Tensile deformation behaviors of the electrodeposited 40 nm grain sized Ni,25 nm Ni-1.7 wt.%Co,and 13 nm Ni-8.6 wt.%Co alloys at various strain rates and room temperature were reviewed with emphasis on strain rate sen...Tensile deformation behaviors of the electrodeposited 40 nm grain sized Ni,25 nm Ni-1.7 wt.%Co,and 13 nm Ni-8.6 wt.%Co alloys at various strain rates and room temperature were reviewed with emphasis on strain rate sensitivity and activation volume,respectively.It is found that the strain rate sensitivity and activation volume were strongly grain size dependent.An analytic model based on the bow out of a single dislocation well predicted the relationship between the strain rate sensitivity and the activation volumes for these nanocrystaline metals.展开更多
The activation volume(V∗)and strain-rate sensitivity exponent(m)of CoCrFeMnNi and Al_(0.5)CoCrFeMnNi high entropy alloys(HEAs)with various grain sizes(ranging between 2.4 and 356μm)were measured at different strain r...The activation volume(V∗)and strain-rate sensitivity exponent(m)of CoCrFeMnNi and Al_(0.5)CoCrFeMnNi high entropy alloys(HEAs)with various grain sizes(ranging between 2.4 and 356μm)were measured at different strain rates and strain levels at room temperature.As the strain rate decreased,the plastic strain decreased,and the grain size increased,V∗increased.The enhanced solid-solution strengthening by addition of aluminum decreased V∗.The Hassen plot was modified to capture the grain-size depen-dence of V∗by considering the grain-size dependence of the dislocation density.As the plastic strain increased,the strain rate decreased,and the grain size decreased,m decreased.The behavior of m could be quantitatively predicted by using equations derived for the grain-size-dependent V∗and flow stress.The difference in the grain-size dependence of m between conventional face centered cubic(FCC)metals and FCC HEAs over the nanograin size range could not be explained in terms of a relatively large Hall-Petch slope of the FCC HEAs compared with that of the FCC conventional metals,but was explainable in terms of a substantially higher probability of activation of grain-boundary diffusion-controlled grain-boundary-sliding mechanism at nanograin sizes in the FCC conventional metals than in the FCC HEAs.展开更多
In this study,stress relaxation compression tests were performed to investigate the strain rate sensitivity,activation volume and mobile dislocations in carbon nanotubes/aluminum(CNTs/Al)composites.The results reveal ...In this study,stress relaxation compression tests were performed to investigate the strain rate sensitivity,activation volume and mobile dislocations in carbon nanotubes/aluminum(CNTs/Al)composites.The results reveal that,with the addition of CNTs,the strain rate sensitivity of CNTs/Al increased.Meanwhile,a smaller V*of CNTs/Al compared with pure Al was attributed mainly to the CNT-Al interfaces and partly to the increased forest dislocations cutting activities in grain interior,which was related to the tendency of short ranges order formation during plastic deformation.The incorporation of CNTs also improved the dislocation storage capability and reduced the dislocation velocity,leading to a lower mobile dislocation exhaustion rate.展开更多
Glass forming materials are characterized by a complex relaxation pattern, which evolves over several time decades. Dielectric spectroscopy has proven particularly useful for studying such scenario as it is able to mo...Glass forming materials are characterized by a complex relaxation pattern, which evolves over several time decades. Dielectric spectroscopy has proven particularly useful for studying such scenario as it is able to monitor the dielectric dynamics of a system over a range up to 16 time decades. In this work we study effect of thermodynamic history on activation volume of secondary relaxation inside the glassy forming systems, Poly[(phenyl glycidyl ether)-co-formaldehyde], (PPGE) and 1,18-bis (p methoxyphenyl) cyclohexane (BMPC), with two different type of secondary relaxation. Our results show that at bout systems, activation volume of secondary depends to the thermodynamic history.展开更多
This study examined the behaviors of activation volume and strain rate sensitivity in the transformation-induced plasticity(TRIP)Al_(5)Cr_(20)Fe_(35)Co_(35)Ni_(5)high-entropy alloy(HEA)to understand their dependence o...This study examined the behaviors of activation volume and strain rate sensitivity in the transformation-induced plasticity(TRIP)Al_(5)Cr_(20)Fe_(35)Co_(35)Ni_(5)high-entropy alloy(HEA)to understand their dependence on the plastic strain,strain rate,and grain size through strain rate jump tests.The observed trends in activation volume and strain rate sensitivity as functions of strain,grain size,and strain rate in the TRIP HEA closely resemble those observed in non-TRIP HEAs studied in previous work.This suggests that the fundamental dislocation processes governing activation volume remain largely unaffected by the phase transformation associated with the TRIP effect.However,the TRIP HEA shows a smaller activation volume than the non-TRIP HEA,especially at finer grain sizes.While the strain rate sensitivity is comparable to that of non-TRIP HEAs when calculated using total stress,it appears markedly higher when evaluated using effective stress.A quantitative model was developed to predict activation volume and strain rate sensitivity in TRIP HEAs,incorporating the effects of twinning,phase transformation,and dislocation activity within a unified dislocation strengthening framework.The proposed model successfully captures the complex experimental trends in activation volume and strain rate sensitivity over a range of strain,strain rate,and grain size conditions in the TRIP HEAs,and can be readly extended to non-TRIP HEAs.展开更多
Analysis Method of ^(131)I Activity in Carbon Cartridge and Internal Dose Assessment for Nuclear Medicine Workers.Shuo Wang1,Fei Tuo1,Jian-feng Zhang1,Xiao-liang Li1,Bao-lu Yang1,Qiang Zhou1,Ze-shu Li1,Shu-ying Kong1,...Analysis Method of ^(131)I Activity in Carbon Cartridge and Internal Dose Assessment for Nuclear Medicine Workers.Shuo Wang1,Fei Tuo1,Jian-feng Zhang1,Xiao-liang Li1,Bao-lu Yang1,Qiang Zhou1,Ze-shu Li1,Shu-ying Kong1,and Wei-hao Qin1(1.National Institute for Radiological Protection,Chinese Center for Disease Control and Prevention,Beijing,100088,China.)展开更多
Rationale:This case report describes a couple with recurrent fertilization failure despite undergoing multiple cycles of intracytoplasmic sperm injection(ICSI).The principal clinical concern was suspected oocyte activ...Rationale:This case report describes a couple with recurrent fertilization failure despite undergoing multiple cycles of intracytoplasmic sperm injection(ICSI).The principal clinical concern was suspected oocyte activation deficiency(OAD),in which fertilization is impeded due to the oocyte’s inability to initiate embryogenesis,commonly attributed to inadequate intracellular calcium(Ca^(2+))release following sperm injection.Patient concerns:The couple repeatedly experienced complete or near-complete fertilization failure in previous ICSI cycles,raising suspicion of an underlying oocyte activation defect.Diagnosis:Based on the repeated absence of fertilization post-ICSI and clinical history,a diagnosis of suspected OAD leading to recurrent ICSI fertilization failure was considered.Interventions:Artificial oocyte activation(AOA)using the calcium ionophore A23187 was performed.After ICSI,unfertilized oocytes were exposed to the ionophore to induce Ca^(2+)influx,simulating physiological calcium oscillations essential for oocyte activation.The efficacy of intervention was evaluated through subsequent embryonic development,morphological grading,and chromosomal integrity.Outcomes:Following AOA treatment,successful oocyte activation occurred,resulting in the formation of high-grade embryos with normal developmental progression.Chromosomal analysis revealed no detectable abnormalities,indicating genomic stability.Lessons:Calcium ionophore–mediated AOA may serve as an effective adjunct in cases of recurrent ICSI failure attributed to OAD.This case highlights the importance of individualized therapeutic strategies in assisted reproduction;however,further research is needed to refine protocols,validate broader clinical efficacy,and assess long-term safety,including potential epigenetic risks.展开更多
Activation pruning reduces neural network complexity by eliminating low-importance neuron activations,yet identifying the critical pruning threshold—beyond which accuracy rapidly deteriorates—remains computationally...Activation pruning reduces neural network complexity by eliminating low-importance neuron activations,yet identifying the critical pruning threshold—beyond which accuracy rapidly deteriorates—remains computationally expensive and typically requires exhaustive search.We introduce a thermodynamics-inspired framework that treats activation distributions as energy-filtered physical systems and employs the free energy of activations as a principled evaluation metric.Phase-transition-like phenomena in the free-energy profile—such as extrema,inflection points,and curvature changes—yield reliable estimates of the critical pruning threshold,providing a theoretically grounded means of predicting sharp accuracy degradation.To further enhance efficiency,we propose a renormalized free energy technique that approximates full-evaluation free energy using only the activation distribution of the unpruned network.This eliminates repeated forward passes,dramatically reducing computational overhead and achieving speedups of up to 550×for MLPs.Extensive experiments across diverse vision architectures(MLP,CNN,ResNet,MobileNet,Vision Transformer)and text models(LSTM,BERT,ELECTRA,T5,GPT-2)on multiple datasets validate the generality,robustness,and computational efficiency of our approach.Overall,this work establishes a theoretically grounded and practically effective framework for activation pruning,bridging the gap between analytical understanding and efficient deployment of sparse neural networks.展开更多
Peroxymonosulfate(PMS)-assisted visible-light photocatalytic degradation of organic pollutants using graphitic carbon nitride(g-C_(3)N_(4))presents a promising and environmentally friendly approach.However,pristine g-...Peroxymonosulfate(PMS)-assisted visible-light photocatalytic degradation of organic pollutants using graphitic carbon nitride(g-C_(3)N_(4))presents a promising and environmentally friendly approach.However,pristine g-C_(3)N_(4) suffers from limited visible-light absorption and low charge-carrier mobility.In this study,a phosphorus-doped tubular carbon nitride(5P-TCN)was synthesized via a precursor self-assembly method using phosphoric acid and melamine as raw materials,eliminating the need for organic solvents or templates.The 5P-TCN catalyst demonstrated enhanced visible-light absorption,improved charge transfer capability,and a 5.25-fold increase in specific surface area(31.092 m^(2)/g),which provided abundant active sites to efficiently drive the PMS-assisted photocatalytic reaction.The 5P-TCN/vis/PMS system exhibited exceptional degradation performance for organic pollutants across a broad pH range(3–9),achieving over 92%degradation of Rhodamine B(RhB)within 15 min.Notably,the system retained>98%RhB degradation efficiency after three consecutive operational cycles,demonstrating robust operational stability and reusability.Moreover,key parameters influencing,active radi-cals,degradation pathways,and potential mechanisms for RhB degradation were systematically investigated.This work proposes a green and cost-effective strategy for developing high-efficiency photocatalysts,while demon-strating the exceptional capability of a PMS-assisted photocatalytic system for rapid degradation of RhB.展开更多
Given that platinum-based drugs are widely used clinically as chemotherapeutic agents,their severe toxic side effects have attracted significant attention.Consequently,the development of novel nanoprodrugs based on lo...Given that platinum-based drugs are widely used clinically as chemotherapeutic agents,their severe toxic side effects have attracted significant attention.Consequently,the development of novel nanoprodrugs based on low-toxicity tetravalent platinum(Pt(Ⅳ))com plexes holds substantial research value.Herein,we discovered that coumarin derivatives exhibit inherent antitumor efficacy and significantly enhance superoxide anion radicals(·O_(2)^(-))generation in aqueous solutions under ultrasound(US)irradiation.Given that·O_(2)^(-)is known to mediate the reduction of Pt(Ⅳ)to divalent platinum(Pt(Ⅱ)),we engineered an US-responsive dual-drug nanoprodrug(P-cisPt(Ⅳ)@5-MOP).This nanoprodrug was prepared by covalently conjugating Pt(Ⅳ)and methoxy polyethylene glycol hydroxyl(m PEG-OH)to a poly(_(L)-glutamic acid)(PLG)carrier,followed by encapsulating coumarin derivatives.Under low-intensity US irradiation(1.5 W/cm^(2),1 MHz,10 min),P-cisPt(Ⅳ)@5-MOP achieved a Pt(Ⅳ)reduction rate of 91.4%.Furthermore,upon US exposure,its half-maximal inhibitory concentration(IC_(50))against 4T1 breast cancer cells decreased dramatically from 25.7μmol/L to 0.1μmol/L.Remarkably,this system combined with US therapy yielded a tumor inhibition rate of 90.9%,with 40%of tumor-bea ring mice achieving com plete eradication of tumors,while exhibiting low systemic toxicity.Collectively,this work not only identifies a novel sonosensitizer capable of generating·O_(2)^(-)but also develops a new class of ultrasound-activatable Pt(Ⅳ)nanoprodrug.展开更多
Most Convolutional Neural Network(CNN)interpretation techniques visualize only the dominant cues that the model relies on,but there is no guarantee that these represent all the evidence the model uses for classificati...Most Convolutional Neural Network(CNN)interpretation techniques visualize only the dominant cues that the model relies on,but there is no guarantee that these represent all the evidence the model uses for classification.This limitation becomes critical when hidden secondary cues—potentially more meaningful than the visualized ones—remain undiscovered.This study introduces CasCAM(Cascaded Class Activation Mapping)to address this fundamental limitation through counterfactual reasoning.By asking“if this dominant cue were absent,what other evidence would the model use?”,CasCAM progressively masks the most salient features and systematically uncovers the hierarchy of classification evidence hidden beneath them.Experimental results demonstrate that CasCAM effectively discovers the full spectrum of reasoning evidence and can be universally applied with nine existing interpretation methods.展开更多
Triclosan(TCS) poses harmful risks to ecosystems and human health owing to its endocrine-disrupting effects.Therefore,developing an efficient and sustainable technology to degrade TCS is urgently needed.Herein,cobalt ...Triclosan(TCS) poses harmful risks to ecosystems and human health owing to its endocrine-disrupting effects.Therefore,developing an efficient and sustainable technology to degrade TCS is urgently needed.Herein,cobalt oxyhydroxide @covalent organic frameworks(CoOOH@COFs) S-scheme heterojunction was synthesized,which combined the visible-light-driven photocatalysis and peroxymonosulfate(PMS) activation to synergistically generate abundant reactive oxygen species(ROSs) for TCS degradation.The degradation efficiency of TCS reached 100 % within 8 min in the Vis-CoOOH@COFs/PMS system,and the reaction rate constant was 0.456 min^(-1),which was nearly 1.90 and 2.85 times that of single Co OOH and COFs,and2.36 times that under dark condition,respectively.The density functional theory(DFT) calculations confirmed the energy band bending of CoOOH@COFs and S-scheme charge transport from COFs to Co OOH.Both experimental and theoretical analyses indicated that Co OOH@COFs in photocatalytic-PMS activation systems synergistically facilitated photo-generated carrier separation,enhanced interfacial electron transfer,accelerated PMS activation,and generated multiple ROSs.In particular,photogenerated electrons(e^(-))accelerated the Co(Ⅲ)/Co(Ⅱ) redox cycle,while the PMS captured the e-,which significantly decreased the charge combination of Co OOH@COFs.Radicals(O_(2)^(·-),^(·)OH,and SO_(4)^(·-)) and non-radicals(such as ^(1)O_(2),h^(+),and e^(-)) were both presented in the Vis-CoOOH@COFs/PMS system,with O_(2)^(-) playing a dominant role in TCS degradation.Furthermore,the pathway of TCS degradation and toxicity of intermediates were explored by DFT calculation and transformation product identification.Importantly,the environmentally friendly CoOOH@COFs S-scheme heterojunction exhibited excellent stability and reusability.In conclusion,this study innovatively designed an S-scheme heterojunction in the photocatalytic-PMS activation system,providing guidance and theoretical support for efficient and eco-friendly wastewater treatment.展开更多
Cells of the central nervous system(CNS)are privileged in lying behind the blood-brain barrier(BBB).Unlike blood vessels in other organs,CNS blood vessels are unique in displaying high electrical resistance and low pe...Cells of the central nervous system(CNS)are privileged in lying behind the blood-brain barrier(BBB).Unlike blood vessels in other organs,CNS blood vessels are unique in displaying high electrical resistance and low permeability.With this unique structure and function,the BBB prevents potentially harmful blood components such as serum proteins,inflammatory cytokines,and inflammatory leukocytes from entering the hallowed space of the CNS and wreaking havoc.In addition to these“tightness”properties,the BBB has an array of specialized transporters designed to import essential nutrients.展开更多
In image analysis,high-precision semantic segmentation predominantly relies on supervised learning.Despite significant advancements driven by deep learning techniques,challenges such as class imbalance and dynamic per...In image analysis,high-precision semantic segmentation predominantly relies on supervised learning.Despite significant advancements driven by deep learning techniques,challenges such as class imbalance and dynamic performance evaluation persist.Traditional weighting methods,often based on pre-statistical class counting,tend to overemphasize certain classes while neglecting others,particularly rare sample categories.Approaches like focal loss and other rare-sample segmentation techniques introduce multiple hyperparameters that require manual tuning,leading to increased experimental costs due to their instability.This paper proposes a novel CAWASeg framework to address these limitations.Our approach leverages Grad-CAM technology to generate class activation maps,identifying key feature regions that the model focuses on during decision-making.We introduce a Comprehensive Segmentation Performance Score(CSPS)to dynamically evaluate model performance by converting these activation maps into pseudo mask and comparing them with Ground Truth.Additionally,we design two adaptive weights for each class:a Basic Weight(BW)and a Ratio Weight(RW),which the model adjusts during training based on real-time feedback.Extensive experiments on the COCO-Stuff,CityScapes,and ADE20k datasets demonstrate that our CAWASeg framework significantly improves segmentation performance for rare sample categories while enhancing overall segmentation accuracy.The proposed method offers a robust and efficient solution for addressing class imbalance in semantic segmentation tasks.展开更多
The functional properties of glasses are governed by their formation history and the complex relaxation processes they undergo.However,under extreme conditions,glass behaviors are still elusive.In this study,we employ...The functional properties of glasses are governed by their formation history and the complex relaxation processes they undergo.However,under extreme conditions,glass behaviors are still elusive.In this study,we employ simulations with varied protocols to evaluate the effectiveness of different descriptors in predicting mechanical properties across both low-and high-pressure regimes.Our findings demonstrate that conventional structural and configurational descriptors fail to correlate with the mechanical response following pressure release,whereas the activation energy descriptor exhibits robust linearity with shear modulus after correcting for pressure effects.Notably,the soft mode parameter emerges as an ideal and computationally efficient alternative for capturing this mechanical behavior.These findings provide critical insights into the influence of pressure on glassy properties,integrating the distinct features of compressed glasses into a unified theoretical framework.展开更多
The dissolution of iron from the cathode and electrode/electrolyte interface(EEI)during long cycles significantly accelerates the aging process of LiFePO_(4)(LFP)/graphite batteries;there is a lack of systematic under...The dissolution of iron from the cathode and electrode/electrolyte interface(EEI)during long cycles significantly accelerates the aging process of LiFePO_(4)(LFP)/graphite batteries;there is a lack of systematic understanding of the spatial distribution of the EEI interface layer and the dissolve of Fe ions,especially in terms of the mechanism of the cathode-electrolyte interphase(CEI),solid electrolyte interphase(SEI),and iron dissolution.In this study,aged cells were subjected to continuous activation with constant current and multi-step segmented indirect activation(IA)and analyzed for capacity fade,impedance growth,and active Li^(+)mass loss at the EEI and nanoscale levels.The interaction between dissolved Fe^(2+)and the EEI in LFP/graphite pouch batteries was proposed and verified.The findings indicate that during IA process,the electric field facilitates the migration of solvated ions toward the electrodes,while simultaneously inhibiting the formation of organic species such as ROCO_(2)Li.The SEI primarily consists of a mixture of organic and inorganic small molecules,forming a continuous and uniform film on the electrode surface.This study demonstrates that IA favors the formation of a uniform EEI and offers constructive insights for advancing accelerated lifetime prediction strategies in lithium-ion batteries.展开更多
Activation of spinal cord neural stem cells(NSCs)and subsequent neurogenesis holds a promising alternative for spinal cord injury(SCI)repair.Our previous study demonstrated that complement C3a,derived from reactive as...Activation of spinal cord neural stem cells(NSCs)and subsequent neurogenesis holds a promising alternative for spinal cord injury(SCI)repair.Our previous study demonstrated that complement C3a,derived from reactive astrocytes,inhibits NSC proliferation by suppressing protein aggregate clearance through the deubiquitinating enzyme ubiquitin carboxy-terminal hydrolase L1(UCHL1)-proteasome system post-SCI.However,the potential molecular mechanism by which C3a modulates NSC activation via this pathway remains unclear.Here,we revealed that C3a/C3a receptor(C3aR)signaling activated NF-κB p65,which in turn inhibited Nrf2 activity and UCHL1 expression,resulting in diminished proteasome activity and the accumulation of protein aggregates,and ultimately impaired NSC activation.Both knockdown of NF-κB p65 and Nrf2 upregulation restored UCHL1 expression and proteasome activity in vitro,promoting NSC activation by enhancing protein aggregate clearance.Mechanistically,we found that NF-κB p65 regulated Nrf2 activity through a dual mechanism:(1)promoting Keap1-dependent ubiquitination and proteasome degradation of Nrf2;(2)inhibiting protein kinase C-mediated Nrf2 phosphorylation and nuclear translocation.Using the dual-luciferase reporter assay and chromatin immunoprecipitation(ChIP)analysis,we further identified UCHL1 as a direct transcriptional target of Nrf2.Importantly,in vivo experiments using SCI mice confirmed that either C3aR blockade,NF-κB p65 knockdown,or Nrf2 overexpression could rescue SCI-induced UCHL1 downregulation.Together,this study uncovers the C3a-NF-κB p65-Nrf2-UCHL1-proteasome axis as a critical regulator of NSC activation after SCI.This may provide novel molecular targets and intervention strategies for SCI repair.展开更多
Itaconate,a macrophage-specific anti-inflammatory metabolite,has recently emerged as a critical regulator in rheumatoid arthritis pathogenesis.We found that itaconate is a TNF-αresponsive metabolite significantly ele...Itaconate,a macrophage-specific anti-inflammatory metabolite,has recently emerged as a critical regulator in rheumatoid arthritis pathogenesis.We found that itaconate is a TNF-αresponsive metabolite significantly elevated in the serum and synovial fluid of rheumatoid arthritis patients and we demonstrated that itaconate is primarily produced by inflammatory macrophages rather than osteoclasts or osteoblasts.In TNF-transgenic and Irg1−/−hybrid mice,a more severe bone destruction phenotype was observed.展开更多
The La_(1.7)Pr_(0.3)Mg_(16)Ni hydrogen storage alloy was prepared by medium-frequency induction melting,and then the composite hydrogen storage alloy powder of La_(1.7)Pr_(0.3)Mg_(16)Ni+x wt.%(x=0,2,4,and 6)graphene w...The La_(1.7)Pr_(0.3)Mg_(16)Ni hydrogen storage alloy was prepared by medium-frequency induction melting,and then the composite hydrogen storage alloy powder of La_(1.7)Pr_(0.3)Mg_(16)Ni+x wt.%(x=0,2,4,and 6)graphene was prepared by ball milling for 10 h.The effect of the addition of graphene on the activation and hydrogen de/absorption properties of La_(1.7)Pr_(0.3)Mg_(16)Ni alloy was studied.The result demonstrated that these composite alloys were composed of La_(2)Mg_(17),La_(2)Ni_(3),and Mg_(2)Ni phases.After saturated hydrogen absorption,it was composed of LaH_(3),Mg_(2)NiH_(4),and MgH_(2)phases,while during the dehydrogenation process,it was composed of LaH_(3),Mg,and Mg_(2)Ni phases.The addition of graphene can help get a more homogeneous granule after ball milling and accelerate the first activation of dehydrogenation/hydrogen absorption.The hydrogen release activation energy of the alloys first decreases and then increases as the graphene content increases from x=0 wt.%to x=6 wt.%.The minimum activation energy of the composite hydrogen storage alloy is 51.22 kJ mol^(-1) when x=4 wt.%.展开更多
Rheumatoid arthritis(RA)is an autoimmune disease characterized by inflammation and abnormal osteoclast activation,leading to bone destruction.We previously demonstrated that the large extracellular loop(LEL)of Tm4sf19...Rheumatoid arthritis(RA)is an autoimmune disease characterized by inflammation and abnormal osteoclast activation,leading to bone destruction.We previously demonstrated that the large extracellular loop(LEL)of Tm4sf19 is important for its function in osteoclast differentiation,and LEL-Fc,a competitive inhibitor of Tm4sf19,effectively suppresses osteoclast multinucleation and prevent bone loss associated with osteoporosis.This study aimed to investigate the role of Tm4sf19 in RA,an inflammatory and abnormal osteoclast disease,using a mouse model of collagen-induced arthritis(CIA).Tm4sf19 expression was observed in macrophages and osteoclasts within the inflamed synovium,and Tm4sf19 expression was increased together with inflammatory genes in the joint bones of CIA-induced mice compared with the sham control group.Inhibition of Tm4sf19 by LEL-Fc demonstrated both preventive and therapeutic effects in a CIA mouse model,reducing the CIA score,swelling,inflammation,cartilage damage,and bone damage.Knockout of Tm4sf19 gene or inhibition of Tm4sf19 activity by LEL-Fc suppressed LPS/IFN-γ-induced TLR4-mediated inflammatory signaling in macrophages.LEL-Fc disrupted not only the interaction between Tm4sf19 and TLR4/MD2,but also the interaction between TLR4 and MD2.μCT analysis showed that LEL-Fc treatment significantly reduced joint bone destruction and bone loss caused by hyperactivated osteoclasts in CIA mice.Taken together,these findings suggest that LELFc may be a potential treatment for RA and RA-induced osteoporosis by simultaneously targeting joint inflammation and bone destruction caused by abnormal osteoclast activation.展开更多
基金The work is financially supported by the Foundation of National Key Basic Research and Development Program(No 2004CB619301)the Project 985-Automotive Engineering of Jilin University
文摘Tensile deformation behaviors of the electrodeposited 40 nm grain sized Ni,25 nm Ni-1.7 wt.%Co,and 13 nm Ni-8.6 wt.%Co alloys at various strain rates and room temperature were reviewed with emphasis on strain rate sensitivity and activation volume,respectively.It is found that the strain rate sensitivity and activation volume were strongly grain size dependent.An analytic model based on the bow out of a single dislocation well predicted the relationship between the strain rate sensitivity and the activation volumes for these nanocrystaline metals.
基金supported by the Mid-Career Re-searcher Program through the National Research Foundation of Ko-rea funded by the Ministry of Education,Scienceand Technology (No.NRF-2020R1A2C1008105).
文摘The activation volume(V∗)and strain-rate sensitivity exponent(m)of CoCrFeMnNi and Al_(0.5)CoCrFeMnNi high entropy alloys(HEAs)with various grain sizes(ranging between 2.4 and 356μm)were measured at different strain rates and strain levels at room temperature.As the strain rate decreased,the plastic strain decreased,and the grain size increased,V∗increased.The enhanced solid-solution strengthening by addition of aluminum decreased V∗.The Hassen plot was modified to capture the grain-size depen-dence of V∗by considering the grain-size dependence of the dislocation density.As the plastic strain increased,the strain rate decreased,and the grain size decreased,m decreased.The behavior of m could be quantitatively predicted by using equations derived for the grain-size-dependent V∗and flow stress.The difference in the grain-size dependence of m between conventional face centered cubic(FCC)metals and FCC HEAs over the nanograin size range could not be explained in terms of a relatively large Hall-Petch slope of the FCC HEAs compared with that of the FCC conventional metals,but was explainable in terms of a substantially higher probability of activation of grain-boundary diffusion-controlled grain-boundary-sliding mechanism at nanograin sizes in the FCC conventional metals than in the FCC HEAs.
文摘In this study,stress relaxation compression tests were performed to investigate the strain rate sensitivity,activation volume and mobile dislocations in carbon nanotubes/aluminum(CNTs/Al)composites.The results reveal that,with the addition of CNTs,the strain rate sensitivity of CNTs/Al increased.Meanwhile,a smaller V*of CNTs/Al compared with pure Al was attributed mainly to the CNT-Al interfaces and partly to the increased forest dislocations cutting activities in grain interior,which was related to the tendency of short ranges order formation during plastic deformation.The incorporation of CNTs also improved the dislocation storage capability and reduced the dislocation velocity,leading to a lower mobile dislocation exhaustion rate.
文摘Glass forming materials are characterized by a complex relaxation pattern, which evolves over several time decades. Dielectric spectroscopy has proven particularly useful for studying such scenario as it is able to monitor the dielectric dynamics of a system over a range up to 16 time decades. In this work we study effect of thermodynamic history on activation volume of secondary relaxation inside the glassy forming systems, Poly[(phenyl glycidyl ether)-co-formaldehyde], (PPGE) and 1,18-bis (p methoxyphenyl) cyclohexane (BMPC), with two different type of secondary relaxation. Our results show that at bout systems, activation volume of secondary depends to the thermodynamic history.
基金financially supported by the Mid-Career Researcher Program through the National Research Foundation of Korea funded by the Ministry of Education,Science and Technology(No.RS-2024-00350484)。
文摘This study examined the behaviors of activation volume and strain rate sensitivity in the transformation-induced plasticity(TRIP)Al_(5)Cr_(20)Fe_(35)Co_(35)Ni_(5)high-entropy alloy(HEA)to understand their dependence on the plastic strain,strain rate,and grain size through strain rate jump tests.The observed trends in activation volume and strain rate sensitivity as functions of strain,grain size,and strain rate in the TRIP HEA closely resemble those observed in non-TRIP HEAs studied in previous work.This suggests that the fundamental dislocation processes governing activation volume remain largely unaffected by the phase transformation associated with the TRIP effect.However,the TRIP HEA shows a smaller activation volume than the non-TRIP HEA,especially at finer grain sizes.While the strain rate sensitivity is comparable to that of non-TRIP HEAs when calculated using total stress,it appears markedly higher when evaluated using effective stress.A quantitative model was developed to predict activation volume and strain rate sensitivity in TRIP HEAs,incorporating the effects of twinning,phase transformation,and dislocation activity within a unified dislocation strengthening framework.The proposed model successfully captures the complex experimental trends in activation volume and strain rate sensitivity over a range of strain,strain rate,and grain size conditions in the TRIP HEAs,and can be readly extended to non-TRIP HEAs.
文摘Analysis Method of ^(131)I Activity in Carbon Cartridge and Internal Dose Assessment for Nuclear Medicine Workers.Shuo Wang1,Fei Tuo1,Jian-feng Zhang1,Xiao-liang Li1,Bao-lu Yang1,Qiang Zhou1,Ze-shu Li1,Shu-ying Kong1,and Wei-hao Qin1(1.National Institute for Radiological Protection,Chinese Center for Disease Control and Prevention,Beijing,100088,China.)
文摘Rationale:This case report describes a couple with recurrent fertilization failure despite undergoing multiple cycles of intracytoplasmic sperm injection(ICSI).The principal clinical concern was suspected oocyte activation deficiency(OAD),in which fertilization is impeded due to the oocyte’s inability to initiate embryogenesis,commonly attributed to inadequate intracellular calcium(Ca^(2+))release following sperm injection.Patient concerns:The couple repeatedly experienced complete or near-complete fertilization failure in previous ICSI cycles,raising suspicion of an underlying oocyte activation defect.Diagnosis:Based on the repeated absence of fertilization post-ICSI and clinical history,a diagnosis of suspected OAD leading to recurrent ICSI fertilization failure was considered.Interventions:Artificial oocyte activation(AOA)using the calcium ionophore A23187 was performed.After ICSI,unfertilized oocytes were exposed to the ionophore to induce Ca^(2+)influx,simulating physiological calcium oscillations essential for oocyte activation.The efficacy of intervention was evaluated through subsequent embryonic development,morphological grading,and chromosomal integrity.Outcomes:Following AOA treatment,successful oocyte activation occurred,resulting in the formation of high-grade embryos with normal developmental progression.Chromosomal analysis revealed no detectable abnormalities,indicating genomic stability.Lessons:Calcium ionophore–mediated AOA may serve as an effective adjunct in cases of recurrent ICSI failure attributed to OAD.This case highlights the importance of individualized therapeutic strategies in assisted reproduction;however,further research is needed to refine protocols,validate broader clinical efficacy,and assess long-term safety,including potential epigenetic risks.
基金output of a research project implemented as part of the Basic Research Program at HSE University。
文摘Activation pruning reduces neural network complexity by eliminating low-importance neuron activations,yet identifying the critical pruning threshold—beyond which accuracy rapidly deteriorates—remains computationally expensive and typically requires exhaustive search.We introduce a thermodynamics-inspired framework that treats activation distributions as energy-filtered physical systems and employs the free energy of activations as a principled evaluation metric.Phase-transition-like phenomena in the free-energy profile—such as extrema,inflection points,and curvature changes—yield reliable estimates of the critical pruning threshold,providing a theoretically grounded means of predicting sharp accuracy degradation.To further enhance efficiency,we propose a renormalized free energy technique that approximates full-evaluation free energy using only the activation distribution of the unpruned network.This eliminates repeated forward passes,dramatically reducing computational overhead and achieving speedups of up to 550×for MLPs.Extensive experiments across diverse vision architectures(MLP,CNN,ResNet,MobileNet,Vision Transformer)and text models(LSTM,BERT,ELECTRA,T5,GPT-2)on multiple datasets validate the generality,robustness,and computational efficiency of our approach.Overall,this work establishes a theoretically grounded and practically effective framework for activation pruning,bridging the gap between analytical understanding and efficient deployment of sparse neural networks.
文摘Peroxymonosulfate(PMS)-assisted visible-light photocatalytic degradation of organic pollutants using graphitic carbon nitride(g-C_(3)N_(4))presents a promising and environmentally friendly approach.However,pristine g-C_(3)N_(4) suffers from limited visible-light absorption and low charge-carrier mobility.In this study,a phosphorus-doped tubular carbon nitride(5P-TCN)was synthesized via a precursor self-assembly method using phosphoric acid and melamine as raw materials,eliminating the need for organic solvents or templates.The 5P-TCN catalyst demonstrated enhanced visible-light absorption,improved charge transfer capability,and a 5.25-fold increase in specific surface area(31.092 m^(2)/g),which provided abundant active sites to efficiently drive the PMS-assisted photocatalytic reaction.The 5P-TCN/vis/PMS system exhibited exceptional degradation performance for organic pollutants across a broad pH range(3–9),achieving over 92%degradation of Rhodamine B(RhB)within 15 min.Notably,the system retained>98%RhB degradation efficiency after three consecutive operational cycles,demonstrating robust operational stability and reusability.Moreover,key parameters influencing,active radi-cals,degradation pathways,and potential mechanisms for RhB degradation were systematically investigated.This work proposes a green and cost-effective strategy for developing high-efficiency photocatalysts,while demon-strating the exceptional capability of a PMS-assisted photocatalytic system for rapid degradation of RhB.
基金financially supported by the National Natural Science Foundation of China(Nos.52533015,52495013,52403211,52573183,52273157,52073279 and 52025035)Jilin Province,China(Nos.20250601009RC and 20230508102RC)Youth Innovation Promotion Association of the Chinese Academy of Sciences(No.2022224)。
文摘Given that platinum-based drugs are widely used clinically as chemotherapeutic agents,their severe toxic side effects have attracted significant attention.Consequently,the development of novel nanoprodrugs based on low-toxicity tetravalent platinum(Pt(Ⅳ))com plexes holds substantial research value.Herein,we discovered that coumarin derivatives exhibit inherent antitumor efficacy and significantly enhance superoxide anion radicals(·O_(2)^(-))generation in aqueous solutions under ultrasound(US)irradiation.Given that·O_(2)^(-)is known to mediate the reduction of Pt(Ⅳ)to divalent platinum(Pt(Ⅱ)),we engineered an US-responsive dual-drug nanoprodrug(P-cisPt(Ⅳ)@5-MOP).This nanoprodrug was prepared by covalently conjugating Pt(Ⅳ)and methoxy polyethylene glycol hydroxyl(m PEG-OH)to a poly(_(L)-glutamic acid)(PLG)carrier,followed by encapsulating coumarin derivatives.Under low-intensity US irradiation(1.5 W/cm^(2),1 MHz,10 min),P-cisPt(Ⅳ)@5-MOP achieved a Pt(Ⅳ)reduction rate of 91.4%.Furthermore,upon US exposure,its half-maximal inhibitory concentration(IC_(50))against 4T1 breast cancer cells decreased dramatically from 25.7μmol/L to 0.1μmol/L.Remarkably,this system combined with US therapy yielded a tumor inhibition rate of 90.9%,with 40%of tumor-bea ring mice achieving com plete eradication of tumors,while exhibiting low systemic toxicity.Collectively,this work not only identifies a novel sonosensitizer capable of generating·O_(2)^(-)but also develops a new class of ultrasound-activatable Pt(Ⅳ)nanoprodrug.
基金supported by the Basic Science Research Program through the National Research Foundation of Korea(NRF),funded by the Ministry of Education(RS-2023-00249743).
文摘Most Convolutional Neural Network(CNN)interpretation techniques visualize only the dominant cues that the model relies on,but there is no guarantee that these represent all the evidence the model uses for classification.This limitation becomes critical when hidden secondary cues—potentially more meaningful than the visualized ones—remain undiscovered.This study introduces CasCAM(Cascaded Class Activation Mapping)to address this fundamental limitation through counterfactual reasoning.By asking“if this dominant cue were absent,what other evidence would the model use?”,CasCAM progressively masks the most salient features and systematically uncovers the hierarchy of classification evidence hidden beneath them.Experimental results demonstrate that CasCAM effectively discovers the full spectrum of reasoning evidence and can be universally applied with nine existing interpretation methods.
文摘Triclosan(TCS) poses harmful risks to ecosystems and human health owing to its endocrine-disrupting effects.Therefore,developing an efficient and sustainable technology to degrade TCS is urgently needed.Herein,cobalt oxyhydroxide @covalent organic frameworks(CoOOH@COFs) S-scheme heterojunction was synthesized,which combined the visible-light-driven photocatalysis and peroxymonosulfate(PMS) activation to synergistically generate abundant reactive oxygen species(ROSs) for TCS degradation.The degradation efficiency of TCS reached 100 % within 8 min in the Vis-CoOOH@COFs/PMS system,and the reaction rate constant was 0.456 min^(-1),which was nearly 1.90 and 2.85 times that of single Co OOH and COFs,and2.36 times that under dark condition,respectively.The density functional theory(DFT) calculations confirmed the energy band bending of CoOOH@COFs and S-scheme charge transport from COFs to Co OOH.Both experimental and theoretical analyses indicated that Co OOH@COFs in photocatalytic-PMS activation systems synergistically facilitated photo-generated carrier separation,enhanced interfacial electron transfer,accelerated PMS activation,and generated multiple ROSs.In particular,photogenerated electrons(e^(-))accelerated the Co(Ⅲ)/Co(Ⅱ) redox cycle,while the PMS captured the e-,which significantly decreased the charge combination of Co OOH@COFs.Radicals(O_(2)^(·-),^(·)OH,and SO_(4)^(·-)) and non-radicals(such as ^(1)O_(2),h^(+),and e^(-)) were both presented in the Vis-CoOOH@COFs/PMS system,with O_(2)^(-) playing a dominant role in TCS degradation.Furthermore,the pathway of TCS degradation and toxicity of intermediates were explored by DFT calculation and transformation product identification.Importantly,the environmentally friendly CoOOH@COFs S-scheme heterojunction exhibited excellent stability and reusability.In conclusion,this study innovatively designed an S-scheme heterojunction in the photocatalytic-PMS activation system,providing guidance and theoretical support for efficient and eco-friendly wastewater treatment.
基金supported by the NIH RF1 grant NS119477 jointly funded by NINDS and NIA(to RM).
文摘Cells of the central nervous system(CNS)are privileged in lying behind the blood-brain barrier(BBB).Unlike blood vessels in other organs,CNS blood vessels are unique in displaying high electrical resistance and low permeability.With this unique structure and function,the BBB prevents potentially harmful blood components such as serum proteins,inflammatory cytokines,and inflammatory leukocytes from entering the hallowed space of the CNS and wreaking havoc.In addition to these“tightness”properties,the BBB has an array of specialized transporters designed to import essential nutrients.
基金supported by the Funds for Central-Guided Local Science and Technology Development(Grant No.202407AC110005)Key Technologies for the Construction of a Whole-Process Intelligent Service System for Neuroendocrine Neoplasm.Supported by 2023 Opening Research Fund of Yunnan Key Laboratory of Digital Communications(YNJTKFB-20230686,YNKLDC-KFKT-202304).
文摘In image analysis,high-precision semantic segmentation predominantly relies on supervised learning.Despite significant advancements driven by deep learning techniques,challenges such as class imbalance and dynamic performance evaluation persist.Traditional weighting methods,often based on pre-statistical class counting,tend to overemphasize certain classes while neglecting others,particularly rare sample categories.Approaches like focal loss and other rare-sample segmentation techniques introduce multiple hyperparameters that require manual tuning,leading to increased experimental costs due to their instability.This paper proposes a novel CAWASeg framework to address these limitations.Our approach leverages Grad-CAM technology to generate class activation maps,identifying key feature regions that the model focuses on during decision-making.We introduce a Comprehensive Segmentation Performance Score(CSPS)to dynamically evaluate model performance by converting these activation maps into pseudo mask and comparing them with Ground Truth.Additionally,we design two adaptive weights for each class:a Basic Weight(BW)and a Ratio Weight(RW),which the model adjusts during training based on real-time feedback.Extensive experiments on the COCO-Stuff,CityScapes,and ADE20k datasets demonstrate that our CAWASeg framework significantly improves segmentation performance for rare sample categories while enhancing overall segmentation accuracy.The proposed method offers a robust and efficient solution for addressing class imbalance in semantic segmentation tasks.
基金supported by the National Natural Science Foundation of China (Grant Nos.T2325004 and 52161160330)the National Natural Science Foundation of China (Grants No.12504233)+2 种基金Advanced MaterialsNational Science and Technology Major Project (Grant No.2024ZD0606900)the Talent Hub for “AI+New Materials” Basic Researchthe Key Research and Development Program of Ningbo (Grant No.2025Z088)。
文摘The functional properties of glasses are governed by their formation history and the complex relaxation processes they undergo.However,under extreme conditions,glass behaviors are still elusive.In this study,we employ simulations with varied protocols to evaluate the effectiveness of different descriptors in predicting mechanical properties across both low-and high-pressure regimes.Our findings demonstrate that conventional structural and configurational descriptors fail to correlate with the mechanical response following pressure release,whereas the activation energy descriptor exhibits robust linearity with shear modulus after correcting for pressure effects.Notably,the soft mode parameter emerges as an ideal and computationally efficient alternative for capturing this mechanical behavior.These findings provide critical insights into the influence of pressure on glassy properties,integrating the distinct features of compressed glasses into a unified theoretical framework.
基金supported by the National Key R&D Program of China(2021YFB2401800)the support from Beijing Nova Program(20230484241)+2 种基金the support from the China Postdoctoral Science Foundation(2024M754084)the Postdoctoral Fellowship Program of CPSF(GZB20230931)the support from Initial Energy Science&Technology Co.,Ltd(IEST)。
文摘The dissolution of iron from the cathode and electrode/electrolyte interface(EEI)during long cycles significantly accelerates the aging process of LiFePO_(4)(LFP)/graphite batteries;there is a lack of systematic understanding of the spatial distribution of the EEI interface layer and the dissolve of Fe ions,especially in terms of the mechanism of the cathode-electrolyte interphase(CEI),solid electrolyte interphase(SEI),and iron dissolution.In this study,aged cells were subjected to continuous activation with constant current and multi-step segmented indirect activation(IA)and analyzed for capacity fade,impedance growth,and active Li^(+)mass loss at the EEI and nanoscale levels.The interaction between dissolved Fe^(2+)and the EEI in LFP/graphite pouch batteries was proposed and verified.The findings indicate that during IA process,the electric field facilitates the migration of solvated ions toward the electrodes,while simultaneously inhibiting the formation of organic species such as ROCO_(2)Li.The SEI primarily consists of a mixture of organic and inorganic small molecules,forming a continuous and uniform film on the electrode surface.This study demonstrates that IA favors the formation of a uniform EEI and offers constructive insights for advancing accelerated lifetime prediction strategies in lithium-ion batteries.
基金supported by the National Natural Science Foundation of China(82071362 and 82270669)Key Project of the Regional Joint Fund of Guangdong Province(2023B1515120077)+3 种基金Basic Research Program of Shenzhen Science and Technology Innovation Commission(JCYJ20210324123001003 and JCYJ20220530144801003)Shenzhen Key Laboratory of Bone Tissue Repair and Translational Research(ZDSYS20230626091402006)the Innovation and Entrepreneurship Training Program for College Students,Sun Yat-sen University(20242150)the Leading Innovation and Entrepreneurship Team Program of Zhejiang Province,China(2023R01005).
文摘Activation of spinal cord neural stem cells(NSCs)and subsequent neurogenesis holds a promising alternative for spinal cord injury(SCI)repair.Our previous study demonstrated that complement C3a,derived from reactive astrocytes,inhibits NSC proliferation by suppressing protein aggregate clearance through the deubiquitinating enzyme ubiquitin carboxy-terminal hydrolase L1(UCHL1)-proteasome system post-SCI.However,the potential molecular mechanism by which C3a modulates NSC activation via this pathway remains unclear.Here,we revealed that C3a/C3a receptor(C3aR)signaling activated NF-κB p65,which in turn inhibited Nrf2 activity and UCHL1 expression,resulting in diminished proteasome activity and the accumulation of protein aggregates,and ultimately impaired NSC activation.Both knockdown of NF-κB p65 and Nrf2 upregulation restored UCHL1 expression and proteasome activity in vitro,promoting NSC activation by enhancing protein aggregate clearance.Mechanistically,we found that NF-κB p65 regulated Nrf2 activity through a dual mechanism:(1)promoting Keap1-dependent ubiquitination and proteasome degradation of Nrf2;(2)inhibiting protein kinase C-mediated Nrf2 phosphorylation and nuclear translocation.Using the dual-luciferase reporter assay and chromatin immunoprecipitation(ChIP)analysis,we further identified UCHL1 as a direct transcriptional target of Nrf2.Importantly,in vivo experiments using SCI mice confirmed that either C3aR blockade,NF-κB p65 knockdown,or Nrf2 overexpression could rescue SCI-induced UCHL1 downregulation.Together,this study uncovers the C3a-NF-κB p65-Nrf2-UCHL1-proteasome axis as a critical regulator of NSC activation after SCI.This may provide novel molecular targets and intervention strategies for SCI repair.
基金supported by the National Natural Science Foundation of China(NSFC)(No.82130073,No.82372430,No.31871431,No.31821002,No.32101011,No.22177073)Shanghai Frontiers Science Center of Degeneration and Regeneration in Skeletal System+3 种基金Shanghai Science and Technology Committee(No.23ZR1437600,No.24410710600,No.24141901302)Shenzhen Medical Research Fund(No.B2302005)The Open Project Funding of Shanghai Key Laboratory of Orthopedics(No.KFKT202201)Biomaterials and Regenerative Medicine Institute Cooperative,Research Project,Shanghai Jiao Tong University School of Medicine(No.2022LHA01).
文摘Itaconate,a macrophage-specific anti-inflammatory metabolite,has recently emerged as a critical regulator in rheumatoid arthritis pathogenesis.We found that itaconate is a TNF-αresponsive metabolite significantly elevated in the serum and synovial fluid of rheumatoid arthritis patients and we demonstrated that itaconate is primarily produced by inflammatory macrophages rather than osteoclasts or osteoblasts.In TNF-transgenic and Irg1−/−hybrid mice,a more severe bone destruction phenotype was observed.
基金supported by the Inner Mongolia Natural Science Foundation(2021MS05064)China Northern Rare Earth Group High-Tech Co.,Ltd.(Bayan Obo rare earth resources extraction and application research and key technology development,2022151).
文摘The La_(1.7)Pr_(0.3)Mg_(16)Ni hydrogen storage alloy was prepared by medium-frequency induction melting,and then the composite hydrogen storage alloy powder of La_(1.7)Pr_(0.3)Mg_(16)Ni+x wt.%(x=0,2,4,and 6)graphene was prepared by ball milling for 10 h.The effect of the addition of graphene on the activation and hydrogen de/absorption properties of La_(1.7)Pr_(0.3)Mg_(16)Ni alloy was studied.The result demonstrated that these composite alloys were composed of La_(2)Mg_(17),La_(2)Ni_(3),and Mg_(2)Ni phases.After saturated hydrogen absorption,it was composed of LaH_(3),Mg_(2)NiH_(4),and MgH_(2)phases,while during the dehydrogenation process,it was composed of LaH_(3),Mg,and Mg_(2)Ni phases.The addition of graphene can help get a more homogeneous granule after ball milling and accelerate the first activation of dehydrogenation/hydrogen absorption.The hydrogen release activation energy of the alloys first decreases and then increases as the graphene content increases from x=0 wt.%to x=6 wt.%.The minimum activation energy of the composite hydrogen storage alloy is 51.22 kJ mol^(-1) when x=4 wt.%.
基金supported by GILO Foundation.This research is in part supported by Korea Drug Development Fund funded by Ministry of Science and ICT,Ministry of Trade,Industry,and Energy,and Ministry of Health and Welfare(RS-2023-00282595,Republic of Korea).
文摘Rheumatoid arthritis(RA)is an autoimmune disease characterized by inflammation and abnormal osteoclast activation,leading to bone destruction.We previously demonstrated that the large extracellular loop(LEL)of Tm4sf19 is important for its function in osteoclast differentiation,and LEL-Fc,a competitive inhibitor of Tm4sf19,effectively suppresses osteoclast multinucleation and prevent bone loss associated with osteoporosis.This study aimed to investigate the role of Tm4sf19 in RA,an inflammatory and abnormal osteoclast disease,using a mouse model of collagen-induced arthritis(CIA).Tm4sf19 expression was observed in macrophages and osteoclasts within the inflamed synovium,and Tm4sf19 expression was increased together with inflammatory genes in the joint bones of CIA-induced mice compared with the sham control group.Inhibition of Tm4sf19 by LEL-Fc demonstrated both preventive and therapeutic effects in a CIA mouse model,reducing the CIA score,swelling,inflammation,cartilage damage,and bone damage.Knockout of Tm4sf19 gene or inhibition of Tm4sf19 activity by LEL-Fc suppressed LPS/IFN-γ-induced TLR4-mediated inflammatory signaling in macrophages.LEL-Fc disrupted not only the interaction between Tm4sf19 and TLR4/MD2,but also the interaction between TLR4 and MD2.μCT analysis showed that LEL-Fc treatment significantly reduced joint bone destruction and bone loss caused by hyperactivated osteoclasts in CIA mice.Taken together,these findings suggest that LELFc may be a potential treatment for RA and RA-induced osteoporosis by simultaneously targeting joint inflammation and bone destruction caused by abnormal osteoclast activation.
