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排序方式: 共有222条查询结果,搜索用时 15 毫秒
111.
112.
Grice CA Tays K Khatuya H Gustin DJ Butler CR Wei J Sehon CA Sun S Gu Y Jiang W Thurmond RL Karlsson L Edwards JP 《Bioorganic & medicinal chemistry letters》2006,16(8):2209-2212
A series of competitive, reversible cathepsin S (CatS) inhibitors was investigated. An earlier disclosure detailed the discovery of the 4-(2-keto-1-benzimidazolinyl)-piperidin-1-yl moiety as an effective replacement for the 4-arylpiperazin-1-yl group found in our screening hit. Continued investigation into replacements for the 4-aryl piperazine resulted in the identification of potentially useful CatS inhibitors with enzymatic and cellular activity similar to that of JNJ 10329670 as disclosed in a previous publication. 相似文献
113.
Legiewicz M Zolotukhin AS Pilkington GR Purzycka KJ Mitchell M Uranishi H Bear J Pavlakis GN Le Grice SF Felber BK 《The Journal of biological chemistry》2010,285(53):42097-42104
Retrovirus replication requires specialized transport mechanisms to export genomic mRNA from the nucleus to the cytoplasm of the infected cell. This regulation is mediated by a combination of viral and/or cellular factors that interact with cis-acting RNA export elements linking the viral RNA to the cellular CRM1 or NXF1 nuclear export pathways. Endogenous type D murine LTR retrotransposons (musD) were reported to contain an RNA export element located upstream of the 3'-LTR. Although functionally equivalent, the musD export element, termed the musD transport element, is distinct from the other retroviral RNA export elements, such as the constitutive transport element of simian/Mason-Pfizer monkey retroviruses and the RNA transport element found in rodent intracisternal A-particle LTR retrotransposons. We demonstrate here that the minimal RNA transport element (musD transport element) of musD comprises multiple secondary structure elements that presumably serve as recognition signals for the cellular export machinery. We identified two classes of tertiary interactions, namely kissing loops and a pseudoknot. This work constitutes the first example of an RNA transport element requiring such structural motifs to mediate nuclear export. 相似文献
114.
Alejandro Santillan Kelly J. McClure Brett D. Allison Brian Lord Jamin D. Boggs Kirsten L. Morton Anita M. Everson Diane Nepomuceno Michael A. Letavic Alice Lee-Dutra Timothy W. Lovenberg Nicholas I. Carruthers Cheryl A. Grice 《Bioorganic & medicinal chemistry letters》2010,20(21):6226-6230
Previous research on histamine H3 antagonists has led to the development of a pharmacophore model consisting of a central phenyl core flanked by two alkylamine groups. Recent investigation of the replacement of the central phenyl core with heteroaromatic fragments resulted in the preparation of novel 3,5-, 3,6- and 3,7-substituted indole and 3,5-substituted benzothiophene analogs that demonstrate good to excellent hH3 affinities. Select analogs were profiled in a rat pharmacokinetic model. 相似文献
115.
Uzoezi Ozomaro Guiqing Cai Yuji Kajiwara Seungtai Yoon Vladimir Makarov Richard Delorme Catalina Betancur Stephan Ruhrmann Peter Falkai Hans J?rgen Grabe Wolfgang Maier Michael Wagner Leonhard Lennertz Rainald Moessner Dennis L. Murphy Joseph D. Buxbaum Stephan Züchner Dorothy E. Grice 《PloS one》2013,8(8)
Obsessive compulsive disorder (OCD) is a syndrome characterized by recurrent and intrusive thoughts and ritualistic behaviors or mental acts that a person feels compelled to perform. Twin studies, family studies, and segregation analyses provide compelling evidence that OCD has a strong genetic component. The SLITRK1 gene encodes a developmentally regulated stimulator of neurite outgrowth and previous studies have implicated rare variants in this gene in disorders in the OC spectrum, specifically Tourette syndrome (TS) and trichotillomania (TTM). The objective of the current study was to evaluate rare genetic variation in SLITRK1 in risk for OCD and to functionally characterize associated coding variants. We sequenced SLITRK1 coding exons in 381 individuals with OCD as well as in 356 control samples and identified three novel variants in seven individuals. We found that the combined mutation load in OCD relative to controls was significant (p = 0.036). We identified a missense N400I change in an individual with OCD, which was not found in more than 1000 control samples (P<0.05). In addition, we showed the the N400I variant failed to enhance neurite outgrowth in primary neuronal cultures, in contrast to wildtype SLITRK1, which enhanced neurite outgrowth in this assay. These important functional differences in the N400I variant, as compared to the wildtype SLITRK1 sequence, may contribute to OCD and OC spectrum symptoms. A synonymous L63L change identified in an individual with OCD and an additional missense change, T418S, was found in four individuals with OCD and in one individual without an OCD spectrum disorder. Examination of additional samples will help assess the role of rare SLITRK1 variation in OCD and in related psychiatric illness. 相似文献
116.
Will B. Kirby Paul E. Bellamy Andrew J. Stanbury Andrew J. Bladon Phil V. Grice Simon Gillings 《Bird Study》2013,60(3):348-357
Capsule At both landscape and local scales, breeding persistence in a declining Hawfinch population was greatest where broadleaved woodland cover was high, while at a fine scale, nest sites were associated with openings in the woodland canopy.Aims To assess which components of habitat are associated with Hawfinch occupancy at landscape (10-km), local (tetrad) and fine (nest) spatial scales, during a period of population decline and range contraction.Methods Bird Atlas 2008–11 data were used to determine areas of Hawfinch loss and persistence over 20 years. Current habitat was measured and compared to look for correlates that helped explain the differing status at both 10-km and tetrad scales. Fine scale habitat data collected at nest sites were compared with random locations to investigate within-wood nest site selection.Results At both 10-km and tetrad scales, Hawfinch persistence is more likely where woodland cover is greater. Recent woodland management was less evident in tetrads where the species persisted. At the nest site scale, the only relationship detected was for nests to be close to canopy openings.Conclusions Maintaining and increasing broadleaved woodland area is likely to benefit Hawfinch. Within woods, maintenance and creation of open areas may enhance nesting opportunities. 相似文献
117.
Alex J.G. Lewis Laura Daniells Elisabeth C. Charman Phil Grice Ken Smith 《Bird Study》2013,60(3):326-337
Capsule Birds selected younger woodland patches with fewer conifers and higher soil moisture content; within these patches, they selected areas with higher vegetation cover at 2–4 m, and less bracken. Aims For an apparently stable population, to investigate habitat differences between occupied and unoccupied woodland patches and habitat selection within occupied woodlands. Methods We surveyed woodland patches for breeding Willow Tits in April 2006 in an area with an apparently stable population. Habitat was measured at points spread throughout each woodland patch and at points where Willow Tits were located. We compared habitat between occupied and unoccupied sites. In addition, within occupied sites, we examined habitat differences between Willow Tit locations and the points spread throughout the wood. Results We surveyed 65 woodland patches, of which 29 were occupied. Willow Tits were more likely to be found in deciduous woodland that was younger and had higher levels of soil moisture. Probability of occupancy fell from 60% for woods aged 20–25 years to only around 15–30% for woods aged over 80 years. Within occupied woods, Willow Tits were more likely to be found in areas with more vegetation cover at the 2–4 m level and in areas with less bracken. Conclusions Habitat management for Willow Tits should involve provision of young woodland patches with moist soils. Changes to the age structure and/or the soil moisture content of woods may be implicated in the dramatic decline of Willow Tits in Britain. 相似文献
118.
Danaë K. Stevens Guy Q. A. Anderson Philip V. Grice Ken Norris Nigel Butcher 《Bird Study》2013,60(2):179-187
Capsule Avian predators are principally responsible. Aims To document the fate of Spotted Flycatcher nests and to identify the species responsible for nest predation. Methods During 2005–06, purpose-built, remote, digital nest-cameras were deployed at 65 out of 141 Spotted Flycatcher nests monitored in two study areas, one in south Devon and the second on the border of Bedfordshire and Cambridgeshire. Results Of the 141 nests monitored, 90 were successful (non-camera nests, 49 out of 76 successful, camera nests, 41 out of 65). Fate was determined for 63 of the 65 nests monitored by camera, with 20 predation events documented, all of which occurred during daylight hours. Avian predators carried out 17 of the 20 predations, with the principal nest predator identified as Eurasian Jay Garrulus glandarius. The only mammal recorded predating nests was the Domestic Cat Felis catus, the study therefore providing no evidence that Grey Squirrels Sciurus carolinensis are an important predator of Spotted Flycatcher nests. There was no evidence of differences in nest survival rates at nests with and without cameras. Nest remains following predation events gave little clue as to the identity of the predator species responsible. Conclusions Nest-cameras can be useful tools in the identification of nest predators, and may be deployed with no subsequent effect on nest survival. The majority of predation of Spotted Flycatcher nests in this study was by avian predators, principally the Jay. There was little evidence of predation by mammalian predators. Identification of specific nest predators enhances studies of breeding productivity and predation risk. 相似文献
119.
Zhou Y Grice K Chikaraishi Y Stuart-Williams H Farquhar GD Ohkouchi N 《Phytochemistry》2011,72(2-3):207-213
The hydrogen isotopic ratios ((2)H/(1)H) of land plant leaf water and the carbon-bound hydrogen of leaf wax lipids are valuable indicators for climatic, physiological, metabolic and geochemical studies. Temperature will exert a profound effect on the stable isotopic composition of leaf water and leaf lipids as it directly influences the isotopic equilibrium (IE) during leaf water evaporation and cellular water dissociation. It is also expected to affect the kinetics of enzymes involved in lipid biosynthesis, and therefore the balance of hydrogen inputs along different biochemical routes. We conducted a controlled growth experiment to examine the effect of temperature on the stable hydrogen isotopic composition of leaf water and the biological and biochemical isotopic fractionations during lipid biosynthesis. We find that leaf water (2)H enrichment at 20°C is lower than that at 30°C. This is contrary to the expectation that at lower temperatures leaf water should be more enriched in (2)H due to a larger equilibrium isotope effect associated with evapotranspiration from the leaf if all other variables are held constant. A hypothesis is presented to explain the apparent discrepancy whereby lower temperature-induced down-regulation of available aquaporin water channels and/or partial closure of transmembrane water channel forces water flow to "detour" to a more convoluted apoplastic pathway, effectively increasing the length over which diffusion acts against advection as described by the Péclet effect (Farquhar and Lloyd, 1993) and decreasing the average leaf water enrichment. The impact of temperature on leaf water enrichment is not reflected in the biological isotopic fractionation or the biochemical isotopic fractionation during lipid biosynthesis. Neither the biological nor biochemical fractionations at 20°C are significantly different from that at 30°C, implying that temperature has a negligible effect on the isotopic fractionation during lipid biosynthesis. 相似文献
120.
Kim JA Yang SY Wamiru A McMahon JB Le Grice SF Beutler JA Kim YH 《Bioorganic & medicinal chemistry letters》2011,21(10):2840-2844
Two new monoterpene glycosides, distyloside A-B (1-2), and a new megastigmane glucoside, iso-dihydrodendranthemoside A (3) were isolated from twigs and leaves of Distylium racemosum, along with five known phenolic compounds (4-8). The structures were established via spectroscopic techniques and chemical transformations, and the absolute stereochemistry of 3 was determined by Mosher’s esterification. A homogeneous fluorescence resonance energy transfer (FRET) quenching assay was used to determine the inhibitory activity of isolates (1-8) on the ribonuclease H enzymes from HIV-1, 2, human, and Escherichia coli. Among them, 6″-O-galloylsalidroside (6) showed potent inhibitory effects with an IC50 value of 3.5 μM on HIV-2, and 1.7 μM on human RNase H, respectively. 相似文献