Background Despite increasing in vitro research,direct evidence of how abnormalα-synuclein(α-Syn)dysregulates vesicular transport and synaptic function in the human brain is lacking.Methods We performed a transcript...Background Despite increasing in vitro research,direct evidence of how abnormalα-synuclein(α-Syn)dysregulates vesicular transport and synaptic function in the human brain is lacking.Methods We performed a transcriptome analysis using brain tissues from a multiple system atrophy(MSA)mouse model,which develops humanα-Syn-positive glial cytoplasmic inclusion-like structures and neuronal cytoplasmic inclusion-like structures after tamoxifen injection.We then performed histologic and biochemical analyses using brain samples from 71 human cases(Parkinson’s disease,n=10;dementia with Lewy bodies[DLB],n=19;MSA,n=15;control:n=27),a human blood sample(control:n=1),and cultured cells.Results Based on the transcriptome of the MSA mouse model,we identified 10 vesicular transport proteins,including synaptotagmin 13(SYT13),that might interact withα-Syn.Immunohistochemistry using human brain samples demonstrated that of the 10 vesicular transport proteins identified in the transcriptome analysis,only SYT13 was incorporated into both Lewy bodies and glial cytoplasmic inclusions.Proximity ligation assays revealed that SYT13 exhibited a higher degree of interactions with phosphorylatedα-Syn than with endogenousα-Syn.Immunoprecipitation confirmed that SYT13 bound predominantly to phosphorylatedα-Syn,SYT1,and the soluble N-ethylmaleimide-sensitive attachment protein receptor(SNARE)complexes.Filter trap assays revealed interactions between SYT13 and soluble toxicβ-sheet-richα-Syn oligomers.Furthermore,fraction analysis showed a significant increase of SYT13 protein levels at the synapses in DLB and MSA.Notably,a correlation was observed between the levels of SYT13 and aggregatedα-Syn at the synapses.SYT13 was observed to regulate extracellular vesicle release in association with SYT1 and the SNARE complexes in SH-SY5Y cells.SYT13 overexpression in SH-SY5Y cells impaired extracellular vesicle release.Consistently,the numbers of extracellular vesicles were significantly reduced in the brain homogenates of DLB and MSA cases compared with those in controls.Conclusions Abnormalα-Syn impairs extracellular vesicle release through interactions with SYT13 in synucleinopathies.Our findings provide insights into therapeutic strategies for alleviating dysregulations of vesicular transport and synaptic function in patients with synucleinopathies.展开更多
Charcot-Marie-Tooth disease(CMT) is a heterogeneous group of inherited peripheral neuro pathies;it is characterized by muscle weakness and wasting,as well as sensory dysfunction,that typically begins during adolescenc...Charcot-Marie-Tooth disease(CMT) is a heterogeneous group of inherited peripheral neuro pathies;it is characterized by muscle weakness and wasting,as well as sensory dysfunction,that typically begins during adolescence and ultimately leads to lifelong disability.Occurring in~1 in 2500individuals,CMT is the most common hereditary neuromuscular condition and results from mutations in> 100 different genes.CMT is grouped into type1(CMT1),where demyelination and loss of nerve conduction velocity occur,type 2(CMT2),where motor and sensory axons degenerate without loss of myelination/nerve conduction velocity,and intermediate CMT,where both demyelination and axon loss present alongside intermediate nerve condu ction velocities.展开更多
Anorectal melanoma is a rare tumor representing less than 1% of anorectal cancers and around 0.3% of malignant melanomas. Its prognosis is particularly poor due to the early occurrence of metastases. We report the cas...Anorectal melanoma is a rare tumor representing less than 1% of anorectal cancers and around 0.3% of malignant melanomas. Its prognosis is particularly poor due to the early occurrence of metastases. We report the case of a 65-year-old man presenting with rectorrhagia and anal pain, initially diagnosed as hemorrhoidal disease. Subsequent proctological examination revealed an ulcerating-bourging tumor, confirmed histologically as an anorectal melanoma. After a normal extension workup, an abdominoperineal amputation was performed. Anorectal melanoma is a pathology with a poor prognosis, requiring early diagnosis to improve chances of survival.展开更多
Against the backdrop of increasingly prominent global energy shortages and environmental issues,the development of efficient energy conversion and storage technologies has become crucial.Zero-dimensional(0D)metal oxid...Against the backdrop of increasingly prominent global energy shortages and environmental issues,the development of efficient energy conversion and storage technologies has become crucial.Zero-dimensional(0D)metal oxide composites exhibit significant application value in the field of energy chemistry due to their unique properties,such as quantum size effect and high specific surface area.From a broad perspective,this paper reviews the main synthesis methods of these composites,including sol-gel method,hydrothermal/solvothermal method,precipitation method,and template method,while analyzing the characteristics of each method.It further discusses their applications in photocatalytic hydrogen production,fuel cells,lithium-ion batteries,and supercapacitors.Additionally,the current challenges,such as material dispersibility and interface bonding,are pointed out,and future development directions are prospected,aiming to provide references for related research.展开更多
Epilepsy affects over 50 million people worldwide.Drug-resistant epilepsy(DRE)accounts for up to a third of these cases,and neuro-inflammation is thought to play a role in such cases.Despite being a long-debated issue...Epilepsy affects over 50 million people worldwide.Drug-resistant epilepsy(DRE)accounts for up to a third of these cases,and neuro-inflammation is thought to play a role in such cases.Despite being a long-debated issue in the field of DRE,the mechanisms underlying neuroinflammation have yet to be fully elucidated.The pro-inflammatory microenvironment within the brain tissue of people with DRE has been probed using single-cell multimodal transcriptomics.Evidence suggests that inflammatory cells and pro-inflammatory cytokines in the nervous system can lead to extensive biochemical changes,such as connexin hemichannel excitability and disruption of neurotransmitter homeostasis.The presence of inflammation may give rise to neuronal network abnormalities that suppress endogenous antiepileptic systems.We focus on the role of neuroinflammation and brain network anomalies in DRE from multiple perspectives to identify critical points for clinical application.We hope to provide an insightful overview to advance the quest for better DRE treatments.展开更多
In the pharmaceutical industry,model-based prediction is a crucial stage in process development that allows pharmaceutical companies to simulate different scenarios toward improving process efficiency,reducing costs,a...In the pharmaceutical industry,model-based prediction is a crucial stage in process development that allows pharmaceutical companies to simulate different scenarios toward improving process efficiency,reducing costs,and enhancing product quality.Nevertheless,ensuring the quality of formulated pharmaceutical products through the management of raw material variations has always been a challenging task.In this work,data-driven chance-constrained recurrent neural networks(CCRNNs)are developed to address the issue arising from raw material uncertainty.Our goal is to explore how,by proactively incorporating uncertainty into the model training process,more accurate predictions and enhanced robustness can be realized.The proposed approach is tested on a fluid bed dryer(FBD)from a continuous pharmaceutical manufacturing pilot plant.The results demonstrate that CCRNN models offer more robust and accurate predictions for the critical quality attribute(CQA)-in this case,moisture content-when material variations occur,compared with conventional recurrent neural network-based models.展开更多
The first liver transplantation(LT)in humans was performed by Thomas Starzl on March 1,1963[1,2](Fig.1).During the period 1963-1983,this challenging procedure was performed in four centers only,one in the USA and thre...The first liver transplantation(LT)in humans was performed by Thomas Starzl on March 1,1963[1,2](Fig.1).During the period 1963-1983,this challenging procedure was performed in four centers only,one in the USA and three in Western Europe:Denver,Cambridge,Hannover and Groningen.Their collected experience including only 540 cases(meaning 27(!)cases yearly)was the basis of the 1983 National Institutes of Health(NIH)development consensus conference leading to the conclusion that LT could become“a promising alternative to the current therapy in the management of the late phase of several forms of serious liver disease…candidates are those who exhausted alternative medical and surgical treatments…and are approaching the terminal phase of their illness”.Patients presenting liver tumors and inherited,liver based,metabolic diseases could also be considered for LT[3].This conference put forward ten absolute and five relative contraindications restricting thereby the access to LT to a minority of very well selected liver diseased patients.展开更多
Introduction Late age-related macular degeneration(AMD)is one of the leading causes of blindness globally(1).In their recent study published in JAMA Ophthalmology,Hallak et al.explore the potential of an emerging ther...Introduction Late age-related macular degeneration(AMD)is one of the leading causes of blindness globally(1).In their recent study published in JAMA Ophthalmology,Hallak et al.explore the potential of an emerging therapeutic opportunity of Janus kinase inhibitor(JAKi)in the role of systemic inflammation in AMD pathogenesis(2).This study offers a real-world examination of the relationship between JAKi and AMD,comparing the incidence of AMD in patients treated with JAKi and those receiving other immunotherapies for existing autoimmune diseases.展开更多
Objective:This article describes a new method(VS-FPM)for analysis of unstained tissues based on the application of supervised machine learning to generate brightfield hematoxylin and eosin(H&E)images from phase im...Objective:This article describes a new method(VS-FPM)for analysis of unstained tissues based on the application of supervised machine learning to generate brightfield hematoxylin and eosin(H&E)images from phase images recovered using Fourier ptychographic microscopy(FPM).Impact Statement:VS-FPM has several advantages for label-free digital pathology.Capture of complex image information simplifies model training and allows post-capture refocusing.FPM images combine high resolution with a large field of view,and the hardware is low-cost and compatible with many existing brightfield microscope systems.Introduction:By generating realistic histologically stained images from label-free image data,virtual staining(VS)methods have the potential to streamline clinical workflows,improve image consistency,and enable new ways of visualizing and analyzing histological tissues.Methods:We trained a conditional generative adversarial network to translate high-resolution FPM images of unstained tissues to brightfield H&E images and assessed the method using diagnosis of colonic polyps as a test case.Results:We found no statistically significant difference between the spatial resolution of FPM images captured at 4×magnification and images from a pathology slide scanner at 20×magnification.Visual assessment and image similarity metrics showed that VS-FPM images of unstained tissues closely resemble images of chemically H&Estained tissues.However,the spatial resolution of virtual H&E images was approximately 20%lower than equivalent images of chemically stained tissues.Using VS-FPM,board-certified pathologists were able to accurately distinguish normal from dysplastic tissues and derive correct pathological diagnoses.Conclusion:VS-FPM is a reliable,accessible VS method that also overcomes many other limitations inherent to histopathology microscopy.展开更多
The Gannan Yellow River source area(YRSA)is a typical ecological fragile region.Assessing the temporal and spatial patterns of resource and environmental carrying capacity(RECC)is crucial for both ecological security ...The Gannan Yellow River source area(YRSA)is a typical ecological fragile region.Assessing the temporal and spatial patterns of resource and environmental carrying capacity(RECC)is crucial for both ecological security and sustainable development of the Yellow River Basin and the YRSA.Based on RECC theory,this study developed a novel index system focused on human-livestock-grassland relationships to accurately capture resource and environmental carrying characteristics in pastoral regions.By establishing region-specific evaluation thresholds and using a comprehensive index approach,we analyzed spatial and temporal patterns of resource carrying capacity(RCC),environmental carrying capacity(ECC),and resource and environmental carrying capacity(RECC)in the Gannan region from 2005 to 2020.The results indicate that:1)The RECC followed an increasing–decreasing–increasing trajectory from 2005 to 2020,with values ranging from 0.30 to 0.69.The RECC in pastoral areas was not only higher but also exhibited greater variability compared to that in agricultural areas.2)The RCC remained at a low level,with values between 0.06 to 0.098.The index of water consumption per ten thousand Yuan of GDP increased significantly,suggesting that improvements in water use efficiency contributed to the enhancement of RCC.3)The ECC increased notably,shifting from the middle to a very high level,with values ranging from 0.233 to 0.611.ECC emerged as a key determinant of RECC,exhibiting a temporal trend closely aligned with that of RECC.Changes in ECC were primarily driven by factors such as overgrazing rates,the extent of grassland rodent control,and the area of grassland for reseeding and improvement.Based on these findings,future priorities should include the adoption of efficient water-saving irrigation technologies,the promotion of rotational grazing practices,and the optimization of land management strategies.展开更多
基金supported by Hirosaki University Priority Research Grant for Future Innovation(YM),JSPS KAKENHI(24K10654(YM),20K16592(TK),23K06802(FM)and 23K24209(KW))the Collaborative Research Project of the Brain Research Institute,Niigata University(YM,AK),AMED(JP23wm0425019 and 24zf0127012(AK))+1 种基金Grants-in-Aid from the Research Committee of CNS Degenerative Diseases,Research on Policy PlanningEvaluation for Rare and Intractable Diseases,Health,Labour and Welfare Sciences Research Grants,the Ministry of Health,Labour and Welfare,Japan(AK).CB is supported by Alzheimer’s Research UK and the MSA Trust.
文摘Background Despite increasing in vitro research,direct evidence of how abnormalα-synuclein(α-Syn)dysregulates vesicular transport and synaptic function in the human brain is lacking.Methods We performed a transcriptome analysis using brain tissues from a multiple system atrophy(MSA)mouse model,which develops humanα-Syn-positive glial cytoplasmic inclusion-like structures and neuronal cytoplasmic inclusion-like structures after tamoxifen injection.We then performed histologic and biochemical analyses using brain samples from 71 human cases(Parkinson’s disease,n=10;dementia with Lewy bodies[DLB],n=19;MSA,n=15;control:n=27),a human blood sample(control:n=1),and cultured cells.Results Based on the transcriptome of the MSA mouse model,we identified 10 vesicular transport proteins,including synaptotagmin 13(SYT13),that might interact withα-Syn.Immunohistochemistry using human brain samples demonstrated that of the 10 vesicular transport proteins identified in the transcriptome analysis,only SYT13 was incorporated into both Lewy bodies and glial cytoplasmic inclusions.Proximity ligation assays revealed that SYT13 exhibited a higher degree of interactions with phosphorylatedα-Syn than with endogenousα-Syn.Immunoprecipitation confirmed that SYT13 bound predominantly to phosphorylatedα-Syn,SYT1,and the soluble N-ethylmaleimide-sensitive attachment protein receptor(SNARE)complexes.Filter trap assays revealed interactions between SYT13 and soluble toxicβ-sheet-richα-Syn oligomers.Furthermore,fraction analysis showed a significant increase of SYT13 protein levels at the synapses in DLB and MSA.Notably,a correlation was observed between the levels of SYT13 and aggregatedα-Syn at the synapses.SYT13 was observed to regulate extracellular vesicle release in association with SYT1 and the SNARE complexes in SH-SY5Y cells.SYT13 overexpression in SH-SY5Y cells impaired extracellular vesicle release.Consistently,the numbers of extracellular vesicles were significantly reduced in the brain homogenates of DLB and MSA cases compared with those in controls.Conclusions Abnormalα-Syn impairs extracellular vesicle release through interactions with SYT13 in synucleinopathies.Our findings provide insights into therapeutic strategies for alleviating dysregulations of vesicular transport and synaptic function in patients with synucleinopathies.
基金funding from the Medical Research Council (MR/S006990/1, MR/Y010949/1)the Rosetrees Trust (M806)the UCL Neurogenetic Therapies Programme funded by The Sigrid Rausing Trust and the UCL Therapeutic Acceleration Support scheme supported by funding from MRC IAA 2021 UCL MR/X502984/1 (to JNS)。
文摘Charcot-Marie-Tooth disease(CMT) is a heterogeneous group of inherited peripheral neuro pathies;it is characterized by muscle weakness and wasting,as well as sensory dysfunction,that typically begins during adolescence and ultimately leads to lifelong disability.Occurring in~1 in 2500individuals,CMT is the most common hereditary neuromuscular condition and results from mutations in> 100 different genes.CMT is grouped into type1(CMT1),where demyelination and loss of nerve conduction velocity occur,type 2(CMT2),where motor and sensory axons degenerate without loss of myelination/nerve conduction velocity,and intermediate CMT,where both demyelination and axon loss present alongside intermediate nerve condu ction velocities.
文摘Anorectal melanoma is a rare tumor representing less than 1% of anorectal cancers and around 0.3% of malignant melanomas. Its prognosis is particularly poor due to the early occurrence of metastases. We report the case of a 65-year-old man presenting with rectorrhagia and anal pain, initially diagnosed as hemorrhoidal disease. Subsequent proctological examination revealed an ulcerating-bourging tumor, confirmed histologically as an anorectal melanoma. After a normal extension workup, an abdominoperineal amputation was performed. Anorectal melanoma is a pathology with a poor prognosis, requiring early diagnosis to improve chances of survival.
文摘Against the backdrop of increasingly prominent global energy shortages and environmental issues,the development of efficient energy conversion and storage technologies has become crucial.Zero-dimensional(0D)metal oxide composites exhibit significant application value in the field of energy chemistry due to their unique properties,such as quantum size effect and high specific surface area.From a broad perspective,this paper reviews the main synthesis methods of these composites,including sol-gel method,hydrothermal/solvothermal method,precipitation method,and template method,while analyzing the characteristics of each method.It further discusses their applications in photocatalytic hydrogen production,fuel cells,lithium-ion batteries,and supercapacitors.Additionally,the current challenges,such as material dispersibility and interface bonding,are pointed out,and future development directions are prospected,aiming to provide references for related research.
基金supported by the National Natural Science Foundation of China(82030037)the Translational and Application Project of Brain-inspired and Network Neuroscience on Brain Disorders(11000023T000002036286).
文摘Epilepsy affects over 50 million people worldwide.Drug-resistant epilepsy(DRE)accounts for up to a third of these cases,and neuro-inflammation is thought to play a role in such cases.Despite being a long-debated issue in the field of DRE,the mechanisms underlying neuroinflammation have yet to be fully elucidated.The pro-inflammatory microenvironment within the brain tissue of people with DRE has been probed using single-cell multimodal transcriptomics.Evidence suggests that inflammatory cells and pro-inflammatory cytokines in the nervous system can lead to extensive biochemical changes,such as connexin hemichannel excitability and disruption of neurotransmitter homeostasis.The presence of inflammation may give rise to neuronal network abnormalities that suppress endogenous antiepileptic systems.We focus on the role of neuroinflammation and brain network anomalies in DRE from multiple perspectives to identify critical points for clinical application.We hope to provide an insightful overview to advance the quest for better DRE treatments.
基金Financial support from the Engineering and Physical Sciences Research Council grant EP/V034723/1(RiFTMaP)is gratefully acknowledged.
文摘In the pharmaceutical industry,model-based prediction is a crucial stage in process development that allows pharmaceutical companies to simulate different scenarios toward improving process efficiency,reducing costs,and enhancing product quality.Nevertheless,ensuring the quality of formulated pharmaceutical products through the management of raw material variations has always been a challenging task.In this work,data-driven chance-constrained recurrent neural networks(CCRNNs)are developed to address the issue arising from raw material uncertainty.Our goal is to explore how,by proactively incorporating uncertainty into the model training process,more accurate predictions and enhanced robustness can be realized.The proposed approach is tested on a fluid bed dryer(FBD)from a continuous pharmaceutical manufacturing pilot plant.The results demonstrate that CCRNN models offer more robust and accurate predictions for the critical quality attribute(CQA)-in this case,moisture content-when material variations occur,compared with conventional recurrent neural network-based models.
文摘The first liver transplantation(LT)in humans was performed by Thomas Starzl on March 1,1963[1,2](Fig.1).During the period 1963-1983,this challenging procedure was performed in four centers only,one in the USA and three in Western Europe:Denver,Cambridge,Hannover and Groningen.Their collected experience including only 540 cases(meaning 27(!)cases yearly)was the basis of the 1983 National Institutes of Health(NIH)development consensus conference leading to the conclusion that LT could become“a promising alternative to the current therapy in the management of the late phase of several forms of serious liver disease…candidates are those who exhausted alternative medical and surgical treatments…and are approaching the terminal phase of their illness”.Patients presenting liver tumors and inherited,liver based,metabolic diseases could also be considered for LT[3].This conference put forward ten absolute and five relative contraindications restricting thereby the access to LT to a minority of very well selected liver diseased patients.
基金supported by Health Education England/National Institute for Health Research(NIHR)(Clinical Lectureship CL-2020-18-009 for C.H.).
文摘Introduction Late age-related macular degeneration(AMD)is one of the leading causes of blindness globally(1).In their recent study published in JAMA Ophthalmology,Hallak et al.explore the potential of an emerging therapeutic opportunity of Janus kinase inhibitor(JAKi)in the role of systemic inflammation in AMD pathogenesis(2).This study offers a real-world examination of the relationship between JAKi and AMD,comparing the incidence of AMD in patients treated with JAKi and those receiving other immunotherapies for existing autoimmune diseases.
基金funded by a proof-of-concept award from Wellcome/EPSRC Centre for Interventional and Surgical Science(award 203145Z/16/Z)the NIHR UCLH Biomedical Research Centre(award 187809).A.P.L.was funded by The Pathological Society of Great Britain and Ireland.
文摘Objective:This article describes a new method(VS-FPM)for analysis of unstained tissues based on the application of supervised machine learning to generate brightfield hematoxylin and eosin(H&E)images from phase images recovered using Fourier ptychographic microscopy(FPM).Impact Statement:VS-FPM has several advantages for label-free digital pathology.Capture of complex image information simplifies model training and allows post-capture refocusing.FPM images combine high resolution with a large field of view,and the hardware is low-cost and compatible with many existing brightfield microscope systems.Introduction:By generating realistic histologically stained images from label-free image data,virtual staining(VS)methods have the potential to streamline clinical workflows,improve image consistency,and enable new ways of visualizing and analyzing histological tissues.Methods:We trained a conditional generative adversarial network to translate high-resolution FPM images of unstained tissues to brightfield H&E images and assessed the method using diagnosis of colonic polyps as a test case.Results:We found no statistically significant difference between the spatial resolution of FPM images captured at 4×magnification and images from a pathology slide scanner at 20×magnification.Visual assessment and image similarity metrics showed that VS-FPM images of unstained tissues closely resemble images of chemically H&Estained tissues.However,the spatial resolution of virtual H&E images was approximately 20%lower than equivalent images of chemically stained tissues.Using VS-FPM,board-certified pathologists were able to accurately distinguish normal from dysplastic tissues and derive correct pathological diagnoses.Conclusion:VS-FPM is a reliable,accessible VS method that also overcomes many other limitations inherent to histopathology microscopy.
基金funded by the Gansu Provincial Science and Technology Program in China(Grant No.22ZD6FA005)。
文摘The Gannan Yellow River source area(YRSA)is a typical ecological fragile region.Assessing the temporal and spatial patterns of resource and environmental carrying capacity(RECC)is crucial for both ecological security and sustainable development of the Yellow River Basin and the YRSA.Based on RECC theory,this study developed a novel index system focused on human-livestock-grassland relationships to accurately capture resource and environmental carrying characteristics in pastoral regions.By establishing region-specific evaluation thresholds and using a comprehensive index approach,we analyzed spatial and temporal patterns of resource carrying capacity(RCC),environmental carrying capacity(ECC),and resource and environmental carrying capacity(RECC)in the Gannan region from 2005 to 2020.The results indicate that:1)The RECC followed an increasing–decreasing–increasing trajectory from 2005 to 2020,with values ranging from 0.30 to 0.69.The RECC in pastoral areas was not only higher but also exhibited greater variability compared to that in agricultural areas.2)The RCC remained at a low level,with values between 0.06 to 0.098.The index of water consumption per ten thousand Yuan of GDP increased significantly,suggesting that improvements in water use efficiency contributed to the enhancement of RCC.3)The ECC increased notably,shifting from the middle to a very high level,with values ranging from 0.233 to 0.611.ECC emerged as a key determinant of RECC,exhibiting a temporal trend closely aligned with that of RECC.Changes in ECC were primarily driven by factors such as overgrazing rates,the extent of grassland rodent control,and the area of grassland for reseeding and improvement.Based on these findings,future priorities should include the adoption of efficient water-saving irrigation technologies,the promotion of rotational grazing practices,and the optimization of land management strategies.
