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
The prolonged and intricate history of oncological treatments has transitioned significantly since the introduction of chemotherapy.Substantial therapeutic benefits in cancer therapy have been achieved by the integrat...The prolonged and intricate history of oncological treatments has transitioned significantly since the introduction of chemotherapy.Substantial therapeutic benefits in cancer therapy have been achieved by the integration of conventional treatments with molecular biosciences and omics technologies.Human epidermal growth factor receptor,hormone receptors,and angiogenesis factors are among the established therapies in tumor reduction and managing side effects.Novel targeted therapies like KRAS G12C,Claudin-18 isoform 2(CLDN18.2),Trophoblast cell-surface antigen 2(TROP2),and epigenetic regulators emphasize their promise in advancing precision medicine.However,in many cases,the resistance mechanisms associated with these interventions render them ineffective in carrying out their functions.The purpose of this review is to provide a comprehensive and up-to-date examination of both established and emerging drug targets and mechanisms of treatment resistance in oncology.This review seeks to elucidate recent advancements,address persisting challenges,and explore opportunities for innovative developments in cancer target research.Additionally,it explores the growing role of artificial intelligence in reshaping cancer drug discovery and development frameworks as potential avenues for future research.In conclusion,innovative approaches in oncology,supported by pharmacological research,ongoing clinical trials,molecular biosciences,and artificial intelligence,are poised to significantly transform cancer treatment.展开更多
Background:Giant cell arteritis(GCA),the most common systemic vasculitis affecting elderly individuals,currently lacks specific therapies.This study aimed to systematically identify therapeutic targets for GCA through...Background:Giant cell arteritis(GCA),the most common systemic vasculitis affecting elderly individuals,currently lacks specific therapies.This study aimed to systematically identify therapeutic targets for GCA through integration of large-scale multi-omics datasets.Methods:We constructed a multi-stage analytical framework encompassing 32 proteomic datasets(covering 2914 unique plasma proteins)and 6 transcriptomic datasets.Multi-omics integration strategies,including two-sample Mendelian randomization,colocalization analysis,and functional enrichment analysis,were employed to identify and validate causal relationships between candidate targets and GCA risk across 4 independent European-ancestry GCA cohorts.Single-cell RNA sequencing analysis of peripheral blood mononuclear cells from untreated GCA patients was performed to characterize hub gene-immune cell relationships.Results:We identified 43 plasma proteins causally associated with GCA[false discovery rate(FDR)<0.05],with 17 representing novel therapeutic targets.Through dual validation using proteome-wide association studies and transcriptome-wide association studies,we identified 13 high-confidence candidate targets with distinct tissue-specific expression patterns.Unc-51 like kinase 3(ULK3)emerged as the strongest protective factor(odds ratio=0.47,95%confidence interval:0.37–0.71)through autophagy regulation,while SLAMF7 represents an immediate drug repositioning opportunity as the target of food and drug administration-approved elotuzumab.Five targets have existing approved drugs(SLAMF7,ICAM1,IL18,IL6ST,CTSS).Single-cell analysis revealed profound disruption of hub gene-immune cell relationships in untreated GCA patients,with cell-type-specific alterations in inflammatory gene expression,and TYMP as the most critical hub gene.Conclusions:This study provides a clinically-actionable atlas of 43 potential therapeutic targets in GCA,identifying novel mechanisms including autophagy modulation and metabolic reprogramming,with immediate drug repositioning opportunities and precision medicine strategies based on tissue-specific and cell-type-specific expression patterns.These findings require experimental validation before clinical translation.展开更多
MicroRNAs(miRNAs),small non-coding RNAs ranging from 19 to 25 nucleotides in length,are key regulators of gene expression that function primarily by inhibiting the translation of target mRNAs.Recent studies have sugge...MicroRNAs(miRNAs),small non-coding RNAs ranging from 19 to 25 nucleotides in length,are key regulators of gene expression that function primarily by inhibiting the translation of target mRNAs.Recent studies have suggested that miRNAs play important roles in regulating key aspects in the pathology of Alzheimer's disease,including the modulation and accumulation of amyloid-beta and tau proteins.Moreover,miRNAs have been implicated in the regulation of neuroinflammation thro ugh various inflammatory pathways,notably the nuclear factor kappa B signaling cascade.Additional emerging evidence has shown that miRNAs regulate synaptic growth and maturation,and they perform promising roles in regulating neuronal death and development.miRNAs also offer a novel avenue for direct reprogramming of neurons,representing a promising strategy for Alzheimer's disease treatment.The regulation of miRNA biogenesis and the post-transcriptional modifications of miRNAs are critical factors in Alzheimer's disease pathology,influencing miRNA activity and disease progression.In this review,we comprehensively explore the role of different miRNAs in regulating various pathological processes associated with Alzheimer's disease,focusing primarily on four representative miRNAs:miR-9,miR-29,miR-126,and miR-146a for further exploration.We also discuss the influence of miRNA biogenesis on Alzheimer's disease,emphasizing how dysregulation of miRNA processing may contribute to the disease.Additionally,we highlight the potential of miRNAs as both diagnostic biomarke rs and therapeutic targets in Alzheimer's disease,along with promising vector delive ry strategies aimed at improving clinical outcomes.Finally,we discuss the challenges and limitations associated with the use of miRNAs in the diagnosis and treatment of Alzheimer's disease.By reviewing the current clinical applications of miRNAs as biomarkers and therapeutic agents,we aim to provide insights that will inform future research and development in this promising field.展开更多
Recently,Tian et al.published a research paper with significant breakthroughs in Cell[1].The study found that targeting the signalling pathways named Serpine2-lowdensity lipoprotein receptor-related protein 1(Lrp1)and...Recently,Tian et al.published a research paper with significant breakthroughs in Cell[1].The study found that targeting the signalling pathways named Serpine2-lowdensity lipoprotein receptor-related protein 1(Lrp1)and ectonucleoside triphosphate diphosphohydrolase 1(CD39)-adenosine A_(3)receptor(A_(3)AR)is a promising strategy for the treatment of vascular dementia.The Serpine2-Lrp1 signalling pathway primarily exerts its therapeutic effects on myelin regeneration by regulating the differentiation of oligodendrocyte precursor cells.Serpine2 is a secretory serine protease inhibitor regulates proteolytic homeostasis.It may also bind to cell surface receptors such as Lrp1 to directly activate signalling pathways.As a transmembrane glycoprotein receptor,Lrpl mediates the endocytic clearance of ligands.展开更多
To improve the effect of destroying time-sensitive target （TST）, a method of operational effectiveness evaluation is presented and some influential factors are analyzed based on the combat flow of system for destroy...To improve the effect of destroying time-sensitive target （TST）, a method of operational effectiveness evaluation is presented and some influential factors are analyzed based on the combat flow of system for destroying TST. Considering the possible operation modes of the system, a waved operation mode and a continuous operation mode are put forward at first. At the same time, some relative formulas are modified. In examples, the influential factors and operation modes are analyzed based on the system effectiveness. From simulation results, some design and operation strategies of the system for destroying time sensitive targets are concluded, which benefit to the improvement of the system effectiveness.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
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
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
Acute pancreatitis(AP)is a common but potentially devastating disease characterized at onset patho-physiologically by premature activation of digestive enzymes within the pancreas.Despite an abundance of preclinical r...Acute pancreatitis(AP)is a common but potentially devastating disease characterized at onset patho-physiologically by premature activation of digestive enzymes within the pancreas.Despite an abundance of preclinical research and,until recently,a series of disappointing clinical trials,no specific disease mod-ifying pharmacological treatment has yet been approved for this condition.Recent novel approaches to understanding the molecular pathogenesis of AP provide us with renewed optimism for translational drug discovery.Although digestive enzyme activation is the hallmark of AP,a critical mechanism that initiates AP is intracellular calcium(Ca2+)overload in pancreatic parenchymal cells,which triggers mitochondrial dysfunction,endoplasmic reticulum(ER)stress,and impairs autophagic flux.These processes are piv-otal to the disease and present a range of drug targets,associated with the inflammatory responses that drive local and systemic inflammation in AP.Progress in translation has now been made,targeting the ORAI channel with the inhibitor zegocractin(Auxora)to reduce pancreatic injury and inflammatory re-sponses in human AP.Herein we evaluated potential drug targets for the early treatment of AP,focused on intra-acinar mechanisms of injury central to the onset and severity of AP.Our analysis highlights the opportunities and progress in translating these molecular insights into clinical therapies.展开更多
Sini Decoction(SNT)is a traditional formula recognized for its efficacy in warming the spleen and stomach and dispersing cold.However,elucidating the mechanism of action of SNT remains challenging due to its complex m...Sini Decoction(SNT)is a traditional formula recognized for its efficacy in warming the spleen and stomach and dispersing cold.However,elucidating the mechanism of action of SNT remains challenging due to its complex multiple components.This study utilized a synergistic approach combining two-dimensional fluorescence difference in gel electrophoresis(2D-DIGE)-based drug affinity responsive target stability(DARTS)with label-free quantitative proteomics techniques to identify the direct and indirect protein targets of SNT in myocardial infarction.The analysis identified 590 proteins,with 30 proteins showing significant upregulation and 51 proteins showing downregulation when comparing the SNT group with the model group.Through the integration of 2D-DIGE DARTS with proteomics data and pharmacological assessments,the findings indicate that protein disulfide-isomerase A3(PDIA3)may serve as a potential protein target through which SNT provides protective effects on myocardial cells during myocardial infarction.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
Time synchronization is a prerequisite for ensuring determinism in time-sensitive networking(TSN).While time synchronization errors cannot be overlooked,pursuing minimal time errors may incur unnecessary costs.Using c...Time synchronization is a prerequisite for ensuring determinism in time-sensitive networking(TSN).While time synchronization errors cannot be overlooked,pursuing minimal time errors may incur unnecessary costs.Using complex network theory,this study proposes a hierarchy for TSN and introduces the concept of bounded time error.A coupling model between traffic scheduling and time synchronization is established,deriving functional relationships among end-to-end delay,delay jitter,gate window,and time error.These relationships illustrate that time errors can trigger jumps in delay and delay jitter.To evaluate different time errors impact on traffic scheduling performance,an end-to-end transmission experiment scheme is designed,along with the construction of a TSN test platform implementing two representative cases.Case A is a closed TSN domain scenario with pure TSN switches emulating closed factory floor network.Case B depicts remote factory interconnection where TSN domains link via non-TSN domains composed of OpenFlow switches.Results from Case A show that delay and delay jitter on a single node are most significantly affected by time errors,up to one gating cycle.End-to-end delay jitter tends to increase with the number of hops.When the ratio of time error bound to window exceeds 10%,the number of schedulable traffic flows decreases rapidly.Case B reveals that when time error is below 1μs,the number of schedulable traffic flows begins to increase significantly,approaching full schedulability at errors below 0.6μs.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
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
Elucidation of ligand-protein interactions provides new insights into the physiological functions and mechanisms of ligand molecules,enabling new ideas for the treatment of diseases,and drug discovery and development....Elucidation of ligand-protein interactions provides new insights into the physiological functions and mechanisms of ligand molecules,enabling new ideas for the treatment of diseases,and drug discovery and development.Most ligand-protein binding occurs only in specific regions of proteins.The identification of protein targets and binding regions is crucial for drug discovery and development,as well as for the in-depth study of drug-protein conformational relationships[1].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.
文摘The prolonged and intricate history of oncological treatments has transitioned significantly since the introduction of chemotherapy.Substantial therapeutic benefits in cancer therapy have been achieved by the integration of conventional treatments with molecular biosciences and omics technologies.Human epidermal growth factor receptor,hormone receptors,and angiogenesis factors are among the established therapies in tumor reduction and managing side effects.Novel targeted therapies like KRAS G12C,Claudin-18 isoform 2(CLDN18.2),Trophoblast cell-surface antigen 2(TROP2),and epigenetic regulators emphasize their promise in advancing precision medicine.However,in many cases,the resistance mechanisms associated with these interventions render them ineffective in carrying out their functions.The purpose of this review is to provide a comprehensive and up-to-date examination of both established and emerging drug targets and mechanisms of treatment resistance in oncology.This review seeks to elucidate recent advancements,address persisting challenges,and explore opportunities for innovative developments in cancer target research.Additionally,it explores the growing role of artificial intelligence in reshaping cancer drug discovery and development frameworks as potential avenues for future research.In conclusion,innovative approaches in oncology,supported by pharmacological research,ongoing clinical trials,molecular biosciences,and artificial intelligence,are poised to significantly transform cancer treatment.
基金supported by grants from the Fundamental Research Funds for the Central Universities(No.2025ZFJH03)the Central Guidance Fund for Local Science and Technology Development(No.2024ZY01054)the CAMS Innovation Fund for Medical Sciences(No.2019-I2M-5-045).
文摘Background:Giant cell arteritis(GCA),the most common systemic vasculitis affecting elderly individuals,currently lacks specific therapies.This study aimed to systematically identify therapeutic targets for GCA through integration of large-scale multi-omics datasets.Methods:We constructed a multi-stage analytical framework encompassing 32 proteomic datasets(covering 2914 unique plasma proteins)and 6 transcriptomic datasets.Multi-omics integration strategies,including two-sample Mendelian randomization,colocalization analysis,and functional enrichment analysis,were employed to identify and validate causal relationships between candidate targets and GCA risk across 4 independent European-ancestry GCA cohorts.Single-cell RNA sequencing analysis of peripheral blood mononuclear cells from untreated GCA patients was performed to characterize hub gene-immune cell relationships.Results:We identified 43 plasma proteins causally associated with GCA[false discovery rate(FDR)<0.05],with 17 representing novel therapeutic targets.Through dual validation using proteome-wide association studies and transcriptome-wide association studies,we identified 13 high-confidence candidate targets with distinct tissue-specific expression patterns.Unc-51 like kinase 3(ULK3)emerged as the strongest protective factor(odds ratio=0.47,95%confidence interval:0.37–0.71)through autophagy regulation,while SLAMF7 represents an immediate drug repositioning opportunity as the target of food and drug administration-approved elotuzumab.Five targets have existing approved drugs(SLAMF7,ICAM1,IL18,IL6ST,CTSS).Single-cell analysis revealed profound disruption of hub gene-immune cell relationships in untreated GCA patients,with cell-type-specific alterations in inflammatory gene expression,and TYMP as the most critical hub gene.Conclusions:This study provides a clinically-actionable atlas of 43 potential therapeutic targets in GCA,identifying novel mechanisms including autophagy modulation and metabolic reprogramming,with immediate drug repositioning opportunities and precision medicine strategies based on tissue-specific and cell-type-specific expression patterns.These findings require experimental validation before clinical translation.
基金National Natural Science Foundation of China,No.82405067(to YW)。
文摘MicroRNAs(miRNAs),small non-coding RNAs ranging from 19 to 25 nucleotides in length,are key regulators of gene expression that function primarily by inhibiting the translation of target mRNAs.Recent studies have suggested that miRNAs play important roles in regulating key aspects in the pathology of Alzheimer's disease,including the modulation and accumulation of amyloid-beta and tau proteins.Moreover,miRNAs have been implicated in the regulation of neuroinflammation thro ugh various inflammatory pathways,notably the nuclear factor kappa B signaling cascade.Additional emerging evidence has shown that miRNAs regulate synaptic growth and maturation,and they perform promising roles in regulating neuronal death and development.miRNAs also offer a novel avenue for direct reprogramming of neurons,representing a promising strategy for Alzheimer's disease treatment.The regulation of miRNA biogenesis and the post-transcriptional modifications of miRNAs are critical factors in Alzheimer's disease pathology,influencing miRNA activity and disease progression.In this review,we comprehensively explore the role of different miRNAs in regulating various pathological processes associated with Alzheimer's disease,focusing primarily on four representative miRNAs:miR-9,miR-29,miR-126,and miR-146a for further exploration.We also discuss the influence of miRNA biogenesis on Alzheimer's disease,emphasizing how dysregulation of miRNA processing may contribute to the disease.Additionally,we highlight the potential of miRNAs as both diagnostic biomarke rs and therapeutic targets in Alzheimer's disease,along with promising vector delive ry strategies aimed at improving clinical outcomes.Finally,we discuss the challenges and limitations associated with the use of miRNAs in the diagnosis and treatment of Alzheimer's disease.By reviewing the current clinical applications of miRNAs as biomarkers and therapeutic agents,we aim to provide insights that will inform future research and development in this promising field.
基金support from the Sichuan Science and Technology Program(2024JDHJ0043 and 2025YFHZ0121).
文摘Recently,Tian et al.published a research paper with significant breakthroughs in Cell[1].The study found that targeting the signalling pathways named Serpine2-lowdensity lipoprotein receptor-related protein 1(Lrp1)and ectonucleoside triphosphate diphosphohydrolase 1(CD39)-adenosine A_(3)receptor(A_(3)AR)is a promising strategy for the treatment of vascular dementia.The Serpine2-Lrp1 signalling pathway primarily exerts its therapeutic effects on myelin regeneration by regulating the differentiation of oligodendrocyte precursor cells.Serpine2 is a secretory serine protease inhibitor regulates proteolytic homeostasis.It may also bind to cell surface receptors such as Lrp1 to directly activate signalling pathways.As a transmembrane glycoprotein receptor,Lrpl mediates the endocytic clearance of ligands.
基金supported by the National Natural Science Foundation of China (60774064)the Aerospace Science Foundation (05D53022)the Youth for NPU Teachers Scientific and Technological Innovation Foundation (W016210)
文摘To improve the effect of destroying time-sensitive target （TST）, a method of operational effectiveness evaluation is presented and some influential factors are analyzed based on the combat flow of system for destroying TST. Considering the possible operation modes of the system, a waved operation mode and a continuous operation mode are put forward at first. At the same time, some relative formulas are modified. In examples, the influential factors and operation modes are analyzed based on the system effectiveness. From simulation results, some design and operation strategies of the system for destroying time sensitive targets are concluded, which benefit to the improvement of the system effectiveness.
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.
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.
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 grants from the National Nat-ural Science Foundation of China(82122010 and 82070659)the National High Level Hospital Clinical Research Funding(2022-PUMCH-E-003)+1 种基金the CAMS Innovation Fund for Medical Science(2022-I2M-1-004)an NIHR Senior Investigator Award。
文摘Acute pancreatitis(AP)is a common but potentially devastating disease characterized at onset patho-physiologically by premature activation of digestive enzymes within the pancreas.Despite an abundance of preclinical research and,until recently,a series of disappointing clinical trials,no specific disease mod-ifying pharmacological treatment has yet been approved for this condition.Recent novel approaches to understanding the molecular pathogenesis of AP provide us with renewed optimism for translational drug discovery.Although digestive enzyme activation is the hallmark of AP,a critical mechanism that initiates AP is intracellular calcium(Ca2+)overload in pancreatic parenchymal cells,which triggers mitochondrial dysfunction,endoplasmic reticulum(ER)stress,and impairs autophagic flux.These processes are piv-otal to the disease and present a range of drug targets,associated with the inflammatory responses that drive local and systemic inflammation in AP.Progress in translation has now been made,targeting the ORAI channel with the inhibitor zegocractin(Auxora)to reduce pancreatic injury and inflammatory re-sponses in human AP.Herein we evaluated potential drug targets for the early treatment of AP,focused on intra-acinar mechanisms of injury central to the onset and severity of AP.Our analysis highlights the opportunities and progress in translating these molecular insights into clinical therapies.
基金supported by the National Natural Science Foundation of China(Nos.82073814,82122066,and 82104328)the"Dawn"Program of the Shanghai Education Commission(No.22SG34)+1 种基金the National Key Research and Development Program of the Ministry of China(No.2022YFC2704603)Shanghai Sailing Program(No.20YF1458900).
文摘Sini Decoction(SNT)is a traditional formula recognized for its efficacy in warming the spleen and stomach and dispersing cold.However,elucidating the mechanism of action of SNT remains challenging due to its complex multiple components.This study utilized a synergistic approach combining two-dimensional fluorescence difference in gel electrophoresis(2D-DIGE)-based drug affinity responsive target stability(DARTS)with label-free quantitative proteomics techniques to identify the direct and indirect protein targets of SNT in myocardial infarction.The analysis identified 590 proteins,with 30 proteins showing significant upregulation and 51 proteins showing downregulation when comparing the SNT group with the model group.Through the integration of 2D-DIGE DARTS with proteomics data and pharmacological assessments,the findings indicate that protein disulfide-isomerase A3(PDIA3)may serve as a potential protein target through which SNT provides protective effects on myocardial cells during myocardial infarction.
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supported in part by the Science and Technology Research and Development Foundation of China Academy of Railway Sciences Corporation Limited(Grant No.2023YJ364)in part by National Key R&D Program of China(Grant No.2022YFC3803700)in part by the project of Beijing Laboratory of Advanced Information Networks.
文摘Time synchronization is a prerequisite for ensuring determinism in time-sensitive networking(TSN).While time synchronization errors cannot be overlooked,pursuing minimal time errors may incur unnecessary costs.Using complex network theory,this study proposes a hierarchy for TSN and introduces the concept of bounded time error.A coupling model between traffic scheduling and time synchronization is established,deriving functional relationships among end-to-end delay,delay jitter,gate window,and time error.These relationships illustrate that time errors can trigger jumps in delay and delay jitter.To evaluate different time errors impact on traffic scheduling performance,an end-to-end transmission experiment scheme is designed,along with the construction of a TSN test platform implementing two representative cases.Case A is a closed TSN domain scenario with pure TSN switches emulating closed factory floor network.Case B depicts remote factory interconnection where TSN domains link via non-TSN domains composed of OpenFlow switches.Results from Case A show that delay and delay jitter on a single node are most significantly affected by time errors,up to one gating cycle.End-to-end delay jitter tends to increase with the number of hops.When the ratio of time error bound to window exceeds 10%,the number of schedulable traffic flows decreases rapidly.Case B reveals that when time error is below 1μs,the number of schedulable traffic flows begins to increase significantly,approaching full schedulability at errors below 0.6μs.
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 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Elucidation of ligand-protein interactions provides new insights into the physiological functions and mechanisms of ligand molecules,enabling new ideas for the treatment of diseases,and drug discovery and development.Most ligand-protein binding occurs only in specific regions of proteins.The identification of protein targets and binding regions is crucial for drug discovery and development,as well as for the in-depth study of drug-protein conformational relationships[1].
