目的:探讨凋亡相关基因bax、bcl-2在R anv ier区部分切除后骺板软骨组织中的表达。方法:切除12mm长的新西兰大耳白兔的胫骨近端R anv ier区,于术后1、4周处死实验兔,从免疫组化方面观察凋亡相关基因bax、bcl-2在R anv ier区部分切除后...目的:探讨凋亡相关基因bax、bcl-2在R anv ier区部分切除后骺板软骨组织中的表达。方法:切除12mm长的新西兰大耳白兔的胫骨近端R anv ier区,于术后1、4周处死实验兔,从免疫组化方面观察凋亡相关基因bax、bcl-2在R anv ier区部分切除后不同周龄的兔胫骨近端骺板软骨组织中表达的变化特征。结果:随着R anv ier区部分切除后,骨桥形成前骺板软骨组织中的软骨细胞凋亡率明显低于对照组,骨桥形成后软骨细胞凋亡率明显高于对照组。结论:R anv ier区和骨桥对骺板软骨细胞的凋亡率有促进作用,骨桥的促进作用更明显。展开更多
Over the recent years, it has been found that microglia pseudopodia contact synapses, detect sick ones and prune them, even in adult animals. Myelinated nerves also carry out plasticity in which microglia remove myeli...Over the recent years, it has been found that microglia pseudopodia contact synapses, detect sick ones and prune them, even in adult animals. Myelinated nerves also carry out plasticity in which microglia remove myelin debris by phagocytosis. However, it remains unknown whether microglia explore structures on nerve fibers, such as Ranvier’s node(RN) or myelin sheath, before they become debris. By double or triple staining RNs or myelin sheathes and microglia in healthy rat corpus callosum, this study unveiled direct contacts of microglia pseudopodia with RNs and with para-and inter-nodal myelin sheathes, which was then verified by electron microscopic observations. Our data indicated that microglia also explore unmyelinated nerve fibers. Furthermore, we used the animals with matured white matter;therefore, microglia may be actively involved in plasticity of matured white matter tracts as it does for synapse pruning, instead of only passively phagocytize myelin debris.展开更多
The localization of ion channels on myelinated axon is closely related with the saltatory conduction of action potential (AP). Abnormal changes in these channels contribute to multiple mental diseases. The development...The localization of ion channels on myelinated axon is closely related with the saltatory conduction of action potential (AP). Abnormal changes in these channels contribute to multiple mental diseases. The development of cryo-Electron Tomography (cryo-ET) has provided a promising prospect for peering into ion channels in their native environment at high resolution. Previous achievements are reviewed here on cryo-ET. Accordingly, a cryo-ET workflow is designed for understanding ion channels localization in myelinated axon, especially nodes of Ranvier, which are significant for the saltatory conduction involved in the propagation of high-speed AP. The workflow is divided into six parts: the preparation of neural cultures with myelin, antibodies and immunofluorescence staining, frozen-hydrated sample preparation, cryo-ET imaging, cryo-correlative light and electron microscopy (cryo-CLEM) imaging, three-dimensional (3D) reconstruction and refinement. The purpose is to conceive a possible solution for the problems related to ion channel compounds including localization, conformation dynamics, accessory structures of ion channel and transient regulatory factors, and thus provide insights into treating neurological diseases caused by abnormal ion channels activity.展开更多
Myelinated axons of the peripheral and central nervous system（PNS＆CNS）are divided into molecularly distinct excitable domains,including the axon initial segment（AIS）and nodes of Ranvier.The AIS is composed of a d...Myelinated axons of the peripheral and central nervous system（PNS＆CNS）are divided into molecularly distinct excitable domains,including the axon initial segment（AIS）and nodes of Ranvier.The AIS is composed of a dense network of cytoskeletal proteins,cell adhesion molecules,and voltage gated ion channels and is located at the proximal most region of the axon（Koleand Stuart, 2012）.展开更多
The myelination of axons was the last major evolution in the vertebrate nervous system.Myelin promotes the speed of action potential by two orders,and modulates the conduction of neurons,important for learning new ski...The myelination of axons was the last major evolution in the vertebrate nervous system.Myelin promotes the speed of action potential by two orders,and modulates the conduction of neurons,important for learning new skills.However,the intrinsic mechanism for high-speed information propagation in myelin in the nervous systems is still unclear.We propose that myelinated nerve fibres serve as dielectric waveguides for the high-frequency electromagnetic information in a certain mid-infrared to terahertz spectral range.Based on the structure characteristics of myelinated nerve composed of periodic nodes of Ranvier and myelin sheath,the energy for the signal propagation is supplied and amplified when crossing the nodes of Ranvier via a periodic relay.In this work,we exploit the quasi-quantum model of amplification for neural terahertz/infrared information at the nodes of Ranvier,and prove the existence of biomolecular ensemble for three-energy-level amplification,revealing the essential mechanism of high-speed electromagnetic information transmitting in myelinated nerves.展开更多
The neuro-glial interface extends far beyond mechanical support alone and includes interactions through coagulation cascade proteins. Here, we systematically review the evidence indicating that synaptic and node of Ra...The neuro-glial interface extends far beyond mechanical support alone and includes interactions through coagulation cascade proteins. Here, we systematically review the evidence indicating that synaptic and node of Ranvier glia cell components modulate synaptic transmission and axonal conduction by a coagulation cascade protein system, leading us to propose the concept of the neuro-glial coagulonome. In the peripheral nervous system, the main thrombin receptor protease activated receptor 1 (PAR1) is located on the Schwann microvilli at the node of Ranvier and at the neuromuscular junction. PAR1 activation effects can be both neuroprotective or harmful, depending on thrombin activity levels. Low physiological levels of thrombin induce neuroprotective effects in the Schwann cells which are mediated by the endothelial protein C receptor. High levels of thrombin induce conduction deficits, as found in experimental autoimmune neuritis, the animal model for Guillaine-Barre syndrome. In the central nervous system, PAR1 is located on the peri-synaptic astrocyte end-feet. Its activation by high thrombin levels is involved in the pathology of primary inflammatory brain diseases such as multiple sclerosis, as well as in other central nervous system insults, including trauma, neoplasms, epilepsy and vascular injury. Following activation of PAR1 by high thrombin levels the seizure threshold is lowered. On the other hand, PAR1 activation by lower levels of thrombin in the central nervous system protects against a future ischemic insult. This review presents the known structure and function of the neuro-glial coagulonome, focusing on coagulation, thrombin and PAR1 in a pathway which may be either physiological (neuroprotective) or detrimental in peripheral nervous system and central nervous system diseases. Understanding the neuro-glial coagulonome may open opportunities for novel pharmacological interventions in neurological diseases.展开更多
Studies have shown that a combined application of several ion channel inhibitors immediately after central nervous system injury can inhibit secondary degeneration. However, for clinical use, it is necessary to determ...Studies have shown that a combined application of several ion channel inhibitors immediately after central nervous system injury can inhibit secondary degeneration. However, for clinical use, it is necessary to determine how long after injury the combined treatment of several ion channel inhibitors can be delayed and efficacy maintained. In this study, we delivered Ca^2＋ entry-inhibiting P2X7 receptor antagonist oxidized-ATP and AMPA receptor antagonist YM872 to the optic nerve injury site via an iPRECIO-@ pump immediately, 6 hours, 24 hours and 7 days after partial optic nerve transection surgery. In addition, all of the ion channel inhibitor treated rats were administered with calcium channel antagonist lomerizine hydrochloride. It is important to note that as a result of implantation of the particular pumps required for programmable delivery of therapeutics directly to the injury site, seromas occurred in a significant proportion of animals, indicating infection around the pumps in these animals. Improvements in visual function were observed only when treatment was delayed by 6 hours; phosphorylated Tau was reduced when treatment was delayed by 24 hours or 7 days. Improvements in structure of node/paranode of Ranvier and reductions in oxidative stress indicators were also only observed when treatment was delayed for 6 hours, 24 hours, or 7 days. Benefits of ion channel inhibitors were only observed with time-delayed treatment, suggesting that delayed therapy of Ca^2＋ ion channel inhibitors produces better neuroprotective effects on secondary degeneration, at least in the presence of seromas.展开更多
文摘目的:探讨凋亡相关基因bax、bcl-2在R anv ier区部分切除后骺板软骨组织中的表达。方法:切除12mm长的新西兰大耳白兔的胫骨近端R anv ier区,于术后1、4周处死实验兔,从免疫组化方面观察凋亡相关基因bax、bcl-2在R anv ier区部分切除后不同周龄的兔胫骨近端骺板软骨组织中表达的变化特征。结果:随着R anv ier区部分切除后,骨桥形成前骺板软骨组织中的软骨细胞凋亡率明显低于对照组,骨桥形成后软骨细胞凋亡率明显高于对照组。结论:R anv ier区和骨桥对骺板软骨细胞的凋亡率有促进作用,骨桥的促进作用更明显。
基金supported by R01 NS063878 and P30 MH062261 (to H.X., H.S.F.)
文摘Over the recent years, it has been found that microglia pseudopodia contact synapses, detect sick ones and prune them, even in adult animals. Myelinated nerves also carry out plasticity in which microglia remove myelin debris by phagocytosis. However, it remains unknown whether microglia explore structures on nerve fibers, such as Ranvier’s node(RN) or myelin sheath, before they become debris. By double or triple staining RNs or myelin sheathes and microglia in healthy rat corpus callosum, this study unveiled direct contacts of microglia pseudopodia with RNs and with para-and inter-nodal myelin sheathes, which was then verified by electron microscopic observations. Our data indicated that microglia also explore unmyelinated nerve fibers. Furthermore, we used the animals with matured white matter;therefore, microglia may be actively involved in plasticity of matured white matter tracts as it does for synapse pruning, instead of only passively phagocytize myelin debris.
文摘The localization of ion channels on myelinated axon is closely related with the saltatory conduction of action potential (AP). Abnormal changes in these channels contribute to multiple mental diseases. The development of cryo-Electron Tomography (cryo-ET) has provided a promising prospect for peering into ion channels in their native environment at high resolution. Previous achievements are reviewed here on cryo-ET. Accordingly, a cryo-ET workflow is designed for understanding ion channels localization in myelinated axon, especially nodes of Ranvier, which are significant for the saltatory conduction involved in the propagation of high-speed AP. The workflow is divided into six parts: the preparation of neural cultures with myelin, antibodies and immunofluorescence staining, frozen-hydrated sample preparation, cryo-ET imaging, cryo-correlative light and electron microscopy (cryo-CLEM) imaging, three-dimensional (3D) reconstruction and refinement. The purpose is to conceive a possible solution for the problems related to ion channel compounds including localization, conformation dynamics, accessory structures of ion channel and transient regulatory factors, and thus provide insights into treating neurological diseases caused by abnormal ion channels activity.
基金supported by National Institutes of Health Grants NS069688 and NS044916, TIRR Foundationthe Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
文摘Myelinated axons of the peripheral and central nervous system（PNS＆CNS）are divided into molecularly distinct excitable domains,including the axon initial segment（AIS）and nodes of Ranvier.The AIS is composed of a dense network of cytoskeletal proteins,cell adhesion molecules,and voltage gated ion channels and is located at the proximal most region of the axon（Koleand Stuart, 2012）.
基金the National Natural Science Foundation of China(Grant Nos.51677145,and 11622542).
文摘The myelination of axons was the last major evolution in the vertebrate nervous system.Myelin promotes the speed of action potential by two orders,and modulates the conduction of neurons,important for learning new skills.However,the intrinsic mechanism for high-speed information propagation in myelin in the nervous systems is still unclear.We propose that myelinated nerve fibres serve as dielectric waveguides for the high-frequency electromagnetic information in a certain mid-infrared to terahertz spectral range.Based on the structure characteristics of myelinated nerve composed of periodic nodes of Ranvier and myelin sheath,the energy for the signal propagation is supplied and amplified when crossing the nodes of Ranvier via a periodic relay.In this work,we exploit the quasi-quantum model of amplification for neural terahertz/infrared information at the nodes of Ranvier,and prove the existence of biomolecular ensemble for three-energy-level amplification,revealing the essential mechanism of high-speed electromagnetic information transmitting in myelinated nerves.
文摘The neuro-glial interface extends far beyond mechanical support alone and includes interactions through coagulation cascade proteins. Here, we systematically review the evidence indicating that synaptic and node of Ranvier glia cell components modulate synaptic transmission and axonal conduction by a coagulation cascade protein system, leading us to propose the concept of the neuro-glial coagulonome. In the peripheral nervous system, the main thrombin receptor protease activated receptor 1 (PAR1) is located on the Schwann microvilli at the node of Ranvier and at the neuromuscular junction. PAR1 activation effects can be both neuroprotective or harmful, depending on thrombin activity levels. Low physiological levels of thrombin induce neuroprotective effects in the Schwann cells which are mediated by the endothelial protein C receptor. High levels of thrombin induce conduction deficits, as found in experimental autoimmune neuritis, the animal model for Guillaine-Barre syndrome. In the central nervous system, PAR1 is located on the peri-synaptic astrocyte end-feet. Its activation by high thrombin levels is involved in the pathology of primary inflammatory brain diseases such as multiple sclerosis, as well as in other central nervous system insults, including trauma, neoplasms, epilepsy and vascular injury. Following activation of PAR1 by high thrombin levels the seizure threshold is lowered. On the other hand, PAR1 activation by lower levels of thrombin in the central nervous system protects against a future ischemic insult. This review presents the known structure and function of the neuro-glial coagulonome, focusing on coagulation, thrombin and PAR1 in a pathway which may be either physiological (neuroprotective) or detrimental in peripheral nervous system and central nervous system diseases. Understanding the neuro-glial coagulonome may open opportunities for novel pharmacological interventions in neurological diseases.
基金financial support from the National Health and Medical Research Council(NHMRC),Australia(APP1061791)an NHMRC Career Development Fellowship(APP1087114)
文摘Studies have shown that a combined application of several ion channel inhibitors immediately after central nervous system injury can inhibit secondary degeneration. However, for clinical use, it is necessary to determine how long after injury the combined treatment of several ion channel inhibitors can be delayed and efficacy maintained. In this study, we delivered Ca^2＋ entry-inhibiting P2X7 receptor antagonist oxidized-ATP and AMPA receptor antagonist YM872 to the optic nerve injury site via an iPRECIO-@ pump immediately, 6 hours, 24 hours and 7 days after partial optic nerve transection surgery. In addition, all of the ion channel inhibitor treated rats were administered with calcium channel antagonist lomerizine hydrochloride. It is important to note that as a result of implantation of the particular pumps required for programmable delivery of therapeutics directly to the injury site, seromas occurred in a significant proportion of animals, indicating infection around the pumps in these animals. Improvements in visual function were observed only when treatment was delayed by 6 hours; phosphorylated Tau was reduced when treatment was delayed by 24 hours or 7 days. Improvements in structure of node/paranode of Ranvier and reductions in oxidative stress indicators were also only observed when treatment was delayed for 6 hours, 24 hours, or 7 days. Benefits of ion channel inhibitors were only observed with time-delayed treatment, suggesting that delayed therapy of Ca^2＋ ion channel inhibitors produces better neuroprotective effects on secondary degeneration, at least in the presence of seromas.
