共查询到20条相似文献，搜索用时 31 毫秒
1.
Opposing activities protect against age-onset proteotoxicity 总被引：1，自引：0，他引：1
Cohen E Bieschke J Perciavalle RM Kelly JW Dillin A 《Science (New York, N.Y.)》2006,313(5793):1604-1610
2.
Meyer-Luehmann M Coomaraswamy J Bolmont T Kaeser S Schaefer C Kilger E Neuenschwander A Abramowski D Frey P Jaton AL Vigouret JM Paganetti P Walsh DM Mathews PM Ghiso J Staufenbiel M Walker LC Jucker M 《Science (New York, N.Y.)》2006,313(5794):1781-1784
Protein aggregation is an established pathogenic mechanism in Alzheimer's disease, but little is known about the initiation of this process in vivo. Intracerebral injection of dilute, amyloid-beta (Abeta)-containing brain extracts from humans with Alzheimer's disease or beta-amyloid precursor protein (APP) transgenic mice induced cerebral beta-amyloidosis and associated pathology in APP transgenic mice in a time- and concentration-dependent manner. The seeding activity of brain extracts was reduced or abolished by Abeta immunodepletion, protein denaturation, or by Abeta immunization of the host. The phenotype of the exogenously induced amyloidosis depended on both the host and the source of the agent, suggesting the existence of polymorphic Abeta strains with varying biological activities reminiscent of prion strains. 相似文献
3.
Zhou Y Su Y Li B Liu F Ryder JW Wu X Gonzalez-DeWhitt PA Gelfanova V Hale JE May PC Paul SM Ni B 《Science (New York, N.Y.)》2003,302(5648):1215-1217
A subset of nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to preferentially reduce the secretion of the highly amyloidogenic, 42-residue amyloid-beta peptide Abeta42. We found that Rho and its effector, Rho-associated kinase, preferentially regulated the amount of Abeta42 produced in vitro and that only those NSAIDs effective as Rho inhibitors lowered Abeta42. Administration of Y-27632, a selective Rock inhibitor, also preferentially lowered brain levels of Abeta42 in a transgenic mouse model of Alzheimer's disease. Thus, the Rho-Rock pathway may regulate amyloid precursor protein processing, and a subset of NSAIDs can reduce Abeta42 through inhibition of Rho activity. 相似文献
4.
Solution structure of kistrin, a potent platelet aggregation inhibitor and GP IIb-IIIa antagonist. 总被引：11，自引：0，他引：11
The structure of kistrin, which is a member of a homologous family of glycoprotein IIb-IIIa (GP IIb-IIIa) antagonists and potent protein inhibitors of platelet aggregation, has been determined by two-dimensional nuclear magnetic resonance (NMR) spectroscopy. The 68-residue protein consists of a series of tightly packed loops held together by six disulfide bonds and has almost no regular secondary structure. Kistrin has an Arg-Gly-Asp (RGD) adhesion site recognition sequence important for binding to GP IIb-IIIa that is located at the apex of a long loop across the surface of the protein. 相似文献
5.
Platelet-activating factor-induced aggregation of human platelets specifically inhibited by triazolobenzodiazepines 总被引：6，自引：0，他引：6
Platelet-activating factor (PAF), a naturally occurring phospholipid, is a potent activator of various biological processes, including platelet aggregation. The mechanisms by which PAF acts are largely unknown, partly because of the lack of specific inhibitors for PAF-elicited responses. It was found that in washed human platelets the psychotropic triazolobenzodiazepine drugs alprazolam and triazolam potently inhibited PAF-induced changes in shape, aggregation, and secretion. The effects were specific for PAF activation, since the responses of human platelets to adenosine diphosphate, thrombin, epinephrine, collagen, arachidonate, and the calcium ionophore A23187 were not inhibited by the triazolobenzodiazepines. These psychotropic drugs should be useful in investigating the possibility that PAF or PAF-like phospholipids play a role in neuronal function and in elucidating biochemical mechanisms activated specifically by PAF in a variety of cells. 相似文献
6.
Genetic evidence suggests that inhibition of amyloid fibril formation by small molecules should be effective against amyloid diseases. Known amyloid inhibitors appear to function by shifting the aggregation equilibrium away from the amyloid state. Here, we describe a series of transthyretin amyloidosis inhibitors that functioned by increasing the kinetic barrier associated with misfolding, preventing amyloidogenesis by stabilizing the native state. The trans-suppressor mutation, threonine 119 --> methionine 119, which is known to ameliorate familial amyloid disease, also functioned through kinetic stabilization, implying that this small-molecule strategy should be effective in treating amyloid diseases. 相似文献
7.
Chemical reaction outcomes are often rationalized on the basis of independent analyses of steric and electronic effects. We applied three-dimensional free energy relationships correlating steric and electronic effects to design and optimize a ligand class for the enantioselective Nozaki-Hiyama-Kishi propargylation of ketones. The resultant mathematical model describing the steric and electronic parameter relationship is highly reliant on the synergistic interactions of these two effects. 相似文献
8.
Sieber JJ Willig KI Kutzner C Gerding-Reimers C Harke B Donnert G Rammner B Eggeling C Hell SW Grubmüller H Lang T 《Science (New York, N.Y.)》2007,317(5841):1072-1076
Most plasmalemmal proteins organize in submicrometer-sized clusters whose architecture and dynamics are still enigmatic. With syntaxin 1 as an example, we applied a combination of far-field optical nanoscopy, biochemistry, fluorescence recovery after photobleaching (FRAP) analysis, and simulations to show that clustering can be explained by self-organization based on simple physical principles. On average, the syntaxin clusters exhibit a diameter of 50 to 60 nanometers and contain 75 densely crowded syntaxins that dynamically exchange with freely diffusing molecules. Self-association depends on weak homophilic protein-protein interactions. Simulations suggest that clustering immobilizes and conformationally constrains the molecules. Moreover, a balance between self-association and crowding-induced steric repulsions is sufficient to explain both the size and dynamics of syntaxin clusters and likely of many oligomerizing membrane proteins that form supramolecular structures. 相似文献
9.
Gas-phase clusters, which are weakly bound aggregates comprised of either atoms or molecules, often display properties that lie between those of the gaseous and condensed states. Interesting questions arise concerning how large a cluster must be before it will display bulk properties. Currently there is extensive research activity directed toward studies of their formation and varying properties and reactivity as a function of the degree of aggregation. Results serve to elucidate at the molecular level the course of change of a system to be followed from the gas to the condensed state, thereby enabling a spanning of the states of matter. 相似文献
10.
The incidence of Alzheimer's disease (AD) and that of prion disorders (PrD) could not be more different. One-third of octogenarians succumb to AD, whereas Creutzfeldt-Jakob disease typically affects one individual in a million each year. However, these diseases have many common features impinging on the metabolism of neuronal membrane proteins: the amyloid precursor protein APP in the case of AD, and the cellular prion protein PrPC in PrD. APP begets the Abeta peptide, whereas PrPC begets the malignant prion protein PrPSc. Both Abeta and PrPSc are associated with disease, but we do not know what triggers their accumulation and neurotoxicity. A great deal has been learned, however, about protein folding, misfolding, and aggregation; an entirely new class of intramembrane proteases has been identified; and unsuspected roles for the immune system have been uncovered. There is reason to expect that prion research will profit from advances in the understanding of AD, and vice versa. 相似文献
11.
The van der Waals picture focuses on the differing roles of the strong short-ranged repulsive intermolecular forces and the longer ranged attractions in determining the structure and dynamics of dense fluids and solids. According to this physical picture, the attractive interactions help fix the volume of the system, but the arrangements and motions of molecules within that volume are determined primarily by the local packing and steric effects produced by the repulsive forces. This very useful approach, its limitations, and its successful application to a wide variety of static and dynamic phenomena in condensed matter systems are reviewed. 相似文献
12.
This review puts into perspective the present state and prospects for controlling quantum phenomena in atoms and molecules. The topics considered include the nature of physical and chemical control objectives, the development of possible quantum control rules of thumb, the theoretical design of controls and their laboratory realization, quantum learning and feedback control in the laboratory, bulk media influences, and the ability to utilize coherent quantum manipulation as a means for extracting microscopic information. The preview of the field presented here suggests that important advances in the control of molecules and the capability of learning about molecular interactions may be reached through the application of emerging theoretical concepts and laboratory technologies. 相似文献
13.
The fluid mosaic model of the structure of cell membranes 总被引：433，自引：0，他引：433
A fluid mosaic model is presented for the gross organization and structure of the proteins and lipids of biological membranes. The model is consistent with the restrictions imposed by thermodynamics. In this model, the proteins that are integral to the membrane are a heterogeneous set of globular molecules, each arranged in an amphipathic structure, that is, with the ionic and highly polar groups protruding from the membrane into the aqueous phase, and the nonpolar groups largely buried in the hydrophobic interior of the membrane. These globular molecules are partially embedded in a matrix of phospholipid. The bulk of the phospholipid is organized as a discontinuous, fluid bilayer, although a small fraction of the lipid may interact specifically with the membrane proteins. The fluid mosaic structure is therefore formally analogous to a two-dimensional oriented solution of integral proteins (or lipoproteins) in the viscous phospholipid bilayer solvent. Recent experiments with a wide variety of techniqes and several different membrane systems are described, all of which abet consistent with, and add much detail to, the fluid mosaic model. It therefore seems appropriate to suggest possible mechanisms for various membrane functions and membrane-mediated phenomena in the light of the model. As examples, experimentally testable mechanisms are suggested for cell surface changes in malignant transformation, and for cooperative effects exhibited in the interactions of membranes with some specific ligands. Note added in proof: Since this article was written, we have obtained electron microscopic evidence (69) that the concanavalin A binding sites on the membranes of SV40 virus-transformed mouse fibroblasts (3T3 cells) are more clustered than the sites on the membranes of normal cells, as predicted by the hypothesis represented in Fig. 7B. T-here has also appeared a study by Taylor et al. (70) showing the remarkable effects produced on lymphocytes by the addition of antibodies directed to their surface immunoglobulin molecules. The antibodies induce a redistribution and pinocytosis of these surface immunoglobulins, so that within about 30 minutes at 37 degrees C the surface immunoglobulins are completely swept out of the membrane. These effects do not occur, however, if the bivalent antibodies are replaced by their univalent Fab fragments or if the antibody experiments are carried out at 0 degrees C instead of 37 degrees C. These and related results strongly indicate that the bivalent antibodies produce an aggregation of the surface immunoglobulin molecules in the plane of the membrane, which can occur only if the immunoglobulin molecules are free to diffuse in the membrane. This aggregation then appears to trigger off the pinocytosis of the membrane components by some unknown mechanism. Such membrane transformations may be of crucial importance in the induction of an antibody response to an antigen, as well as iv other processes of cell differentiation. 相似文献
14.
Lang P Stolpa JC Freiberg BA Crawford F Kappler J Kupfer A Cambier JC 《Science (New York, N.Y.)》2001,291(5508):1537-1540
Previous findings suggest that during cognate T cell-B cell interactions, major histocompatability complex (MHC) class II molecules transduce signals, leading to Src-family kinase activation, Ca2+ mobilization, and proliferation. Here, we show that antigen stimulation of resting B cells induces MHC class II molecules to associate with Immunoglobulin (Ig)-alpha/Ig-beta (CD79a/CD79b) heterodimers, which function as signal transducers upon MHC class II aggregation by the T cell receptor (TCR). The B cell receptor (BCR) and MHC class II/Ig-alpha/Ig-beta are distinct complexes, yet class II-associated Ig-alpha/beta appears to be derived from BCR. Hence, Ig-alpha/beta are used in a sequential fashion for transduction of antigen and cognate T cell help signals. 相似文献
15.
Partial charge distribution on first and second neighbor atoms to nitrogen in choline and ethanolamine have been calculated. Coulombic and steric parameters were then utilized to evaluate the interaction of a negative test charge with the two molecules. Both the position and the magnitude of the maximum of interaction energy in the two systems were significantly different. The results suggest that ethanolamine interacts more strongly with anions than choline does. This is due principally to steric repulsion of the negative charge by the methyl groups in choline. 相似文献
16.
Ertekin-Taner N Graff-Radford N Younkin LH Eckman C Baker M Adamson J Ronald J Blangero J Hutton M Younkin SG 《Science (New York, N.Y.)》2000,290(5500):2303-2304
Plasma Abeta42 (amyloid beta42 peptide) is invariably elevated in early-onset familial Alzheimer's disease (AD), and it is also increased in the first-degree relatives of patients with typical late-onset AD (LOAD). To detect LOAD loci that increase Abeta42, we used plasma Abeta42 as a surrogate trait and performed linkage analysis on extended AD pedigrees identified through a LOAD patient with extremely high plasma Abeta. Here, we report linkage to chromosome 10 with a maximal lod score of 3.93 at 81 centimorgans close to D10S1225. Remarkably, linkage to the same region was obtained independently in a genome-wide screen of LOAD sibling pairs. These results provide strong evidence for a novel LOAD locus on chromosome 10 that acts to increase Abeta. 相似文献
17.
The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics 总被引：3，自引：0，他引：3
It has been more than 10 years since it was first proposed that the neurodegeneration in Alzheimer's disease (AD) may be caused by deposition of amyloid beta-peptide (Abeta) in plaques in brain tissue. According to the amyloid hypothesis, accumulation of Abeta in the brain is the primary influence driving AD pathogenesis. The rest of the disease process, including formation of neurofibrillary tangles containing tau protein, is proposed to result from an imbalance between Abeta production and Abeta clearance. 相似文献
18.
Stereospecific action of pyrethroid insecticides on the gamma-aminobutyric acid receptor-ionophore complex 总被引：1，自引：0，他引：1
The potent alpha-cyano-3-phenoxybenzyl pyrethroids, including cypermethrin, deltamethrin, and fenvalerate, act stereospecifically to inhibit binding to rat brain synaptic membranes of sulfur-35-labeled t-butylbicyclophosphorothionate, a new radioligand for the picrotoxinin binding site. Scatchard analysis indicates that picrotoxinin inhibition of t-butylbicyclophosphorothionate binding is competitive whereas cypermethrin inhibition possibly involves a closely associated site in the gamma-aminobutyric acid receptor-ionophore complex. Studies with 37 pyrethroids reveal an absolute correlation, that is, no false positives or negatives, between mouse intracerebral toxicity and in vitro inhibition: all toxic cyano compounds but none of their nontoxic stereoisomers are inhibitors; cis isomers are more potent than trans isomers as both toxicants and inhibitors; and noncyano pyrethroids are much less potent or are inactive. 相似文献
19.
By means of scanning tunneling microscopy, it is observed that molecules of the form n-alkylcyanobiphenyl, where n = 8 to 12, form two-dimensional crystalline domains when adsorbed onto graphite. The layer spacings measured by tunneling microscopy are 20% larger than those measured previously on bulk material by x-ray diffraction. The structure of the adsorbed molecules is quite different from that of the bulk. 相似文献
20.
Molecular crowding on the cell surface 总被引：6，自引：0，他引：6
Strong steric interactions among proteins on crowded living cell surfaces were revealed by measurements of the equilibrium spatial distributions of proteins in applied potential gradients. The fraction of accessible surface occupied by mobile surface proteins can be accurately represented by including steric exclusion in the statistical thermodynamic analysis of the data. The analyses revealed enhanced, concentration-dependent activity coefficients, implying unanticipated thermodynamic activity even at typical cell surface receptor concentrations. 相似文献