全文获取类型
收费全文 | 9031篇 |
免费 | 798篇 |
国内免费 | 756篇 |
出版年
2024年 | 19篇 |
2023年 | 136篇 |
2022年 | 299篇 |
2021年 | 521篇 |
2020年 | 349篇 |
2019年 | 409篇 |
2018年 | 377篇 |
2017年 | 275篇 |
2016年 | 432篇 |
2015年 | 589篇 |
2014年 | 742篇 |
2013年 | 700篇 |
2012年 | 836篇 |
2011年 | 710篇 |
2010年 | 476篇 |
2009年 | 383篇 |
2008年 | 476篇 |
2007年 | 458篇 |
2006年 | 344篇 |
2005年 | 301篇 |
2004年 | 229篇 |
2003年 | 219篇 |
2002年 | 159篇 |
2001年 | 150篇 |
2000年 | 139篇 |
1999年 | 163篇 |
1998年 | 103篇 |
1997年 | 90篇 |
1996年 | 79篇 |
1995年 | 57篇 |
1994年 | 57篇 |
1993年 | 33篇 |
1992年 | 56篇 |
1991年 | 43篇 |
1990年 | 23篇 |
1989年 | 31篇 |
1988年 | 22篇 |
1987年 | 29篇 |
1986年 | 13篇 |
1985年 | 20篇 |
1984年 | 12篇 |
1983年 | 6篇 |
1982年 | 5篇 |
1981年 | 3篇 |
1980年 | 2篇 |
1979年 | 3篇 |
1978年 | 3篇 |
1976年 | 1篇 |
1975年 | 1篇 |
1965年 | 1篇 |
排序方式: 共有10000条查询结果,搜索用时 140 毫秒
991.
Ali Morsi El-Kadi Virginie Bros-Facer Wenhan Deng Amelia Philpott Eleanor Stoddart Gareth Banks Graham S. Jackson Elizabeth M. C. Fisher Michael R. Duchen Linda Greensmith Anthony L. Moore Majid Hafezparast 《The Journal of biological chemistry》2010,285(24):18627-18639
Amyotrophic lateral sclerosis (ALS) is a debilitating and fatal late-onset neurodegenerative disease. Familial cases of ALS (FALS) constitute ∼10% of all ALS cases, and mutant superoxide dismutase 1 (SOD1) is found in 15–20% of FALS. SOD1 mutations confer a toxic gain of unknown function to the protein that specifically targets the motor neurons in the cortex and the spinal cord. We have previously shown that the autosomal dominant Legs at odd angles (Loa) mutation in cytoplasmic dynein heavy chain (Dync1h1) delays disease onset and extends the life span of transgenic mice harboring human mutant SOD1G93A. In this study we provide evidence that despite the lack of direct interactions between mutant SOD1 and either mutant or wild-type cytoplasmic dynein, the Loa mutation confers significant reductions in the amount of mutant SOD1 protein in the mitochondrial matrix. Moreover, we show that the Loa mutation ameliorates defects in mitochondrial respiration and membrane potential observed in SOD1G93A motor neuron mitochondria. These data suggest that the Loa mutation reduces the vulnerability of mitochondria to the toxic effects of mutant SOD1, leading to improved mitochondrial function in SOD1G93A motor neurons. 相似文献
992.
Wanyin Deng Carmen L. de Hoog Hong B. Yu Yuling Li Matthew A. Croxen Nikhil A. Thomas Jose L. Puente Leonard J. Foster B. Brett Finlay 《The Journal of biological chemistry》2010,285(9):6790-6800
Enteropathogenic Escherichia coli, enterohemorrhagic E. coli, and Citrobacter rodentium belong to the family of attaching and effacing (A/E) bacterial pathogens. They intimately attach to host intestinal epithelial cells, trigger the effacement of intestinal microvilli, and cause diarrheal disease. Central to their pathogenesis is a type III secretion system (T3SS) encoded by a pathogenicity island called the locus of enterocyte effacement (LEE). The T3SS is used to inject both LEE- and non-LEE-encoded effector proteins into the host cell, where these effectors modulate host signaling pathways and immune responses. Identifying the effectors and elucidating their functions are central to understanding the molecular pathogenesis of these pathogens. Here we analyzed the type III secretome of C. rodentium using the highly sensitive and quantitative SILAC (stable isotope labeling with amino acids in cell culture)-based mass spectrometry. This approach not only confirmed nearly all known secreted proteins and effectors previously identified by conventional biochemical and proteomic techniques, but also identified several new secreted proteins. The T3SS-dependent secretion of these new proteins was validated, and five of them were translocated into cultured cells, representing new or additional effectors. Deletion mutants for genes encoding these effectors were generated in C. rodentium and tested in a murine infection model. This study comprehensively characterizes the type III secretome of C. rodentium, expands the repertoire of type III secreted proteins and effectors for the A/E pathogens, and demonstrates the simplicity and sensitivity of using SILAC-based quantitative proteomics as a tool for identifying substrates for protein secretion systems. 相似文献
993.
Shufen Huang Wen Shan Yew Philip K. Moore Lih-Wen Deng 《Journal of molecular biology》2010,396(3):708-718
In recent years, increased interest has been directed towards hydrogen sulfide (H2S) as the third gasotransmitter and its role in various diseases. Cystathionine-γ-lyase (CSE) is one of the enzymes responsible for the endogenous production of H2S in mammals. With the aid of the crystal structures of human CSE and site-directed mutagenesis studies, we have identified several amino acid residues in CSE that are actively involved in the catalysis of H2S production. Contrary to reports suggesting that Tyr114 is required for substrate binding, our results reveal a significant increase in the production of H2S upon mutation of Tyr114 to phenylalanine. This is attributed to an increased rate of pyridoxal 5′-phosphate (PLP) regeneration due to weakened π-stacking interactions between Phe114 and PLP. Thr189 is also identified as a crucial residue where hydrogen bonding to Asp187 keeps the latter in an optimal position for hydrogen bonding to the pyridoxal nitrogen of PLP. Furthermore, mutation of Glu339 to lysine, alanine or tyrosine reveals the importance of the hydrophobicity of the 339th amino acid in determining the specificity of the enzyme for the catalysis of α,γ-elimination or α,β-elimination reaction. Our study also shows that the rate of H2S production is increased with increasing exogenous PLP concentration, hence supporting our hypothesis that apo-CSE is formed during the catalysis of H2S production. Taken together, these findings suggest novel routes towards the design of activators or inhibitors that modulate the production of H2S; these modulators may also serve as lead compounds in the development of drugs or mechanistic probes in the study of various H2S-related diseases. 相似文献
994.
Four new complexes, {[Mn(imH)2(pdc)]·H2O}n (1), [Zn2(pdc)2(H2O)5]·2H2O (2), [Zn(imH)2(pdc)]·H2O (3), {[Zn2(pdc)2(bpy)(H2O)2]·5H2O}n (4) [imH = imidazole pdc = pyridine 2,6-dicarboxylate, bpy = 4,4′-bipyridine] have been synthesized under hydrothermal conditions and structurally characterized by elemental analysis, IR, PXRD, single-crystal X-ray diffraction and thermogravimetric analyses. All the four complexes display a three-dimensional (3D) open framework with one-dimensional (1D) channels that are filled with lattice water molecules. Particularly, in 4, the lattice water molecules form an infinite water chain. Both 1 and 4 consist of 1D polymeric chains. While 2 contains a dinuclear Zn(II) unit, and 3 is a mononuclear complex. Further, the result of thermal analysis of 1 and 2 shows the robustness of the overall supramolecular three-dimensional architecture. Complexes 1, 3, and 4 exhibit strong fluorescent emissions in the solid state at room temperature and could be significant in the field of photoactive materials. 相似文献
995.
Novel chitosan/ZnO nanoparticle (CS/nano-ZnO) composite membranes were prepared via the method of sol-cast transformation and studied by UV-vis absorption spectroscopy (UV-vis), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), scanning electron microscopy (SEM), and energy dispersive X-ray fluorescence spectrometry (EDX). The characterization revealed that ZnO nanoparticles dispersed homogeneously within the chitosan matrix. The mechanical and antibacterial properties of the product were investigated. The results showed that the ZnO content had an effect on the mechanical properties of CS/nano-ZnO composite membranes, and that the antibacterial activities of CS membranes for Bacillus subtilis, Escherichia coli, and Staphylococcus aureus were enhanced by the incorporation of ZnO. Further, CS/nano-ZnO composite membranes with 6-10 wt % ZnO exhibited high antibacterial activities. 相似文献
996.
Vasoactive intestinal peptide (VIP) is a well-known anti-inflammatory neuropeptide. The capacity of VIP can be exhibited through inhibiting inflammatory responses, shifting the Th1/Th2 balance in favor of anti-inflammatory Th2 immunity and inducing regulatory T cells (Tregs) with suppressive activity. In addition to pro-inflammatory Th1 response, Th17 are also believed to play important roles in the pathogenesis of rheumatoid arthritis (RA). In this study, we used collagen-induced arthritis (CIA) model in Wistar rats to investigate the role of VIP in the balance of CD4+ CD25+ Tregs and Th17 on RA. Data presented here showed that administration of VIP decreased incidence and severity of CIA. Disease suppression was associated with the upregulation of CD4+ CD25+ Tregs, downregulation of Th17- and Th1-type response and influence on the RANK/RANKL/OPG system. The results provide novel evidence that the therapeutic effects of VIP on CIA rats were associated with the balance of CD4+ CD25+ Tregs and Th17. 相似文献
997.
Ruchuon Wanna Zhihong Xu Yahui Liu Haixin Yu Lijun Ren Lihua He Jiancheng Li 《Entomologia Experimentalis et Applicata》2010,137(2):111-119
The effects of the mixed biocide Bacillus thuringiensis Berliner with abamectin (BtA) on the development of the parasitoid Microplitis mediator (Haliday) (Hymenoptera: Braconidae) and its cotton bollworm host, Helicoverpa armigera (Hübner) (Lepidoptera: Noctuidae), were evaluated in the laboratory. Weight gain in larvae of H. armigera was initially delayed, but larval developmental period increased and pupal weight increased when they were fed on a diet containing BtA. Due to increased longevity of the host larvae, the susceptible period to parasitization of H. armigera by M. mediator increased when the host larvae were reared on diets containing BtA at concentrations of 0.5, 1, 2, and 4 μg g?1. The longevity of female and male parasitoids significantly decreased when newly emerged wasps were fed a honey solution containing 200 μg ml?1 BtA in comparison with those fed only a honey solution. Mean longevity was significantly prolonged when parasitoids were fed a honey solution and BtA–honey solution in comparison with those fed BtA–distilled water, distilled water, or nothing. There were no significant differences compared with the control in any biological characteristics for the offspring of female parasitoids fed the honey solutions containing BtA at concentrations of 50, 100, and 200 μg ml?1; characteristics measured include the egg‐larval period, pupal weight, male and female pupal periods, adult fresh weight, and adult longevity. When female parasitoids parasitized host larvae that had been fed the diet containing BtA, their male and female pupal periods were significantly prolonged compared with the control (without BtA). 相似文献
998.
999.
Beta-subunit of cardiac Na+-K+-ATPase dictates the concentration of the functional enzyme in caveolae 总被引:1,自引:0,他引:1
Previous studies showed the presence of a significant fraction of Na+-K+-ATPase -subunits in cardiac myocyte caveolae, suggesting the caveolar interactions of Na+-K+-ATPase with its signaling partners. Because both - and -subunits are required for ATPase activity, to clarify the status of the pumping function of caveolar Na+-K+-ATPase, we have examined the relative distribution of two major subunit isoforms (1 and 1) in caveolar and noncaveolar membranes of adult rat cardiac myocytes. When cell lysates treated with high salt (Na2CO3 or KCl) concentrations were fractionated by a standard density gradient procedure, the resulting light caveolar membranes contained 3040% of 1-subunits and 8090% of 1-subunits. Use of Na2CO3 was shown to inactivate Na+-K+-ATPase; however, caveolar membranes obtained by the KCl procedure were not denatured and contained 75% of total myocyte Na+-K+-ATPase activity. Sealed isolated caveolae exhibited active Na+ transport. Confocal microscopy supported the presence of ,-subunits in caveolae, and immunoprecipitation showed the association of the subunits with caveolin oligomers. The findings indicate that cardiac caveolar inpocketings are the primary portals for active Na+-K+ fluxes, and the sites where the pumping and signaling functions of Na+-K+-ATPase are integrated. Preferential concentration of 1-subunit in caveolae was cell specific; it was also noted in neonatal cardiac myocytes but not in fibroblasts and A7r5 cells. Uneven distributions of 1 and 1 in early and late endosomes of myocytes suggested different internalization routes of two subunits as a source of selective localization of active Na+-K+-ATPase in cardiac caveolae. cardiac myocyte; caveolin; oligomer; ouabain; sodium pump 相似文献
1000.