实验性癫痫大鼠补体C3b受体的表达

目的：建立大鼠的实验性癫痫模型，探讨实验性癫痫大鼠补体C3b受体的表达，进一步揭示癫痫的免疫炎症机制．方法：采用皮下注射海仁酸方法建立实验性癫痫大鼠模型；采用免疫组织化学染色方法观察实验性癫痫大鼠补体C3b受体的表达．结果：给大鼠皮下注射海仁酸可成功地建立实验性癫痫大鼠模型，其大脑海马锥状细胞层可见到神经元的变性，并可见补体C3b受体的明显表达．结论：实验性癫痫大鼠大脑海马硬化发生过程中，存在着补体系统参与的免疫反应发生，并引起炎症反应、     

帕金森病发生的肠道多巴胺调控机制

多巴胺(Dopamine,DA)是肠-脑轴中关键的神经递质,在中枢及外周均有广泛分布。帕金森症(Parkinson′s disease,PD)发生是由脑DA系统结构与功能退行性丢失所致,而脑DA补充调控的PD诊疗仍为传统主流。新近研究表明,DA及其受体调节肠道运动,PD患者肠神经变性早于中枢神经变性的发生,并伴有肠道DA减少及胃肠神经功能紊乱等非运动症状。本文综述了多巴胺在肠-脑轴的表达、分布、功能及PD发生的肠道多巴胺调控新机制,为基于肠道多巴胺的PD早期诊疗策略提供启示。     

癫痫患者额叶脑组织A型GABA受体α1亚型基因表达定量研究

目的: 研究A型GABA受体?1亚型(GABRA1)在癫痫患者病灶额叶脑组织中的表达变化与癫痫发病机制的关系. 方法采用TaqMan探针荧光定量PCR检测GABRA1在癫痫患者病灶额叶脑组织及对照组额叶脑组织中的表达量的差异. 结果对照组及癫痫患者额叶GABRA1平均相对表达强度为3.785±1.444和4.399±2.89, 两者间无显著差异(P> 0.05). 结论额叶脑组织中GABAA受体与癫痫的发生没有相关性.     

NMDA受体NR2B亚单位拮抗剂与神经系统退行性疾病

谷氨酸（Glu）是脊椎动物中枢神经系统中的主要兴奋性神经递质，其受体可分为代谢型和离子型两大类。离子型受体由三种组成：AMPA受体，KA受体及NMDA受体。其中NMDA受体被认为是突触可塑性及皮质和海马神经元长时程增强效应（Long-term potentiation，LTP）的主要调控者，构成了中枢神经系统的重要功能如学习和记忆的基础。NMDA受体的过度激活在多种神经系统退行性疾病的发生和发展过程中发挥着重要作用。但是，由于非选择性NMDA受体拮抗剂的选择性较低，故在发挥明显的治疗作用的同时也发生了严重的副反应，影响了其临床应用。而NMDA受体的NR2B亚单位的分布相对较集中，选择性NR2B受体拮抗剂受到了越来越多的关注。本文就近年来NMDA受体NR2B亚单位拮抗剂在神经系统退行性疾病中的研究进展作一综述。     

雄性大鼠海马多巴胺受体的增龄性改变

采用放射配基结合分析法初步观察了大鼠海马多巴胺(Dopamine,简称DA)受体的增龄性变化及腹腔注射使DA受体不可逆失活的EEDQ(N-乙氧羰基-2乙氧基-2双氧喹啉)后,DA受体的恢复情况.结果表明老年大鼠海马DA受体结合力较青年大鼠差异不明显,注射EEDQ后两者DA受体亲和力均明显降低,但恢复时青年大鼠恢复的速度快于老年鼠者.表明老年大鼠海马DA受体比青年大鼠更容易受到伤害,恢复也更困难,这些变化可能与老年期的一些表现及老年病的学习记忆紊乱有一定关系.     

雄性大鼠海马多巴胺受体的增龄性改变

采用放射配基结合分析法初步观察了大量海马多巴胺（Dopamine,简称DA）受体的增龄性变化及腹腔注射使DA受体不可逆失活的EEDQ（N－乙氧羰基－2乙氧基－2双氧喹啉）后,DA受体的恢复情况,结果表明老年大鼠海马DA受体结合力较青年大鼠差异不明显,注射EEDQ后两者DA受体亲和力均明显降低,但恢复时青年大鼠恢复的速度快于老年鼠者,表明老年大鼠海马DA受体比青年大鼠更容易受到伤害,恢复也更困难,这些变化可能与老年期的一些表现及老年病的学习记忆紊乱有一定关系。     

酪氨酸羟化酶与帕金森病的关系研究

酪氨酸羟化酶(Tyrosine hydroxylase, TH)是多巴胺(Dopamine,DA)生物合成途径的关键酶,帕金森病(Parkinson's disease, PD)是由于黑质纹状体DA严重不足导致的一种神经变性疾病.研究了TH主导的DA代谢调节与PD发生的相互关系,TH结构、DA代谢的调节以及TH在PD发生发展和治疗中的作用.     

酪氨酸蛋白激酶受体c-Met及靶点药物研究进展

酪氨酸激酶受体c-Met在细胞的代谢、分化以及死亡细胞的信号传导过程中起着重要的作用,其与配体结合,可活化其信号通路,参与胚胎发育、组织损伤修复以及肿瘤的发生和发展。因而,以酪氨酸激酶受体c-Met为靶点的抗肿瘤药物已经成为肿瘤研究中十分活跃的领域,为抗肿瘤治疗提供了新方法。     

1α,25—双羟维生素D3作用于靶细胞的机制

1α,25-双羟维生素D3[1α，25（OH）2D3]作用于靶细胞后产生2种不同的信号传导系统，基因效应和非基因效应。前者是指1α，25（OH）2D3与维生素D核受体（nVDR）结合。nVDR再与视黄酸X受体（RXR）发生异二聚化反应。在转录因子（TF）的作用下，使促靶基因转录。后者是指1α，25(OH)2D3与维生素D膜受体（mVDR）结合，随之引发一系列信号传导，促使细胞膜上的Ca^2 -通道迅速打开，探讨1α，25（OH）2D3的作用机制有利于开发治疗维生素D内分泌系统疾病的新药。本文就目前有关1α，25（OH）2D3作用于靶细胞的机制的研究成果进行综述。     

组蛋白修饰与癫痫的发生发展研究进展

癫痫是由脑部神经元异常同步或过度放电导致的一种慢性脑部疾病。在神经系统疾病中，癫痫已成为仅次于脑血管病的第二大严重威胁人类健康的疾病，且其发病机制至今未明。表观遗传机制是调节基因表达的一种方式，其中组蛋白修饰是主要的表观遗传修饰之一。组蛋白修饰的异常与癫痫的发生发展密切相关，本文对组蛋白修饰与癫痫的关系进行综述，以期从组蛋白修饰的角度阐明两者之间的关系，为癫痫的防治提供新思路。     

成年雄性斑胸草雀脑多巴胺D1受体的分布

多巴胺是脑内关键的神经递质,它通过与多巴胺受体的作用及其下游的一系列反应来影响基因表达、神经调节和行为活动.在成年鸣禽中,中脑多巴胺能神经元投射到X区、HVC和RA等鸣唱相关核团,释放多巴胺的量受一定社会情境的影响,从而表现出directed song和undirected song等不同鸣唱行为.获得斑胸草雀脑中多巴胺受体的表达情况,为与社会情境有关的鸣唱行为及其他和多巴胺相关的行为活动的神经机制探究提供了基础,并可促进行为学、电生理等方面的研究.我们发现D1受体在斑胸草雀脑中的分布与其mRNA的分布基本一致:在脑的绝大部分区域都有分布;主要鸣唱核团HVC和RA有表达,与其周围区域差异不明显;LMAN中表达量较少;DLM中的表达量较高,并与其周围区域差异明显.但是纹状体内的表达与其周围区域的差异性没有mRNA明显;GCT中的表达量较多,与周围区域差异明显.     

Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine.

Dopamine receptors belong to the family of G protein-coupled receptors. On the basis of the homology between these receptors, three different dopamine receptors (D1, D2, D3) have been cloned. Dopamine receptors are primary targets for drugs used in the treatment of psychomotor disorders such as Parkinson's disease and schizophrenia. In the management of socially withdrawn and treatment-resistant schizophrenics, clozapine is one of the most favoured antipsychotics because it does not cause tardive dyskinesia. Clozapine, however, has dissociation constants for binding to D2 and D3 that are 4 to 30 times the therapeutic free concentration of clozapine in plasma water. This observation suggests the existence of other types of dopamine receptors which are more sensitive to clozapine. Here we report the cloning of a gene that encodes such a receptor (D4). The D4 receptor gene has high homology to the human dopamine D2 and D3 receptor genes. The pharmacological characteristics of this receptor resembles that of the D2 and D3 receptors, but its affinity for clozapine is one order of magnitude higher. Recognition and characterization of this clozapine neuroleptic site may prove useful in the design of new types of drugs.     

Activation of NMDA receptors blocks GABAergic inhibition in an in vitro model of epilepsy

The application of tetanic electrical stimuli to the stratum radiatum fibre pathway in the hippocampus in vitro produces an NMDA (N-methyl-D-aspartate) receptor-dependent enhancement of synaptic efficacy. Repeated application of such stimuli produces a progressive enhancement of synaptic efficacy leading to the genesis of spontaneous and stimulation-evoked epileptiform discharges. We have used this in vitro approach to explore the cellular mechanisms which underlie the kindling model of epilepsy. Kindling of the stratum radiatum fibre pathway in vitro induced a progressive, long-lasting reduction of both spontaneous and stimulation-evoked GABAergic (gamma-aminobutyric acid-mediated) inhibitory postsynaptic potentials (i.p.s.ps). The reduction of i.p.s.ps by kindling was associated with a profound decrease in the sensitivity of CA1 pyramidal neurons to ionophoretically applied GABA and an increase in sensitivity to NMDA. The reduction of i.p.s.ps and GABA sensitivity was prevented by kindling in the presence of the NMDA receptor antagonist D-2-amino-5-phosphonovalerate (D-APV). These results demonstrate that kindling-like stimulus patterns produce a reduction of GABAergic inhibition in the hippocampus resulting from a stimulus-induced postsynaptic activation of NMDA receptors. The modulation of GABAergic inhibition by NMDA receptors may cause the synaptic plasticity which underlies the kindling model of epilepsy.     

Human dopamine D1 receptor encoded by an intronless gene on chromosome 5

Receptors for dopamine have been classified into two functional types, D1 and D2. They belong to the family of receptors acting through G (or guanine nucleotide-binding) proteins. D2 receptors inhibit adenylyl cyclase, but D1 receptors stimulate adenylyl cyclase and activate cyclic AMP-dependent protein kinases. Dopamine D1 and D2 receptors are targets of drug therapy in many psychomotor disorders, including Parkinson's disease and schizophrenia, and may also have a role in drug addiction and alcoholism. D1 receptors regulate neuron growth and differentiation, influence behaviour and modify dopamine D2 receptor-mediated events. We report here the cloning of the D1 receptor gene, which resides on an intronless region on the long arm of chromosome 5, near two other members of the G-linked receptor family. The expressed protein, encoded by 446 amino acids, binds drugs with affinities identical to the native human D1 receptor. The presence of a D1 receptor gene restriction fragment length polymorphism will be helpful for future disease linkage studies.     

Molecular cloning and expression of the gene for a human D1 dopamine receptor

The diverse physiological actions of dopamine are mediated by its interaction with two basic types of G protein-coupled receptor, D1 and D2, which stimulate and inhibit, respectively, the enzyme adenylyl cyclase. Alterations in the number or activity of these receptors may be a contributory factor in diseases such as Parkinson's disease and schizophrenia. Here we describe the isolation and characterization of the gene encoding a human D1 dopamine receptor. The coding region of this gene is intronless, unlike the gene encoding the D2 dopamine receptor. The D1 receptor gene encodes a protein of 446 amino acids having a predicted relative molecular mass of 49,300 and a transmembrane topology similar to that of other G protein-coupled receptors. Transient or stable expression of the cloned gene in host cells established specific ligand binding and functional activity characteristic of a D1 dopamine receptor coupled to stimulation of adenylyl cyclase. Northern blot analysis and in situ hybridization revealed that the messenger RNA for this receptor is most abundant in caudate, nucleus accumbens and olfactory tubercle, with little or no mRNA detectable in substantia nigra, liver, kidney, or heart. Several observations from this work in conjunction with results from other studies are consistent with the idea that other D1 dopamine receptor subtypes may exist.     

Cloning of the gene for a human dopamine D5 receptor with higher affinity for dopamine than D1.

Dopamine receptors belong to a superfamily of receptors that exert their biological effects through guanine nucleotide-binding (G) proteins. Two main dopamine receptor subtypes have been identified, D1 and D2, which differ in their pharmacological and biochemical characteristics. D1 stimulates adenylyl cyclase activity, whereas D2 inhibits it. Both receptors are primary targets for drugs used to treat many psychomotor diseases, including Parkinson's disease and schizophrenia. Whereas the dopamine D1 receptor has been cloned, biochemical and behavioural data indicate that dopamine D1-like receptors exist which either are not linked to adenylyl cyclase or display different pharmacological activities. We report here the cloning of a gene encoding a 477-amino-acid protein with strong homology to the cloned D1 receptor. The receptor, called D5, binds drugs with a pharmacological profile similar to that of the cloned D1 receptor, but displays a 10-fold higher affinity for the endogenous agonist, dopamine. As with D1, the dopamine D5 receptor stimulates adenylyl cyclase activity. Northern blot and in situ hybridization analyses reveal that the receptor is neuron-specific, localized primarily within limbic regions of the brain; no messenger RNA was detected in kidney, liver, heart or parathyroid gland. The existence of a dopamine D1-like receptor with these characteristics had not been predicted and may represent an alternative pathway for dopamine-mediated events and regulation of D2 receptor activity.     

Cloning and expression of human and rat D1 dopamine receptors

The importance of the dopaminergic system in brain function has been emphasized by its association with neurological and psychiatric disorders such as Parkinson's disease and schizophrenia. On the basis of their biochemical and pharmacological characteristics, dopamine receptors are classified into D1 and D2 subtypes. As the most abundant dopamine receptor in the central nervous system, D1 receptors seem to mediate some behavioural responses, modulate activity of D2 dopamine receptors, and regulate neuron growth and differentiation. The D dopamine receptor has been cloned by low-stringency screening. We report here the cloning of human and rat D1 dopamine receptors by applying an approach based on the polymerase chain reaction. The cloned human D1 dopamine receptor has been characterized on the basis of four criteria: the deduced amino-acid sequence, which reveals that it is a G protein-coupled receptor; the tissue distribution of its messenger RNA, which is compatible with that of the D1 dopamine receptor; its pharmacological profile when transfected into COS-7 cells; and its ability to stimulate the accumulation of cyclic AMP in human 293 cells.     

Localization of D-2 dopamine receptors to intrinsic striatal neurones by quantitative autoradiography

Recent work with positron emission and single photon emission computed tomography has demonstrated the feasibility of studying striatal dopamine receptors in the living human brain. For the proper interpretation of these studies in normal and diseased states, the cellular localization of these receptors must be definitively established. It has been claimed, on the basis of receptor binding studies with tissue homogenates in rats, that 30-50% of striatal D-2 dopamine receptors are located on axons or terminals of the corticostriatal pathway. This finding has been incorporated into major reviews and classifications of dopamine receptors. The recent development of quantitative autoradiographic methods for diffusible ligands has facilitated the study of neurotransmitter receptors in cytoarchitechtonically intact tissue. Because this technique provides the necessary anatomic resolution that is lacking in homogenate binding studies, we have used it to re-examine the localization of striatal dopamine receptors. Here we present evidence that D-2 receptors are located exclusively on kainic acid-sensitive intrinsic neuronal elements in the striatum. We report that discrete cortical ablation does not alter 3H-spiperone binding to rat striatum and thus our results do not support the existence of D-2 dopamine receptors on the terminals of the corticostriatal pathway.     

塔中I号断裂带中上奥陶统灰岩裂缝类型划分

中上奥陶统(O2+3)灰岩是塔中油气区主要的储集层,由于基质的孔隙度和渗透率极低,裂缝在储层中既是油气聚集的空间,也是油气运移的主要通道。不同类型裂缝的成因、产状、规模、以及对油气的孔、渗能力都各不相同,对它的研究有助于寻找油气的聚集与富集规律。依据对塔中I号断裂带裂缝调查的结果,按照裂缝的成因,充填物的类型、特征,以及不同充填物充填的裂缝之间的切割关系,将O2+3灰岩储层中的裂缝分为不同的大类;然后根据裂缝的产状、性质等,再将裂缝细分为不同的亚类型。结果表明:该地区裂缝类型复杂,发育有2类成岩缝和5类(期)构造裂缝,每期构造缝都发育了不同产状和性质的裂缝。     

HMM用于G蛋白偶联受体超家族的识别

采用了一种HMM(隐马尔可夫模型 )的方法用于G蛋白偶联受体超家族层次各类别之间进行识别 ,具体考虑了ACDE与B类超家族 ,以及BCDE与A类超家族的分辨 ,取得了不错的效果 ,类之间的识别准确率可以达到10 0 % .研究过程中 ,考虑了G蛋白偶联受体一级结构信息和数据自身特性 ,合理地利用了G蛋白偶联受体一级结构序列的不等长特性 ,同时在模型的预测方面采用了双模型的预测机制 .