全文获取类型
收费全文 | 2053篇 |
免费 | 155篇 |
国内免费 | 55篇 |
出版年
2023年 | 15篇 |
2022年 | 12篇 |
2021年 | 33篇 |
2020年 | 22篇 |
2019年 | 24篇 |
2018年 | 62篇 |
2017年 | 60篇 |
2016年 | 115篇 |
2015年 | 153篇 |
2014年 | 163篇 |
2013年 | 159篇 |
2012年 | 226篇 |
2011年 | 255篇 |
2010年 | 144篇 |
2009年 | 82篇 |
2008年 | 108篇 |
2007年 | 124篇 |
2006年 | 76篇 |
2005年 | 81篇 |
2004年 | 101篇 |
2003年 | 39篇 |
2002年 | 29篇 |
2001年 | 26篇 |
2000年 | 5篇 |
1999年 | 5篇 |
1998年 | 5篇 |
1997年 | 9篇 |
1996年 | 1篇 |
1995年 | 7篇 |
1994年 | 5篇 |
1993年 | 37篇 |
1992年 | 18篇 |
1991年 | 5篇 |
1990年 | 6篇 |
1989年 | 10篇 |
1988年 | 3篇 |
1987年 | 9篇 |
1986年 | 2篇 |
1985年 | 4篇 |
1984年 | 1篇 |
1982年 | 1篇 |
1980年 | 2篇 |
1979年 | 1篇 |
1978年 | 1篇 |
1957年 | 5篇 |
1956年 | 12篇 |
排序方式: 共有2263条查询结果,搜索用时 78 毫秒
111.
112.
Aurélie Gardarin Stéphane Chédin Gilles Lagniel Jean‐Christophe Aude Emmanuel Godat Patrice Catty Jean Labarre 《Molecular microbiology》2010,76(4):1034-1048
Cadmium (Cd2+) is a very toxic metal that causes DNA damage, oxidative stress and apoptosis. Despite many studies, the cellular and molecular mechanisms underlying its high toxicity are not clearly understood. We show here that very low doses of Cd2+ cause ER stress in Saccharomyces cerevisiae as evidenced by the induction of the unfolded protein response (UPR) and the splicing of HAC1 mRNA. Furthermore, mutant strains (Δire1 and Δhac1) unable to induce the UPR are hypersensitive to Cd2+, but not to arsenite and mercury. The full functionality of the pathways involved in ER stress response is required for Cd2+ tolerance. The data also suggest that Cd2+‐induced ER stress and Cd2+ toxicity are a direct consequence of Cd2+ accumulation in the ER. Cd2+ does not inhibit disulfide bond formation but perturbs calcium metabolism. In particular, Cd2+ activates the calcium channel Cch1/Mid1, which also contributes to Cd2+ entry into the cell. The results reinforce the interest of using yeast as a cellular model to study toxicity mechanisms in eukaryotic cells. 相似文献
113.
114.
Annabelle Fernandez Delphine Lechardeur Aurélie Derré-Bobillot Elisabeth Couvé Philippe Gaudu Alexandra Gruss 《PLoS pathogens》2010,6(4)
Streptococcus agalactiae is a major neonatal pathogen whose infectious route involves septicemia. This pathogen does not synthesize heme, but scavenges it from blood to activate a respiration metabolism, which increases bacterial cell density and is required for full virulence. Factors that regulate heme pools in S. agalactiae are unknown. Here we report that one main strategy of heme and protoporphyrin IX (PPIX) homeostasis in S. agalactiae is based on a regulated system of efflux using two newly characterized operons, gbs1753 gbs1752 (called pefA pefB), and gbs1402 gbs1401 gbs1400 (called pefR pefC pefD), where pef stands for ‘porphyrin-regulated efflux’. In vitro and in vivo data show that PefR, a MarR-superfamily protein, is a repressor of both operons. Heme or PPIX both alleviate PefR-mediated repression. We show that bacteria inactivated for both Pef efflux systems display accrued sensitivity to these porphyrins, and give evidence that they accumulate intracellularly. The ΔpefR mutant, in which both pef operons are up-regulated, is defective for heme-dependent respiration, and attenuated for virulence. We conclude that this new efflux regulon controls intracellular heme and PPIX availability in S. agalactiae, and is needed for its capacity to undergo respiration metabolism, and to infect the host. 相似文献
115.
Dynamin and other proteins of the dynamin superfamily are widely used by cells to sever lipid bilayers. During this process, a short helical dynamin polymer (one to three helical turns) assembles around a membrane tubule and reduces its radius and pitch upon guanosine triphosphate hydrolysis. This deformation is thought to be crucial for dynamin's severing action and results in an observable twisting of the helix. Here, we quantitatively characterize the dynamics of this deformation by studying long dynamin helices (many helical turns). We perform in vitro experiments where we attach small beads to the dynamin helix and track their rotation in real time, thus collecting information about the space and time dependence of the deformation. We develop a theoretical formalism to predict the dynamics of a mechanically continuous helix deforming on long timescales. Longer helices deform more slowly, as predicted by theory. This could account for the previously reported observation that they are less fission-competent. Comparison between experiments and our model indicates that the deformation dynamics is dominated by the draining of the membrane out of the helix, allowing quantification of helix-membrane interactions. 相似文献
116.
Barrila J Radtke AL Crabbé A Sarker SF Herbst-Kralovetz MM Ott CM Nickerson CA 《Nature reviews. Microbiology》2010,8(11):791-801
Appropriately simulating the three-dimensional (3D) environment in which tissues normally develop and function is crucial for engineering in vitro models that can be used for the meaningful dissection of host-pathogen interactions. This Review highlights how the rotating wall vessel bioreactor has been used to establish 3D hierarchical models that range in complexity from a single cell type to multicellular co-culture models that recapitulate the 3D architecture of tissues observed in vivo. The application of these models to the study of infectious diseases is discussed. 相似文献
117.
Cazet A Lefebvre J Adriaenssens E Julien S Bobowski M Grigoriadis A Tutt A Tulasne D Le Bourhis X Delannoy P 《Molecular cancer research : MCR》2010,8(11):1526-1535
The disialoganglioside G(D3) is overexpressed in ~50% of invasive ductal breast carcinoma, and the G(D3) synthase gene (ST8SIA1) displays higher expression among estrogen receptor-negative breast cancer tumors, associated with a decreased overall survival of breast cancer patients. However, no relationship between ganglioside expression and breast cancer development and aggressiveness has been reported. We have previously shown that overexpression of G(D3) synthase induces the accumulation of b- and c-series gangliosides (G(D3), G(D2), and G(T3)) at the cell surface of MDA-MB-231 breast cancer cells together with the acquisition of a proliferative phenotype in the absence of serum. Here, we show that phosphoinositide 3-kinase/Akt and mitogen-activated protein kinase/extracellular signal-regulated kinase pathways are constitutively activated in G(D3) synthase-expressing cells. Analysis of phosphorylation of tyrosine kinase receptors shows a specific c-Met constitutive activation in G(D3) synthase-expressing cells, in the absence of its ligand, hepatocyte growth factor/scatter factor. In addition, inhibition of c-Met or downstream signaling pathways reverses the proliferative phenotype. We also show that G(D3) synthase expression enhances tumor growth in severe combined immunodeficient mice. Finally, a higher expression of ST8SIA1 and MET in the basal subtype of human breast tumors are observed. Altogether, our results show that G(D3) synthase expression is sufficient to enhance the tumorigenicity of MDA-MB-231 breast cancer cells through a ganglioside-dependent activation of the c-Met receptor. 相似文献
118.
119.
120.
Bertin A Durand D Renouard M Livolant F Mangenot S 《European biophysics journal : EBJ》2007,36(8):1083-1094
The conformation of recombinant Nucleosome Core Particles (NCPs) lacking H2A and H2B histone tails (gH2AgH2B) are studied.
The migration of these particles in acrylamide native gels is slowed down compared to intact reconstituted NCPs. gH2AgH2B
NCPs are also much more sensitive to nuclease digestion than intact NCPs. Small angle X-ray scattering (SAXS) experiments
point out that the absence of H2A and H2B tails produces small but significant conformational changes of the octamers conformation
(without wrapped DNA), whereas gH2AgH2B NCP conformations are significantly altered. A separation of about 25–30 bp from the
core could account for the experimental curves, but other types of DNA superhelix deformation cannot be excluded. The distorted
gH2AgH2B octamer may not allow the correct winding of DNA around the core. The absence of the H2A and H2B tails would further
prevent the secondary sliding of the DNA around the core and therefore impedes the stabilisation of the particle. Cryo-electron
microscopy on the same particles also shows a detachment of DNA portions from the particle core. The effect is even stronger
because the vitrification of the samples worsens the instability of gH2AgH2B NCPs. 相似文献