This paper studies cooperative robust parallel operation of multiple actuators over an undirected communication graph.The plant is modeled as an uncertain linear system,and the actuators are linear and identical.Based...This paper studies cooperative robust parallel operation of multiple actuators over an undirected communication graph.The plant is modeled as an uncertain linear system,and the actuators are linear and identical.Based on the internal model principle,a distributed dynamic output feedback control law is proposed to achieve both robust output regulation of the closed-loop system and plant input sharing among the actuators.A practical example of five motors cooperatively driving an uncertain shaft under an external load torque is presented to show the effectiveness of the proposed control law.展开更多
Active inflammation in“inactive”progressive multiple sclerosis:Traditionally,the distinction between relapsing-remitting multiple sclerosis and progressive multiple sclerosis(PMS)has been framed as an inflammatory v...Active inflammation in“inactive”progressive multiple sclerosis:Traditionally,the distinction between relapsing-remitting multiple sclerosis and progressive multiple sclerosis(PMS)has been framed as an inflammatory versus degenerative dichotomy.This was based on a broad misconception regarding essentially all neurodegenerative conditions,depicting the degenerative process as passive and immune-independent occurring as a late byproduct of active inflammation in the central nervous system(CNS),which is(solely)systemically driven.展开更多
Safer,smarter,faster...In China,people prefer high-speed trains to flights if the journey time is under five hours.High-speed train travel is set to become even more attractive with the addition of a new member to the...Safer,smarter,faster...In China,people prefer high-speed trains to flights if the journey time is under five hours.High-speed train travel is set to become even more attractive with the addition of a new member to the high-speed train family:the CR450,the world’s fastest electric multiple unit(EMU).展开更多
Neurodegenerative diseases,which are characterized by progressive neuronal loss and the lack of disease-modifying therapies,are becoming a major global health challenge.The existing neuromodulation techniques,such as ...Neurodegenerative diseases,which are characterized by progressive neuronal loss and the lack of disease-modifying therapies,are becoming a major global health challenge.The existing neuromodulation techniques,such as deep brain stimulation and transcranial magnetic stimulation,show limitations such as invasiveness,restricted cortical targeting,and irreversible tissue effects.In this context,low-intensity transcranial ultrasound has emerged as a promising noninvasive alternative that can penetrate deep into the brain and modulate neuroplasticity.This review comprehensively assesses the therapeutic mechanisms,efficacy,and translational potential of low-intensity transcranial ultrasound in treating neurodegenerative diseases,with emphasis on its role in promoting neuronal regeneration,modulating neuroinflammation,and enhancing functional recovery.We summarize the findings of previous studies and systematically illustrate the potential of low-intensity transcranial ultrasound in regulating cell death mechanisms,enhancing neural repair and regeneration,and alleviating symptoms associated with neurodegenerative diseases.Preclinical findings indicate that low-intensity transcranial ultrasound can enhance the release of neurotrophic factors(e.g.,brain-derived neurotrophic factor),promote autophagy to clear protein aggregates,modulate microglial activation,and temporarily open the blood-brain barrier to facilitate targeted drug delivery.Existing clinical trial data show that low-intensity transcranial ultrasound can reduce amyloid-βplaques,improve motor and cognitive deficits,and promote remyelination in various disease models.Early clinical trials suggest that low-intensity transcranial ultrasound may enhance cognitive scores in Alzheimer’s disease and alleviate motor symptoms in Parkinson’s disease,all while demonstrating a favorable safety profile.Past studies support the notion that by integrating safety,precision,and reversibility,low-intensity transcranial ultrasound can transform the treatment landscape for neurodegenerative disease.However,more advancements are necessary for future clinical application of low-intensity transcranial ultrasound,including optimizing parameters such as frequency,intensity,and duty cycle;considering individual anatomical differences;and confirming long-term efficacy.We believe establishing standardized protocols,conducting larger trials,and investigating the underlying mechanisms to clarify dose-response relationships and refine personalized application strategies are essential in this regard.Future research should focus on translating preclinical findings into clinical practice,addressing technical challenges,and exploring combination therapies with pharmacological or gene interventions.展开更多
BACKGROUND The accurate prediction of lymph node metastasis(LNM)is crucial for managing locally advanced(T3/T4)colorectal cancer(CRC).However,both traditional histopathology and standard slide-level deep learning ofte...BACKGROUND The accurate prediction of lymph node metastasis(LNM)is crucial for managing locally advanced(T3/T4)colorectal cancer(CRC).However,both traditional histopathology and standard slide-level deep learning often fail to capture the sparse and diagnostically critical features of metastatic potential.AIM To develop and validate a case-level multiple-instance learning(MIL)framework mimicking a pathologist's comprehensive review and improve T3/T4 CRC LNM prediction.METHODS The whole-slide images of 130 patients with T3/T4 CRC were retrospectively collected.A case-level MIL framework utilising the CONCH v1.5 and UNI2-h deep learning models was trained on features from all haematoxylin and eosinstained primary tumour slides for each patient.These pathological features were subsequently integrated with clinical data,and model performance was evaluated using the area under the curve(AUC).RESULTS The case-level framework demonstrated superior LNM prediction over slide-level training,with the CONCH v1.5 model achieving a mean AUC(±SD)of 0.899±0.033 vs 0.814±0.083,respectively.Integrating pathology features with clinical data further enhanced performance,yielding a top model with a mean AUC of 0.904±0.047,in sharp contrast to a clinical-only model(mean AUC 0.584±0.084).Crucially,a pathologist’s review confirmed that the model-identified high-attention regions correspond to known high-risk histopathological features.CONCLUSION A case-level MIL framework provides a superior approach for predicting LNM in advanced CRC.This method shows promise for risk stratification and therapy decisions,requiring further validation.展开更多
AIM:To investigate the changes of retinal vascular parameters and retinal layer thickness in patients with multiple sclerosis(MS).METHODS:This single-centered case-control study was performed on a MS group of 42 patie...AIM:To investigate the changes of retinal vascular parameters and retinal layer thickness in patients with multiple sclerosis(MS).METHODS:This single-centered case-control study was performed on a MS group of 42 patients diagnosed with MS and a control group of 43 healthy hospital staff matched in terms of age and sex at Iran University,department of neurology and ophthalmology from March 2020 to March 2021.The ophthalmic parameters of each patient were recorded,and optical coherence tomography was used to evaluate the retinal thickness in the layers.RESULTS:This study enrolled a total of 85 participants,with a mean age of 40.44±11.52 years,including 61 females(72%).The control group consisted of 43 individuals with a mean age of 39.49±11.07 years,while the MS group comprised 42 participants with a mean age of 41.40±12.01 years.The mean disease duration in the MS group was 8.45±6.04 a.The thickness of the ganglion cell layer in the right eye was significantly lower in the MS group compared to the control group(P=0.034).In addition,except for the left nasal sector(P=0.106),the mean peripapillary neurofibrillation in all examined sectors were significantly lower in the MS group than in the control group(P<0.05).The average vessel density in both the deep and superficial capillary plexuses across all regions of both eyes was lower in the MS group than in the control group,with all comparisons for the superficial capillary plexus showing statistical significance(P<0.05 for all except the left nasal sector).CONCLUSION:The thickness of the retina of patients with MS is significantly reduced.Therefore,optical coherence tomography results can be used as a reliable tool to evaluate disease progression and prognosis in MS patients.展开更多
Root rot is a prevalent soil-borne fungal disease in citrus.Citron C-05(Citrus medica)stands out as a germplasm within Citrus spp.due to its complete resistance to citrus canker and favorable characteristics such as s...Root rot is a prevalent soil-borne fungal disease in citrus.Citron C-05(Citrus medica)stands out as a germplasm within Citrus spp.due to its complete resistance to citrus canker and favorable characteristics such as single embryo and easy rooting.However,Citron C-05 was found to be highly susceptible to root rot during cultivation,with the specific pathogens previously unknown.In this study,four candidate fungal species were isolated from Citron C-05 roots.Sequence analysis of ITS,EF-1a,RPB1,and RPB2 identified two Fusarium solani strains,Rr-2 and Rr-4,as the candidates causing root rot in Citron C-05.Resistance tests showed these two pathogens increased root damage rate from 10.30%to 35.69%in Citron C-05,sour orange(Citrus aurantium),sweet orange(Citrus sinensis)and pummelo(Citrus grandis).F.solani exhibited the weak pathogenicity towards trifoliate orange(Poncirus trifoliata).DAB staining revealed none of reddish-brown precipitation in the four susceptible citrus germplasm after infection with F.solani,while trifoliate orange exhibited significant H2O2 accumulation.Trypan blue staining indicated increased cell death in the four susceptible citrus germplasm following infection with these two pathogens but not in trifoliate orange.These findings provide a comprehensive understanding of citrus root rot and support future research on the mechanisms of root rot resistance in citrus.展开更多
Psittacosis pneumonia is a zoonotic disease caused by Chlamydia psittaci infection,with the lungs being the most affected organ.[1]Rhabdomyolysis is a clinical syndrome characterized by the massive release of intracel...Psittacosis pneumonia is a zoonotic disease caused by Chlamydia psittaci infection,with the lungs being the most affected organ.[1]Rhabdomyolysis is a clinical syndrome characterized by the massive release of intracellular components—such as myoglobin and creatine kinase—into the bloodstream due to skeletal muscle injury or necrosis.Common causes include trauma,medications,metabolic disorders,and infections.When psittacosis pneumonia is complicated by rhabdomyolysis,patients often develop multiple organ dysfunction and have a poor prognosis,necessitating early clinical intervention.展开更多
To investigate the influencesof non-plastic silt and soil aging on the re-liquefaction resistance of sands,a series of undrained triaxial tests was performed on sand-silt mixtures with finescontent ranging from 0%to 1...To investigate the influencesof non-plastic silt and soil aging on the re-liquefaction resistance of sands,a series of undrained triaxial tests was performed on sand-silt mixtures with finescontent ranging from 0%to 100%,as well as on undisturbed and reconstituted non-plastic sandy soils retrieved from earth structures with a history of earthquake-induced damage.The specimens on sand-silt mixtures were produced under an initial degree of compaction of 95%.In these tests,liquefaction histories were applied three times to a single specimen under the same cyclic stress ratio after the respective consolidation stages with the measurements of the shear wave velocities.The following conclusions can be obtained from the test results:(1)The liquefaction resistance obtained in the firstto third cyclicloading stages decreased initially with increasing finescontent up to about 45%,while it increased afterward.Therefore,the susceptibility of sands containing a relatively large amount of non-plastic silt to reliquefaction may be more significantthan that of clean sands;(2)The liquefaction resistance and the shear wave velocity decreased significantlyduring the second cyclic-loading stage and after the second consolidation,respectively,despite an increase in the specimen density caused by the first liquefaction history,while they increased in the third stage.The possible reason for this change would be the disturbance of soil structures due to liquefaction,which may be partially evaluated by the volumetric strain during the respective consolidation stages,and the stress-induced anisotropy formed in the previous liquefaction stage;and(3)The liquefaction resistance and the shear wave velocity of the undisturbed specimens,which were measured in the firstto third stages,were larger than those of the reconstituted ones due to the aging effects,respectively.That is,the aging effects may not necessarily be eliminated by the subsequent liquefaction history and may remain partially in some cases.展开更多
Peroxisome proliferator-activated receptor alpha is a member of the nuclear hormone receptor superfamily and functions as a transcription factor involved in regulating cellular metabolism.Previous studies have shown t...Peroxisome proliferator-activated receptor alpha is a member of the nuclear hormone receptor superfamily and functions as a transcription factor involved in regulating cellular metabolism.Previous studies have shown that PPARαplays a key role in the onset and progression of neurodegenerative diseases.Consequently,peroxisome proliferator-activated receptor alpha agonists have garnered increasing attention as potential treatments for neurological disorders.This review aims to clarify the research progress regarding peroxisome proliferator-activated receptor alpha in nervous system diseases.Peroxisome proliferator-activated receptor alpha is present in all cell types within adult mouse and adult neural tissues.Although it is conventionally believed to be primarily localized in the nucleus,its function may be regulated by a dynamic balance between cytoplasmic and nuclear shuttling.Both endogenous and exogenous peroxisome proliferator-activated receptor alpha agonists bind to the peroxisome proliferator-activated response element to exert their biological effects.Peroxisome proliferator-activated receptor alpha plays a significant therapeutic role in neurodegenerative diseases.For instance,peroxisome proliferator-activated receptor alpha agonist gemfibrozil has been shown to reduce levels of soluble and insoluble amyloid-beta in the hippocampus of Alzheimer's disease mouse models through the autophagy-lysosomal pathway.Additionally,peroxisome proliferator-activated receptor alpha is essential for the normal development and functional maintenance of the substantia nigra,and it can mitigate motor dysfunction in Parkinson's disease mouse models.Furthermore,peroxisome proliferator-activated receptor alpha has been found to reduce neuroinflammation and oxidative stress in various neurological diseases.In summary,peroxisome proliferator-activated receptor alpha plays a crucial role in the onset and progression of multiple nervous system diseases,and peroxisome proliferator-activated receptor alpha agonists hold promise as new therapeutic agents for the treatment of neurodegenerative diseases,providing new options for patient care.展开更多
Neuroinflammation is a key process in the pathogenesis of various neurodegenerative diseases,such as multiple sclerosis(MS),Alzheimer's disease,and traumatic brain injury.Even for disorders historically unrelated ...Neuroinflammation is a key process in the pathogenesis of various neurodegenerative diseases,such as multiple sclerosis(MS),Alzheimer's disease,and traumatic brain injury.Even for disorders historically unrelated to neuroinflammation,such as Alzheimer's disease,it is now shown to precede pathological protein aggregations.展开更多
Myelination,the continuous ensheathment of neuronal axons,is a lifelong process in the nervous system that is essential for the precise,temporospatial conduction of action potentials between neurons.Myelin also provid...Myelination,the continuous ensheathment of neuronal axons,is a lifelong process in the nervous system that is essential for the precise,temporospatial conduction of action potentials between neurons.Myelin also provides intercellular metabolic support to axons.Even minor disruptions in the integrity of myelin can impair neural performance and increase susceptibility to neurological diseases.In fact,myelin degeneration is a well-known neuropathological condition that is associated with normal aging and several neurodegenerative diseases,including multiple sclerosis and Alzheimer’s disease.In the central nervous system,compact myelin sheaths are formed by fully mature oligodendrocytes.However,the entire oligodendrocyte lineage is susceptible to changes in the biological microenvironment and other risk factors that arise as the brain ages.In addition to their well-known role in action potential propagation,oligodendrocytes also provide intercellular metabolic support to axons by transferring energy metabolites and delivering exosomes.Therefore,myelin degeneration in the aging central nervous system is a significant contributor to the development of neurodegenerative diseases.Interventions that mitigate age-related myelin degeneration can improve neurological function in aging individuals.In this review,we investigate the changes in myelin that are associated with aging and their underlying mechanisms.We also discuss recent advances in understanding how myelin degeneration in the aging brain contributes to neurodegenerative diseases and explore the factors that can prevent,slow down,or even reverse age-related myelin degeneration.Future research will enhance our understanding of how reducing age-related myelin degeneration can be used as a therapeutic target for delaying or preventing neurodegenerative diseases.展开更多
Alpha-synuclein and Parkinson's disease:Neuronal damage and inflammation caused by the aggregation of alpha-synuclein(α-syn)are central to a group of disorders known as synucleopathies,which includes Parkinson...Alpha-synuclein and Parkinson's disease:Neuronal damage and inflammation caused by the aggregation of alpha-synuclein(α-syn)are central to a group of disorders known as synucleopathies,which includes Parkinson's disease(PD),dementia with Lewy bodies,and multiple system atrophy,among others.PD,the most common synucleinopathy,is the second most prevalent neurodegenerative disease after Alzheimer's disease,and it is the fastest growing.Its primary hallmark is the degeneration of dopaminergic neurons in the substantia nigra pars compacta,disrupting the communication with the striatum.展开更多
Subcritical reactors(SCRs)or subcritical assemblies(SCAs)are the main infrastructure for designing power reactors.These reactors are widely used for training and research because of their high level of inherent safety...Subcritical reactors(SCRs)or subcritical assemblies(SCAs)are the main infrastructure for designing power reactors.These reactors are widely used for training and research because of their high level of inherent safety.The objective of this study is to design a subcritical reactor using a pressurized water reactor(PWR)conventional fuel following two safety points.In the first approach,deeply placed SCR cores with an infinite multiplication factor(k_(∞))of less than unity were identified using the DRAGON lattice code.In the second approach,subcritical reactor cores with an effective multiplication factor(k_(eff))of less than unity were determined by coupling the cell calculations of the DRAGON lattice code and core calculations of the DONJON code.For the deeply subcritical reactor design,it was found that the reactor would remain inherently subcritical while using fuel rods with ^(235)U enrichment of up to 0.9%,regardless of the pitch of the fuel rods.In the second approach,the optimal pitches(1.3 to 2.3 cm)were determined for different fuel enrichment values from 1 to 5%.Subsequently,the k_(eff) was obtained for a fuel rod arrangement of 8×8 to 80×80,and the states in which the reactor would be subcritical were determined for different fuel enrichments at the corresponding optimal pitch.To validate the models used in the DRAGON and DONJON codes,the k_(eff) of the Isfahan Light Water Subcritical Reactor(LWSCR)was experimentally measured and compared with the results of the calculations.Finally,the effects of fuel and moderator temperature changes were investigated to ensure that the designed assemblies remained in the subcritical state at all operational temperatures.展开更多
Multi-organ-on-a-chip(MOOC)technology represents a pivotal direction in the organ-on-a-chip field,seeking to emulate the complex interactions of multiple human organs in vitro through microfluidic systems.This technol...Multi-organ-on-a-chip(MOOC)technology represents a pivotal direction in the organ-on-a-chip field,seeking to emulate the complex interactions of multiple human organs in vitro through microfluidic systems.This technology overcomes the limitations of traditional single-organ models,providing a novel platform for investigating complex disease mechanisms and evaluating drug efficacy and toxicity.Although it demonstrates broad application prospects,its development still faces critical bottlenecks,including inadequate physiological coupling between organs,short functional maintenance durations,and limited real-time monitoring capabilities.Contemporary research is advancing along three key directions,including functional coupling,sensor integration,and full-process automation systems,to propel the technology toward enhanced levels of physiological relevance and predictive accuracy.展开更多
Chemical exchange saturation transfer magnetic resonance imaging is an advanced imaging technique that enables the detection of compounds at low concentrations with high sensitivity and spatial resolution and has been...Chemical exchange saturation transfer magnetic resonance imaging is an advanced imaging technique that enables the detection of compounds at low concentrations with high sensitivity and spatial resolution and has been extensively studied for diagnosing malignancy and stroke.In recent years,the emerging exploration of chemical exchange saturation transfer magnetic resonance imaging for detecting pathological changes in neurodegenerative diseases has opened up new possibilities for early detection and repetitive scans without ionizing radiation.This review serves as an overview of chemical exchange saturation transfer magnetic resonance imaging with detailed information on contrast mechanisms and processing methods and summarizes recent developments in both clinical and preclinical studies of chemical exchange saturation transfer magnetic resonance imaging for Alzheimer’s disease,Parkinson’s disease,multiple sclerosis,and Huntington’s disease.A comprehensive literature search was conducted using databases such as PubMed and Google Scholar,focusing on peer-reviewed articles from the past 15 years relevant to clinical and preclinical applications.The findings suggest that chemical exchange saturation transfer magnetic resonance imaging has the potential to detect molecular changes and altered metabolism,which may aid in early diagnosis and assessment of the severity of neurodegenerative diseases.Although promising results have been observed in selected clinical and preclinical trials,further validations are needed to evaluate their clinical value.When combined with other imaging modalities and advanced analytical methods,chemical exchange saturation transfer magnetic resonance imaging shows potential as an in vivo biomarker,enhancing the understanding of neuropathological mechanisms in neurodegenerative diseases.展开更多
Vitamin D deficiency(VDD)represents a significant nutritional concern among children and adolescents.The estimated prevalence of VDD in China is 46.8%in this population^([1]).VDD during childhood and adolescence has b...Vitamin D deficiency(VDD)represents a significant nutritional concern among children and adolescents.The estimated prevalence of VDD in China is 46.8%in this population^([1]).VDD during childhood and adolescence has been associated with the onset of various conditions,including acute respiratory infections,asthma,atopic dermatitis,and food allergies^([2]).Multiple factors,including age,sun exposure,adiposity,and genetics,influence vitamin D levels^([2,3]).Increasing attention has been directed toward understanding the environmental determinants that may influence vitamin D status.Given the potential of metallic pollutants to disrupt endocrine function and their ubiquity in the environment,investigating the effects of metal exposure on human vitamin D status,particularly in vulnerable populations,is imperative.展开更多
N^(6)-methyladenosine RNA methylation,an essential post-transcriptional modification,dynamically regulates RNA metabolism and plays a crucial role in neuronal function.Growing evidence suggests that dysregulated N^(6)...N^(6)-methyladenosine RNA methylation,an essential post-transcriptional modification,dynamically regulates RNA metabolism and plays a crucial role in neuronal function.Growing evidence suggests that dysregulated N^(6)-methyladenosine modification contributes to the pathogenesis of neurodegenerative diseases,including Alzheimer’s disease,Parkinson’s disease,multiple sclerosis,and amyotrophic lateral sclerosis.However,the precise mechanisms by which N^(6)-methyladenosine modification influences these conditions remain unclear.This review summarizes the role of m6A modification and its associated regulators in neurodegeneration,focusing on their involvement in key pathological processes.In Alzheimer’s disease,m6A modification contributes to synaptic dysfunction,mitochondrial damage,and neuronal apoptosis.Evidence from APP/PS1,5xFAD,tau transgenic,and Drosophila models demonstrates that regulators such as methyltransferase-like 3 and fat mass and obesity-associated protein influence Alzheimer’s disease progression through neuroinflammation,circular RNAs dysregulation,and autophagy-related mechanisms.In Parkinson’s disease,altered N^(6)-methyladenosine regulator expression affects dopaminergic neuron survival and stress responses by modulating mRNA stability and autophagy-related lncRNAs.In multiple sclerosis and amyotrophic lateral sclerosis,N^(6)-methyladenosine affects immune activation,myelin repair,and the regulation of disease-associated genes such as TDP-43.Beyond N^(6)-methyladenosine,other RNA methylation modifications-such as m1A,m5C,m7G,uracil,and pseudouridine-are implicated in neurodegenerative diseases through their regulation of mitochondrial function,RNA metabolism,and neuronal stress responses.Additionally,N^(6)-methyladenosine exhibits cell type-specific functions:in microglia,it regulates inflammatory activation and phagocytic function;in astrocytes,it modulates metabolic homeostasis and glutamate-associated neurotoxicity;in neurons,it affects synaptic function and neurodegeneration-related gene expression;and in adult neural stem cells,it controls differentiation,neurogenesis,and cognitive plasticity.Recently,several small-molecule inhibitors targeting methyltransferase-like 3 or fat mass and obesity-associated protein have been developed to modulate N^(6)-methyladenosine modification,providing new opportunities for disease intervention,with the targeting of N⁶-methyladenosine-related pathways emerging as a promising therapeutic strategy.However,challenges persist in optimizing the specificity and delivery of these therapeutic approaches.展开更多
Neurodegenerative diseases are a group of illnesses characterized by the gradual deterioration of the central nervous system,leading to a decline in patients'cognitive,motor,and emotional abilities.Neuroinflammati...Neurodegenerative diseases are a group of illnesses characterized by the gradual deterioration of the central nervous system,leading to a decline in patients'cognitive,motor,and emotional abilities.Neuroinflammation plays a significant role in the progression of these diseases.However,there is limited research on therapeutic approaches to specifically target neuroinflammation.The role of T lymphocytes,which are crucial mediators of the adaptive immune response,in neurodegenerative diseases has been increasingly recognized.This review focuses on the involvement of T lymphocytes in the neuroinflammation associated with neurodegenerative diseases.The pathogenesis of neurodegenerative diseases is complex,involving multiple mechanisms and pathways that contribute to the gradual degeneration of neurons,and T cells are a key component of these processes.One of the primary factors driving neuroinflammation in neurodegenerative diseases is the infiltration of T cells and other neuroimmune cells,including microglia,astrocytes,B cells,and natural killer cells.Different subsets of CD4~+T cells,such as Th1,Th2,Th17,and regulatory T cells,can differentiate into various cell types and perform distinct roles within the neuroinflammatory environment of neurodegenerative diseases.Additionally,CD8~+T cells,which can directly regulate immune responses and kill target cells,also play several important roles in neurodegenerative diseases.Clinical trials investigating targeted T cell therapies for neurodegenerative diseases have shown that,while some patients respond positively,others may not respond as well and may even experience adverse effects.Targeting T cells precisely is challenging due to the complexity of immune responses in the central nervous system,which can lead to undesirable side effects.However,with new insights into the pathophysiology of neurodegenerative diseases,there is hope for the establishment of a solid theoretical foundation upon which innovative treatment strategies that target T cells can be developed in the future.展开更多
Multiple sclerosis is a severe autoimmune disorder that is mainly mediated by pathogenic cluster of CD4^(+)T cell subsets.Despite advancements in the management of multiple sclerosis,there is a critical need for more ...Multiple sclerosis is a severe autoimmune disorder that is mainly mediated by pathogenic cluster of CD4^(+)T cell subsets.Despite advancements in the management of multiple sclerosis,there is a critical need for more effective and safer treatments.In the present study,we administered Lycium barbarum glycopeptide to a mouse model of experimental autoimmune encephalomyelitis-an animal model of multiple sclerosis-and evaluated its effects on pathogenic CD4^(+)T cell activation both in vivo and in vitro.Lycium barbarum glycopeptide significantly mitigated the clinical severity of experimental autoimmune encephalomyelitis,as demonstrated by reduced demyelination and neuroinflammation.Moreover,Lycium barbarum glycopeptide treatment decreased the infiltration of peripheral leukocytes into the central nervous system and suppressed pro-inflammatory cytokine expression.Lycium barbarum glycopeptide also modulated pathogenic CD4^(+)T cell activation by inhibiting T helper 1/T helper 17 cell differentiation while promoting regulatory T cell expansion.Notably,no side effects were observed,suggesting the long-term safety and tolerability of Lycium barbarum glycopeptide.Furthermore,RNA sequencing data indicated that Lycium barbarum glycopeptide inhibits activator protein-1,an essential regulator of T cell activation and differentiation.This finding was supported by the reversal of T helper/T helper 17 cell response suppression upon AP-1 blockade.Collectively,these results highlight the potential of Lycium barbarum glycopeptide as an innovative therapeutic agent for CD4^(+)T cell-associated autoimmune or inflammatory diseases,such as multiple sclerosis.展开更多
基金Supported by the Shenzhen Key Laboratory of Control Theory and Intelligent Systems (ZDSYS20220330161800001)the National Natural Science Foundation of China (62303207)the Guangdong Basic and Applied Basic Research Foundation (2024A1515010725)。
文摘This paper studies cooperative robust parallel operation of multiple actuators over an undirected communication graph.The plant is modeled as an uncertain linear system,and the actuators are linear and identical.Based on the internal model principle,a distributed dynamic output feedback control law is proposed to achieve both robust output regulation of the closed-loop system and plant input sharing among the actuators.A practical example of five motors cooperatively driving an uncertain shaft under an external load torque is presented to show the effectiveness of the proposed control law.
文摘Active inflammation in“inactive”progressive multiple sclerosis:Traditionally,the distinction between relapsing-remitting multiple sclerosis and progressive multiple sclerosis(PMS)has been framed as an inflammatory versus degenerative dichotomy.This was based on a broad misconception regarding essentially all neurodegenerative conditions,depicting the degenerative process as passive and immune-independent occurring as a late byproduct of active inflammation in the central nervous system(CNS),which is(solely)systemically driven.
文摘Safer,smarter,faster...In China,people prefer high-speed trains to flights if the journey time is under five hours.High-speed train travel is set to become even more attractive with the addition of a new member to the high-speed train family:the CR450,the world’s fastest electric multiple unit(EMU).
基金supported by STI2030-Major Project,No,2021ZD0204200(to LX).
文摘Neurodegenerative diseases,which are characterized by progressive neuronal loss and the lack of disease-modifying therapies,are becoming a major global health challenge.The existing neuromodulation techniques,such as deep brain stimulation and transcranial magnetic stimulation,show limitations such as invasiveness,restricted cortical targeting,and irreversible tissue effects.In this context,low-intensity transcranial ultrasound has emerged as a promising noninvasive alternative that can penetrate deep into the brain and modulate neuroplasticity.This review comprehensively assesses the therapeutic mechanisms,efficacy,and translational potential of low-intensity transcranial ultrasound in treating neurodegenerative diseases,with emphasis on its role in promoting neuronal regeneration,modulating neuroinflammation,and enhancing functional recovery.We summarize the findings of previous studies and systematically illustrate the potential of low-intensity transcranial ultrasound in regulating cell death mechanisms,enhancing neural repair and regeneration,and alleviating symptoms associated with neurodegenerative diseases.Preclinical findings indicate that low-intensity transcranial ultrasound can enhance the release of neurotrophic factors(e.g.,brain-derived neurotrophic factor),promote autophagy to clear protein aggregates,modulate microglial activation,and temporarily open the blood-brain barrier to facilitate targeted drug delivery.Existing clinical trial data show that low-intensity transcranial ultrasound can reduce amyloid-βplaques,improve motor and cognitive deficits,and promote remyelination in various disease models.Early clinical trials suggest that low-intensity transcranial ultrasound may enhance cognitive scores in Alzheimer’s disease and alleviate motor symptoms in Parkinson’s disease,all while demonstrating a favorable safety profile.Past studies support the notion that by integrating safety,precision,and reversibility,low-intensity transcranial ultrasound can transform the treatment landscape for neurodegenerative disease.However,more advancements are necessary for future clinical application of low-intensity transcranial ultrasound,including optimizing parameters such as frequency,intensity,and duty cycle;considering individual anatomical differences;and confirming long-term efficacy.We believe establishing standardized protocols,conducting larger trials,and investigating the underlying mechanisms to clarify dose-response relationships and refine personalized application strategies are essential in this regard.Future research should focus on translating preclinical findings into clinical practice,addressing technical challenges,and exploring combination therapies with pharmacological or gene interventions.
基金Supported by Chongqing Medical Scientific Research Project(Joint Project of Chongqing Health Commission and Science and Technology Bureau),No.2023MSXM060.
文摘BACKGROUND The accurate prediction of lymph node metastasis(LNM)is crucial for managing locally advanced(T3/T4)colorectal cancer(CRC).However,both traditional histopathology and standard slide-level deep learning often fail to capture the sparse and diagnostically critical features of metastatic potential.AIM To develop and validate a case-level multiple-instance learning(MIL)framework mimicking a pathologist's comprehensive review and improve T3/T4 CRC LNM prediction.METHODS The whole-slide images of 130 patients with T3/T4 CRC were retrospectively collected.A case-level MIL framework utilising the CONCH v1.5 and UNI2-h deep learning models was trained on features from all haematoxylin and eosinstained primary tumour slides for each patient.These pathological features were subsequently integrated with clinical data,and model performance was evaluated using the area under the curve(AUC).RESULTS The case-level framework demonstrated superior LNM prediction over slide-level training,with the CONCH v1.5 model achieving a mean AUC(±SD)of 0.899±0.033 vs 0.814±0.083,respectively.Integrating pathology features with clinical data further enhanced performance,yielding a top model with a mean AUC of 0.904±0.047,in sharp contrast to a clinical-only model(mean AUC 0.584±0.084).Crucially,a pathologist’s review confirmed that the model-identified high-attention regions correspond to known high-risk histopathological features.CONCLUSION A case-level MIL framework provides a superior approach for predicting LNM in advanced CRC.This method shows promise for risk stratification and therapy decisions,requiring further validation.
文摘AIM:To investigate the changes of retinal vascular parameters and retinal layer thickness in patients with multiple sclerosis(MS).METHODS:This single-centered case-control study was performed on a MS group of 42 patients diagnosed with MS and a control group of 43 healthy hospital staff matched in terms of age and sex at Iran University,department of neurology and ophthalmology from March 2020 to March 2021.The ophthalmic parameters of each patient were recorded,and optical coherence tomography was used to evaluate the retinal thickness in the layers.RESULTS:This study enrolled a total of 85 participants,with a mean age of 40.44±11.52 years,including 61 females(72%).The control group consisted of 43 individuals with a mean age of 39.49±11.07 years,while the MS group comprised 42 participants with a mean age of 41.40±12.01 years.The mean disease duration in the MS group was 8.45±6.04 a.The thickness of the ganglion cell layer in the right eye was significantly lower in the MS group compared to the control group(P=0.034).In addition,except for the left nasal sector(P=0.106),the mean peripapillary neurofibrillation in all examined sectors were significantly lower in the MS group than in the control group(P<0.05).The average vessel density in both the deep and superficial capillary plexuses across all regions of both eyes was lower in the MS group than in the control group,with all comparisons for the superficial capillary plexus showing statistical significance(P<0.05 for all except the left nasal sector).CONCLUSION:The thickness of the retina of patients with MS is significantly reduced.Therefore,optical coherence tomography results can be used as a reliable tool to evaluate disease progression and prognosis in MS patients.
基金supported by Joint Funds of the National Natural Science Foundation of China(Grant No.U21A20228).
文摘Root rot is a prevalent soil-borne fungal disease in citrus.Citron C-05(Citrus medica)stands out as a germplasm within Citrus spp.due to its complete resistance to citrus canker and favorable characteristics such as single embryo and easy rooting.However,Citron C-05 was found to be highly susceptible to root rot during cultivation,with the specific pathogens previously unknown.In this study,four candidate fungal species were isolated from Citron C-05 roots.Sequence analysis of ITS,EF-1a,RPB1,and RPB2 identified two Fusarium solani strains,Rr-2 and Rr-4,as the candidates causing root rot in Citron C-05.Resistance tests showed these two pathogens increased root damage rate from 10.30%to 35.69%in Citron C-05,sour orange(Citrus aurantium),sweet orange(Citrus sinensis)and pummelo(Citrus grandis).F.solani exhibited the weak pathogenicity towards trifoliate orange(Poncirus trifoliata).DAB staining revealed none of reddish-brown precipitation in the four susceptible citrus germplasm after infection with F.solani,while trifoliate orange exhibited significant H2O2 accumulation.Trypan blue staining indicated increased cell death in the four susceptible citrus germplasm following infection with these two pathogens but not in trifoliate orange.These findings provide a comprehensive understanding of citrus root rot and support future research on the mechanisms of root rot resistance in citrus.
文摘Psittacosis pneumonia is a zoonotic disease caused by Chlamydia psittaci infection,with the lungs being the most affected organ.[1]Rhabdomyolysis is a clinical syndrome characterized by the massive release of intracellular components—such as myoglobin and creatine kinase—into the bloodstream due to skeletal muscle injury or necrosis.Common causes include trauma,medications,metabolic disorders,and infections.When psittacosis pneumonia is complicated by rhabdomyolysis,patients often develop multiple organ dysfunction and have a poor prognosis,necessitating early clinical intervention.
基金supported by JSPS KAKENHI(Grant Nos.JP22K04305 and JP19K15083).
文摘To investigate the influencesof non-plastic silt and soil aging on the re-liquefaction resistance of sands,a series of undrained triaxial tests was performed on sand-silt mixtures with finescontent ranging from 0%to 100%,as well as on undisturbed and reconstituted non-plastic sandy soils retrieved from earth structures with a history of earthquake-induced damage.The specimens on sand-silt mixtures were produced under an initial degree of compaction of 95%.In these tests,liquefaction histories were applied three times to a single specimen under the same cyclic stress ratio after the respective consolidation stages with the measurements of the shear wave velocities.The following conclusions can be obtained from the test results:(1)The liquefaction resistance obtained in the firstto third cyclicloading stages decreased initially with increasing finescontent up to about 45%,while it increased afterward.Therefore,the susceptibility of sands containing a relatively large amount of non-plastic silt to reliquefaction may be more significantthan that of clean sands;(2)The liquefaction resistance and the shear wave velocity decreased significantlyduring the second cyclic-loading stage and after the second consolidation,respectively,despite an increase in the specimen density caused by the first liquefaction history,while they increased in the third stage.The possible reason for this change would be the disturbance of soil structures due to liquefaction,which may be partially evaluated by the volumetric strain during the respective consolidation stages,and the stress-induced anisotropy formed in the previous liquefaction stage;and(3)The liquefaction resistance and the shear wave velocity of the undisturbed specimens,which were measured in the firstto third stages,were larger than those of the reconstituted ones due to the aging effects,respectively.That is,the aging effects may not necessarily be eliminated by the subsequent liquefaction history and may remain partially in some cases.
基金supported by grants from Tianjin Scientific Research Project in Key Areas of Traditional Chinese Medicine,Tianjin Municipal Health Commission,No.2024012(to JL)Tianjin Municipal Education Commission Project,No.2021KJ217(to CS)。
文摘Peroxisome proliferator-activated receptor alpha is a member of the nuclear hormone receptor superfamily and functions as a transcription factor involved in regulating cellular metabolism.Previous studies have shown that PPARαplays a key role in the onset and progression of neurodegenerative diseases.Consequently,peroxisome proliferator-activated receptor alpha agonists have garnered increasing attention as potential treatments for neurological disorders.This review aims to clarify the research progress regarding peroxisome proliferator-activated receptor alpha in nervous system diseases.Peroxisome proliferator-activated receptor alpha is present in all cell types within adult mouse and adult neural tissues.Although it is conventionally believed to be primarily localized in the nucleus,its function may be regulated by a dynamic balance between cytoplasmic and nuclear shuttling.Both endogenous and exogenous peroxisome proliferator-activated receptor alpha agonists bind to the peroxisome proliferator-activated response element to exert their biological effects.Peroxisome proliferator-activated receptor alpha plays a significant therapeutic role in neurodegenerative diseases.For instance,peroxisome proliferator-activated receptor alpha agonist gemfibrozil has been shown to reduce levels of soluble and insoluble amyloid-beta in the hippocampus of Alzheimer's disease mouse models through the autophagy-lysosomal pathway.Additionally,peroxisome proliferator-activated receptor alpha is essential for the normal development and functional maintenance of the substantia nigra,and it can mitigate motor dysfunction in Parkinson's disease mouse models.Furthermore,peroxisome proliferator-activated receptor alpha has been found to reduce neuroinflammation and oxidative stress in various neurological diseases.In summary,peroxisome proliferator-activated receptor alpha plays a crucial role in the onset and progression of multiple nervous system diseases,and peroxisome proliferator-activated receptor alpha agonists hold promise as new therapeutic agents for the treatment of neurodegenerative diseases,providing new options for patient care.
基金supported by FWO(Fonds voor Wetenschappelijk Onderzoek),grant number G07562NFWO(to BB)。
文摘Neuroinflammation is a key process in the pathogenesis of various neurodegenerative diseases,such as multiple sclerosis(MS),Alzheimer's disease,and traumatic brain injury.Even for disorders historically unrelated to neuroinflammation,such as Alzheimer's disease,it is now shown to precede pathological protein aggregations.
基金supported by grants from Guangdong Basic and Applied Basic Research Foundation,No.2021A1515110801(to SW)the National Natural Science Foundation of China,No.82301511(to SW)+1 种基金“Double First-Class”Construction Project of NPU,Nos.0515023GH0202320(to JC),0515023SH0201320(to JC)973 Program,No.2011CB504100(to JC).
文摘Myelination,the continuous ensheathment of neuronal axons,is a lifelong process in the nervous system that is essential for the precise,temporospatial conduction of action potentials between neurons.Myelin also provides intercellular metabolic support to axons.Even minor disruptions in the integrity of myelin can impair neural performance and increase susceptibility to neurological diseases.In fact,myelin degeneration is a well-known neuropathological condition that is associated with normal aging and several neurodegenerative diseases,including multiple sclerosis and Alzheimer’s disease.In the central nervous system,compact myelin sheaths are formed by fully mature oligodendrocytes.However,the entire oligodendrocyte lineage is susceptible to changes in the biological microenvironment and other risk factors that arise as the brain ages.In addition to their well-known role in action potential propagation,oligodendrocytes also provide intercellular metabolic support to axons by transferring energy metabolites and delivering exosomes.Therefore,myelin degeneration in the aging central nervous system is a significant contributor to the development of neurodegenerative diseases.Interventions that mitigate age-related myelin degeneration can improve neurological function in aging individuals.In this review,we investigate the changes in myelin that are associated with aging and their underlying mechanisms.We also discuss recent advances in understanding how myelin degeneration in the aging brain contributes to neurodegenerative diseases and explore the factors that can prevent,slow down,or even reverse age-related myelin degeneration.Future research will enhance our understanding of how reducing age-related myelin degeneration can be used as a therapeutic target for delaying or preventing neurodegenerative diseases.
基金supported by the Spanish Ministry of Science and Innovation via a doctoral grant[FPU22/03656].supported by the Spanish Ministry of Science and Innovation(PID2022-137963OB-I00)Generalitat de Catalunya(2021-SGR-00635 AGAUR)+1 种基金CERCA Programme(Generalitat de Catalunya)by ICREA,ICREA-Academia 2020(to SV)。
文摘Alpha-synuclein and Parkinson's disease:Neuronal damage and inflammation caused by the aggregation of alpha-synuclein(α-syn)are central to a group of disorders known as synucleopathies,which includes Parkinson's disease(PD),dementia with Lewy bodies,and multiple system atrophy,among others.PD,the most common synucleinopathy,is the second most prevalent neurodegenerative disease after Alzheimer's disease,and it is the fastest growing.Its primary hallmark is the degeneration of dopaminergic neurons in the substantia nigra pars compacta,disrupting the communication with the striatum.
文摘Subcritical reactors(SCRs)or subcritical assemblies(SCAs)are the main infrastructure for designing power reactors.These reactors are widely used for training and research because of their high level of inherent safety.The objective of this study is to design a subcritical reactor using a pressurized water reactor(PWR)conventional fuel following two safety points.In the first approach,deeply placed SCR cores with an infinite multiplication factor(k_(∞))of less than unity were identified using the DRAGON lattice code.In the second approach,subcritical reactor cores with an effective multiplication factor(k_(eff))of less than unity were determined by coupling the cell calculations of the DRAGON lattice code and core calculations of the DONJON code.For the deeply subcritical reactor design,it was found that the reactor would remain inherently subcritical while using fuel rods with ^(235)U enrichment of up to 0.9%,regardless of the pitch of the fuel rods.In the second approach,the optimal pitches(1.3 to 2.3 cm)were determined for different fuel enrichment values from 1 to 5%.Subsequently,the k_(eff) was obtained for a fuel rod arrangement of 8×8 to 80×80,and the states in which the reactor would be subcritical were determined for different fuel enrichments at the corresponding optimal pitch.To validate the models used in the DRAGON and DONJON codes,the k_(eff) of the Isfahan Light Water Subcritical Reactor(LWSCR)was experimentally measured and compared with the results of the calculations.Finally,the effects of fuel and moderator temperature changes were investigated to ensure that the designed assemblies remained in the subcritical state at all operational temperatures.
基金supported by the Shenzhen Medical Research Fund(Grant No.A2303049)Guangdong Basic and Applied Basic Research(Grant No.2023A1515010647)+1 种基金National Natural Science Foundation of China(Grant No.22004135)Shenzhen Science and Technology Program(Grant No.RCBS20210706092409020,GXWD20201231165807008,20200824162253002).
文摘Multi-organ-on-a-chip(MOOC)technology represents a pivotal direction in the organ-on-a-chip field,seeking to emulate the complex interactions of multiple human organs in vitro through microfluidic systems.This technology overcomes the limitations of traditional single-organ models,providing a novel platform for investigating complex disease mechanisms and evaluating drug efficacy and toxicity.Although it demonstrates broad application prospects,its development still faces critical bottlenecks,including inadequate physiological coupling between organs,short functional maintenance durations,and limited real-time monitoring capabilities.Contemporary research is advancing along three key directions,including functional coupling,sensor integration,and full-process automation systems,to propel the technology toward enhanced levels of physiological relevance and predictive accuracy.
基金supported by The University of Hong Kong,China(109000487,109001694,204610401,and 204610519)National Natural Science Foundation of China(82402225)(to JH).
文摘Chemical exchange saturation transfer magnetic resonance imaging is an advanced imaging technique that enables the detection of compounds at low concentrations with high sensitivity and spatial resolution and has been extensively studied for diagnosing malignancy and stroke.In recent years,the emerging exploration of chemical exchange saturation transfer magnetic resonance imaging for detecting pathological changes in neurodegenerative diseases has opened up new possibilities for early detection and repetitive scans without ionizing radiation.This review serves as an overview of chemical exchange saturation transfer magnetic resonance imaging with detailed information on contrast mechanisms and processing methods and summarizes recent developments in both clinical and preclinical studies of chemical exchange saturation transfer magnetic resonance imaging for Alzheimer’s disease,Parkinson’s disease,multiple sclerosis,and Huntington’s disease.A comprehensive literature search was conducted using databases such as PubMed and Google Scholar,focusing on peer-reviewed articles from the past 15 years relevant to clinical and preclinical applications.The findings suggest that chemical exchange saturation transfer magnetic resonance imaging has the potential to detect molecular changes and altered metabolism,which may aid in early diagnosis and assessment of the severity of neurodegenerative diseases.Although promising results have been observed in selected clinical and preclinical trials,further validations are needed to evaluate their clinical value.When combined with other imaging modalities and advanced analytical methods,chemical exchange saturation transfer magnetic resonance imaging shows potential as an in vivo biomarker,enhancing the understanding of neuropathological mechanisms in neurodegenerative diseases.
基金supported by grants from the National Natural Science Foundation of China(G.F.Wang,grant number 82204071)(P.Y.Su,grant numbers 81874268 and 82473655)the Research Funds of the Center for Big Data and Population Health of IHM(P.Y.Su,No.JKS2023016)Anhui Provincial Health Commission Scientific Research Project(Y.Zhou,No.AHWJ2023A30027)。
文摘Vitamin D deficiency(VDD)represents a significant nutritional concern among children and adolescents.The estimated prevalence of VDD in China is 46.8%in this population^([1]).VDD during childhood and adolescence has been associated with the onset of various conditions,including acute respiratory infections,asthma,atopic dermatitis,and food allergies^([2]).Multiple factors,including age,sun exposure,adiposity,and genetics,influence vitamin D levels^([2,3]).Increasing attention has been directed toward understanding the environmental determinants that may influence vitamin D status.Given the potential of metallic pollutants to disrupt endocrine function and their ubiquity in the environment,investigating the effects of metal exposure on human vitamin D status,particularly in vulnerable populations,is imperative.
基金supported by the National Nature Science Foundation of China(General Program),Nos.82271237,82071218(both to JC),and 82230042(to ZY)the Foundation of Key Laboratory of Neurology,Hebei Medical University,Ministry of Education,China,No.2023001(to JC).
文摘N^(6)-methyladenosine RNA methylation,an essential post-transcriptional modification,dynamically regulates RNA metabolism and plays a crucial role in neuronal function.Growing evidence suggests that dysregulated N^(6)-methyladenosine modification contributes to the pathogenesis of neurodegenerative diseases,including Alzheimer’s disease,Parkinson’s disease,multiple sclerosis,and amyotrophic lateral sclerosis.However,the precise mechanisms by which N^(6)-methyladenosine modification influences these conditions remain unclear.This review summarizes the role of m6A modification and its associated regulators in neurodegeneration,focusing on their involvement in key pathological processes.In Alzheimer’s disease,m6A modification contributes to synaptic dysfunction,mitochondrial damage,and neuronal apoptosis.Evidence from APP/PS1,5xFAD,tau transgenic,and Drosophila models demonstrates that regulators such as methyltransferase-like 3 and fat mass and obesity-associated protein influence Alzheimer’s disease progression through neuroinflammation,circular RNAs dysregulation,and autophagy-related mechanisms.In Parkinson’s disease,altered N^(6)-methyladenosine regulator expression affects dopaminergic neuron survival and stress responses by modulating mRNA stability and autophagy-related lncRNAs.In multiple sclerosis and amyotrophic lateral sclerosis,N^(6)-methyladenosine affects immune activation,myelin repair,and the regulation of disease-associated genes such as TDP-43.Beyond N^(6)-methyladenosine,other RNA methylation modifications-such as m1A,m5C,m7G,uracil,and pseudouridine-are implicated in neurodegenerative diseases through their regulation of mitochondrial function,RNA metabolism,and neuronal stress responses.Additionally,N^(6)-methyladenosine exhibits cell type-specific functions:in microglia,it regulates inflammatory activation and phagocytic function;in astrocytes,it modulates metabolic homeostasis and glutamate-associated neurotoxicity;in neurons,it affects synaptic function and neurodegeneration-related gene expression;and in adult neural stem cells,it controls differentiation,neurogenesis,and cognitive plasticity.Recently,several small-molecule inhibitors targeting methyltransferase-like 3 or fat mass and obesity-associated protein have been developed to modulate N^(6)-methyladenosine modification,providing new opportunities for disease intervention,with the targeting of N⁶-methyladenosine-related pathways emerging as a promising therapeutic strategy.However,challenges persist in optimizing the specificity and delivery of these therapeutic approaches.
基金supported by Yunnan Provincial Science and Technology Department,Nos.202403AC100007(to NZ),202301AY070001-239(to JY)Yunnan Revitalization Talent Support Program,Nos.2019-069(to ZY)and 2019-300(to JY)+1 种基金the National Natural Science Foundation of China,Nos.32260196(to JY)a grant from Kunming Medical University,No.2024S085(to KL)。
文摘Neurodegenerative diseases are a group of illnesses characterized by the gradual deterioration of the central nervous system,leading to a decline in patients'cognitive,motor,and emotional abilities.Neuroinflammation plays a significant role in the progression of these diseases.However,there is limited research on therapeutic approaches to specifically target neuroinflammation.The role of T lymphocytes,which are crucial mediators of the adaptive immune response,in neurodegenerative diseases has been increasingly recognized.This review focuses on the involvement of T lymphocytes in the neuroinflammation associated with neurodegenerative diseases.The pathogenesis of neurodegenerative diseases is complex,involving multiple mechanisms and pathways that contribute to the gradual degeneration of neurons,and T cells are a key component of these processes.One of the primary factors driving neuroinflammation in neurodegenerative diseases is the infiltration of T cells and other neuroimmune cells,including microglia,astrocytes,B cells,and natural killer cells.Different subsets of CD4~+T cells,such as Th1,Th2,Th17,and regulatory T cells,can differentiate into various cell types and perform distinct roles within the neuroinflammatory environment of neurodegenerative diseases.Additionally,CD8~+T cells,which can directly regulate immune responses and kill target cells,also play several important roles in neurodegenerative diseases.Clinical trials investigating targeted T cell therapies for neurodegenerative diseases have shown that,while some patients respond positively,others may not respond as well and may even experience adverse effects.Targeting T cells precisely is challenging due to the complexity of immune responses in the central nervous system,which can lead to undesirable side effects.However,with new insights into the pathophysiology of neurodegenerative diseases,there is hope for the establishment of a solid theoretical foundation upon which innovative treatment strategies that target T cells can be developed in the future.
基金supported by the National Natural Science Foundational of China,Nos.U24A20692(to CJZ),82371355(to CJZ),and 82101414(to MH)National NaturalScience Foundational of China for Excellent Young Scholars,No.82022019(to CJZ)+5 种基金Sichuan Special Fund for Distinguished Young Scholars,No.24NSFJQ0052(to CJZ)The Innovationand Entrepreneurial Team of Sichuan Tianfu Emei Program,No.CZ2024018(to CJZ)Funding for Distinguished Young Scholars of Sichuan Provincial People’sHospital,No.30420230005Funding for Distinguished Young Scholars of University of Electronic Science and Technology of China,No.A1098531023601381(toCJZ)Sichuan Science and Technology Support Project,No.2023YFS0212(to BH)Project of Sichuan Provincial Health Commission,No.19PJ265(to LD).
文摘Multiple sclerosis is a severe autoimmune disorder that is mainly mediated by pathogenic cluster of CD4^(+)T cell subsets.Despite advancements in the management of multiple sclerosis,there is a critical need for more effective and safer treatments.In the present study,we administered Lycium barbarum glycopeptide to a mouse model of experimental autoimmune encephalomyelitis-an animal model of multiple sclerosis-and evaluated its effects on pathogenic CD4^(+)T cell activation both in vivo and in vitro.Lycium barbarum glycopeptide significantly mitigated the clinical severity of experimental autoimmune encephalomyelitis,as demonstrated by reduced demyelination and neuroinflammation.Moreover,Lycium barbarum glycopeptide treatment decreased the infiltration of peripheral leukocytes into the central nervous system and suppressed pro-inflammatory cytokine expression.Lycium barbarum glycopeptide also modulated pathogenic CD4^(+)T cell activation by inhibiting T helper 1/T helper 17 cell differentiation while promoting regulatory T cell expansion.Notably,no side effects were observed,suggesting the long-term safety and tolerability of Lycium barbarum glycopeptide.Furthermore,RNA sequencing data indicated that Lycium barbarum glycopeptide inhibits activator protein-1,an essential regulator of T cell activation and differentiation.This finding was supported by the reversal of T helper/T helper 17 cell response suppression upon AP-1 blockade.Collectively,these results highlight the potential of Lycium barbarum glycopeptide as an innovative therapeutic agent for CD4^(+)T cell-associated autoimmune or inflammatory diseases,such as multiple sclerosis.
