全文获取类型
收费全文 | 4622篇 |
免费 | 400篇 |
国内免费 | 3篇 |
出版年
2023年 | 29篇 |
2022年 | 77篇 |
2021年 | 155篇 |
2020年 | 72篇 |
2019年 | 81篇 |
2018年 | 115篇 |
2017年 | 95篇 |
2016年 | 161篇 |
2015年 | 251篇 |
2014年 | 287篇 |
2013年 | 337篇 |
2012年 | 420篇 |
2011年 | 378篇 |
2010年 | 267篇 |
2009年 | 211篇 |
2008年 | 283篇 |
2007年 | 262篇 |
2006年 | 226篇 |
2005年 | 192篇 |
2004年 | 205篇 |
2003年 | 193篇 |
2002年 | 166篇 |
2001年 | 35篇 |
2000年 | 30篇 |
1999年 | 48篇 |
1998年 | 45篇 |
1997年 | 32篇 |
1996年 | 27篇 |
1995年 | 25篇 |
1994年 | 26篇 |
1993年 | 27篇 |
1992年 | 18篇 |
1991年 | 23篇 |
1990年 | 25篇 |
1989年 | 13篇 |
1988年 | 13篇 |
1987年 | 12篇 |
1986年 | 19篇 |
1985年 | 7篇 |
1984年 | 15篇 |
1983年 | 11篇 |
1982年 | 19篇 |
1981年 | 9篇 |
1980年 | 7篇 |
1979年 | 7篇 |
1978年 | 11篇 |
1977年 | 10篇 |
1974年 | 9篇 |
1969年 | 5篇 |
1965年 | 5篇 |
排序方式: 共有5025条查询结果,搜索用时 15 毫秒
231.
Alexey?TeplyakovEmail author Sadhana?Pullalarevu Galina?Obmolova Victoria?Doseeva Andrey?Galkin Osnat?Herzberg Miroslawa?Dauter Zbigniew?Dauter Gary?L?GillilandEmail author 《BMC structural biology》2004,4(1):5
Background
The yffB (PA3664) gene of Pseudomonas aeruginosa encodes an uncharacterized protein of 13 kDa molecular weight with a marginal sequence similarity to arsenate reductase from Escherichia coli. The crystal structure determination of YffB was undertaken as part of a structural genomics effort in order to assist with the functional assignment of the protein. 相似文献232.
233.
234.
Austerlitz F Dick CW Dutech C Klein EK Oddou-Muratorio S Smouse PE Sork VL 《Molecular ecology》2004,13(4):937-954
Pollen dispersal is a critical process that shapes genetic diversity in natural populations of plants. Estimating the pollen dispersal curve can provide insight into the evolutionary dynamics of populations and is essential background for making predictions about changes induced by perturbations. Specifically, we would like to know whether the dispersal curve is exponential, thin-tailed (decreasing faster than exponential), or fat-tailed (decreasing slower than the exponential). In the latter case, rare events of long-distance dispersal will be much more likely. Here we generalize the previously developed TWOGENER method, assuming that the pollen dispersal curve belongs to particular one- or two-parameter families of dispersal curves and estimating simultaneously the parameters of the dispersal curve and the effective density of reproducing individuals in the population. We tested this method on simulated data, using an exponential power distribution, under thin-tailed, exponential and fat-tailed conditions. We find that even if our estimates show some bias and large mean squared error (MSE), we are able to estimate correctly the general trend of the curve - thin-tailed or fat-tailed - and the effective density. Moreover, the mean distance of dispersal can be correctly estimated with low bias and MSE, even if another family of dispersal curve is used for the estimation. Finally, we consider three case studies based on forest tree species. We find that dispersal is fat-tailed in all cases, and that the effective density estimated by our model is below the measured density in two of the cases. This latter result may reflect the difficulty of estimating two parameters, or it may be a biological consequence of variance in reproductive success of males in the population. Both the simulated and empirical findings demonstrate the strong potential of TWOGENER for evaluating the shape of the dispersal curve and the effective density of the population (d(e)). 相似文献
235.
Marto T. Núñez Claudia Núñez-Millacura Victoria Tapia Patricia Muñoz Dora Mazariegos Miguel Arredondo Pablo Muñoz Casilda Mura Ricardo B. Maccioni 《Biometals》2003,16(1):83-90
The love-hate relationship between iron and living matter has generated mechanisms to maintain iron concentration in a narrow range, above and below which deleterious effects occur. At the cellular level, iron homeostasis is accomplished by the activity of the IRP proteins, which, under conditions of iron depletion, up-regulate the expression of the iron acquisition proteins TfR and DMT1. It has been shown that hydrogen peroxide activates IRP1 and that this activation mediates a potentially harmful increase in cell iron uptake. Here we show that IRP1 activity is also induced by iron-mediated oxidative stress. When cells were incubated with up to 20 M of iron, a typical decrease in IRP1 and IRP2 activity was observed. Interestingly, when iron was further increased to 40 or 80 M, IRP1 was reactivated in three of the four different cell lines tested, i.e., Caco-2 cells, N2A cells and HepG2 cells. In the fourth cell line (K562) IRP1 activity did not increase, but neither did it decrease. This response to iron was largely abrogated when the antioxidant N-acetyl cysteine was added along with iron to the culture medium. Thus, the effect of iron was mediated by oxidative stress. Increases in IRP1 activity were accompanied by increases in cell iron uptake, an indication that the activated IRP1 was functional in the activation of iron uptake. Hence, this iron-induced iron uptake feedback loop results in the increase of intracellular iron and increased oxidative stress. 相似文献
236.
The TIME FOR COFFEE gene maintains the amplitude and timing of Arabidopsis circadian clocks 下载免费PDF全文
Hall A Bastow RM Davis SJ Hanano S McWatters HG Hibberd V Doyle MR Sung S Halliday KJ Amasino RM Millar AJ 《The Plant cell》2003,15(11):2719-2729
Plants synchronize developmental and metabolic processes with the earth's 24-h rotation through the integration of circadian rhythms and responses to light. We characterize the time for coffee (tic) mutant that disrupts circadian gating, photoperiodism, and multiple circadian rhythms, with differential effects among rhythms. TIC is distinct in physiological functions and genetic map position from other rhythm mutants and their homologous loci. Detailed rhythm analysis shows that the chlorophyll a/b-binding protein gene expression rhythm requires TIC function in the mid to late subjective night, when human activity may require coffee, in contrast to the function of EARLY-FLOWERING3 (ELF3) in the late day to early night. tic mutants misexpress genes that are thought to be critical for circadian timing, consistent with our functional analysis. Thus, we identify TIC as a regulator of the clock gene circuit. In contrast to tic and elf3 single mutants, tic elf3 double mutants are completely arrhythmic. Even the robust circadian clock of plants cannot function with defects at two different phases. 相似文献
237.
An atomic model for actin binding by the CH domains and spectrin-repeat modules of utrophin and dystrophin 总被引:1,自引:0,他引:1
Sutherland-Smith AJ Moores CA Norwood FL Hatch V Craig R Kendrick-Jones J Lehman W 《Journal of molecular biology》2003,329(1):15-33
Utrophin and dystrophin link cytoskeletal F-actin filaments to the plasmalemma. Genetic strategies to replace defective dystrophin with utrophin in individuals with muscular dystrophy requires full characterization of these proteins. Both contain homologous N-terminal actin-binding motifs composed of a pair of calponin-homology (CH) domains (CH1 and CH2) that are connected by spectrin-repeat modules to C-terminal membrane-binding sequences. Here, electron microscopy and 3D reconstruction of F-actin decorated with utrophin and dystrophin actin-binding constructs were performed using Utr261 (utrophin's CH domain pair), Utr416 (utrophin's CH domains and first spectrin-repeat) and Dys246 (dystrophin's CH domain pair). The lozenge-like utrophin CH domain densities localized to the upper surface of actin subdomain 1 and extended azimuthally over subdomain 2 toward subdomains 3 and 4. The cylinder-shaped spectrin-repeat was located at the end of the CH domain pair and was aligned longitudinally along the cleft between inner and outer actin domains, where tropomyosin is present when on thin filaments. The connection between the spectrin-repeat module and the CH domains defined the orientation of CH1 and CH2 on actin. Resolution of utrophin's CH domains and spectrin-repeats permitted docking of crystal structures into respective EM densities, leading to an atomic model where both CH and spectrin-domains bind actin. The CH domain-actin interaction for dystrophin was found to be more complex than for utrophin. Binding assays showed that Utr261 and Utr416 interacted with F-actin as monomers, whereas Dys246 appeared to associate as a dimer, consistent with a bilobed Dys246 structure observed on F-actin in electron microscope reconstructions. One of the lobes was similar in shape, position and orientation to the monomeric CH domains of Utr261, while the other lobe apparently represented a second set of CH domains in the dimeric Dys246. The extensive contact made by dystrophin on actin may be used in vivo to help muscles dissipate mechanical stress from the contractile apparatus to the extracellular matrix. 相似文献
238.
Traditionally, proteins have been viewed as a construct based on elements of secondary structure and their arrangement in three-dimensional space. In a departure from this perspective we show that protein structures can be modelled as network systems that exhibit small-world, single-scale, and to some degree, scale-free properties. The phenomenological network concept of degrees of separation is applied to three-dimensional protein structure networks and reveals how amino acid residues can be connected to each other within six degrees of separation. This work also illuminates the unique features of protein networks in comparison to other networks currently studied. Recognising that proteins are networks provides a means of rationalising the robustness in the overall three-dimensional fold of a protein against random mutations and suggests an alternative avenue to investigate the determinants of protein structure, function and folding. 相似文献
239.
Dockrell DH Marriott HM Prince LR Ridger VC Ince PG Hellewell PG Whyte MK 《Journal of immunology (Baltimore, Md. : 1950)》2003,171(10):5380-5388
The role of alveolar macrophages (AM) in host defense against pulmonary infection has been difficult to establish using in vivo models. This may reflect a reliance on models of fulminant infection. To establish a unique model of resolving infection, with which to address the function of AM, C57BL/6 mice received low-dose intratracheal administration of pneumococci. Administration of low doses of pneumococci produced a resolving model of pulmonary infection characterized by clearance of bacteria without features of pneumonia. AM depletion in this model significantly increased bacterial outgrowth in the lung. Interestingly, a significant increase in the number of apoptotic AM was noted with the low-dose infection as compared with mock infection. Caspase inhibition in this model decreased AM apoptosis and increased the number of bacteremic mice, indicating a novel role for caspase activation in pulmonary innate defense against pneumococci. These results suggest that AM play a key role in clearance of bacteria from the lung during subclinical infection and that induction of AM apoptosis contributes to the microbiologic host defense against pneumococci. 相似文献
240.
Platelet-derived growth factor (PDGF) exerts neurotrophic and neuromodulatory effects on the CNS. To determine the permeability of the blood-brain barrier (BBB) to PDGF, we examined the blood-to-brain influx of radioactively labeled PDGF isoforms (PDGF-AA and PDGF-BB) by multiple-time regression analysis after intravenous (i.v.) injection and by in-situ perfusion, and also determined the physicochemical characteristics which affect their permeation across the BBB, including lipophilicity (measured by octanol:buffer partition coefficient), hydrogen bonding (measured by differences in octanol : buffer and isooctane : buffer partition coefficients), serum protein binding (measured by capillary electrophoresis), and stability of PDGF in blood 10 min after i.v. injection (measured by HPLC). After i.v. bolus injection, neither 125I-PDGF-AA nor 125I-PDGF-BB crossed the BBB, their influx rates being similar to that of the vascular marker 99mTc-albumin. 125I-PDGF-AA degraded significantly faster in blood than 125I-PDGF-BB. PDGF-BB, however, was completely bound to a large protein in serum whereas PDGF-AA showed no binding. Thus, degradation might explain the poor blood-to-brain influx of PDGF-AA, whereas protein binding could explain the poor influx of circulating PDGF-BB. Despite their lack of permeation in the intact mouse, both 125I-PDGF-AA and 125I-PDGF-BB entered the brain by perfusion in blood-free buffer, and the significantly faster rate of 125I-PDGF-AA than 125I-PDGF-BB may be explained by the lower hydrogen bonding potential of 125I-PDGF-AA. Thus, the lack of significant distribution of PDGF from blood to brain is not because of the intrinsic barrier function of the BBB but probably because of degradation and protein binding. Information from these studies could be useful in the design of analogues for delivery of PDGF as a therapeutic agent. 相似文献