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排序方式: 共有627条查询结果,搜索用时 31 毫秒
101.
Ian Stansfield Caterina Ercolani Angela Mackay Immacolata Conte Marco Pompei Uwe Koch Nadia Gennari Claudio Giuliano Michael Rowley Frank Narjes 《Bioorganic & medicinal chemistry letters》2009,19(3):627-632
We report the evolutionary path from an open-chain series to conformationally constrained tetracyclic indole inhibitors of HCV NS5B-polymerase, where the C2 aromatic is tethered to the indole nitrogen. SAR studies led to the discovery of zwitterionic compounds endowed with good intrinsic enzyme affinity and cell-based potency, as well as superior DMPK profiles to their acyclic counterparts, and ultimately to the identification of a pre-clinical candidate with an excellent predicted human pharmacokinetic profile. 相似文献
102.
Secondary Metabolites Produced by the Marine Bacterium Halobacillus salinus That Inhibit Quorum Sensing-Controlled Phenotypes in Gram-Negative Bacteria
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Margaret E. Teasdale Jiayuan Liu Joselynn Wallace Fatemeh Akhlaghi David C. Rowley 《Applied microbiology》2009,75(3):567-572
Certain bacteria use cell-to-cell chemical communication to coordinate community-wide phenotypic expression, including swarming motility, antibiotic biosynthesis, and biofilm production. Here we present a marine gram-positive bacterium that secretes secondary metabolites capable of quenching quorum sensing-controlled behaviors in several gram-negative reporter strains. Isolate C42, a Halobacillus salinus strain obtained from a sea grass sample, inhibits bioluminescence production by Vibrio harveyi in cocultivation experiments. With the use of bioassay-guided fractionation, two phenethylamide metabolites were identified as the active agents. The compounds additionally inhibit quorum sensing-regulated violacein biosynthesis by Chromobacterium violaceum CV026 and green fluorescent protein production by Escherichia coli JB525. Bacterial growth was unaffected at concentrations below 200 μg/ml. Evidence is presented that these nontoxic metabolites may act as antagonists of bacterial quorum sensing by competing with N-acyl homoserine lactones for receptor binding. 相似文献
103.
The ITGAV rs3738919 variant and susceptibility to rheumatoid arthritis in four Caucasian sample sets
Jade E Hollis-Moffatt Kerry A Rowley Amanda J Phipps-Green Marilyn E Merriman Nicola Dalbeth Peter Gow Andrew A Harrison John Highton Peter BB Jones Lisa K Stamp Pille Harrison B Paul Wordsworth Tony R Merriman 《Arthritis research & therapy》2009,11(5):R152
Introduction
Angiogenesis is an important process in the development of destructive synovial pannus in rheumatoid arthritis (RA). The ITGAV +gene encodes a cell cycle-associated antigen, integrin ανβ 3, which plays a role in RA angiogenesis. Previously, two independent studies identified an association between the major allele of the ITGAV single-nucleotide polymorphism (SNP) rs3738919 and RA. We therefore tested this association in an independent study using New Zealand (NZ) and Oxford (UK) RA case control samples.Methods
We compared genotype frequencies in 740 NZ Caucasian RA patients and 553 controls genotyped for rs3738919, using a polymerase chain reaction-restriction fragment length polymorphism assay. A TaqMan genotyping SNP assay was used to type 713 Caucasian RA patients and 515 control samples from Oxford for the rs3738919 variant. Association of rs3738919 with RA was tested in these two sample sets using the chi-square goodness-of-fit test. The Mantel-Haenszel test was used to perform a meta-analysis, combining the genetic results from four independent Caucasian case control cohorts, consisting of 3,527 cases and 4,126 controls. Haplotype analysis was also performed using SNPs rs3911238, rs10174098 and rs3738919 in the Wellcome Trust Case Control Consortium, NZ and Oxford case control samples.Results
We found no evidence for association between ITGAV and RA in either the NZ or Oxford sample set (odds ratio [OR] = 0.88, Pallelic = 0.11 and OR = 1.18, Pallelic = 0.07, respectively). Inclusion of these data in a meta-analysis (random effects) of four independent cohorts (3,527 cases and 4,126 controls) weakens support for the hypothesis that rs3738919 plays a role in the development of RA (ORcombined = 0.92, 95% confidence interval 0.80 to 1.07; P = 0.29). No consistent haplotype associations were evident.Conclusions
Association of ITGAV SNP rs7378919 with RA was not replicated in NZ or Oxford case control sample sets. Meta-analysis of these and previously published data lends limited support for a role for the ITGAV in RA in Caucasians of European ancestry. 相似文献104.
105.
Jones P Altamura S Chakravarty PK Cecchetti O De Francesco R Gallinari P Ingenito R Meinke PT Petrocchi A Rowley M Scarpelli R Serafini S Steinkühler C 《Bioorganic & medicinal chemistry letters》2006,16(23):5948-5952
Histone deacetylase (HDAC) inhibitors offer a promising strategy for cancer therapy and the first generation HDAC inhibitors are currently in clinical trials. A structurally novel series of HDAC inhibitors based on the natural cyclic tetrapeptide Apicidin is described. Selected screening of the sample collection looking for L-2-amino-8-oxodecanoic acid (L-Aoda) derivatives identified a small acyclic lead molecule 1 with the unusual ketone zinc binding group. SAR studies around this lead resulted in optimization to potent, low molecular weight, selective, non-hydroxamic acid HDAC inhibitors, equipotent to current clinical candidates. 相似文献
106.
The escalation of antibiotic resistance among Gram-positive pathogens presents increasing treatment challenges and requires the development of innovative therapeutic agents. Here, we present the antimicrobial properties of structurally unusual bisanthraquinone metabolites produced by a marine streptomycete and four semi-synthetic derivatives. Biological activities were measured against clinically derived isolates of vancomycin-resistant Enterococcus faecium (VRE), and methicillin-susceptible, methicillin-resistant, and tetracycline-resistant Staphylococcus aureus (MSSA, MRSA, and TRSA, respectively). The most potent antibiotic displayed MIC50 values of 0.11, 0.23, and 0.90 μM against a panel (n = 25 each) of clinical MSSA, MRSA, and VRE, respectively, and was determined to be bactericidal by time-kill analysis. 相似文献
107.
Barron DA Strand DW Ressler SJ Dang TD Hayward SW Yang F Ayala GE Ittmann M Rowley DR 《PloS one》2010,5(10):e13751
TGF-β1 is overexpressed in wound repair and in most proliferative disorders including benign prostatic hyperplasia and prostate cancer. The stromal microenvironment at these sites is reactive and typified by altered phenotype, matrix deposition, inflammatory responses, and alterations in nerve density and biology. TGF-β1 is known to modulate several stromal responses; however there are few transgenic models to study its integrated biology. To address the actions of TGF-β1 in prostate disorders, we targeted expression of an epitope tagged and constitutively active TGF-β1 via the enhanced probasin promoter to the murine prostate gland epithelium. Transgenic mice developed age-dependent lesions leading to severe, yet focal attenuation of epithelium, and a discontinuous basal lamina. These changes were associated with elevated fibroplasia and frequency of collagenous micronodules in collapsed acini, along with an induced inflammation in nerve ganglia and small vessels. Elevated recruitment of CD115+ myeloid cells but not mature macrophages was observed in nerve ganglia, also in an age-dependent manner. Similar phenotypic changes were observed using a human prostate epithelium tissue recombination xenograft model, where epithelial cells engineered to overexpress TGF-β1 induced fibrosis and altered matrix deposition concurrent with inflammation in the stromal compartment. Together, these data suggest that elevated TGF-β1 expression induces a fibroplasia stromal response associated with breach of epithelial wall structure and inflammatory involvement of nerve ganglia and vessels. The novel findings of ganglia and vessel inflammation associated with formation of collagenous micronodules in collapsed acini is important as each of these are observed in human prostate carcinoma and may play a role in disease progression. 相似文献
108.
Development and optimisation of a sex pheromone lure for monitoring populations of saddle gall midge,Haplodiplosis marginata
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Charlotte Rowley Tom W. Pope Andrew Cherrill Simon R. Leather G. Mandela Fernández‐Grandon David R. Hall 《Entomologia Experimentalis et Applicata》2017,163(1):82-92
Saddle gall midge, Haplodiplosis marginata (von Roser) (Diptera: Cecidomyiidae), is a sporadic pest of cereals in Northern and Central Europe and is of increasing importance in the UK. Recently, the major component of the sex pheromone produced by adult female H. marginata was reported to be 2‐nonyl butyrate. The importance of absolute configuration on attractiveness, the effects on trap catches of the addition of minor pheromone components, dispenser type, and pheromone loading are described in the development of an optimised pheromone lure with which to trap H. marginata males. In analyses of volatiles collected from virgin female H. marginata by gas chromatography (GC) coupled with electroantennographic recording (EAG) from the antenna of a male H. marginata, two EAG responses were observed. Analyses by coupled GC‐mass spectrometry (MS) indicated these were due to 2‐nonyl butyrate and a trace amount (1%) of 2‐heptyl butyrate. A similar trace amount of 2‐nonanol was detected in GC‐MS analyses but this compound did not elicit an EAG response when the synthetic compound was tested, whereas the other two compounds did. These three compounds were not observed in collections of volatiles made from male H. marginata. The 2‐nonyl butyrate was shown to be the (R)‐enantiomer. In field trapping tests (R)‐2‐nonyl butyrate was at least 10× more attractive to male H. marginata than the racemic compound, and the (S)‐enantiomer was unattractive. Addition of the potential minor components individually or together at the naturally occurring ratios did not increase or reduce the attractiveness of the lure. Polyethylene vials and rubber septa were equally effective as pheromone dispensers, lasting for at least 5 weeks in the field in the UK, although laboratory tests indicated release from the former was more uniform and more likely to last longer in the field. Increasing loading of pheromone in the dispenser increased attractiveness. Traps baited with polyethylene vials containing 0.5 mg of (R)‐2‐nonyl butyrate are recommended for monitoring H. marginata and these are far more sensitive than water or sticky traps currently used for monitoring this pest. 相似文献
109.
The human prostate gland is one of the only internal organs that continue to enlarge throughout adulthood. The specific mechanisms that regulate this growth, as well as the pathological changes leading to the phenotype observed in the disease benign prostatic hyperplasia (BPH), are essentially unknown. Recent studies and their associated findings have made clear that many complex alterations occur, involving persistent and chronic inflammation, circulating hormonal level deregulation, and aberrant wound repair processes. BPH has been etiologically characterized as a progressive, albeit discontinuous, hyperplasia of both the glandular epithelial and the stromal cell compartments coordinately yielding an expansion of the prostate gland and clinical symptoms. Interestingly, the inflammatory and repair responses observed in BPH are also key components of general wound repair in post-natal tissues. These responses include altered expression of chemokines, cytokines, matrix remodeling factors, chronic inflammatory processes, altered immune surveillance and recognition, as well as the formation of a prototypical 'reactive' stroma, which is similar to that observed across various fibroplasias and malignancies of a variety of tissue sites. Stromal tissue, both embryonic mesenchyme and adult reactive stroma myofibroblasts, has been shown to exert potent and functional regulatory control over epithelial proliferation and differentiation as well as immunoresponsive modulation. Thus, the functional biology of a reactive stroma, within the context of an adult disease typified by epithelial and stromal aberrant hyperplasia, is critical to understand within the context of prostate disease and beyond. The mechanisms that regulate reactive stroma biology in BPH represent targets of opportunity for new therapeutic approaches that may extend to other tissue contexts. Accordingly, this review seeks to address the dissection of important factors, signaling pathways, genes, and other regulatory components that mediate the interplay between epithelium and stromal responses in BPH. 相似文献
110.
The swimming behavior of the cercaria of the digenetic trematode Proterometra macrostoma changes in response to light. However, this cercaria does not possess obvious eyes or eyespots. Using behavioral assays, we were able to show that both intact and distome-removed cercariae swim significantly greater vertical distances under dim, red light than under brighter, white light. Electrophysiological experiments confirmed this result and further showed that the transverse band of the tail, known to control cercariae swimming behavior, was necessary and sufficient for the display of the light-dependent swimming behavior. Together, these data show that the distome is not required for light-dependent swimming behavior in P. macrostoma cercariae and indirectly demonstrates the presence of photoreceptors in the transverse band of the cercaria tail. 相似文献