全文获取类型
收费全文 | 19671篇 |
免费 | 2006篇 |
国内免费 | 11篇 |
出版年
2023年 | 79篇 |
2022年 | 158篇 |
2021年 | 338篇 |
2020年 | 223篇 |
2019年 | 247篇 |
2018年 | 304篇 |
2017年 | 329篇 |
2016年 | 448篇 |
2015年 | 796篇 |
2014年 | 877篇 |
2013年 | 974篇 |
2012年 | 1372篇 |
2011年 | 1317篇 |
2010年 | 897篇 |
2009年 | 817篇 |
2008年 | 1112篇 |
2007年 | 1216篇 |
2006年 | 972篇 |
2005年 | 1020篇 |
2004年 | 1029篇 |
2003年 | 971篇 |
2002年 | 923篇 |
2001年 | 324篇 |
2000年 | 322篇 |
1999年 | 287篇 |
1998年 | 266篇 |
1997年 | 173篇 |
1996年 | 134篇 |
1995年 | 130篇 |
1994年 | 150篇 |
1993年 | 127篇 |
1992年 | 201篇 |
1991年 | 198篇 |
1990年 | 159篇 |
1989年 | 164篇 |
1988年 | 157篇 |
1987年 | 158篇 |
1986年 | 144篇 |
1985年 | 165篇 |
1984年 | 160篇 |
1983年 | 121篇 |
1982年 | 93篇 |
1981年 | 110篇 |
1980年 | 92篇 |
1979年 | 95篇 |
1978年 | 99篇 |
1977年 | 70篇 |
1976年 | 84篇 |
1974年 | 91篇 |
1971年 | 74篇 |
排序方式: 共有10000条查询结果,搜索用时 0 毫秒
961.
An in vitro method of determining the activity of antibiotics in combination which is simple and convenient to perform and which could be used routinely in clinical microbiology laboratories is desirable. We investigated the activity, against Pseudomonas aeruginosa and Burkholderia cepacia complex clinical isolates, of ceftazidime and tobramycin in combination using a broth macrodilution sensitivity method based on breakpoint minimum inhibitory concentrations and compared the results obtained using this method with those obtained using the microtitre checkerboard method. There was good agreement in interpretation of results between the two methods for both P. aeruginosa (90%) and B. cepacia complex isolates (70%) with tobramycin and for P. aeruginosa isolates (70%) with ceftazidime. As the breakpoint combination sensitivity testing method employs only four tubes and does not require initial determination of individual antibiotic minimum inhibitory concentrations, it is simpler and more convenient for determining the activity of antibiotics in combination than the microtitre checkerboard method. The use of this method in routine microbiology laboratories to determine the activity of antibiotic combinations against clinical isolates should optimise treatment of infection by ensuring that appropriate antibiotic combinations are prescribed. 相似文献
962.
963.
Biotelemetry: a mechanistic approach to ecology 总被引:1,自引:0,他引:1
Cooke SJ Hinch SG Wikelski M Andrews RD Kuchel LJ Wolcott TG Butler PJ 《Trends in ecology & evolution》2004,19(6):334-343
Remote measurement of the physiology, behaviour and energetic status of free-living animals is made possible by a variety of techniques that we refer to collectively as 'biotelemetry'. This set of tools ranges from transmitters that send their signals to receivers up to a few kilometers away to those that send data to orbiting satellites and, more frequently, to devices that log data. They enable researchers to document, for long uninterrupted periods, how undisturbed organisms interact with each other and their environment in real time. In spite of advances enabling the monitoring of many physiological and behavioural variables across a range of taxa of various sizes, these devices have yet to be embraced widely by the ecological community. Our review suggests that this technology has immense potential for research in basic and applied animal ecology. Efforts to incorporate biotelemetry into broader ecological research programs should yield novel information that has been challenging to collect historically from free-ranging animals in their natural environments. Examples of research that would benefit from biotelemetry include the assessment of animal responses to different anthropogenic perturbations and the development of life-time energy budgets. 相似文献
964.
A novel CDK5-dependent pathway for regulating GSK3 activity and kinesin-driven motility in neurons 总被引:9,自引:0,他引:9
Morfini G Szebenyi G Brown H Pant HC Pigino G DeBoer S Beffert U Brady ST 《The EMBO journal》2004,23(11):2235-2245
Neuronal transmission of information requires polarized distribution of membrane proteins within axonal compartments. Membrane proteins are synthesized and packaged in membrane-bounded organelles (MBOs) in neuronal cell bodies and later transported to axons by microtubule-dependent motor proteins. Molecular mechanisms underlying targeted delivery of MBOs to discrete axonal subdomains (i.e. nodes of Ranvier or presynaptic terminals) are poorly understood, but regulatory pathways for microtubule motors may be an essential step. In this work, pharmacological, biochemical and in vivo experiments define a novel regulatory pathway for kinesin-driven motility in axons. This pathway involves enzymatic activities of cyclin-dependent kinase 5 (CDK5), protein phosphatase 1 (PP1) and glycogen synthase kinase-3 (GSK3). Inhibition of CDK5 activity in axons leads to activation of GSK3 by PP1, phosphorylation of kinesin light chains by GSK3 and detachment of kinesin from transported cargoes. We propose that regulating the activity and localization of components in this pathway allows nerve cells to target organelle delivery to specific subcellular compartments. Implications of these findings for pathogenesis of neurodegenerative diseases such as Alzheimer's disease are discussed. 相似文献
965.
Phosphorylation of BCL-2 within an unstructured loop inhibits its antiapoptotic effect. We found that phosphorylated BCL-2 predominantly localized to the endoplasmic reticulum (ER) and tested whether phosphorylation would control its activity at this organelle, where Ca(2+) dynamics serve as a critical control point for apoptosis. Phosphorylation greatly inhibits the ability of BCL-2 to lower [Ca(2+)](er) and protect against Ca(2+)-dependent death stimuli. Cells expressing nonphosphorylatable BCL-2(AAA) exhibited increased leak of Ca(2+) from the ER and further diminished steady-state [Ca(2+)](er) stores when compared to cells expressing BCL-2(wt). Consequently, when BCL-2 is phosphorylated, Ca(2+) discharge from the ER is increased, with a secondary increase in mitochondrial Ca(2+) uptake. We also demonstrate that phosphorylation of BCL-2 inhibits its binding to proapoptotic family members. This inhibitory mechanism manifested at the ER, where phosphorylated BCL-2 was unable to bind proapoptotic members. [Ca(2+)](er) proved coordinate with the capacity of BCL-2 to bind proapoptotic BH3-only members, further integrating the apoptotic pathway and Ca(2+) modulation. Unexpectedly, the regulation of ER Ca(2+) dynamics is a principal avenue whereby BCL-2 phosphorylation alters susceptibility to apoptosis. 相似文献
966.
AL-12182, a novel 11-oxa prostaglandin analog with topical ocular hypotensive activity in the monkey
Selliah RD Hellberg MR Sharif NA McLaughlin MA Williams GW Scott DA Earnest D Haggard KS Dean WD Delgado P Gaines MS Conrow RE Klimko PG 《Bioorganic & medicinal chemistry letters》2004,14(17):4525-4528
A series of 11-oxa prostaglandin analogs was evaluated for FP receptor binding and activation. Several compounds having aryloxy-terminated lower chains were found to be potent agonists. Topical ocular dosing of AL-12182, the isopropyl ester prodrug of the potent agonist 13, lowered intraocular pressure in the monkey by 40% accompanied by minimal conjunctival hyperemia in the rabbit. AL-12182 was synthesized on multigram scale starting with D-sorbitol. 相似文献
967.
Dinsmore CJ Zartman CB Bergman JM Abrams MT Buser CA Culberson JC Davide JP Ellis-Hutchings M Fernandes C Graham SL Hartman GD Huber HE Lobell RB Mosser SD Robinson RG Williams TM 《Bioorganic & medicinal chemistry letters》2004,14(3):639-643
A series of macrocyclic piperazinone compounds with dual farnesyltransferase/geranylgeranyltransferase-I inhibitory activity was prepared. These compounds were found to be potent inhibitors of protein prenylation in cell culture. A hypothesis for the binding mode of compound 3o in FPTase is proposed. 相似文献
968.
Jablonowski JA Chai W Li X Rudolph DA Murray WV Youngman MA Dax SL Nepomuceno D Bonaventure P Lovenberg TW Carruthers NI 《Bioorganic & medicinal chemistry letters》2004,14(5):1239-1242
Through SAR studies of a piperidinylindoline cinnamide HTS lead, the first potent, non-peptide, low molecular weight selective Neuropeptide Y Y2 (NPY Y2) antagonists have been synthesized. The SAR studies around the piperidinyl, the indolinyl, and the cinnamyl moieties are discussed. 相似文献
969.
Sutton JC Bolton SA Davis ME Hartl KS Jacobson B Mathur A Ogletree ML Slusarchyk WA Zahler R Seiler SM Bisacchi GS 《Bioorganic & medicinal chemistry letters》2004,14(9):2233-2239
A series of nonguanidine N1-activated C4-carboxy azetidinone tryptase inhibitors was prepared by solid-phase methodology to quickly assess the SAR associated with distal functionality on the N1-activating group. From these studies, potent inhibitors with improved specificity were discovered. 相似文献
970.
Parmee ER He J Mastracchio A Edmondson SD Colwell L Eiermann G Feeney WP Habulihaz B He H Kilburn R Leiting B Lyons K Marsilio F Patel RA Petrov A Di Salvo J Wu JK Thornberry NA Weber AE 《Bioorganic & medicinal chemistry letters》2004,14(1):43-46
Substituted 4-amino cyclohexylglycine analogues were evaluated for DP-IV inhibitory properties. Bis-sulfonamide 15e was an extremely potent 2.6 nM inhibitor of the enzyme with excellent selectivity over all counterscreens. 2,4-difluorobenzenesulfonamide 15b and 1-naphthyl amide 16b, however, combined an acceptable in vitro profile with good pharmacokinetic properties in the rat, and 15b was orally efficacious at 3 mpk in an OGTT in lean mice. 相似文献