BACKGROUND Approximately half of all new cases of gastric cancer(GC)and related deaths occur in China.More than 80%of patients with GC are diagnosed at an advanced stage,which results in poor prognosis.Although HER2-d...BACKGROUND Approximately half of all new cases of gastric cancer(GC)and related deaths occur in China.More than 80%of patients with GC are diagnosed at an advanced stage,which results in poor prognosis.Although HER2-directed therapy and immune checkpoint inhibitors have been somewhat successful,new drugs are still needed for the treatment of GC.Notably,several gene fusion-targeted drugs have been approved by the United States Food and Drug Administration for solid tumors,including GC,such as larotrectinib for NTRK fusion-positive cancers and zenocutuzumab for NRG1 fusion-positive cancers.However,gene fusions involving targetable genes have not been well characterized in Chinese patients with GC.AIM To identify the profile of fusions involving targetable genes in Chinese patients with GC using clinical specimens and determine the distribution of patients with gene fusion variants among the molecular subtypes of GC.METHODS We retrospectively analyzed gene fusion events in tumor tissue samples from 954 Chinese patients with GC.Clinicopathological characteristics were obtained from their medical records.Genetic alterations,such as single nucleotide variants,indels,amplifications,and gene fusions,were identified using a targeted sequencing panel containing 825 genes.Fusions were validated by fluorescence in situ hybridization(FISH)using break-apart probes.The microsatellite instability(MSI)status was evaluated using MSIsensor from the targeted sequencing panel data.Tumor mutational burden(TMB)was calculated using the total number of nonsynonymous mutations divided by the total genomic targeted region.Chi-square analysis was used to determine the enrichment of gene fusions associated with the molecular subtypes of GC.RESULTS We found that 1.68%(16/954)of patients harbored 20 fusion events involving targetable genes.RARA fusions(n=5)were the most common,followed by FGFR2,BRAF,MET,FGFR3,RET,ALK,EGFR,NTRK2,and NRG1 fusions.Two of the RARA fusions,EML4-ALK(E6:E20)and EGFRSEPTIN14(E7:E10),have been identified in other tumors but not in GC.Surprisingly,18 gene fusion events were previously not reported in any cancer types.Twelve of the eighteen novel gene fusions included complete exons encoding functional domains of targetable genes,such as the tyrosine kinase domain of receptor tyrosine kinases and the DNA-and ligand-binding domains of RARA.Consistent with the results of detection using the targeted sequencing fusion panel,the results of FISH(fluorescence in situ hybridization)confirmed the rearrangement of FGFR2 and BRAF in tumors from patients 04 and 09,respectively.Genetic analysis indicated that the fusion genes were significantly enriched in patients with ERBB2 amplification(P=0.02);however,there were no significant differences between fusion-positive and fusion-negative patients in age,sex,MSI status,and TMB.CONCLUSION We characterized the landscape of fusions involving targetable genes in a Chinese GC cohort and found that 1.68%of patients with GC harbor potential targetable gene fusions,which were enriched in patients with ERBB2 amplification.Gene fusion detection may provide a potential treatment strategy for patients with GC with disease progression following standard therapy.展开更多
Hydrogen peroxide(H2 O2), as important products of oxygen metabolism, plays an important role in many biological processes, such as immune responses and cellular signal transduction. However, abnormal production of H2...Hydrogen peroxide(H2 O2), as important products of oxygen metabolism, plays an important role in many biological processes, such as immune responses and cellular signal transduction. However, abnormal production of H2 O2 can damage cellular biomolecules, which was closely associated with many diseases.Thus, it is urgent to monitor the level change of H2 O2 in living cells, particularly at subcellular levels.Toward this end, a wide variety of H2 O2 fluorescent probes have been designed, developed and applied for imaging of H2 O2 in subcellular levels. In this review, we highlight the representative cases of H2 O2 fluorescent probes with mitochondria, nuclei and lysosomes-targetable ability. The review contains organelle target strategies, structures, fluorescence behavior and biological applications of these probes.展开更多
Metastatic pancreatic cancer(MPC) is one of the most aggressive malignancies, known to be chemo-resistant and have been recently considered resistant to some targeted therapies(TT). Erlotinib combined to gemcitabine i...Metastatic pancreatic cancer(MPC) is one of the most aggressive malignancies, known to be chemo-resistant and have been recently considered resistant to some targeted therapies(TT). Erlotinib combined to gemcitabine is the only targeted therapy that showed an overall survival benefit in MPC. New targets and therapeutic approaches, based on new-TT, are actually being evaluated in MPC going from immunotherapy, epigenetics, tumor suppressor gene and oncogenes to stromal matrix regulators. We aim in this paper to present the major causes rendering MPC an untargetable malignancy and to focus on the new therapeutic modalities based on TT in MPC.展开更多
Considering that hydrogen peroxide(H2O2)plays significant roles in oxidative stress,the cellular signal transduction and essential biological process regulation,the detection and imaging of H2O2 in living systems unde...Considering that hydrogen peroxide(H2O2)plays significant roles in oxidative stress,the cellular signal transduction and essential biological process regulation,the detection and imaging of H2O2 in living systems undertakes critical responsibility.Herein,we have developed a novel two-photon fluorescence turn on probe,named as Pyp-B for mitochondria H2O2 detection in living systems.Selectivity studies show that probe Pyp-B exhibit highly sensitive response toward H2O2 than other reactive oxygen species(ROS)and reactive nitrogen species(RNS)as well as biologically relevant species.The fluorescence colocalization studies demonstrate that the probe can localize in the mitochondria solely.Furthermore,as a bio-compatibility molecule,the highly selective and sensitive of fluorescence probe Pyp-B have been confirmed by its cell imaging application of H2O2 in living A549 cells and zebrafishes under the physiological conditions.展开更多
Epithelioid sarcoma(EpS)is a high-grade malignancy of unknown histogenesis first described in 1970[1],characterized by high rates of relapse and metastasis,with 5-year survival rates of 60%-75%[2].The only Food and Dr...Epithelioid sarcoma(EpS)is a high-grade malignancy of unknown histogenesis first described in 1970[1],characterized by high rates of relapse and metastasis,with 5-year survival rates of 60%-75%[2].The only Food and Drug Administration(FDA)-approved targeted therapy,the enhancer of zeste homology 2(EZH2)inhibitor tazemetostat,achieved transient responses in only 15%of patients[2].展开更多
The cure rate for chronic neurodegenerative diseases remains low,creating an urgent need for improved intervention methods.Recent studies have shown that enhancing mitochondrial function can mitigate the effects of th...The cure rate for chronic neurodegenerative diseases remains low,creating an urgent need for improved intervention methods.Recent studies have shown that enhancing mitochondrial function can mitigate the effects of these diseases.This paper comprehensively reviews the relationship between mitochondrial dysfunction and chronic neurodegenerative diseases,aiming to uncover the potential use of targeted mitochondrial interventions as viable therapeutic options.We detail five targeted mitochondrial intervention strategies for chronic neurodegenerative diseases that act by promoting mitophagy,inhibiting mitochondrial fission,enhancing mitochondrial biogenesis,applying mitochondria-targeting antioxidants,and transplanting mitochondria.Each method has unique advantages and potential limitations,making them suitable for various therapeutic situations.Therapies that promote mitophagy or inhibit mitochondrial fission could be particularly effective in slowing disease progression,especially in the early stages.In contrast,those that enhance mitochondrial biogenesis and apply mitochondria-targeting antioxidants may offer great benefits during the middle stages of the disease by improving cellular antioxidant capacity and energy metabolism.Mitochondrial transplantation,while still experimental,holds great promise for restoring the function of damaged cells.Future research should focus on exploring the mechanisms and effects of these intervention strategies,particularly regarding their safety and efficacy in clinical settings.Additionally,the development of innovative mitochondria-targeting approaches,such as gene editing and nanotechnology,may provide new solutions for treating chronic neurodegenerative diseases.Implementing combined therapeutic strategies that integrate multiple intervention methods could also enhance treatment outcomes.展开更多
Alzheimer's disease,a progressively degenerative neurological disorder,is the most common cause of dementia in the elderly.While its precise etiology remains unclear,researchers have identified diverse pathologica...Alzheimer's disease,a progressively degenerative neurological disorder,is the most common cause of dementia in the elderly.While its precise etiology remains unclear,researchers have identified diverse pathological characteristics and molecular pathways associated with its progression.Advances in scientific research have increasingly highlighted the crucial role of non-coding RNAs in the progression of Alzheimer's disease.These non-coding RNAs regulate several biological processes critical to the advancement of the disease,offering promising potential as therapeutic targets and diagnostic biomarkers.Therefore,this review aims to investigate the underlying mechanisms of Alzheimer's disease onset,with a particular focus on microRNAs,long non-coding RNAs,and circular RNAs associated with the disease.The review elucidates the potential pathogenic processes of Alzheimer's disease and provides a detailed description of the synthesis mechanisms of the three aforementioned non-coding RNAs.It comprehensively summarizes the various non-coding RNAs that have been identified to play key regulatory roles in Alzheimer's disease,as well as how these noncoding RNAs influence the disease's progression by regulating gene expression and protein functions.For example,miR-9 targets the UBE4B gene,promoting autophagy-mediated degradation of Tau protein,thereby reducing Tau accumulation and delaying Alzheimer's disease progression.Conversely,the long non-coding RNA BACE1-AS stabilizes BACE1 mRNA,promoting the generation of amyloid-βand accelerating Alzheimer's disease development.Additionally,circular RNAs play significant roles in regulating neuroinflammatory responses.By integrating insights from these regulatory mechanisms,there is potential to discover new therapeutic targets and potential biomarkers for early detection and management of Alzheimer's disease.This review aims to enhance the understanding of the relationship between Alzheimer's disease and non-coding RNAs,potentially paving the way for early detection and novel treatment strategies.展开更多
Ufmylation is an ubiquitin-like post-translational modification characterized by the covalent binding of mature UFM1 to target proteins.Although the consequences of ufmylation on target proteins are not fully understo...Ufmylation is an ubiquitin-like post-translational modification characterized by the covalent binding of mature UFM1 to target proteins.Although the consequences of ufmylation on target proteins are not fully understood,its importance is evident from the disorders resulting from its dysfunction.Numerous case reports have established a link between biallelic loss-of-function and/or hypomorphic variants in ufmylation-related genes and a spectrum of pediatric neurodevelopmental disorders.展开更多
Neural machine interface technology is a pioneering approach that aims to address the complex challenges of neurological dysfunctions and disabilities resulting from conditions such as congenital disorders,traumatic i...Neural machine interface technology is a pioneering approach that aims to address the complex challenges of neurological dysfunctions and disabilities resulting from conditions such as congenital disorders,traumatic injuries,and neurological diseases.Neural machine interface technology establishes direct connections with the brain or peripheral nervous system to restore impaired motor,sensory,and cognitive functions,significantly improving patients'quality of life.This review analyzes the chronological development and integration of various neural machine interface technologies,including regenerative peripheral nerve interfaces,targeted muscle and sensory reinnervation,agonist–antagonist myoneural interfaces,and brain–machine interfaces.Recent advancements in flexible electronics and bioengineering have led to the development of more biocompatible and highresolution electrodes,which enhance the performance and longevity of neural machine interface technology.However,significant challenges remain,such as signal interference,fibrous tissue encapsulation,and the need for precise anatomical localization and reconstruction.The integration of advanced signal processing algorithms,particularly those utilizing artificial intelligence and machine learning,has the potential to improve the accuracy and reliability of neural signal interpretation,which will make neural machine interface technologies more intuitive and effective.These technologies have broad,impactful clinical applications,ranging from motor restoration and sensory feedback in prosthetics to neurological disorder treatment and neurorehabilitation.This review suggests that multidisciplinary collaboration will play a critical role in advancing neural machine interface technologies by combining insights from biomedical engineering,clinical surgery,and neuroengineering to develop more sophisticated and reliable interfaces.By addressing existing limitations and exploring new technological frontiers,neural machine interface technologies have the potential to revolutionize neuroprosthetics and neurorehabilitation,promising enhanced mobility,independence,and quality of life for individuals with neurological impairments.By leveraging detailed anatomical knowledge and integrating cutting-edge neuroengineering principles,researchers and clinicians can push the boundaries of what is possible and create increasingly sophisticated and long-lasting prosthetic devices that provide sustained benefits for users.展开更多
Pericytes are multi-functional mural cells of the central nervous system that cover the capillary endothelial cells. Pericytes play a vital role in nervous system development, significantly influencing the formation, ...Pericytes are multi-functional mural cells of the central nervous system that cover the capillary endothelial cells. Pericytes play a vital role in nervous system development, significantly influencing the formation, maturation, and maintenance of the central nervous system. An expanding body of studies has revealed that pericytes establish carefully regulated interactions with oligodendrocytes, microglia, and astrocytes. These communications govern numerous critical brain processes, including angiogenesis, neurovascular unit homeostasis, blood–brain barrier integrity, cerebral blood flow regulation, and immune response initiation. Glial cells and pericytes participate in dynamic and reciprocal interactions, with each influencing and adjusting the functionality of the other. Pericytes have the ability to control astrocyte polarization, trigger differentiation of oligodendrocyte precursor cells, and initiate immunological responses in microglia. Various neurological disorders that compromise the integrity of the blood–brain barrier can disrupt these communications, impair waste clearance, and hinder cerebral blood circulation, contributing to neuroinflammation. In the context of neurodegeneration, these disruptions exacerbate pathological processes, such as neuronal damage, synaptic dysfunction, and impaired tissue repair. This article explores the complex interactions between pericytes and various glial cells in both healthy and pathological states of the central nervous system. It highlights their essential roles in neurovascular function and disease progression, providing important insights that may enhance our understanding of the molecular mechanisms underlying these interactions and guide potential therapeutic strategies for neurodegenerative disorders in future research.展开更多
In recent years,exosomes have garnered extensive attention as therapeutic agents and early diagnostic markers in neurodegenerative disease research.Exosomes are small and can effectively cross the blood-brain barrier,...In recent years,exosomes have garnered extensive attention as therapeutic agents and early diagnostic markers in neurodegenerative disease research.Exosomes are small and can effectively cross the blood-brain barrier,allowing them to target deep brain lesions.Recent studies have demonstrated that exosomes derived from different cell types may exert therapeutic effects by regulating the expression of various inflammatory cytokines,mRNAs,and disease-related proteins,thereby halting the progression of neurodegenerative diseases and exhibiting beneficial effects.However,exosomes are composed of lipid bilayer membranes and lack the ability to recognize specific target cells.This limitation can lead to side effects and toxicity when they interact with non-specific cells.Growing evidence suggests that surface-modified exosomes have enhanced targeting capabilities and can be used as targeted drug-delivery vehicles that show promising results in the treatment of neurodegenerative diseases.In this review,we provide an up-to-date overview of existing research aimed at devising approaches to modify exosomes and elucidating their therapeutic potential in neurodegenerative diseases.Our findings indicate that exosomes can efficiently cross the blood-brain barrier to facilitate drug delivery and can also serve as early diagnostic markers for neurodegenerative diseases.We introduce the strategies being used to enhance exosome targeting,including genetic engineering,chemical modifications(both covalent,such as click chemistry and metabolic engineering,and non-covalent,such as polyvalent electrostatic and hydrophobic interactions,ligand-receptor binding,aptamer-based modifications,and the incorporation of CP05-anchored peptides),and nanomaterial modifications.Research into these strategies has confirmed that exosomes have significant therapeutic potential for neurodegenerative diseases.However,several challenges remain in the clinical application of exosomes.Improvements are needed in preparation,characterization,and optimization methods,as well as in reducing the adverse reactions associated with their use.Additionally,the range of applications and the safety of exosomes require further research and evaluation.展开更多
A large body of evidence has highlighted the role of non-coding RNAs in neurodevelopment and neuroinflammation.This evidence has led to increasing speculation that non-coding RNAs may be involved in the pathophysiolog...A large body of evidence has highlighted the role of non-coding RNAs in neurodevelopment and neuroinflammation.This evidence has led to increasing speculation that non-coding RNAs may be involved in the pathophysiological mechanisms underlying hydrocephalus,one of the most common neurological conditions worldwide.In this review,we first outline the basic concepts and incidence of hydrocephalus along with the limitations of existing treatments for this condition.Then,we outline the definition,classification,and biological role of non-coding RNAs.Subsequently,we analyze the roles of non-coding RNAs in the formation of hydrocephalus in detail.Specifically,we have focused on the potential significance of non-coding RNAs in the pathophysiology of hydrocephalus,including glymphatic pathways,neuroinflammatory processes,and neurological dysplasia,on the basis of the existing evidence.Lastly,we review the potential of non-coding RNAs as biomarkers of hydrocephalus and for the creation of innovative treatments.展开更多
Background:Stomach cancer(SC)is one of the most lethal malignancies worldwide due to late-stage diagnosis and limited treatment.The transcriptomic,epigenomic,and proteomic,etc.,omics datasets generated by high-through...Background:Stomach cancer(SC)is one of the most lethal malignancies worldwide due to late-stage diagnosis and limited treatment.The transcriptomic,epigenomic,and proteomic,etc.,omics datasets generated by high-throughput sequencing technology have become prominent in biomedical research,and they reveal molecular aspects of cancer diagnosis and therapy.Despite the development of advanced sequencing technology,the presence of high-dimensionality in multi-omics data makes it challenging to interpret the data.Methods:In this study,we introduce RankXLAN,an explainable ensemble-based multi-omics framework that integrates feature selection(FS),ensemble learning,bioinformatics,and in-silico validation for robust biomarker detection,potential therapeutic drug-repurposing candidates’identification,and classification of SC.To enhance the interpretability of the model,we incorporated explainable artificial intelligence(SHapley Additive exPlanations analysis),as well as accuracy,precision,F1-score,recall,cross-validation,specificity,likelihood ratio(LR)+,LR−,and Youden index results.Results:The experimental results showed that the top four FS algorithms achieved improved results when applied to the ensemble learning classification model.The proposed ensemble model produced an area under the curve(AUC)score of 0.994 for gene expression,0.97 for methylation,and 0.96 for miRNA expression data.Through the integration of bioinformatics and ML approach of the transcriptomic and epigenomic multi-omics dataset,we identified potential marker genes,namely,UBE2D2,HPCAL4,IGHA1,DPT,and FN3K.In-silico molecular docking revealed a strong binding affinity between ANKRD13C and the FDA-approved drug Everolimus(binding affinity−10.1 kcal/mol),identifying ANKRD13C as a potential therapeutic drug-repurposing target for SC.Conclusion:The proposed framework RankXLAN outperforms other existing frameworks for serum biomarker identification,therapeutic target identification,and SC classification with multi-omics datasets.展开更多
Tau plays a crucial role in several neurodegenerative diseases,collectively referred to as tauopathies.Therefore,targeting potential pathological changes in tau could enable useful therapeutic interventions.However,ta...Tau plays a crucial role in several neurodegenerative diseases,collectively referred to as tauopathies.Therefore,targeting potential pathological changes in tau could enable useful therapeutic interventions.However,tau is not an easy target because it dynamically interacts with microtubules and other cellular components,which presents a challenge for tau-targeted drugs.New cellular models could aid the development of mechanism-based tau-targeted therapies.展开更多
The etiopathogenesis of gastrointestinal diseases is varied in nature.Various etiogenic factors described are infective,inflammatory,viral,bacterial,parasitic,dietary and lifestyle change.Rare causative agents are imm...The etiopathogenesis of gastrointestinal diseases is varied in nature.Various etiogenic factors described are infective,inflammatory,viral,bacterial,parasitic,dietary and lifestyle change.Rare causative agents are immunological,and others associated as idiopathic,are undiagnosed by all possible means.Some of the rare diseases are congenital in nature,passing from the parent to the child.Many of the undiagnosed diseases are now being diagnosed as genetic and the genes have been implicated as a causative agent.There is a search for newer treatments for such diseases,which is called genomic medicine.Genomic medicine is an emerging medical discipline that involves the use of genomic information about an individual.This is used both for diagnostic as well as therapeutic decisions to improve the current health domain and pave the way for policymakers for its clinical use.In the developing era of precision medicine,genomics,epigenomics,environmental exposure,and other data would be used to more accurately guide individual diagnosis and treatment.Genomic medicine is already making an impact in the fields of oncology,pharmacology,rare,infectious and many undiagnosed diseases.It is beginning to fuel new approaches in certain medical specialties.Oncology is at the leading edge of incorporating genomics,as diagnostics for genetic and genomic markers are increasingly included in cancer screening,and to guide tailored treatment strategies.Genetics and genetic medicine have been reported to play a role in gastroenterology in several ways,including genetic testing(hereditary pancreatitis and hereditary gastrointestinal cancer syndromes).Genetic testing can also help subtype diseases,such as classifying pancreatitis as idiopathic or hereditary.Gene therapy is a promising approach for treating gastrointestinal diseases that are not effectively treated by conventional pharmaceuticals and surgeries.Gene therapy strategies include gene addition,gene editing,messenger RNA therapy,and gene silencing.Understanding genetic determinants,advances in genetics,have led to a better understanding of the genetic factors that contribute to human disease.Family-member risk stratification and genetic diagnosis can help identify family members who are at risk,which can lead to preventive treatments,lifestyle recommendations,and routine follow ups.Selecting target genes helps identify the gene targets associated with each gastrointestinal disease.Common gastrointestinal diseases associated with genetic abnormalities include-inflammatory bowel disease,gastroesophageal reflux disease,non-alcoholic fatty liver disease,and irritable bowel syndrome.With advancing tools and technology,research in the search of newer and individualized treatment,genes and genetic medicines are expected to play a significant role in human health and gastroenterology.展开更多
In this study,a fifth-degree cubature particle filter(5CPF)is proposed to address the limited estimation accuracy in traditional particle filter algorithms for bearings-only tracking(BOT).This algorithm calculates the...In this study,a fifth-degree cubature particle filter(5CPF)is proposed to address the limited estimation accuracy in traditional particle filter algorithms for bearings-only tracking(BOT).This algorithm calculates the recommended density function by introducing a fifth-degree cubature Kalman filter algorithm to guide particle sampling,which effectively alleviates the problem of particle degradation and significantly improves the estimation accuracy of the filter.However,the 5CPF algorithm exhibits high computational complexity,particularly in scenarios with a large number of particles.Therefore,we propose the extended Kalman filter(EKF)-5CPF algorithm,which employs an EKF to replace the time update step for each particle in the 5CPF.This enhances the algorithm’s real-time capability while maintaining the high precision advantage of the 5CPF algorithm.In addition,we construct bearing-only dual-station and single-motion station target tracking systems,and the filtering performances of 5CPF and EKF-5CPF algorithms under different conditions are analyzed.The results show that both the 5CPF algorithm and EKF-5CPF have strong robustness and can adapt to different noise environments.Furthermore,both algorithms significantly outperform traditional nonlinear filtering algorithms in terms of convergence speed,tracking accuracy,and overall stability.展开更多
Accurate time delay estimation of target echo signals is a critical component of underwater target localization.In active sonar systems,echo signal processing is vulnerable to the effects of reverberation and noise in...Accurate time delay estimation of target echo signals is a critical component of underwater target localization.In active sonar systems,echo signal processing is vulnerable to the effects of reverberation and noise in the maritime environment.This paper proposes a novel method for estimating target time delay using multi-bright spot echoes,assuming the target’s size and depth are known.Aiming to effectively enhance the extraction of geometric features from the target echoes and mitigate the impact of reverberation and noise,the proposed approach employs the fractional order Fourier transform-frequency sliced wavelet transform to extract multi-bright spot echoes.Using the highlighting model theory and the target size information,an observation matrix is constructed to represent multi-angle incident signals and obtain the theoretical scattered echo signals from different angles.Aiming to accurately estimate the target’s time delay,waveform similarity coefficients and mean square error values between the theoretical return signals and received signals are computed across various incident angles and time delays.Simulation results show that,compared to the conventional matched filter,the proposed algorithm reduces the relative error by 65.9%-91.5%at a signal-to noise ratio of-25 dB,and by 66.7%-88.9%at a signal-to-reverberation ratio of−10 dB.This algorithm provides a new approach for the precise localization of submerged targets in shallow water environments.展开更多
Owing to the emergence of drug resistance and high morbidity,the need for novel antiviral drugs with novel targets is highly sought after.Marine-derived compounds mostly possess potent antiviral activity and serve as ...Owing to the emergence of drug resistance and high morbidity,the need for novel antiviral drugs with novel targets is highly sought after.Marine-derived compounds mostly possess potent antiviral activity and serve as a primary source for developing novel antiviral drugs,making the rapid discovery and evaluation of marine antiviral agents particularly crucial.Thus,future research should place greater emphasis on the identification of novel antiviral targets through the combination of artificial intelligence(AI)and structural pharmacology,as well as expanding the marine resource and target databases.展开更多
Recombinant tissue plasminogen activator is commonly used for hematoma evacuation in minimally invasive surgery following intracerebral hemorrhage.However,during minimally invasive surgery,recombinant tissue plasminog...Recombinant tissue plasminogen activator is commonly used for hematoma evacuation in minimally invasive surgery following intracerebral hemorrhage.However,during minimally invasive surgery,recombinant tissue plasminogen activator may come into contact with brain tissue.Therefore,a thorough assessment of its safety is required.In this study,we established a mouse model of intracerebral hemorrhage induced by type VII collagenase.We observed that the administration of recombinant tissue plasminogen activator without hematoma aspiration significantly improved the neurological function of mice with intracerebral hemorrhage,reduced pathological damage,and lowered the levels of apoptosis and autophagy in the tissue surrounding the hematoma.In an in vitro model of intracerebral hemorrhage using primary cortical neurons induced by hemin,the administration of recombinant tissue plasminogen activator suppressed neuronal apoptosis,autophagy,and endoplasmic reticulum stress.Transcriptome sequencing analysis revealed that recombinant tissue plasminogen activator upregulated the phosphoinositide 3-kinase/RAC-alpha serine/threonine-protein kinase/mammalian target of rapamycin pathway in neurons.Moreover,the phosphoinositide 3-kinase inhibitor LY294002 abrogated the neuroprotective effects of recombinant tissue plasminogen activator in inhibiting excessive apoptosis,autophagy,and endoplasmic reticulum stress.Furthermore,to specify the domain of recombinant tissue plasminogen activator responsible for its neuroprotective effects,various inhibitors were used to target distinct domains.It has been revealed that the epidermal growth factor receptor inhibitor AG-1478 reversed the effect of recombinant tissue plasminogen activator on the phosphoinositide 3-kinase/RAC-alpha serine/threonineprotein kinase/mammalian target of rapamycin pathway.These findings suggest that recombinant tissue plasminogen activator exerts a direct neuroprotective effect on neurons following intracerebral hemorrhage,possibly through activation of the phosphoinositide 3-kinase/RAC-alpha serine/threonine-protein kinase/mammalian target of rapamycin pathway.展开更多
RAS is one of the most well-known proto-oncogenes. Its gain-of-function mutations occur in approximately 30% of all human cancers. As the most frequently mutated RAS isoform, KRAS is intensively studied in the past ye...RAS is one of the most well-known proto-oncogenes. Its gain-of-function mutations occur in approximately 30% of all human cancers. As the most frequently mutated RAS isoform, KRAS is intensively studied in the past years. Despite its well-recognized importance in cancer malignancy,continuous efforts in the past three decades failed to develop approved therapies for KRAS mutant cancer. KRAS has thus long been considered to be undruggable. Encouragingly, recent studies have aroused renewed interest in the development of KRAS inhibitors either directly towards mutant KRAS or against the crucial steps required for KRAS activation. This review summarizes the most recent progress in the exploration of KRAS-targeted anticancer strategies and hopefully provides useful insights for the field.展开更多
文摘BACKGROUND Approximately half of all new cases of gastric cancer(GC)and related deaths occur in China.More than 80%of patients with GC are diagnosed at an advanced stage,which results in poor prognosis.Although HER2-directed therapy and immune checkpoint inhibitors have been somewhat successful,new drugs are still needed for the treatment of GC.Notably,several gene fusion-targeted drugs have been approved by the United States Food and Drug Administration for solid tumors,including GC,such as larotrectinib for NTRK fusion-positive cancers and zenocutuzumab for NRG1 fusion-positive cancers.However,gene fusions involving targetable genes have not been well characterized in Chinese patients with GC.AIM To identify the profile of fusions involving targetable genes in Chinese patients with GC using clinical specimens and determine the distribution of patients with gene fusion variants among the molecular subtypes of GC.METHODS We retrospectively analyzed gene fusion events in tumor tissue samples from 954 Chinese patients with GC.Clinicopathological characteristics were obtained from their medical records.Genetic alterations,such as single nucleotide variants,indels,amplifications,and gene fusions,were identified using a targeted sequencing panel containing 825 genes.Fusions were validated by fluorescence in situ hybridization(FISH)using break-apart probes.The microsatellite instability(MSI)status was evaluated using MSIsensor from the targeted sequencing panel data.Tumor mutational burden(TMB)was calculated using the total number of nonsynonymous mutations divided by the total genomic targeted region.Chi-square analysis was used to determine the enrichment of gene fusions associated with the molecular subtypes of GC.RESULTS We found that 1.68%(16/954)of patients harbored 20 fusion events involving targetable genes.RARA fusions(n=5)were the most common,followed by FGFR2,BRAF,MET,FGFR3,RET,ALK,EGFR,NTRK2,and NRG1 fusions.Two of the RARA fusions,EML4-ALK(E6:E20)and EGFRSEPTIN14(E7:E10),have been identified in other tumors but not in GC.Surprisingly,18 gene fusion events were previously not reported in any cancer types.Twelve of the eighteen novel gene fusions included complete exons encoding functional domains of targetable genes,such as the tyrosine kinase domain of receptor tyrosine kinases and the DNA-and ligand-binding domains of RARA.Consistent with the results of detection using the targeted sequencing fusion panel,the results of FISH(fluorescence in situ hybridization)confirmed the rearrangement of FGFR2 and BRAF in tumors from patients 04 and 09,respectively.Genetic analysis indicated that the fusion genes were significantly enriched in patients with ERBB2 amplification(P=0.02);however,there were no significant differences between fusion-positive and fusion-negative patients in age,sex,MSI status,and TMB.CONCLUSION We characterized the landscape of fusions involving targetable genes in a Chinese GC cohort and found that 1.68%of patients with GC harbor potential targetable gene fusions,which were enriched in patients with ERBB2 amplification.Gene fusion detection may provide a potential treatment strategy for patients with GC with disease progression following standard therapy.
基金the National Natural Science Foundation of China (Nos. 21705102, 21775096)the Shanxi Province Science Foundation for Youths (No. 201701D221061)+1 种基金Shanxi Province Foundation for Returnees (No. 2017-026)Scientific Instrument Center of Shanxi University (No. 201512)
文摘Hydrogen peroxide(H2 O2), as important products of oxygen metabolism, plays an important role in many biological processes, such as immune responses and cellular signal transduction. However, abnormal production of H2 O2 can damage cellular biomolecules, which was closely associated with many diseases.Thus, it is urgent to monitor the level change of H2 O2 in living cells, particularly at subcellular levels.Toward this end, a wide variety of H2 O2 fluorescent probes have been designed, developed and applied for imaging of H2 O2 in subcellular levels. In this review, we highlight the representative cases of H2 O2 fluorescent probes with mitochondria, nuclei and lysosomes-targetable ability. The review contains organelle target strategies, structures, fluorescence behavior and biological applications of these probes.
文摘Metastatic pancreatic cancer(MPC) is one of the most aggressive malignancies, known to be chemo-resistant and have been recently considered resistant to some targeted therapies(TT). Erlotinib combined to gemcitabine is the only targeted therapy that showed an overall survival benefit in MPC. New targets and therapeutic approaches, based on new-TT, are actually being evaluated in MPC going from immunotherapy, epigenetics, tumor suppressor gene and oncogenes to stromal matrix regulators. We aim in this paper to present the major causes rendering MPC an untargetable malignancy and to focus on the new therapeutic modalities based on TT in MPC.
基金the financial support from the National Natural Science Foundation of China(No.81860630)the China Postdoctoral Science Foundation(No.2019M662968)GuangdongBasic and Applied Basic Research Foundation(Nos.2019A1515110356,2019A1515110877)。
文摘Considering that hydrogen peroxide(H2O2)plays significant roles in oxidative stress,the cellular signal transduction and essential biological process regulation,the detection and imaging of H2O2 in living systems undertakes critical responsibility.Herein,we have developed a novel two-photon fluorescence turn on probe,named as Pyp-B for mitochondria H2O2 detection in living systems.Selectivity studies show that probe Pyp-B exhibit highly sensitive response toward H2O2 than other reactive oxygen species(ROS)and reactive nitrogen species(RNS)as well as biologically relevant species.The fluorescence colocalization studies demonstrate that the probe can localize in the mitochondria solely.Furthermore,as a bio-compatibility molecule,the highly selective and sensitive of fluorescence probe Pyp-B have been confirmed by its cell imaging application of H2O2 in living A549 cells and zebrafishes under the physiological conditions.
基金supported by a grant from the SMARCB1 associationsupported by grants from the Dr.Rolf M.Schwiete foundation(2021-007,2022-031)+11 种基金the Matthias-Lackas foundationthe Dr.Leopold und Carmen Ellinger foundationthe Deutsche Forschungsgemeinschaft(DFG 458891500)the Cancer Grand Challenges project PROTECTthe German Cancer Aid(DKH-7011411,DKH-70114278,DKH-70115315,DKH-70115914)the Ministry of Education and Research(BMBF,SMART-CARE and HEROES-AYA)the KiKa foundation(#486)the Fight Kids Cancer foundation(FKC-NEWtargets)the KiTZ-Foundation in memory of Kirstin Diehl,the KiTZPMC twinning programthe German Cancer Consortium(DKTK,PRedictAHR)the Barbara and Wilfried Mohr foundationThe laboratory of Thomas G.P.Grünewald is co-funded by the European Union(ERC,CANCERHARAKIRI,101122595).
文摘Epithelioid sarcoma(EpS)is a high-grade malignancy of unknown histogenesis first described in 1970[1],characterized by high rates of relapse and metastasis,with 5-year survival rates of 60%-75%[2].The only Food and Drug Administration(FDA)-approved targeted therapy,the enhancer of zeste homology 2(EZH2)inhibitor tazemetostat,achieved transient responses in only 15%of patients[2].
基金partly supported by the Yan’an University Qin Chuanyuan“Scientist+Engineer”Team Special Fund,No.2023KXJ-012(to YL)Yan’an University Transformation of Scientific and Technological Achievements Fund,No.2023CGZH-001(to YL)+2 种基金College Students Innovation and Entrepreneurship Training Program,Nos.D2023158,202410719056(to XS,JM)Yan’an University Production and Cultivation Project,No.CXY202001(to YL)Kweichow Moutai Hospital Research and Talent Development Fund Project,No.MTyk2022-25(to XO)。
文摘The cure rate for chronic neurodegenerative diseases remains low,creating an urgent need for improved intervention methods.Recent studies have shown that enhancing mitochondrial function can mitigate the effects of these diseases.This paper comprehensively reviews the relationship between mitochondrial dysfunction and chronic neurodegenerative diseases,aiming to uncover the potential use of targeted mitochondrial interventions as viable therapeutic options.We detail five targeted mitochondrial intervention strategies for chronic neurodegenerative diseases that act by promoting mitophagy,inhibiting mitochondrial fission,enhancing mitochondrial biogenesis,applying mitochondria-targeting antioxidants,and transplanting mitochondria.Each method has unique advantages and potential limitations,making them suitable for various therapeutic situations.Therapies that promote mitophagy or inhibit mitochondrial fission could be particularly effective in slowing disease progression,especially in the early stages.In contrast,those that enhance mitochondrial biogenesis and apply mitochondria-targeting antioxidants may offer great benefits during the middle stages of the disease by improving cellular antioxidant capacity and energy metabolism.Mitochondrial transplantation,while still experimental,holds great promise for restoring the function of damaged cells.Future research should focus on exploring the mechanisms and effects of these intervention strategies,particularly regarding their safety and efficacy in clinical settings.Additionally,the development of innovative mitochondria-targeting approaches,such as gene editing and nanotechnology,may provide new solutions for treating chronic neurodegenerative diseases.Implementing combined therapeutic strategies that integrate multiple intervention methods could also enhance treatment outcomes.
文摘Alzheimer's disease,a progressively degenerative neurological disorder,is the most common cause of dementia in the elderly.While its precise etiology remains unclear,researchers have identified diverse pathological characteristics and molecular pathways associated with its progression.Advances in scientific research have increasingly highlighted the crucial role of non-coding RNAs in the progression of Alzheimer's disease.These non-coding RNAs regulate several biological processes critical to the advancement of the disease,offering promising potential as therapeutic targets and diagnostic biomarkers.Therefore,this review aims to investigate the underlying mechanisms of Alzheimer's disease onset,with a particular focus on microRNAs,long non-coding RNAs,and circular RNAs associated with the disease.The review elucidates the potential pathogenic processes of Alzheimer's disease and provides a detailed description of the synthesis mechanisms of the three aforementioned non-coding RNAs.It comprehensively summarizes the various non-coding RNAs that have been identified to play key regulatory roles in Alzheimer's disease,as well as how these noncoding RNAs influence the disease's progression by regulating gene expression and protein functions.For example,miR-9 targets the UBE4B gene,promoting autophagy-mediated degradation of Tau protein,thereby reducing Tau accumulation and delaying Alzheimer's disease progression.Conversely,the long non-coding RNA BACE1-AS stabilizes BACE1 mRNA,promoting the generation of amyloid-βand accelerating Alzheimer's disease development.Additionally,circular RNAs play significant roles in regulating neuroinflammatory responses.By integrating insights from these regulatory mechanisms,there is potential to discover new therapeutic targets and potential biomarkers for early detection and management of Alzheimer's disease.This review aims to enhance the understanding of the relationship between Alzheimer's disease and non-coding RNAs,potentially paving the way for early detection and novel treatment strategies.
文摘Ufmylation is an ubiquitin-like post-translational modification characterized by the covalent binding of mature UFM1 to target proteins.Although the consequences of ufmylation on target proteins are not fully understood,its importance is evident from the disorders resulting from its dysfunction.Numerous case reports have established a link between biallelic loss-of-function and/or hypomorphic variants in ufmylation-related genes and a spectrum of pediatric neurodevelopmental disorders.
基金supported in part by the National Natural Science Foundation of China,Nos.81927804(to GL),82260456(to LY),U21A20479(to LY)Science and Technology Planning Project of Shenzhen,No.JCYJ20230807140559047(to LY)+3 种基金Key-Area Research and Development Program of Guangdong Province,No.2020B0909020004(to GL)Guangdong Basic and Applied Research Foundation,No.2023A1515011478(to LY)the Science and Technology Program of Guangdong Province,No.2022A0505090007(to GL)Ministry of Science and Technology,Shenzhen,No.QN2022032013L(to LY)。
文摘Neural machine interface technology is a pioneering approach that aims to address the complex challenges of neurological dysfunctions and disabilities resulting from conditions such as congenital disorders,traumatic injuries,and neurological diseases.Neural machine interface technology establishes direct connections with the brain or peripheral nervous system to restore impaired motor,sensory,and cognitive functions,significantly improving patients'quality of life.This review analyzes the chronological development and integration of various neural machine interface technologies,including regenerative peripheral nerve interfaces,targeted muscle and sensory reinnervation,agonist–antagonist myoneural interfaces,and brain–machine interfaces.Recent advancements in flexible electronics and bioengineering have led to the development of more biocompatible and highresolution electrodes,which enhance the performance and longevity of neural machine interface technology.However,significant challenges remain,such as signal interference,fibrous tissue encapsulation,and the need for precise anatomical localization and reconstruction.The integration of advanced signal processing algorithms,particularly those utilizing artificial intelligence and machine learning,has the potential to improve the accuracy and reliability of neural signal interpretation,which will make neural machine interface technologies more intuitive and effective.These technologies have broad,impactful clinical applications,ranging from motor restoration and sensory feedback in prosthetics to neurological disorder treatment and neurorehabilitation.This review suggests that multidisciplinary collaboration will play a critical role in advancing neural machine interface technologies by combining insights from biomedical engineering,clinical surgery,and neuroengineering to develop more sophisticated and reliable interfaces.By addressing existing limitations and exploring new technological frontiers,neural machine interface technologies have the potential to revolutionize neuroprosthetics and neurorehabilitation,promising enhanced mobility,independence,and quality of life for individuals with neurological impairments.By leveraging detailed anatomical knowledge and integrating cutting-edge neuroengineering principles,researchers and clinicians can push the boundaries of what is possible and create increasingly sophisticated and long-lasting prosthetic devices that provide sustained benefits for users.
文摘Pericytes are multi-functional mural cells of the central nervous system that cover the capillary endothelial cells. Pericytes play a vital role in nervous system development, significantly influencing the formation, maturation, and maintenance of the central nervous system. An expanding body of studies has revealed that pericytes establish carefully regulated interactions with oligodendrocytes, microglia, and astrocytes. These communications govern numerous critical brain processes, including angiogenesis, neurovascular unit homeostasis, blood–brain barrier integrity, cerebral blood flow regulation, and immune response initiation. Glial cells and pericytes participate in dynamic and reciprocal interactions, with each influencing and adjusting the functionality of the other. Pericytes have the ability to control astrocyte polarization, trigger differentiation of oligodendrocyte precursor cells, and initiate immunological responses in microglia. Various neurological disorders that compromise the integrity of the blood–brain barrier can disrupt these communications, impair waste clearance, and hinder cerebral blood circulation, contributing to neuroinflammation. In the context of neurodegeneration, these disruptions exacerbate pathological processes, such as neuronal damage, synaptic dysfunction, and impaired tissue repair. This article explores the complex interactions between pericytes and various glial cells in both healthy and pathological states of the central nervous system. It highlights their essential roles in neurovascular function and disease progression, providing important insights that may enhance our understanding of the molecular mechanisms underlying these interactions and guide potential therapeutic strategies for neurodegenerative disorders in future research.
基金supported by the National Natural Science Foundation of China,No.22103055(to JG)the Natural Science Foundation of Hebei Province,No.F2024110001(to HC)Open Project of Tianjin Key Laboratory of Optoelectronic Detection Technology and System,Nos.2024LODTS215(to NL),2024LODTS216(to XS).
文摘In recent years,exosomes have garnered extensive attention as therapeutic agents and early diagnostic markers in neurodegenerative disease research.Exosomes are small and can effectively cross the blood-brain barrier,allowing them to target deep brain lesions.Recent studies have demonstrated that exosomes derived from different cell types may exert therapeutic effects by regulating the expression of various inflammatory cytokines,mRNAs,and disease-related proteins,thereby halting the progression of neurodegenerative diseases and exhibiting beneficial effects.However,exosomes are composed of lipid bilayer membranes and lack the ability to recognize specific target cells.This limitation can lead to side effects and toxicity when they interact with non-specific cells.Growing evidence suggests that surface-modified exosomes have enhanced targeting capabilities and can be used as targeted drug-delivery vehicles that show promising results in the treatment of neurodegenerative diseases.In this review,we provide an up-to-date overview of existing research aimed at devising approaches to modify exosomes and elucidating their therapeutic potential in neurodegenerative diseases.Our findings indicate that exosomes can efficiently cross the blood-brain barrier to facilitate drug delivery and can also serve as early diagnostic markers for neurodegenerative diseases.We introduce the strategies being used to enhance exosome targeting,including genetic engineering,chemical modifications(both covalent,such as click chemistry and metabolic engineering,and non-covalent,such as polyvalent electrostatic and hydrophobic interactions,ligand-receptor binding,aptamer-based modifications,and the incorporation of CP05-anchored peptides),and nanomaterial modifications.Research into these strategies has confirmed that exosomes have significant therapeutic potential for neurodegenerative diseases.However,several challenges remain in the clinical application of exosomes.Improvements are needed in preparation,characterization,and optimization methods,as well as in reducing the adverse reactions associated with their use.Additionally,the range of applications and the safety of exosomes require further research and evaluation.
基金supported by the National Natural Science Foundation of China,Nos.82171347,82371362the Natural Science Foundation of Hunan Province,No.2022JJ30971the Scientific Research Project of Hunan Provincial Health Commission of China,No.202204040024(all to GX).
文摘A large body of evidence has highlighted the role of non-coding RNAs in neurodevelopment and neuroinflammation.This evidence has led to increasing speculation that non-coding RNAs may be involved in the pathophysiological mechanisms underlying hydrocephalus,one of the most common neurological conditions worldwide.In this review,we first outline the basic concepts and incidence of hydrocephalus along with the limitations of existing treatments for this condition.Then,we outline the definition,classification,and biological role of non-coding RNAs.Subsequently,we analyze the roles of non-coding RNAs in the formation of hydrocephalus in detail.Specifically,we have focused on the potential significance of non-coding RNAs in the pathophysiology of hydrocephalus,including glymphatic pathways,neuroinflammatory processes,and neurological dysplasia,on the basis of the existing evidence.Lastly,we review the potential of non-coding RNAs as biomarkers of hydrocephalus and for the creation of innovative treatments.
基金the Deanship of Research and Graduate Studies at King Khalid University,KSA,for funding this work through the Large Research Project under grant number RGP2/164/46.
文摘Background:Stomach cancer(SC)is one of the most lethal malignancies worldwide due to late-stage diagnosis and limited treatment.The transcriptomic,epigenomic,and proteomic,etc.,omics datasets generated by high-throughput sequencing technology have become prominent in biomedical research,and they reveal molecular aspects of cancer diagnosis and therapy.Despite the development of advanced sequencing technology,the presence of high-dimensionality in multi-omics data makes it challenging to interpret the data.Methods:In this study,we introduce RankXLAN,an explainable ensemble-based multi-omics framework that integrates feature selection(FS),ensemble learning,bioinformatics,and in-silico validation for robust biomarker detection,potential therapeutic drug-repurposing candidates’identification,and classification of SC.To enhance the interpretability of the model,we incorporated explainable artificial intelligence(SHapley Additive exPlanations analysis),as well as accuracy,precision,F1-score,recall,cross-validation,specificity,likelihood ratio(LR)+,LR−,and Youden index results.Results:The experimental results showed that the top four FS algorithms achieved improved results when applied to the ensemble learning classification model.The proposed ensemble model produced an area under the curve(AUC)score of 0.994 for gene expression,0.97 for methylation,and 0.96 for miRNA expression data.Through the integration of bioinformatics and ML approach of the transcriptomic and epigenomic multi-omics dataset,we identified potential marker genes,namely,UBE2D2,HPCAL4,IGHA1,DPT,and FN3K.In-silico molecular docking revealed a strong binding affinity between ANKRD13C and the FDA-approved drug Everolimus(binding affinity−10.1 kcal/mol),identifying ANKRD13C as a potential therapeutic drug-repurposing target for SC.Conclusion:The proposed framework RankXLAN outperforms other existing frameworks for serum biomarker identification,therapeutic target identification,and SC classification with multi-omics datasets.
文摘Tau plays a crucial role in several neurodegenerative diseases,collectively referred to as tauopathies.Therefore,targeting potential pathological changes in tau could enable useful therapeutic interventions.However,tau is not an easy target because it dynamically interacts with microtubules and other cellular components,which presents a challenge for tau-targeted drugs.New cellular models could aid the development of mechanism-based tau-targeted therapies.
文摘The etiopathogenesis of gastrointestinal diseases is varied in nature.Various etiogenic factors described are infective,inflammatory,viral,bacterial,parasitic,dietary and lifestyle change.Rare causative agents are immunological,and others associated as idiopathic,are undiagnosed by all possible means.Some of the rare diseases are congenital in nature,passing from the parent to the child.Many of the undiagnosed diseases are now being diagnosed as genetic and the genes have been implicated as a causative agent.There is a search for newer treatments for such diseases,which is called genomic medicine.Genomic medicine is an emerging medical discipline that involves the use of genomic information about an individual.This is used both for diagnostic as well as therapeutic decisions to improve the current health domain and pave the way for policymakers for its clinical use.In the developing era of precision medicine,genomics,epigenomics,environmental exposure,and other data would be used to more accurately guide individual diagnosis and treatment.Genomic medicine is already making an impact in the fields of oncology,pharmacology,rare,infectious and many undiagnosed diseases.It is beginning to fuel new approaches in certain medical specialties.Oncology is at the leading edge of incorporating genomics,as diagnostics for genetic and genomic markers are increasingly included in cancer screening,and to guide tailored treatment strategies.Genetics and genetic medicine have been reported to play a role in gastroenterology in several ways,including genetic testing(hereditary pancreatitis and hereditary gastrointestinal cancer syndromes).Genetic testing can also help subtype diseases,such as classifying pancreatitis as idiopathic or hereditary.Gene therapy is a promising approach for treating gastrointestinal diseases that are not effectively treated by conventional pharmaceuticals and surgeries.Gene therapy strategies include gene addition,gene editing,messenger RNA therapy,and gene silencing.Understanding genetic determinants,advances in genetics,have led to a better understanding of the genetic factors that contribute to human disease.Family-member risk stratification and genetic diagnosis can help identify family members who are at risk,which can lead to preventive treatments,lifestyle recommendations,and routine follow ups.Selecting target genes helps identify the gene targets associated with each gastrointestinal disease.Common gastrointestinal diseases associated with genetic abnormalities include-inflammatory bowel disease,gastroesophageal reflux disease,non-alcoholic fatty liver disease,and irritable bowel syndrome.With advancing tools and technology,research in the search of newer and individualized treatment,genes and genetic medicines are expected to play a significant role in human health and gastroenterology.
基金Supported by the Guangxi Special Program for Technological Innovation Guidance(No.GuiKeAC25069006).
文摘In this study,a fifth-degree cubature particle filter(5CPF)is proposed to address the limited estimation accuracy in traditional particle filter algorithms for bearings-only tracking(BOT).This algorithm calculates the recommended density function by introducing a fifth-degree cubature Kalman filter algorithm to guide particle sampling,which effectively alleviates the problem of particle degradation and significantly improves the estimation accuracy of the filter.However,the 5CPF algorithm exhibits high computational complexity,particularly in scenarios with a large number of particles.Therefore,we propose the extended Kalman filter(EKF)-5CPF algorithm,which employs an EKF to replace the time update step for each particle in the 5CPF.This enhances the algorithm’s real-time capability while maintaining the high precision advantage of the 5CPF algorithm.In addition,we construct bearing-only dual-station and single-motion station target tracking systems,and the filtering performances of 5CPF and EKF-5CPF algorithms under different conditions are analyzed.The results show that both the 5CPF algorithm and EKF-5CPF have strong robustness and can adapt to different noise environments.Furthermore,both algorithms significantly outperform traditional nonlinear filtering algorithms in terms of convergence speed,tracking accuracy,and overall stability.
基金Supported by the State Key Laboratory of Acoustics and Marine Information Chinese Academy of Sciences(SKL A202507).
文摘Accurate time delay estimation of target echo signals is a critical component of underwater target localization.In active sonar systems,echo signal processing is vulnerable to the effects of reverberation and noise in the maritime environment.This paper proposes a novel method for estimating target time delay using multi-bright spot echoes,assuming the target’s size and depth are known.Aiming to effectively enhance the extraction of geometric features from the target echoes and mitigate the impact of reverberation and noise,the proposed approach employs the fractional order Fourier transform-frequency sliced wavelet transform to extract multi-bright spot echoes.Using the highlighting model theory and the target size information,an observation matrix is constructed to represent multi-angle incident signals and obtain the theoretical scattered echo signals from different angles.Aiming to accurately estimate the target’s time delay,waveform similarity coefficients and mean square error values between the theoretical return signals and received signals are computed across various incident angles and time delays.Simulation results show that,compared to the conventional matched filter,the proposed algorithm reduces the relative error by 65.9%-91.5%at a signal-to noise ratio of-25 dB,and by 66.7%-88.9%at a signal-to-reverberation ratio of−10 dB.This algorithm provides a new approach for the precise localization of submerged targets in shallow water environments.
文摘Owing to the emergence of drug resistance and high morbidity,the need for novel antiviral drugs with novel targets is highly sought after.Marine-derived compounds mostly possess potent antiviral activity and serve as a primary source for developing novel antiviral drugs,making the rapid discovery and evaluation of marine antiviral agents particularly crucial.Thus,future research should place greater emphasis on the identification of novel antiviral targets through the combination of artificial intelligence(AI)and structural pharmacology,as well as expanding the marine resource and target databases.
基金supported by the National Natural Science Foundation of China,Nos.92148206,82071330(both to ZT)a grant from the Major Program of Hubei Province,No.2023BAA005(to ZT)+1 种基金a grant from the Key Research and Discovery Program of Hubei Province,No.2021BCA109(to ZT)the Research Foundation of Tongji Hospital,No.2022B37(to PZ)。
文摘Recombinant tissue plasminogen activator is commonly used for hematoma evacuation in minimally invasive surgery following intracerebral hemorrhage.However,during minimally invasive surgery,recombinant tissue plasminogen activator may come into contact with brain tissue.Therefore,a thorough assessment of its safety is required.In this study,we established a mouse model of intracerebral hemorrhage induced by type VII collagenase.We observed that the administration of recombinant tissue plasminogen activator without hematoma aspiration significantly improved the neurological function of mice with intracerebral hemorrhage,reduced pathological damage,and lowered the levels of apoptosis and autophagy in the tissue surrounding the hematoma.In an in vitro model of intracerebral hemorrhage using primary cortical neurons induced by hemin,the administration of recombinant tissue plasminogen activator suppressed neuronal apoptosis,autophagy,and endoplasmic reticulum stress.Transcriptome sequencing analysis revealed that recombinant tissue plasminogen activator upregulated the phosphoinositide 3-kinase/RAC-alpha serine/threonine-protein kinase/mammalian target of rapamycin pathway in neurons.Moreover,the phosphoinositide 3-kinase inhibitor LY294002 abrogated the neuroprotective effects of recombinant tissue plasminogen activator in inhibiting excessive apoptosis,autophagy,and endoplasmic reticulum stress.Furthermore,to specify the domain of recombinant tissue plasminogen activator responsible for its neuroprotective effects,various inhibitors were used to target distinct domains.It has been revealed that the epidermal growth factor receptor inhibitor AG-1478 reversed the effect of recombinant tissue plasminogen activator on the phosphoinositide 3-kinase/RAC-alpha serine/threonineprotein kinase/mammalian target of rapamycin pathway.These findings suggest that recombinant tissue plasminogen activator exerts a direct neuroprotective effect on neurons following intracerebral hemorrhage,possibly through activation of the phosphoinositide 3-kinase/RAC-alpha serine/threonine-protein kinase/mammalian target of rapamycin pathway.
文摘RAS is one of the most well-known proto-oncogenes. Its gain-of-function mutations occur in approximately 30% of all human cancers. As the most frequently mutated RAS isoform, KRAS is intensively studied in the past years. Despite its well-recognized importance in cancer malignancy,continuous efforts in the past three decades failed to develop approved therapies for KRAS mutant cancer. KRAS has thus long been considered to be undruggable. Encouragingly, recent studies have aroused renewed interest in the development of KRAS inhibitors either directly towards mutant KRAS or against the crucial steps required for KRAS activation. This review summarizes the most recent progress in the exploration of KRAS-targeted anticancer strategies and hopefully provides useful insights for the field.
