normal-circumferential plane and least in the circumferential-rolling plane,whereas apcontent decreases in an opposite trend.Along the ND,the aspect ratio and content of apis relatively high in the outer and inner surface areas but lowest in the central area,and these inhomogeneous characteristics can be gradually diminished with the forming pass increasing.Furthermore,the variation of hardness inhomogeneity factor indicates that a four-pass forming with the total reduction ratio of 63%could obtain a homogenous microstructure along the ND of the TA15 alloy spun cylindrical part.
文摘Corrigendum Text:On page 2 of this letter,there is a misprint in the unit.The unit of the geometrical dimension of the spherical hohlraums on this page should always be“mm”rather than“mm”,i.e.in the second paragraph,“…with 800 J per beam at 0.35 mm…”should be“…with 800 J per beam at 0.35 mm…”,“The slit of 400 mm width is parallel…”should be“The slit of 400 mm width is parallel…”,“The laser focal diameter is about 500 mm…”should be“The laser focal diameter is about 500 mm…”;in the third paragraph,“…we take 850 mm as the radius…”should be“…we take 850 mm as the radius…”,“The LEH radius R_(L) is 400 mm…”should be“The LEH radius R_(L) is 400 mm…”,“…the radius of the cylindrical LEH outer ring is taken as 1.5 R_(L)=600 mm”should be“…the radius of the cylindrical LEH outer ring is taken as 1.5 R_(L)=600 mm”.This mistake does not affect any of the main results of the original letter.
基金This work is supported by the National Natural Science Foundation of China under grants Nos.11405011 and 11475033.
文摘We present our recent laser-plasmas instability(LPI)comparison experiment at the SGIII laser facility between the spherical and cylindrical hohlraums.Three kinds of filling are considered:vacuum,gas-filling with or without a capsule inside.A spherical hohlraum of 3.6 mm in diameter,and a cylindrical hohlraum of 2.4 mm?4.3 mm are used.The capsule diameter is 0.96 mm.A flat-top laser pulse with 3 ns duration and up to 92.73 kJ energy is used.The experiment has shown that the LPI level in the spherical hohlraum is close to that of the outer beam in the cylindrical hohlraum,while much lower than that of the inner beam.The experiment is further simulated by using our 2-dimensional radiation hydrodynamic code LARED-Integration,and the laser back-scattering fraction and the stimulated Raman scatter(SRS)spectrum are post-processed by the high efficiency code of laser interaction with plasmas HLIP.According to the simulation,the plasma waves are strongly damped and the SRS is mainly developed at the plasma conditions of electron density from 0.08 n_(c) to 0.1 n_(c) and electron temperature from 1.5 keV to 2.0 keV inside the hohlraums.However,obvious differences between the simulation and experiment are found,such as that the SRS back-scattering is underestimated,and the numerical SRS spectrum peaks at a larger wavelength and at a later time than the data.These dif-ferences indicate that the development of a 3D radiation hydrodynamic code,with more accurate physics models,is mandatory for spherical hohlraum study.
基金National Natural Science Foundation of China(No.61871072).
文摘This paper presents a 220-GHz-band 7-m wireless link with a 45-Gbps transmission data rate by using 16 quadrature amplitude modulation(16-QAM).Super-heterodyne transceiver modules are developed for transmission and reception of the modulated signals,which consist of a Schottky barrier diodes(SBD)based sub-harmonic mixer(SHM),an InP HEMT low noise amplifier(LNA),a waveguide band-pass filter(BPF),and a 108-GHz local oscillator(LO)multiplier chain.The transmitter features a peak transmit power of 1.41 dBm,and the IF frequency varies from 5 GHz to 20 GHz.Besides,the receiver features a conversion gain of 9.3 dB in average and a noise temperature of 3052.8 K.The measured results indicate that the transceiver modules enable data transmission of a 45-Gbps 16-QAM signal with Signal-Noise-Ratio(SNR)from 11.59 dB to 15.36 dB in a 7-m line-of-sight channel.
基金supported by the Development Foundation of CAEP(2013A0102002)the National Natural Science Foundation of China(Grant Nos.11405011 and 11475033).
文摘The octahedral spherical hohlraums have natural superiority in maintaining high radiation symmetry during the entire capsule implosion process in indirect drive inertial confinement fusion.While,in contrast to the cylindrical hohlraums,the narrow space between the laser beams and the spherical hohlraum wall is usually commented.In this Letter,we address this crucial issue and report our experimental work conducted on the SGIII-prototype laser facility which unambiguously demonstrates that a simple design of cylindrical laser entrance hole(LEH)can dramatically improve the laser propagation inside the spherical hohlraums.In addition,the laser beam deflection in the hohlraum is observed for the first time in the experiments.Our 2-dimensional simulation results also verify qualitatively the advantages of the spherical hohlraums with cylindrical LEHs.Our results imply the prospect of adopting the cylindrical LEHs in future spherical ignition hohlraum design.
基金supported by the National Natural Science Foundation of China(81730061,81802008)the Guangdong Basic and Applied Basic Research Foundation(2021A1515011272).
文摘Zika virus(ZIKV)evolves non-structural proteins to evade immune response and ensure efficient replication in the host cells.Cholesterol metabolic enzyme 7-dehydrocholesterol reductase(DHCR7)was recently reported to impact innate immune responses in ZIKV infection.However,the vital non-structural protein and mechanisms involved in DHCR7-mediated viral evasion are not well elucidated.In this study,we demonstrated that ZIKV infection facilitated DHCR7 expression.Notably,the upregulated DHCR7 in turn facilitated ZIKV infection and blocking DHCR7 suppressed ZIKV infection.Mechanically,ZIKV non-structural protein 4B(NS4B)interacted with DHCR7 to induce DHCR7 expression.Moreover,DHCR7 inhibited TANK-binding kinase 1(TBK1)and interferon regulatory factor 3(IRF3)phosphorylation,which resulted in the reduction of interferon-beta(IFN-β)and interferon-stimulated genes(ISGs)productions.Therefore,we propose that ZIKV NS4B binds to DHCR7 to repress TBK1 and IRF3 activation,which in turn inhibits IFN-βand ISGs,and thereby facilitating ZIKV evasion.This study broadens the insights on how viral non-structural proteins antagonize innate immunity to facilitate viral infection via cholesterol metabolic enzymes and intermediates.
基金the National Natural Science Foundation of China(21975212)the Industry Leading Key Projects of Fujian Province(2022H0057)the High-level talent start-up Foundation of Xiamen Institute of Technology for financial support。
文摘Recycling graphite anode from spent lithium-ion batteries(SLIBs)is regarded as a crucial approach to promoting sustainable energy storage industry.However,the recycled graphite(RG)generally presents degraded structure and performance.Herein,the residual fluoride self-activated effect is proposed for the upgraded utilization of RG.Simple and low-energy water immersion treatment not only widens the interlayer spacing,but also retains appropriate fluoride on the surface of RG.Theoretical analysis and experiments demonstrate that the residual fluoride can optimize Li~+migration and deposition kinetics,resulting in better Li~+intercalation/deintercalation in the interlayer and more stable Li metal plating/stripping on the surface of RG,As a result,the designed LFP||RG full cells achieve ultrahigh reversibility(~100%Coulombic efficiency),high capacity retention(67%after 200 cycles,0.85 N/P ratio),and commendable adaptability(stable cycling without short-circuiting,0.15 N/P ratio).The energy density is improved from 334 Wh kg^(-1)of 1.1 N/P ratio to 367 Wh kg^(-1)of 0.85 N/P ratio(total mass based on cathode and anode).The exploration of RG by residual fluoride self-activated effect achieves upgraded utilization beyond fresh commercial graphite and highlights a new strategy for efficient reuse of SLIBs.
基金Project supported in part by the National Natural Science Foundation of China(Grant No.61871072)。
文摘This article presents the design and performance of a terahertz on-chip coupled-grounded coplanar waveguide(GCPW)power combiner using a 50μm-thick InP process.The proposed topology uses two coupled-GCPW lines at the end of the input port to substitute two quarter-wavelength GCPW lines,which is different from the conventional Wilkinson power combiner and can availably minimize the coverage area.According to the results obtained,for the frequency range of 210-250 GHz,the insertion losses for each two-way combiner and four-way combiner were lower than 1.05 dB and1.35 dB,respectively,and the in-band return losses were better than 11 dB.Moreover,the proposed on-chip GCPW-based combiners achieved a compromise in low-loss,broadband,and small-size,which can find wide applications in terahertz bands,such as power amplifiers and signal distribution networks.
基金This work was supported by the National Science Foundation of China(grant No.81770318)Beijing Municipal Natural Science Foundation(grant No.7192051).
文摘Tyrosine kinase inhibitors(TKIs)are a novel category of antitumor agents with remarkable efficacy in extending pa-tient survival.However,clinical use of TKIs has been hindered by the major adverse effect of atrial fibrillation(AF).Recent studies have revealed that TKIs induce metabolic alterations and remodeling in cardiomyocytes,thus perturb-ing energy metabolism.Specifically,mitochondrial dysfunction and shifts in cardiac substrate utilization have been implicated in the mechanisms underlying TKI-induced AF.In light of these findings,this article reviews the energy metabolism-associated pathways involved in TKI-induced AF,identifies precise therapeutic targets for managing this condition,and discusses evidence that may contribute to the development of novel TKIs without cardiac adverse ef-fects.
基金This work received support from the National Science Foundation of China through grant Nos.81870244,82170318,and 81770318,as well as from the Beijing Municipal Science and Technology Commission(Z181100001718174).
文摘Atrial fibrillation ablation procedures have become a focus of research among electrophysiologists,with the aim of increasing success rates while minimizing complications.One major concern is phrenic nerve injury(PNI).Despite advancements in ablation strategies,equipment,and monitoring methods,the incidence of PNI during these procedures remains substantial,particularly during cryoballoon ablation,which has a reported PNI incidence of 3.5%.This review examines recent studies,to provide a comprehensive overview of PNI mechanisms,clinical features,prognosis,and methods for prevention during ablation.
基金supported by National Institute on Aging of the National Institutes of Health under Award Number R01 AG068997 and P01 AG066603(to X.C.).
文摘Skeletal interoception regulates bone homeostasis through the prostaglandin E2(PGE2)concentration in bone.Vertebral endplates undergo ossification and become highly porous during intervertebral disc degeneration and aging.We found that the PGE2 concentration was elevated in porous endplates to generate spinal pain.Importantly,treatment with a high-dose cyclooxygenase 2 inhibitor(celecoxib,80 mg·kg−1 per day)decreased the prostaglandin E2 concentration and attenuated spinal pain in mice with lumbar spine instability.However,this treatment impaired bone formation in porous endplates,and spinal pain recurred after discontinuing the treatment.Interestingly,low-dose celecoxib(20 mg·kg−1 per day,which is equivalent to one-quarter of the clinical maximum dosage)induced a latent inhibition of spinal pain at 3 weeks post-treatment,which persisted even after discontinuing treatment.Furthermore,when the prostaglandin E2 concentration was maintained at the physiological level with low-dose celecoxib,endplate porosity was reduced significantly,which was associated with decreased sensory nerve innervation and spinal pain.These findings suggest that low-dose celecoxib may help to maintain skeletal interoception and decrease vertebral endplate porosity,thereby reducing sensory innervation and spinal pain in mice.
基金supported by the National Fundamental Research Program of China(Contact No.11475033 and 11405011)CAEP(Contact No.2013A0102002).
文摘In this paper,we give a review of our theoretical and experimental progress in octahedral spherical hohlraum study.From our theoretical study,the octahedral spherical hohlraums with 6 Laser Entrance Holes(LEHs)of octahedral symmetry have robust high symmetry during the capsule implosion at hohlraum-to-capsule radius ratio larger than 3.7.In addition,the octahedral spherical hohlraums also have potential superiority on low backscattering without supplementary technology.We studied the laser arrangement and constraints of the octahedral spherical hohlraums,and gave a design on the laser arrangement for ignition octahedral hohlraums.As a result,the injection angle of laser beams of 50°-60°was proposed as the optimum candidate range for the octahedral spherical hohlraums.We proposed a novel octahedral spherical hohlraum with cylindrical LEHs and LEH shields,in order to increase the laser coupling efficiency and improve the capsule symmetry and to mitigate the influence of the wall blowoff on laser transport.We studied on the sensitivity of the octahedral spherical hohlraums to random errors and compared the sensitivity among the octahedral spherical hohlraums,the rugby hohlraums and the cylindrical hohlraums,and the results show that the octahedral spherical hohlraums are robust to these random errors while the cylindrical hohlraums are the most sensitive.Up till to now,we have carried out three experiments on the spherical hohlraum with 2 LEHs on Shenguang(SG)laser facilities,including demonstration of improving laser transport by using the cylindrical LEHs in the spherical hohlraums,spherical hohlraum energetics on the SGIII prototype laser facility,and comparisons of laser plasma instabilities between the spherical hohlraums and the cylindrical hohlraums on the SGIII laser facility.
文摘Photocatalytic solar fuel generation is currently a hot topic because of its potential for solving the energy crisis owing to its low cost and zero-carbon emissions.However,the rapid bulk recombination of photoexcited carrier pairs is a fundamental disadvantage.To resolve this problem,we synthesized a dual cocatalysts system of cobalt phosphide(Co P)and molybdenum carbide(Mo_(2)C)embedded on strontium titanate(Sr TiO_(3))nanofibers.Compared with those of pristine SrTiO_(3) and binary samples,the dual cocatalysts system(denoted SCM)showed a significant improvement in the hydrogen evolution and CO_(2) reduction performance.Further,the structure of SCM effectively promoted spatial charge separation and enhanced the photocatalytic performance.In addition,the Schottky junction formed between the SrTiO_(3) and cocatalysts enabled the rapid transfer of photoexcited electrons from SrTiO_(3) to the cocatalysts,resulting in effective separation and prolonged photoexcited electron lifetimes.The electron migration route between SrTiO_(3) and the cocatalysts was determined by in situ irradiation X-ray spectroscopy,and band structures of Sr TiO_(3) and the cocatalysts are proposed based on results obtained from UV-vis diffraction reflection spectroscopy and ultraviolet photoelectron spectroscopy measurements.On the basis of our results,the dual cocatalysts unambiguously boosts charge separation and enhances photocatalytic performance.In summary,we have investigated the flux of photoexcited electrons in a dual cocatalysts system and provided a theoretical basis and ideas for subsequent research.
基金supported by the National Natural Science Foundation of China(Grant Nos.82170318,81870243,82170310,and 82300315)the Guangdong Province Basic and Applied Basic Research Fund Project(No.2024A1515012174).
文摘Background:Ibrutinib,a potent Bruton’s tyrosine kinase inhibitor with marked efficacy against hematological malignancies,is associated with the heightened risk of atrial fibrillation(AF).Although ibrutinib-induced AF is linked to enhanced oxidative stress,the underlying mechanisms remain unclear.Objective:This research aimed to explore the molecular mechanism and regulatory target in ibrutinib-induced AF.Methods:We performed in vivo electrophysiology studies using ibrutinib-treated mice,and then employed proteomic and single-cell transcriptomic analyses to identify the underlying targets and mechanisms.The effects of A-kinase anchoring protein 1(AKAP1)depletion on mitochondrial quality surveillance(MQS)were evaluated using both in vivo and ex vivo AKAP1 overexpression models.Results:Atrial AKAP1 expression was significantly reduced in ibrutinib-treated mice,leading to inducible AF,atrial fibrosis,and mitochondrial fragmentation.These pathological changes were effectively mitigated in an overexpression model of ibrutinib-treated mice injected with an adeno-associated virus carrying Akap1.In ibrutinib-treated atrial myocytes,AKAP1 down-regulation promoted dynamin-related protein 1(DRP1)translocation into mitochondria by facilitating DRP1 dephosphorylation at Ser637,thereby mediating excessive mitochondrial fission.Impaired MQS was also suggested by defective mitochondrial respiration,mitochondrial metabolic reprogramming,and suppressed mitochondrial biogenesis,accompanied by excessive oxidative stress and inflammatory activation.The ibrutinib-mediated MQS disturbance can be markedly improved with the inducible expression of the AKAP1 lentiviral system.Conclusions:Our findings emphasize the key role of AKAP1-mediated MQS disruption in ibrutinib-induced AF,which explains the previously observed reactive oxygen species overproduction.Hence,AKAP1 activation can be employed to prevent and treat ibrutinib-induced AF.
