全文获取类型
收费全文 | 2410篇 |
免费 | 181篇 |
国内免费 | 2篇 |
专业分类
2593篇 |
出版年
2024年 | 3篇 |
2023年 | 7篇 |
2022年 | 35篇 |
2021年 | 46篇 |
2020年 | 43篇 |
2019年 | 64篇 |
2018年 | 61篇 |
2017年 | 59篇 |
2016年 | 85篇 |
2015年 | 120篇 |
2014年 | 157篇 |
2013年 | 195篇 |
2012年 | 214篇 |
2011年 | 208篇 |
2010年 | 119篇 |
2009年 | 99篇 |
2008年 | 142篇 |
2007年 | 162篇 |
2006年 | 123篇 |
2005年 | 100篇 |
2004年 | 102篇 |
2003年 | 126篇 |
2002年 | 81篇 |
2001年 | 15篇 |
2000年 | 21篇 |
1999年 | 17篇 |
1998年 | 16篇 |
1997年 | 12篇 |
1996年 | 20篇 |
1995年 | 13篇 |
1994年 | 14篇 |
1993年 | 16篇 |
1992年 | 7篇 |
1991年 | 7篇 |
1990年 | 9篇 |
1989年 | 7篇 |
1988年 | 3篇 |
1986年 | 10篇 |
1985年 | 5篇 |
1984年 | 6篇 |
1983年 | 7篇 |
1982年 | 4篇 |
1981年 | 5篇 |
1979年 | 2篇 |
1977年 | 3篇 |
1976年 | 4篇 |
1975年 | 4篇 |
1969年 | 3篇 |
1962年 | 2篇 |
1958年 | 2篇 |
排序方式: 共有2593条查询结果,搜索用时 15 毫秒
131.
Helguero LA Lamb C Molinolo AA Lanari C 《The Journal of steroid biochemistry and molecular biology》2003,84(1):9-14
We have evaluated the progesterone receptor (PR) binding patterns in progestin-dependent and -independent murine mammary carcinomas; all variants regress completely after antiprogestin treatment. These studies revealed the presence of a high affinity, low capacity-binding site (K(d): 43 +/- 9 pM; Q=9 +/- 3 fmol/mg protein) and of the classical lower affinity, high capacity-binding site (K(d): 9.2 +/- 4.2 nM; Q=376 +/- 64 fmol/mg protein). These sites could also be detected in uterus. Antiprogestins were able to bind to both sites. In vitro, medroxyprogesterone acetate (MPA) was stimulatory along a biphasic curve with two slopes, one at very low concentrations (EC(50): 1.5 +/- 0.7 fM) and the other at values compatible with the described K(d) for the PR (EC(50): 0.33 +/- 0.3 nM). 相似文献
132.
Pérez-Vázquez V Saavedra-Molina A Uribe S 《Journal of bioenergetics and biomembranes》2003,35(3):231-241
The yeast mitochondrial unspecific channel (YMUC) sensitivity to inorganic (Ca2+ or Mg2+) or organic (hexyl or octyl-guanidine) cations was measured. The rate of oxygen consumption in State 3 and State 4, the transmembrane potential (), mitochondrial swelling, and the polyethylene-glycol mediated recontraction were used to follow opening of the YMUC. Addition of 0.4 mM PO4 did not close the YMUC, although it did enhance the sensitivity to Ca2+ (I50 decreased from 50 to 0.3 mM) and Mg2+ (I50 decreased from 5 to 0.83 mM Mg2+). The Ca2+ concentration needed to close the YMUC was higher than the concentrations usually observed in the cell. Nonetheless, Mg2+, Ca2+, and PO4 exhibited additive effects. These cations did not inhibit contraction of preswollen mitochondria, suggesting that the YMUC/cation interaction was labile. Octyl-guanidine (OG-I50 7.5 M) was the only cation which inhibited mitochondrial recontraction, probably as a result of membrane binding stabilization through its hydrophobic tail. The PO4-dependent, Ca2+/Mg2+-mediated closure of the YMUC may be a means to control the proportion of oxidative energy producing ATP or being lost as heat. 相似文献
133.
Evan J. Molinelli Anil Korkut Weiqing Wang Martin L. Miller Nicholas P. Gauthier Xiaohong Jing Poorvi Kaushik Qin He Gordon Mills David B. Solit Christine A. Pratilas Martin Weigt Alfredo Braunstein Andrea Pagnani Riccardo Zecchina Chris Sander 《PLoS computational biology》2013,9(12)
We present a powerful experimental-computational technology for inferring network models that predict the response of cells to perturbations, and that may be useful in the design of combinatorial therapy against cancer. The experiments are systematic series of perturbations of cancer cell lines by targeted drugs, singly or in combination. The response to perturbation is quantified in terms of relative changes in the measured levels of proteins, phospho-proteins and cellular phenotypes such as viability. Computational network models are derived de novo, i.e., without prior knowledge of signaling pathways, and are based on simple non-linear differential equations. The prohibitively large solution space of all possible network models is explored efficiently using a probabilistic algorithm, Belief Propagation (BP), which is three orders of magnitude faster than standard Monte Carlo methods. Explicit executable models are derived for a set of perturbation experiments in SKMEL-133 melanoma cell lines, which are resistant to the therapeutically important inhibitor of RAF kinase. The resulting network models reproduce and extend known pathway biology. They empower potential discoveries of new molecular interactions and predict efficacious novel drug perturbations, such as the inhibition of PLK1, which is verified experimentally. This technology is suitable for application to larger systems in diverse areas of molecular biology. 相似文献
134.
135.
The BCL-2 family member Noxa induces apoptosis by antagonizing the prosurvival protein MCL-1. In this issue of Molecular Cell, Lowman et al. (2010) uncover a glucose-dependent phosphoregulatory mechanism that inactivates Noxa's apoptotic function and triggers its capacity to modulate glucose metabolism. 相似文献
136.
Jill E. Chrencik Akshay Patny Iris K. Leung Brian Korniski Thomas L. Emmons Troii Hall Robin A. Weinberg Jennifer A. Gormley Jennifer M. Williams Jacqueline E. Day Jeffrey L. Hirsch James R. Kiefer Joseph W. Leone H. David Fischer Cynthia D. Sommers Horng-Chih Huang E.J. Jacobsen Ruth E. Tenbrink Alfredo G. Tomasselli Timothy E. Benson 《Journal of molecular biology》2010,400(3):413-8450
Janus kinases (JAKs) are critical regulators of cytokine pathways and attractive targets of therapeutic value in both inflammatory and myeloproliferative diseases. Although the crystal structures of active JAK1 and JAK2 kinase domains have been reported recently with the clinical compound CP-690550, the structures of both TYK2 and JAK3 with CP-690550 have remained outstanding. Here, we report the crystal structures of TYK2, a first in class structure, and JAK3 in complex with PAN-JAK inhibitors CP-690550 ((3R,4R)-3-[4-methyl-3-[N-methyl-N-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropionitrile) and CMP-6 (tetracyclic pyridone 2-t-butyl-9-fluoro-3,6-dihydro-7H-benz[h]-imidaz[4,5-f]isoquinoline-7-one), both of which bind in the ATP-binding cavities of both JAK isozymes in orientations similar to that observed in crystal structures of JAK1 and JAK2. Additionally, a complete thermodynamic characterization of JAK/CP-690550 complex formation was completed by isothermal titration calorimetry, indicating the critical role of the nitrile group from the CP-690550 compound. Finally, computational analysis using WaterMap further highlights the critical positioning of the CP-690550 nitrile group in the displacement of an unfavorable water molecule beneath the glycine-rich loop. Taken together, the data emphasize the outstanding properties of the kinome-selective JAK inhibitor CP-690550, as well as the challenges in obtaining JAK isozyme-selective inhibitors due to the overall structural and sequence similarities between the TYK2, JAK1, JAK2 and JAK3 isozymes. Nevertheless, subtle amino acid variations of residues lining the ligand-binding cavity of the JAK enzymes, as well as the global positioning of the glycine-rich loop, might provide the initial clues to obtaining JAK-isozyme selective inhibitors. 相似文献
137.
138.
We investigated the role of constitutive morphology and previous experience in predator avoidance in two anuran species associated with different larval habitats. In Rana temporaria, deeper tails and larger body size conferred selective advantage against dragonfly predation. Previous experience with predators had a positive influence on the survival of R. temporaria tadpoles equivalent to predator selection. By contrast, survival in Bufo bufo seems unrelated to tail shape or experience. This suggests that B. bufo lacks constitutive morphological defenses against insect predators, and that morphological and behavioral defenses could result more effective than chemical deterrents for these insect predators. A key novelty of this study is the observation that Rana tadpoles having prior experience with predators have an enhanced success in further encounters, and this occurs before the morphological induced defense has been established. This induced modification for R. temporaria, and its lack of for B. bufo, may be an important determinant of larval survival. 相似文献
139.
Urbina-Cano P Bobadilla-Morales L Ramírez-Herrera MA Corona-Rivera JR Mendoza-Magaña ML Troyo-Sanromán R Corona-Rivera A 《Journal of applied genetics》2006,47(4):377-382
Dietary polyphenolics, such as curcumin, have shown antioxidant and anti-inflammatory effects. Some antioxidants cause DNA
strand breaks in excess of transition metal ions, such as copper. The aim of this study was to evaluate thein vitro effect of curcumin in the presence of increasing concentrations of copper to induce DNA damage in murine leukocytes by the
comet assay. Balb-C mouse lymphocytes were exposed to 50 μM curcumin and various concentrations of copper (10 μM, 100 μM and
200 μM). Cellular DNA damage was detected by means of the alkaline comet assay. Our results show that 50 μM curcumin in the
presence of 100–200 μM copper induced DNA damage in murine lymphocytes. Curcumin did not inhibit the oxidative DNA damage
caused by 50 μM H2O2 in mouse lymphocytes. Moreover, 50 μM curcumin alone was capable of inducing DNA strand breaks under the tested conditions.
The increased DNA damage by 50 μM curcumin was observed in the presence of various concentrations of copper, as detected by
the alkaline comet assay. 相似文献
140.
The ratfish,Callorhinchus callorhinchus, a representative of the Holocephali, has a natural serum hemagglutinin (M
r 960 000), composed of heavy (M
r 71000), light (M
r 22 500), and J (M
r 16 000) chains. To approach the mechanisms that generate diversity at this level of evolution, the amino terminal sequence
of the heavy and light chains was determined by automated microsequencing. The chains are unblocked and have modest internal
sequence heterogeneity. The heavy chains show sequence similarity with the terminal region of the heavy chain from the horned
shark,Heterodontus francisci, and other species. In contrast to the heavy chain, the ratfish light chains display low sequence similarity with their shark
kappa counterparts. However, their similarity with the variable region of the chicken lambda light chains is about 75%. 相似文献