Cloning and characterization of a new intercellular adhesion molecule ICAM-R.

The human intercellular adhesion molecules ICAM-1, ICAM-2 and their counter-receptors, the beta 2 or leukointegrins, mediate a variety of homotypic and heterotypic leukocyte and endothelial cell-cell adhesions central to immunocompetence. It has been found that cell-cell adhesion which is dependent on expression of the leukocyte function-associated antigen LFA-1 is not always blocked completely by antibodies raised against ICAM-1 and ICAM-2. Other leukointegrin ligands therefore probably exist, such as a glycoprotein of M(r) 124K that binds LFA-1 and has been designated ICAM-3 on the basis of this function. We have molecularly cloned a new member of the ICAM family, ICAM-R, which is related to ICAM-1 and ICAM-2. The complementary DNA encoding ICAM-R is 1,781 base pairs long and the protein has five extracellular immunoglobulin-family type domains. The mature cell-surface form of the ICAM-R protein has an M(r) which varies from 116 to 140K in a cell type-specific fashion. Overall identities in protein sequence with ICAM-1 and ICAM-2 are 48% and 31% respectively, with the degree of similarity varying between individual domains. The high level of expression of ICAM-R on resting leukocytes of all lineages and its lack of expression on either resting or cytokine-activated endothelial cells indicates a pattern of expression distinct from ICAM-1 and ICAM-2. In common with ICAM-1 and ICAM-2, ICAM-R is a ligand for the beta 2-integrin CD11a/LFA-1 (CD18).     

Neural adhesion molecule L1 as a member of the immunoglobulin superfamily with binding domains similar to fibronectin

Diverse glycoproteins of cell surfaces and extracellular matrices operationally termed 'adhesion molecules' are important in the specification of cell interactions during development, maintenance and regeneration of the nervous system. These adhesion molecules have distinct functions involving different cells at different developmental stages, but may cooperate when expressed together. Families of adhesion molecules which share common carbohydrate domains do exist, despite the structural and functional diversity of these glycoproteins. These include the Ca2+-independent neural adhesion molecules: N-CAM, myelin associated glycoprotein (MAG) and L1. L1 is involved in neuron-neuron adhesion, neurite fasciculation, outgrowth of neurites, cerebellar granule cell migration, neurite outgrowth on Schwann cells and interactions among epithelial cells of intestinal crypts. We show here that in addition to sharing carbohydrate epitopes with N-CAM and MAG, L1 is also a member of the immunoglobulin superfamily. It contains six C2 domains and also shares three type III domains with the extracellular matrix adhesion molecule fibronectin.     

ELAM-1 is an adhesion molecule for skin-homing T cells.

Endothelial cell leukocyte adhesion molecule-1 (ELAM-1) has been described as an inducible endothelial cell-adhesion molecule for neutrophils, and is believed to have a key role in the extravasation of these cells at sites of acute inflammation. Here we report that ELAM-1-transfected COS cells also bind a unique skin-associated subset of circulating memory T cells defined by the expression of the cutaneous lymphocyte-associated antigen. T cells expressing this antigen bind at least as well as neutrophils to expressed ELAM-1, whereas other lymphocytes in the peripheral blood bind poorly, or not at all. Immunohistological survey of chronically inflamed tissue specimens revealed that vascular expression of ELAM-1 occurs at cutaneous sites in preference to noncutaneous sites. We conclude that at sites of chronic inflammation, ELAM-1 may function as a skin vascular addressin, a tissue-selective endothelial cell-adhesion molecule for skin-homing memory T lymphocytes.     

Activation-independent binding of human memory T cells to adhesion molecule ELAM-1.

The induction of an ensemble of adhesion molecules on endothelial cells by inflammatory cytokines is likely to be crucial to the differential migration of T-lymphocyte subsets into inflammatory sites. Two molecular pathways involving the VLA-4 and LFA-1 integrins are known to mediate T-cell adhesion to activated endothelium. Here we show that a third pathway involving the rapidly inducible endothelial cell-surface adhesion molecule ELAM-1 contributes to the binding of resting CD4+ T cells to IL-1-induced human endothelial cells. All three pathways contribute to the greater adhesion to endothelium of memory T cells than naive T cells. There are two unique features of T-cell adhesion to purified ELAM-1: first, ELAM-1 exclusively mediates adhesion of memory T cells; second, memory T-cell binding to ELAM-1 is independent of acute activation events that regulate integrin-mediated adhesion. Thus, ELAM-1 may be of primary importance in the initial attachment of memory T cells to inflamed endothelium in vivo and to the preferential migration of memory T cells into tissue and inflammatory sites.     

Crystal structure at 2.8 A resolution of a soluble form of the cell adhesion molecule CD2.

The crystal structure of a soluble form of the T lymphocyte antigen CD2 provides the first complete view of the extracellular region of a cell adhesion molecule. The topology of the molecule, which comprises two immunoglobulin-like domains, is the same as that of the first two domains of CD4 but the relative domain orientation is altered by a fairly flexible linker region. The putative ligand-binding beta-sheet forms a flat surface towards the top of the molecule. Crystal contacts between these surfaces suggest a plausible model for the adhesive interaction.     

体育游戏在体育教学中的作用以及应注意的问题

随着我国大众体育的迅速发展、学校体育教学改革的不断深化和体育事业的兴旺发展，体育游戏这一健身效果好、趣味性强、易于发展的项目，越来越受到重视，并被广泛运用于体育教学的实践课程中．笔者通过以下观点，对体育游戏在体育教学q-的作用及应注意的问题提出了新的教学思路，以供参考．     

体育游戏在体育教学中的作用以及应注意的问题

随着我国大众体育的迅速发展、学校体育教学改革的不断深化和体育事业的兴旺发展,体育游戏这一健身效果好、趣味性强、易于发展的项目,越来越受到重视,并被广泛运用于体育教学的实践课程中.笔者通过以下观点,对体育游戏在体育教学中的作用及应注意的问题提出了新的教学思路,以供参考.     

T-cell recognition of an immunodominant myelin basic protein epitope in multiple sclerosis.

Multiple sclerosis is thought to be an autoimmune disease of the central nervous system mediated by T cells specific for a myelin antigen. Myelin basic protein has been studied as a potential autoantigen in the disease because of its role as an encephalitogen in experimental autoimmune encephalomyelitis and post-viral encephalomyelitis and because of the presence in the blood of multiple sclerosis patients of in vivo-activated T cells reactive to myelin basic protein. Immune involvement in multiple sclerosis has been further suggested by the association with the major histocompatibility complex class II phenotype DR2, DQw1. To define the T-cell specificity toward myelin basic protein, 15,824 short-term T-cell lines were established from multiple sclerosis subjects, subjects with other neurological diseases, and normal controls. Here we report a higher frequency of T-cell lines reactive with a DR2-associated region of myelin basic protein between residues 84-102 in patients with multiple sclerosis compared with controls. A second region, identified between residues 143-168, was recognized equally in multiple sclerosis patients and controls and was associated with the DRw11 phenotype. These DR2 and DRw11 associations were also observed among T-cell lines generated from family members of a multiple sclerosis patient. The immunodominant 84-102 peptide from myelin basic protein was both DR2- and DQw1-restricted among different T-cell lines. These results raise the possibility that this immunodominant region may be encephalitogenic in some DR2+ individuals.     

The mucosal vascular addressin is a tissue-specific endothelial cell adhesion molecule for circulating lymphocytes

Tissue position-dependent or address-dependent expression of cell adhesion molecules has been proposed to play a part in cellular positioning in a variety of systems, for example during neural development, the metastasis of neoplasms, and the tissue-specific homing of lymphocytes. The extravasation of blood-borne lymphocytes is regulated by interactions with the endothelium of specialised venules, such as the high endothelial venules (HEV) in organized lymph nodes and mucosal lymphoid tissues. At least three separate lymphocyte-HEV recognition systems have been described, one mediating tissue-selective lymphocyte interactions with HEV in peripheral lymph nodes, another in mucosal lymphoid organs, and a third in inflamed synovium. We have previously identified a tissue-specific 'vascular addressin' in the mouse which is selectively expressed by venules mediating lymphocyte-homing into mucosal tissues. To determine whether this addressin is a specific adhesion molecule for lymphocytes, we have isolated it by monoclonal antibody-affinity chromatography and inserted it into supported phospholipid planar membranes. Lymphocytes bind to membranes containing the addressin, but not to phospholipid bilayers or to control glycophorin-reconstituted membranes. Only those lymphocytes and lymphoma cell lines capable of binding to mucosal HEV adhere well to the isolated addressin; peripheral lymph node HEV-specific or HEV-non-binding cell lines do not bind. Binding is blocked by anti-addressin antibody MECA-367. We conclude that the mucosal vascular addressin is a tissue-specific endothelial cell-adhesion molecule for lymphocytes, and suggest that it could regulate lymphocyte traffic into mucosal tissues by mediating attachment of blood-borne cells to endothelium.     

Selective inhibition of cotranslational translocation of vascular cell adhesion molecule 1

Increased expression of vascular cell adhesion molecule 1 (VCAM1) is associated with a variety of chronic inflammatory conditions, making its expression and function a target for therapeutic intervention. We have recently identified CAM741, a derivative of a fungus-derived cyclopeptolide that acts as a selective inhibitor of VCAM1 synthesis in endothelial cells. Here we show that the compound represses the biosynthesis of VCAM1 in cells by blocking the process of cotranslational translocation, which is dependent on the signal peptide of VCAM1. CAM741 does not inhibit targeting of the VCAM1 nascent chains to the translocon channel but prevents translocation to the luminal side of the endoplasmic reticulum (ER), through a process that involves the translocon component Sec61beta. Consequently, the VCAM1 precursor protein is synthesized towards the cytosolic compartment of the cells, where it is degraded. Our results indicate that the inhibition of cotranslational translocation with low-molecular-mass compounds, using specificity conferred by signal peptides, can modulate the biosynthesis of certain secreted and/or membrane proteins. In addition, they highlight cotranslational translocation at the ER membrane as a potential target for drug discovery.     

平面P波在饱和半空间中凹陷地形周围的散射规律

对平面P波在饱和半空间中凹陷地形周围的散射规律进行了研究,分析了入射波频率、边界渗透条件、孔隙率、泊松比等对散射的影响.研究表明,饱和情况(透水或不透水)与干土情况凹陷地形附近地表位移的差别很大,饱和情况与干土情况的地表位移出现相位漂移,饱和情况地表位移波长相对较大.当孔隙率较低时,边界渗透条件对地表位移幅值的影响很小,而当孔隙率较大时,边界渗透条件的影响则不可忽视:在不透水情况下,水平和竖向地表位移幅值的峰值均相对较大.随着入射频率的升高,孔隙率的影响逐渐增大,而且不透水情况下孔隙率的影响相对较大.随着泊松比的增大,水平位移幅值逐渐减小,竖向位移幅值则逐渐增大.泊松比较小时,边界渗透条件对位移幅值的影响较大;泊松比较大时,边界渗透条件对位移幅值的影响则较小.随着入射频率的升高,泊松比的影响逐渐增大.当孔隙率较小时,孔隙水压幅值较小但空间变化比较剧烈;随着孔隙率的增大,孔隙水压逐渐增大但空间变化逐渐平缓.当孔隙率达到临界状态时,孔隙水压显著增大;这与SV波入射情况完全不同.当入射频率较高时,孔隙水压幅值较大,且孔隙水压的空间变化比较复杂.     

Trembler mouse carries a point mutation in a myelin gene.

The autosomal dominant trembler mutation (Tr), maps to mouse chromosome 11 (ref. 2) and manifests as a Schwann-cell defect characterized by severe hypomyelination and continuing Schwann-cell proliferation throughout life. Affected animals move clumsily and develop tremor and transient seizures at a young age. We have recently described a potentially growth-regulating myelin protein, peripheral myelin protein-22 (PMP-22; refs 7, 8), which is expressed by Schwann cells and found in peripheral myelin. We now report the assignment of the gene for PMP-22 to mouse chromosome 11. Cloning and sequencing of PMP-22 complementary DNAs from inbred Tr mice reveals a point mutation that substitutes an aspartic acid residue for a glycine in a putative membrane-associated domain of the PMP-22 protein. Our results identify the PMP-22 gene as a likely candidate for the mouse trembler locus and will encourage the search for mutations in the corresponding human gene in pedigrees with hypertrophic neuropathies such as Charcot-Marie-Tooth and Dejerine-Sottas diseases (hereditary motor and sensory neuropathies I and III).     

Sodium channel density in hypomyelinated brain increased by myelin basic protein gene deletion.

Trophic control over the expression and membrane distribution of voltage-dependent ion channels is one of the principal organizing events underlying the maturation of excitable cells. The myelin sheath is a major structural determinant of regional ion channel topography in central axons, but the exact molecular signals that mediate local interactions between the oligodendrocyte and axolemma are not known. We have found that large caliber fibre pathways in the brain of the mutant mouse shiverer (shi, gene on chromosome 18), whose developmental fate of myelination is averted by deletion of five exons in the myelin basic protein gene, have a striking excess of sodium channels. As cytoplasmic membranes of shiverer oligodendroglia still adhere to axons, the evidence indicates that myelin basic protein or a myelin basic protein-dependent glial transmembrane signal associated with compact myelin formation, rather than a simple glial-axon contact inhibition or an intrinsic genetic program of neuronal differentiation, could be critical in downregulating sodium channel density in axons. Here we use the shiverer mutant to show that mature central nervous system projection neurons with large caliber unmyelinated fibres sustain functional excitability by increasing sodium channel density. This axon plasticity, triggered by the absence of a single glial protein, contributes to the unexpectedly mild degree of neurological impairment in the mutant brain without myelin, and may be a potentially inducible mechanism determining the recovery of function from dysmyelinating disease.