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961.
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
962.
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
963.
Wiscount CM Williams PD Tran LO Embrey MW Fisher TE Sherman V Homnick CF Donnette Staas D Lyle TA Wai JS Vacca JP Wang Z Felock PJ Stillmock KA Witmer MV Miller MD Hazuda DJ Day AM Gabryelski LJ Ecto LT Schleif WA DiStefano DJ Kochansky CJ Anari MR 《Bioorganic & medicinal chemistry letters》2008,18(16):4581-4583
A series of 10-hydroxy-7,8-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-diones was synthesized and tested for their inhibition of HIV-1 replication in cell culture. Structure-activity studies indicated that high antiviral potency against wild-type virus as well as viruses containing integrase mutations that confer resistance to three different structural classes of integrase inhibitors could be achieved by incorporation of small aliphatic groups at certain positions on the core template. An optimal compound from this study, 16, inhibits integrase strand-transfer activity with an IC(50) value of 10 nM, inhibits HIV-1 replication in cell culture with an IC(95) value of 35 nM in the presence of 50% normal human serum, and displays modest pharmacokinetic properties in rats (i.v. t(1/2)=5.3 h, F=17%). 相似文献
964.
Hung CY Hsu MH Huang LJ Hwang CS Lee O Wu CY Chen CH Kuo SC 《Bioorganic & medicinal chemistry》2008,16(8):4222-4232
As part of our continuing search for potential differentiation agents, 1-benzyl-3-(4-pyridinylmethylidenyl)indolin-2-one (14) was selected as lead compound, and its new pyridinyl and quinolinyl analogs were synthesized and evaluated for differentiation-inducing activity toward HL-60 cells. Most of the tested compounds enhanced the ATRA-induced differentiation; among them, 1-(1-phenylethyl)-3-(3-quinolinylmethylidenyl)indolin-2-one (25) was the most promising one. The two isomers, 25Z and 25E; consisting 25 were found to have similar differentiation activity. The combination of 25 with all trans retinoic acid (ATRA) was found to induce complete differentiation of HL-60 cells and arrest the cells in the G(0)/G(1) phase of the cell cycle. Beside its excellent differentiation activity, 25 also exhibited relatively low cytotoxicity toward normal cells. Therefore, compound 25 is recommended as a candidate for further development of novel enhancer of ATRA-induced differentiation in HL-60 cells. 相似文献
965.
Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to inhibit cancer cell growth, induce apoptosis and decrease tumor metastasis. We have previously reported that a NSAID NS398 repressed the expression of matrix metalloproteinase-2 (MMP-2) via inhibition of the extracellular signal-regulated kinase (ERK) signaling pathway. In this study, we investigate the underlying mechanism of this inhibition. In vitro kinase assay indicated that NS398 could not directly inhibit c-Raf, MEK1 and ERK enzymatic activity. We found that NS398 increased the inhibitory phosphorylation of Ser259 in c-Raf, attenuated membrane recruitment of c-Raf and inhibited Ras/c-Raf interaction to attenuate activation of this kinase. This is a general effect for NSAIDs because sulindac sulfide, aspirin and indomethacin also inhibited the binding of c-Raf to Ras. Immunofluorescent staining verified that NS398 reduced the serum-induced membrane recruitment of c-Raf in cells. However, overexpression of constitutively active c-Raf only partly reversed NS398-induced inhibition of MMP-2 expression. Interestingly, we found that NS398 up-regulated the expression of mitogen-activated protein kinase phosphatase-1 (MKP-1) and MKP-3. Block of MKP activity by sodium orthovanadate also partly counteracted the inhibitory effect of NS398. Overexpression of constitutively active c-Raf and treatment of sodium orthovanadate together completely reversed the inhibition of MMP-2 by NS398. Taken together, we conclude that NS398 and other NSAIDs act via inhibition of Ras/c-Raf interaction and up-regulation of MKPs to suppress the ERK-mediated signaling. 相似文献
966.
Lee CL Chang FR Hsieh PW Chiang MY Wu CC Huang ZY Lan YH Chen M Lee KH Yen HF Hung WC Wu YC 《Phytochemistry》2008,69(1):276-287
Seventeen ent-abietane diterpenes, including gelomulides K-X (1-14), and three known compounds, were isolated from a dichloromethane-soluble extract of Gelonium aequoreum through bioassay-guided fractionation. Their structures were identified by spectroscopic methods, and stereochemistry was confirmed by X-ray crystallographic analysis, CD spectral data, and Mosher's method. The isolates were evaluated for in vitro cytotoxic activity, and compounds 1 and 3 showed moderate cytotoxicity against lung (A549), breast (MDA-MB-231 and MCF7), and liver (HepG2) cancer cell lines. 相似文献
967.
Banana bunchy top virus (BBTV), a complex circular single‐stranded DNA virus with multiple genomic components, is a destructive pathogen in banana‐cultivating areas worldwide. Based on symptoms (such as vein clearing, green streak on pseudostem, leaf atrophy, bunchy top and stunting) as well as polymerase chain reaction (PCR) amplification patterns with different primer pairs, all BBTV isolates collected from Taiwan and other countries can be divided into five distinctive strains. Three primer pairs, C1, stem‐loop common region (CR‐SL) and TS were used for PCR amplifications. Strain 1, which induces conspicuous symptoms, is a common severe strain; it reacted positively with C1 and CR‐SL but negatively with TS in the PCR assays, so its PCR pattern was indicated as ‘+/+/?’ for C1, CR‐SL and TS primer pairs, respectively. Strain 2 seemed to be a Taiwan‐specific severe strain which induced severe symptoms, and its PCR pattern was ‘+/+/+’ as it showed positive reactions with all three primer pairs. Strain 3, causing the most severe symptoms, is a Malaysia‐specific severe strain whose PCR pattern is ‘?/+/?’. Strain 4 induced moderately severe symptoms and is an intermediate strain whose PCR pattern is ‘?/+/?’. Strain 5 is a mild strain; it did not induce symptoms in banana and it reacted positively with C1, CR‐SL and TS primer pairs. Interestingly, an additional 537‐bp fragment was amplified from Strain 5 with the CR‐SL primer pair. The PCR pattern of Strain 5 is therefore indicated as ‘+/++/+’. This study demonstrates that various BBTV strains exist in nature and they differ biologically and also molecularly. 相似文献
968.
Timothy H Rainer Peter A Cameron DeVilliers Smit Kim L Ong Alex Ng Wing Hung David Chan Po Nin Anil T Ahuja Louis Chan Yik Si Joseph J Y Sung 《BMJ (Clinical research ed.)》2003,326(7403):1354-1358
Objectives To determine the clinical and radiological features of
severe acute respiratory syndrome (SARS) and to evaluate the accuracy of the
World Health Organization''s guidelines on defining cases of SARS.Design Prospective observational study.Setting A newly set up SARS screening clinic in the emergency
department of a university hospital in Hong Kong''s New Territories.Participants 556 hospital staff, patients, and relatives who
attended the screening clinic and who had had contact with someone with
SARS.Main outcome measure Number of confirmed cases of SARS.Results Of the 556 people, 141 were admitted to hospital, and 97 had
confirmed SARS. Fever, chills, malaise, myalgia, rigor, loss of appetite,
vomiting, diarrhoea, and neck pain but not respiratory tract symptoms were
significantly more common among the 97 patients than among the other patients.
The overall accuracy of the WHO guidelines for identifying suspected SARS was
83% and their negative predictive value was 86% (95% confidence interval 83%
to 89%). They had a sensitivity of 26% (17% to 36%) and a specificity of 96%
(93% to 97%).Conclusions Current WHO guidelines for diagnosing suspected SARS may
not be sufficiently sensitive in assessing patients before admission to
hospital. Daily follow up, evaluation of non-respiratory, systemic symptoms,
and chest radiography would be better screening tools. 相似文献
969.
Although the theoretical value of biomass yield can be calculated from metabolic network stoichiometry, the growth rate is difficult to predict. Since the rate and yield can vary independently, no simple relationship has been discovered between these two variables. In this work, we analyzed the well-accepted enzyme kinetics and uncovered a hidden boundary for growth rate, which is determined by the square-root of three physiological parameters: biomass yield, the substrate turnover number, and the maximum synthesis rate of the turnover enzyme. Cells cannot grow faster than the square-root of the product of these parameters. This analysis is supported by experimental data and involves essentially no assumptions except (i) the cell is not undergoing a downshift transition, (ii) substrate uptake enzyme activity is proportional to its copy number. This simple boundary (not correlation) has escaped notice for many decades and suggests that the yield calculation does not predict the growth rate, but gives an upper limit for the growth rate. The relationship also explains how growth rate is affected by the yield and sheds lights on strain design for product formation. 相似文献
970.
Ing-Marie Viklund Pontus Aspenström Vannary Meas-Yedid Jolanta Kopec Daniel Ågren Gunter Schneider Mauro D'Amato Jean-Christophe Olivo-Marin Guy Tran Van Nhieu Sven Pettersson 《Experimental cell research》2009,315(6):1040-220
We have previously identified a new gene with sequence homology to the WASP-family of actin regulators denoted WAFL (WASP and FKBP-like). Here we report a possible biological function for WAFL, by demonstrating an association to early endosomes via its central coiled-coil domain. Further we show by functional and structural studies that WAFL is associated with both microtubules and the actin filament system, the two means of transport of early endosomes. In addition, WAFL interacts with WASP-interacting protein (WIP) and actin, thus linking WAFL to actin dynamics. The use of RNAi depletion of WAFL shows that WAFL-deficient cells display delayed transport of endosomal cargo. Our findings are compatible with a model whereby WAFL is involved in the transport of early endosomes at the level of transition between microfilament-based and microtubule-based movement. 相似文献