A soluble form of CD4 (T4) protein inhibits AIDS virus infection

CD4 (T4) is a glycoprotein of relative molecular mass 55,000 (Mr 55K) on the surface of T lymphocytes which is thought to interact with class II MHC (major histocompatibility complex) molecules, mediating efficient association of helper T cells with antigen-bearing targets. The CD4 protein is also the receptor for HIV, a T-lymphotropic RNA virus responsible for the human acquired immune deficiency syndrome (AIDS) (refs 4-7). To define the mechanisms of interaction of CD4 with the surface of antigen-presenting cells and with HIV, we have isolated the CD4 gene and expressed this gene in several different cellular environments. Here we describe an efficient expression system in which a recombinant, soluble form of CD4 (sCD4) is secreted into tissue culture supernatants. This sCD4 retains the structural and biological properties of CD4 on the cell surface, binds to the envelope glycoprotein (gp110) of HIV and inhibits the binding of virus to CD4+ lymphocytes, resulting in a striking inhibition of virus infectivity.     

Intercellular adhesion molecule-1 is an endothelial cell adhesion receptor for Plasmodium falciparum

The primary event in the pathogenesis of severe malaria in Plasmodium falciparum infection is thought to be adherence of trophozoite- and schizont-infected erythrocytes to capillary endothelium, a process called sequestration. Identifying the endothelial molecules used as receptors is an essential step in understanding this disease process. Recent work implicates the membrane glycoprotein CD36 (platelet glycoprotein IV; refs 2-5) and the multi-functional glycoprotein thrombospondin as receptors. Although CD36 has a widespread distribution on microvascular endothelium, it may not be expressed on all capillary beds where sequestration occurs, especially in the brain. The role of thrombospondin in cell adhesion, in vitro or in vivo, is less certain. We have noticed that some parasites bind to human umbilical-vein endothelial cells independently of CD36 or thrombospondin. To screen for alternative receptors, we have developed a novel cell-adhesion assay using transfected COS cells, which confirms that CD36 is a cell-adhesion receptor. In addition, we find that an endothelial-binding line of P. falciparum binds to COS cells transfected with a complementary DNA encoding intercellular adhesion molecule-1. As this molecule is widely distributed on capillaries and is inducible, this finding may be relevant to the pathogenesis of severe malaria.     

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.     

Regulation of leukocyte migration by activation of the leukocyte adhesion molecule-1 (LAM-1) selectin.

A central feature of host defence is the ability of leukocytes to enter tissues in response to immune or inflammatory stimuli. The leukocyte adhesion molecule-1 (LAM-1) regulates the migration of human leukocytes by mediating the binding both of lymphocytes to high endothelial venules of peripheral lymph nodes and of neutrophils to endothelium at inflammatory sites. As lymphocytes and neutrophils express the same LAM-1 protein, it is not clear how lineage-specific differences in leukocyte migration are controlled. We now report that the affinity of LAM-1 for a carbohydrate-based ligand, PPME, is dramatically increased following lymphocyte and neutrophil activation by lineage-specific stimuli. In addition, activation of lymphocytes by physiological stimuli enhanced LAM-1-dependent binding to high endothelial venules. Thus, transient changes in LAM-1 affinity after leukocyte stimulation probably directly influence leukocyte migration.     

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).     

A soluble CD4 protein selectively inhibits HIV replication and syncytium formation

The CD4 (T4) molecule is expressed on a subset of T lymphocytes involved in class II MHC recognition, and is probably the physiological receptor for one or more monomorphic regions of class II MHC (refs 1-3). CD4 also functions as a receptor for the human immunodeficiency virus (HIV) exterior envelope glycoprotein (gp120) (refs 4-9), being essential for virus entry into the host cell and for membrane fusion, which contributes to cell-to-cell transmission of the virus and to its cytopathic effects. We have used a baculovirus expression system to generate mg quantities of a hydrophilic extracellular segment of CD4. Concentrations of soluble CD4 in the nanomolar range, like certain anti-CD4 monoclonal antibodies, inhibit syncytium formation and HIV infection by binding gp120-expressing cells. Perhaps more importantly, class II specific T-cell interactions are uninhibited by soluble CD4 protein, whereas they are virtually abrogated by equivalent amounts of anti-T4 antibody. This may reflect substantial differences in CD4 affinity for gp120 and class II MHC.     

血府逐瘀汤对动脉粥样硬化大鼠细胞间黏附分子和脂质过氧化物的影响

为探讨血府逐瘀汤对动脉粥样硬化(atherosclerosis,AS)大鼠主动脉壁细胞间黏附分子-1(ICAM-1)表达水平和脂质过氧化物的影响,将40只大鼠随机分为正常对照组、模型组、血脂康组、血府逐瘀汤高剂量组、血府逐瘀汤低剂量组,对照组饲喂正常饲料,模型组给予高脂饲料,治疗组在给予高脂饲料的同时给予治疗药物,12周后免疫组化法观察主动脉壁ICAM-1的表达水平、检测血清超氧化物歧化酶(SOD)、丙二醛(MDA)的含量.结果显示:模型组ICAM-1的表达水平呈强阳性表达,治疗组各组均呈弱阳性表达,各组间均有统计学意义(P<0.05).治疗组SOD水平较模型组显著升高,MDA含量显著降低,各组间均有统计学意义(P<0.05).这说明血府逐瘀汤可以通过下调ICAM-1的表达,清除脂质过氧化物、保护内皮细胞起到抗AS的作用.     

A kind of 1form metrics in two dimensional Finsler space

ＩｎｔｒｏｄｕｃｔｉｏｎＬｅｔＬ（ｘ,ｙ）ｂｅａｆｕｎｃｔｉｏｎｏｎａｔａｎｇｅｎｔｂｕｎｄｌｅＴＭ,ｗｈｅｒｅｘ∈Ｍａｎｄｙ∈ＴｘＭ．ＩｆＬｓａｔｉｓｆｉｅｓｆｏｕｒｃｏｎｄｉｔｉｏｎｓ：（１°）Ｌ（ｘ,ｙ）ｉｓｐｏｓｉｔｉｖｅｌｙｈｏｍｏｇｅｎｅｏｕｓｏｆｄｅｇｒｅｅｏｎｅｉｎｙ,ｔｈａｔｉｓ,Ｌ（ｘ,λｙ）＝λＬ（ｘ,ｙ）ｆｏｒａｎｙｒｅａｌｎｕｍｂｅｒλ＞０;（２°）ｄｅｔ（ｇｉｊ）≠０,ｗｈｅｒｅｇｉｊ（ｘ,ｙ）＝·ｉ·ｊＦ,Ｆ＝１２Ｌ２．（３°）Ｌｉｓｄｉｆｆｅｒｅｎｔｉａｌｉｎ…     

Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein

Viruses have developed diverse non-immune strategies to counteract host-mediated mechanisms that confer resistance to infection. The Vif (virion infectivity factor) proteins are encoded by primate immunodeficiency viruses, most notably human immunodeficiency virus-1 (HIV-1). These proteins are potent regulators of virus infection and replication and are consequently essential for pathogenic infections in vivo. HIV-1 Vif seems to be required during the late stages of virus production for the suppression of an innate antiviral phenotype that resides in human T lymphocytes. Thus, in the absence of Vif, expression of this phenotype renders progeny virions non-infectious. Here, we describe a unique cellular gene, CEM15, whose transient or stable expression in cells that do not normally express CEM15 recreates this phenotype, but whose antiviral action is overcome by the presence of Vif. Because the Vif:CEM15 regulatory circuit is critical for HIV-1 replication, perturbing the circuit may be a promising target for future HIV/AIDS therapies.     

ZN_1蜗杆成形磨削砂轮修整研究

成形磨削是精密蜗杆磨削加工的发展趋势,而蜗杆磨削的齿形精度主要取决于成形砂轮廓形的精度。根据齿轮啮合原理建立ZN1蜗杆磨削加工的数学模型,用已知的蜗杆齿面形状求出了砂轮的廓形,通过MATLAB编程计算得到成形砂轮的轴向截形。利用三维建模技术验证了数学建模过程和计算结果的正确性,进而对砂轮修整安装参数进行了分析,得出了砂轮截形的变化规律。     

一类有限生成的可解群

设G是个有限生成的可解群，若G的每个循环子群诱导出的G的次正规群列的严格降链是有限的，那么G必为FN－群，由此可以证明次正规子群的亏数均≤2的有限生在可解群的导出长度至多为5，其幂零长度至多为4，这推广了McCaughan-Stonehewer、Casolo等人的结果。     

Xyloadenosine analogue of (A2'p)2A inhibits replication of herpes simplex viruses 1 and 2

Molecules of the structure ppp(A2'p)2A containing a 2' leads to 5' phosphodiester bond, commonly abbreviated as 2-5A, are synthesized in interferon-treated virally-infected cells and have been implicated in several systems as contributing to interferon's antiviral activity. The 2-5A binds to and subsequently activates an endogenous endonuclease, ultimately resulting in degradation of RNA. We have been interested in the use of 2-5A analogues to achieve antiviral activity without the use of interferon. For this approach to be successful, analogues must be synthesized with an increased stability (native 2-5A is rapidly degraded by cellular phosphodiesterases) and with increased ability to enter intact cells. Removal of the highly-negative charged 5' terminal phosphates from ppp(A2'p)2A results in formation of the 'core' species, (A2'p)2A, which should be able to penetrate intact cells more readily. While Kimchi et al. have shown that 2-5A core has an antimitogenic effect in mouse spleen lymphocytes and 3T3 fibroblasts, Williams and Kerr have reported lack of antiviral activity against Semliki Forest virus or encephalomyocarditis virus by exogenously-administered 2-5A core. We have previously determined that (xyloA2'p)2xyloA (abbreviated as xylo 2-5A core), the xyloadenosine analogue of the 5'-terminally dephosphorylated 2-5A core, is over 100 times more stable than the parent 2-5A core species. We now report that this xylo 2-5A core inhibits replication of herpes simplex viruses 1 and 2 in vitro, with greater than 100 times the activity of the parent 2-5A core. The mechanism of antiviral action of the 2-5A core analogue appears to involve a pathway different from that activated by the parent 5' triphosphorylated 2-5A species.     

一类具有潜伏感染细胞的时滞HIV-1传染病模型

提出了一类具有潜伏感染细胞的时滞HIV-1传染病模型,定义了基本再生数R_0,给出了无病平衡点P_0(x_0,0,0)和慢性感染平衡点P~*(x~*,ω~*,y~*,v~*)的存在条件.首先利用线性化方法,得到了无病平衡点和慢性感染平衡点的局部渐近稳定性.进一步通过构造相应的Lyapunov函数,并结合LaSalle不变集原理,证明了当R_0≤1时,无病平衡点P_0(x_0,0,0,0)是全局渐近稳定的;当R_01时,慢性感染平衡点P~*(x~*,ω~*,y~*,v~*)是全局渐近稳定的,但无病平衡点Po (x_0,0,0,0)是不稳定的.结果表明,模型中的潜伏感染时滞和感染时滞并不影响模型的全局稳定性,并通过数值模拟验证了所得结论.     

ICAM, an adhesion ligand of LFA-1, is homologous to the neural cell adhesion molecule NCAM

Antigen-specific cell contacts in the immune system are strengthened by antigen-nonspecific interactions, mediated in part by lymphocyte-function associated (LFA) antigens. The LFA-1 antigen is widely expressed on cells of haematopoietic origin and is a major receptor of T cells, B cells and granulocytes. LFA-1 mediates the leukocyte adhesion reactions underlying cytolytic conjugate formation, helper T-cell interactions, and antibody-dependent killing by natural killer cells and granulocytes. Recently, ICAM-1 (intercellular adhesion molecule-1) has been defined as a ligand for LFA-1. Monoclonal antibodies to ICAM-1 block T lymphocyte adhesion to fibroblasts and endothelial cells and disrupt the interaction between cytotoxic T cells and target cells. In addition, purified ICAM-1 reconstituted into artificial membranes binds LFA-1+ cells. ICAM-1 is found on leukocytes, fibroblasts, epithelial cells and endothelial cells and its expression is regulated by inflammatory cytokines. LFA-1 has been placed in the integrin family of cell surface receptors by virtue of the high sequence similarity between the LFA-1 and integrin beta chains. The adhesion ligands of the integrin family are glycoproteins bearing the Arg-Gly-Asp (RGD) sequence motif, for example, fibronectin, fibrinogen, vitronectin and von Willebrand factor. Here we show that a complementary DNA clone ICAM-1 contains no RGD motifs, but instead is homologous to the neural cell adhesion molecule NCAM.     

非齐次椭圆方程的一个极限形式

从传导问题中获得了一类非齐次椭圆方程Dirichlet问题的极限形式. 当2个理想导体之间的距离足够小时, 建立其最优的全局梯度估计, 从而给出了电场强度的爆破率.      

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.