全文获取类型
收费全文 | 439篇 |
免费 | 56篇 |
专业分类
495篇 |
出版年
2021年 | 10篇 |
2020年 | 4篇 |
2019年 | 5篇 |
2018年 | 4篇 |
2017年 | 6篇 |
2016年 | 4篇 |
2015年 | 14篇 |
2014年 | 14篇 |
2013年 | 18篇 |
2012年 | 17篇 |
2011年 | 26篇 |
2010年 | 12篇 |
2009年 | 12篇 |
2008年 | 19篇 |
2007年 | 17篇 |
2006年 | 19篇 |
2005年 | 19篇 |
2004年 | 20篇 |
2003年 | 18篇 |
2002年 | 18篇 |
2001年 | 16篇 |
2000年 | 19篇 |
1999年 | 13篇 |
1998年 | 6篇 |
1996年 | 6篇 |
1995年 | 4篇 |
1994年 | 4篇 |
1993年 | 4篇 |
1992年 | 7篇 |
1991年 | 9篇 |
1990年 | 3篇 |
1989年 | 10篇 |
1988年 | 6篇 |
1987年 | 7篇 |
1986年 | 5篇 |
1985年 | 3篇 |
1984年 | 9篇 |
1982年 | 5篇 |
1981年 | 6篇 |
1980年 | 5篇 |
1979年 | 12篇 |
1978年 | 4篇 |
1977年 | 4篇 |
1976年 | 3篇 |
1974年 | 7篇 |
1973年 | 4篇 |
1972年 | 3篇 |
1971年 | 6篇 |
1967年 | 4篇 |
1958年 | 2篇 |
排序方式: 共有495条查询结果,搜索用时 15 毫秒
41.
We isolated 20 anonymous nuclear loci (8556 bp in total) from the Taiwan Hwamei (Garrulax taewanus), an endemic songbird of Taiwan. A panel of nine to 15 individuals with unknown relationship was used to characterize polymorphism of these loci. We identified 46 single nucleotide polymorphic sites (SNPs) in 15 polymorphic loci. Frequency of SNPs was one per every 186 bp in average. Nucleotide diversity, θ, ranged from 0.00054 to 0.00371 per locus. We also tested cross‐species applicability of these loci on 17 species from eight different passerine families. All 20 loci could be successfully amplified (ranged from one to 16 species, mean = 7.9 species). 相似文献
42.
The effect of neurotensin on submaximally-stimulated hepatobiliary and pancreatic secretion was studied in 6 healthy subjects. An intravenous infusion of neurotensin 1.4 ± 0.3 pmol/kg/min, designed to reproduce plasma neurotensin immunoreactivity levels within the physiological range, produced a significant increase in pancreatic bicarbonate output. Plasma concentrations of pancreatic polypeptide rose by 83 ± 16 pmol/l and were associated with a small reduction in trypsin, but no significant change in bilirubin outputs. 相似文献
43.
1. The effect of ammonia on purine and pyrimidine nucleotide biosynthesis was studied in rat liver and brain in vitro. The incorporation of NaH14CO3 into acid-soluble uridine nucleotide (UMP) in liver homogenates and minces was increased 2.5–4-fold on incubation with 10mm-NH4Cl plus N-acetyl-l-glutamate, but not with either compound alone. 2. The incorporation of NaH14CO3 into orotic acid was increased 3–4-fold in liver homogenate with NH4Cl plus acetylglutamate. 3. The 5-phosphoribosyl 1-pyrophosphate content of liver homogenate was decreased by 50% after incubation for 10min with 10mm-NH4Cl plus acetylglutamate. 4. Concomitant with this decrease in free phosphoribosyl pyrophosphate was a 40–50% decrease in the rates of purine nucleotide synthesis, both de novo and from the preformed base. 5. Subcellular fractionation of liver indicated that the effects of NH4Cl plus acetylglutamate on pyrimidine and purine biosynthesis required a mitochondrial fraction. This effect of NH4Cl plus acetylglutamate could be duplicated in a mitochondria-free liver fraction with carbamoyl phosphate. 6. A similar series of experiments carried out with rat brain demonstrated a significant, though considerably smaller, effect on UMP synthesis de novo and purine base reutilization. 7. These data indicate that excessive amounts of ammonia may interfere with purine nucleotide biosynthesis by stimulating production of carbamoyl phosphate through the mitochondrial synthetase, with the excess carbamoyl phosphate in turn increasing pyrimidine nucleotide synthesis de novo and diminishing the phosphoribosyl pyrophosphate available for purine biosynthesis. 相似文献
44.
Jamie L. Schafer Moritz Ries Natasha Guha Michelle Connole Arnaud D. Colantonio Emmanuel J. Wiertz Nancy A. Wilson Amitinder Kaur David T. Evans 《PLoS pathogens》2015,11(9)
Natural killer (NK) cell responses in primates are regulated in part through interactions between two highly polymorphic molecules, the killer-cell immunoglobulin-like receptors (KIRs) on NK cells and their major histocompatibility complex (MHC) class I ligands on target cells. We previously reported that the binding of a common MHC class I molecule in the rhesus macaque, Mamu-A1*002, to the inhibitory receptor Mamu-KIR3DL05 is stabilized by certain simian immunodeficiency virus (SIV) peptides, but not by others. Here we investigated the functional implications of these interactions by testing SIV peptides bound by Mamu-A1*002 for the ability to modulate Mamu-KIR3DL05+ NK cell responses. Twenty-eight of 75 SIV peptides bound by Mamu-A1*002 suppressed the cytolytic activity of primary Mamu-KIR3DL05+ NK cells, including three immunodominant CD8+ T cell epitopes previously shown to stabilize Mamu-A1*002 tetramer binding to Mamu-KIR3DL05. Substitutions at C-terminal positions changed inhibitory peptides into disinhibitory peptides, and vice versa, without altering binding to Mamu-A1*002. The functional effects of these peptide variants on NK cell responses also corresponded to their effects on Mamu-A1*002 tetramer binding to Mamu-KIR3DL05. In assays with mixtures of inhibitory and disinhibitory peptides, low concentrations of inhibitory peptides dominated to suppress NK cell responses. Consistent with the inhibition of Mamu-KIR3DL05+ NK cells by viral epitopes presented by Mamu-A1*002, SIV replication was significantly higher in Mamu-A1*002+ CD4+ lymphocytes co-cultured with Mamu-KIR3DL05+ NK cells than with Mamu-KIR3DL05- NK cells. These results demonstrate that viral peptides can differentially affect NK cell responses by modulating MHC class I interactions with inhibitory KIRs, and provide a mechanism by which immunodeficiency viruses may evade NK cell responses. 相似文献
45.
Seungwon Choi Kelsey P. Taylor Marios Chatzigeorgiou Zhitao Hu William R. Schafer Joshua M. Kaplan 《PLoS genetics》2015,11(7)
C. elegans undergoes periods of behavioral quiescence during larval molts (termed lethargus) and as adults. Little is known about the circuit mechanisms that establish these quiescent states. Lethargus and adult locomotion quiescence is dramatically reduced in mutants lacking the neuropeptide receptor NPR-1. Here, we show that the aroused locomotion of npr-1 mutants results from the exaggerated activity in multiple classes of sensory neurons, including nociceptive (ASH), touch sensitive (ALM and PLM), and stretch sensing (DVA) neurons. These sensory neurons accelerate locomotion via both neuropeptide and glutamate release. The relative contribution of these sensory neurons to arousal differs between larval molts and adults. Our results suggest that a broad network of sensory neurons dictates transitions between aroused and quiescent behavioral states. 相似文献
46.
Fiona E McCann Andrew C Palfreeman Melanie Andrews Dany P Perocheau Julia J Inglis Peter Schafer Marc Feldmann Richard O Williams Fionula M Brennan 《Arthritis research & therapy》2010,12(3):R107
Introduction
Type 4 phosphodiesterases (PDE4) play an important role in immune cells through the hydrolysis of the second messenger, cAMP. Inhibition of PDE4 has previously been shown to suppress immune and inflammatory responses, demonstrating PDE4 to be a valid therapeutic target for immune-mediated pathologies. We assessed the anti-inflammatory effects of a novel PDE4 inhibitor, apremilast, in human synovial cells from rheumatoid arthritis (RA) patients, as well as two murine models of arthritis. 相似文献47.
Polymerization of actin filaments powers many dynamic cellular events and is directed by a small group of actin nucleators. In this issue, Ahuja et al. (2007) identify and characterize a new actin nucleator called cordon-bleu (Cobl) that may drive morphogenesis of the central nervous system during development. 相似文献
48.
Dendritic cells infected with vpr-positive human immunodeficiency virus type 1 induce CD8+ T-cell apoptosis via upregulation of tumor necrosis factor alpha
下载免费PDF全文
![点击此处可从《Journal of virology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Majumder B Venkatachari NJ Schafer EA Janket ML Ayyavoo V 《Journal of virology》2007,81(14):7388-7399
Human immunodeficiency virus type 1 (HIV-1) viral protein R (Vpr) plays a crucial role in viral replication and pathogenesis by inducing cell cycle arrest, apoptosis, translocation of preintegration complex, potentiation of glucocorticoid action, impairment of dendritic cell (DC) maturation, and T-cell activation. Recent studies involving the direct effects of Vpr on DCs and T cells indicated that HIV-1 containing Vpr selectively impairs phenotypic maturation, cytokine network, and antigen presentation in DCs and dysregulates costimulatory molecules and cytokine production in T cells. Here, we have further investigated the indirect effect of HIV-1 Vpr(+) virus-infected DCs on the bystander CD8(+) T-cell population. Our results indicate that HIV-1 Vpr(+) virus-infected DCs dysregulate CD8(+) T-cell proliferation and induce apoptosis. Vpr-containing virus-infected DC-mediated CD8(+) T-cell killing occurred in part through enhanced tumor necrosis factor alpha production by infected DCs and subsequent induction of death receptor signaling and activation of the caspase 8-dependent pathway in CD8(+) T cells. Collectively, these results provide evidence that Vpr could be one of the important contributors to the host immune escape by HIV-1 through its ability to dysregulate both directly and indirectly the DC biology and T-cell functions. 相似文献
49.
Regulation of nicotinic receptor trafficking by the transmembrane Golgi protein UNC-50 总被引:1,自引:0,他引:1
Eimer S Gottschalk A Hengartner M Horvitz HR Richmond J Schafer WR Bessereau JL 《The EMBO journal》2007,26(20):4313-4323
Nicotinic acetylcholine receptors (AChRs) are pentameric ligand-gated ion channels that mediate fast synaptic transmission at the neuromuscular junction (NMJ). After assembly in the endoplasmic reticulum (ER), AChRs must be transported to the plasma membrane through the secretory apparatus. Little is known about specific molecules that mediate this transport. Here we identify a gene that is required for subtype-specific trafficking of assembled nicotinic AChRs in Caenorhabditis elegans. unc-50 encodes an evolutionarily conserved integral membrane protein that localizes to the Golgi apparatus. In the absence of UNC-50, a subset of AChRs present in body-wall muscle are sorted to the lysosomal system and degraded. However, the trafficking of a second AChR type and of GABA ionotropic receptors expressed in the same muscle cells is not affected in unc-50 mutants. These results suggest that, in addition to ER quality control, assembled AChRs are sorted within the Golgi system by a mechanism that controls the amount of cell-surface AChRs in a subtype-specific way. 相似文献
50.