Transfer RNA(tRNA)-derived fragments,a new type of tRNA-derived small RNA(tsRNA),can be cleaved from tRNA by enzymes to regulate target gene expression at the transcriptional and translational levels.tsRNAs are not on...Transfer RNA(tRNA)-derived fragments,a new type of tRNA-derived small RNA(tsRNA),can be cleaved from tRNA by enzymes to regulate target gene expression at the transcriptional and translational levels.tsRNAs are not only degradation fragments but also have biological functions,including those in immune inflammation,metabolic disorders,and cell death.tsRNA dysregulation is closely associated with multiple diseases,including various cancers and acute pancreatitis(AP).AP is a common gastrointestinal disease,and its incidence increases annually.AP development is associated with tsRNAs,which regulate cell injury and induce inflammation,especially pyroptosis and ferroptosis.Notably,serum tRF36 has the potential to serve as a non-invasive diagnostic biomarker and leads to pancreatic acinar cell ferroptosis causing inflammation to promote AP.We show the characteristics of tsRNAs and their diagnostic value and function in AP,and discuss the potential opportunities and challenges of using tsRNAs in clinical applications and research.展开更多
To address the challenges of high complexity,poor real-time performance,and low detection rates for small target vehicles in existing vehicle object detection algorithms,this paper proposes a real-time lightweight arc...To address the challenges of high complexity,poor real-time performance,and low detection rates for small target vehicles in existing vehicle object detection algorithms,this paper proposes a real-time lightweight architecture based on You Only Look Once(YOLO)v5m.Firstly,a lightweight upsampling operator called Content-Aware Reassembly of Features(CARAFE)is introduced in the feature fusion layer of the network to maximize the extraction of deep-level features for small target vehicles,reducing the missed detection rate and false detection rate.Secondly,a new prediction layer for tiny targets is added,and the feature fusion network is redesigned to enhance the detection capability for small targets.Finally,this paper applies L1 regularization to train the improved network,followed by pruning and fine-tuning operations to remove redundant channels,reducing computational and parameter complexity and enhancing the detection efficiency of the network.Training is conducted on the VisDrone2019-DET dataset.The experimental results show that the proposed algorithmreduces parameters and computation by 63.8% and 65.8%,respectively.The average detection accuracy improves by 5.15%,and the detection speed reaches 47 images per second,satisfying real-time requirements.Compared with existing approaches,including YOLOv5m and classical vehicle detection algorithms,our method achieves higher accuracy and faster speed for real-time detection of small target vehicles in edge computing.展开更多
Immune checkpoint inhibitors(ICIs)are used to relieve and refuel anti-tumor immunity by blocking the interaction,transcription,and translation of co-inhibitory immune checkpoints or degrading co-inhibitory immune chec...Immune checkpoint inhibitors(ICIs)are used to relieve and refuel anti-tumor immunity by blocking the interaction,transcription,and translation of co-inhibitory immune checkpoints or degrading co-inhibitory immune checkpoints.Thousands of small molecule drugs or biological materials,especially antibody-based ICIs,are actively being studied and antibodies are currently widely used.Limitations,such as anti-tumor efficacy,poor membrane permeability,and unneglected tolerance issues of antibody-based ICIs,remain evident but are thought to be overcome by small molecule drugs.Recent structural studies have broadened the scope of candidate immune checkpoint molecules,as well as innovative chemical inhibitors.By way of comparison,small molecule drug-based ICIs represent superior oral bioavailability and favorable pharmacokinetic features.Several ongoing clinical trials are exploring the synergetic effect of ICIs and other therapeutic strategies based on multiple ICI functions,including immune regulation,anti-angiogenesis,and cell cycle regulation.In this review we summarized the current progression of small molecule ICIs and the mechanism underlying immune checkpoint proteins,which will lay the foundation for further exploration.展开更多
Addressing the challenges in detecting surface floating litter in artificial lakes,including complex environments,uneven illumination,and susceptibility to noise andweather,this paper proposes an efficient and lightwe...Addressing the challenges in detecting surface floating litter in artificial lakes,including complex environments,uneven illumination,and susceptibility to noise andweather,this paper proposes an efficient and lightweight Ghost-YOLO(You Only Look Once)v8 algorithm.The algorithmintegrates advanced attention mechanisms and a smalltarget detection head to significantly enhance detection performance and efficiency.Firstly,an SE(Squeeze-and-Excitation)mechanism is incorporated into the backbone network to fortify the extraction of resilient features and precise target localization.This mechanism models feature channel dependencies,enabling adaptive adjustment of channel importance,thereby improving recognition of floating litter targets.Secondly,a 160×160 small-target detection layer is designed in the feature fusion neck to mitigate semantic information loss due to varying target scales.This design enhances the fusion of deep and shallow semantic information,improving small target feature representation and enabling better capture and identification of tiny floating litter.Thirdly,to balance performance and efficiency,the GhostConv module replaces part of the conventional convolutions in the feature fusion neck.Additionally,a novel C2fGhost(CSPDarknet53 to 2-Stage Feature Pyramid Networks Ghost)module is introduced to further reduce network parameters.Lastly,to address the challenge of occlusion,a newloss function,WIoU(Wise Intersection over Union)v3 incorporating a flexible and non-monotonic concentration approach,is adopted to improve detection rates for surface floating litter.The outcomes of the experiments demonstrate that the Ghost-YOLO v8 model proposed in this paper performs well in the dataset Marine,significantly enhances precision and recall by 3.3 and 7.6 percentage points,respectively,in contrast with the base model,mAP@0.5 and mAP 0.5:0.95 improve by 5.3 and 4.4 percentage points and reduces the computational volume by 1.88MB,the FPS value hardly decreases,and the efficient real-time identification of floating debris on the water’s surface can be achieved costeffectively.展开更多
With the rapid development of deep learning-based detection algorithms,deep learning is widely used in the field of infrared small target detection.However,well-designed adversarial samples can fool human visual perce...With the rapid development of deep learning-based detection algorithms,deep learning is widely used in the field of infrared small target detection.However,well-designed adversarial samples can fool human visual perception,directly causing a serious decline in the detection quality of the recognition model.In this paper,an adversarial defense technology for small infrared targets is proposed to improve model robustness.The adversarial samples with strong migration can not only improve the generalization of defense technology,but also save the training cost.Therefore,this study adopts the concept of maximizing multidimensional feature distortion,applying noise to clean samples to serve as subsequent training samples.On this basis,this study proposes an inverse perturbation elimination method based on Generative Adversarial Networks(GAN)to realize the adversarial defense,and design the generator and discriminator for infrared small targets,aiming to make both of them compete with each other to continuously improve the performance of the model,find out the commonalities and differences between the adversarial samples and the original samples.Through experimental verification,our defense algorithm is not only able to cope with multiple attacks but also performs well on different recognition models compared to commonly used defense algorithms,making it a plug-and-play efficient adversarial defense technique.展开更多
In order to address the problem of high false alarm rate and low probabilities of infrared small target detection in complex low-altitude background,an infrared small target detection method based on improved weighted...In order to address the problem of high false alarm rate and low probabilities of infrared small target detection in complex low-altitude background,an infrared small target detection method based on improved weighted local contrast is proposed in this paper.First,the ratio information between the target and local background is utilized as an enhancement factor.The local contrast is calculated by incorporating the heterogeneity between the target and local background.Then,a local product weighted method is designed based on the spatial dissimilarity between target and background to further enhance target while suppressing background.Finally,the location of target is obtained by adaptive threshold segmentation.As experimental results demonstrate,the method shows superior performance in several evaluation metrics compared with six existing algorithms on different datasets containing targets such as unmanned aerial vehicles(UAV).展开更多
Detection of maneuvering small targets has always been an important yet challenging task for radar signal processing.One primary reason is that target variable motions within coherent processing interval generate ener...Detection of maneuvering small targets has always been an important yet challenging task for radar signal processing.One primary reason is that target variable motions within coherent processing interval generate energy migrations across multiple resolution bins,which severely deteriorate the parameter estimation performance.A coarse-to-fine strategy for the detection of maneuvering small targets is proposed.Integration of small points segmented coherently is performed first,and then an optimal inter-segment integration is utilized to derive the coarse estimation of the chirp rate.Sparse fractional Fourier transform(FrFT)is then employed to refine the coarse estimation at a significantly reduced computational complexity.Simulation results verify the proposed scheme that achieves an efficient and reliable maneuvering target detection with-16dB input signal-to-noise ratio(SNR),while requires no exact a priori knowledge on the motion parameters.展开更多
In order to solve the problems that the current synthetic aperture radar(SAR)image target detection method cannot adapt to targets of different sizes,and the complex image background leads to low detection accuracy,an...In order to solve the problems that the current synthetic aperture radar(SAR)image target detection method cannot adapt to targets of different sizes,and the complex image background leads to low detection accuracy,an improved SAR image small target detection method based on YOLOv7 was proposed in this study.The proposed method improved the feature extraction network by using Switchable Around Convolution(SAConv)in the backbone network to help the model capture target information at different scales,thus improving the feature extraction ability for small targets.Based on the attention mechanism,the DyHead module was embedded in the target detection head to reduce the impact of complex background,and better focus on the small targets.In addition,the NWD loss function was introduced and combined with CIoU loss.Compared to the CIoU loss function typically used in YOLOv7,the NWD loss function pays more attention to the processing of small targets,so as to further improve the detection ability of small targets.The experimental results on the HRSID dataset indicate that the proposed method achieved mAP@0.5 and mAP@0.95 scores of 93.5%and 71.5%,respectively.Compared to the baseline model,this represents an increase of 7.2%and 7.6%,respectively.The proposed method can effectively complete the task of SAR image small target detection.展开更多
BACKGROUND Liver cancer is a highly malignant tumor with significant clinical impact.Chemotherapy alone often yields suboptimal outcomes in both the short and long term,characterized by high rates of local recurrence ...BACKGROUND Liver cancer is a highly malignant tumor with significant clinical impact.Chemotherapy alone often yields suboptimal outcomes in both the short and long term,characterized by high rates of local recurrence and distant metastasis,leading to a poor long-term prognosis.AIM To evaluate the clinical efficacy of small particle drug-eluting beads-transarterial chemoembolization(DEB-TACE)combined with targeted therapy for the treatment of unresectable liver cancer.METHODS We analyzed clinical data from 74 patients with unresectable liver cancer admitted between January 2019 and December 2020.Based on the different treatment regimens administered,patients were divided into the control(36 patients receiving sorafenib alone)and joint(38 patients receiving small particle DEB-TACE combined with sorafenib)groups.We compared liver function indicators[alanine aminotransferase(ALT),aspartate aminotransferase(AST),total bilirubin(TBIL),albumin(ALB)]and serum tumor markers[alpha fetoprotein(AFP)]before and after treatment in both groups.Short-term efficacy measures[complete response(CR),partial response,progression disease,stable disease,objective response rate(ORR),and disease control rate(DCR)]were assessed post-treatment.Long-term follow-up evaluated median overall survival(OS),progression-free survival(PFS),and adverse reaction rates between the two groups.RESULTS One month post-treatment,the joint group demonstrated significantly higher rates of CR,ORR,and DCR compared to the control group(P<0.05).Three days after treatment,the joint group showed elevated levels of ALT,AST,and TBIL but reduced levels of ALB and AFP compared to the control group(P<0.05).The median OS was 18 months for the control group and 25 months for the joint group,while the median PFS was 15 months for the control group and 22 months for the joint group,with significant differences observed(log-rank:χ2=7.824,6.861,respectively;P=0.005,0.009,respectively).The incidence of adverse reactions was not significantly different between the groups(P>0.05).CONCLUSION The combination of small particle DEB-TACE and sorafenib significantly improves both short-and long-term outcomes in the treatment of unresectable liver cancer while preserving liver function.展开更多
Infrared small target detection is a common task in infrared image processing.Under limited computa⁃tional resources.Traditional methods for infrared small target detection face a trade-off between the detection rate ...Infrared small target detection is a common task in infrared image processing.Under limited computa⁃tional resources.Traditional methods for infrared small target detection face a trade-off between the detection rate and the accuracy.A fast infrared small target detection method tailored for resource-constrained conditions is pro⁃posed for the YOLOv5s model.This method introduces an additional small target detection head and replaces the original Intersection over Union(IoU)metric with Normalized Wasserstein Distance(NWD),while considering both the detection accuracy and the detection speed of infrared small targets.Experimental results demonstrate that the proposed algorithm achieves a maximum effective detection speed of 95 FPS on a 15 W TPU,while reach⁃ing a maximum effective detection accuracy of 91.9 AP@0.5,effectively improving the efficiency of infrared small target detection under resource-constrained conditions.展开更多
BACKGROUND Recent advancements in nanomedicine have highlighted the potential of exosome(Ex)-based therapies,utilizing naturally derived nanoparticles,as a novel approach to targeted cancer treatment.AIM To explore th...BACKGROUND Recent advancements in nanomedicine have highlighted the potential of exosome(Ex)-based therapies,utilizing naturally derived nanoparticles,as a novel approach to targeted cancer treatment.AIM To explore the targetability and anticancer effectiveness of small interfering peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 RNA(siPIN1)-loaded soluble a proliferation-inducing ligand(sAPRIL)-targeted Exs(designated as tEx[p])in the treatment of colon cancer models.METHODS tEx was generated by harvesting conditioned media from adipose-derived stem cells that had undergone transformation using pDisplay vectors encoding sAPRIL-binding peptide sequences.Subsequently,tEx[p]were created by incorporating PIN1 siRNA into the tEx using the Exofect kit.The therapeutic efficacy of these Exs was evaluated using both in vitro and in vivo models of colon cancer.RESULTS The tEx[p]group exhibited superior anticancer effects in comparison to other groups,including tEx,Ex[p],and Ex,demonstrated by the smallest tumor size,the slowest tumor growth rate,and the lightest weight of the excised tumors observed in the tEx[p]group(P<0.05).Moreover,analyses of the excised tumor tissues,using western blot analysis and immunohistochemical staining,revealed that tEx[p]treatment resulted in the highest increase in Ecadherin expression and the most significant reduction in the mesenchymal markers Vimentin and Snail(P<0.05),suggesting a more effective inhibition of epithelial-mesenchymal transition tEx[p],likely due to the enhanced delivery of siPIN1.CONCLUSION The use of bioengineered Exs targeting sAPRIL and containing siPIN1 demonstrated superior efficacy in inhibiting tumor growth and epithelial-mesenchymal transition,highlighting their potential as a therapeutic strategy for colon cancer.展开更多
Peripheral nerve injury is a common neurological condition that often leads to severe functional limitations and disabilities.Research on the pathogenesis of peripheral nerve injury has focused on pathological changes...Peripheral nerve injury is a common neurological condition that often leads to severe functional limitations and disabilities.Research on the pathogenesis of peripheral nerve injury has focused on pathological changes at individual injury sites,neglecting multilevel pathological analysis of the overall nervous system and target organs.This has led to restrictions on current therapeutic approaches.In this paper,we first summarize the potential mechanisms of peripheral nerve injury from a holistic perspective,covering the central nervous system,peripheral nervous system,and target organs.After peripheral nerve injury,the cortical plasticity of the brain is altered due to damage to and regeneration of peripheral nerves;changes such as neuronal apoptosis and axonal demyelination occur in the spinal cord.The nerve will undergo axonal regeneration,activation of Schwann cells,inflammatory response,and vascular system regeneration at the injury site.Corresponding damage to target organs can occur,including skeletal muscle atrophy and sensory receptor disruption.We then provide a brief review of the research advances in therapeutic approaches to peripheral nerve injury.The main current treatments are conducted passively and include physical factor rehabilitation,pharmacological treatments,cell-based therapies,and physical exercise.However,most treatments only partially address the problem and cannot complete the systematic recovery of the entire central nervous system-peripheral nervous system-target organ pathway.Therefore,we should further explore multilevel treatment options that produce effective,long-lasting results,perhaps requiring a combination of passive(traditional)and active(novel)treatment methods to stimulate rehabilitation at the central-peripheral-target organ levels to achieve better functional recovery.展开更多
Axonal remodeling is a critical aspect of ischemic brain repair processes and contributes to spontaneous functional recovery.Our previous in vitro study demonstrated that exosomes/small extracellular vesicles(sEVs)iso...Axonal remodeling is a critical aspect of ischemic brain repair processes and contributes to spontaneous functional recovery.Our previous in vitro study demonstrated that exosomes/small extracellular vesicles(sEVs)isolated from cerebral endothelial cells(CEC-sEVs)of ischemic brain promote axonal growth of embryonic cortical neurons and that microRNA 27a(miR-27a)is an elevated miRNA in ischemic CEC-sEVs.In the present study,we investigated whether normal CEC-sEVs engineered to enrich their levels of miR-27a(27a-sEVs)further enhance axonal growth and improve neurological outcomes after ischemic stroke when compared with treatment with non-engineered CEC-sEVs.27a-sEVs were isolated from the conditioned medium of healthy mouse CECs transfected with a lentiviral miR-27a expression vector.Small EVs isolated from CECs transfected with a scramble vector(Scra-sEVs)were used as a control.Adult male mice were subjected to permanent middle cerebral artery occlusion and then were randomly treated with 27a-sEVs or Scra-sEVs.An array of behavior assays was used to measure neurological function.Compared with treatment of ischemic stroke with Scra-sEVs,treatment with 27a-sEVs significantly augmented axons and spines in the peri-infarct zone and in the corticospinal tract of the spinal grey matter of the denervated side,and significantly improved neurological outcomes.In vitro studies demonstrated that CEC-sEVs carrying reduced miR-27a abolished 27a-sEV-augmented axonal growth.Ultrastructural analysis revealed that 27a-sEVs systemically administered preferentially localized to the pre-synaptic active zone,while quantitative reverse transcription-polymerase chain reaction and Western Blot analysis showed elevated miR-27a,and reduced axonal inhibitory proteins Semaphorin 6A and Ras Homolog Family Member A in the peri-infarct zone.Blockage of the Clathrin-dependent endocytosis pathway substantially reduced neuronal internalization of 27a-sEVs.Our data provide evidence that 27a-sEVs have a therapeutic effect on stroke recovery by promoting axonal remodeling and improving neurological outcomes.Our findings also suggest that suppression of axonal inhibitory proteins such as Semaphorin 6A may contribute to the beneficial effect of 27a-sEVs on axonal remodeling.展开更多
BACKGROUND Small cell lung cancer(SCLC)is the most malignant type of lung cancer.Even in the latent period and early stage of the tumor,SCLC is prone to produce distant metastases with complex and diverse clinical man...BACKGROUND Small cell lung cancer(SCLC)is the most malignant type of lung cancer.Even in the latent period and early stage of the tumor,SCLC is prone to produce distant metastases with complex and diverse clinical manifestations.SCLC is most closely related to paraneoplastic syndrome,and some cases present as paraneoplastic peripheral neuropathy(PPN).PPN in SCLC appears early,lacks specificity,and often occurs before diagnosis of the primary tumor.It is easy to be misdiagnosed as a primary disease of the nervous system,leading to missed diagnosis and delayed diagnosis and treatment.CASE SUMMARY This paper reports two cases of SCLC with limb weakness as the first symptom.The first symptoms of one patient were rash,limb weakness,and abnormal electromyography.The patient was repeatedly referred to the hospital for limb weakness and rash for>1 year,during which time,treatment with hormones and immunosuppressants did not lead to significant improvement,and the condition gradually aggravated.The patient was later diagnosed with SCLC,and the dyskinesia did not worsen as the dermatomyositis improved after antineoplastic and hormone therapy.The second case presented with limb numbness and weakness as the first symptom,but the patient did not pay attention to it.Later,the patient was diagnosed with SCLC after facial edema caused by tumor thrombus invading the vein.However,he was diagnosed with extensive SCLC and died 1 year after diagnosis.CONCLUSION The two cases had PPN and abnormal electromyography,highlighting its correlation with early clinical indicators of SCLC.展开更多
Several studies have found that transplantation of neural progenitor cells(NPCs)promotes the survival of injured neurons.However,a poor integration rate and high risk of tumorigenicity after cell transplantation limit...Several studies have found that transplantation of neural progenitor cells(NPCs)promotes the survival of injured neurons.However,a poor integration rate and high risk of tumorigenicity after cell transplantation limits their clinical application.Small extracellular vesicles(sEVs)contain bioactive molecules for neuronal protection and regeneration.Previous studies have shown that stem/progenitor cell-derived sEVs can promote neuronal survival and recovery of neurological function in neurodegenerative eye diseases and other eye diseases.In this study,we intravitreally transplanted sEVs derived from human induced pluripotent stem cells(hiPSCs)and hiPSCs-differentiated NPCs(hiPSC-NPC)in a mouse model of optic nerve crush.Our results show that these intravitreally injected sEVs were ingested by retinal cells,especially those localized in the ganglion cell layer.Treatment with hiPSC-NPC-derived sEVs mitigated optic nerve crush-induced retinal ganglion cell degeneration,and regulated the retinal microenvironment by inhibiting excessive activation of microglia.Component analysis further revealed that hiPSC-NPC derived sEVs transported neuroprotective and anti-inflammatory miRNA cargos to target cells,which had protective effects on RGCs after optic nerve injury.These findings suggest that sEVs derived from hiPSC-NPC are a promising cell-free therapeutic strategy for optic neuropathy.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
Recent advances in research on extracellular vesicles have significantly enhanced their potential as therapeutic agents for neurological diseases.Owing to their therapeutic properties and ability to cross the blood–b...Recent advances in research on extracellular vesicles have significantly enhanced their potential as therapeutic agents for neurological diseases.Owing to their therapeutic properties and ability to cross the blood–brain barrier,extracellular vesicles are recognized as promising drug delivery vehicles for various neurological conditions,including ischemic stroke,traumatic brain injury,neurodegenerative diseases,glioma,and psychosis.However,the clinical application of natural extracellular vesicles is hindered by their limited targeting ability and short clearance from the body.To address these limitations,multiple engineering strategies have been developed to enhance the targeting capabilities of extracellular vesicles,thereby enabling the delivery of therapeutic contents to specific tissues or cells.Therefore,this review aims to highlight the latest advancements in natural and targeting-engineered extracellular vesicles,exploring their applications in treating traumatic brain injury,ischemic stroke,Parkinson's disease,Alzheimer's disease,amyotrophic lateral sclerosis,glioma,and psychosis.Additionally,we summarized recent clinical trials involving extracellular vesicles and discussed the challenges and future prospects of using targeting-engineered extracellular vesicles for drug delivery in treating neurological diseases.This review offers new insights for developing highly targeted therapies in this field.展开更多
The process of neurite outgrowth and branching is a crucial aspect of neuronal development and regeneration.Axons and dendrites,sometimes referred to as neurites,are extensions of a neuron's cellular body that are...The process of neurite outgrowth and branching is a crucial aspect of neuronal development and regeneration.Axons and dendrites,sometimes referred to as neurites,are extensions of a neuron's cellular body that are used to start networks.Here we explored the effects of diethyl(3,4-dihydroxyphenethylamino)(quinolin-4-yl)methylphosphonate(DDQ)on neurite developmental features in HT22 neuronal cells.In this work,we examined the protective effects of DDQ on neuronal processes and synaptic outgrowth in differentiated HT22cells expressing mutant Tau(mTau)cDNA.To investigate DDQ chara cteristics,cell viability,biochemical,molecular,western blotting,and immunocytochemistry were used.Neurite outgrowth is evaluated through the segmentation and measurement of neural processes.These neural processes can be seen and measured with a fluorescence microscope by manually tracing and measuring the length of the neurite growth.These neuronal processes can be observed and quantified with a fluorescent microscope by manually tracing and measuring the length of the neuronal HT22.DDQ-treated mTau-HT22 cells(HT22 cells transfected with cDNA mutant Tau)were seen to display increased levels of synaptophysin,MAP-2,andβ-tubulin.Additionally,we confirmed and noted reduced levels of both total and p-Tau,as well as elevated levels of microtubule-associated protein 2,β-tubulin,synaptophysin,vesicular acetylcholine transporter,and the mitochondrial biogenesis protein-pe roxisome prolife rator-activated receptor-gamma coactivator-1α.In mTa u-expressed HT22 neurons,we observed DDQ enhanced the neurite characteristics and improved neurite development through increased synaptic outgrowth.Our findings conclude that mTa u-HT22(Alzheimer's disease)cells treated with DDQ have functional neurite developmental chara cteristics.The key finding is that,in mTa u-HT22 cells,DDQ preserves neuronal structure and may even enhance nerve development function with mTa u inhibition.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
基金Supported by the Central South University Innovation-Driven Research Programme,No.2023CXQD075。
文摘Transfer RNA(tRNA)-derived fragments,a new type of tRNA-derived small RNA(tsRNA),can be cleaved from tRNA by enzymes to regulate target gene expression at the transcriptional and translational levels.tsRNAs are not only degradation fragments but also have biological functions,including those in immune inflammation,metabolic disorders,and cell death.tsRNA dysregulation is closely associated with multiple diseases,including various cancers and acute pancreatitis(AP).AP is a common gastrointestinal disease,and its incidence increases annually.AP development is associated with tsRNAs,which regulate cell injury and induce inflammation,especially pyroptosis and ferroptosis.Notably,serum tRF36 has the potential to serve as a non-invasive diagnostic biomarker and leads to pancreatic acinar cell ferroptosis causing inflammation to promote AP.We show the characteristics of tsRNAs and their diagnostic value and function in AP,and discuss the potential opportunities and challenges of using tsRNAs in clinical applications and research.
基金funded by the General Project of Key Research and Develop-ment Plan of Shaanxi Province(No.2022NY-087).
文摘To address the challenges of high complexity,poor real-time performance,and low detection rates for small target vehicles in existing vehicle object detection algorithms,this paper proposes a real-time lightweight architecture based on You Only Look Once(YOLO)v5m.Firstly,a lightweight upsampling operator called Content-Aware Reassembly of Features(CARAFE)is introduced in the feature fusion layer of the network to maximize the extraction of deep-level features for small target vehicles,reducing the missed detection rate and false detection rate.Secondly,a new prediction layer for tiny targets is added,and the feature fusion network is redesigned to enhance the detection capability for small targets.Finally,this paper applies L1 regularization to train the improved network,followed by pruning and fine-tuning operations to remove redundant channels,reducing computational and parameter complexity and enhancing the detection efficiency of the network.Training is conducted on the VisDrone2019-DET dataset.The experimental results show that the proposed algorithmreduces parameters and computation by 63.8% and 65.8%,respectively.The average detection accuracy improves by 5.15%,and the detection speed reaches 47 images per second,satisfying real-time requirements.Compared with existing approaches,including YOLOv5m and classical vehicle detection algorithms,our method achieves higher accuracy and faster speed for real-time detection of small target vehicles in edge computing.
基金supported by the National Natural Science Foundation of China(Grant Nos.82203539 and 92259102)Provincial Cooperation Project of Science and Technology Department of Sichuan Province(Grant No.2023YFSY0043)the National Key Research and Development Program of China(Grant No.2023YFC3402100).
文摘Immune checkpoint inhibitors(ICIs)are used to relieve and refuel anti-tumor immunity by blocking the interaction,transcription,and translation of co-inhibitory immune checkpoints or degrading co-inhibitory immune checkpoints.Thousands of small molecule drugs or biological materials,especially antibody-based ICIs,are actively being studied and antibodies are currently widely used.Limitations,such as anti-tumor efficacy,poor membrane permeability,and unneglected tolerance issues of antibody-based ICIs,remain evident but are thought to be overcome by small molecule drugs.Recent structural studies have broadened the scope of candidate immune checkpoint molecules,as well as innovative chemical inhibitors.By way of comparison,small molecule drug-based ICIs represent superior oral bioavailability and favorable pharmacokinetic features.Several ongoing clinical trials are exploring the synergetic effect of ICIs and other therapeutic strategies based on multiple ICI functions,including immune regulation,anti-angiogenesis,and cell cycle regulation.In this review we summarized the current progression of small molecule ICIs and the mechanism underlying immune checkpoint proteins,which will lay the foundation for further exploration.
基金Supported by the fund of the Henan Province Science and Technology Research Project(No.242102210213).
文摘Addressing the challenges in detecting surface floating litter in artificial lakes,including complex environments,uneven illumination,and susceptibility to noise andweather,this paper proposes an efficient and lightweight Ghost-YOLO(You Only Look Once)v8 algorithm.The algorithmintegrates advanced attention mechanisms and a smalltarget detection head to significantly enhance detection performance and efficiency.Firstly,an SE(Squeeze-and-Excitation)mechanism is incorporated into the backbone network to fortify the extraction of resilient features and precise target localization.This mechanism models feature channel dependencies,enabling adaptive adjustment of channel importance,thereby improving recognition of floating litter targets.Secondly,a 160×160 small-target detection layer is designed in the feature fusion neck to mitigate semantic information loss due to varying target scales.This design enhances the fusion of deep and shallow semantic information,improving small target feature representation and enabling better capture and identification of tiny floating litter.Thirdly,to balance performance and efficiency,the GhostConv module replaces part of the conventional convolutions in the feature fusion neck.Additionally,a novel C2fGhost(CSPDarknet53 to 2-Stage Feature Pyramid Networks Ghost)module is introduced to further reduce network parameters.Lastly,to address the challenge of occlusion,a newloss function,WIoU(Wise Intersection over Union)v3 incorporating a flexible and non-monotonic concentration approach,is adopted to improve detection rates for surface floating litter.The outcomes of the experiments demonstrate that the Ghost-YOLO v8 model proposed in this paper performs well in the dataset Marine,significantly enhances precision and recall by 3.3 and 7.6 percentage points,respectively,in contrast with the base model,mAP@0.5 and mAP 0.5:0.95 improve by 5.3 and 4.4 percentage points and reduces the computational volume by 1.88MB,the FPS value hardly decreases,and the efficient real-time identification of floating debris on the water’s surface can be achieved costeffectively.
基金supported in part by the National Natural Science Foundation of China under Grant 62073164the Shanghai Aerospace Science and Technology Innovation Foundation under Grant SAST2022-013.
文摘With the rapid development of deep learning-based detection algorithms,deep learning is widely used in the field of infrared small target detection.However,well-designed adversarial samples can fool human visual perception,directly causing a serious decline in the detection quality of the recognition model.In this paper,an adversarial defense technology for small infrared targets is proposed to improve model robustness.The adversarial samples with strong migration can not only improve the generalization of defense technology,but also save the training cost.Therefore,this study adopts the concept of maximizing multidimensional feature distortion,applying noise to clean samples to serve as subsequent training samples.On this basis,this study proposes an inverse perturbation elimination method based on Generative Adversarial Networks(GAN)to realize the adversarial defense,and design the generator and discriminator for infrared small targets,aiming to make both of them compete with each other to continuously improve the performance of the model,find out the commonalities and differences between the adversarial samples and the original samples.Through experimental verification,our defense algorithm is not only able to cope with multiple attacks but also performs well on different recognition models compared to commonly used defense algorithms,making it a plug-and-play efficient adversarial defense technique.
基金supported by the National Natural Science Foundation of China (No.U1833203),the National Natural Science Foundation of China (No.62301036)the Aviation Science Foundation (No.2020Z019055001)China Postdoctoral Science Foundation Funded Project (No.2022M720446)。
文摘In order to address the problem of high false alarm rate and low probabilities of infrared small target detection in complex low-altitude background,an infrared small target detection method based on improved weighted local contrast is proposed in this paper.First,the ratio information between the target and local background is utilized as an enhancement factor.The local contrast is calculated by incorporating the heterogeneity between the target and local background.Then,a local product weighted method is designed based on the spatial dissimilarity between target and background to further enhance target while suppressing background.Finally,the location of target is obtained by adaptive threshold segmentation.As experimental results demonstrate,the method shows superior performance in several evaluation metrics compared with six existing algorithms on different datasets containing targets such as unmanned aerial vehicles(UAV).
基金supported in part by the National Natural Science Foundation of China (Nos.62171029,61931015,U1833203)Natural Science Foundation of Beijing Municipality (No.4172052)supported in part by the Basic Research Program of Jiangsu Province (No.SBK2019042353)。
文摘Detection of maneuvering small targets has always been an important yet challenging task for radar signal processing.One primary reason is that target variable motions within coherent processing interval generate energy migrations across multiple resolution bins,which severely deteriorate the parameter estimation performance.A coarse-to-fine strategy for the detection of maneuvering small targets is proposed.Integration of small points segmented coherently is performed first,and then an optimal inter-segment integration is utilized to derive the coarse estimation of the chirp rate.Sparse fractional Fourier transform(FrFT)is then employed to refine the coarse estimation at a significantly reduced computational complexity.Simulation results verify the proposed scheme that achieves an efficient and reliable maneuvering target detection with-16dB input signal-to-noise ratio(SNR),while requires no exact a priori knowledge on the motion parameters.
文摘In order to solve the problems that the current synthetic aperture radar(SAR)image target detection method cannot adapt to targets of different sizes,and the complex image background leads to low detection accuracy,an improved SAR image small target detection method based on YOLOv7 was proposed in this study.The proposed method improved the feature extraction network by using Switchable Around Convolution(SAConv)in the backbone network to help the model capture target information at different scales,thus improving the feature extraction ability for small targets.Based on the attention mechanism,the DyHead module was embedded in the target detection head to reduce the impact of complex background,and better focus on the small targets.In addition,the NWD loss function was introduced and combined with CIoU loss.Compared to the CIoU loss function typically used in YOLOv7,the NWD loss function pays more attention to the processing of small targets,so as to further improve the detection ability of small targets.The experimental results on the HRSID dataset indicate that the proposed method achieved mAP@0.5 and mAP@0.95 scores of 93.5%and 71.5%,respectively.Compared to the baseline model,this represents an increase of 7.2%and 7.6%,respectively.The proposed method can effectively complete the task of SAR image small target detection.
文摘BACKGROUND Liver cancer is a highly malignant tumor with significant clinical impact.Chemotherapy alone often yields suboptimal outcomes in both the short and long term,characterized by high rates of local recurrence and distant metastasis,leading to a poor long-term prognosis.AIM To evaluate the clinical efficacy of small particle drug-eluting beads-transarterial chemoembolization(DEB-TACE)combined with targeted therapy for the treatment of unresectable liver cancer.METHODS We analyzed clinical data from 74 patients with unresectable liver cancer admitted between January 2019 and December 2020.Based on the different treatment regimens administered,patients were divided into the control(36 patients receiving sorafenib alone)and joint(38 patients receiving small particle DEB-TACE combined with sorafenib)groups.We compared liver function indicators[alanine aminotransferase(ALT),aspartate aminotransferase(AST),total bilirubin(TBIL),albumin(ALB)]and serum tumor markers[alpha fetoprotein(AFP)]before and after treatment in both groups.Short-term efficacy measures[complete response(CR),partial response,progression disease,stable disease,objective response rate(ORR),and disease control rate(DCR)]were assessed post-treatment.Long-term follow-up evaluated median overall survival(OS),progression-free survival(PFS),and adverse reaction rates between the two groups.RESULTS One month post-treatment,the joint group demonstrated significantly higher rates of CR,ORR,and DCR compared to the control group(P<0.05).Three days after treatment,the joint group showed elevated levels of ALT,AST,and TBIL but reduced levels of ALB and AFP compared to the control group(P<0.05).The median OS was 18 months for the control group and 25 months for the joint group,while the median PFS was 15 months for the control group and 22 months for the joint group,with significant differences observed(log-rank:χ2=7.824,6.861,respectively;P=0.005,0.009,respectively).The incidence of adverse reactions was not significantly different between the groups(P>0.05).CONCLUSION The combination of small particle DEB-TACE and sorafenib significantly improves both short-and long-term outcomes in the treatment of unresectable liver cancer while preserving liver function.
文摘Infrared small target detection is a common task in infrared image processing.Under limited computa⁃tional resources.Traditional methods for infrared small target detection face a trade-off between the detection rate and the accuracy.A fast infrared small target detection method tailored for resource-constrained conditions is pro⁃posed for the YOLOv5s model.This method introduces an additional small target detection head and replaces the original Intersection over Union(IoU)metric with Normalized Wasserstein Distance(NWD),while considering both the detection accuracy and the detection speed of infrared small targets.Experimental results demonstrate that the proposed algorithm achieves a maximum effective detection speed of 95 FPS on a 15 W TPU,while reach⁃ing a maximum effective detection accuracy of 91.9 AP@0.5,effectively improving the efficiency of infrared small target detection under resource-constrained conditions.
基金Supported by the National Research Foundation of Korea,No.NRF-2018R1D1A1B07047144.
文摘BACKGROUND Recent advancements in nanomedicine have highlighted the potential of exosome(Ex)-based therapies,utilizing naturally derived nanoparticles,as a novel approach to targeted cancer treatment.AIM To explore the targetability and anticancer effectiveness of small interfering peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 RNA(siPIN1)-loaded soluble a proliferation-inducing ligand(sAPRIL)-targeted Exs(designated as tEx[p])in the treatment of colon cancer models.METHODS tEx was generated by harvesting conditioned media from adipose-derived stem cells that had undergone transformation using pDisplay vectors encoding sAPRIL-binding peptide sequences.Subsequently,tEx[p]were created by incorporating PIN1 siRNA into the tEx using the Exofect kit.The therapeutic efficacy of these Exs was evaluated using both in vitro and in vivo models of colon cancer.RESULTS The tEx[p]group exhibited superior anticancer effects in comparison to other groups,including tEx,Ex[p],and Ex,demonstrated by the smallest tumor size,the slowest tumor growth rate,and the lightest weight of the excised tumors observed in the tEx[p]group(P<0.05).Moreover,analyses of the excised tumor tissues,using western blot analysis and immunohistochemical staining,revealed that tEx[p]treatment resulted in the highest increase in Ecadherin expression and the most significant reduction in the mesenchymal markers Vimentin and Snail(P<0.05),suggesting a more effective inhibition of epithelial-mesenchymal transition tEx[p],likely due to the enhanced delivery of siPIN1.CONCLUSION The use of bioengineered Exs targeting sAPRIL and containing siPIN1 demonstrated superior efficacy in inhibiting tumor growth and epithelial-mesenchymal transition,highlighting their potential as a therapeutic strategy for colon cancer.
基金supported by grants from the Natural Science Foundation of Tianjin(General Program),Nos.23JCYBJC01390(to RL),22JCYBJC00220(to XC),and 22JCYBJC00210(to QL).
文摘Peripheral nerve injury is a common neurological condition that often leads to severe functional limitations and disabilities.Research on the pathogenesis of peripheral nerve injury has focused on pathological changes at individual injury sites,neglecting multilevel pathological analysis of the overall nervous system and target organs.This has led to restrictions on current therapeutic approaches.In this paper,we first summarize the potential mechanisms of peripheral nerve injury from a holistic perspective,covering the central nervous system,peripheral nervous system,and target organs.After peripheral nerve injury,the cortical plasticity of the brain is altered due to damage to and regeneration of peripheral nerves;changes such as neuronal apoptosis and axonal demyelination occur in the spinal cord.The nerve will undergo axonal regeneration,activation of Schwann cells,inflammatory response,and vascular system regeneration at the injury site.Corresponding damage to target organs can occur,including skeletal muscle atrophy and sensory receptor disruption.We then provide a brief review of the research advances in therapeutic approaches to peripheral nerve injury.The main current treatments are conducted passively and include physical factor rehabilitation,pharmacological treatments,cell-based therapies,and physical exercise.However,most treatments only partially address the problem and cannot complete the systematic recovery of the entire central nervous system-peripheral nervous system-target organ pathway.Therefore,we should further explore multilevel treatment options that produce effective,long-lasting results,perhaps requiring a combination of passive(traditional)and active(novel)treatment methods to stimulate rehabilitation at the central-peripheral-target organ levels to achieve better functional recovery.
基金supported by the NIH grants,R01 NS111801(to ZGZ)American Heart Association 16SDG29860003(to YZ)。
文摘Axonal remodeling is a critical aspect of ischemic brain repair processes and contributes to spontaneous functional recovery.Our previous in vitro study demonstrated that exosomes/small extracellular vesicles(sEVs)isolated from cerebral endothelial cells(CEC-sEVs)of ischemic brain promote axonal growth of embryonic cortical neurons and that microRNA 27a(miR-27a)is an elevated miRNA in ischemic CEC-sEVs.In the present study,we investigated whether normal CEC-sEVs engineered to enrich their levels of miR-27a(27a-sEVs)further enhance axonal growth and improve neurological outcomes after ischemic stroke when compared with treatment with non-engineered CEC-sEVs.27a-sEVs were isolated from the conditioned medium of healthy mouse CECs transfected with a lentiviral miR-27a expression vector.Small EVs isolated from CECs transfected with a scramble vector(Scra-sEVs)were used as a control.Adult male mice were subjected to permanent middle cerebral artery occlusion and then were randomly treated with 27a-sEVs or Scra-sEVs.An array of behavior assays was used to measure neurological function.Compared with treatment of ischemic stroke with Scra-sEVs,treatment with 27a-sEVs significantly augmented axons and spines in the peri-infarct zone and in the corticospinal tract of the spinal grey matter of the denervated side,and significantly improved neurological outcomes.In vitro studies demonstrated that CEC-sEVs carrying reduced miR-27a abolished 27a-sEV-augmented axonal growth.Ultrastructural analysis revealed that 27a-sEVs systemically administered preferentially localized to the pre-synaptic active zone,while quantitative reverse transcription-polymerase chain reaction and Western Blot analysis showed elevated miR-27a,and reduced axonal inhibitory proteins Semaphorin 6A and Ras Homolog Family Member A in the peri-infarct zone.Blockage of the Clathrin-dependent endocytosis pathway substantially reduced neuronal internalization of 27a-sEVs.Our data provide evidence that 27a-sEVs have a therapeutic effect on stroke recovery by promoting axonal remodeling and improving neurological outcomes.Our findings also suggest that suppression of axonal inhibitory proteins such as Semaphorin 6A may contribute to the beneficial effect of 27a-sEVs on axonal remodeling.
基金Supported by Science and Technology Plan Project of Jiaxing,No.2021AD30044Supporting Discipline of Neurology in Jiaxing,No.2023-ZC-006Affiliated Hospital of Jiaxing University,No.2020-QMX-16.
文摘BACKGROUND Small cell lung cancer(SCLC)is the most malignant type of lung cancer.Even in the latent period and early stage of the tumor,SCLC is prone to produce distant metastases with complex and diverse clinical manifestations.SCLC is most closely related to paraneoplastic syndrome,and some cases present as paraneoplastic peripheral neuropathy(PPN).PPN in SCLC appears early,lacks specificity,and often occurs before diagnosis of the primary tumor.It is easy to be misdiagnosed as a primary disease of the nervous system,leading to missed diagnosis and delayed diagnosis and treatment.CASE SUMMARY This paper reports two cases of SCLC with limb weakness as the first symptom.The first symptoms of one patient were rash,limb weakness,and abnormal electromyography.The patient was repeatedly referred to the hospital for limb weakness and rash for>1 year,during which time,treatment with hormones and immunosuppressants did not lead to significant improvement,and the condition gradually aggravated.The patient was later diagnosed with SCLC,and the dyskinesia did not worsen as the dermatomyositis improved after antineoplastic and hormone therapy.The second case presented with limb numbness and weakness as the first symptom,but the patient did not pay attention to it.Later,the patient was diagnosed with SCLC after facial edema caused by tumor thrombus invading the vein.However,he was diagnosed with extensive SCLC and died 1 year after diagnosis.CONCLUSION The two cases had PPN and abnormal electromyography,highlighting its correlation with early clinical indicators of SCLC.
基金supported by the National Natural Science Foundation of China,No.82271114the Natural Science Foundation of Zhejiang Province of China,No.LZ22H120001(both to ZLC).
文摘Several studies have found that transplantation of neural progenitor cells(NPCs)promotes the survival of injured neurons.However,a poor integration rate and high risk of tumorigenicity after cell transplantation limits their clinical application.Small extracellular vesicles(sEVs)contain bioactive molecules for neuronal protection and regeneration.Previous studies have shown that stem/progenitor cell-derived sEVs can promote neuronal survival and recovery of neurological function in neurodegenerative eye diseases and other eye diseases.In this study,we intravitreally transplanted sEVs derived from human induced pluripotent stem cells(hiPSCs)and hiPSCs-differentiated NPCs(hiPSC-NPC)in a mouse model of optic nerve crush.Our results show that these intravitreally injected sEVs were ingested by retinal cells,especially those localized in the ganglion cell layer.Treatment with hiPSC-NPC-derived sEVs mitigated optic nerve crush-induced retinal ganglion cell degeneration,and regulated the retinal microenvironment by inhibiting excessive activation of microglia.Component analysis further revealed that hiPSC-NPC derived sEVs transported neuroprotective and anti-inflammatory miRNA cargos to target cells,which had protective effects on RGCs after optic nerve injury.These findings suggest that sEVs derived from hiPSC-NPC are a promising cell-free therapeutic strategy for optic neuropathy.
基金supported by the Natural Science Foundation of Fujian Province,No.2021J02035(to WX).
文摘Regulated cell death is a form of cell death that is actively controlled by biomolecules.Several studies have shown that regulated cell death plays a key role after spinal cord injury.Pyroptosis and ferroptosis are newly discovered types of regulated cell deaths that have been shown to exacerbate inflammation and lead to cell death in damaged spinal cords.Autophagy,a complex form of cell death that is interconnected with various regulated cell death mechanisms,has garnered significant attention in the study of spinal cord injury.This injury triggers not only cell death but also cellular survival responses.Multiple signaling pathways play pivotal roles in influencing the processes of both deterioration and repair in spinal cord injury by regulating pyroptosis,ferroptosis,and autophagy.Therefore,this review aims to comprehensively examine the mechanisms underlying regulated cell deaths,the signaling pathways that modulate these mechanisms,and the potential therapeutic targets for spinal cord injury.Our analysis suggests that targeting the common regulatory signaling pathways of different regulated cell deaths could be a promising strategy to promote cell survival and enhance the repair of spinal cord injury.Moreover,a holistic approach that incorporates multiple regulated cell deaths and their regulatory pathways presents a promising multi-target therapeutic strategy for the management of spinal cord injury.
基金supported by the National Natural Science Foundation of China,Nos.82171363,82371381(to PL),82171458(to XJ)Key Research and Development Project of Shaa nxi Province,Nos.2024SF-YBXM-404(to KY)。
文摘Recent advances in research on extracellular vesicles have significantly enhanced their potential as therapeutic agents for neurological diseases.Owing to their therapeutic properties and ability to cross the blood–brain barrier,extracellular vesicles are recognized as promising drug delivery vehicles for various neurological conditions,including ischemic stroke,traumatic brain injury,neurodegenerative diseases,glioma,and psychosis.However,the clinical application of natural extracellular vesicles is hindered by their limited targeting ability and short clearance from the body.To address these limitations,multiple engineering strategies have been developed to enhance the targeting capabilities of extracellular vesicles,thereby enabling the delivery of therapeutic contents to specific tissues or cells.Therefore,this review aims to highlight the latest advancements in natural and targeting-engineered extracellular vesicles,exploring their applications in treating traumatic brain injury,ischemic stroke,Parkinson's disease,Alzheimer's disease,amyotrophic lateral sclerosis,glioma,and psychosis.Additionally,we summarized recent clinical trials involving extracellular vesicles and discussed the challenges and future prospects of using targeting-engineered extracellular vesicles for drug delivery in treating neurological diseases.This review offers new insights for developing highly targeted therapies in this field.
基金supported by NIH grants AG079264(to PHR)and AG071560(to APR)。
文摘The process of neurite outgrowth and branching is a crucial aspect of neuronal development and regeneration.Axons and dendrites,sometimes referred to as neurites,are extensions of a neuron's cellular body that are used to start networks.Here we explored the effects of diethyl(3,4-dihydroxyphenethylamino)(quinolin-4-yl)methylphosphonate(DDQ)on neurite developmental features in HT22 neuronal cells.In this work,we examined the protective effects of DDQ on neuronal processes and synaptic outgrowth in differentiated HT22cells expressing mutant Tau(mTau)cDNA.To investigate DDQ chara cteristics,cell viability,biochemical,molecular,western blotting,and immunocytochemistry were used.Neurite outgrowth is evaluated through the segmentation and measurement of neural processes.These neural processes can be seen and measured with a fluorescence microscope by manually tracing and measuring the length of the neurite growth.These neuronal processes can be observed and quantified with a fluorescent microscope by manually tracing and measuring the length of the neuronal HT22.DDQ-treated mTau-HT22 cells(HT22 cells transfected with cDNA mutant Tau)were seen to display increased levels of synaptophysin,MAP-2,andβ-tubulin.Additionally,we confirmed and noted reduced levels of both total and p-Tau,as well as elevated levels of microtubule-associated protein 2,β-tubulin,synaptophysin,vesicular acetylcholine transporter,and the mitochondrial biogenesis protein-pe roxisome prolife rator-activated receptor-gamma coactivator-1α.In mTa u-expressed HT22 neurons,we observed DDQ enhanced the neurite characteristics and improved neurite development through increased synaptic outgrowth.Our findings conclude that mTa u-HT22(Alzheimer's disease)cells treated with DDQ have functional neurite developmental chara cteristics.The key finding is that,in mTa u-HT22 cells,DDQ preserves neuronal structure and may even enhance nerve development function with mTa u inhibition.
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.