全文获取类型
收费全文 | 1087篇 |
免费 | 100篇 |
专业分类
1187篇 |
出版年
2024年 | 1篇 |
2023年 | 2篇 |
2022年 | 9篇 |
2021年 | 23篇 |
2020年 | 14篇 |
2019年 | 16篇 |
2018年 | 20篇 |
2017年 | 26篇 |
2016年 | 34篇 |
2015年 | 71篇 |
2014年 | 64篇 |
2013年 | 75篇 |
2012年 | 98篇 |
2011年 | 106篇 |
2010年 | 70篇 |
2009年 | 69篇 |
2008年 | 59篇 |
2007年 | 65篇 |
2006年 | 57篇 |
2005年 | 59篇 |
2004年 | 64篇 |
2003年 | 72篇 |
2002年 | 52篇 |
2001年 | 3篇 |
2000年 | 1篇 |
1999年 | 5篇 |
1998年 | 11篇 |
1997年 | 8篇 |
1996年 | 1篇 |
1995年 | 6篇 |
1994年 | 3篇 |
1993年 | 2篇 |
1991年 | 6篇 |
1989年 | 2篇 |
1988年 | 1篇 |
1985年 | 1篇 |
1984年 | 2篇 |
1983年 | 2篇 |
1981年 | 2篇 |
1977年 | 1篇 |
1975年 | 1篇 |
1968年 | 1篇 |
1964年 | 1篇 |
1950年 | 1篇 |
排序方式: 共有1187条查询结果,搜索用时 15 毫秒
91.
Background
An in silico analysis of the mitochondrial protein import apparatus from a variety of species; including Chlamydomonas reinhardtii, Chlorella variabilis, Ectocarpus siliculosus, Cyanidioschyzon merolae, Physcomitrella patens, Selaginella moellendorffii, Picea glauca, Oryza sativa and Arabidopsis thaliana was undertaken to determine if components differed within and between plant and non-plant species. 相似文献92.
Cortessis VK Thomas DC Levine AJ Breton CV Mack TM Siegmund KD Haile RW Laird PW 《Human genetics》2012,131(10):1565-1589
Changes in epigenetic marks such as DNA methylation and histone acetylation are associated with a broad range of disease traits, including cancer, asthma, metabolic disorders, and various reproductive conditions. It seems plausible that changes in epigenetic state may be induced by environmental exposures such as malnutrition, tobacco smoke, air pollutants, metals, organic chemicals, other sources of oxidative stress, and the microbiome, particularly if the exposure occurs during key periods of development. Thus, epigenetic changes could represent an important pathway by which environmental factors influence disease risks, both within individuals and across generations. We discuss some of the challenges in studying epigenetic mediation of pathogenesis and describe some unique opportunities for exploring these phenomena. 相似文献
93.
94.
Conrad DM Hanniman EA Watson CL Mader JS Hoskin DW 《Journal of cellular biochemistry》2004,92(2):387-399
Ryanodine receptors (RyR) are involved in regulating intracellular Ca(++) mobilization in T lymphocytes. However, the importance of RyR signaling during T cell activation has not yet been determined. In this study, we have used the RyR-selective antagonists, ruthenium red and dantrolene, to determine the effect of RyR blockade on T cell receptor-mediated activation events and cytokine-dependent T cell proliferation. Both ruthenium red and dantrolene inhibited DNA synthesis and cell division, as well as the synthesis of interleukin (IL)-2 by T lymphocytes responding to mitogenic anti-CD3 antibody. Blockade of RyR at initiation of culture or as late as 24 h after T cell receptor stimulation inhibited T cell proliferation, suggesting a requirement for sustained RyR signaling during cell cycle progression. Although flow cytometry revealed that RyR blockade had little effect on activation-induced expression of the alpha chain (CD25) of the high affinity IL-2 receptor, the inhibitory effect of RyR antagonists could not be reversed by the addition of exogenous IL-2 at initiation of culture. In addition, both ruthenium red and dantrolene had a strong inhibitory effect on IL-2-dependent proliferation of CTLL-2 T cells. These data indicate that RyR are involved in regulating IL-2 receptor signaling that drives T cell progression through the cell cycle. We conclude that RyR-associated Ca(++) signaling regulates T cell proliferation by promoting both IL-2 synthesis and IL-2-dependent cell cycle progression. 相似文献
95.
Sutherland-Smith M Campos JM Cramer C Thorstadt C Toone W Morris PJ 《Journal of wildlife diseases》2004,40(4):731-736
A combination of medetomidine, Telazol, and ketamine hydrochloride was used to immobilize captive Chacoan peccaries (Catagonus wagneri) for translocation within Paraguay during August-October 2002. Animals were darted in enclosed areas of varying size. The average dose used was 32.5+/-7.2 microg/kg of medetomidine, 0.63+/-0.2 mg/kg of Telazol, and 3.9+/-0.65 mg/kg of ketamine. First effects were noted at 4.3+/-2.1 min, and ability to handle the animals was achieved by 12.6+/-3.7 min. Heart and respiratory rates declined and oxygen saturation increased during anesthesia. Muscle relaxation was good. Atipamezole was used to antagonize the medetomidine, although recoveries were still slow. This drug combination provided adequate immobilization of Chacoan peccaries; however, this protocol would not be considered to be reversible, and confinement during recovery is recommended. 相似文献
96.
Elzie CA Murphy-Ullrich JE 《The international journal of biochemistry & cell biology》2004,36(6):1090-1101
Thrombospondin 1 (TSP1) was first recognized as a thrombin-sensitive protein associated with platelet membranes. It is secreted by numerous cell types and its expression is predominant in areas of active tissue remodeling. Thrombospondins 1 and 2 are large, trimeric, matricellular proteins, composed of multiple structural motifs which interact with a diverse array of receptors and molecules. Thrombospondin's capacity to bind multiple receptors renders it multifunctional. The functions of its isolated domains can be overlapping or contradictory. In this review, we focus on the N-terminus of the molecule, first recognized for its strong heparin binding properties and characterized by its susceptibility to proteolytic cleavage from the stalk region of thrombospondin. The N-terminus, called the heparin binding domain (HBD), interacts with a variety of macromolecules including heparan sulfate proteoglycans at the membrane and in the matrix, LDL receptor-related protein (LRP), sulfated glycolipids, calreticulin, and integrins. The HBD mediates endocytosis of thrombospondin. It functions both as a soluble and an insoluble modulator of cell adhesion and motility. In contrast to thrombospondin, the HBD has pro-angiogenic activity. We propose that the HBD of thrombospondins 1 and 2 are found primarily in the cellular microenvironment in conditions of cellular injury, stress and tissue remodeling and that the HBD conveys multiple signals involved in cellular adaptation to injury. 相似文献
97.
Misra UK Gonzalez-Gronow M Gawdi G Hart JP Johnson CE Pizzo SV 《The Journal of biological chemistry》2002,277(44):42082-42087
The low density lipoprotein receptor-related protein (LRP) is a scavenger receptor that binds to many proteins, some of which trigger signal transduction. Receptor-recognized forms of alpha(2)-Macroglobulin (alpha(2)M*) bind to LRP, but the pattern of signal transduction differs significantly from that observed with other LRP ligands. For example, neither Ni(2+) nor the receptor-associated protein, which blocks binding of all known ligands to LRP, block alpha(2)M*-induced signal transduction. In the current study, we employed alpha(2)-macroglobulin (alpha(2)M)-agarose column chromatography to purify cell surface membrane binding proteins from 1-LN human prostate cancer cells and murine macrophages. The predominant binding protein purified from 1-LN prostate cancer cells was Grp 78 with small amounts of LRP, a fact that is consistent with our previous observations that there is little LRP present on the surface of these cells. The ratio of LRP:Grp 78 is much higher in macrophages. Flow cytometry was employed to demonstrate the presence of Grp 78 on the cell surface of 1-LN cells. Purified Grp 78 binds to alpha(2)M* with high affinity (K(d) approximately 150 pm). A monoclonal antibody directed against Grp 78 both abolished alpha(2)M*-induced signal transduction and co-precipitated LRP. Ligand blotting with alpha(2)M* showed binding to both Grp 78 and LRP heavy chains in these preparations. Use of RNA interference to silence LRP expression had no effect on alpha(2)M*-mediated signaling. We conclude that Grp 78 is essential for alpha(2)M*-induced signal transduction and that a "co-receptor" relationship exists with LRP like that seen with several other ligands and receptors such as the uPA/uPAR (urinary type plasminogen activator or urokinase/uPA receptor) system. 相似文献
98.
Polymorphisms of G-protein coupled receptor (GPCR) genes are associated with disease risk and modification, and the response to receptor-directed therapy. Genomic sequencing ( approximately 1700 automated runs) from as many as 120 chromosomes from 60 multiethnic individuals was performed to confirm non-synonymous coding polymorphisms reported in the dbSNP database from 25 randomly selected GPCR genes. These polymorphisms were in regions of the receptors responsible for structural integrity, ligand binding, G-protein coupling and phosphoregulation. However, most of these putative polymorphisms could not be confirmed (false positive rate of 68%). Based on these results, we suggest that the variability of the superfamily is not well defined, and we caution against exclusive reliance on databases for selection of candidate GPCR polymorphisms for disease association and pharmacogenetic studies. 相似文献
99.
Nephrogenesis starts with the reciprocal induction of two embryonically distinct analages, metanephric mesenchyme and ureteric bud. This complex process requires the refined and coordinated expression of numerous developmental genes, such as inv. Mice that are homozygous for a mutation in the inv gene (inv/inv) develop renal cysts resembling autosomal-recessive polycystic kidney disease. The gene locus containing inv has been proposed to serve as a common modifier for some human and rodent polycystic kidney disease phenotypes. We generated polyclonal antibodies to inversin to study its subcellular distribution, potential binding partners, and functional aspects in cultured murine proximal tubule cells. A 125-kDa inversin protein isoform was found at cell-cell junctions. Two inversin isoforms, 140- and 90-kDa, were identified in the nuclear and perinuclear compartments. Plasma membrane allocation of inversin is dependent upon cell-cell contacts and was redistributed when cell adhesion was disrupted after incubation of the cell monolayer with low-calcium/EGTA medium. We further show that the membrane-associated 125-kDa inversin forms a complex with N-cadherin and the catenins. The 90-kDa nuclear inversin complexes with beta-catenin. These findings indicate that the inv gene product functions in several cellular compartments, including the nucleus and cell-cell adhesion sites. 相似文献
100.
Duffy JL Kirk BA Kevin NJ Chapman KT Schleif WA Olsen DB Stahlhut M Rutkowski CA Kuo LC Jin L Lin JH Emini EA Tata JR 《Bioorganic & medicinal chemistry letters》2003,13(19):3323-3326
Transposition of the pyridyl nitrogen from the P(3) substituent to the P(1)' substituent in HIV-1 protease inhibitors (PI) affords compounds such as 3 with an improved inhibitory profile against multiple P450 isoforms. These compounds also displayed increased potency, with 3 inhibiting viral spread (CIC(95)) at <8 nM for every strain of PI-resistant HIV-1 tested. The poor to modest bioavailability of these compounds may correlate in part to their aqueous solubility. 相似文献