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
Diabetes involves multi-organ complications that seriously threaten human life and health,and has become a major public health problem of global concern.Unfortunately,clinical management strategies for diabetic compli...Diabetes involves multi-organ complications that seriously threaten human life and health,and has become a major public health problem of global concern.Unfortunately,clinical management strategies for diabetic complications are still in their“infancy”,restricted by a limited understanding of their complex pathological mechanism.As is well established,lipid metabolism disorder is the characteristic pathological factors of diabetes,but the detailed molecular mechanisms driving the progression of multi-organ complications remain obscure.Protein S-acylation(often referred to as S-palmitoylation)is a reversible lipid modification that reversibly binds fatty acids to protein-specific cysteine(Cys)residues through palmitoyl acyl transferases(PATs,also known as DHHCs)and deacylation enzymes,which is involved in the pathological progression of a variety of complex diseases such as cancer,neurological disorders and metabolic syndrome.Notably,recent studies have shown that protein S-acylation drives the progression of diabetes and its multiple complications,and targeted intervention in the protein S-acylation process significantly alleviates the progression of diabetes and its complications,suggesting that protein S-acylation may be a common pathological link and intervention target of diabetes complications.Therefore,this review systematically comprehends the contribution of protein S-acylation to the progression of diabetes and its complications,summarizes the influence of the diabetic environment on S-acylation related enzymes,as well as providing an in-depth analysis of current drugs,measures,and challenges in targeting S-acylation.Finally,the accessibility of targeting protein S-acylation to prevent diabetes and its complications and the focus of future in-depth studies are envisioned,with a view to providing comprehensive and in-depth references and rationale for future novel strategies targeting protein S-acylation to prevent and treat diabetes and its multi-organ complications.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
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
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
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
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
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
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
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
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
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 Diabetic neuropathy(DN)is a progressive disorder with limited effective treatment options.AIM To identify potential therapeutic targets for DN by integrating plasma proteomic and transcriptomic data.METHODS...BACKGROUND Diabetic neuropathy(DN)is a progressive disorder with limited effective treatment options.AIM To identify potential therapeutic targets for DN by integrating plasma proteomic and transcriptomic data.METHODS A comprehensive analytical framework was developed to identify multi-omics biomarkers of DN.Protein-protein interaction network and Gene Ontology analyses were performed to explore the biological functions of biomarkers.Tier 1 target proteins were further analyzed.Candidate drug prediction and molecular docking studies were conducted to identify potential treatments while assessing the side effects of key target proteins.The mediation of immune cells in the association between proteins and DN was examined through two-step network Mendelian randomization(MR)analysis.RESULTS Nine DN-associated proteins were identified by analyzing protein quantitative trait loci from extensive genome-wide association study data.BTN3A1 and MICB were confirmed using MR,summary data-based MR,and colocalization analyses.Of the nine,HSPA1B,PSMB9,BTN3A1,SCGN,NOTUM,and MICB showed negative associations with DN,whereas WARS,BRD2,and CSNK2B were positive.Gene Ontology analysis indicated enrichment in inflammatory response and neuronal injury pathways.BTN3A1 and MICB were identified as Tier 1 targets.Drug prediction and molecular docking analyses indicated cyclosporin A as a potential therapeutic candidate.Two-step network MR analysis showed that MICB mediated DN through human leukocyte antigen-DR++monocytes.These integrated findings point to an immune-mediated mechanism with translational potential and nominate BTN3A1 and MICB for focused functional validation.CONCLUSION Our integrated multi-omics approach identified two promising therapeutic targets for DN,laying the groundwork for new treatment strategies and enhancing our understanding of MICB’s role in DN.展开更多
Carnosine(β-alanyl-L-histidine)is a naturally occurring endogenous peptide widely distributed in excitable tissues,such as the heart and brain.Over the years,several beneficial effects of carnosine have been discusse...Carnosine(β-alanyl-L-histidine)is a naturally occurring endogenous peptide widely distributed in excitable tissues,such as the heart and brain.Over the years,several beneficial effects of carnosine have been discussed well in scientific literature.In particular,this dipeptide is well-known for its antioxidant,anti-inflammatory,and anti-aggregation activities.It is of great interest in the context of numerous systemic and neurodegenerative diseases,besides performing important“side activities”such as metal chelation and pH-buffering.Despite a plethora of preclinical and clinical data supporting carnosine’s therapeutic potential,researchers are still searching for new pharmacological targets that better highlight carnosine’s overall multimodal mechanism of action and allow its disease-specific use.The aim of the present mini-review,after quickly summarizing the current knowledge of carnosine biological properties,is to pinpoint the role of some non-canonical factors/pathways positively modulated by this dipeptide,highlighting their perspective role as future pharmacological targets.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
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
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supported by National Natural Science Foundation of China(No.82304909)National Natural Science Foundation of China(No.82174112)Tianjin Science and Technology Innovation Base Construction(No.24ZYJDSY00280).
文摘Diabetes involves multi-organ complications that seriously threaten human life and health,and has become a major public health problem of global concern.Unfortunately,clinical management strategies for diabetic complications are still in their“infancy”,restricted by a limited understanding of their complex pathological mechanism.As is well established,lipid metabolism disorder is the characteristic pathological factors of diabetes,but the detailed molecular mechanisms driving the progression of multi-organ complications remain obscure.Protein S-acylation(often referred to as S-palmitoylation)is a reversible lipid modification that reversibly binds fatty acids to protein-specific cysteine(Cys)residues through palmitoyl acyl transferases(PATs,also known as DHHCs)and deacylation enzymes,which is involved in the pathological progression of a variety of complex diseases such as cancer,neurological disorders and metabolic syndrome.Notably,recent studies have shown that protein S-acylation drives the progression of diabetes and its multiple complications,and targeted intervention in the protein S-acylation process significantly alleviates the progression of diabetes and its complications,suggesting that protein S-acylation may be a common pathological link and intervention target of diabetes complications.Therefore,this review systematically comprehends the contribution of protein S-acylation to the progression of diabetes and its complications,summarizes the influence of the diabetic environment on S-acylation related enzymes,as well as providing an in-depth analysis of current drugs,measures,and challenges in targeting S-acylation.Finally,the accessibility of targeting protein S-acylation to prevent diabetes and its complications and the focus of future in-depth studies are envisioned,with a view to providing comprehensive and in-depth references and rationale for future novel strategies targeting protein S-acylation to prevent and treat diabetes and its multi-organ complications.
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 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.
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.
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(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.
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].
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.
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Supported by the Key Project of the Affiliated Hospital of North Sichuan Medical College,No.2023ZD008the Project of the Doctoral Initiation Fund,No.2023GC002+3 种基金Scientific Research and Development Program Project,No.2024PTZK008Sichuan Province Clinical Key Specialty Construction Project,No.2023GZZKP002Science and Technology Project of Nanchong,No.22SXQT0364Research Development Plan Project of Affiliated Hospital of North Sichuan Medical College,No.2024MPZK003.
文摘BACKGROUND Diabetic neuropathy(DN)is a progressive disorder with limited effective treatment options.AIM To identify potential therapeutic targets for DN by integrating plasma proteomic and transcriptomic data.METHODS A comprehensive analytical framework was developed to identify multi-omics biomarkers of DN.Protein-protein interaction network and Gene Ontology analyses were performed to explore the biological functions of biomarkers.Tier 1 target proteins were further analyzed.Candidate drug prediction and molecular docking studies were conducted to identify potential treatments while assessing the side effects of key target proteins.The mediation of immune cells in the association between proteins and DN was examined through two-step network Mendelian randomization(MR)analysis.RESULTS Nine DN-associated proteins were identified by analyzing protein quantitative trait loci from extensive genome-wide association study data.BTN3A1 and MICB were confirmed using MR,summary data-based MR,and colocalization analyses.Of the nine,HSPA1B,PSMB9,BTN3A1,SCGN,NOTUM,and MICB showed negative associations with DN,whereas WARS,BRD2,and CSNK2B were positive.Gene Ontology analysis indicated enrichment in inflammatory response and neuronal injury pathways.BTN3A1 and MICB were identified as Tier 1 targets.Drug prediction and molecular docking analyses indicated cyclosporin A as a potential therapeutic candidate.Two-step network MR analysis showed that MICB mediated DN through human leukocyte antigen-DR++monocytes.These integrated findings point to an immune-mediated mechanism with translational potential and nominate BTN3A1 and MICB for focused functional validation.CONCLUSION Our integrated multi-omics approach identified two promising therapeutic targets for DN,laying the groundwork for new treatment strategies and enhancing our understanding of MICB’s role in DN.
文摘Carnosine(β-alanyl-L-histidine)is a naturally occurring endogenous peptide widely distributed in excitable tissues,such as the heart and brain.Over the years,several beneficial effects of carnosine have been discussed well in scientific literature.In particular,this dipeptide is well-known for its antioxidant,anti-inflammatory,and anti-aggregation activities.It is of great interest in the context of numerous systemic and neurodegenerative diseases,besides performing important“side activities”such as metal chelation and pH-buffering.Despite a plethora of preclinical and clinical data supporting carnosine’s therapeutic potential,researchers are still searching for new pharmacological targets that better highlight carnosine’s overall multimodal mechanism of action and allow its disease-specific use.The aim of the present mini-review,after quickly summarizing the current knowledge of carnosine biological properties,is to pinpoint the role of some non-canonical factors/pathways positively modulated by this dipeptide,highlighting their perspective role as future pharmacological targets.
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.
