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41.
Gregory JL Morand EF McKeown SJ Ralph JA Hall P Yang YH McColl SR Hickey MJ 《Journal of immunology (Baltimore, Md. : 1950)》2006,177(11):8072-8079
Macrophage migration inhibitory factor (MIF) was originally identified for its ability to inhibit the random migration of macrophages in vitro. MIF is now recognized as an important mediator in a range of inflammatory disorders. We recently observed that the absence of MIF is associated with a reduction in leukocyte-endothelial cell interactions induced by a range of inflammatory mediators, suggesting that one mechanism whereby MIF acts during inflammatory responses is by promoting leukocyte recruitment. However, it is unknown whether MIF is capable of inducing leukocyte recruitment independently of additional inflammatory stimuli. In this study, we report that MIF is capable of inducing leukocyte adhesion and transmigration in postcapillary venules in vivo. Moreover, leukocytes recruited in response to MIF were predominantly CD68(+) cells of the monocyte/macrophage lineage. Abs against the monocyte-selective chemokine CCL2 (JE/MCP-1) and its receptor CCR2, but not CCL3 and CXCL2, significantly inhibited MIF-induced monocyte adhesion and transmigration. CCL2(-/-) mice displayed a similar reduction in MIF-induced recruitment indicating a critical role of CCL2 in the MIF-induced response. This hypothesis was supported by findings that MIF induced CCL2 release from primary microvascular endothelial cells. These data demonstrate a previously unrecognized function of this pleiotropic cytokine: induction of monocyte migration into tissues. This function may be critical to the ability of MIF to promote diseases such as atherosclerosis and rheumatoid arthritis, in which macrophages are key participants. 相似文献
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Gawain McColl Blaine R. Roberts Adam P. Gunn Keyla A. Perez Deborah J. Tew Colin L. Masters Kevin J. Barnham Robert A. Cherny Ashley I. Bush 《The Journal of biological chemistry》2009,284(34):22697-22702
Transgenic expression of human amyloid β (Aβ) peptide in body wall muscle cells of Caenorhabditis elegans has been used to better understand aspects of Alzheimer disease (AD). In human aging and AD, Aβ undergoes post-translational changes including covalent modifications, truncations, and oligomerization. Amino truncated Aβ is increasingly recognized as potentially contributing to AD pathogenesis. Here we describe surface-enhanced laser desorption ionization-time of flight mass spectrometry mass spectrometry of Aβ peptide in established transgenic C. elegans lines. Surprisingly, the Aβ being expressed is not full-length 1–42 (amino acids) as expected but rather a 3–42 truncation product. In vitro analysis demonstrates that Aβ3–42 self-aggregates like Aβ1–42, but more rapidly, and forms fibrillar structures. Similarly, Aβ3–42 is also the more potent initiator of Aβ1–40 aggregation. Seeded aggregation via Aβ3–42 is further enhanced via co-incubation with the transition metal Cu(II). Although unexpected, the C. elegans model of Aβ expression can now be co-opted to study the proteotoxic effects and processing of Aβ3–42.Numerous studies support a role for aggregating Aβ3 in mediating the toxicity that underlies AD (1, 2). However, several key questions remain central to understanding how AD and Aβ pathology are related. What is the connection between Aβ aggregation and toxicity? Is there a specific toxic Aβ conformation or species? How and why does aging impact on Aβ precipitation? Significant effort to address these questions has been invested in the use of vertebrate and simple invertebrate model organisms to simulate neurodegenerative diseases through transgenic expression of human Aβ (3). From these models, several novel insights into the proteotoxicity of Aβ have been gained (4–7).Human Aβ (e.g. in brain, cerebrospinal fluid, or plasma) is not found as a single species but rather as diverse mixtures of various modified, truncated, and cross-linked forms (8–10). Specific truncations, covalent modifications, and cross-linked oligomers of Aβ have potentially important roles in determining Aβ-associated neurotoxicity. For example, N-terminal truncations of Aβ have increased abundance in AD, rapidly aggregate, and are neurotoxic (9, 11). Furthermore, the N-terminal glutamic acid residue of Aβ3–42 can be cyclized to pyroglutamate (Aβ3(pE)-42) (12), which may be particularly important in AD pathogenesis (13, 14). Aβ3(pE)-42 is a significant fraction of total Aβ in AD brain (15), accounting for more than 50% of Aβ accumulated in plaques (16). Aβ3(pE)-42 seeds Aβ aggregation (17), confers proteolytic resistance, and is neurotoxic (13). Recently, glutaminyl cyclase (QC) has been proposed to catalyze, in vivo, pyroglutamate formation of Aβ3(pE)-40/42 (14, 18). Aβ1–42 itself cannot be cyclized by QC to Aβ3(pE)-42 (19), unlike Aβ that commences with an N-terminal glutamic acid-residue (e.g. Aβ3–42 and Aβ11–42) (20). QC has broad expression in mammalian brain (21, 22), and its inhibition attenuates accumulation of Aβ3(pE)-42 into plaques and improves cognition in a transgenic mouse model of AD that overexpresses human amyloid precursor protein (14). N-terminal truncations at position 3 have been reported in senile plaques (23, 24); however, the process that generates Aβ3–42 is unknown. Currently there are no reported animal models of Aβ3–42 expression.Advances in surface-enhanced laser desorption ionization-time of flight mass spectrometry (SELDI-TOF MS) analysis now facilitate accurate identification of particular Aβ species. Using this technology, we examined well characterized C. elegans transgenic models of AD that develop amyloid aggregates (25, 26) to see whether the human Aβ they express is post-translationally modified. 相似文献
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Immunoglobulin A (IgA) was found in mucus scraped from the surface of the human antrum. Fresh human gastric mucosa removed at operation was washed free of loosely adhering material and the gelatinous mucus lining the tissue scraped. The scrapings were separated by gel filtration on Sephadex G-200 and on Sepharose 4B into two carbohydrate-containing fractions. One of these fractions was shown by immunodiffusion to contain IgA which differs from human colostral secretory IgA by being devoid of secretory component activity. Moreover, secretory component was not detected in our unfractionated gastric mucosal scrapings. It is concluded that, contrary to the general belief, the predominant immunoglobulin A of human gastric mucus is not associated with the secretory component. Our results do not exclude the possibility that, as in serum, small amounts of secretory IgA and of the secretory component may be present in gastric secretions, however if so, the levels of these compounds would fall below the level of sensitivity of our methods. 相似文献
47.
S R McColl R Paquin A D Beaulieu 《Biochemical and biophysical research communications》1990,172(3):1209-1216
We tested a wide range of pro-inflammatory cytokines for their capacity to activate protein synthesis in neutrophils as analyzed b y [35S] methionine metabolic labelling experiments. Of all the cytokines tested, only GM-CSF and TNF alpha stimulated significant synthesis and secretion of a 23 kD protein which resolved into two bands on two dimensional gels. Under non-reducing conditions on one dimensional gels, its migration pattern remained the same indicating that the two bands most likely represent isoforms of the same protein. Immunoisolation studies using antibodies directed against size-relevant molecules did not lead to the identification of this molecule. The fact that this 23 kD molecule is induced in a highly specific and selective manner by GM-CSF and TNF alpha indicates that it may play a key role in some of the responses of neutrophils to these two cytokines. Therefore, full characterization of this 23 kD protein could provide important new knowledge on the mechanisms by which these two cytokines exert their biological effects on neutrophils. 相似文献
48.
Helicobacter pylori utilises urea for amino acid synthesis 总被引:2,自引:0,他引:2
C.L. Williams T. Preston M. Hossack C. Slater K.E.L. McColl 《FEMS immunology and medical microbiology》1996,13(1):87-94
Abstract Helicobacter pylori has one of the highest urease activities of all known bacteria. Its enzymatic production of ammonia protects the organism from acid damage by gastric juice. The possibility that the urease activity allows the bacterium to utilise urea as a nitrogen source for the synthesis of amino acids was investigated. H. pylori (NCTC 11638) was incubated with 50 mM urea, enriched to 5 atom% excess 15 N, that is the excess enrichment of 15 N above the normal background, in the presence of either NaCl pH 6.0, or 0.2M citrate pH 6.0. E. coli (NCTC 9001) was used as a urease-negative control. 15 N enrichment was detected by isotope ratio mass spectrometry. H. pylori showed intracellular incorporation of 15 N in the presence of citrate buffer pH 6.0 but there was no significant incorporation of 15 N in unbuffered saline or by E. coli in either pH 6.0 citrate buffer or unbuffered saline. The intracellular fate of the urea-nitrogen was determined by means of gas chromatography/mass spectrometry following incubation with 15 N enriched 5 mM urea in the presence of either 0.2 M citrate buffer pH 6.0 or 0.2 M acetate buffer pH 6.0. After 5 min incubation in either buffer the 15 n label appeared in glutamate, glutamine, phenylalanine, aspartate and alanine. It appears, therefore, that at pH and urea concentrations typical of the gastric mucosal surface, H. pylori utilises exogenous urea as a nitrogen source for amino acid synthesis. The ammonia produced by H. pylori urease activity thus facilitates the organism's nitrogen metabolism at neutral pH as well as protecting it from acid damage at low pH. 相似文献
49.
Procko E McColl SR 《BioEssays : news and reviews in molecular, cellular and developmental biology》2005,27(2):153-163
Cell signalling mediators derived from membrane phospholipids are frequent participants in biological processes. The family of phosphoinositide 3-kinases (PI3Ks) phosphorylate the membrane lipid phosphatidylinositol, generating second messengers that direct diverse responses. These PI3K products are fundamental for leukocyte migration or chemotaxis, a pivotal event during the immune response. This system is therefore of significant biomedical interest. This review focuses on the biochemistry and signalling pathways of PI3K, with particular emphasis on chemokine (chemotactic cytokine)-directed responses. The key objectives of chemotaxis are motility and direction. The latter--direction--requires distinct events at the front and back of a cell. In light of this, the coordinated localisation of signalling factors, an event choreographed by a sharp intracellular gradient of PI3K-derived products, is a common theme. 相似文献
50.
Nelson?DuránEmail author Priscyla?D?Marcato Oswaldo?L?Alves Gabriel?IH?De Souza Elisa?Esposito 《Journal of nanobiotechnology》2005,3(1):8
Extracellular production of metal nanoparticles by several strains of the fungus Fusarium oxysporum was carried out. It was found that aqueous silver ions when exposed to several Fusarium oxysporum strains are reduced in solution, thereby leading to the formation of silver hydrosol. The silver nanoparticles were in the
range of 20–50 nm in dimensions. The reduction of the metal ions occurs by a nitrate-dependent reductase and a shuttle quinone
extracellular process. The potentialities of this nanotechnological design based in fugal biosynthesis of nanoparticles for
several technical applications are important, including their high potential as antibacterial material. 相似文献