Beta thalassemia(β-thalassemia)syndromes are a heterogeneous group of inherited hemoglobinopathies caused by molecular defects in the beta-globin gene that lead to the impaired synthesis of beta-globin chains of the ...Beta thalassemia(β-thalassemia)syndromes are a heterogeneous group of inherited hemoglobinopathies caused by molecular defects in the beta-globin gene that lead to the impaired synthesis of beta-globin chains of the hemoglobin.The hallmarks of the disease include ineffective erythropoiesis,chronic hemolytic anemia,and iron overload.Clinical presentation ranges from asymptomatic carriers to severe anemia requiring lifelong blood transfusions with subsequent devastating complications.The management of patients with severeβ-thalassemia represents a global health problem,particularly in low-income countries.Until recently,management strategies were limited to regular transfusions and iron chelation therapy,with allogeneic hematopoietic stem cell transplantation available only for a subset of patients.Better understanding of the underlying pathophysiological mechanisms ofβ-thalassemia syndromes and associated clinical phenotypes has paved the way for novel therapeutic options,including pharmacologic enhancers of effective erythropoiesis and gene therapy.展开更多
Understanding plant diversity within geographical ranges and identifying key species that drive community variation can provide crucial insights for the management of grasslands.However,the contribution of both local ...Understanding plant diversity within geographical ranges and identifying key species that drive community variation can provide crucial insights for the management of grasslands.However,the contribution of both local sites and plant species to beta diversity in grassland ecosystems has yet to be accurately assessed.This study applied the ecological uniqueness approach to examine both local contributions to beta diversity(LCBD)and species contributions to beta diversity(SCBD)across six major geographical ranges in alpine grasslands.We found that LCBD was driven by species turnover,with climate,plant communities,and their interactions influencing LCBD across spatial scales.LCBD values were high in areas with low evapotranspiration,high rainfall variability,and low species and functional richness.Precipitation seasonality predicted large-scale LCBD dynamics,while plant community abundance explained local LCBD variation.In addition,we found that SCBD were confined to species with moderate occupancy,although these species contributed less to plant biological traits.Our findings are crucial for understanding how ecological characteristics influence plant beta diversity in grasslands and how it responds to environmental and community factors.In addition,these findings have successfully identified key sites and priority plants for conservation,indicating that using standardized quadrats can support the assessment of the ecological uniqueness in grassland ecosystems.We hope these insights will inform the development of conservation strategies,thereby supporting regional plant diversity and resisting vegetation homogenization.展开更多
In this paper,the density-independent fractional diffusion-reaction(FDR)equation involving quadratic nonlinearity is investigated.The fractional derivative is illustrated in the beta derivative sense.We firstly propos...In this paper,the density-independent fractional diffusion-reaction(FDR)equation involving quadratic nonlinearity is investigated.The fractional derivative is illustrated in the beta derivative sense.We firstly propose Bernoulli(G'/G)-expansion method to study nonlinear fractional differential equations(NFDEs).Subsequently,closed form solutions of the density-independent FDR equation are acquired successfully.In order to better understand the dynamic behaviors of these solutions,3D,contour map and line plots are given by the computer simulation.The results show that the proposed method is a reliable and efficient approach.展开更多
Understanding how and why assemblage dissimilarity changes along spatial gradient is a great challenge in ecology,because answers to these questions depend on the analytical types,dimensions,and components of beta div...Understanding how and why assemblage dissimilarity changes along spatial gradient is a great challenge in ecology,because answers to these questions depend on the analytical types,dimensions,and components of beta diversity we concerned.To obtain a comprehensive understanding of assemblage dissimilarity and its implications for biodiversity conservation in the Himalayas,we explored the elevational patterns and determinants of beta diversity and its turnover and nestedness components of pairwise and multiple types and taxonomic and phylogenetic dimensions simultaneously.Patterns of beta diversity and their components of different types and dimensions were calculated based on 96 sampling quadrats along an 1800-5400 m elevational gradient.We examined whether and how these patterns differed from random expectations using null models.Furthermore,we used random forest methods to quantify the role of environmental variables representing climate,topography,and human disturbance in determining these patterns.We found that beta diversity and its turnover component,regardless of its types and dimensions,shown a hump-shaped elevational patterns.Both pairwise and multiple phylogenetic beta diversity were remarkably lower than their taxonomic counterpart.These patterns were significantly less than random expectation and were mostly associated with climate variables.In summary,our results suggested that assemblage dissimilarity of seed plants was mostly originate from the replacement of closely related species determined by climate-driven environmental filtering.Accordingly,conservation efforts should better cover elevations with different climate types to maximalize biodiversity conservation,rather than only focus on elevations with highest species richness.Our study demonstrated that comparisons of beta diversity of different types,dimensions,and components could be conductive to consensus on the origin and mechanism of assemblage dissimilarity.展开更多
Objective Patients with severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection frequently develop central nervous system damage,yet the mechanisms driving this pathology remain unclear.This study investi...Objective Patients with severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection frequently develop central nervous system damage,yet the mechanisms driving this pathology remain unclear.This study investigated the primary pathways and key factors underlying brain tissue damage induced by the SARS-CoV-2 beta variant(lineage B.1.351).Methods K18-hACE2 and C57BL/6 mice were intranasally infected with the SARS-CoV-2 beta variant.Viral replication,pathological phenotypes,and brain transcriptomes were analyzed.Gene Ontology(GO)analysis was performed to identify altered pathways.Expression changes of host genes were verified using reverse transcription-quantitative polymerase chain reaction and Western blot.Results Pathological alterations were observed in the lungs of both mouse strains.However,only K18-hACE2 mice exhibited elevated viral RNA loads and infectious titers in the brain at 3 days post-infection,accompanied by neuropathological injury and weight loss.GO analysis of infected K18-hACE2 brain tissue revealed significant dysregulation of genes associated with innate immunity and antiviral defense responses,including type I interferons,pro-inflammatory cytokines,Toll-like receptor signaling components,and interferon-stimulated genes.Neuroinflammation was evident,alongside activation of apoptotic and pyroptotic pathways.Furthermore,altered neural cell marker expression suggested viral-induced neuroglial activation,resulting in caspase 4 and lipocalin 2 release and disruption of neuronal molecular networks.Conclusion These findings elucidate mechanisms of neuropathogenicity associated with the SARS-CoV-2 beta variant and highlight therapeutic targets to mitigate COVID-19-related neurological dysfunction.展开更多
Alzheimer's disease(AD)is a neurodegenerative disease characterized by a progressive decline in cognitive functions.Given that AD undermines the quality of life for millions and has an extended asymptomatic period...Alzheimer's disease(AD)is a neurodegenerative disease characterized by a progressive decline in cognitive functions.Given that AD undermines the quality of life for millions and has an extended asymptomatic period,exploring the full AD pathogenesis and seeking the optimal therapeutic solution have become critical and imperative.This allows researchers to intervene,delay,and potentially prevent AD progression.Several clinical imaging methods are utilized routinely to diagnose and monitor AD,such as magnetic resonance imaging(MRI),functional magnetic resonance imaging(fMRI),positron emission tomography(PET),and single photon emission computed tomography(SPECT).Nevertheless,due to their intrinsic drawbacks and restrictions,such as radiation concerns,high cost,long acquisition time,and low spatial resolution,their applications in AD research are limited,especially at the cellular and molecular levels.In contrast,optical microscopic imaging methods overcome these limitations,offering researchers a variety of approaches with distinct advantages to explore AD pathology on diverse models.In this review,we provide a comprehensive overview of commonly utilized optical microscopic imaging techniques in AD research and introduce their contributions to image amyloid beta(Aβ)species.These techniques include fluorescence microscopy(FM),confocal microscopy(CM),two-photon fluorescence microscopy(TPFM),super-resolution microscopy(SRM),expansion microscopy(ExM),and light-sheet fluorescence microscopy(LSFM).In addition,we introduce some related topics,such as the development of near-infrared(NIR)Aβprobes,the Aβplaque hypothesis,and Aβoligomer hypothesis,and the roles of microglia and astrocytes in AD progression.We believe optical microscopic imaging methods continue to play an indispensable role in deciphering the full pathogenesis of AD and advancing therapeutic strategies.展开更多
BACKGROUND Alzheimer’s disease(AD)is a progressive neurodegenerative disorder currently lacking effective therapeutic interventions.Pathological hallmarks of AD include intracellular neurofibrillary tangles(NFTs)and ...BACKGROUND Alzheimer’s disease(AD)is a progressive neurodegenerative disorder currently lacking effective therapeutic interventions.Pathological hallmarks of AD include intracellular neurofibrillary tangles(NFTs)and extracellular amyloid beta(Aβ)plaques.Neuroplastin 65(NP65),highly expressed in the brain,has been previously shown to mitigate cognitive impairments and decrease Aβplaques in the AD mouse model,suggesting that NP65 is involved in AD neuropathology.However,direct evidence linking NP65 expression to AD pathogenesis in human brain remains absent.AIM To quantify NP65 isoform expression gradients across distinct neuroanatomical regions in the healthy brain and investigate the alterations of NP65 expression in the AD brain.METHODS Immunohistochemical,immunofluorescent and western blot analyses were used to investigate NP65 expression in 19 postmortem brains(AD=10,controls=9).Double immunostaining with 6E10 and or phosphorylated-microtubule-associated protein tau(AT-8,a marker for NFT)markers was performed to assess NP65 colocalization with Aβplaques and NFTs.RESULTS In controls,NP65 was highly expressed in a wide-range of brain areas.AD cases showed significantly increased NP65 immunoreactivity across multiple brain regions,including the frontal and temporal cortex,hippocampus,and cerebellum,compared to controls.Western blot analysis consistently confirmed significantly elevated NP65 expression in the hippocampus of AD patients relative to controls.Double immunostaining demonstrated partial colocalization of NP65 with NFTs and Aβplaques in AD brain tissue.CONCLUSION Our findings demonstrate a significant increase of NP65 protein,which colocalizes with NFTs and Aβplaques in AD brains,providing direct evidence supporting a critical role of NP65 expression in the neuropathological mechanisms of this disease.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
文摘Beta thalassemia(β-thalassemia)syndromes are a heterogeneous group of inherited hemoglobinopathies caused by molecular defects in the beta-globin gene that lead to the impaired synthesis of beta-globin chains of the hemoglobin.The hallmarks of the disease include ineffective erythropoiesis,chronic hemolytic anemia,and iron overload.Clinical presentation ranges from asymptomatic carriers to severe anemia requiring lifelong blood transfusions with subsequent devastating complications.The management of patients with severeβ-thalassemia represents a global health problem,particularly in low-income countries.Until recently,management strategies were limited to regular transfusions and iron chelation therapy,with allogeneic hematopoietic stem cell transplantation available only for a subset of patients.Better understanding of the underlying pathophysiological mechanisms ofβ-thalassemia syndromes and associated clinical phenotypes has paved the way for novel therapeutic options,including pharmacologic enhancers of effective erythropoiesis and gene therapy.
基金the National Key Research and Development Program of China(2023YFF1304302)the Qaidam basin and Qilian Mountains germplasm resources collection project(Grant No.SJCZFY2022-1-6)。
文摘Understanding plant diversity within geographical ranges and identifying key species that drive community variation can provide crucial insights for the management of grasslands.However,the contribution of both local sites and plant species to beta diversity in grassland ecosystems has yet to be accurately assessed.This study applied the ecological uniqueness approach to examine both local contributions to beta diversity(LCBD)and species contributions to beta diversity(SCBD)across six major geographical ranges in alpine grasslands.We found that LCBD was driven by species turnover,with climate,plant communities,and their interactions influencing LCBD across spatial scales.LCBD values were high in areas with low evapotranspiration,high rainfall variability,and low species and functional richness.Precipitation seasonality predicted large-scale LCBD dynamics,while plant community abundance explained local LCBD variation.In addition,we found that SCBD were confined to species with moderate occupancy,although these species contributed less to plant biological traits.Our findings are crucial for understanding how ecological characteristics influence plant beta diversity in grasslands and how it responds to environmental and community factors.In addition,these findings have successfully identified key sites and priority plants for conservation,indicating that using standardized quadrats can support the assessment of the ecological uniqueness in grassland ecosystems.We hope these insights will inform the development of conservation strategies,thereby supporting regional plant diversity and resisting vegetation homogenization.
基金Supported by the National Natural Science Foundation of China(11901111)Guangzhou Science and Technology Plan Project(202201011602)。
文摘In this paper,the density-independent fractional diffusion-reaction(FDR)equation involving quadratic nonlinearity is investigated.The fractional derivative is illustrated in the beta derivative sense.We firstly propose Bernoulli(G'/G)-expansion method to study nonlinear fractional differential equations(NFDEs).Subsequently,closed form solutions of the density-independent FDR equation are acquired successfully.In order to better understand the dynamic behaviors of these solutions,3D,contour map and line plots are given by the computer simulation.The results show that the proposed method is a reliable and efficient approach.
基金supported by the National Natural Science Foundation of China(grant number 31901109)Guangdong Basic and Applied Basic Research Foundation(grant number 2021A1515110744).
文摘Understanding how and why assemblage dissimilarity changes along spatial gradient is a great challenge in ecology,because answers to these questions depend on the analytical types,dimensions,and components of beta diversity we concerned.To obtain a comprehensive understanding of assemblage dissimilarity and its implications for biodiversity conservation in the Himalayas,we explored the elevational patterns and determinants of beta diversity and its turnover and nestedness components of pairwise and multiple types and taxonomic and phylogenetic dimensions simultaneously.Patterns of beta diversity and their components of different types and dimensions were calculated based on 96 sampling quadrats along an 1800-5400 m elevational gradient.We examined whether and how these patterns differed from random expectations using null models.Furthermore,we used random forest methods to quantify the role of environmental variables representing climate,topography,and human disturbance in determining these patterns.We found that beta diversity and its turnover component,regardless of its types and dimensions,shown a hump-shaped elevational patterns.Both pairwise and multiple phylogenetic beta diversity were remarkably lower than their taxonomic counterpart.These patterns were significantly less than random expectation and were mostly associated with climate variables.In summary,our results suggested that assemblage dissimilarity of seed plants was mostly originate from the replacement of closely related species determined by climate-driven environmental filtering.Accordingly,conservation efforts should better cover elevations with different climate types to maximalize biodiversity conservation,rather than only focus on elevations with highest species richness.Our study demonstrated that comparisons of beta diversity of different types,dimensions,and components could be conductive to consensus on the origin and mechanism of assemblage dissimilarity.
基金supported by the National Key Research and Development Program of China(2023YFC3041500).
文摘Objective Patients with severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection frequently develop central nervous system damage,yet the mechanisms driving this pathology remain unclear.This study investigated the primary pathways and key factors underlying brain tissue damage induced by the SARS-CoV-2 beta variant(lineage B.1.351).Methods K18-hACE2 and C57BL/6 mice were intranasally infected with the SARS-CoV-2 beta variant.Viral replication,pathological phenotypes,and brain transcriptomes were analyzed.Gene Ontology(GO)analysis was performed to identify altered pathways.Expression changes of host genes were verified using reverse transcription-quantitative polymerase chain reaction and Western blot.Results Pathological alterations were observed in the lungs of both mouse strains.However,only K18-hACE2 mice exhibited elevated viral RNA loads and infectious titers in the brain at 3 days post-infection,accompanied by neuropathological injury and weight loss.GO analysis of infected K18-hACE2 brain tissue revealed significant dysregulation of genes associated with innate immunity and antiviral defense responses,including type I interferons,pro-inflammatory cytokines,Toll-like receptor signaling components,and interferon-stimulated genes.Neuroinflammation was evident,alongside activation of apoptotic and pyroptotic pathways.Furthermore,altered neural cell marker expression suggested viral-induced neuroglial activation,resulting in caspase 4 and lipocalin 2 release and disruption of neuronal molecular networks.Conclusion These findings elucidate mechanisms of neuropathogenicity associated with the SARS-CoV-2 beta variant and highlight therapeutic targets to mitigate COVID-19-related neurological dysfunction.
基金supported by NIH(R01AG055413),(R01AG085562),(R21AG059134),(R21AG078749),and(S10OD028609)awards(C.R.).NIH Office of the Director,National Institute on Aging.
文摘Alzheimer's disease(AD)is a neurodegenerative disease characterized by a progressive decline in cognitive functions.Given that AD undermines the quality of life for millions and has an extended asymptomatic period,exploring the full AD pathogenesis and seeking the optimal therapeutic solution have become critical and imperative.This allows researchers to intervene,delay,and potentially prevent AD progression.Several clinical imaging methods are utilized routinely to diagnose and monitor AD,such as magnetic resonance imaging(MRI),functional magnetic resonance imaging(fMRI),positron emission tomography(PET),and single photon emission computed tomography(SPECT).Nevertheless,due to their intrinsic drawbacks and restrictions,such as radiation concerns,high cost,long acquisition time,and low spatial resolution,their applications in AD research are limited,especially at the cellular and molecular levels.In contrast,optical microscopic imaging methods overcome these limitations,offering researchers a variety of approaches with distinct advantages to explore AD pathology on diverse models.In this review,we provide a comprehensive overview of commonly utilized optical microscopic imaging techniques in AD research and introduce their contributions to image amyloid beta(Aβ)species.These techniques include fluorescence microscopy(FM),confocal microscopy(CM),two-photon fluorescence microscopy(TPFM),super-resolution microscopy(SRM),expansion microscopy(ExM),and light-sheet fluorescence microscopy(LSFM).In addition,we introduce some related topics,such as the development of near-infrared(NIR)Aβprobes,the Aβplaque hypothesis,and Aβoligomer hypothesis,and the roles of microglia and astrocytes in AD progression.We believe optical microscopic imaging methods continue to play an indispensable role in deciphering the full pathogenesis of AD and advancing therapeutic strategies.
基金the National Natural Science Foundation of China,No.81771441 and No.81371213the Natural Science Foundation of Shanghai,No.21ZR1468400.
文摘BACKGROUND Alzheimer’s disease(AD)is a progressive neurodegenerative disorder currently lacking effective therapeutic interventions.Pathological hallmarks of AD include intracellular neurofibrillary tangles(NFTs)and extracellular amyloid beta(Aβ)plaques.Neuroplastin 65(NP65),highly expressed in the brain,has been previously shown to mitigate cognitive impairments and decrease Aβplaques in the AD mouse model,suggesting that NP65 is involved in AD neuropathology.However,direct evidence linking NP65 expression to AD pathogenesis in human brain remains absent.AIM To quantify NP65 isoform expression gradients across distinct neuroanatomical regions in the healthy brain and investigate the alterations of NP65 expression in the AD brain.METHODS Immunohistochemical,immunofluorescent and western blot analyses were used to investigate NP65 expression in 19 postmortem brains(AD=10,controls=9).Double immunostaining with 6E10 and or phosphorylated-microtubule-associated protein tau(AT-8,a marker for NFT)markers was performed to assess NP65 colocalization with Aβplaques and NFTs.RESULTS In controls,NP65 was highly expressed in a wide-range of brain areas.AD cases showed significantly increased NP65 immunoreactivity across multiple brain regions,including the frontal and temporal cortex,hippocampus,and cerebellum,compared to controls.Western blot analysis consistently confirmed significantly elevated NP65 expression in the hippocampus of AD patients relative to controls.Double immunostaining demonstrated partial colocalization of NP65 with NFTs and Aβplaques in AD brain tissue.CONCLUSION Our findings demonstrate a significant increase of NP65 protein,which colocalizes with NFTs and Aβplaques in AD brains,providing direct evidence supporting a critical role of NP65 expression in the neuropathological mechanisms of this disease.
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.
