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951.
Brett M. Macey Matthew J. Jenny Heidi R. Williams Lindy K. Thibodeaux Marion Beal Jonas S. Almeida Charles Cunningham Annalaura Mancia Gregory W. Warr Erin J. Burge A. Fred Holland Paul S. Gross Sonomi Hikima Karen G. Burnett Louis Burnett Robert W. Chapman 《Comparative biochemistry and physiology. Part A, Molecular & integrative physiology》2010,155(3):341-349
Heavy metals, such as copper, zinc and cadmium, represent some of the most common and serious pollutants in coastal estuaries. In the present study, we used a combination of linear and artificial neural network (ANN) modelling to detect and explore interactions among low-dose mixtures of these heavy metals and their impacts on fundamental physiological processes in tissues of the Eastern oyster, Crassostrea virginica. Animals were exposed to Cd (0.001–0.400 μM), Zn (0.001–3.059 μM) or Cu (0.002–0.787 μM), either alone or in combination for 1 to 27 days. We measured indicators of acid–base balance (hemolymph pH and total CO2), gas exchange (Po2), immunocompetence (total hemocyte counts, numbers of invasive bacteria), antioxidant status (glutathione, GSH), oxidative damage (lipid peroxidation; LPx), and metal accumulation in the gill and the hepatopancreas. Linear analysis showed that oxidative membrane damage from tissue accumulation of environmental metals was correlated with impaired acid–base balance in oysters. ANN analysis revealed interactions of metals with hemolymph acid–base chemistry in predicting oxidative damage that were not evident from linear analyses. These results highlight the usefulness of machine learning approaches, such as ANNs, for improving our ability to recognize and understand the effects of sub-acute exposure to contaminant mixtures. 相似文献
952.
Phosphatidylinositol 3-kinase (PI3K) mediates receptor tyrosine kinase and G protein coupled receptor (GPCR) signaling by phosphorylating phosphoinositides to elicit various biological responses. Gαq has previously been shown to inhibit class IA PI3K by interacting with the p110α subunit. However, it is not known if PI3Ks can associate with other Gαq family members such as Gα16. Here, we demonstrated that class IA PI3Ks, p85/p110α and p85/p110β, could form stable complexes with wild type Gα16 and its constitutively active mutant (Gα16QL) in HEK293 cells. In contrast, no interaction between Gα16 and class IB PI3K was observed. The Gα16/p110α signaling complex could be detected in hematopoietic cells that endogenously express Gα16. Overexpression of class I PI3Ks did not inhibit Gα16QL-induced IP3 production and, unlike p63RhoGEF, class IA PI3Ks did not attenuate the binding of PLCβ2 to Gα16QL. On the contrary, the function of class IA PI3Ks was suppressed by Gα16QL as revealed by diminished production of PIP3 as well as inhibition of EGF-induced Akt phosphorylation. Taken together, these results suggest that Gα16 can bind to class IA PI3Ks and inhibit the PI3K signaling pathway. 相似文献
953.
Marko Milisavljevic Taryn Hearty Tony Y. T. Wong Elodie Portales-Casamar Elizabeth M. Simpson Wyeth W. Wasserman 《Mammalian genome》2010,21(5-6):224-230
Laboratory Animal Management Assistant (LAMA) is an internet-based system for tracking large laboratory mouse colonies. It has a user-friendly interface with powerful search capabilities that ease day-to-day tasks such as tracking breeding cages and weaning litters. LAMA was originally developed to manage hundreds of new mouse strains generated by a large functional genomics program, the Pleiades Promoter Project (http://www.pleiades.org). The software system has proven to be highly flexible, suitable for diverse management approaches to mouse colonies. It allows custom tagging and grouping of animals, simplifying project-specific handling and access to data. Finally, LAMA was developed in close collaboration with mouse technicians to ease the transition from paper- or Excel-based management systems to computerized tracking, allowing data export in a popular spreadsheet format and automatic printing of cage cards. LAMA is an open-access software tool, freely available to the research community at http://launchpad.net/mousedb. 相似文献
954.
Hung-Hsin Chao Cheng-Hsien Chen Ju-Chi Liu Jia-Wei Lin Kar-Lok Wong Tzu-Hurng Cheng 《The Journal of nutritional biochemistry》2010,21(7):580-588
The heart is unable to synthesize l-carnitine and is strictly dependent on the l-carnitine provided by the blood stream; however, additional studies are needed to better understand the mechanism of l-carnitine supplementation to the heart. The aim of this study was to evaluate the effects of l-carnitine on angiotensin II (Ang II)-induced cardiac fibroblast proliferation and to explore its intracellular mechanism(s). Cultured rat cardiac fibroblasts were pretreated with l-carnitine (1-30 mM) then stimulated with Ang II (100 nM). Ang II increased fibroblast proliferation and endothelin-1 expression, which were partially inhibited by l-carnitine. l-Carnitine also attenuated Ang II-induced NADPH oxidase activity, reactive oxygen species formation, extracellular signal-regulated kinase phosphorylation, activator protein-1-mediated reporter activity and sphingosine-1-phosphate generation. In addition, l-carnitine increased prostacyclin (PGI2) generation in cardiac fibroblasts. siRNA transfection of PGI2 synthase significantly reduced l-carnitine-induced PGI2 and its anti-proliferation effects on cardiac fibroblasts. Furthermore, blockading potential PGI2 receptors, including immunoprecipitation (IP) receptors and peroxisome proliferator-activated receptors alpha (PPARα) and delta , revealed that siRNA-mediated blockage of PPARα considerably reduced the anti-proliferation effect of l-carnitine. In summary, these results suggest that l-carnitine attenuates Ang II-induced effects (including NADPH oxidase activation, sphingosine-1-phosphate generation and cell proliferation) in part through PGI2 and PPARα-signaling pathways. 相似文献
955.
Girijavallabhan VM Chen L Dai C Feltz RJ Firmansjah L Li D Kim SH Kozlowski JA Lavey BJ Kosinski A Piwinski JJ Popovici-Muller J Rizvi R Rosner KE Shankar BB Shih NY Siddiqui MA Tong L Wong MK Yang DY Yang L Yu W Zhou G Guo Z Orth P Madison V Bian H Lundell D Niu X Shah H Sun J Umland S 《Bioorganic & medicinal chemistry letters》2010,20(24):7283-7287
Our research on hydantoin based TNF-α converting enzyme (TACE) inhibitors has led to an acetylene containing series that demonstrates sub-nanomolar potency (K(i)) as well as excellent activity in human whole blood. These studies led to the discovery of highly potent TACE inhibitors with good DMPK profiles. 相似文献
956.
Xia Y Chackalamannil S Greenlee WJ Wang Y Hu Z Root Y Wong J Kong J Ahn HS Boykow G Hsieh Y Kurowski S Chintala M 《Bioorganic & medicinal chemistry letters》2010,20(22):6676-6679
An analog of the thrombin receptor antagonist vorapaxar (SCH 530348) with increased aqueous solubility, compound 9c (SCH 602539), was discovered through incorporation of polar substituents on the pyridine ring of the himbacine-derived lead series. This analog retained the excellent potency, pharmacokinetic and safety properties of vorapaxar while increasing the aqueous solubility by 20-fold. Also presented are in vivo evaluations of this compound in a cynomolgus monkey platelet aggregation assay and in a Folts model of thrombosis in anesthetized monkeys. 相似文献
957.
Nina Klee Pui Ee Wong Beatriz Baragaña Farah El Mazouni Margaret A. Phillips Michael P. Barrett Ian H. Gilbert 《Bioorganic & medicinal chemistry letters》2010,20(15):4364-4366
Trypanosoma brucei, the parasite that causes human African trypanosomiasis, is auxotrophic for purines and has specialist nucleoside transporters to import these metabolites. In particular, the P2 aminopurine transporter can also selectively accumulate melamine derivatives. In this Letter, we report the coupling of the melamine moiety to 2-hydroxy APA, a potent ornithine decarboxylase inhibitor, with the aim of selectively delivering this compound to the parasite. The best compound described here shows an increased in vitro trypanocidal activity compared with the parent. 相似文献
958.
959.
Shuk-Yan Cheng Marcus Chun-Wah Yuen Pik-Ling Lam Roberto Gambari Raymond Siu-Ming Wong Gregory Yin-Ming Cheng Paul Bo-San Lai See-Wai Tong Kit-Wah Chan Fung-Yi Lau Stanton Hon-Lung Kok Kim-Hung Lam Chung-Hin Chui 《Bioorganic & medicinal chemistry letters》2010,20(14):4147-4151
The use of chitosan as the wall of microcapsule designed for delivery of encapsulated celecoxib is reported. Microcapsules were characterised with respect to size and encapsulation efficiency of celecoxib. In vivo animals demonstrated that both free celecoxib administration and chitosan/celecoxib microcapsules administration lead to a significant inhibition of cyclooxygenase-2 protein expression in the hepatocytes when compared with vehicle control mice. Interestingly, microcapsule containing celecoxib showed a better inhibition of cyclooxygenase-2 protein expression when compared with a simple oral administration of free celecoxib. Gas-chromatography–mass-spectrometry analysis showed that in mice treated with free celecoxib or chitosan/celecoxib microcapsules, their plasma concentration of celecoxib was similar. Microcapsules-based biomaterials as oral drug delivery vehicles may help to improve the absorption efficiency of therapeutic drugs. 相似文献
960.
Henderson IR Deleris A Wong W Zhong X Chin HG Horwitz GA Kelly KA Pradhan S Jacobsen SE 《PLoS genetics》2010,6(10):e1001182