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排序方式: 共有6165条查询结果,搜索用时 15 毫秒
991.
Ruebsam F Webber SE Tran MT Tran CV Murphy DE Zhao J Dragovich PS Kim SH Li LS Zhou Y Han Q Kissinger CR Showalter RE Lardy M Shah AM Tsan M Patel R Lebrun LA Kamran R Sergeeva MV Bartkowski DM Nolan TG Norris DA Kirkovsky L 《Bioorganic & medicinal chemistry letters》2008,18(12):3616-3621
Pyrrolo[1,2-b]pyridazin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Structure-based design led to the discovery of compound 3 k, which displayed potent inhibitory activities in biochemical and replicon assays (IC(50) (1b)<10nM; EC(50) (1b)=12 nM) as well as good stability towards human liver microsomes (HLM t(1/2)>60 min). 相似文献
992.
Ellis DA Blazel JK Webber SE Tran CV Dragovich PS Sun Z Ruebsam F McGuire HM Xiang AX Zhao J Li LS Zhou Y Han Q Kissinger CR Showalter RE Lardy M Shah AM Tsan M Patel R LeBrun LA Kamran R Bartkowski DM Nolan TG Norris DA Sergeeva MV Kirkovsky L 《Bioorganic & medicinal chemistry letters》2008,18(16):4628-4632
4-(1,1-Dioxo-1,4-dihydro-1lambda(6)-benzo[1,4]thiazin-3-yl)-5-hydroxy-2H-pyridazin-3-one analogs were discovered as a novel class of inhibitors of HCV NS5B polymerase. Structure-based design led to the identification of compound 3a that displayed potent inhibitory activities in biochemical and replicon assays (1b IC(50)<10 nM; 1b EC(50)=1.1 nM) as well as good stability toward human liver microsomes (HLM t(1/2)>60 min). 相似文献
993.
Biphenyl amide p38 kinase inhibitors 3: Improvement of cellular and in vivo activity 总被引:1,自引:0,他引:1
Angell R Aston NM Bamborough P Buckton JB Cockerill S deBoeck SJ Edwards CD Holmes DS Jones KL Laine DI Patel S Smee PA Smith KJ Somers DO Walker AL 《Bioorganic & medicinal chemistry letters》2008,18(15):4428-4432
The biphenyl amides (BPAs) are a novel series of p38α MAP kinase inhibitor. The optimisation of the series to give compounds that are potent in an in vivo disease model is discussed. SAR is presented and rationalised with reference to the crystallographic binding mode. 相似文献
994.
Patel SD Habeski WM Min H Zhang J Roof R Snyder B Bora G Campbell B Li C Hidayetoglu D Johnson DS Chaudhry A Charlton ME Kablaoui NM 《Bioorganic & medicinal chemistry letters》2008,18(20):5689-5693
The discovery of the CNS-penetrant and selective alpha(2C) adrenergic receptor antagonist N-{2-[4-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-[1,4]diazepan-1-yl]-ethyl}-2-phenoxy-nicotinamide, 13 is described. Structure-activity studies demonstrate the structural requirements for binding affinity, functional activity, and selectivity over other alpha(2)-AR subtypes. 相似文献
995.
Ellsworth BA Meng W Patel M Girotra RN Wu G Sher PM Hagan DL Obermeier MT Humphreys WG Robertson JG Wang A Han S Waldron TL Morgan NN Whaley JM Washburn WN 《Bioorganic & medicinal chemistry letters》2008,18(17):4770-4773
Inhibition of sodium-dependent glucose transporter 2 (SGLT2), the transporter that is responsible for renal re-uptake of glucose, leads to glucosuria in animals. SGLT-mediated glucosuria provides a mechanism to shed excess plasma glucose to ameliorate diabetes-related hyperglycemia and associated complications. The current study demonstrates that the proper relationship of a 4′-substituted benzyl group to a β-1C-phenylglucoside is important for potent and selective SGLT2 inhibition. The lead C-arylglucoside (7a) demonstrates superior metabolic stability to its O-arylglucoside counterpart (4) and it promotes glucosuria when administered in vivo. 相似文献
996.
Srivastava BK Soni R Joharapurkar A Sairam KV Patel JZ Goswami A Shedage SA Kar SS Salunke RP Gugale SB Dhawas A Kadam P Mishra B Sadhwani N Unadkat VB Mitra P Jain MR Patel PR 《Bioorganic & medicinal chemistry letters》2008,18(3):963-968
Design, synthesis and conformational analysis of few imidazole and oxazole as bioisosters of 4S-(-)-3-(4-chlorophenyl)-N-methyl-N'-[(4-chlorophenyl)-sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole-1-caboxamidine (SLV-319) 2 is reported. Computer assisted conformational analysis gave a direct clue for the loss of CB1 antagonistic activity of the ligands without a fine docking simulation for the homology model. 相似文献
997.
Objective
To review: 1) Pathophysiology of postoperative atrial fibrillation (POAF); 2) Risk factors for POAF; 3) Prophylaxis of POAF; 4) Treatment of POAF; and 5) Future directions.Methods
We searched the Medline database for articles published between January, 1966 to September, 2008. We used the following keywords: Atrial fibrillation, Postoperative atrial fibrillation, Coronary Artery Bypass, and antiarrhythmic agents. Additionally, we searched references from all relevant articles.Conclusions
POAF occurs in 25-60% of patients depending on the type of cardiac surgery performed. POAF generally occurs on postoperative day 2 or 3. POAF is associated with an increased risk of morbidity and mortality, and longer hospital stay. Prophylactic treatments reduce the likelihood of POAF. In patients who experience POAF, rhythm strategies should be used in those who are symptomatic and hemodynamically unstable. All other patients should be managed with rate strategies. 相似文献998.
Sunter JD Patel SP Skilton RA Githaka N Knowles DP Scoles GA Nene V de Villiers E Bishop RP 《Gene》2008,415(1-2):13-22
Reassociation kinetics and flow cytometry data indicate that ixodid tick genomes are large, relative to most arthropods, containing>or=10(9) base pairs. The molecular basis for this is unknown. We have identified a novel small interspersed element with features of a tRNA-derived SINE, designated Ruka, in genomic sequences of Rhipicephalus appendiculatus and Boophilus (Rhipicephalus) microplus ticks. The SINE was also identified in expressed sequence tag (EST) databases derived from several tissues in four species of ixodid ticks, namely R. appendiculatus, B. (R.) microplus, Amblyomma variegatum and also the more distantly related Ixodes scapularis. Secondary structure predictions indicated that Ruka could adopt a tRNA structure that was, atypically, most similar to a serine tRNA. By extrapolation the frequency of occurrence in the randomly selected BAC clone sequences is consistent with approximately 65,000 copies of Ruka in the R. appendiculatus genome. Real time PCR analyses on genomic DNA indicate copy numbers for specific Ruka subsets between 5800 and 38,000. Several putative conserved Ruka insertion sites were identified in EST sequences of three ixodid tick species based on the flanking sequences associated with the SINEs, indicating that some Ruka transpositions probably occurred prior to speciation within the metastriate division of the Ixodidae. The data strongly suggest that Class I transposable elements form a significant component of tick genomes and may partially account for the large genome sizes observed. 相似文献
999.
Among age-related neurodegenerative diseases, Parkinson's disease (PD) represents the best example for which oxidative stress has been strongly implicated. The etiology of PD remains unknown, yet recent epidemiological studies have linked exposure to environmental agents, including pesticides, with an increased risk of developing the disease. As a result, the environmental hypothesis of PD has developed, which speculates that chemical agents in the environment are capable of producing selective dopaminergic cell death, thus contributing to disease development. The use of environmental agents such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, rotenone, paraquat, dieldrin, and maneb in toxicant-based models of PD has become increasingly popular and provided valuable insight into the neurodegenerative process. Understanding the unique and shared mechanisms by which these environmental agents act as selective dopaminergic toxicants is critical in identifying pathways involved in PD pathogenesis. In this review, we discuss the neurotoxic properties of these compounds with specific focus on the induction of oxidative stress. We highlight landmark studies along with recent advances that support the role of reactive oxygen and reactive nitrogen species from a variety of cellular sources as potent contributors to the neurotoxicity of these environmental agents. Finally, human risk and the implications of these studies in our understanding of PD-related neurodegeneration are discussed. 相似文献
1000.
The roles of thiol-derived radicals in the use of 2',7'-dichlorodihydrofluorescein as a probe for oxidative stress 总被引:1,自引:1,他引:0
2',7'-Dichlorodihydrofluorescein (DCFH2) is one of the most widely used probes for detecting intracellular oxidative stress, but requires a catalyst to be oxidized by hydrogen peroxide or superoxide and reacts nonspecifically with oxidizing radicals. Thiyl radicals are produced when many radicals are "repaired" by thiols, but are oxidizing agents and thus potentially capable of oxidizing DCFH2. The aim of this study was to investigate the reactivity of thiol-derived radicals toward DCFH2 and its oxidized, fluorescent form 2',7'-dichlorofluorescein (DCF). Thiyl radicals derived from oxidation of glutathione (GSH) or cysteine (CysSH) oxidized DCFH2 with rate constants at pH 7.4 of approximately 4 or approximately 2x10(7) M(-1) s(-1), respectively. Both the rates of oxidation and the yields of DCF were pH-dependent. Glutathione-derived radicals interacted with DCF, resulting in the formation of DCFH* absorbing at 390 nm and loss of fluorescence; in contrast, cysteine-derived radicals did not cause any depletion of DCF fluorescence. We postulate that the observed apparent difference in reactivity between GS* and CysS* toward DCF is related to the formation of carbon-centered, reducing radicals from base-catalyzed isomerization of GS*. DCF formation from interaction of DCFH2 with GS* was inhibited by oxygen in a concentration-dependent manner over the physiological range. These data indicate that in applying DCFH2 to measure oxidizing radicals in biological systems, we have to consider not only the initial competition between thiols and DCFH2 for the oxidizing radicals, but also subsequent reactions of thiol-derived radicals, together with variables--including pH and oxygen concentration--which control thiyl radical chemistry. 相似文献