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71.
BACKGROUND: Insect symbionts employ multiple strategies to enhance their spread through populations, and some play a dual role as both a mutualist and a reproductive manipulator. It has recently been found that this is the case for some strains of Wolbachia, which both cause cytoplasmic incompatibility and protect their hosts against viruses. Here, we carry out the first test as to whether a male-killing strain of Wolbachia also provides a direct benefit to its host by providing antiviral protection to its host Drosophila bifasciata. We infected flies with two positive sense RNA viruses known to replicate in a range of Drosophila species (Drosophila C virus and Flock House virus) and measure the rate of death in Wolbachia positive and negative host lines with the same genetic background. RESULTS: Both viruses caused considerable mortality to D. bifasciata flies, with Drosophila C virus killing 43% more flies than the uninfected controls and Flock House virus killing 78% more flies than the uninfected controls. However, viral induced mortality was unaffected by the presence of Wolbachia. CONCLUSION: In the first male-killing Wolbachia strain tested for antiviral effects, we found no evidence that it conferred protection against two RNA viruses. We show that although antiviral resistance is widespread across the Wolbachia phylogeny, the trait seems to have been lost or gained along some lineages. We discuss the potential mechanisms of this, and can seemingly discount protection against these viruses as a reason why this symbiont has spread through Drosophila populations. 相似文献
72.
Background
Microsatellites (or short tandem repeats, STRs) are the genetic markers of choice for studying Aspergillus fumigatus molecular epidemiology due to its reproducibility and high discrimination power. However, the specificity of these markers must be investigated in a group of isolates from closely related species. The aim of this work was to test a microsatellite-based PCR multiplex previously designed for A. fumigatus in a set of species belonging to section Fumigati, namely Aspergillus fumigatiaffinis, Aspergillus lentulus, Aspergillus novofumigatus, Aspergillus unilateralis, Aspergillus viridinutans, Neosartorya fischeri, Neosartorya hiratsukae, Neosartorya pseudofischeri and Neosartorya udagawae.Results
The reference A. fumigatus strain ATCC 46645 was easily genotyped in standard conditions showing a final electrophoretic profile of 8 expected peaks corresponding to each microsatellite locus. Inversely, no peaks were observed for all other species from section Fumigati, with an exception for marker MC6b in A. unilateralis. By screening the genome sequence of Neosartorya fischeri NRRL 181, the results showed that MC3, MC6a and MC7 might be employed for N. fischeri genotyping since these markers present several repeats of each motif. The accumulation of insertions and deletions was frequently observed in the genomic regions surrounding the microsatellites, including those where the A. fumigatus primers are located. The amplification of microsatellite markers in less stringent amplification conditions resulted in a distinct electrophoretic profile for species within section Fumigati.Conclusions
Therefore, the microsatellite-based PCR multiplex allow simple identification of A. fumigatus and, with a slight modification of temperature conditions, it also allows discriminating other pathogenic species within section Fumigati, particularly A. fumigatiaffinis, N. fischeri and N. udagawae. 相似文献73.
The tobacco mosaic virus resistance gene, N 总被引:1,自引:0,他引:1
74.
Ruel R Thibeault C L'Heureux A Martel A Cai ZW Wei D Qian L Barrish JC Mathur A D'Arienzo C Hunt JT Kamath A Marathe P Zhang Y Derbin G Wautlet B Mortillo S Jeyaseelan R Henley B Tejwani R Bhide RS Trainor GL Fargnoli J Lombardo LJ 《Bioorganic & medicinal chemistry letters》2008,18(9):2985-2989
We report herein a series of substituted N-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amines as inhibitors of vascular endothelial growth factor receptor-2 tyrosine kinase. Through structure–activity relationship studies, biochemical potency, pharmacokinetics, and kinase selectivity were optimized to afford BMS-645737 (13), a compound with good preclinical in vivo activity against human tumor xenograft models. 相似文献
75.
Liver X receptor-dependent repression of matrix metalloproteinase-9 expression in macrophages 总被引:6,自引:0,他引:6
Castrillo A Joseph SB Marathe C Mangelsdorf DJ Tontonoz P 《The Journal of biological chemistry》2003,278(12):10443-10449
Matrix metalloproteinases (MMPs) are zinc endopeptidases that degrade extracellular matrix (ECM) components during normal and pathogenic tissue remodeling. Inappropriate expression of these enzymes contributes to the development of vascular pathology, including atherosclerosis. MMP-9 is expressed in its active form in atherosclerotic lesions and is believed to play an important role in vascular remodeling, smooth muscle cell migration, and plaque instability. We demonstrate here that the liver X receptors (LXRs) LXRalpha and LXRbeta inhibit basal and cytokine-inducible expression of MMP-9. Treatment of murine peritoneal macrophages with the synthetic LXR agonists GW3965 or T1317 reduces MMP-9 mRNA expression and blunts its induction by pro-inflammatory stimuli including lipopolysaccharide, interleukin-1beta, and tumor necrosis factor alpha. In contrast, macrophage expression of MMP-12 and MMP-13 is not altered by LXR ligands. We further show that the ability of LXR ligands to regulate MMP-9 expression is strictly receptor-dependent and is not observed in macrophages obtained from LXRalphabeta null mice. Analysis of the 5'-flanking region of the MMP-9 gene indicates that LXR/RXR heterodimers do not bind directly to the MMP-9 promoter. Rather, activation of LXRs represses MMP-9 expression, at least in part through antagonism of the NFkappaB signaling pathway. These observations identify the regulation of macrophage MMP-9 expression as a mechanism whereby activation of LXRs may impact macrophage inflammatory responses. 相似文献
76.
de Assis EF Silva AR Caiado LF Marathe GK Zimmerman GA Prescott SM McIntyre TM Bozza PT de Castro-Faria-Neto HC 《Journal of immunology (Baltimore, Md. : 1950)》2003,171(4):2090-2098
Oxidized low density lipoprotein (LDL) has an important proinflammatory role in atherogenesis. In this study, we investigated the ability of oxidized LDL (oxLDL) and its phospholipid components to induce lipid body formation in leukocytes. Incubation of mouse peritoneal macrophages with oxidized, but not with native LDL led to lipid body formation within 1 h. This was blocked by platelet-activating factor (PAF) receptor antagonists or by preincubation of oxLDL with rPAF acetylhydrolase. HPLC fractions of phospholipids purified from oxLDL induced calcium flux in neutrophils as well as lipid body formation in macrophages. Injection of the bioactive phospholipid fractions or butanoyl and butenoyl PAF, a phospholipid previously shown to be present in oxLDL, into the pleural cavity of mice induced lipid body formation in leukocytes recovered after 3 h. The 5-lipoxygenase and cyclooxygenase-2 colocalized within lipid bodies formed after stimulation with oxLDL, bioactive phospholipid fractions, or butanoyl and butenoyl PAF. Lipid body formation was inhibited by 5-lipoxygenase antagonists, but not by cyclooxygenase-2 inhibitors. Azelaoyl-phosphatidylcholine, a peroxisome proliferator-activated receptor-gamma agonist in oxLDL phospholipid fractions, induced formation of lipid bodies at late time points (6 h) and synergized with suboptimal concentrations of oxLDL. We conclude that lipid body formation is an important proinflammatory effect of oxLDL and that PAF-like phospholipids and peroxisome proliferator-activated receptor-gamma agonists generated during LDL oxidation are important mediators in this phenomenon. 相似文献
77.
Kriska T Marathe GK Schmidt JC McIntyre TM Girotti AW 《The Journal of biological chemistry》2007,282(1):100-108
Phospholipid hydroperoxide (PLOOH) degrading activity of high density lipoprotein (HDL)-derived paraoxonase-1 (PON1) was investigated, using peroxidized 1-palmitoyl-2-oleoyl phosphatidylcholine (PCOOH) as substrate and high performance thin layer chromatography for quantitative peroxide analysis. Incubation of PCOOH with PON1 resulted in decay of the latter and reciprocal buildup of oleic acid hydroperoxide (OAOOH) at rates unaffected by GSH or other reductants. A serine esterase inhibitor blocked this activity and a recombinant PON1 was devoid of it, raising the possibility that the activity represents platelet-activating factor acetylhydrolase (PAF-AH), an esterase that co-purifies with PON1 from HDL. This was verified by showing that a recombinant PAF-AH recapitulates the ability of natural PON1 to hydrolyze PCOOH and release OAOOH while having essentially no effect on parental PC. Furthermore, recombinant PAF-AH and natural PON1 were shown to have similar K(m) values for PCOOH hydrolysis. Finally, we found that recombinant PAF-AH, but not PON1, catalyzes PLOOH hydrolysis in peroxidized low density lipoprotein. We conclude from this study that PON1 is neither a PLOOH peroxidase nor hydrolase and that the phospholipase A(2)-like activity previously attributed to PON1 in natural enzyme preparations was actually due to novel PLOOH hydrolytic activity of contaminating PAF-AH. 相似文献
78.
Kathleen A. Alexander Claire E. Sanderson Madav Marathe Bryan L. Lewis Caitlin M. Rivers Jeffrey Shaman John M. Drake Eric Lofgren Virginia M. Dato Marisa C. Eisenberg Stephen Eubank 《PLoS neglected tropical diseases》2015,9(6)
An Ebola outbreak of unprecedented scope emerged in West Africa in December 2013 and presently continues unabated in the countries of Guinea, Sierra Leone, and Liberia. Ebola is not new to Africa, and outbreaks have been confirmed as far back as 1976. The current West African Ebola outbreak is the largest ever recorded and differs dramatically from prior outbreaks in its duration, number of people affected, and geographic extent. The emergence of this deadly disease in West Africa invites many questions, foremost among these: why now, and why in West Africa? Here, we review the sociological, ecological, and environmental drivers that might have influenced the emergence of Ebola in this region of Africa and its spread throughout the region. Containment of the West African Ebola outbreak is the most pressing, immediate need. A comprehensive assessment of the drivers of Ebola emergence and sustained human-to-human transmission is also needed in order to prepare other countries for importation or emergence of this disease. Such assessment includes identification of country-level protocols and interagency policies for outbreak detection and rapid response, increased understanding of cultural and traditional risk factors within and between nations, delivery of culturally embedded public health education, and regional coordination and collaboration, particularly with governments and health ministries throughout Africa. Public health education is also urgently needed in countries outside of Africa in order to ensure that risk is properly understood and public concerns do not escalate unnecessarily. To prevent future outbreaks, coordinated, multiscale, early warning systems should be developed that make full use of these integrated assessments, partner with local communities in high-risk areas, and provide clearly defined response recommendations specific to the needs of each community. 相似文献
79.
Micaela B. Reddy Kuo-Hsiung Yang Gauri Rao Craig R. Rayner Jing Nie Chandrasena Pamulapati Bindumadhav M. Marathe Alan Forrest Elena A. Govorkova 《PloS one》2015,10(10)
The ferret is a suitable small animal model for preclinical evaluation of efficacy of antiviral drugs against various influenza strains, including highly pathogenic H5N1 viruses. Rigorous pharmacokinetics/pharmacodynamics (PK/PD) assessment of ferret data has not been conducted, perhaps due to insufficient information on oseltamivir PK. Here, based on PK data from several studies on both uninfected and influenza-infected groups (i.e., with influenza A viruses of H5N1 and H3N2 subtypes and an influenza B virus) and several types of anesthesia we developed a population PK model for the active compound oseltamivir carboxylate (OC) in the ferret. The ferret OC population PK model incorporated delayed first-order input, two-compartment distribution, and first-order elimination to successfully describe OC PK. Influenza infection did not affect model parameters, but anesthesia did. The conclusion that OC PK was not influenced by influenza infection must be viewed with caution because the influenza infections in the studies included here resulted in mild clinical symptoms in terms of temperature, body weight, and activity scores. Monte Carlo simulations were used to determine that administration of a 5.08 mg/kg dose of oseltamivir phosphate to ferret every 12 h for 5 days results in the same median OC area under the plasma concentration-time curve 0–12 h (i.e., 3220 mg h/mL) as that observed in humans during steady state at the approved dose of 75 mg twice daily for 5 days. Modeling indicated that PK variability for OC in the ferret model is high, and can be affected by anesthesia. Therefore, for proper interpretation of PK/PD data, sparse PK sampling to allow the OC PK determination in individual animals is important. Another consideration in appropriate design of PK/PD studies is achieving an influenza infection with pronounced clinical symptoms and efficient virus replication, which will allow adequate evaluation of drug effects. 相似文献
80.
Mastalerz H Chang M Chen P Dextraze P Fink BE Gavai A Goyal B Han WC Johnson W Langley D Lee FY Marathe P Mathur A Oppenheimer S Ruediger E Tarrant J Tokarski JS Vite GD Vyas DM Wong H Wong TW Zhang H Zhang G 《Bioorganic & medicinal chemistry letters》2007,17(7):2036-2042
Novel C-5 substituted pyrrolotriazines were optimized for dual EGFR and HER2 protein tyrosine kinase inhibition. The lead compound exhibited promising oral efficacy in both EGFR and HER2 driven human tumor xenograft models. It is hypothesized that its C-5 morpholine side chain binds in the ribose phosphate portion of the ATP binding pocket. 相似文献