The automatic stealth task of military time-sensitive targets plays a crucial role in maintaining national military security and mastering battlefield dynamics in military applications.We propose a novel Military Time...The automatic stealth task of military time-sensitive targets plays a crucial role in maintaining national military security and mastering battlefield dynamics in military applications.We propose a novel Military Time-sensitive Targets Stealth Network via Real-time Mask Generation(MTTSNet).According to our knowledge,this is the first technology to automatically remove military targets in real-time from videos.The critical steps of MTTSNet are as follows:First,we designed a real-time mask generation network based on the encoder-decoder framework,combined with the domain expansion structure,to effectively extract mask images.Specifically,the ASPP structure in the encoder could achieve advanced semantic feature fusion.The decoder stacked high-dimensional information with low-dimensional information to obtain an effective mask layer.Subsequently,the domain expansion module guided the adaptive expansion of mask images.Second,a context adversarial generation network based on gated convolution was constructed to achieve background restoration of mask positions in the original image.In addition,our method worked in an end-to-end manner.A particular semantic segmentation dataset for military time-sensitive targets has been constructed,called the Military Time-sensitive Target Masking Dataset(MTMD).The MTMD dataset experiment successfully demonstrated that this method could create a mask that completely occludes the target and that the target could be hidden in real time using this mask.We demonstrated the concealment performance of our proposed method by comparing it to a number of well-known and highly optimized baselines.展开更多
Regulated cell death is a form of cell death that is actively controlled by biomolecules.Several studies have shown that regulated cell death plays a key role after spinal cord injury.Pyroptosis and ferroptosis are ne...Regulated cell death is a form of cell death that is actively controlled by biomolecules.Several studies have shown that regulated cell death plays a key role after spinal cord injury.Pyroptosis and ferroptosis are newly discovered types of regulated cell deaths that have been shown to exacerbate inflammation and lead to cell death in damaged spinal cords.Autophagy,a complex form of cell death that is interconnected with various regulated cell death mechanisms,has garnered significant attention in the study of spinal cord injury.This injury triggers not only cell death but also cellular survival responses.Multiple signaling pathways play pivotal roles in influencing the processes of both deterioration and repair in spinal cord injury by regulating pyroptosis,ferroptosis,and autophagy.Therefore,this review aims to comprehensively examine the mechanisms underlying regulated cell deaths,the signaling pathways that modulate these mechanisms,and the potential therapeutic targets for spinal cord injury.Our analysis suggests that targeting the common regulatory signaling pathways of different regulated cell deaths could be a promising strategy to promote cell survival and enhance the repair of spinal cord injury.Moreover,a holistic approach that incorporates multiple regulated cell deaths and their regulatory pathways presents a promising multi-target therapeutic strategy for the management of spinal cord injury.展开更多
Chronic atrophic gastritis(CAG)is an important stage of precancerous lesions of gastric cancer.Effective treatment and regulation of CAG are essential to prevent its progression to malignancy.Traditional Chinese medic...Chronic atrophic gastritis(CAG)is an important stage of precancerous lesions of gastric cancer.Effective treatment and regulation of CAG are essential to prevent its progression to malignancy.Traditional Chinese medicine(TCM)has shown multi-targeted efficacy in CAG treatment,with advantages in enhancing gastric mucosal barrier defense,improving microcirculation,modulating inflammatory and immune responses,and promoting lesion healing,etc.Clinical studies and meta-analyses indicate that TCM provides significant benefits,with specific Chinese herbal compounds and monomers demonstrating protective effects on the gastric mucosa through mechanisms including anti-inflammation,antioxidation,and regulation of cellular proliferation and apoptosis,etc.Finally,it is pointed out that the efficacy of TCM in the treatment of CAG requires standardized research and unified standards,and constantly clarifies and improves the evaluation criteria of each dimension of gastric mucosal barrier function.展开更多
It is difficult to improve both energy consumption and detection accuracy simultaneously,and even to obtain the trade-off between them,when detecting and tracking moving targets,especially for Underwater Wireless Sens...It is difficult to improve both energy consumption and detection accuracy simultaneously,and even to obtain the trade-off between them,when detecting and tracking moving targets,especially for Underwater Wireless Sensor Networks(UWSNs).To this end,this paper investigates the relationship between the Degree of Target Change(DoTC)and the detection period,as well as the impact of individual nodes.A Hierarchical Detection and Tracking Approach(HDTA)is proposed.Firstly,the network detection period is determined according to DoTC,which reflects the variation of target motion.Secondly,during the network detection period,each detection node calculates its own node detection period based on the detection mutual information.Taking DoTC as pheromone,an ant colony algorithm is proposed to adaptively adjust the network detection period.The simulation results show that the proposed HDTA with the optimizations of network level and node level significantly improves the detection accuracy by 25%and the network energy consumption by 10%simultaneously,compared to the traditional adaptive period detection schemes.展开更多
Oral squamous cell carcinoma(OSCC)is the most common head and neck malignancy worldwide,accounting for more than 90%of all oral cancers,and is characterized by high invasiveness and poor long-term prognosis.Its etiolo...Oral squamous cell carcinoma(OSCC)is the most common head and neck malignancy worldwide,accounting for more than 90%of all oral cancers,and is characterized by high invasiveness and poor long-term prognosis.Its etiology is multifactorial,involving tobacco use,alcohol consumption,and human papillomavirus(HPV)infection.Oral leukoplakia and erythroplakia are the main precancerous lesions lesions,with oral leukoplakia being the most common.Both OSCC and premalignant lesions are closely associated with aberrant activation of multiple signaling pathways.Post-translational modifications(such as ubiquitination and deubiquitination)play key roles in regulating these pathways by controlling protein stability and activity.Growing evidence indicates that dysregulated ubiquitination/deubiquitination can mediate OSCC initiation and progression via aberrant activation of signaling pathways.The ubiquitination/deubiquitination process mainly involves E3 ligases(E3s)that catalyze substrate ubiquitination,deubiquitinating enzymes(DUBs)that remove ubiquitin chains,and the 26S proteasome complex that degrades ubiquitinated substrates.Abnormal expression or mutation of E3s and DUBs can lead to altered stability of critical tumorrelated proteins,thereby driving OSCC initiation and progression.Therefore,understanding the aberrantly activated signaling pathways in OSCC and the ubiquitination/deubiquitination mechanisms within these pathways will help elucidate the molecular mechanisms and improve OSCC treatment by targeting relevant components.Here,we summarize four aberrantly activated signaling pathways in OSCC―the PI3K/AKT/mTOR pathway,Wnt/β-catenin pathway,Hippo pathway,and canonical NF-κB pathway―and systematically review the regulatory mechanisms of ubiquitination/deubiquitination within these pathways,along with potential drug targets.PI3K/AKT/mTOR pathway is aberrantly activated in approximately 70%of OSCC cases.It is modulated by E3s(e.g.,FBXW7 and NEDD4)and DUBs(e.g.,USP7 and USP10):FBXW7 and USP10 inhibit signaling,while NEDD4 and USP7 potentiate it.Aberrant activation of the Wnt/β-catenin pathway leads toβ-catenin nuclear translocation and induction of cell proliferation.This pathway is modulated by E3s(e.g.,c-Cbl and RNF43)and DUBs(e.g.,USP9X and USP20):c-Cbl and RNF43 inhibit signaling,while USP9X and USP20 potentiate it.Hippo pathway inactivation permits YAP/TAZ to enter the nucleus and promotes cancer cell metastasis.This pathway is modulated by E3s(e.g.,CRL4^(DCAF1) and SIAH2)and DUBs(e.g.,USP1 and USP21):CRL4^(DCAF1) and SIAH2 inhibit signaling,while USP1 and USP21 potentiate it.Persistent activation of the canonical NF-κB pathway is associated with an inflammatory microenvironment and chemotherapy resistance.This pathway is modulated by E3s(e.g.,TRAF6 and LUBAC)and DUBs(e.g.,A20 and CYLD):A20 and CYLD inhibit signaling,while TRAF6 and LUBAC potentiate it.Targeting these E3s and DUBs provides directions for OSCC drug research.Small-molecule inhibitors such as YCH2823(a USP7 inhibitor),GSK2643943A(a USP20 inhibitor),and HOIPIN-8(a LUBAC inhibitor)have shown promising antitumor activity in preclinical models;PROTAC molecules,by binding to surface sites of target proteins and recruiting E3s,achieve targeted ubiquitination and degradation of proteins insensitive to small-molecule inhibitors,for example,PU7-1-mediated USP7 degradation,offering new strategies to overcome traditional drug limitations.Currently,NX-1607(a Cbl-b inhibitor)has entered phase I clinical trials,with preliminary results confirming its safety and antitumor activity.Future research on aberrant E3s and DUBs in OSCC and the development of highly specific inhibitors will be of great significance for OSCC precision therapy.展开更多
Prodrugs need to be converted to active drugs to exert their pharmacological activities.Identifying the direct targets of active drugs is essential to elucidate the pharmacological mechanisms of prodrugs,but remains c...Prodrugs need to be converted to active drugs to exert their pharmacological activities.Identifying the direct targets of active drugs is essential to elucidate the pharmacological mechanisms of prodrugs,but remains challenging,especially for active drugs with low stability.展开更多
The rise of time-sensitive applications with broad geographical scope drives the development of time-sensitive networking(TSN)from intra-domain to inter-domain to ensure overall end-to-end connectivity requirements in...The rise of time-sensitive applications with broad geographical scope drives the development of time-sensitive networking(TSN)from intra-domain to inter-domain to ensure overall end-to-end connectivity requirements in heterogeneous deployments.When multiple TSN networks interconnect over non-TSN networks,all devices in the network need to be syn-chronized by sharing a uniform time reference.How-ever,most non-TSN networks are best-effort.Path delay asymmetry and random noise accumulation can introduce unpredictable time errors during end-to-end time synchronization.These factors can degrade syn-chronization performance.Therefore,cross-domain time synchronization becomes a challenging issue for multiple TSN networks interconnected by non-TSN networks.This paper presents a cross-domain time synchronization scheme that follows the software-defined TSN(SD-TSN)paradigm.It utilizes a com-bined control plane constructed by a coordinate con-troller and a domain controller for centralized control and management of cross-domain time synchroniza-tion.The general operation flow of the cross-domain time synchronization process is designed.The mecha-nism of cross-domain time synchronization is revealed by introducing a synchronization model and an error compensation method.A TSN cross-domain proto-type testbed is constructed for verification.Results show that the scheme can achieve end-to-end high-precision time synchronization with accuracy and sta-bility.展开更多
Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration.It causes local damage to photoreceptors,retinal pigment epithelium,and choroidal vessels,which leads to permanent central ...Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration.It causes local damage to photoreceptors,retinal pigment epithelium,and choroidal vessels,which leads to permanent central vision loss of patients with neovascular age-related macular degeneration.The pathogenesis of subretinal fibrosis is complex,and the underlying mechanisms are largely unknown.Therefore,there are no effective treatment options.A thorough understanding of the pathogenesis of subretinal fibrosis and its related mechanisms is important to elucidate its complications and explore potential treatments.The current article reviews several aspects of subretinal fibrosis,including the current understanding on the relationship between neovascular age-related macular degeneration and subretinal fibrosis;multimodal imaging techniques for subretinal fibrosis;animal models for studying subretinal fibrosis;cellular and non-cellular constituents of subretinal fibrosis;pathophysiological mechanisms involved in subretinal fibrosis,such as aging,infiltration of macrophages,different sources of mesenchymal transition to myofibroblast,and activation of complement system and immune cells;and several key molecules and signaling pathways participating in the pathogenesis of subretinal fibrosis,such as vascular endothelial growth factor,connective tissue growth factor,fibroblast growth factor 2,platelet-derived growth factor and platelet-derived growth factor receptor-β,transforming growth factor-βsignaling pathway,Wnt signaling pathway,and the axis of heat shock protein 70-Toll-like receptors 2/4-interleukin-10.This review will improve the understanding of the pathogenesis of subretinal fibrosis,allow the discovery of molecular targets,and explore potential treatments for the management of subretinal fibrosis.展开更多
A measurement system for the scattering characteristics of warhead fragments based on high-speed imaging systems offers advantages such as simple deployment,flexible maneuverability,and high spatiotemporal resolution,...A measurement system for the scattering characteristics of warhead fragments based on high-speed imaging systems offers advantages such as simple deployment,flexible maneuverability,and high spatiotemporal resolution,enabling the acquisition of full-process data of the fragment scattering process.However,mismatches between camera frame rates and target velocities can lead to long motion blur tails of high-speed fragment targets,resulting in low signal-to-noise ratios and rendering conventional detection algorithms ineffective in dynamic strong interference testing environments.In this study,we propose a detection framework centered on dynamic strong interference disturbance signal separation and suppression.We introduce a mixture Gaussian model constrained under a joint spatialtemporal-transform domain Dirichlet process,combined with total variation regularization to achieve disturbance signal suppression.Experimental results demonstrate that the proposed disturbance suppression method can be integrated with certain conventional motion target detection tasks,enabling adaptation to real-world data to a certain extent.Moreover,we provide a specific implementation of this process,which achieves a detection rate close to 100%with an approximate 0%false alarm rate in multiple sets of real target field test data.This research effectively advances the development of the field of damage parameter testing.展开更多
An experimental and finite element simulation investigation are conducted to study the deformation patterns of steel targets during the penetration process of tungsten alloy long rods,as well as the influence of stren...An experimental and finite element simulation investigation are conducted to study the deformation patterns of steel targets during the penetration process of tungsten alloy long rods,as well as the influence of strength of the target on the deformation patterns.The experimental results revealed slight mass loss in the first layer of the steel target during the transient entrance phase,with an extremely negligible loss in target mass during the quasi-steady penetration phase.The results of macro-analysis,micro-analysis and simulation show that the eroded target material migrated towards the periphery of the crater,causing an increase in the target's thickness,remained within the target,instead of flowing out of the crater.Therefore,the process of long rods penetrating the metal target is considered as a process of backward extrusion.By combining the backward extrusion theory with energy conservation,a penetration depth model for long rods penetrating a metal target,taking into account both the diameter of the crater and the friction coefficient between the rod and the target,has been established.Although the model is not yet perfect,it innovatively applies the principles of solid mechanics to the study of long rod penetration.Additionally,it takes into account the friction coefficient between the rod and the target during the penetration process.Therefore,this model provides a new research direction for future studies on long rod penetration.展开更多
Microglia(MG)are immune effector cells in the central nervous system(CNS)and play a pivotal role in the pathogenesis of various CNS diseases.Alzheimer's disease(AD)is defined as a severe chronic degenerative neuro...Microglia(MG)are immune effector cells in the central nervous system(CNS)and play a pivotal role in the pathogenesis of various CNS diseases.Alzheimer's disease(AD)is defined as a severe chronic degenerative neurological disease in humans.The amyloid cascade hypothesis is a hypothesis on the pathogenesis of AD that suggests that abnormal extracellular aggregation ofβ-amyloid(Aβ)peptides is the main cause of the disease.Although this hypothesis has been found to be convincing,a growing body of evidence suggests that it does not fully explain the pathogenesis of AD.Neuroinflammation is a crucial element in the pathogenesis of AD,as evidenced by elevated levels of inflammatory markers and the identification of AD risk genes associated with innate immune function.This paper will first summarize the impact of microglia-mediated neuroinflammation on AD,exploring the phenotypic changes that follow microglia activation.Secondly,the interactions between microglia,Aβ,microtubule-associated protein,apolipoprotein E and neurons are thoroughly investigated,with particular focus on the interactive mechanisms.Furthermore,the recent progress and prospects of microglia as a diagnostic and therapeutic target for AD are analysed.A review of the literature on the mechanisms regulating MG for AD at home and abroad revealed that acupuncture modulation of microglia could help to delay the progression of AD.This was followed by an extensive discussion of the clinical possibilities and scientific validity of acupuncture treatment for AD,with the aim of providing new insights for acupuncture modulation of MG targeting for the treatment of AD.展开更多
The development of adrenergic agonists(AAs)for asthma has provided important mechanistic insights into acupuncture-based target discovery and treatment strategies.This review describes the historical evolution of AA t...The development of adrenergic agonists(AAs)for asthma has provided important mechanistic insights into acupuncture-based target discovery and treatment strategies.This review describes the historical evolution of AA therapy,including the precise optimization of nonselective toβ2-selective agonists,im-provement from short-acting to ultra-long-acting agents,shift from targeted monotherapy to combination regimens,and alterations in drug formulation.Additionally,this review summarizes recent advances in acupuncture treatment for asthma,including the development of novel targeted therapies,application of acupuncture-based combination regimens,and optimization of the mode of administration.Taken to-gether,this article discusses key insights from research on AA that inform acupuncture approaches,with a focus on:(1)precision targeting:identifying acupuncture-specific targets to improve efficacy;(2)syn-ergistic treatment:employing multi-target combination regimens to enhance therapeutic outcomes;(3)formulation innovation:advancing acupuncture delivery methods to improve patient compliance;and(4)evidence-based development:strengthening clinical research to generate high-quality evidence to inform the discovery of novel targets and treatment strategies for asthma.展开更多
This study combines ground penetrating radar(GPR)and convolutional neural networks for the intelligent detection of underground road targets.The target location was realized using a gradient-class activation map(Grad-...This study combines ground penetrating radar(GPR)and convolutional neural networks for the intelligent detection of underground road targets.The target location was realized using a gradient-class activation map(Grad-CAM).First,GPR technology was used to detect roads and obtain radar images.This study constructs a radar image dataset containing 3000 underground road radar targets,such as underground pipelines and holes.Based on the dataset,a ResNet50 network was used to classify and train different underground targets.During training,the accuracy of the training set gradually increases and finally fluctuates approximately 85%.The loss function gradually decreases and falls between 0.2 and 0.3.Finally,targets were located using Grad-CAM.The positioning results of single and multiple targets are consistent with the actual position,indicating that the method can eff ectively realize the intelligent detection of underground targets in GPR.展开更多
This article summarizes recent advances in the understanding of RNA-binding proteins(RBPs),with a focus on their roles in exercise-induced mRNA regulation and their implications for schizophrenia(SZ).RBPs are critical...This article summarizes recent advances in the understanding of RNA-binding proteins(RBPs),with a focus on their roles in exercise-induced mRNA regulation and their implications for schizophrenia(SZ).RBPs are critical regulators of mRNA stability,splicing,transport,translation,and degradation,directly influencing gene expression through sequence-and structure-specific binding.In the nervous system,RBPs sustain synaptic plasticity,neural development,and neuronal homeostasis.Emerging evidence shows that exercise modulates the expression and activity of RBPs,thereby influencing mRNA translation and neurotransmitter signaling,which may underlie its beneficial effects on brain function.Dysregulation of specific RBPs has been identified in SZ,implicating them in disrupted synaptic transmission,impaired plasticity,and neuroinflammation.RBPs involved in memory and emotional regulation show marked dysfunction in SZ patients.Some RBPs have been proposed as potential biomarkers for early diagnosis and treatment monitoring.Moreover,therapeutic modulation of RBPs,through pharmacological or behavioral interventions such as exercise,may restore neuronal function by targeting post-transcriptional gene regulation.Exercise,as a non-invasive modulator of RBP expression,holds promise as an adjunctive strategy in SZ treatment,particularly in early stages.Further research into RBP-mediated pathways may offer novel insights into SZ pathophysiology and inform the development of targeted interventions.展开更多
Background:Lung cancer is a leading cause of cancer-related deaths globally,due to its complex genetic foundations.This study aims to identify genomic markers in blood and lung tissue that could serve as therapeutic t...Background:Lung cancer is a leading cause of cancer-related deaths globally,due to its complex genetic foundations.This study aims to identify genomic markers in blood and lung tissue that could serve as therapeutic targets.Methods:Employing Mendelian randomization analysis,we explored the association between lung cancer risk and expression quantitative trait loci to pinpoint relevant genes.Results:Analysis revealed five genes-CASP8,HLA-C,ERAP1,SLC5A11,and PSMA4-significantly associated with lung cancer risk.Notably,CASP8 acts as a protective factor,whereas HLA-C,ERAP1,SLC5A11,and PSMA4 are linked to increased risk,suggesting their potential as targets for new treatments.Conclusions:The study enhances our understanding of the genetic basis of lung cancer,identifying CASP8 as a protective gene and four other genes as risk factors.These insights offer new directions for research and the development of targeted therapies,contributing to the advancement of personalized medicine and potentially improving patient outcomes.展开更多
When a fire breaks out in a high-rise building,the occlusion of smoke and obstacles results in dearth of crucial information concerning people in distress,thereby creating a challenge in their detection.Given the rest...When a fire breaks out in a high-rise building,the occlusion of smoke and obstacles results in dearth of crucial information concerning people in distress,thereby creating a challenge in their detection.Given the restricted sensing range of a single unmanned aerial vehicle(UAV)cam-era,enhancing the target recognition rate becomes challenging without target information.To tackle this issue,this paper proposes a multi-agent autonomous collaborative detection method for multi-targets in complex fire environments.The objective is to achieve the fusion of multi-angle visual information,effectively increasing the target’s information dimension,and ultimately address-ing the problem of low target recognition rate caused by the lack of target information.The method steps are as follows:first,the you only look once version5(YOLOv5)is used to detect the target in the image;second,the detected targets are tracked to monitor their movements and trajectories;third,the person re-identification(ReID)model is employed to extract the appearance features of targets;finally,by fusing the visual information from multi-angle cameras,the method achieves multi-agent autonomous collaborative detection.The experimental results show that the method effectively combines the visual information from multi-angle cameras,resulting in improved detec-tion efficiency for people in distress.展开更多
We investigate the spatial and temporal correlations of hot-electron generation in high-intensity laser interaction with massive and thin copper targets under conditions relevant to inertial confinement fusion.Using K...We investigate the spatial and temporal correlations of hot-electron generation in high-intensity laser interaction with massive and thin copper targets under conditions relevant to inertial confinement fusion.Using Ka time-resolved imaging,it is found that in the case of massive targets,the hot-electron generation follows the laser pulse intensity with a short delay needed for favorable plasma formation.Conversely,a significant delay in the x-ray emission compared with the laser pulse intensity profile is observed in the case of thin targets.Theoretical analysis and numerical simulations suggest that this is related to radiation preheating of the foil and the increase in hot-electron lifetime in a hot expanding plasma.展开更多
With the application of hypervelocity weapons in warfare,comprehensively evaluating their destructive effects is of particular interest for protective engineering.Existing studies mostly focused on the depth of penetr...With the application of hypervelocity weapons in warfare,comprehensively evaluating their destructive effects is of particular interest for protective engineering.Existing studies mostly focused on the depth of penetration by hypervelocity projectile,while investigation on stress waves associated with hypervelocity penetration was very limited.To clarify the generation and propagation of stress waves in concrete targets induced by hypervelocity projectile penetration,in the present study,six spherical projectile penetration tests on concrete targets were firstly conducted with projectile velocity ranged from 1875 m/s to 3940 m/s,in which the stress waves were carefully measured by the PVDF transducers.Then corresponding numerical models were developed and validated,and based on the validated numerical model the mechanisms of generation and propagation of stress waves were clarified.It was found that the stress waves observed during hypervelocity penetration are generated by the continuous interactions of projectile and target during penetration,and have unique characteristics such as the directionality and the"two peaks"phenomenon when compared with the stress waves generated by charge explosion.Finally,the effects of projectile velocity,projectile material,and target strength on the stress waves below the penetration depth we re numerically investigated,and two important indexes for evaluating the stress waves by hypervelocity penetration were proposed.展开更多
Pose estimation of spacecraft targets is a key technology for achieving space operation tasks,such as the cleaning of failed satellites and the detection and scanning of non-cooperative targets.This paper reviews the ...Pose estimation of spacecraft targets is a key technology for achieving space operation tasks,such as the cleaning of failed satellites and the detection and scanning of non-cooperative targets.This paper reviews the target pose estimation methods based on image feature extraction and PnP,the target estimation methods based on registration,and the spacecraft target pose estimation methods based on deep learning,and introduces the corresponding research methods.展开更多
Recent advances in drug development and bioactive molecules that covalently target lysine residues have shown substantial progress.Both reversible and irreversible covalent inhibitors are developed for targeting lysin...Recent advances in drug development and bioactive molecules that covalently target lysine residues have shown substantial progress.Both reversible and irreversible covalent inhibitors are developed for targeting lysine residues.The identification of protein targets and binding sites of these lysine-targeting molecules in the whole proteome is crucial to understand their proteome-wide selectivity.For covalent inhibitors,the pull down-based methods including activity-based protein profiling(ABPP)are commonly used to profile their target proteins.For covalent reversible inhibitors,it is not easy to pull down the potential protein targets as the captured proteins may get off beads because of the reversible manner.Here,we report a pair of isotope-labelled click-free probes to competitively identify the protein targets of lysine-targeting covalent reversible small molecules.This pair of isotopic probes consists of a lysinereactive warhead,a desthiobiotin moiety and isotopicable linker.This integrated probe could eliminate the background proteins induced by the click chemistry during the pull-down process.To demonstrate the feasibility of our newly-developed probes for the protein target identification,we selected the natural product Gossypol in that we proved for the first time that it could modify the lysine residue in a covalent reversible manner.Finally,we confirmed that this pair of integrated probes can be used in a competitive manner to precisely identify the protein target as well as binding sites of Gossypol.Interestingly,pretreatment of Gossypol could stop the antibody from recognizing Gossypol-binding proteins.Together,our isotope-labeled click-free probes could be used for whole-proteome profiling of lysine-targeting covalent reversible small molecules.展开更多
基金supported in part by the National Natural Science Foundation of China(Grant No.62276274)Shaanxi Natural Science Foundation(Grant No.2023-JC-YB-528)Chinese aeronautical establishment(Grant No.201851U8012)。
文摘The automatic stealth task of military time-sensitive targets plays a crucial role in maintaining national military security and mastering battlefield dynamics in military applications.We propose a novel Military Time-sensitive Targets Stealth Network via Real-time Mask Generation(MTTSNet).According to our knowledge,this is the first technology to automatically remove military targets in real-time from videos.The critical steps of MTTSNet are as follows:First,we designed a real-time mask generation network based on the encoder-decoder framework,combined with the domain expansion structure,to effectively extract mask images.Specifically,the ASPP structure in the encoder could achieve advanced semantic feature fusion.The decoder stacked high-dimensional information with low-dimensional information to obtain an effective mask layer.Subsequently,the domain expansion module guided the adaptive expansion of mask images.Second,a context adversarial generation network based on gated convolution was constructed to achieve background restoration of mask positions in the original image.In addition,our method worked in an end-to-end manner.A particular semantic segmentation dataset for military time-sensitive targets has been constructed,called the Military Time-sensitive Target Masking Dataset(MTMD).The MTMD dataset experiment successfully demonstrated that this method could create a mask that completely occludes the target and that the target could be hidden in real time using this mask.We demonstrated the concealment performance of our proposed method by comparing it to a number of well-known and highly optimized baselines.
基金supported by the Natural Science Foundation of Fujian Province,No.2021J02035(to WX).
文摘Regulated cell death is a form of cell death that is actively controlled by biomolecules.Several studies have shown that regulated cell death plays a key role after spinal cord injury.Pyroptosis and ferroptosis are newly discovered types of regulated cell deaths that have been shown to exacerbate inflammation and lead to cell death in damaged spinal cords.Autophagy,a complex form of cell death that is interconnected with various regulated cell death mechanisms,has garnered significant attention in the study of spinal cord injury.This injury triggers not only cell death but also cellular survival responses.Multiple signaling pathways play pivotal roles in influencing the processes of both deterioration and repair in spinal cord injury by regulating pyroptosis,ferroptosis,and autophagy.Therefore,this review aims to comprehensively examine the mechanisms underlying regulated cell deaths,the signaling pathways that modulate these mechanisms,and the potential therapeutic targets for spinal cord injury.Our analysis suggests that targeting the common regulatory signaling pathways of different regulated cell deaths could be a promising strategy to promote cell survival and enhance the repair of spinal cord injury.Moreover,a holistic approach that incorporates multiple regulated cell deaths and their regulatory pathways presents a promising multi-target therapeutic strategy for the management of spinal cord injury.
基金Supported by the Scientific and Technological Innovation Project of China Academy of Chinese Medical Sciences,No.CI2021A00806High Level Chinese Medical Hospital Promotion Project,No.HLCMHPP2023086the Fundamental Research Funds for the Central Public Welfare Research Institutes,No.ZZ17-XRZ-041.
文摘Chronic atrophic gastritis(CAG)is an important stage of precancerous lesions of gastric cancer.Effective treatment and regulation of CAG are essential to prevent its progression to malignancy.Traditional Chinese medicine(TCM)has shown multi-targeted efficacy in CAG treatment,with advantages in enhancing gastric mucosal barrier defense,improving microcirculation,modulating inflammatory and immune responses,and promoting lesion healing,etc.Clinical studies and meta-analyses indicate that TCM provides significant benefits,with specific Chinese herbal compounds and monomers demonstrating protective effects on the gastric mucosa through mechanisms including anti-inflammation,antioxidation,and regulation of cellular proliferation and apoptosis,etc.Finally,it is pointed out that the efficacy of TCM in the treatment of CAG requires standardized research and unified standards,and constantly clarifies and improves the evaluation criteria of each dimension of gastric mucosal barrier function.
文摘It is difficult to improve both energy consumption and detection accuracy simultaneously,and even to obtain the trade-off between them,when detecting and tracking moving targets,especially for Underwater Wireless Sensor Networks(UWSNs).To this end,this paper investigates the relationship between the Degree of Target Change(DoTC)and the detection period,as well as the impact of individual nodes.A Hierarchical Detection and Tracking Approach(HDTA)is proposed.Firstly,the network detection period is determined according to DoTC,which reflects the variation of target motion.Secondly,during the network detection period,each detection node calculates its own node detection period based on the detection mutual information.Taking DoTC as pheromone,an ant colony algorithm is proposed to adaptively adjust the network detection period.The simulation results show that the proposed HDTA with the optimizations of network level and node level significantly improves the detection accuracy by 25%and the network energy consumption by 10%simultaneously,compared to the traditional adaptive period detection schemes.
文摘Oral squamous cell carcinoma(OSCC)is the most common head and neck malignancy worldwide,accounting for more than 90%of all oral cancers,and is characterized by high invasiveness and poor long-term prognosis.Its etiology is multifactorial,involving tobacco use,alcohol consumption,and human papillomavirus(HPV)infection.Oral leukoplakia and erythroplakia are the main precancerous lesions lesions,with oral leukoplakia being the most common.Both OSCC and premalignant lesions are closely associated with aberrant activation of multiple signaling pathways.Post-translational modifications(such as ubiquitination and deubiquitination)play key roles in regulating these pathways by controlling protein stability and activity.Growing evidence indicates that dysregulated ubiquitination/deubiquitination can mediate OSCC initiation and progression via aberrant activation of signaling pathways.The ubiquitination/deubiquitination process mainly involves E3 ligases(E3s)that catalyze substrate ubiquitination,deubiquitinating enzymes(DUBs)that remove ubiquitin chains,and the 26S proteasome complex that degrades ubiquitinated substrates.Abnormal expression or mutation of E3s and DUBs can lead to altered stability of critical tumorrelated proteins,thereby driving OSCC initiation and progression.Therefore,understanding the aberrantly activated signaling pathways in OSCC and the ubiquitination/deubiquitination mechanisms within these pathways will help elucidate the molecular mechanisms and improve OSCC treatment by targeting relevant components.Here,we summarize four aberrantly activated signaling pathways in OSCC―the PI3K/AKT/mTOR pathway,Wnt/β-catenin pathway,Hippo pathway,and canonical NF-κB pathway―and systematically review the regulatory mechanisms of ubiquitination/deubiquitination within these pathways,along with potential drug targets.PI3K/AKT/mTOR pathway is aberrantly activated in approximately 70%of OSCC cases.It is modulated by E3s(e.g.,FBXW7 and NEDD4)and DUBs(e.g.,USP7 and USP10):FBXW7 and USP10 inhibit signaling,while NEDD4 and USP7 potentiate it.Aberrant activation of the Wnt/β-catenin pathway leads toβ-catenin nuclear translocation and induction of cell proliferation.This pathway is modulated by E3s(e.g.,c-Cbl and RNF43)and DUBs(e.g.,USP9X and USP20):c-Cbl and RNF43 inhibit signaling,while USP9X and USP20 potentiate it.Hippo pathway inactivation permits YAP/TAZ to enter the nucleus and promotes cancer cell metastasis.This pathway is modulated by E3s(e.g.,CRL4^(DCAF1) and SIAH2)and DUBs(e.g.,USP1 and USP21):CRL4^(DCAF1) and SIAH2 inhibit signaling,while USP1 and USP21 potentiate it.Persistent activation of the canonical NF-κB pathway is associated with an inflammatory microenvironment and chemotherapy resistance.This pathway is modulated by E3s(e.g.,TRAF6 and LUBAC)and DUBs(e.g.,A20 and CYLD):A20 and CYLD inhibit signaling,while TRAF6 and LUBAC potentiate it.Targeting these E3s and DUBs provides directions for OSCC drug research.Small-molecule inhibitors such as YCH2823(a USP7 inhibitor),GSK2643943A(a USP20 inhibitor),and HOIPIN-8(a LUBAC inhibitor)have shown promising antitumor activity in preclinical models;PROTAC molecules,by binding to surface sites of target proteins and recruiting E3s,achieve targeted ubiquitination and degradation of proteins insensitive to small-molecule inhibitors,for example,PU7-1-mediated USP7 degradation,offering new strategies to overcome traditional drug limitations.Currently,NX-1607(a Cbl-b inhibitor)has entered phase I clinical trials,with preliminary results confirming its safety and antitumor activity.Future research on aberrant E3s and DUBs in OSCC and the development of highly specific inhibitors will be of great significance for OSCC precision therapy.
基金support from the National Natural Science Foundation of China(Grant Nos.:U21A20407 and 81973467).
文摘Prodrugs need to be converted to active drugs to exert their pharmacological activities.Identifying the direct targets of active drugs is essential to elucidate the pharmacological mechanisms of prodrugs,but remains challenging,especially for active drugs with low stability.
基金supported in part by National Key R&D Program of China(Grant No.2022YFC3803700)in part by the National Natural Science Foundation of China(Grant No.92067102)in part by the project of Beijing Laboratory of Advanced Information Networks.
文摘The rise of time-sensitive applications with broad geographical scope drives the development of time-sensitive networking(TSN)from intra-domain to inter-domain to ensure overall end-to-end connectivity requirements in heterogeneous deployments.When multiple TSN networks interconnect over non-TSN networks,all devices in the network need to be syn-chronized by sharing a uniform time reference.How-ever,most non-TSN networks are best-effort.Path delay asymmetry and random noise accumulation can introduce unpredictable time errors during end-to-end time synchronization.These factors can degrade syn-chronization performance.Therefore,cross-domain time synchronization becomes a challenging issue for multiple TSN networks interconnected by non-TSN networks.This paper presents a cross-domain time synchronization scheme that follows the software-defined TSN(SD-TSN)paradigm.It utilizes a com-bined control plane constructed by a coordinate con-troller and a domain controller for centralized control and management of cross-domain time synchroniza-tion.The general operation flow of the cross-domain time synchronization process is designed.The mecha-nism of cross-domain time synchronization is revealed by introducing a synchronization model and an error compensation method.A TSN cross-domain proto-type testbed is constructed for verification.Results show that the scheme can achieve end-to-end high-precision time synchronization with accuracy and sta-bility.
基金supported by grants from National Key R&D Program of China,No.2023YFC2506100(to JZ)the National Natural Science Foundation of China,No.82171062(to JZ).
文摘Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration.It causes local damage to photoreceptors,retinal pigment epithelium,and choroidal vessels,which leads to permanent central vision loss of patients with neovascular age-related macular degeneration.The pathogenesis of subretinal fibrosis is complex,and the underlying mechanisms are largely unknown.Therefore,there are no effective treatment options.A thorough understanding of the pathogenesis of subretinal fibrosis and its related mechanisms is important to elucidate its complications and explore potential treatments.The current article reviews several aspects of subretinal fibrosis,including the current understanding on the relationship between neovascular age-related macular degeneration and subretinal fibrosis;multimodal imaging techniques for subretinal fibrosis;animal models for studying subretinal fibrosis;cellular and non-cellular constituents of subretinal fibrosis;pathophysiological mechanisms involved in subretinal fibrosis,such as aging,infiltration of macrophages,different sources of mesenchymal transition to myofibroblast,and activation of complement system and immune cells;and several key molecules and signaling pathways participating in the pathogenesis of subretinal fibrosis,such as vascular endothelial growth factor,connective tissue growth factor,fibroblast growth factor 2,platelet-derived growth factor and platelet-derived growth factor receptor-β,transforming growth factor-βsignaling pathway,Wnt signaling pathway,and the axis of heat shock protein 70-Toll-like receptors 2/4-interleukin-10.This review will improve the understanding of the pathogenesis of subretinal fibrosis,allow the discovery of molecular targets,and explore potential treatments for the management of subretinal fibrosis.
文摘A measurement system for the scattering characteristics of warhead fragments based on high-speed imaging systems offers advantages such as simple deployment,flexible maneuverability,and high spatiotemporal resolution,enabling the acquisition of full-process data of the fragment scattering process.However,mismatches between camera frame rates and target velocities can lead to long motion blur tails of high-speed fragment targets,resulting in low signal-to-noise ratios and rendering conventional detection algorithms ineffective in dynamic strong interference testing environments.In this study,we propose a detection framework centered on dynamic strong interference disturbance signal separation and suppression.We introduce a mixture Gaussian model constrained under a joint spatialtemporal-transform domain Dirichlet process,combined with total variation regularization to achieve disturbance signal suppression.Experimental results demonstrate that the proposed disturbance suppression method can be integrated with certain conventional motion target detection tasks,enabling adaptation to real-world data to a certain extent.Moreover,we provide a specific implementation of this process,which achieves a detection rate close to 100%with an approximate 0%false alarm rate in multiple sets of real target field test data.This research effectively advances the development of the field of damage parameter testing.
基金supported by the National Natural Science Foundation of China(Grant Nos.12102201,U2341244).
文摘An experimental and finite element simulation investigation are conducted to study the deformation patterns of steel targets during the penetration process of tungsten alloy long rods,as well as the influence of strength of the target on the deformation patterns.The experimental results revealed slight mass loss in the first layer of the steel target during the transient entrance phase,with an extremely negligible loss in target mass during the quasi-steady penetration phase.The results of macro-analysis,micro-analysis and simulation show that the eroded target material migrated towards the periphery of the crater,causing an increase in the target's thickness,remained within the target,instead of flowing out of the crater.Therefore,the process of long rods penetrating the metal target is considered as a process of backward extrusion.By combining the backward extrusion theory with energy conservation,a penetration depth model for long rods penetrating a metal target,taking into account both the diameter of the crater and the friction coefficient between the rod and the target,has been established.Although the model is not yet perfect,it innovatively applies the principles of solid mechanics to the study of long rod penetration.Additionally,it takes into account the friction coefficient between the rod and the target during the penetration process.Therefore,this model provides a new research direction for future studies on long rod penetration.
文摘Microglia(MG)are immune effector cells in the central nervous system(CNS)and play a pivotal role in the pathogenesis of various CNS diseases.Alzheimer's disease(AD)is defined as a severe chronic degenerative neurological disease in humans.The amyloid cascade hypothesis is a hypothesis on the pathogenesis of AD that suggests that abnormal extracellular aggregation ofβ-amyloid(Aβ)peptides is the main cause of the disease.Although this hypothesis has been found to be convincing,a growing body of evidence suggests that it does not fully explain the pathogenesis of AD.Neuroinflammation is a crucial element in the pathogenesis of AD,as evidenced by elevated levels of inflammatory markers and the identification of AD risk genes associated with innate immune function.This paper will first summarize the impact of microglia-mediated neuroinflammation on AD,exploring the phenotypic changes that follow microglia activation.Secondly,the interactions between microglia,Aβ,microtubule-associated protein,apolipoprotein E and neurons are thoroughly investigated,with particular focus on the interactive mechanisms.Furthermore,the recent progress and prospects of microglia as a diagnostic and therapeutic target for AD are analysed.A review of the literature on the mechanisms regulating MG for AD at home and abroad revealed that acupuncture modulation of microglia could help to delay the progression of AD.This was followed by an extensive discussion of the clinical possibilities and scientific validity of acupuncture treatment for AD,with the aim of providing new insights for acupuncture modulation of MG targeting for the treatment of AD.
基金Supported by National Natural Science Foundation of China:No.82374583,82274646.
文摘The development of adrenergic agonists(AAs)for asthma has provided important mechanistic insights into acupuncture-based target discovery and treatment strategies.This review describes the historical evolution of AA therapy,including the precise optimization of nonselective toβ2-selective agonists,im-provement from short-acting to ultra-long-acting agents,shift from targeted monotherapy to combination regimens,and alterations in drug formulation.Additionally,this review summarizes recent advances in acupuncture treatment for asthma,including the development of novel targeted therapies,application of acupuncture-based combination regimens,and optimization of the mode of administration.Taken to-gether,this article discusses key insights from research on AA that inform acupuncture approaches,with a focus on:(1)precision targeting:identifying acupuncture-specific targets to improve efficacy;(2)syn-ergistic treatment:employing multi-target combination regimens to enhance therapeutic outcomes;(3)formulation innovation:advancing acupuncture delivery methods to improve patient compliance;and(4)evidence-based development:strengthening clinical research to generate high-quality evidence to inform the discovery of novel targets and treatment strategies for asthma.
基金supported in part by the National Natural Science Fund of China under Grant 52074306in part by the National Key Research and Development Program of China under Grant 2019YFC1805504in part by the Fundamental Research Funds for the Central Universities under Grant 2023JCCXHH02。
文摘This study combines ground penetrating radar(GPR)and convolutional neural networks for the intelligent detection of underground road targets.The target location was realized using a gradient-class activation map(Grad-CAM).First,GPR technology was used to detect roads and obtain radar images.This study constructs a radar image dataset containing 3000 underground road radar targets,such as underground pipelines and holes.Based on the dataset,a ResNet50 network was used to classify and train different underground targets.During training,the accuracy of the training set gradually increases and finally fluctuates approximately 85%.The loss function gradually decreases and falls between 0.2 and 0.3.Finally,targets were located using Grad-CAM.The positioning results of single and multiple targets are consistent with the actual position,indicating that the method can eff ectively realize the intelligent detection of underground targets in GPR.
文摘This article summarizes recent advances in the understanding of RNA-binding proteins(RBPs),with a focus on their roles in exercise-induced mRNA regulation and their implications for schizophrenia(SZ).RBPs are critical regulators of mRNA stability,splicing,transport,translation,and degradation,directly influencing gene expression through sequence-and structure-specific binding.In the nervous system,RBPs sustain synaptic plasticity,neural development,and neuronal homeostasis.Emerging evidence shows that exercise modulates the expression and activity of RBPs,thereby influencing mRNA translation and neurotransmitter signaling,which may underlie its beneficial effects on brain function.Dysregulation of specific RBPs has been identified in SZ,implicating them in disrupted synaptic transmission,impaired plasticity,and neuroinflammation.RBPs involved in memory and emotional regulation show marked dysfunction in SZ patients.Some RBPs have been proposed as potential biomarkers for early diagnosis and treatment monitoring.Moreover,therapeutic modulation of RBPs,through pharmacological or behavioral interventions such as exercise,may restore neuronal function by targeting post-transcriptional gene regulation.Exercise,as a non-invasive modulator of RBP expression,holds promise as an adjunctive strategy in SZ treatment,particularly in early stages.Further research into RBP-mediated pathways may offer novel insights into SZ pathophysiology and inform the development of targeted interventions.
基金We thanks to the Education Department of Hebei Province(Project No.:QN2016145)the University Student Research Project of Chengde Medical University(2023004)for the funding support.
文摘Background:Lung cancer is a leading cause of cancer-related deaths globally,due to its complex genetic foundations.This study aims to identify genomic markers in blood and lung tissue that could serve as therapeutic targets.Methods:Employing Mendelian randomization analysis,we explored the association between lung cancer risk and expression quantitative trait loci to pinpoint relevant genes.Results:Analysis revealed five genes-CASP8,HLA-C,ERAP1,SLC5A11,and PSMA4-significantly associated with lung cancer risk.Notably,CASP8 acts as a protective factor,whereas HLA-C,ERAP1,SLC5A11,and PSMA4 are linked to increased risk,suggesting their potential as targets for new treatments.Conclusions:The study enhances our understanding of the genetic basis of lung cancer,identifying CASP8 as a protective gene and four other genes as risk factors.These insights offer new directions for research and the development of targeted therapies,contributing to the advancement of personalized medicine and potentially improving patient outcomes.
文摘When a fire breaks out in a high-rise building,the occlusion of smoke and obstacles results in dearth of crucial information concerning people in distress,thereby creating a challenge in their detection.Given the restricted sensing range of a single unmanned aerial vehicle(UAV)cam-era,enhancing the target recognition rate becomes challenging without target information.To tackle this issue,this paper proposes a multi-agent autonomous collaborative detection method for multi-targets in complex fire environments.The objective is to achieve the fusion of multi-angle visual information,effectively increasing the target’s information dimension,and ultimately address-ing the problem of low target recognition rate caused by the lack of target information.The method steps are as follows:first,the you only look once version5(YOLOv5)is used to detect the target in the image;second,the detected targets are tracked to monitor their movements and trajectories;third,the person re-identification(ReID)model is employed to extract the appearance features of targets;finally,by fusing the visual information from multi-angle cameras,the method achieves multi-agent autonomous collaborative detection.The experimental results show that the method effectively combines the visual information from multi-angle cameras,resulting in improved detec-tion efficiency for people in distress.
基金funding via EUROfusion Enabling research Project No.AWP21-ENR-01-CEA-02“Advancing Shock Ignition for Direct-Drive Inertial Fusion,”the framework of the EUROfusion Consortium,funded by the European Union via the Euratom Research and Training Programme (Grant Agreement No.101052200-EUROfusion)+2 种基金the Czech Ministry of Education,Youth and Sports (CMEYS) for funding the operation of the PALS facility (Grant No.LM2023068)the EuroHPC Joint Undertaking for awarding access to Karolina at IT4Innovations (VSB-TU),Czechia under Project No.EHPC-REG-2023R02-006(DD-23-157)the Ministry of Education,Youth and Sports of the Czech Republic through e-INFRA CZ (Grant No.ID:90140)
文摘We investigate the spatial and temporal correlations of hot-electron generation in high-intensity laser interaction with massive and thin copper targets under conditions relevant to inertial confinement fusion.Using Ka time-resolved imaging,it is found that in the case of massive targets,the hot-electron generation follows the laser pulse intensity with a short delay needed for favorable plasma formation.Conversely,a significant delay in the x-ray emission compared with the laser pulse intensity profile is observed in the case of thin targets.Theoretical analysis and numerical simulations suggest that this is related to radiation preheating of the foil and the increase in hot-electron lifetime in a hot expanding plasma.
基金supported by the National Natural Science Foundation of China(Grant Nos.52178515 and 12472399)。
文摘With the application of hypervelocity weapons in warfare,comprehensively evaluating their destructive effects is of particular interest for protective engineering.Existing studies mostly focused on the depth of penetration by hypervelocity projectile,while investigation on stress waves associated with hypervelocity penetration was very limited.To clarify the generation and propagation of stress waves in concrete targets induced by hypervelocity projectile penetration,in the present study,six spherical projectile penetration tests on concrete targets were firstly conducted with projectile velocity ranged from 1875 m/s to 3940 m/s,in which the stress waves were carefully measured by the PVDF transducers.Then corresponding numerical models were developed and validated,and based on the validated numerical model the mechanisms of generation and propagation of stress waves were clarified.It was found that the stress waves observed during hypervelocity penetration are generated by the continuous interactions of projectile and target during penetration,and have unique characteristics such as the directionality and the"two peaks"phenomenon when compared with the stress waves generated by charge explosion.Finally,the effects of projectile velocity,projectile material,and target strength on the stress waves below the penetration depth we re numerically investigated,and two important indexes for evaluating the stress waves by hypervelocity penetration were proposed.
文摘Pose estimation of spacecraft targets is a key technology for achieving space operation tasks,such as the cleaning of failed satellites and the detection and scanning of non-cooperative targets.This paper reviews the target pose estimation methods based on image feature extraction and PnP,the target estimation methods based on registration,and the spacecraft target pose estimation methods based on deep learning,and introduces the corresponding research methods.
基金supported by funding from The National Natural Science Foundation of China(No.22177136)the CAMS Innovation Fund for Medical Sciences(CIFMS)(No.2022-I2M-2-002).
文摘Recent advances in drug development and bioactive molecules that covalently target lysine residues have shown substantial progress.Both reversible and irreversible covalent inhibitors are developed for targeting lysine residues.The identification of protein targets and binding sites of these lysine-targeting molecules in the whole proteome is crucial to understand their proteome-wide selectivity.For covalent inhibitors,the pull down-based methods including activity-based protein profiling(ABPP)are commonly used to profile their target proteins.For covalent reversible inhibitors,it is not easy to pull down the potential protein targets as the captured proteins may get off beads because of the reversible manner.Here,we report a pair of isotope-labelled click-free probes to competitively identify the protein targets of lysine-targeting covalent reversible small molecules.This pair of isotopic probes consists of a lysinereactive warhead,a desthiobiotin moiety and isotopicable linker.This integrated probe could eliminate the background proteins induced by the click chemistry during the pull-down process.To demonstrate the feasibility of our newly-developed probes for the protein target identification,we selected the natural product Gossypol in that we proved for the first time that it could modify the lysine residue in a covalent reversible manner.Finally,we confirmed that this pair of integrated probes can be used in a competitive manner to precisely identify the protein target as well as binding sites of Gossypol.Interestingly,pretreatment of Gossypol could stop the antibody from recognizing Gossypol-binding proteins.Together,our isotope-labeled click-free probes could be used for whole-proteome profiling of lysine-targeting covalent reversible small molecules.
