全文获取类型
收费全文 | 11151篇 |
免费 | 978篇 |
国内免费 | 5篇 |
出版年
2023年 | 45篇 |
2022年 | 93篇 |
2021年 | 179篇 |
2020年 | 116篇 |
2019年 | 148篇 |
2018年 | 195篇 |
2017年 | 174篇 |
2016年 | 322篇 |
2015年 | 485篇 |
2014年 | 575篇 |
2013年 | 670篇 |
2012年 | 890篇 |
2011年 | 876篇 |
2010年 | 539篇 |
2009年 | 507篇 |
2008年 | 693篇 |
2007年 | 696篇 |
2006年 | 644篇 |
2005年 | 657篇 |
2004年 | 653篇 |
2003年 | 596篇 |
2002年 | 571篇 |
2001年 | 108篇 |
2000年 | 72篇 |
1999年 | 118篇 |
1998年 | 179篇 |
1997年 | 111篇 |
1996年 | 97篇 |
1995年 | 96篇 |
1994年 | 101篇 |
1993年 | 91篇 |
1992年 | 71篇 |
1991年 | 60篇 |
1990年 | 43篇 |
1989年 | 49篇 |
1988年 | 44篇 |
1987年 | 43篇 |
1986年 | 39篇 |
1985年 | 49篇 |
1984年 | 37篇 |
1983年 | 51篇 |
1982年 | 63篇 |
1981年 | 43篇 |
1980年 | 26篇 |
1979年 | 33篇 |
1978年 | 36篇 |
1977年 | 19篇 |
1976年 | 20篇 |
1975年 | 17篇 |
1973年 | 18篇 |
排序方式: 共有10000条查询结果,搜索用时 62 毫秒
991.
Connective tissue growth factor is required for normal follicle development and ovulation 总被引:1,自引:0,他引:1
Nagashima T Kim J Li Q Lydon JP DeMayo FJ Lyons KM Matzuk MM 《Molecular endocrinology (Baltimore, Md.)》2011,25(10):1740-1759
Connective tissue growth factor (CTGF) is a cysteine-rich protein the synthesis and secretion of which are hypothesized to be selectively regulated by activins and other members of the TGF-β superfamily. To investigate the in vivo roles of CTGF in female reproduction, we generated Ctgf ovarian and uterine conditional knockout (cKO) mice. Ctgf cKO mice exhibit severe subfertility and multiple reproductive defects including disrupted follicle development, decreased ovulation rates, increased numbers of corpus luteum, and smaller but functionally normal uterine horns. Steroidogenesis is disrupted in the Ctgf cKO mice, leading to increased levels of serum progesterone. We show that disrupted follicle development is accompanied by a significant increase in granulosa cell apoptosis. Moreover, despite normal cumulus expansion, Ctgf cKO mice exhibit a significant decrease in oocytes ovulated, likely due to impaired ovulatory process. During analyses of mRNA expression, we discovered that Ctgf cKO granulosa cells show gene expression changes similar to our previously reported granulosa cell-specific knockouts of activin and Smad4, the common TGF-β family intracellular signaling protein. We also discovered a significant down-regulation of Adamts1, a progesterone-regulated gene that is critical for the remodeling of extracellular matrix surrounding granulosa cells of preovulatory follicles. These findings demonstrate that CTGF is a downstream mediator in TGF-β and progesterone signaling cascades and is necessary for normal follicle development and ovulation. 相似文献
992.
Clark CA Spitzer KA Laskin CA Koren G 《CMAJ》2011,183(18):2145; author reply 2145-2145; author reply 2146
993.
While our understanding of gene-based biology has greatly improved, it is clear that the function of the genome and most diseases cannot be fully explained by genes and other regulatory elements. Genes and the genome represent distinct levels of genetic organization with their own coding systems; Genes code parts like protein and RNA, but the genome codes the structure of genetic networks, which are defined by the whole set of genes, chromosomes and their topological interactions within a cell. Accordingly, the genetic code of DNA offers limited understanding of genome functions. In this perspective, we introduce the genome theory which calls for the departure of gene-centric genomic research. To make this transition for the next phase of genomic research, it is essential to acknowledge the importance of new genome-based biological concepts and to establish new technology platforms to decode the genome beyond sequencing. 相似文献
994.
Allcock RW Blakli H Jiang Z Johnston KA Morgan KM Rosair GM Iwase K Kohno Y Adams DR 《Bioorganic & medicinal chemistry letters》2011,21(11):3307-3312
Ibudilast [1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one] is a nonselective phosphodiesterase inhibitor used clinically to treat asthma. Efforts to selectively develop the PDE3- and PDE4-inhibitory activity of ibudilast led to replacement of the isopropyl ketone by a pyridazinone heterocycle. Structure-activity relationship exploration in the resulting 6-(pyrazolo[1,5-a]pyridin-3-yl)pyridazin-3(2H)-ones revealed that the pyridazinone lactam functionality is a critical determinant for PDE3-inhibitory activity, with the nitrogen preferably unsubstituted. PDE4 inhibition is strongly promoted by introduction of a hydrophobic substituent at the pyridazinone N(2) centre and a methoxy group at C-7′ in the pyrazolopyridine. Migration of the pyridazinone ring connection from the pyrazolopyridine 3′-centre to C-4′ strongly enhances PDE4 inhibition. These studies establish a basis for development of potent PDE4-selective and dual PDE3/4-selective inhibitors derived from ibudilast. 相似文献
995.
Narayan S Carlson EM Cheng H Condon K Du H Eckley S Hu Y Jiang Y Kumar V Lewis BM Saxton P Schuck E Seletsky BM Tendyke K Zhang H Zheng W Littlefield BA Towle MJ Yu MJ 《Bioorganic & medicinal chemistry letters》2011,21(6):1634-1638
Eribulin mesylate is a newly approved treatment for locally advanced and metastatic breast cancer. We targeted oral bioavailability and efficacy against multidrug resistant (MDR) tumors for further work. The design, synthesis and evaluation of novel amine-containing analogs of eribulin mesylate are described in this part. Attenuation of basicity of the amino group(s) in the C32 side-chain region led to compounds with low susceptibility to PgP-mediated drug efflux. These compounds were active against MDR tumor cell lines in vitro and in xenograft models in vivo, in addition to being orally bioavailable. 相似文献
996.
Narayan S Carlson EM Cheng H Du H Hu Y Jiang Y Lewis BM Seletsky BM Tendyke K Zhang H Zheng W Littlefield BA Towle MJ Yu MJ 《Bioorganic & medicinal chemistry letters》2011,21(6):1630-1633
Eribulin mesylate (Halaven™), a totally synthetic analog of the marine polyether macrolide halichondrin B, has recently been approved in the United States as a treatment for breast cancer. It is also currently under regulatory review in Japan and the European Union. Our continuing medicinal chemistry efforts on this scaffold have focused on oral bioavailability, brain penetration and efficacy against multidrug resistant (MDR) tumors by lowering the susceptibility of these compounds to P-glycoprotein (P-gp)-mediated drug efflux. Replacement of the 1,2-amino alcohol C32 side chain of eribulin with fragments neutral at physiologic pH led to the identification of analogs with significantly lower P-gp susceptibility. The analogs maintained low- to sub-nM potency in vitro against both sensitive and MDR cell lines. Within this series, increasing lipophilicity generally led to decreased P-gp susceptibility. In addition to potency in cell culture, these compounds showed in vivo activity in mouse xenograft models. 相似文献
997.
Sexton KE Barrett S Bridgwood K Carroll M Dettling D Du D Fakhoury S Fedij V Hu LY Kostlan C Pocalyko D Raheja N Smith Y Shanmugasundaram V Wade K 《Bioorganic & medicinal chemistry letters》2011,21(18):5230-5233
A series of pantolactam based compounds were identified as potent antagonists for the androgen receptor (AR). Those that possessed properties suitable for topical delivery were evaluated in the validated Hamster Ear Model. Several compounds were found to be efficacious in reducing wax esters, a major component of sebum, initiating further preclinical work on these compounds. 相似文献
998.
Cushing TD Baichwal V Berry K Billedeau R Bordunov V Broka C Browner MF Cardozo M Cheng P Clark D Dalrymple S DeGraffenreid M Gill A Hao X Hawley RC He X Labadie SS Labelle M Lehel C Lu PP McIntosh J Miao S Parast C Shin Y Sjogren EB Smith ML Talamas FX Tonn G Walker KM Walker NP Wesche H Whitehead C Wright M Jaen JC 《Bioorganic & medicinal chemistry letters》2011,21(1):423-426
A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKβ. In this Letter we document our efforts at further optimization of this series, culminating in 2 with submicromolar potency in a HWB assay and efficacy in a CIA mouse model. 相似文献
999.
Zheng X Hudyma TW Martin SW Bergstrom C Ding M He F Romine J Poss MA Kadow JF Chang CH Wan J Witmer MR Morin P Camac DM Sheriff S Beno BR Rigat KL Wang YK Fridell R Lemm J Qiu D Liu M Voss S Pelosi L Roberts SB Gao M Knipe J Gentles RG 《Bioorganic & medicinal chemistry letters》2011,21(10):2925-2929
Herein, we present initial SAR studies on a series of bridged 2-arylindole-based NS5B inhibitors. The introduction of bridging elements between the indole N1 and the ortho-position of the 2-aryl moiety resulted in conformationally constrained heterocycles that possess multiple additional vectors for further exploration. The binding mode and pharmacokinetic (PK) properties of select examples, including: 13-cyclohexyl-6-oxo-6,7-dihydro-5H-indolo[2,1-d][1,4]benzodiazepine-10-carboxylic acid (7) (IC50 = 0.07 μM, %F = 18), are reported. 相似文献
1000.
Croft DR Crighton D Samuel MS Lourenco FC Munro J Wood J Bensaad K Vousden KH Sansom OJ Ryan KM Olson MF 《Cell research》2011,21(4):666-682
The central arbiter of cell fate in response to DNA damage is p53, which regulates the expression of genes involved in cell cycle arrest, survival and apoptosis. Although many responses initiated by DNA damage have been characterized, the role of actin cytoskeleton regulators is largely unknown. We now show that RhoC and LIM kinase 2 (LIMK2) are direct p53 target genes induced by genotoxic agents. Although RhoC and LIMK2 have well-established roles in actin cytoskeleton regulation, our results indicate that activation of LIMK2 also has a pro-survival function following DNA damage. LIMK inhibition by siRNA-mediated knockdown or selective pharmacological blockade sensitized cells to radio- or chemotherapy, such that treatments that were sub-lethal when administered singly resulted in cell death when combined with LIMK inhibition. Our findings suggest that combining LIMK inhibitors with genotoxic therapies could be more efficacious than single-agent administration, and highlight a novel connection between actin cytoskeleton regulators and DNA damage-induced cell survival mechanisms. 相似文献