The fibrotic scar due to excessive deposition of extracellular matrix(ECM)after spinal cord injury(SCI)remains one of formidable challenges to axonal regeneration.Previous therapeutic strategies mainly focus on elimin...The fibrotic scar due to excessive deposition of extracellular matrix(ECM)after spinal cord injury(SCI)remains one of formidable challenges to axonal regeneration.Previous therapeutic strategies mainly focus on eliminating fibrotic scars by blocking(Göritz et al.,2011)or inhibiting(Dias et al.,2018)the generation of scar-forming stromal cells,as well as inducing their migratory defect(Hellal et al.,2011;Ruschel et al.,2015).展开更多
Recent studies have indicated that stroke can lead to neuronal iron overload and lipid peroxidation.Lycium barbarum glycopeptide,which has a low molecular weight and potent antioxidant properties,may mitigate ferropto...Recent studies have indicated that stroke can lead to neuronal iron overload and lipid peroxidation.Lycium barbarum glycopeptide,which has a low molecular weight and potent antioxidant properties,may mitigate ferroptosis in stroke.We hypothesized that Lycium barbarum glycopeptide can effectively mitigate iron overload within ischemic neurons due to its robust antioxidant properties.The aims of this study were to investigate the effects of Lycium barbarum glycopeptide on ferroptotic damage following brain ischemia and explore the underlying mechanisms.A rat model of middle cerebral artery occlusion was established using the intraluminal filament method,and the rats were treated with Lycium barbarum glycopeptide for 7 consecutive days,beginning 24 hours after ischemia.Liproxstatin-1,a ferroptosis inhibitor,and Erastin,a ferroptosis activator,were used as controls.We found that treatment with Lycium barbarum glycopeptide resulted in significant reductions in infarct volume(as detected by triphenyltetrazolium chloride staining staining and magnetic resonance imaging)and neuronal death(as measured by Nissl staining),as well as improvements in sensory and motor functions in rats subjected to middle cerebral artery occlusion.Furthermore,treatment with Lycium barbarum glycopeptide alleviated anxiety and depression-like behaviors and improved memory.Additionally,Lycium barbarum glycopeptide effectively reduced the iron ion content in the ischemic penumbra of the cortex.Moreover,treatment with Lycium barbarum glycopeptide downregulated the expression of ferroptotic and oxidant proteins such as transferrin receptor 1,divalent metal transporter 1,and Acyl-CoA synthetase long-chain family member 4 and upregulated the expression of anti-ferroptotic and antioxidant proteins such as ferroportin 1,solute carrier family 7 member 11,glutathione,and glutathione peroxidase 4.However,these beneficial effects were reversed when ferroptosis was induced with the activator Erastin.Therefore,the positive effects of Lycium barbarum glycopeptide in ischemic stroke are likely mediated through activation of the anti-ferroptotic pathway and the antioxidative System Xc-glutathione-glutathione peroxidase 4 pathway.Overall,our findings highlight the potential use of Lycium barbarum glycopeptide as a neuroprotective agent targeting both ferroptosis and oxidation to decrease ischemic brain damage.展开更多
Photoreceptor degeneration is a major cause of vision impairment in retinal diseases,for which no effective treatment currently exists.Previous research by our team demonstrated that Lycium barbarum glycopeptide and l...Photoreceptor degeneration is a major cause of vision impairment in retinal diseases,for which no effective treatment currently exists.Previous research by our team demonstrated that Lycium barbarum glycopeptide and luteolin can independently promote photoreceptor survival and function in degenerated mouse retinas,although with limited efficacy.This study evaluated whether a combination of Lycium barbarum glycopeptide and luteolin provides enhanced therapeutic benefits compared with either compound alone.Wild-type mice received a daily oral gavage of Lycium barbarum glycopeptide and luteolin for 7 days prior to intraperitoneal injection of N-nitroso-N-methylurea to induce photoreceptor damage.The treatment continued for an additional week after injury.Retinal structure and function were subsequently assessed using electroretinogram recordings,visual behavior testing,and immunostaining.Western blot analysis was conducted to investigate the underlying protective mechanisms.The results showed that the Lycium barbarum glycopeptide-luteolin mixture significantly increased photoreceptor survival,improved retinal light response,and enhanced visual behavior.Importantly,the combination outperformed either compound alone in protective efficacy.Mechanistic analysis indicated that the mixture suppressed retinal inflammation and modulated the extracellular signal-regulated kinase and Bcl-2-associated X protein/B-cell lymphoma 2 signaling pathways.These findings suggest that the combination of Lycium barbarum glycopeptide and luteolin represents a promising therapeutic strategy for photoreceptor degeneration.展开更多
In the words of the late Sir Colin Blakemore,neurologists have historically sought to infer brain functions in a manner akin to to king a hammer to a computeranalyzing localized anatomical lesions caused by trauma,tum...In the words of the late Sir Colin Blakemore,neurologists have historically sought to infer brain functions in a manner akin to to king a hammer to a computeranalyzing localized anatomical lesions caused by trauma,tumors,or strokes,noting deficits,and inferring what functions certain brain regions may be responsible for.This approach exemplifies a deletion heuristic,where the absence of a specific function reveals insights about the underlying structures or mechanisms responsible for it.By observing what is lost when a particular brain region is damaged,throughout the history of the field,neurologists have pieced together the intricate relationship between anatomy and function.展开更多
Parkinson’s disease(PD)is a progressive age-related neurodegenerative disorder clinically defined by motor symptoms and pathologically by the loss of dopaminergic(DA)neurons in the substantia nigra pars compacta.Thes...Parkinson’s disease(PD)is a progressive age-related neurodegenerative disorder clinically defined by motor symptoms and pathologically by the loss of dopaminergic(DA)neurons in the substantia nigra pars compacta.These neurons are characterized by the presence of the cytoplasmic pigment neuromelanin(NM),and their degeneration is closely associated with the accumulation ofα-synuclein(α-syn)into intraneuronal inclusions known as Lewy bodies(LBs),which represent a neuropathological hallmark of PD.展开更多
As joint operations have become a key trend in modern military development,unmanned aerial vehicles(UAVs)play an increasingly important role in enhancing the intelligence and responsiveness of combat systems.However,t...As joint operations have become a key trend in modern military development,unmanned aerial vehicles(UAVs)play an increasingly important role in enhancing the intelligence and responsiveness of combat systems.However,the heterogeneity of aircraft,partial observability,and dynamic uncertainty in operational airspace pose significant challenges to autonomous collision avoidance using traditional methods.To address these issues,this paper proposes an adaptive collision avoidance approach for UAVs based on deep reinforcement learning.First,a unified uncertainty model incorporating dynamic wind fields is constructed to capture the complexity of joint operational environments.Then,to effectively handle the heterogeneity between manned and unmanned aircraft and the limitations of dynamic observations,a sector-based partial observation mechanism is designed.A Dynamic Threat Prioritization Assessment algorithm is also proposed to evaluate potential collision threats from multiple dimensions,including time to closest approach,minimum separation distance,and aircraft type.Furthermore,a Hierarchical Prioritized Experience Replay(HPER)mechanism is introduced,which classifies experience samples into high,medium,and low priority levels to preferentially sample critical experiences,thereby improving learning efficiency and accelerating policy convergence.Simulation results show that the proposed HPER-D3QN algorithm outperforms existing methods in terms of learning speed,environmental adaptability,and robustness,significantly enhancing collision avoidance performance and convergence rate.Finally,transfer experiments on a high-fidelity battlefield airspace simulation platform validate the proposed method's deployment potential and practical applicability in complex,real-world joint operational scenarios.展开更多
The development of clinical candidates that modify the natural progression of sporadic Parkinson's disease and related synucleinopathies is a praiseworthy endeavor,but extremely challenging.Therapeutic candidates ...The development of clinical candidates that modify the natural progression of sporadic Parkinson's disease and related synucleinopathies is a praiseworthy endeavor,but extremely challenging.Therapeutic candidates that were successful in preclinical Parkinson's disease animal models have repeatedly failed when tested in clinical trials.While these failures have many possible explanations,it is perhaps time to recognize that the problem lies with the animal models rather than the putative candidate.In other words,the lack of adequate animal models of Parkinson's disease currently represents the main barrier to preclinical identification of potential disease-modifying therapies likely to succeed in clinical trials.However,this barrier may be overcome by the recent introduction of novel generations of viral vectors coding for different forms of alpha-synuclein species and related genes.Although still facing several limitations,these models have managed to mimic the known neuropathological hallmarks of Parkinson's disease with unprecedented accuracy,delineating a more optimistic scenario for the near future.展开更多
Radiation-induced brain injury remains one of the most severe complications of radiotherapy for head and neck tumors,with limited options for prevention and treatment.In situ neural regeneration technology has demonst...Radiation-induced brain injury remains one of the most severe complications of radiotherapy for head and neck tumors,with limited options for prevention and treatment.In situ neural regeneration technology has demonstrated promising therapeutic effects in various neurodegenerative and neurotrauma conditions.In this study,we overexpressed the neural transcription factor NeuroD1 using in situ neural regeneration technology in a radiation-induced brain injury mouse model.This approach converted reactive astrocytes into neurons,increased neuronal density,protected endogenous neurons,decreased microglial activation,reduced peripheral CD8+T cell infiltration,and diminished angiogenesis in the injured area,leading to a significant reduction in lesion volume.Additionally,we explored the potential mechanisms of NeuroD1 in situ neural regeneration technology through bulk RNA sequencing,which showed an upregulation of neurogenesis-related genes and a downregulation of immune response-related and angiogenesis-related genes.Furthermore,our findings suggested that NeuroD1 in situ neural regeneration technology converted reactive astrocytes into neurons and reduced microglial activation in a thalamic hemorrhagic stroke mouse model.In summary,this study supports NeuroD1 in situ neural regeneration technology as a potential therapeutic approach for treating radiation-induced brain injury and hemorrhagic stroke,and offers new insights into the therapeutic role of NeuroD1 in delayed brain injury.展开更多
Adult-born oligodendrocytes are continuously produced in the brains of rodents.The functional role of these cells has been linked to the motor-related activities of healthy animals and is vital for acquiring new motor...Adult-born oligodendrocytes are continuously produced in the brains of rodents.The functional role of these cells has been linked to the motor-related activities of healthy animals and is vital for acquiring new motor skills.However,the relationship between these cells and the control of motor-related activities has not been investigated in pathological conditions.Therefore,the aim of this study is to investigate the role of oligodendrocytes in depression-related motor deficits and the effects of training.Psychomotor retardation is a key symptom of depression.Consistent with the impairments observed in rodent motor performance,the proliferation and activation of adult-born oligodendrocytes are altered in a corticosterone-induced stress paradigm.Therapeutic rotarod training can alleviate these symptoms by reversing the aforementioned changes.Notably,these alterations are particularly pronounced in layer I of the motor cortex.Thus,this study provides evidence of the potential functional involvement of adult-born oligodendrocytes in the motor impairments observed in the depressed animals.Additionally,it offers preliminary results for further investigation into layer I of the motor cortex in relation to these pathological conditions.展开更多
Crack detection accuracy in computer vision is often constrained by limited annotated datasets.Although Generative Adversarial Networks(GANs)have been applied for data augmentation,they frequently introduce blurs and ...Crack detection accuracy in computer vision is often constrained by limited annotated datasets.Although Generative Adversarial Networks(GANs)have been applied for data augmentation,they frequently introduce blurs and artifacts.To address this challenge,this study leverages Denoising Diffusion Probabilistic Models(DDPMs)to generate high-quality synthetic crack images,enriching the training set with diverse and structurally consistent samples that enhance the crack segmentation.The proposed framework involves a two-stage pipeline:first,DDPMs are used to synthesize high-fidelity crack images that capture fine structural details.Second,these generated samples are combined with real data to train segmentation networks,thereby improving accuracy and robustness in crack detection.Compared with GAN-based approaches,DDPM achieved the best fidelity,with the highest Structural Similarity Index(SSIM)(0.302)and lowest Learned Perceptual Image Patch Similarity(LPIPS)(0.461),producing artifact-free images that preserve fine crack details.To validate its effectiveness,six segmentation models were tested,among which LinkNet consistently achieved the best performance,excelling in both region-level accuracy and structural continuity.Incorporating DDPM-augmented data further enhanced segmentation outcomes,increasing F1 scores by up to 1.1%and IoU by 1.7%,while also improving boundary alignment and skeleton continuity compared with models trained on real images alone.Experiments with varying augmentation ratios showed consistent improvements,with F1 rising from 0.946(no augmentation)to 0.957 and IoU from 0.897 to 0.913 at the highest ratio.These findings demonstrate the effectiveness of diffusion-based augmentation for complex crack detection in structural health monitoring.展开更多
1.Yeast studies on the benefit of simvastatin in reducing levels of amyloid betaian Macreadie,Sudip Dhakal,Mishal Subhan,Ken Gardiner,Joshua Fraser RMIT University,Melbourne,Victoria,Australia A large-scale epidemiolo...1.Yeast studies on the benefit of simvastatin in reducing levels of amyloid betaian Macreadie,Sudip Dhakal,Mishal Subhan,Ken Gardiner,Joshua Fraser RMIT University,Melbourne,Victoria,Australia A large-scale epidemiology study on statins previously showed that simvastatin was unique among statins in reducing the incidence of dementia.Since amyloid beta(Aβ42)is the protein that is most associated with Alzheimer's disease,this study has focused on how simvastatin influences the turnover of native Aβ42 and Aβ42 fused with green昀uorescent protein(GFP),in the simplest eukaryotic model organism,saccharomyces cerevisiae.Previous studies have established that yeast constitutively producing Aβ42 fused to GFP offer a convenient means of analyzing yeast cellular responses to Aβ42.展开更多
Spinal and bulbar muscular atrophy is a neurodegenerative disease caused by extended CAG trinucleotide repeats in the androgen receptor gene,which encodes a ligand-dependent transcription facto r.The mutant androgen r...Spinal and bulbar muscular atrophy is a neurodegenerative disease caused by extended CAG trinucleotide repeats in the androgen receptor gene,which encodes a ligand-dependent transcription facto r.The mutant androgen receptor protein,characterized by polyglutamine expansion,is prone to misfolding and forms aggregates in both the nucleus and cytoplasm in the brain in spinal and bulbar muscular atrophy patients.These aggregates alter protein-protein interactions and compromise transcriptional activity.In this study,we reported that in both cultured N2a cells and mouse brain,mutant androgen receptor with polyglutamine expansion causes reduced expression of mesencephalic astrocyte-de rived neurotrophic factor.Overexpressio n of mesencephalic astrocyte-derived neurotrophic factor amelio rated the neurotoxicity of mutant androgen receptor through the inhibition of mutant androgen receptor aggregation.Conversely.knocking down endogenous mesencephalic astrocyte-derived neurotrophic factor in the mouse brain exacerbated neuronal damage and mutant androgen receptor aggregation.Our findings suggest that inhibition of mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor is a potential mechanism underlying neurodegeneration in spinal and bulbar muscular atrophy.展开更多
Direct in vivo conversion of astrocytes into functional new neurons induced by neural transcription factors has been recognized as a potential new therapeutic intervention for neural injury and degenerative disorders....Direct in vivo conversion of astrocytes into functional new neurons induced by neural transcription factors has been recognized as a potential new therapeutic intervention for neural injury and degenerative disorders. However, a few recent studies have claimed that neural transcription factors cannot convert astrocytes into neurons, attributing the converted neurons to pre-existing neurons mis-expressing transgenes. In this study, we overexpressed three distinct neural transcription factors––NeuroD1, Ascl1, and Dlx2––in reactive astrocytes in mouse cortices subjected to stab injury, resulting in a series of significant changes in astrocyte properties. Initially, the three neural transcription factors were exclusively expressed in the nuclei of astrocytes. Over time, however, these astrocytes gradually adopted neuronal morphology, and the neural transcription factors was gradually observed in the nuclei of neuron-like cells instead of astrocytes. Furthermore,we noted that transcription factor-infected astrocytes showed a progressive decrease in the expression of astrocytic markers AQP4(astrocyte endfeet signal), CX43(gap junction signal), and S100β. Importantly, none of these changes could be attributed to transgene leakage into preexisting neurons. Therefore, our findings suggest that neural transcription factors such as NeuroD1, Ascl1, and Dlx2 can effectively convert reactive astrocytes into neurons in the adult mammalian brain.展开更多
The vast majority of in vitro studies have demonstrated that PINK1 phosphorylates Parkin to work together in mitophagy to protect against neuronal degeneration.However,it remains largely unclear how PINK1 and Parkin a...The vast majority of in vitro studies have demonstrated that PINK1 phosphorylates Parkin to work together in mitophagy to protect against neuronal degeneration.However,it remains largely unclear how PINK1 and Parkin are expressed in mammalian brains.This has been difficult to address because of the intrinsically low levels of PINK1 and undetectable levels of phosphorylated Parkin in small animals.Understanding this issue is critical for elucidating the in vivo roles of PINK1 and Parkin.Recently,we showed that the PINK1 kinase is selectively expressed as a truncated form(PINK1–55)in the primate brain.In the present study,we used multiple antibodies,including our recently developed monoclonal anti-PINK1,to validate the selective expression of PINK1 in the primate brain.We found that PINK1 was stably expressed in the monkey brain at postnatal and adulthood stages,which is consistent with the findings that depleting PINK1 can cause neuronal loss in developing and adult monkey brains.PINK1 was enriched in the membrane-bound fractionations,whereas Parkin was soluble with a distinguishable distribution.Immunofluorescent double staining experiments showed that PINK1 and Parkin did not colocalize under physiological conditions in cultured monkey astrocytes,though they did colocalize on mitochondria when the cells were exposed to mitochondrial stress.These findings suggest that PINK1 and Parkin may have distinct roles beyond their well-known function in mitophagy during mitochondrial damage.展开更多
The presence of endogenous neural stem/progenitor cells in the adult mammalian brain suggests that the central nervous system can be repaired and regenerated after injury.However,whether it is possible to stimulate ne...The presence of endogenous neural stem/progenitor cells in the adult mammalian brain suggests that the central nervous system can be repaired and regenerated after injury.However,whether it is possible to stimulate neurogenesis and reconstruct cortical layers II to VI in non-neurogenic regions,such as the cortex,remains unknown.In this study,we implanted a hyaluronic acid collagen gel loaded with basic fibroblast growth factor into the motor cortex immediately following traumatic injury.Our findings reveal that this gel effectively stimulated the proliferation and migration of endogenous neural stem/progenitor cells,as well as their differentiation into mature and functionally integrated neurons.Importantly,these new neurons reconstructed the architecture of cortical layers II to VI,integrated into the existing neural circuitry,and ultimately led to improved brain function.These findings offer novel insight into potential clinical treatments for traumatic cerebral cortex injuries.展开更多
文摘The fibrotic scar due to excessive deposition of extracellular matrix(ECM)after spinal cord injury(SCI)remains one of formidable challenges to axonal regeneration.Previous therapeutic strategies mainly focus on eliminating fibrotic scars by blocking(Göritz et al.,2011)or inhibiting(Dias et al.,2018)the generation of scar-forming stromal cells,as well as inducing their migratory defect(Hellal et al.,2011;Ruschel et al.,2015).
基金National Nature Science Foundation of China,No.30971530(to YR)The National 111 Project,No.B14036(to KFS)Key Basic Study and Functional Product Research of Wolfberry Grant of Ningxia Hui Autonomous Region(to KFS).
文摘Recent studies have indicated that stroke can lead to neuronal iron overload and lipid peroxidation.Lycium barbarum glycopeptide,which has a low molecular weight and potent antioxidant properties,may mitigate ferroptosis in stroke.We hypothesized that Lycium barbarum glycopeptide can effectively mitigate iron overload within ischemic neurons due to its robust antioxidant properties.The aims of this study were to investigate the effects of Lycium barbarum glycopeptide on ferroptotic damage following brain ischemia and explore the underlying mechanisms.A rat model of middle cerebral artery occlusion was established using the intraluminal filament method,and the rats were treated with Lycium barbarum glycopeptide for 7 consecutive days,beginning 24 hours after ischemia.Liproxstatin-1,a ferroptosis inhibitor,and Erastin,a ferroptosis activator,were used as controls.We found that treatment with Lycium barbarum glycopeptide resulted in significant reductions in infarct volume(as detected by triphenyltetrazolium chloride staining staining and magnetic resonance imaging)and neuronal death(as measured by Nissl staining),as well as improvements in sensory and motor functions in rats subjected to middle cerebral artery occlusion.Furthermore,treatment with Lycium barbarum glycopeptide alleviated anxiety and depression-like behaviors and improved memory.Additionally,Lycium barbarum glycopeptide effectively reduced the iron ion content in the ischemic penumbra of the cortex.Moreover,treatment with Lycium barbarum glycopeptide downregulated the expression of ferroptotic and oxidant proteins such as transferrin receptor 1,divalent metal transporter 1,and Acyl-CoA synthetase long-chain family member 4 and upregulated the expression of anti-ferroptotic and antioxidant proteins such as ferroportin 1,solute carrier family 7 member 11,glutathione,and glutathione peroxidase 4.However,these beneficial effects were reversed when ferroptosis was induced with the activator Erastin.Therefore,the positive effects of Lycium barbarum glycopeptide in ischemic stroke are likely mediated through activation of the anti-ferroptotic pathway and the antioxidative System Xc-glutathione-glutathione peroxidase 4 pathway.Overall,our findings highlight the potential use of Lycium barbarum glycopeptide as a neuroprotective agent targeting both ferroptosis and oxidation to decrease ischemic brain damage.
基金Natural Science Foundation of Guangdong Province,No.2023A1515012397(to YX)the National Natural Science Foundation of China,No.82074169(to XM)+2 种基金the Guangdong Basic and Applied Basic Research Foundation,No.2021A1515012473(to XM)and Project of Administration of Traditional Chinese Medicine of Guangdong Province,No.20202045(to XM)Aier Eye Hospital Group,No.AF2019001(to ST,KFS,YX,and XM).
文摘Photoreceptor degeneration is a major cause of vision impairment in retinal diseases,for which no effective treatment currently exists.Previous research by our team demonstrated that Lycium barbarum glycopeptide and luteolin can independently promote photoreceptor survival and function in degenerated mouse retinas,although with limited efficacy.This study evaluated whether a combination of Lycium barbarum glycopeptide and luteolin provides enhanced therapeutic benefits compared with either compound alone.Wild-type mice received a daily oral gavage of Lycium barbarum glycopeptide and luteolin for 7 days prior to intraperitoneal injection of N-nitroso-N-methylurea to induce photoreceptor damage.The treatment continued for an additional week after injury.Retinal structure and function were subsequently assessed using electroretinogram recordings,visual behavior testing,and immunostaining.Western blot analysis was conducted to investigate the underlying protective mechanisms.The results showed that the Lycium barbarum glycopeptide-luteolin mixture significantly increased photoreceptor survival,improved retinal light response,and enhanced visual behavior.Importantly,the combination outperformed either compound alone in protective efficacy.Mechanistic analysis indicated that the mixture suppressed retinal inflammation and modulated the extracellular signal-regulated kinase and Bcl-2-associated X protein/B-cell lymphoma 2 signaling pathways.These findings suggest that the combination of Lycium barbarum glycopeptide and luteolin represents a promising therapeutic strategy for photoreceptor degeneration.
文摘In the words of the late Sir Colin Blakemore,neurologists have historically sought to infer brain functions in a manner akin to to king a hammer to a computeranalyzing localized anatomical lesions caused by trauma,tumors,or strokes,noting deficits,and inferring what functions certain brain regions may be responsible for.This approach exemplifies a deletion heuristic,where the absence of a specific function reveals insights about the underlying structures or mechanisms responsible for it.By observing what is lost when a particular brain region is damaged,throughout the history of the field,neurologists have pieced together the intricate relationship between anatomy and function.
文摘Parkinson’s disease(PD)is a progressive age-related neurodegenerative disorder clinically defined by motor symptoms and pathologically by the loss of dopaminergic(DA)neurons in the substantia nigra pars compacta.These neurons are characterized by the presence of the cytoplasmic pigment neuromelanin(NM),and their degeneration is closely associated with the accumulation ofα-synuclein(α-syn)into intraneuronal inclusions known as Lewy bodies(LBs),which represent a neuropathological hallmark of PD.
基金supported by the National Key Research and Development Program of China(No.2022YFB4300902).
文摘As joint operations have become a key trend in modern military development,unmanned aerial vehicles(UAVs)play an increasingly important role in enhancing the intelligence and responsiveness of combat systems.However,the heterogeneity of aircraft,partial observability,and dynamic uncertainty in operational airspace pose significant challenges to autonomous collision avoidance using traditional methods.To address these issues,this paper proposes an adaptive collision avoidance approach for UAVs based on deep reinforcement learning.First,a unified uncertainty model incorporating dynamic wind fields is constructed to capture the complexity of joint operational environments.Then,to effectively handle the heterogeneity between manned and unmanned aircraft and the limitations of dynamic observations,a sector-based partial observation mechanism is designed.A Dynamic Threat Prioritization Assessment algorithm is also proposed to evaluate potential collision threats from multiple dimensions,including time to closest approach,minimum separation distance,and aircraft type.Furthermore,a Hierarchical Prioritized Experience Replay(HPER)mechanism is introduced,which classifies experience samples into high,medium,and low priority levels to preferentially sample critical experiences,thereby improving learning efficiency and accelerating policy convergence.Simulation results show that the proposed HPER-D3QN algorithm outperforms existing methods in terms of learning speed,environmental adaptability,and robustness,significantly enhancing collision avoidance performance and convergence rate.Finally,transfer experiments on a high-fidelity battlefield airspace simulation platform validate the proposed method's deployment potential and practical applicability in complex,real-world joint operational scenarios.
基金supported by grants PID2020-120308RB-I00 and PID2023-147802OB-I00 funded by MICIU/AEI/10.13039/501100011033FEDER,UE,by Aligning Science Across Parkinson’s(ref.ASAP-020505)through the Michael J.Fox Foundation for Parkinson’s Research+1 种基金by CiberNed Intramural Collaborative Projects(ref.PI2020/09)by the Spanish Fundación Mutua Madrile?a de Investigación Médica(to JLL)。
文摘The development of clinical candidates that modify the natural progression of sporadic Parkinson's disease and related synucleinopathies is a praiseworthy endeavor,but extremely challenging.Therapeutic candidates that were successful in preclinical Parkinson's disease animal models have repeatedly failed when tested in clinical trials.While these failures have many possible explanations,it is perhaps time to recognize that the problem lies with the animal models rather than the putative candidate.In other words,the lack of adequate animal models of Parkinson's disease currently represents the main barrier to preclinical identification of potential disease-modifying therapies likely to succeed in clinical trials.However,this barrier may be overcome by the recent introduction of novel generations of viral vectors coding for different forms of alpha-synuclein species and related genes.Although still facing several limitations,these models have managed to mimic the known neuropathological hallmarks of Parkinson's disease with unprecedented accuracy,delineating a more optimistic scenario for the near future.
基金the National Natural Science Foundation of China,Nos.81925031(to YT)82330099(to YT)+7 种基金82404189(to KZ)the Key-Area Research and Development Program of Guangdong Province,No.2023B0303040003(to YT)STI 2030-Major Projects,No.2022ZD0211603(to YT)Guangzhou Key Projects of Brain Science and Brain-Like Intelligence Technology,No.202206060002(to GC and YS)Science and Technology Project of Guangdong Province,No.2018B030332001(to GC)Guangdong Provincial Pearl River Project,No.2021ZT09Y552(to GC)the Guangdong Basic and Applied Basic Research Foundation,No.2022A1515110189(to KZ)Sun Yat-sen Pilot Scientific Research Fund,No.YXQH202427(to KZ).
文摘Radiation-induced brain injury remains one of the most severe complications of radiotherapy for head and neck tumors,with limited options for prevention and treatment.In situ neural regeneration technology has demonstrated promising therapeutic effects in various neurodegenerative and neurotrauma conditions.In this study,we overexpressed the neural transcription factor NeuroD1 using in situ neural regeneration technology in a radiation-induced brain injury mouse model.This approach converted reactive astrocytes into neurons,increased neuronal density,protected endogenous neurons,decreased microglial activation,reduced peripheral CD8+T cell infiltration,and diminished angiogenesis in the injured area,leading to a significant reduction in lesion volume.Additionally,we explored the potential mechanisms of NeuroD1 in situ neural regeneration technology through bulk RNA sequencing,which showed an upregulation of neurogenesis-related genes and a downregulation of immune response-related and angiogenesis-related genes.Furthermore,our findings suggested that NeuroD1 in situ neural regeneration technology converted reactive astrocytes into neurons and reduced microglial activation in a thalamic hemorrhagic stroke mouse model.In summary,this study supports NeuroD1 in situ neural regeneration technology as a potential therapeutic approach for treating radiation-induced brain injury and hemorrhagic stroke,and offers new insights into the therapeutic role of NeuroD1 in delayed brain injury.
基金supported by Hong Kong Health and Medical Research Fund,No.02133206(to KFS).
文摘Adult-born oligodendrocytes are continuously produced in the brains of rodents.The functional role of these cells has been linked to the motor-related activities of healthy animals and is vital for acquiring new motor skills.However,the relationship between these cells and the control of motor-related activities has not been investigated in pathological conditions.Therefore,the aim of this study is to investigate the role of oligodendrocytes in depression-related motor deficits and the effects of training.Psychomotor retardation is a key symptom of depression.Consistent with the impairments observed in rodent motor performance,the proliferation and activation of adult-born oligodendrocytes are altered in a corticosterone-induced stress paradigm.Therapeutic rotarod training can alleviate these symptoms by reversing the aforementioned changes.Notably,these alterations are particularly pronounced in layer I of the motor cortex.Thus,this study provides evidence of the potential functional involvement of adult-born oligodendrocytes in the motor impairments observed in the depressed animals.Additionally,it offers preliminary results for further investigation into layer I of the motor cortex in relation to these pathological conditions.
基金the National Natural Science Foundation of China(Grant No.:52508343)the Fundamental Research Funds for the Central Universities(Grant No.:B250201004).
文摘Crack detection accuracy in computer vision is often constrained by limited annotated datasets.Although Generative Adversarial Networks(GANs)have been applied for data augmentation,they frequently introduce blurs and artifacts.To address this challenge,this study leverages Denoising Diffusion Probabilistic Models(DDPMs)to generate high-quality synthetic crack images,enriching the training set with diverse and structurally consistent samples that enhance the crack segmentation.The proposed framework involves a two-stage pipeline:first,DDPMs are used to synthesize high-fidelity crack images that capture fine structural details.Second,these generated samples are combined with real data to train segmentation networks,thereby improving accuracy and robustness in crack detection.Compared with GAN-based approaches,DDPM achieved the best fidelity,with the highest Structural Similarity Index(SSIM)(0.302)and lowest Learned Perceptual Image Patch Similarity(LPIPS)(0.461),producing artifact-free images that preserve fine crack details.To validate its effectiveness,six segmentation models were tested,among which LinkNet consistently achieved the best performance,excelling in both region-level accuracy and structural continuity.Incorporating DDPM-augmented data further enhanced segmentation outcomes,increasing F1 scores by up to 1.1%and IoU by 1.7%,while also improving boundary alignment and skeleton continuity compared with models trained on real images alone.Experiments with varying augmentation ratios showed consistent improvements,with F1 rising from 0.946(no augmentation)to 0.957 and IoU from 0.897 to 0.913 at the highest ratio.These findings demonstrate the effectiveness of diffusion-based augmentation for complex crack detection in structural health monitoring.
文摘1.Yeast studies on the benefit of simvastatin in reducing levels of amyloid betaian Macreadie,Sudip Dhakal,Mishal Subhan,Ken Gardiner,Joshua Fraser RMIT University,Melbourne,Victoria,Australia A large-scale epidemiology study on statins previously showed that simvastatin was unique among statins in reducing the incidence of dementia.Since amyloid beta(Aβ42)is the protein that is most associated with Alzheimer's disease,this study has focused on how simvastatin influences the turnover of native Aβ42 and Aβ42 fused with green昀uorescent protein(GFP),in the simplest eukaryotic model organism,saccharomyces cerevisiae.Previous studies have established that yeast constitutively producing Aβ42 fused to GFP offer a convenient means of analyzing yeast cellular responses to Aβ42.
基金supported by the National Key R&D Program of China,No.2021YFA0805200(to SY)the National Natural Science Foundation of China,No.31970954(to SY)two grants from the Department of Science and Technology of Guangdong Province,Nos.2021ZT09Y007,2020B121201006(both to XJL)。
文摘Spinal and bulbar muscular atrophy is a neurodegenerative disease caused by extended CAG trinucleotide repeats in the androgen receptor gene,which encodes a ligand-dependent transcription facto r.The mutant androgen receptor protein,characterized by polyglutamine expansion,is prone to misfolding and forms aggregates in both the nucleus and cytoplasm in the brain in spinal and bulbar muscular atrophy patients.These aggregates alter protein-protein interactions and compromise transcriptional activity.In this study,we reported that in both cultured N2a cells and mouse brain,mutant androgen receptor with polyglutamine expansion causes reduced expression of mesencephalic astrocyte-de rived neurotrophic factor.Overexpressio n of mesencephalic astrocyte-derived neurotrophic factor amelio rated the neurotoxicity of mutant androgen receptor through the inhibition of mutant androgen receptor aggregation.Conversely.knocking down endogenous mesencephalic astrocyte-derived neurotrophic factor in the mouse brain exacerbated neuronal damage and mutant androgen receptor aggregation.Our findings suggest that inhibition of mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor is a potential mechanism underlying neurodegeneration in spinal and bulbar muscular atrophy.
基金supported by the Key Project of Guangzhou City,No.202206060002Science and Technology Project of Guangdong Province,No.2018B030332001Guangdong Provincial Pearl River Project,No.2021ZT09Y552 (all to GC)。
文摘Direct in vivo conversion of astrocytes into functional new neurons induced by neural transcription factors has been recognized as a potential new therapeutic intervention for neural injury and degenerative disorders. However, a few recent studies have claimed that neural transcription factors cannot convert astrocytes into neurons, attributing the converted neurons to pre-existing neurons mis-expressing transgenes. In this study, we overexpressed three distinct neural transcription factors––NeuroD1, Ascl1, and Dlx2––in reactive astrocytes in mouse cortices subjected to stab injury, resulting in a series of significant changes in astrocyte properties. Initially, the three neural transcription factors were exclusively expressed in the nuclei of astrocytes. Over time, however, these astrocytes gradually adopted neuronal morphology, and the neural transcription factors was gradually observed in the nuclei of neuron-like cells instead of astrocytes. Furthermore,we noted that transcription factor-infected astrocytes showed a progressive decrease in the expression of astrocytic markers AQP4(astrocyte endfeet signal), CX43(gap junction signal), and S100β. Importantly, none of these changes could be attributed to transgene leakage into preexisting neurons. Therefore, our findings suggest that neural transcription factors such as NeuroD1, Ascl1, and Dlx2 can effectively convert reactive astrocytes into neurons in the adult mammalian brain.
基金supported by the National Natural Science Foundation of China,Nos.32070534(to WY),32370567(to WY),82371874(to XL),81830032(to XL),82071421(to SL)Key Field Research and Development Program of Guangdong Province,No.2018B030337001(to XL)+2 种基金Guangzhou Key Research Program on Brain Science,No.202007030008(to XL)Department of Science and Technology of Guangdong Province,Nos.2021ZT09Y007,2020B121201006(to XL)Guangdong Basic and Applied Basic Research Foundation,Nos.2022A1515012301(to WY),2023B1515020031(to WY).
文摘The vast majority of in vitro studies have demonstrated that PINK1 phosphorylates Parkin to work together in mitophagy to protect against neuronal degeneration.However,it remains largely unclear how PINK1 and Parkin are expressed in mammalian brains.This has been difficult to address because of the intrinsically low levels of PINK1 and undetectable levels of phosphorylated Parkin in small animals.Understanding this issue is critical for elucidating the in vivo roles of PINK1 and Parkin.Recently,we showed that the PINK1 kinase is selectively expressed as a truncated form(PINK1–55)in the primate brain.In the present study,we used multiple antibodies,including our recently developed monoclonal anti-PINK1,to validate the selective expression of PINK1 in the primate brain.We found that PINK1 was stably expressed in the monkey brain at postnatal and adulthood stages,which is consistent with the findings that depleting PINK1 can cause neuronal loss in developing and adult monkey brains.PINK1 was enriched in the membrane-bound fractionations,whereas Parkin was soluble with a distinguishable distribution.Immunofluorescent double staining experiments showed that PINK1 and Parkin did not colocalize under physiological conditions in cultured monkey astrocytes,though they did colocalize on mitochondria when the cells were exposed to mitochondrial stress.These findings suggest that PINK1 and Parkin may have distinct roles beyond their well-known function in mitophagy during mitochondrial damage.
基金supported by the National Natural Science Foundation of China,Nos.82272171(to ZY),82271403(to XL),81941011(to XL),31971279(to ZY),31730030(to XL)the Natural Science Foundation of Beijing,No.7222004(to HD).
文摘The presence of endogenous neural stem/progenitor cells in the adult mammalian brain suggests that the central nervous system can be repaired and regenerated after injury.However,whether it is possible to stimulate neurogenesis and reconstruct cortical layers II to VI in non-neurogenic regions,such as the cortex,remains unknown.In this study,we implanted a hyaluronic acid collagen gel loaded with basic fibroblast growth factor into the motor cortex immediately following traumatic injury.Our findings reveal that this gel effectively stimulated the proliferation and migration of endogenous neural stem/progenitor cells,as well as their differentiation into mature and functionally integrated neurons.Importantly,these new neurons reconstructed the architecture of cortical layers II to VI,integrated into the existing neural circuitry,and ultimately led to improved brain function.These findings offer novel insight into potential clinical treatments for traumatic cerebral cortex injuries.
