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971.
Helene M. Langevin Kirsten N. Storch Robert R. Snapp Nicole A. Bouffard Gary J. Badger Alan K. Howe Douglas J. Taatjes 《Histochemistry and cell biology》2010,133(4):405-415
Studies in cultured cells have shown that nuclear shape is an important factor influencing nuclear function, and that mechanical
forces applied to the cell can directly affect nuclear shape. In a previous study, we demonstrated that stretching of whole
mouse subcutaneous tissue causes dynamic cytoskeletal remodeling with perinuclear redistribution of α-actin in fibroblasts
within the tissue. We have further shown that the nuclei of these fibroblasts have deep invaginations containing α-actin.
In the current study, we hypothesized that tissue stretch would cause nuclear remodeling with a reduced amount of nuclear
invagination, measurable as a change in nuclear concavity. Subcutaneous areolar connective tissue samples were excised from
28 mice and randomized to either tissue stretch or no stretch for 30 min, then examined with histochemistry and confocal microscopy.
In stretched tissue (vs. non-stretched), fibroblast nuclei had a larger cross-sectional area (P < 0.001), smaller thickness (P < 0.03) in the plane of the tissue, and smaller relative concavity (P < 0.005) indicating an increase in nuclear convexity. The stretch-induced loss of invaginations may have important influences
on gene expression, RNA trafficking and/or cell differentiation. 相似文献
972.
Kildare Miranda Douglas A. Pace Roxana Cintron Juliany C. F. Rodrigues Jianmin Fang Alyssa Smith Peter Rohloff Elvis Coelho Felix De Haas Wanderley De Souza Isabelle Coppens L. David Sibley Silvia N. J. Moreno 《Molecular microbiology》2010,76(6):1358-1375
Toxoplasma gondii belongs to the phylum Apicomplexa and is an important cause of congenital disease and infection in immunocompromised patients. Like most apicomplexans, T. gondii possesses several plant‐like features, such as the chloroplast‐like organelle, the apicoplast. We describe and characterize a novel organelle in T. gondii tachyzoites, which is visible by light microscopy and possesses a broad similarity to the plant vacuole. Electron tomography shows the interaction of this vacuole with other organelles. The presence of a plant‐like vacuolar proton pyrophosphatase (TgVP1), a vacuolar proton ATPase, a cathepsin L‐like protease (TgCPL), an aquaporin (TgAQP1), as well as Ca2+/H+ and Na+/H+ exchange activities, supports similarity to the plant vacuole. Biochemical characterization of TgVP1 in enriched fractions shows a functional similarity to the respective plant enzyme. The organelle is a Ca2+ store and appears to have protective effects against salt stress potentially linked to its sodium transport activity. In intracellular parasites, the organelle fragments, with some markers colocalizing with the late endosomal marker, Rab7, suggesting its involvement with the endocytic pathway. Studies on the characterization of this novel organelle will be relevant to the identification of novel targets for chemotherapy against T. gondii and other apicomplexan parasites as well. 相似文献
973.
974.
Maria A. Argiriadi Anna M. Ericsson Christopher M. Harris David L. Banach David W. Borhani David J. Calderwood Megan D. Demers Jennifer DiMauro Richard W. Dixon Jennifer Hardman Silvia Kwak Biqin Li John A. Mankovich Douglas Marcotte Kelly D. Mullen Baofu Ni M. Pietras Ramkrishna Sadhukhan Silvino Sousa Medha J. Tomlinson Robert V. Talanian 《Bioorganic & medicinal chemistry letters》2010,20(1):330-333
MK2 is a Ser/Thr kinase of significant interest as an anti-inflammatory drug discovery target. Here we describe the development of in vitro tools for the identification and characterization of MK2 inhibitors, including validation of inhibitor interactions with the crystallography construct and determination of the unique binding mode of 2,4-diaminopyrimidine inhibitors in the MK2 active site. Use of these tools in the optimization of a potent and selective inhibitor lead series is described in the accompanying Letter. 相似文献
975.
Qingping Zeng John G. Allen Matthew P. Bourbeau Xianghong Wang Guomin Yao Seifu Tadesse James T. Rider Chester C. Yuan Fang-Tsao Hong Matthew R. Lee Shiwen Zhang Julie A. Lofgren Daniel J. Freeman Suijin Yang Chun Li Elizabeth Tominey Xin Huang Douglas Hoffman Harvey K. Yamane Christopher Fotsch Xiaoling Zhang 《Bioorganic & medicinal chemistry letters》2010,20(5):1559-1564
Through a combination of screening and structure-based rational design, we have discovered a series of N1-(5-(heterocyclyl)-thiazol-2-yl)-3-(4-trifluoromethylphenyl)-1,2-propanediamines that were developed into potent ATP competitive inhibitors of AKT. Studies of linker strand-binding adenine isosteres identified SAR trends in potency and selectivity that were consistent with binding interactions observed in structures of the inhibitors bound to AKT1 and to the counter-screening target PKA. One compound was shown to have acceptable pharmacokinetic properties and to be a potent inhibitor of AKT signaling and of in vivo xenograft tumor growth in a preclinical model of glioblastoma. 相似文献
976.
977.
Y. L. Gu I. C. C. van der Horst Y. L. Douglas T. Svilaas M. A. Mariani F. Zijlstra 《Netherlands heart journal》2010,18(7):348-354
Background/Objectives. We aimed to investigate the incidence and clinical outcome of coronary artery bypass grafting (CABG) performed in contemporary patients with ST-elevation myocardial infarction (STEMI) within 30 days after presentation. Methods. All 1071 patients enrolled in the Thrombus Aspiration during Percutaneous coronary intervention in Acute myocardial infarction Study (TAPAS) were included in this analysis. CABG was indicated for both ischaemic and anatomical reasons according to the current treatment guidelines for STEMI. For all surgical as well as non-surgical patients, clinical outcome was assessed at both 30 days and one year. Results. CABG was performed within 30 days of presentation in 59/1071 (5.5%) patients, in 13 (22%) within 24 hours, in eight (14%) between one and three days, and in 38 (64%) between four and 30 days. Compared with non-surgical patients, surgical patients required more initial intra-aortic balloon pump support (33 vs. 5%, p<0.001) and more often had multi-vessel disease (p<0.001). Overall, rethoracotomy was performed in 9/59 (15%) patients. In patients operated within three days, the rethoracotomy rate was markedly higher than after three days (33 vs. 5%, p=0.004). Cardiac mortality at 30 days and one year was 1.7% in the surgical group and 3.2 and 5.3%, respectively, in the non-surgical group. Conclusion. STEMI patients treated with CABG within three days after presentation are at increased risk of rethoracotomy. However, despite this higher incidence of surgical complications and multiple high-risk features at presentation, surgical management during the acute and subacute phase is associated with excellent 30-day and one-year survival. (Neth Heart J 2010;18:348-54.) 相似文献
978.
Preeti Rajesh Changanamkandath Rajesh Michael D. Wyatt Douglas L. Pittman 《DNA Repair》2010,9(4):458-467
SN1-type methylating agents generate O6-methyl guanine (O6-meG), which is a potently mutagenic, toxic, and recombinogenic DNA adduct. Recognition of O6-meG:T mismatches by mismatch repair (MMR) causes sister chromatid exchanges, which are representative of homologous recombination (HR) events. Although the MMR-dependent mutagenicity and toxicity caused by O6-meG has been studied, the mechanisms of recombination induced by O6-meG are poorly understood. To explore the HR and MMR genetic interactions in mammals, we used the Rad51d and Mlh1 mouse models. Ablation of Mlh1 did not appreciably influence the developmental phenotypes conferred by the absence of Rad51d. Mouse embryonic fibroblasts (MEFs) deficient in Rad51d can only proliferate in p53-deficient background. Therefore, Rad51d?/?Mlh1?/? Trp53?/? MEFs with a combined deficiency of HR and MMR were generated and comparisons between MLH1 and RAD51D status were made. To our knowledge, these MEFs are the first mammalian model system for combined HR and MMR defects. Rad51d-deficient MEFs were 5.3-fold sensitive to N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) compared to the Rad51d-proficient MEFs. A pronounced G2/M arrest in Rad51d-deficient cells was accompanied by an accumulation of γ-H2AX and apoptosis. Mlh1-deficient MEFs were resistant to MNNG and showed no G2/M arrest or apoptosis at the doses used. Importantly, loss of Mlh1 alleviated sensitivity of Rad51d-deficient cells to MNNG, in addition to reducing γ-H2AX, G2/M arrest and apoptosis. Collectively, the data support the hypothesis that MMR-dependent sensitization of HR-deficient cells is specific for O6-meG and suggest that HR resolves DNA intermediates created by MMR recognition of O6-meG:T. This study provides insight into recombinogenic mechanisms of carcinogenesis and chemotherapy resulting from O6-meG adducts. 相似文献
979.
Douglas B. Craig Allison M. Haslam Harlyn J. Silverstein Miki Chikamatsu Elnaz Shadabi Ellert R. Nichols 《The protein journal》2010,29(6):398-406
Single enzyme molecule assays were performed using capillary electrophoresis-based protocols on β-galactosidase from Lactobacillus delbrueckii, Lactobacillus reuteri, Lactobacillus helveticus
and Bacillus circulans. The enzyme was found to show static heterogeneity with respect to catalytic rate and the variance in rate increased with
protein size. This is consistent with the proposal that random errors in translation may be an important underlying component
of enzyme heterogeneity. Additionally these enzymes were found to show static heterogeneity with respect to electrophoretic
mobility. Comparison of wild-type and rpsL E. coli β-galactosidase expressed in the presence and absence of streptomycin suggested that increases in error do not result in
detectable increases in the dynamic heterogeneity of activity with increasing temperature. Finally, a method was developed
to measure the dynamic heterogeneity in electrophoretic mobility. 相似文献
980.
We present MassSieve, a Java‐based platform for visualization and parsimony analysis of single and comparative LC‐MS/MS database search engine results. The success of mass spectrometric peptide sequence assignment algorithms has led to the need for a tool to merge and evaluate the increasing data set sizes that result from LC‐MS/MS‐based shotgun proteomic experiments. MassSieve supports reports from multiple search engines with differing search characteristics, which can increase peptide sequence coverage and/or identify conflicting or ambiguous spectral assignments. 相似文献