Kainate receptor pharmacology and physiology

Glutamate is the primary neurotransmitter in the central nervous system. One of the classes of ionotropic glutamate receptors is kainate receptors. Recent developments in the pharmacology of kainate receptors have resulted in the emergence of several selective agonists and antagonists. These compounds have allowed scientists to begin to probe the functional properties of these receptors in neurons and gain a better understanding of the role of these receptors in the nervous system.     

Mutations in the gene encoding 11-cis retinol dehydrogenase cause delayed dark adaptation and fundus albipunctatus.

The metabolic pathways that produce 11-cis retinal are important for vision because this retinoid is the chromophore residing in rhodopsin and the cone opsins. The all-trans retinal that is generated after cone and rod photopigments absorb photons of light is recycled back to 11-cis retinal by the retinal pigment epithelium and Müller cells of the retina. Several of the enzymes involved have recently been purified and molecularly cloned; here we focus on 11-cis retinol dehydrogenase (encoded by the gene RDH5; chromosome 12q13-14; ref. 4), the first cloned enzyme in this pathway. This microsomal enzyme is abundant in the retinal pigment epithelium, where it has been proposed to catalyse the conversion of 11-cis retinol to 11-cis retinal. We evaluated patients with hereditary retinal diseases featuring subretinal spots (retinitis punctata albescens and fundus albipunctatus) and patients with typical dominant or recessive retinitis pigmentosa for mutations in RDH5. Mutations were found only in two unrelated patients, both with fundus albipunctatus; they segregated with disease in the respective families. Recombinant mutant 11-cis retinol dehydrogenases had reduced activity compared with recombinant enzyme with wild-type sequence. Our results suggest that mutant alleles in RDH5 are a cause of fundus albipunctatus, a rare form of stationary night blindness characterized by a delay in the regeneration of cone and rod photopigments.     

Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia

Autosomal dominant hereditary spastic paraplegia (AD-HSP) is a genetically heterogeneous neurodegenerative disorder characterized by progressive spasticity of the lower limbs. Among the four loci causing AD-HSP identified so far, the SPG4 locus at chromosome 2p2-1p22 has been shown to account for 40-50% of all AD-HSP families. Using a positional cloning strategy based on obtaining sequence of the entire SPG4 interval, we identified a candidate gene encoding a new member of the AAA protein family, which we named spastin. Sequence analysis of this gene in seven SPG4-linked pedigrees revealed several DNA modifications, including missense, nonsense and splice-site mutations. Both SPG4 and its mouse orthologue were shown to be expressed early and ubiquitously in fetal and adult tissues. The sequence homologies and putative subcellular localization of spastin suggest that this ATPase is involved in the assembly or function of nuclear protein complexes.     

Dissociation of dopamine release in the nucleus accumbens from intracranial self-stimulation

Mesolimbic dopamine-releasing neurons appear to be important in the brain reward system. One behavioural paradigm that supports this hypothesis is intracranial self-stimulation (ICS), during which animals repeatedly press a lever to stimulate their own dopamine-releasing neurons electrically. Here we study dopamine release from dopamine terminals in the nucleus accumbens core and shell in the brain by using rapid-responding voltammetric microsensors during electrical stimulation of dopamine cell bodies in the ventral tegmental area/substantia nigra brain regions. In rats in which stimulating electrode placement failed to elicit dopamine release in the nucleus accumbens, ICS behaviour was not learned. In contrast, ICS was acquired when stimulus trains evoked extracellular dopamine in either the core or the shell of the nucleus accumbens. In animals that could learn ICS, experimenter-delivered stimulation always elicited dopamine release. In contrast, extracellular dopamine was rarely observed during ICS itself. Thus, although activation of mesolimbic dopamine-releasing neurons seems to be a necessary condition for ICS, evoked dopamine release is actually diminished during ICS. Dopamine may therefore be a neural substrate for novelty or reward expectation rather than reward itself.     

Chaperone-like activity of the AAA domain of the yeast Yme1 AAA protease

The AAA domain, a conserved Walker-type ATPase module, is a feature of members of the AAA family of proteins, which are involved in many cellular processes, including vesicular transport, organelle biogenesis, microtubule rearrangement and protein degradation. The function of the AAA domain, however, has not been explained. Membrane-anchored AAA proteases of prokaryotic and eukaryotic cells comprise a subfamily of AAA proteins that have metal-dependent peptidase activity and mediate the degradation of non-assembled membrane proteins. Inactivation of an orthologue of this protease family in humans causes neurodegeneration in hereditary spastic paraplegia. Here we investigate the AAA domain of the yeast protein Yme1, a subunit of the iota-AAA protease located in the inner membrane of mitochondria. We show that Yme1 senses the folding state of solvent-exposed domains and specifically degrades unfolded membrane proteins. Substrate recognition and binding are mediated by the amino-terminal region of the AAA domain. The purified AAA domain of Yme1 binds unfolded polypeptides and suppresses their aggregation. Our results indicate that the AAA domain of Ymel has a chaperone-like activity and suggest that the AAA domains of other AAA proteins may have a similar function.     

线性与非线性有限单元分析概论计算方法

本书是关于线性和非线性有限单元法的入门教材，是根据作者在过去12年里为美国新奥尔良大学的多个专业学生讲授这两门课程的基础上逐步编撰而成。本书不同于已有教材，有许多新颖的特点，如重视基础应用，力求最少涉及数学理论；内容涉及的专业范围宽，选用大量不同专业的问题进行引导，可供多种学科背景的学生学习；在讲述理论的同时将相关软件的使用贯穿全书。