全文获取类型
收费全文 | 326篇 |
免费 | 77篇 |
出版年
2014年 | 10篇 |
2013年 | 6篇 |
2012年 | 7篇 |
2011年 | 10篇 |
2010年 | 8篇 |
2009年 | 6篇 |
2008年 | 8篇 |
2007年 | 4篇 |
2006年 | 14篇 |
2005年 | 10篇 |
2004年 | 9篇 |
2003年 | 13篇 |
2002年 | 14篇 |
2001年 | 13篇 |
2000年 | 7篇 |
1999年 | 8篇 |
1998年 | 8篇 |
1997年 | 5篇 |
1995年 | 5篇 |
1994年 | 5篇 |
1992年 | 8篇 |
1991年 | 4篇 |
1990年 | 4篇 |
1989年 | 7篇 |
1988年 | 9篇 |
1987年 | 6篇 |
1986年 | 9篇 |
1985年 | 13篇 |
1984年 | 5篇 |
1983年 | 6篇 |
1982年 | 5篇 |
1981年 | 5篇 |
1979年 | 7篇 |
1978年 | 9篇 |
1977年 | 6篇 |
1976年 | 9篇 |
1974年 | 8篇 |
1973年 | 9篇 |
1972年 | 6篇 |
1969年 | 7篇 |
1967年 | 9篇 |
1966年 | 4篇 |
1965年 | 3篇 |
1959年 | 3篇 |
1957年 | 4篇 |
1954年 | 3篇 |
1946年 | 3篇 |
1944年 | 3篇 |
1927年 | 5篇 |
1926年 | 4篇 |
排序方式: 共有403条查询结果,搜索用时 275 毫秒
71.
72.
Costantini TW Deree J Loomis W Putnam JG Choi S Baird A Eliceiri BP Bansal V Coimbra R 《Life sciences》2009,84(1-2):18-22
AimsUnder normal conditions, the intestinal mucosa acts as a local barrier to prevent the influx of luminal contents. The intestinal epithelial tight junction is comprised of several membrane associated proteins, including zonula occludens-1 (ZO-1) and occludin. Disruption of this barrier can lead to the production of pro-inflammatory mediators and ultimately multiple organ failure. We have previously shown that Pentoxifylline (PTX) decreases histologic gut injury and pro-inflammatory mediator synthesis. We hypothesize that PTX prevents the breakdown of ZO-1 and occludin in an in vitro model of immunostimulated intestinal cell monolayers.Main methodsCaco-2 human enterocytes were grown as confluent monolayers and incubated under control conditions, or with PTX (2 mM), Cytomix (TNF-α, IFN-γ, IL-1), or Cytomix + PTX for 24 h. Occludin and ZO-1 protein levels were analyzed by Western blot. Confocal microscopy was used to assess the cytoplasmic localization of ZO-1 and occludin.Key findingsCytomix stimulation of Caco-2 cells resulted in a 50% decrease in both occludin and ZO-1 protein. Treatment with Cytomix + PTX restored both occludin and ZO-1 protein to control levels. Confocal microscopy images show that Cytomix caused an irregular, undulating appearance of ZO-1 and occludin at the cell junctions. Treatment with PTX prevented the Cytomix-induced changes in ZO-1 and occludin localization.SignificanceTreatment with PTX decreases the pro-inflammatory cytokine induced changes in the intestinal tight junction proteins occludin and ZO-1. Pentoxifylline may be a useful adjunct in the treatment of sepsis and shock by attenuating intestinal barrier breakdown. 相似文献
73.
The UL11 gene of herpes simplex virus type 1 encodes a 96-amino-acid tegument protein that is myristylated, palmitylated, and phosphorylated and is found on the cytoplasmic faces of nuclear, Golgi apparatus-derived, and plasma membranes of infected cells. Although this protein is thought to play a role in virus budding, its specific function is unknown. Purified virions were found to contain approximately 700 copies of the UL11 protein per particle, making it an abundant component of the tegument. Moreover, comparisons of cell-associated and virion-associated UL11 showed that packaging is selective for underphosphorylated forms, as has been reported for several other tegument proteins. Although the mechanism by which UL11 is packaged is unknown, previous studies have identified several sequence motifs in the protein that are important for membrane binding, intracellular trafficking, and interaction with UL16, another tegument protein. To ascertain whether any of these motifs are needed for packaging, a transfection/infection-based assay was used in which mutant forms of the protein must compete with the wild type. In this assay, the entire C-terminal half of UL11 was found to be dispensable. In the N-terminal half, the sites of myristylation and palmitylation, which enable membrane-binding and Golgi apparatus-specific targeting, were found to be essential for efficient packaging. The acidic cluster motif, which is not needed for Golgi apparatus-specific targeting but is involved in recycling the protein from the plasma membrane and for the interaction with UL16, was found to be essential, too. Thus, something other than mere localization of UL11 to Golgi apparatus-derived membranes is needed for packaging. The critical factor is unlikely to be the interaction with UL16 because other mutants that fail to bind this protein (due to removal of the dileucine-like motif or substitutions with foreign acidic clusters) were efficiently packaged. Collectively, these results suggest that UL11 packaging is not driven by a passive mechanism but instead requires trafficking through a specific pathway. 相似文献
74.
Placental Transfer of a Fully Human IgG2 Monoclonal Antibody in the Cynomolgus Monkey,Rat, and Rabbit: A Comparative Assessment from during Organogenesis to Late Gestation 下载免费PDF全文
Graeme J. Moffat Marc W. Retter Gayle Kwon Mark Loomis M. Benjamin Hock Colin Hall Jeanine Bussiere Elise M. Lewis Gary J. Chellman 《Birth defects research. Part B, Developmental and reproductive toxicology》2014,101(2):178-188
Understanding species differences in the placental transfer of monoclonal antibodies is important to inform species selection for nonclinical safety assessment, interpret embryo‐fetal changes observed in these studies, and extrapolate their human relevance. Data presented here for a fully human immunoglobulin G2 monoclonal antibody (IgG2X) revealed that, during organogenesis, in both the cynomolgus monkey (gestation day 35 [gd35]) and the rat (gd10) the extent of IgG2X placental transfer (approximately 0.5% maternal plasma concentration, MPC) was similar to the limited published human data for endogenous IgG. At this early gestational stage, IgG2X placental transfer was approximately 6‐fold higher in the rabbit (gd10). By the end of organogenesis, rat embryonic plasma concentrations (gd16) exceeded those in the cynomolgus monkey (gd50) by approximately 3‐fold. These data suggest that relative to the cynomolgus monkey, the rabbit (and to a lesser extent the rat) may overestimate potential harmful effects to the human embryo during this critical period of development. Beyond organogenesis, fetal IgG2X plasma concentrations increased approximately 10‐fold early in the second trimester (gd50–70) in the cynomolgus monkey and remained relatively unchanged thereafter (at approximately 5% MPC). Late gestational assessment was precluded in rabbits due to immunogenicity, but in rats, fetal IgG2X plasma concentrations increased more than 6‐fold from gd16 to gd21 (reaching approximately 15% MPC). In rats, maternal exposure consistent with that achieved by ICH S6(R1) high‐dose selection criteria resulted in embryonic plasma concentrations, reaching pharmacologically relevant levels during organogenesis. Furthermore, dose proportional exposure in both mothers and embryos indicated that this was unlikely to occur at the lower therapeutic dose levels used in humans 相似文献
75.
76.
The accumulation and localization of four developmentally regulated membrane glycoproteins were examined in a glycosylation mutant of the cellular slime mold Dictyostelium discoideum. As judged by immunoblot procedures using antipeptide antibodies, the levels of three of the glycoproteins, WGA80B, SP29A, and SP29B, were unaffected, but their apparent molecular masses were reduced by 14,000, 3,500 and 3,500 daltons, respectively. The level of the fourth glycoprotein, gp80, was reduced to below detectable limits. The reduced molecular sizes were apparently due to the absence of certain carbohydrate structures as judged by labeling Western blots with anti-carbohydrate antibodies and a lectin. Using immunofluorescence labeling of permeabilized and intact cells, the localization of WGA80B, SP29A, and SP29B, in intracellular vesicles and on the cell surface of prespore cells, was observed to be unaffected in the mutant cells. The developmentally regulated oligosaccharide structure(s) affected by the modB locus does not influence the subcellular localization and accumulation of these three glycoproteins in the prespore cells of this phylogenetically primitive organism. 相似文献
77.
Isolation and characterization of a mucin-glycoprotein from rat submandibular glands 总被引:3,自引:0,他引:3
L A Tabak L Mirels L D Monte A L Ridall M J Levine R E Loomis F Lindauer M S Reddy B J Baum 《Archives of biochemistry and biophysics》1985,242(2):383-392
A blood group A+ mucin-glycoprotein was purified from aqueous extracts of rat submandibular glands by sequential chromatography on columns of Sepharose CL-6B and Sephacryl S-300 in urea-containing buffers. Final purification was facilitated by reductive methylation which appeared to release contaminating (hydrophobic) peptides. Homogeneity of the purified mucin was determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis at varying concentrations of acrylamide, lectin affinity chromatography, and Western blot analysis. In contrast to previously described preparations, the purified mucin contained only trace amounts of N-acetylglucosamine and aromatic amino acids. In addition, only low levels of basic amino acids were present. 相似文献
78.
Adhesion mutants of Dictyostelium discoideum lacking the saccharide determinant recognized by two adhesion-blocking monoclonal antibodies 总被引:6,自引:0,他引:6
A mutant of Dictyostelium discoideum, strain HL260, was isolated based on its failure to bind d-41, a monoclonal antibody that blocks developmentally regulated cell-cell adhesion. The mutant fails to normally acquire cell-cell adhesion as assayed with cells shaken in 10 mM EDTA, but aggregates and and constructs fruiting bodies. Other mutant strains, HL216 and HL220, previously shown to have impaired cell-cell adhesion, also lack the determinant that binds d-41. The three strains all carry mutations in a gene designated mod B, which directs a post-translational modification of several developmentally regulated D. discoideum glycoproteins. Diploids formed between independent mod B mutant haploid strains also lack this determinant and show marked impairment of cell-cell adhesion in EDTA, indicating that mutations in mod B, rather than other mutations not shared by the haploid strains, are related to the adhesion defect. The results are consistent with other evidence that an oligosaccharide carried on several developmentally regulated glycoproteins plays an essential role in EDTA-resistant cell-cell adhesion in D. discoideum. However, this type of adhesion is not essential for morphogenesis in that the only defect detected thus far in mod B mutant strains is that they construct relatively smaller fruiting bodies that contain fewer spores. 相似文献
79.
A comparative study of the inhibition of hepatic aldehyde dehydrogenases in the rat by methyltetrazolethiol, calcium carbimide, and disulfiram 总被引:1,自引:0,他引:1
J F Brien G S Tam R J Cameron N A Steenaart C W Loomis 《Canadian journal of physiology and pharmacology》1985,63(5):438-443
Methyltetrazolethiol (1-methyl-5-mercapto-1,2,3,4-tetrazole, MTT) is a heterocyclic substituent of the cephalosporin antibiotics, cefamandole, cefoperazone, and moxalactam. Pretreatment of rats with MTT has been reported to increase blood acetaldehyde concentration after ethanol administration. The time course of MTT-induced inhibition of hepatic aldehyde dehydrogenases (ALDH) was determined in adult, male Sprague-Dawley rats in comparison with the hepatic ALDH inhibition induced by calcium carbimide (calcium cyanamide, CC) and disulfiram (D). The apparent onset of maximal inhibition of hepatic low Km ALDH occurred at 2 h for 50 mg/kg MTT (subcutaneous, s.c.) and 7 mg/kg CC (oral) and at 24 h for 300 mg/kg D (oral). The relative magnitude of maximal inhibition of low Km ALDH was CC greater than D greater than MTT. The relative duration of enzyme inhibition was D greater than MTT greater than CC. High Km ALDH was only inhibited by CC. Hepatic low Km ALDH was selectively inhibited by s.c. and oral administration of 125 mg/kg MTT. For s.c. administration of 125 mg/kg MTT, the magnitude of maximal enzyme inhibition and the duration of inhibition were greater than for the 50 mg/kg dose. Oral administration of 125 mg/kg MTT produced similar inhibition of hepatic low Km ALDH compared with s.c. administration of the same dose. The time course of blood ethanol and acetaldehyde concentrations was determined for the intravenous infusion of two 0.3-g/kg doses of ethanol to rats that were pretreated orally with saline (1 h), MTT (125 mg/kg, 2 h), or CC (7 mg/kg, 1 h). The relative increase in blood acetaldehyde concentration compared with saline pretreatment was CC greater than MTT. The elimination of ethanol from blood was slower in the MTT- and CC-pretreated animals, and this effect was more pronounced for CC pretreatment. Overall, the data demonstrate that the characteristics of hepatic ALDH inhibition for MTT are different from those of the known ALDH inhibitors, CC and D. 相似文献
80.
Masticatory lubrication. The role of carbohydrate in the lubricating property of a salivary glycoprotein-albumin complex. 总被引:2,自引:1,他引:1 下载免费PDF全文
We report for the first time a masticatory-lubrication assay system to assess the lubricating properties of salivary constituents. The lubricating ability of the proline-rich glycoprotein (PRG) of parotid saliva was enhanced by human serum albumin. The interactive effect of albumin was abolished by chemically deglycosylating the glycoprotein. Fluorescence spectroscopy with a hydrophobic probe verified the existence of a PRG-albumin complex and demonstrated that deglycosylation of the PRG altered the nature of its interaction with albumin. 相似文献