全文获取类型
收费全文 | 2711篇 |
免费 | 387篇 |
国内免费 | 1篇 |
出版年
2021年 | 47篇 |
2020年 | 32篇 |
2018年 | 40篇 |
2017年 | 29篇 |
2016年 | 73篇 |
2015年 | 86篇 |
2014年 | 101篇 |
2013年 | 113篇 |
2012年 | 157篇 |
2011年 | 141篇 |
2010年 | 76篇 |
2009年 | 63篇 |
2008年 | 105篇 |
2007年 | 107篇 |
2006年 | 90篇 |
2005年 | 86篇 |
2004年 | 82篇 |
2003年 | 80篇 |
2002年 | 67篇 |
2001年 | 69篇 |
2000年 | 68篇 |
1999年 | 64篇 |
1998年 | 26篇 |
1997年 | 36篇 |
1996年 | 29篇 |
1995年 | 28篇 |
1994年 | 28篇 |
1993年 | 27篇 |
1992年 | 49篇 |
1991年 | 50篇 |
1990年 | 45篇 |
1989年 | 51篇 |
1988年 | 62篇 |
1987年 | 44篇 |
1986年 | 54篇 |
1985年 | 51篇 |
1984年 | 40篇 |
1983年 | 42篇 |
1982年 | 33篇 |
1981年 | 27篇 |
1980年 | 26篇 |
1979年 | 45篇 |
1978年 | 28篇 |
1977年 | 34篇 |
1976年 | 25篇 |
1973年 | 37篇 |
1972年 | 28篇 |
1971年 | 33篇 |
1970年 | 27篇 |
1968年 | 26篇 |
排序方式: 共有3099条查询结果,搜索用时 265 毫秒
991.
992.
Goh JM Bensley JG Kenna K Sozo F Bocking AD Brien J Walker D Harding R Black MJ 《American journal of physiology. Heart and circulatory physiology》2011,300(2):H645-H651
Prenatal exposure to high levels of ethanol is associated with cardiac malformations, but the effects of lower levels of exposure on the heart are unclear. Our aim was to investigate the effects of daily exposure to ethanol during late gestation, when cardiomyocytes are undergoing maturation, on the developing myocardium. Pregnant ewes were infused with either ethanol (0.75 g/kg) or saline for 1 h each day from gestational days 95 to 133 (term ~145 days); tissues were collected at 134 days. In sheep, cardiomyocytes mature during late gestation as in humans. Within the left ventricle (LV), cardiomyocyte number was determined using unbiased stereology and cardiomyocyte size and nuclearity determined using confocal microscopy. Collagen deposition was quantified using image analysis. Genes relating to cardiomyocyte proliferation and apoptosis were examined using quantitative real-time PCR. Fetal plasma ethanol concentration reached 0.11 g/dL after EtOH infusions. Ethanol exposure induced significant increases in relative heart weight, relative LV wall volume, and cardiomyocyte cross-sectional area. Ethanol exposure advanced LV maturation in that the proportion of binucleated cardiomyocytes increased by 12%, and the number of mononucleated cardiomyocytes was decreased by a similar amount. Apoptotic gene expression increased in the ethanol-exposed hearts, although there were no significant differences between groups in total cardiomyocyte number or interstitial collagen. Daily exposure to a moderate dose of ethanol in late gestation accelerates the maturation of cardiomyocytes and increases cardiomyocyte and LV tissue volume in the fetal heart. These effects on cardiomyocyte growth may program for long-term cardiac vulnerability. 相似文献
993.
994.
Isabel E Mellon C Boyd MJ Chauret N Deschênes D Desmarais S Falgueyret JP Gauthier JY Khougaz K Lau CK Léger S Levorse DA Li CS Massé F Percival MD Roy B Scheigetz J Thérien M Truong VL Wesolowski G Young RN Zamboni R Black WC 《Bioorganic & medicinal chemistry letters》2011,21(3):920-923
The trifluoroethylamine group found in cathepsin K inhibitors like odanacatib can be replaced by a difluoroethylamine group. This change increased the basicity of the nitrogen which positively impacted the log D. This translated into an improved oral bioavailability in pre-clinical species. Difluoroethylamine compounds exhibit a similar potency against cathepsin K and selectivity profile against other cathepsins when compared to trifluoroethylamine analogs. 相似文献
995.
Gauthier JY Belley M Deschênes D Fournier JF Gagné S Gareau Y Hamel M Hénault M Hyjazie H Kargman S Lavallée G Levesque JF Li L Mamane Y Mancini J Morin N Mulrooney E Robichaud J Thérien M Tranmer G Wang Z Wu J Black WC 《Bioorganic & medicinal chemistry letters》2011,21(10):2836-2839
A weak, UDP-competitive antagonist of the pyrimidinergic receptor P2RY14 with a naphthoic acid core was identified through high-throughput screening. Optimization provided compounds with improved potency but poor pharmacokinetics. Acylglucuronidation was determined to be the major route of metabolism. Increasing the electron-withdrawing nature of the substituents markedly reduced glucuronidation and improved the pharmacokinetic profile. Additional optimization led to the identification of compound 38 which is an 8 nM UDP-competitive antagonist of P2Y14 with a good pharmacokinetic profile. 相似文献
996.
Zhou G Ting PC Aslanian R Cao J Kim DW Kuang R Lee JF Schwerdt J Wu H Herr RJ Zych AJ Yang J Lam S Wainhaus S Black TA McNicholas PM Xu Y Walker SS 《Bioorganic & medicinal chemistry letters》2011,21(10):2890-2893
A novel series of pyridazinone analogs has been developed as potent β-1,3-glucan synthase inhibitors through structure-activity relationship study of the lead 5-[4-(benzylsulfonyl)piperazin-1-yl]-4-morpholino-2-phenyl-pyridazin-3(2H)-one (1). The effect of changes to the core structure is described in detail. Optimization of the sulfonamide moiety led to the identification of important compounds with much improved systematic exposure while retaining good antifungal activity against the fungal strains Candida glabrata and Candida albicans. 相似文献
997.
Proto WR Castanys-Munoz E Black A Tetley L Moss CX Juliano L Coombs GH Mottram JC 《The Journal of biological chemistry》2011,286(46):39914-39925
Metacaspases are caspase family cysteine peptidases found in plants, fungi, and protozoa but not mammals. Trypanosoma brucei is unusual in having five metacaspases (MCA1-MCA5), of which MCA1 and MCA4 have active site substitutions, making them possible non-enzymatic homologues. Here we demonstrate that recombinant MCA4 lacks detectable peptidase activity despite maintaining a functional peptidase structure. MCA4 is expressed primarily in the bloodstream form of the parasite and associates with the flagellar membrane via dual myristoylation/palmitoylation. Loss of function phenotyping revealed critical roles for MCA4; rapid depletion by RNAi caused lethal disruption to the parasite's cell cycle, yet the generation of MCA4 null mutant parasites (Δmca4) was possible. Δmca4 had normal growth in axenic culture but markedly reduced virulence in mice. Further analysis revealed that MCA4 is released from the parasite and is specifically processed by MCA3, the only metacaspase that is both palmitoylated and enzymatically active. Accordingly, we have identified that the multiple metacaspases in T. brucei form a membrane-associated proteolytic cascade to generate a pseudopeptidase virulence factor. 相似文献
998.
Henry LK Iwamoto H Field JR Kaufmann K Dawson ES Jacobs MT Adams C Felts B Zdravkovic I Armstrong V Combs S Solis E Rudnick G Noskov SY DeFelice LJ Meiler J Blakely RD 《The Journal of biological chemistry》2011,286(35):30823-30836
Na(+)- and Cl(-)-dependent uptake of neurotransmitters via transporters of the SLC6 family, including the human serotonin transporter (SLC6A4), is critical for efficient synaptic transmission. Although residues in the human serotonin transporter involved in direct Cl(-) coordination of human serotonin transport have been identified, the role of Cl(-) in the transport mechanism remains unclear. Through a combination of mutagenesis, chemical modification, substrate and charge flux measurements, and molecular modeling studies, we reveal an unexpected role for the highly conserved transmembrane segment 1 residue Asn-101 in coupling Cl(-) binding to concentrative neurotransmitter uptake. 相似文献
999.
Elaina M. Melton Ronald L. Cerny Paul A. Watkins Concetta C. DiRusso Paul N. Black 《The Journal of biological chemistry》2011,286(35):30670-30679
The trafficking of fatty acids across the membrane and into downstream metabolic pathways requires their activation to CoA thioesters. Members of the fatty acid transport protein/very long chain acyl-CoA synthetase (FATP/Acsvl) family are emerging as key players in the trafficking of exogenous fatty acids into the cell and in intracellular fatty acid homeostasis. We have expressed two naturally occurring splice variants of human FATP2 (Acsvl1) in yeast and 293T-REx cells and addressed their roles in fatty acid transport, activation, and intracellular trafficking. Although both forms (FATP2a (Mr 70,000) and FATP2b (Mr 65,000 and lacking exon3, which encodes part of the ATP binding site)) were functional in fatty acid import, only FATP2a had acyl-CoA synthetase activity, with an apparent preference toward very long chain fatty acids. To further address the roles of FATP2a or FATP2b in fatty acid uptake and activation, LC-MS/MS was used to separate and quantify different acyl-CoA species (C14–C24) and to monitor the trafficking of different classes of exogenous fatty acids into intracellular acyl-CoA pools in 293T-REx cells expressing either isoform. The use of stable isotopically labeled fatty acids demonstrated FATP2a is involved in the uptake and activation of exogenous fatty acids, with a preference toward n-3 fatty acids (C18:3 and C22:6). Using the same cells expressing FATP2a or FATP2b, electrospray ionization/MS was used to follow the trafficking of stable isotopically labeled n-3 fatty acids into phosphatidylcholine and phosphatidylinositol. The expression of FATP2a resulted in the trafficking of C18:3-CoA and C22:6-CoA into both phosphatidylcholine and phosphatidylinositol but with a distinct preference for phosphatidylinositol. Collectively these data demonstrate FATP2a functions in fatty acid transport and activation and provides specificity toward n-3 fatty acids in which the corresponding n-3 acyl-CoAs are preferentially trafficked into acyl-CoA pools destined for phosphatidylinositol incorporation. 相似文献
1000.