全文获取类型
收费全文 | 1098篇 |
免费 | 89篇 |
出版年
2022年 | 9篇 |
2021年 | 12篇 |
2020年 | 11篇 |
2019年 | 8篇 |
2018年 | 8篇 |
2017年 | 10篇 |
2016年 | 23篇 |
2015年 | 48篇 |
2014年 | 53篇 |
2013年 | 61篇 |
2012年 | 66篇 |
2011年 | 69篇 |
2010年 | 36篇 |
2009年 | 55篇 |
2008年 | 79篇 |
2007年 | 52篇 |
2006年 | 61篇 |
2005年 | 66篇 |
2004年 | 70篇 |
2003年 | 70篇 |
2002年 | 66篇 |
2001年 | 12篇 |
2000年 | 14篇 |
1999年 | 12篇 |
1998年 | 17篇 |
1997年 | 13篇 |
1996年 | 11篇 |
1995年 | 14篇 |
1994年 | 9篇 |
1993年 | 9篇 |
1992年 | 10篇 |
1991年 | 10篇 |
1990年 | 10篇 |
1989年 | 6篇 |
1988年 | 9篇 |
1987年 | 5篇 |
1986年 | 3篇 |
1985年 | 4篇 |
1984年 | 8篇 |
1983年 | 5篇 |
1982年 | 9篇 |
1981年 | 8篇 |
1980年 | 3篇 |
1979年 | 8篇 |
1978年 | 5篇 |
1977年 | 4篇 |
1976年 | 5篇 |
1975年 | 5篇 |
1974年 | 8篇 |
1970年 | 3篇 |
排序方式: 共有1187条查询结果,搜索用时 15 毫秒
61.
Christine?A?WhiteEmail author Lorraine?Robb Lois?A?Salamonsen 《Reproductive biology and endocrinology : RB&E》2004,2(1):76
Background
Implantation of the embryo and successful pregnancy are dependent on the differentiation of endometrial stromal cells into decidual cells. Female interleukin-11 receptor α (IL-11Rα) deficient mice are infertile due to disrupted decidualization, suggesting a critical role for IL-11 and its target genes in implantation. The molecular targets of IL-11 in the uterus are unknown, but it is likely that IL-11 signaling modifies the expression of other genes important in decidualization. This study aimed to identify genes regulated by IL-11 during decidualization in mouse uterus, and to examine their expression and localization as an indication of functional significance during early pregnancy.Methods
Decidualization was artificially induced in pseudopregnant wild type (IL11Ra+/+) and IL-11Rα deficient (IL11Ra-/-) littermates by oil injection into the uterine lumen, and gene expression analyzed by NIA 15K cDNA microarray analysis at subsequent time points. Quantitative real-time RT-PCR was used as an alternative mRNA quantitation method and the expression and cellular localization of the protein products was examined by immunohistochemistry.Results
Among 15,247 DNA probes, 13 showed increased and 4 decreased expression in IL11Ra-/- uterus at 48 h of decidualization. These included 4 genes encoding extracellular matrix proteins; collagen III α1, secreted acidic cysteine-rich glycoprotein (SPARC), biglycan and nidogen-1 (entactin). Immunohistochemistry confirmed increased collagen III and biglycan protein expression in IL11Ra-/- uterus at this time. In both IL11Ra-/- and wild type uterus, collagen III and biglycan were primarily localized to the outer connective tissue and smooth muscle cells of the myometrium, with diffuse staining in the cytoplasm of decidualized stromal cells.Conclusion
These data suggest that IL-11 regulates changes in the uterine extracellular matrix that are necessary for decidualization.62.
63.
Swarup R Kargul J Marchant A Zadik D Rahman A Mills R Yemm A May S Williams L Millner P Tsurumi S Moore I Napier R Kerr ID Bennett MJ 《The Plant cell》2004,16(11):3069-3083
We have investigated the subcellular localization, the domain topology, and the amino acid residues that are critical for the function of the presumptive Arabidopsis thaliana auxin influx carrier AUX1. Biochemical fractionation experiments and confocal studies using an N-terminal yellow fluorescent protein (YFP) fusion observed that AUX1 colocalized with plasma membrane (PM) markers. Because of its PM localization, we were able to take advantage of the steep pH gradient that exists across the plant cell PM to investigate AUX1 topology using YFP as a pH-sensitive probe. The YFP-coding sequence was inserted in selected AUX1 hydrophilic loops to orient surface domains on either apoplastic or cytoplasmic faces of the PM based on the absence or presence of YFP fluorescence, respectively. We were able to demonstrate in conjunction with helix prediction programs that AUX1 represents a polytopic membrane protein composed of 11 transmembrane spanning domains. In parallel, a large aux1 allelic series containing null, partial-loss-of-function, and conditional mutations was characterized to identify the functionally important domains and amino acid residues within the AUX1 polypeptide. Whereas almost all partial-loss-of-function and null alleles cluster in the core permease region, the sole conditional allele aux1-7 modifies the function of the external C-terminal domain. 相似文献
64.
Burne-Taney MJ Ascon DB Daniels F Racusen L Baldwin W Rabb H 《Journal of immunology (Baltimore, Md. : 1950)》2003,171(6):3210-3215
Recent data have demonstrated a role for CD4(+) cells in the pathogenesis of renal ischemia reperfusion injury (IRI). Identifying engagement of adaptive immune cells in IRI suggests that the other major cell of the adaptive immune response, B cells, may also mediate renal IRI. An established model of renal IRI was used: 30 min of renal pedicle clamping was followed by reperfusion in B cell-deficient ( mu MT) and wild-type mice. Renal function was significantly improved in mu MT mice compared with wild-type mice at 24, 48, and 72 h postischemia. mu MT mice also had significantly reduced tubular injury. Both groups of mice had similar renal phagocyte infiltration postischemia assessed by myeloperoxidase levels and similar levels of CD4(+) T cell infiltration postischemia. Peritubular complement C3d staining was also similar in both groups. To identify the contribution of cellular vs soluble mechanism of action, serum transfer into mu MT mice partially restored ischemic phenotype, but B cell transfers did not. These data are the first demonstration of a pathogenic role for B cells in ischemic acute renal failure, with a serum factor as a potential underlying mechanism of action. 相似文献
65.
Identification of the receptor binding domain of the mouse mammary tumor virus envelope protein 下载免费PDF全文
Mouse mammary tumor virus (MMTV) is a betaretrovirus that infects rodent cells and uses mouse transferrin receptor 1 for cell entry. To characterize the interaction of MMTV with its receptor, we aligned the MMTV envelope surface (SU) protein with that of Friend murine leukemia virus (F-MLV) and identified a putative receptor-binding domain (RBD) that included a receptor binding sequence (RBS) of five amino acids and a heparin-binding domain (HBD). Mutation of the HBD reduced virus infectivity, and soluble heparan sulfate blocked infection of cells by wild-type pseudovirus. Interestingly, some but not all MMTV-like elements found in primary and cultured human breast cancer cell lines, termed h-MTVs, had sequence alterations in the putative RBS. Single substitution of one of the amino acids found in an h-MTV RBS variant in the RBD of MMTV, Phe(40) to Ser, did not alter species tropism but abolished both virus binding to cells and infectivity. Neutralizing anti-SU monoclonal antibodies also recognized a glutathione S-transferase fusion protein that contained the five-amino-acid RBS region from MMTV. The critical Phe(40) residue is located on a surface of the MMTV RBD model that is distant from and may be structurally more rigid than the region of F-MLV RBD that contains its critical binding site residues. This suggests that, in contrast to other murine retroviruses, binding to its receptor may result in few or no changes in MMTV envelope protein conformation. 相似文献
66.
The effects of acute administration of nicotine on target biting (defensive) and resident-intruder (offensive) attack of male mice were assessed. In the target biting procedure confined mice received tail shock on a fixed time, 2-min schedule. Under baseline conditions, biting attack directed toward an inanimate target occurred at three distinct rates. A high target biting rate (13.5 +/- 3.8 bites/15 sec) followed shock delivery, an intermediate biting rate (9.6 +/- 4.1 bites/15 sec) occurred during the inter-shock interval, and a low biting rate (1.0 +/- 0.5 bites/15 sec) occurred during a tone stimulus which signalled the impending shock. Nicotine (administered IP, 15 min presession) reduced post-shock and inter-shock interval target biting in a dose-dependent manner (ED50 values estimated at 0.13 and 0.14 mg/kg, respectively) but exerted more variable effects on target biting during the tone. In the resident-intruder paradigm the same mice were exposed to an intruder introduced into its home cage for a 10-min test session. Under baseline conditions, residents directed 20 +/- 3.2 biting attacks toward the intruder during the session with an average latency of 89 +/- 40 sec to the first attack. Nicotine caused a dose-dependent decrease in this attack behavior (ED50 values estimated to be 0.48 and 0.49 mg/kg, respectively). These observations are interpreted to indicate that nicotine has an increased potency at reducing "defensive" aggression. 相似文献
67.
The phosphatidylinositol turnover assay is used widely to measure activation, and inhibition, of G(q)-linked G-protein-coupled receptors. Cells expressing the receptor of interest are labeled by feeding with tritiated myo-inositol. The label is incorporated into cellular phosphatidylinositol 4,5-bisphosphate, which, upon agonist binding to the receptor, is hydrolyzed by phospholipase C to inositol 1,4,5-trisphosphate (IP(3)) and diacylglycerol. In the presence of Li(+), dephosphorylation of IP(3) to inositol is blocked, and the mass of soluble inositol phosphates is a quantitative readout of receptor activation. Current protocols for this assay all involve an anion-exchange chromatography step to separate radiolabeled inositol phosphates from radiolabeled inositol, making the assay cumbersome and difficult to automate. We now describe a scintillation proximity assay to measure soluble inositol phosphate mass in cell extracts, thus obviating the need for the standard chromatography step. The method uses positively charged yttrium silicate beads that bind inositol phosphates, but not inositol. We have used this assay to measure activation of recombinant and endogenous muscarinic acetylcholine receptors and activation of recombinant neuropeptide FF2 receptor coupled to IP(3) production by coexpression of a chimeric G protein. Further, we demonstrate the use and functional validity of this assay in a semiautomated, 384-well format, by characterizing the muscarinic receptor antagonists pirenzepine and atropine. 相似文献
68.
Mitochondria-derived glutamate at the interplay between branched-chain amino acid and glucose-induced insulin secretion 总被引:2,自引:0,他引:2
In pancreatic beta-cells, glutamate has been proposed to mediate insulin secretion as a glucose-derived factor, although it is also considered for its sole catabolic function. Hence, changes in cellular glutamate levels are a matter of debate. Here, we investigated the effects of glucose and the glutamate precursor glutamine on kinetics of glutamate levels together with insulin secretion in INS-1E beta-cells. Preincubation at low (1 mM) glucose resulted in reduced cellular glutamate levels, which were doubled by exposure to glutamine. In glutamine-deprived cells, 5 mM glucose restored glutamate concentrations. Incubation at 15 mM glucose increased cellular glutamate, along with stimulation of insulin secretion, following both glutamine-free and glutamine-rich preincubations. Nuclear magnetic resonance (NMR) spectroscopy of INS-1E cells exposed to 15 mM D-[1-(13)C]glucose revealed glutamate as the major glucose metabolic product. Branched-chain amino acids, such as leucine, reduced cellular glutamate levels at low and intermediate glucose. This study demonstrates that glucose stimulates glutamate generation, whereas branched-chain amino acids promote competitive glutamate expenditure. 相似文献
69.
70.
Lanningham-Foster L Green CL Langkamp-Henken B Davis BA Nguyen KT Bender BS Cousins RJ 《American journal of physiology. Endocrinology and metabolism》2002,282(6):E1197-E1203
Cysteine-rich intestinal protein (CRIP), which contains a double zinc finger motif, is a member of the Group 2 LIM protein family. Our results showed that the developmental regulation of CRIP in neonates was not influenced by conventional vs. specific pathogen-free housing conditions. Thymic and splenic CRIP expression was not developmentally regulated. A line of transgenic (Tg) mice that overexpress the rat CRIP gene was created. When challenged with lipopolysaccharide, the Tg mice lost more weight, exhibited increased mortality, experienced greater diarrhea incidence, and had less serum interferon-gamma (IFN-gamma) and more interleukin (IL)-6 and IL-10. Similarly, splenocytes from the Tg mice produced less IFN-gamma and IL-2 and more IL-10 and IL-6 upon mitogen stimulation. Delayed-type hypersensitivity response was less in the Tg mice. Influenza virus infection produced greater weight loss in the Tg mice, which also showed delayed viral clearance. The observed responses to overexpression of the CRIP gene are consistent with a role for this LIM protein in a cellular pathway that produces an imbalance in cytokine pattern favoring Th2 cytokines. 相似文献