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111.
112.
Contemporary small-molecule drug discovery frequently involves the screening of large compound files as a core activity. Subsequently cost, speed, and safety become critical issues. In order to meet this need, numerous technologies have been developed to allow mix and measure approaches, facilitate miniaturization, and to increase speed and to minimize the use of potentially hazardous reagents such as radioactive materials. However, despite the on-paper advantages of these new technologies, risks can remain undefined. For example, the question of whether the novel method will facilitate identification of active chemical series in a way that is comparable with conventional methods arises. In order to address this question, we have taken the approach of carrying out experiments to directly compare the output of high-throughput screens using a given novel approach and a traditional method. The concordance between the screening methods can then be determined via comparison of the numbers and structures of the active molecules identified. This article describes the approach taken in our laboratory to minimize variability in such experiments and shows data that exemplifies the general result of lower than expected concordance. Statistical modeling was subsequently used to facilitate this interpretation. The model used beta-distribution function to generate a real-activity frequency relationship with added normal random error and occasional outliers to represent assay variability. Hence, the effect of assay parameters such as the threshold, the number of real actives, and the number of outliers and the standard deviation could readily be explored. The model was found to describe the data reasonably and moreover was found to be of great utility when it came to planning further optimal experiments. A key conclusion from the model was that concordance between screening methods could appear poor even when one approach is compared with itself. This occurs simply because the result is a function of assay threshold, standard deviation and the true compound % activity. In response to this finding we have adopted alternative experimental designs that more reliably measure the concordance between screening methods. 相似文献
113.
Han W Wu B Li L Zhao G Woodward R Pettit N Cai L Thon V Wang PG 《The Journal of biological chemistry》2012,287(8):5357-5365
The WaaL-mediated ligation of O-antigen onto the core region of the lipid A-core block is an important step in the lipopolysaccharide (LPS) biosynthetic pathway. Although the LPS biosynthesis has been largely characterized, only a limited amount of in vitro biochemical evidence has been established for the ligation reaction. Such limitations have primarily resulted from the barriers in purifying WaaL homologues and obtaining chemically defined substrates. Accordingly, we describe herein a chemical biology approach that enabled the reconstitution of this ligation reaction. The O-antigen repeating unit (O-unit) of Escherichia coli O86 was first enzymatically assembled via sequential enzymatic glycosylation of a chemically synthesized GalNAc-pyrophosphate-undecaprenyl precursor. Subsequent expression of WaaL through use of a chaperone co-expression system then enabled the demonstration of the in vitro ligation between the synthesized donor (O-unit-pyrophosphate-undecaprenyl) and the isolated lipid A-core acceptor. The previously reported ATP and divalent metal cation dependence were not observed using this system. Further analyses of other donor substrates revealed that WaaL possesses a highly relaxed specificity toward both the lipid moiety and the glycan moiety of the donor. Lastly, three conserved amino acid residues identified by sequence alignment were found essential for the WaaL activity. Taken together, the present work represents an in vitro systematic investigation of the WaaL function using a chemical biology approach, providing a system that could facilitate the elucidation of the mechanism of WaaL-catalyzed ligation reaction. 相似文献
114.
Robert B. Jacobs Frank R. Thompson III Rolf R. Koford Frank A. La Sorte Hope D. Woodward Jane A. Fitzgerald 《The Journal of wildlife management》2012,76(2):372-381
Of 6 million ha of prairie that once covered northern and western Missouri, <36,500 ha remain, with planted, managed, and restored grasslands comprising most contemporary grasslands. Most grasslands are used as pasture or hayfields. Native grasses largely have been replaced by fescue (Festuca spp.) on most private lands (almost 7 million ha). Previously cropped fields set aside under the Conservation Reserve Program (CRP) varied from a mix of cool-season grasses and forbs, or mix of native warm-season grasses and forbs, to simple tall-grass monocultures. We used generalized linear mixed models and distance sampling to assess abundance of 8 species of breeding grassland birds on 6 grassland types commonly associated with farm practices in Missouri and located in landscapes managed for grassland-bird conservation. We selected Bird Conservation Areas (BCAs) for their high percentage of grasslands and grassland-bird species, and for <5% forest cover. We used an information-theoretic approach to assess the relationship between bird abundance and 6 grassland types, 3 measures of vegetative structure, and 2 landscape variables (% grassland and edge density within a 1-km radius). We found support for all 3 levels of model parameters, although there was less support for landscape than vegetation structure effects likely because we studied high-percentage-grassland landscapes (BCAs). Henslow's sparrow (Ammodramus henslowii) counts increased with greater percentage of grassland, vegetation height-density, litter depth, and shrub cover and lower edge density. Henslow's sparrow counts were greatest in hayed native prairie. Dickcissel (Spiza americana) counts increased with greater vegetation height-density and were greatest in planted CRP grasslands. Grasshopper sparrow (A. savannarum) counts increased with lower vegetation height, litter depth, and shrub cover. Based on distance modeling, breeding densities of Henslow's sparrow, dickcissel, and grasshopper sparrow in the 6 grassland types ranged 0.9–2.6, 1.4–3.2, and 0.1–1.5 birds/ha, respectively. We suggest different grassland types and structures (vegetation height, litter depth, shrub cover) are needed to support priority grassland-bird species in Missouri. © 2011 The Wildlife Society. 相似文献
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116.
Bioinsecticides are important in the control of disease vectors, but data regarding their physiological effects on target insects are incomplete. This study describes morphological changes that occur in the midgut of third instar Aedes aegypti L. (Diptera: Culicidae) following treatment with a methanolic extract of Annona coriacea (Magnoliales: Annonaceae). Dissected midguts were subdivided into anterior and posterior regions and analyzed by light and scanning electron microscopy. Insects exposed to the extract displayed intense, destructive cytoplasmic vacuolization in columnar and regenerative midgut cells. The apical surfaces of columnar cells exhibited cytoplasmic protrusions oriented toward the lumen, suggesting that these cells could be involved in apocrine secretory processes and/or apoptosis. We report that A. coriacea extracts induced morphological alterations in the midgut of A. aegypti midgut larvae, supporting the use of plant extracts for control of the dengue vector. 相似文献
117.
Kay C Woodward KD Lawler K Self TJ Dyall SD Kerr ID 《PLoS neglected tropical diseases》2012,6(6):e1693
The ATP binding cassette (ABC) proteins are a family of membrane transporters and regulatory proteins responsible for diverse and critical cellular process in all organisms. To date, there has been no attempt to investigate this class of proteins in the infectious parasite Trichomonas vaginalis. We have utilized a combination of bioinformatics, gene sequence analysis, gene expression and confocal microscopy to investigate the ABC proteins of T. vaginalis. We demonstrate that, uniquely among eukaryotes, T. vaginalis possesses no intact full-length ABC transporters and has undergone a dramatic expansion of some ABC protein sub-families. Furthermore, we provide preliminary evidence that T. vaginalis is able to read through in-frame stop codons to express ABC transporter components from gene pairs in a head-to-tail orientation. Finally, with confocal microscopy we demonstrate the expression and endoplasmic reticulum localization of a number of T. vaginalis ABC transporters. 相似文献
118.
Ben-Shahar OM Szumlinski KK Lominac KD Cohen A Gordon E Ploense KL DeMartini J Bernstein N Rudy NM Nabhan AN Sacramento A Pagano K Carosso GA Woodward N 《Addiction biology》2012,17(4):746-757
Previous studies have shown that brief access to cocaine yields an increase in D2 receptor binding in the medial prefrontal cortex (mPFC), but that extended access to cocaine results in normalized binding of D2 receptors (i.e. the D2 binding returned to control levels). Extended-access conditions have also been shown to produce increased expression of the NR2 subunit of the N-Methyl-D-aspartate receptor in the mPFC. These results implicate disrupted glutamate and dopamine function within this area. Therefore, in the present study, we monitored glutamate and dopamine content within the mPFC during, or 24 hours after, cocaine self-administration in animals that experienced various amounts of exposure to the drug. Na?ve subjects showed decreased glutamate and increased dopamine levels within the mPFC during cocaine self-administration. Exposure to seven 1-hour daily cocaine self-administration sessions did not alter the response to self-administered cocaine, but resulted in decreased basal dopamine levels. While exposure to 17 1-hour sessions also resulted in reduced basal dopamine levels, these animals showed increased dopaminergic, but completely diminished glutamatergic, response to self-administered cocaine. Finally, exposure to 17 cocaine self-administration sessions, the last 10 of which being 6-hour sessions, resulted in diminished glutamatergic response to self-administered cocaine and reduced basal glutamate levels within the mPFC while normalizing (i.e. causing a return to control levels) both the dopaminergic response to self-administered cocaine as well as basal dopamine levels within this area. These data demonstrate directly that the transition to escalated cocaine use involves progressive changes in dopamine and glutamate function within the mPFC. 相似文献
119.