NRBF2 has been identified as the fifth component of PI3KC3 complex and is required for maintaining the kinase activity to promote autophagy.However,the physiological and pathological roles of NRBF2are largely unknown.
Background: The apolipoprotein E (APOE, gene;apoE, protein) ε4 allele is the most commonly identified genetic risk factor for typical late-onset sporadic Alzheimer’s disease (AD). Each APOE ε4 allele roughly triple...Background: The apolipoprotein E (APOE, gene;apoE, protein) ε4 allele is the most commonly identified genetic risk factor for typical late-onset sporadic Alzheimer’s disease (AD). Each APOE ε4 allele roughly triples the relative risk for AD compared to that of the reference allele, APOE ε3. Methods: We have employed hyperspectral fluorescence imaging with an amyloid-specific, conformation-sensing probe, p-FTAA, to elucidate protein aggregate structure and morphology in fresh frozen prefrontal cortex samples from human postmortem AD brain tissue samples from patients homozygous for either APOE ε3 or APOE ε4. Results: As expected APOE ε4/ε4 tissues had a significantly larger load of CAA than APOE ε3/ε3. APOE isoform-dependent morphological differences in amyloid plaques were also observed. Amyloid plaques in APOE ε3/ε3 tissue had small spherical cores and large coronas while amyloid plaques in APOE ε4/ε4 tissues had large irregular and multi-lobulated plaques with relatively smaller coronas. Despite the different morphologies of their cores, the p-FTAA stained APOE ε3/ε3 amyloid plaque cores had spectral properties identical to those of APOE ε4/ε4 plaque cores. Conclusions: These data support the hypothesis that one mechanism by which the APOE ε4 allele affects AD is by modulating the macrostructure of pathological protein deposits in the brain. APOE ε4 is associated with a higher density of amyloid plaques (as compared to APOE ε3). We speculate that multilobulated APOE ε4-associated plaques arise from multiple initiation foci that coalesce as the plaques grow.展开更多
We establish the monotonicity and convexity properties for several special functions involving the generalized elliptic integrals, and present some new analytic inequalities.
Bacterial meningitis is a serious and potentially life-threatening infection that affects the protective layers surrounding the brain and spinal cord,known as the meninges.Several types of bacteria,including Streptoco...Bacterial meningitis is a serious and potentially life-threatening infection that affects the protective layers surrounding the brain and spinal cord,known as the meninges.Several types of bacteria,including Streptococcus pneumoniae,Neisseria meningitidis,and Haemophilus influenzae,can cause this condition.Certain populations,such as infants,children,immunocompromised adults,and the elderly,are particularly vulnerable to these pathogens.Symptoms of bacterial meningitis can manifest suddenly and may include high fever,severe and persistent headache,stiff neck,vomiting,sensitivity to light,and confusion or changes in mental state[1,2].Identifying these symptoms in infants can be more challenging and may lead to long-term disability or death[3].Despite the effectiveness of vaccines,it is crucial to understand how bacteria invade the brain and how our innate immune system responds to infection(Fig.1).展开更多
Messenger RNA(mRNA)has drawn much attention in the medical field.Through various treatment approaches including protein replacement therapies,gene editing,and cell engineering,mRNA is becoming a potential therapeutic ...Messenger RNA(mRNA)has drawn much attention in the medical field.Through various treatment approaches including protein replacement therapies,gene editing,and cell engineering,mRNA is becoming a potential therapeutic strategy for cancers.However,delivery of mRNA into targeted organs and cells can be challenging due to the unstable nature of its naked form and the low cellular uptake.Therefore,in addition to mRNA modification,efforts have been devoted to developing nanoparticles for mRNA delivery.In this review,we introduce four categories of nanoparticle platform systems:lipid,polymer,lipid-polymer hybrid,and protein/peptide-mediated nanoparticles,together with their roles in facilitating mRNA-based cancer immunotherapies.We also highlight promising treatment regimens and their clinical translation.展开更多
Locomotion in mollusc Aplysia is implemented by a pedal rolling wave,a type of axial locomotion.Well-studied examples of axial locomotion(pedal waves in Drosophila larvae and body waves in leech,lamprey,and fish)are g...Locomotion in mollusc Aplysia is implemented by a pedal rolling wave,a type of axial locomotion.Well-studied examples of axial locomotion(pedal waves in Drosophila larvae and body waves in leech,lamprey,and fish)are generated in a segmented nervous system via activation of multiple coupled central pattern generators(CPGs).Pedal waves in molluscs,however,are generated by a single pedal ganglion,and it is unknown whether there are single or multiple CPGs that generate rhythmic activity and phase shifts between different body parts.During locomotion in intact Aplysia,bursting activity in the parapedal commissural nerve(PPCN)was found to occur during tail contraction.A cluster of 20 to 30 P1 root neurons(P1Ns)on the ventral surface of the pedal ganglion,active during the pedal wave,were identified.Computational cluster analysis revealed that there are 2 phases to the motor program:phase I(centered around 168°)and phase II(centered around 357°).PPCN activity occurs during phase II.The majority of P1Ns are motoneurons.Coactive P1Ns tend to be electrically coupled.Two classes of pedal interneurons(PIs)were characterized.Class 1(PI1 and PI2)is active during phase I.Their axons make a loop within the pedal ganglion and contribute to locomotor pattern generation.They are electrically coupled to P1Ns that fire during phase I.Class 2(PI3)is active during phase II and innervates the contralateral pedal ganglion.PI3 may contribute to bilateral coordination.Overall,our findings support the idea that Aplysia pedal waves are generated by a single CPG.展开更多
The rat is a powerful model for the study of human physiology and diseases, and is prefened by physiologists, neuroscientists and toxicologists. However, the lack of robust genetic modification tools has severely limi...The rat is a powerful model for the study of human physiology and diseases, and is prefened by physiologists, neuroscientists and toxicologists. However, the lack of robust genetic modification tools has severely limited the generation of rat genetic models over the last two decades. In the last few years, several gene-targeting strategies have been developed in rats using N-ethyl-N-nitrosourea （ENU）, transposons, zinc-finger nucleases （ZFNs）, bacterial a11ificial chromosome （BAC） mediated transgenesis, and recently established rat embryonic stem （ES） cells. The development and improvement of these approaches to genetic manipulation have created a bright future lbr the use of genetic rat models in investigations of gene function and human diseases. Here, we summarize the strategies used for rat genetic manipulation in current research. We also discuss BAC transgenesis as a potential tool in rat transgenic models.展开更多
The pathophysiology underlying spinal cord injury is complex. Mechanistic understanding of the adaptive responses to injury is critical for targeted therapy aimed at reestablishing lost connections between proximal an...The pathophysiology underlying spinal cord injury is complex. Mechanistic understanding of the adaptive responses to injury is critical for targeted therapy aimed at reestablishing lost connections between proximal and distal neurons. After injury, cell-type specific gene transcription programs govern distinct cellular behaviors, and chromatin regulators play a central role in shaping the chromatin landscape to adjust transcriptional profiles in a contextdependent manner. In this review, we summarize recent progress on the pleiotropic roles of chromatin regulators in mediating the diverse adaptive behaviors of neurons and glial cells after spinal cord injury, and wherever possible, discuss the underlying mechanisms and genomic targets. We specifically draw attention to the perspective that takes into consideration the impact of epigenetic modulation on axon growth potential, together with its effect on woundhealing properties of glial cells. Epigenetic modulation of chromatin state represents an emerging therapeutic direction to promote neural repair and axon regeneration after spinal cord injury.展开更多
Alzheimer's disease(AD)is a prevalent and deleterious neurodegenerative disorder characterized by an irreversible and progressive impairment of cognitive abilities as well as the formation of amyloidβ(Aβ)plaques...Alzheimer's disease(AD)is a prevalent and deleterious neurodegenerative disorder characterized by an irreversible and progressive impairment of cognitive abilities as well as the formation of amyloidβ(Aβ)plaques and neurofibrillary tangles(NFTs)in the brain.By far,the precise mechanisms of AD are not fully understood and no interventions are available to effectively slow down progression of the disease.Autophagy is a conserved degradation pathway that is crucial to maintain cellular homeostasis by targeting damaged organelles,pathogens,and disease-prone protein aggregates to lysosome for degradation.Emerging evidence suggests dysfunctional autophagy clearance pathway as a potential cellular mechanism underlying the pathogenesis of AD in affected neurons.Here we summarize the current evidence for autophagy dysfunction in the pathophysiology of AD and discuss the role of autophagy in the regulation of AD-related protein degradation and neuroinflammation in neurons and glial cells.Finally,we review the autophagy modulators reported in the treatment of AD models and discuss the obstacles and opportunities for potential clinical application of the novel autophagy activators for AD therapy.展开更多
基金supported by the China Ministry of Science and Technology grant(No.Mo ST-2017YFE0120100)The Science and Technology Development Fund,Macao SAR(Nos.024/2017/AMJ,0128/2019/A3)+2 种基金the University of Macao grant(NoMYRG2019-00129-ICMS)(to JHL)supported by GRF/HKBU(Nos.12101417,12100618)HMRF(Nos.17182541,17182551)(to ML)。
文摘NRBF2 has been identified as the fifth component of PI3KC3 complex and is required for maintaining the kinase activity to promote autophagy.However,the physiological and pathological roles of NRBF2are largely unknown.
文摘Background: The apolipoprotein E (APOE, gene;apoE, protein) ε4 allele is the most commonly identified genetic risk factor for typical late-onset sporadic Alzheimer’s disease (AD). Each APOE ε4 allele roughly triples the relative risk for AD compared to that of the reference allele, APOE ε3. Methods: We have employed hyperspectral fluorescence imaging with an amyloid-specific, conformation-sensing probe, p-FTAA, to elucidate protein aggregate structure and morphology in fresh frozen prefrontal cortex samples from human postmortem AD brain tissue samples from patients homozygous for either APOE ε3 or APOE ε4. Results: As expected APOE ε4/ε4 tissues had a significantly larger load of CAA than APOE ε3/ε3. APOE isoform-dependent morphological differences in amyloid plaques were also observed. Amyloid plaques in APOE ε3/ε3 tissue had small spherical cores and large coronas while amyloid plaques in APOE ε4/ε4 tissues had large irregular and multi-lobulated plaques with relatively smaller coronas. Despite the different morphologies of their cores, the p-FTAA stained APOE ε3/ε3 amyloid plaque cores had spectral properties identical to those of APOE ε4/ε4 plaque cores. Conclusions: These data support the hypothesis that one mechanism by which the APOE ε4 allele affects AD is by modulating the macrostructure of pathological protein deposits in the brain. APOE ε4 is associated with a higher density of amyloid plaques (as compared to APOE ε3). We speculate that multilobulated APOE ε4-associated plaques arise from multiple initiation foci that coalesce as the plaques grow.
基金supported by the Natural Science Foundation of China(11701176,61673169,11301127,11626101,11601485)the Science and Technology Research Program of Zhejiang Educational Committee(Y201635325)
文摘We establish the monotonicity and convexity properties for several special functions involving the generalized elliptic integrals, and present some new analytic inequalities.
文摘Bacterial meningitis is a serious and potentially life-threatening infection that affects the protective layers surrounding the brain and spinal cord,known as the meninges.Several types of bacteria,including Streptococcus pneumoniae,Neisseria meningitidis,and Haemophilus influenzae,can cause this condition.Certain populations,such as infants,children,immunocompromised adults,and the elderly,are particularly vulnerable to these pathogens.Symptoms of bacterial meningitis can manifest suddenly and may include high fever,severe and persistent headache,stiff neck,vomiting,sensitivity to light,and confusion or changes in mental state[1,2].Identifying these symptoms in infants can be more challenging and may lead to long-term disability or death[3].Despite the effectiveness of vaccines,it is crucial to understand how bacteria invade the brain and how our innate immune system responds to infection(Fig.1).
基金support from the Maximizing Investigators'Research Awards(R35GM119679,USA)and(R35GM144117,USA)from the National Institute of General Medical Sciences。
文摘Messenger RNA(mRNA)has drawn much attention in the medical field.Through various treatment approaches including protein replacement therapies,gene editing,and cell engineering,mRNA is becoming a potential therapeutic strategy for cancers.However,delivery of mRNA into targeted organs and cells can be challenging due to the unstable nature of its naked form and the low cellular uptake.Therefore,in addition to mRNA modification,efforts have been devoted to developing nanoparticles for mRNA delivery.In this review,we introduce four categories of nanoparticle platform systems:lipid,polymer,lipid-polymer hybrid,and protein/peptide-mediated nanoparticles,together with their roles in facilitating mRNA-based cancer immunotherapies.We also highlight promising treatment regimens and their clinical translation.
基金the National Natural Science Foundation of China(grants 32171011,62250004,32100816,62050071,31861143036,31671097,and 31371104)Natural Science Foundation of Jiangsu Province(grant BK20210183)the National Institutes of Health of USA(grants NS066587 and NS118606)。
文摘Locomotion in mollusc Aplysia is implemented by a pedal rolling wave,a type of axial locomotion.Well-studied examples of axial locomotion(pedal waves in Drosophila larvae and body waves in leech,lamprey,and fish)are generated in a segmented nervous system via activation of multiple coupled central pattern generators(CPGs).Pedal waves in molluscs,however,are generated by a single pedal ganglion,and it is unknown whether there are single or multiple CPGs that generate rhythmic activity and phase shifts between different body parts.During locomotion in intact Aplysia,bursting activity in the parapedal commissural nerve(PPCN)was found to occur during tail contraction.A cluster of 20 to 30 P1 root neurons(P1Ns)on the ventral surface of the pedal ganglion,active during the pedal wave,were identified.Computational cluster analysis revealed that there are 2 phases to the motor program:phase I(centered around 168°)and phase II(centered around 357°).PPCN activity occurs during phase II.The majority of P1Ns are motoneurons.Coactive P1Ns tend to be electrically coupled.Two classes of pedal interneurons(PIs)were characterized.Class 1(PI1 and PI2)is active during phase I.Their axons make a loop within the pedal ganglion and contribute to locomotor pattern generation.They are electrically coupled to P1Ns that fire during phase I.Class 2(PI3)is active during phase II and innervates the contralateral pedal ganglion.PI3 may contribute to bilateral coordination.Overall,our findings support the idea that Aplysia pedal waves are generated by a single CPG.
文摘The rat is a powerful model for the study of human physiology and diseases, and is prefened by physiologists, neuroscientists and toxicologists. However, the lack of robust genetic modification tools has severely limited the generation of rat genetic models over the last two decades. In the last few years, several gene-targeting strategies have been developed in rats using N-ethyl-N-nitrosourea （ENU）, transposons, zinc-finger nucleases （ZFNs）, bacterial a11ificial chromosome （BAC） mediated transgenesis, and recently established rat embryonic stem （ES） cells. The development and improvement of these approaches to genetic manipulation have created a bright future lbr the use of genetic rat models in investigations of gene function and human diseases. Here, we summarize the strategies used for rat genetic manipulation in current research. We also discuss BAC transgenesis as a potential tool in rat transgenic models.
文摘The pathophysiology underlying spinal cord injury is complex. Mechanistic understanding of the adaptive responses to injury is critical for targeted therapy aimed at reestablishing lost connections between proximal and distal neurons. After injury, cell-type specific gene transcription programs govern distinct cellular behaviors, and chromatin regulators play a central role in shaping the chromatin landscape to adjust transcriptional profiles in a contextdependent manner. In this review, we summarize recent progress on the pleiotropic roles of chromatin regulators in mediating the diverse adaptive behaviors of neurons and glial cells after spinal cord injury, and wherever possible, discuss the underlying mechanisms and genomic targets. We specifically draw attention to the perspective that takes into consideration the impact of epigenetic modulation on axon growth potential, together with its effect on woundhealing properties of glial cells. Epigenetic modulation of chromatin state represents an emerging therapeutic direction to promote neural repair and axon regeneration after spinal cord injury.
基金This study was supported by China minister of Science and Technology grant MoST-2017YFE0120100the Science and Technology Development Fund,Macao SAR(No.0110/2018/A3,0128/2019/A3,China)+1 种基金the University of Macao grants(No.MYRG2019-00129-ICMS,China)awarded to Jia-Hong LuNIH/R01NS060123 and R01 R01AG072520(USA)awarded to Zhenyu Yue.
文摘Alzheimer's disease(AD)is a prevalent and deleterious neurodegenerative disorder characterized by an irreversible and progressive impairment of cognitive abilities as well as the formation of amyloidβ(Aβ)plaques and neurofibrillary tangles(NFTs)in the brain.By far,the precise mechanisms of AD are not fully understood and no interventions are available to effectively slow down progression of the disease.Autophagy is a conserved degradation pathway that is crucial to maintain cellular homeostasis by targeting damaged organelles,pathogens,and disease-prone protein aggregates to lysosome for degradation.Emerging evidence suggests dysfunctional autophagy clearance pathway as a potential cellular mechanism underlying the pathogenesis of AD in affected neurons.Here we summarize the current evidence for autophagy dysfunction in the pathophysiology of AD and discuss the role of autophagy in the regulation of AD-related protein degradation and neuroinflammation in neurons and glial cells.Finally,we review the autophagy modulators reported in the treatment of AD models and discuss the obstacles and opportunities for potential clinical application of the novel autophagy activators for AD therapy.
