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81.
82.
Synthesis and activity of small molecule GPR40 agonists 总被引:2,自引:0,他引:2
Garrido DM Corbett DF Dwornik KA Goetz AS Littleton TR McKeown SC Mills WY Smalley TL Briscoe CP Peat AJ 《Bioorganic & medicinal chemistry letters》2006,16(7):1840-1845
The first report on the identification and structure-activity relationships of a novel series of GPR40 agonists based on a 3-(4-{[N-alkyl]amino}phenyl)propanoic acid template is described. Structural modifications to the original screening hit yielded compounds with a 100-fold increase in potency at the human GPR40 receptor and pEC(50)s in the low nanomolar range. The carboxylic acid moiety is not critical for activity but typically elicits an agonistic response higher than those observed with carboxamide replacements. These compounds may prove useful in unraveling the therapeutic potential of this receptor for the treatment of Type 2 diabetes. 相似文献
83.
Carpenter AJ Al-Barazanji KA Barvian KK Bishop MJ Britt CS Cooper JP Goetz AS Grizzle MK Hertzog DL Ignar DM Morgan RO Peckham GE Speake JD Swain WR 《Bioorganic & medicinal chemistry letters》2006,16(19):4994-5000
The identification of an MCH R1 antagonist screening hit led to the optimization of a class of benzimidazole-based MCH R1 antagonists. Structure-activity relationships and efforts to optimize pharmacokinetic properties are detailed along with the demonstration of the effectiveness of an MCH R1 antagonist in an animal model of obesity. 相似文献
84.
Hertzog DL Al-Barazanji KA Bigham EC Bishop MJ Britt CS Carlton DL Cooper JP Daniels AJ Garrido DM Goetz AS Grizzle MK Guo YC Handlon AL Ignar DM Morgan RO Peat AJ Tavares FX Zhou H 《Bioorganic & medicinal chemistry letters》2006,16(18):4723-4727
Optimization of a series of constrained melanin-concentrating hormone receptor 1 (MCH R1) antagonists has provided compounds with potent and selective MCH R1 activity. Details of the optimization process are provided and the use of one of the compounds in an animal model of diet-induced obesity is presented. 相似文献
85.
A highly conserved amino-terminal region of sonic hedgehog is required for the formation of its freely diffusible multimeric form 总被引:1,自引:0,他引:1
Goetz JA Singh S Suber LM Kull FJ Robbins DJ 《The Journal of biological chemistry》2006,281(7):4087-4093
Although members of the Hedgehog (Hh) family were initially described as morphogens, many of these early conclusions were based on experiments that used non-physiologically relevant forms of Hh. Native Hh is modified by cholesterol (HhNp) and palmitate. These hydrophobic modifications are responsible for the ability of Hh to associate with cellular membranes, a property that initially appeared inconsistent with its ability to act far from its site of synthesis. Although it is now clear that Hh family members are capable of acting directly in long-range signaling, the form of Hh capable of this activity remains controversial. We have previously provided evidence for a freely diffusible multimeric form of Sonic Hedgehog (Shh) termed s-ShhNp, which is capable of accumulating in a gradient fashion through a morphogenic field. Here, we provide further evidence that s-ShhNp is the physiologically relevant form of Shh. We show that the biological activity of freely diffusible ShhNp resides in its multimeric form and that this multimeric form is exceedingly stable, even to high concentrations of salt and detergent. Furthermore, we now validate the Shh-Shh interactions previously observed in the crystal structure of human Shh, showing that a highly conserved amino-terminal domain of Shh is important for the formation of s-ShhNp. We also conclusively show that palmitoylation is required for s-ShhNp formation. Thus, our results identify both protein-protein and protein-lipid interactions that are required for s-ShhNp formation, and provide the first structural analyses supporting the existence of Shh multimers. 相似文献
86.
87.
Climate change is expected to alter the distribution of tree species because of critical environmental tolerances related to growth, mortality, reproduction, disturbances, and biotic interactions. How this is realized in 21st century remains uncertain, in large part due to limitations on plant migration and the impacts of landscape fragmentation. Understanding these changes is of particular concern for forest management, which requires information at an appropriately fine spatial resolution. Here we provide a framework and application for tree species vulnerability to climate change in the eastern United States that accounts for influential drivers of future distributions. We used species distribution models to project changes in habitat suitability at 800 m for 40 tree species that vary in physiology, range, and environmental niche. We then developed layers of adaptive capacity based on migration potential, forest fragmentation, and propagule pressure. These were combined into metrics of vulnerability, including an overall index and spatially explicit categories designed to inform management. Despite overall favorable changes in suitability, the majority of species and the landscape were considered vulnerable to climate change. Vulnerability was significantly exacerbated by projections of pests and pathogens for some species. Northern and high‐elevation species tended to be the most vulnerable. There were, however, some notable areas of particular resilience, including most of West Virginia. Our approach combines some of the most important considerations for species vulnerability in a straightforward framework, and can be used as a tool for managers to prioritize species, areas, and actions. 相似文献
88.
We report a case of a girl with Attention deficit hyperactivity disorder (ADHD) and Oppositional defiant disorder (ODD) who experienced a 3-hour episode of nocturnal complex bizarre visual hallucinations when treated with 18 mg Osmotic Release Oral System (OROS) methylphenidate (MPH). Nocturnal polysomnography performed two weeks later revealed REM sleep reduction (17%) and fragmentation . Two episodes of confusional arousals were recorded. This finding is typical of parasomnia associated with NREM sleep - disorder of arousal. We hypothesize that this preexisting sleep impairment represents a factor of vulnerability to MPH sleep side effects. In our search of literature, we found no report of nocturnal hallucination alone during treatment with stimulants. 相似文献
89.
Growing crops for bioenergy or biofuels is increasingly viewed as conflicting with food production. However, energy use continues to rise and food production requires fuel inputs, which have increased with intensification. Focussing on the question of food or fuel is thus not helpful. The bigger, more pertinent, challenge is how the increasing demands for food and energy can be met in the future, particularly when water and land availability will be limited. Energy crop production systems differ greatly in environmental impact. The use of high-input food crops for liquid transport fuels (first-generation biofuels) needs to be phased out and replaced by the use of crop residues and low-input perennial crops (second/advanced-generation biofuels) with multiple environmental benefits. More research effort is needed to improve yields of biomass crops grown on lower grade land, and maximum value should be extracted through the exploitation of co-products and integrated biorefinery systems. Policy must continually emphasize the changes needed and tie incentives to improved greenhous gas reduction and environmental performance of biofuels. 相似文献
90.
G-protein-coupled receptors have extraordinary therapeutic potential as targets for a broad spectrum of diseases. Understanding their function at the molecular level is therefore essential. A variety of crystal structures have made the investigation of the inactive receptor state possible. Recently released X-ray structures of opsin and the β2-adrenergic receptor (β2AR) have provided insight into the active receptor state. In addition, we have contributed to the crystal structure of an irreversible agonist-β2 adrenoceptor complex. These extensive studies and biophysical investigations have revealed that agonist binding leads to a low-affinity conformation of the active state that is suggested to facilitate G-protein binding. The high-affinity receptor state, which promotes signal transduction, is only formed in the presence of both agonist and G-protein. Despite numerous crystal structures, it is not yet clear how ligands tune receptor dynamics and G-protein binding. We have now used molecular dynamics simulations to elucidate the distinct impact of agonist and inverse agonist on receptor conformation and G-protein binding by investigating the influence of the ligands on the structure and dynamics of a complex composed of β2AR and the C-terminal end of the Gαs subunit (GαCT). The simulations clearly showed that the agonist isoprenaline and the inverse agonist carazolol influence the ligand-binding site and the interaction between β2AR and GαCT differently. Isoprenaline induced an inward motion of helix 5, whereas carazolol blocked the rearrangement of the extracellular part of the receptor. Moreover, in the presence of isoprenaline, β2AR and GαCT form a stable interaction that is destabilized by carazolol. 相似文献