全文获取类型
收费全文 | 464篇 |
免费 | 60篇 |
出版年
2022年 | 3篇 |
2021年 | 4篇 |
2019年 | 4篇 |
2015年 | 5篇 |
2014年 | 12篇 |
2013年 | 9篇 |
2012年 | 14篇 |
2011年 | 18篇 |
2010年 | 4篇 |
2009年 | 6篇 |
2008年 | 7篇 |
2007年 | 26篇 |
2006年 | 11篇 |
2005年 | 19篇 |
2004年 | 11篇 |
2003年 | 22篇 |
2002年 | 15篇 |
2001年 | 10篇 |
2000年 | 20篇 |
1999年 | 12篇 |
1998年 | 12篇 |
1997年 | 9篇 |
1996年 | 7篇 |
1995年 | 13篇 |
1994年 | 15篇 |
1992年 | 18篇 |
1991年 | 10篇 |
1990年 | 10篇 |
1989年 | 14篇 |
1988年 | 10篇 |
1987年 | 8篇 |
1986年 | 10篇 |
1985年 | 8篇 |
1984年 | 6篇 |
1983年 | 10篇 |
1982年 | 4篇 |
1981年 | 5篇 |
1979年 | 6篇 |
1978年 | 11篇 |
1976年 | 8篇 |
1975年 | 13篇 |
1974年 | 7篇 |
1973年 | 8篇 |
1972年 | 10篇 |
1971年 | 6篇 |
1970年 | 9篇 |
1969年 | 8篇 |
1967年 | 3篇 |
1966年 | 4篇 |
1956年 | 3篇 |
排序方式: 共有524条查询结果,搜索用时 15 毫秒
431.
Bruno J Chenuel Curtis A Smith Kathleen S Henderson Jerome A Dempsey 《Journal of applied physiology》2005,98(5):1732-1739
We determined the effects of specific carotid body chemoreceptor inhibition on the propensity for apnea during sleep. We reduced the responsiveness of the carotid body chemoreceptors using intravenous dopamine infusions during non-rapid eye movement sleep in six dogs. Then we quantified the difference in end-tidal Pco(2) (Pet(CO(2))) between eupnea and the apneic threshold, the "CO(2) reserve," by gradually reducing Pet(CO(2)) transiently with pressure support ventilation at progressively increased tidal volume until apnea occurred. Dopamine infusions decreased steady-state eupneic ventilation by 15 +/- 6%, causing a mean CO(2) retention of 3.9 +/- 1.9 mmHg and a brief period of ventilatory instability. The apneic threshold Pet(CO(2)) rose 5.1 +/- 1.9 Torr; thus the CO(2) reserve was narrowed from -3.9 +/- 0.62 Torr in control to -2.7 +/- 0.78 Torr with dopamine. This decrease in the CO(2) reserve with dopamine resulted solely from the 20.5 +/- 11.3% increase in plant gain; the slope of the ventilatory response to CO(2) below eupnea was unchanged from normal. We conclude that specific carotid chemoreceptor inhibition with dopamine increases the propensity for apnea during sleep by narrowing the CO(2) reserve below eupnea. This narrowing is due solely to an increase in plant gain as the slope of the ventilatory response to CO(2) below eupnea was unchanged from normal control. These findings have implications for the role of chemoreceptor inhibition/stimulation in the genesis of apnea and breathing periodicity during sleep. 相似文献
432.
A disintegrin and metalloproteinase 10-mediated cleavage and shedding regulates the cell surface expression of CXC chemokine ligand 16 总被引:15,自引:0,他引:15
Gough PJ Garton KJ Wille PT Rychlewski M Dempsey PJ Raines EW 《Journal of immunology (Baltimore, Md. : 1950)》2004,172(6):3678-3685
CXC chemokine ligand (CXCL)16 and scavenger receptor for phosphatidylserine and oxidized low-density lipoprotein were independently identified as a chemokine and a scavenger receptor, respectively, but have since been shown to be identical. CXCL16 is synthesized as a transmembrane protein with its chemokine domain at the end of a mucin-rich stalk. When expressed at the cell surface, CXCL16 functions as a scavenger receptor, binding and internalizing oxidized low-density lipoprotein and bacteria. As a soluble form, CXCL16 is a chemoattractant for activated CD4+ and CD8+ T cells through binding its receptor, CXCR6. In this study, we examined the mechanisms that regulate the conversion between these two functionally distinct forms of CXCL16. We demonstrate that murine CXCL16 is synthesized as an intracellular precursor that is rapidly transported to the cell surface where it undergoes metalloproteinase-dependent cleavage, causing the release of a fragment that constitutes the majority of the CXCL16 extracellular domain. Using a novel retroviral system for the generation of short interfering RNAs, we show that knockdown of a disintegrin and metalloproteinase (ADAM) family protease ADAM10 decreases this constitutive shedding of CXCL16. Furthermore, we show that overexpression of ADAM10 increases CXCL16 shedding, whereas overexpression of a dominant-negative form of ADAM10 lowers shedding of CXCL16 in a similar manner to short interfering RNAs. Through the modulation of ADAM10 function, we demonstrate that ADAM10-mediated constitutive shedding is a key regulator of CXCL16 cell surface expression. The identification of ADAM10 as a major protease responsible for the conversion of CXCL16 from a membrane-bound scavenger receptor to a soluble chemoattractant will provide new information for understanding the physiological function of this molecule. 相似文献
433.
Tumor necrosis factor-alpha-converting enzyme (ADAM17) mediates the cleavage and shedding of fractalkine (CX3CL1) 总被引:15,自引:0,他引:15
Garton KJ Gough PJ Blobel CP Murphy G Greaves DR Dempsey PJ Raines EW 《The Journal of biological chemistry》2001,276(41):37993-38001
Fractalkine (CX3CL1) is an unusual member of the chemokine family that is synthesized with its chemokine domain at the end of a mucin-rich, transmembrane stalk. This membrane-bound localization allows fractalkine to function as an adhesion molecule for cells bearing its receptor, CX3CR1. In addition, fractalkine can be proteolytically released from the cell surface, generating a soluble molecule that functions as a chemoattractant similar to the other members of the chemokine family. In this study, we have examined the mechanisms that regulate the conversion between these two functionally distinct forms of fractalkine. We demonstrate that under normal conditions fractalkine is synthesized as an intracellular precursor that is rapidly transported to the cell surface where it becomes a target for metalloproteinase-dependent cleavage that causes the release of a fragment containing the majority of the fractalkine extracellular domain. We show that the cleavage of fractalkine can be markedly enhanced by stimulating cells with phorbol 12-myristate 13-acetate (PMA), and we identify tumor necrosis factor-alpha converting enzyme (TACE; ADAM17) as the protease responsible for this PMA-induced fractalkine release. In addition, we provide data showing that TACE-mediated fractalkine cleavage occurs at a site distinct from the dibasic juxtamembrane motif that had been suggested previously based on protein sequence homologies. The identification of TACE as a major protease responsible for the conversion of fractalkine from a membrane-bound adhesion molecule to a soluble chemoattractant will provide new information for understanding the physiological function of this chemokine. 相似文献
434.
Andersen H Dempsey D Chervenak R Jennings SR 《Journal of immunology (Baltimore, Md. : 1950)》2000,165(4):2101-2107
Cutaneous infection in the footpads of C57BL/6 mice with HSV-1 results in an accumulation of activated (CD44high CD25+) CD8+ T cells within the draining popliteal lymph node (PLN). These studies were undertaken to evaluate the frequency and phenotype of the CD8+ T cell population within the PLN, recognizing the single immunodominant HSV-1 epitope derived from the viral envelope glycoprotein, glycoprotein B (gB), using an intracellular IFN-gamma-staining assay. It revealed that approximately 6% of the CD8+ T cells were specific for the gB epitope. Phenotypic analysis of the IFN-gamma-producing gB-specific CD8+ T cells generated in the PLN during the course of the acute infection expressed the CD44high CD25+ phenotype on days 3-5 postinfection. Surprisingly, IFN-gamma-producing CD8+ T cells expressed the CD44high CD25- phenotype on days 5-8 postinfection, in contrast to expectations for a CD8+ effector T cell. IFN-gamma-producing CD25- CD8+ T cells were detected in the PLN on day 21 postinfection, long after infectious virus had been cleared. Throughout the response, the spleen was found to be the major reservoir of gB-specific CD8+ T cells, even during the peak of the response. In contrast to the gB-specific CD8+ T cell population within the PLN, the entire gB-specific CD8+ T cell population within the spleen was CD25-. Collectively, these results suggest the generation of subpopulations of virus-specific CD8+ T cells, distinguished by the expression of CD25, during the acute phase of the primary response to a localized viral infection. 相似文献
435.
Molecular dynamics simulations of bee venom apamin, and an analogue having an Asn to Ala substitution at residue 2 (apamin-N2A), were analyzed to explore the contribution of hydrogen bonds involving Asn2 to local (beta-turn residues N2, C3, K4, A5) and global stability. The wild-type peptide retained a stable conformation during 2.4 ns of simulation at 67 degrees C, with high beta-turn stability characterized by backbone-side chain hydrogen bonds involving beta-turn residues K4 and A5, with the N2 side chain amide carbonyl. The loss of stabilizing interactions involving the N2 side chain resulted in the loss of the beta-turn conformation in the apamin N2A simulations (27 or 67 degrees C). This loss of beta-turn stability propagates throughout the peptide structure, with destabilization of the C-terminal helix connected to the N-terminal region by two disulfide bonds. Backbone stability in a synthetic peptide analogue (apamin-N2A) was characterized by NMR and amide hydrogen exchange measurements. Consistent with the simulations, loss of hydrogen bonds involving the N2 side chain resulted in destabilization of both the N-terminal beta-turn and the C-terminal helix. Amide exchange protection factors in the C-terminal helix were reduced by 9-11-fold in apamin N2A as compared with apamin, corresponding to free energy (deltaDeltaG(uf)) of around 1.5 kcal M(-1) at 20 degrees C. This is equivalent to the contribution of hydrogen bond interactions involving the N2 side chain to the stability of the beta-turn. Together with additional measures of exchange protection factors, the three main contributions to backbone stability in apamin that account for virtually the full thermodynamic stability of the peptide have been quantitated. 相似文献
436.
Heparanase expression in invasive trophoblasts and acute vascular damage 总被引:16,自引:0,他引:16
Heparan sulfate proteoglycans play a pivotal role in tissue function, development, inflammation, and immunity. We have identified a novel cDNA encoding human heparanase, an enzyme thought to cleave heparan sulfate in physiology and disease, and have located the HEP gene on human chromosome 4q21. Monoclonal antibodies against human heparanase located the enzyme along invasive extravillous trophoblasts of human placenta and along endothelial cells in organ xenografts targeted by hyperacute rejection, both sites of heparan sulfate digestion. Heparanase deposition was evident in arterial walls in normal tissues; however, vascular heparan sulfate cleavage was coincident with heparanase enzyme during inflammatory episodes. These findings suggest that heparanase elaboration and control of catalytic activity may contribute to the development and pathogenesis of vascular disease and suggest that heparanase intervention might be a useful therapeutic target. 相似文献
437.
The amino terminus of the coat protein of Turnip crinkle virus is the AVR factor recognized by resistant arabidopsis 总被引:1,自引:0,他引:1
Zhao Y DelGrosso L Yigit E Dempsey DA Klessig DF Wobbe KK 《Molecular plant-microbe interactions : MPMI》2000,13(9):1015-1018
We have isolated three naturally occurring strains of Turnip crinkle virus (TCV) that break resistance in Di-17 Arabidopsis. Two mutations in the N terminus of the TCV coat protein, D4N and P5S, were shown to confer this phenotype. Thus, this region of the coat protein is involved in eliciting resistance responses in Arabidopsis. 相似文献
438.
Chris Szent-Gyorgyi Robyn L. Stanfield Susan Andreko Alison Dempsey Mushtaq Ahmed Sarah Capek Alan S. Waggoner Ian A. Wilson Marcel P. Bruchez 《Journal of molecular biology》2013
We report that a symmetric small-molecule ligand mediates the assembly of antibody light chain variable domains (VLs) into a correspondent symmetric ternary complex with novel interfaces. The L5* fluorogen activating protein is a VL domain that binds malachite green (MG) dye to activate intense fluorescence. Crystallography of liganded L5* reveals a 2:1 protein:ligand complex with inclusive C2 symmetry, where MG is almost entirely encapsulated between an antiparallel arrangement of the two VL domains. Unliganded L5* VL domains crystallize as a similar antiparallel VL/VL homodimer. The complementarity-determining regions are spatially oriented to form novel VL/VL and VL/ligand interfaces that tightly constrain a propeller conformer of MG. Binding equilibrium analysis suggests highly cooperative assembly to form a very stable VL/MG/VL complex, such that MG behaves as a strong chemical inducer of dimerization. Fusion of two VL domains into a single protein tightens MG binding over 1000-fold to low picomolar affinity without altering the large binding enthalpy, suggesting that bonding interactions with ligand and restriction of domain movements make independent contributions to binding. Fluorescence activation of a symmetrical fluorogen provides a selection mechanism for the isolation and directed evolution of ternary complexes where unnatural symmetric binding interfaces are favored over canonical antibody interfaces. As exemplified by L5*, these self-reporting complexes may be useful as modulators of protein association or as high-affinity protein tags and capture reagents. 相似文献
439.
440.
Li N Boyd K Dempsey PJ Vignali DA 《Journal of immunology (Baltimore, Md. : 1950)》2007,178(7):4214-4221
TNF-alpha converting enzyme (TACE; ADAM17), a member of the ADAM (a disintegrin and metalloprotease) family of metalloproteases, has been shown to cleave a wide variety of cell surface proteins of immunological importance. Due to the broad expression of TACE and the early postnatal lethality of TACE-deficient mice, it has been difficult to assess the role of TACE in lymphocyte development. Indeed, it is not known whether hemopoietic and/or nonhemopoietic expression of TACE is required for normal lymphocyte development. In the current study, we analyzed the lymphoid system of tace(DeltaZn/DeltaZn) mice and tace(DeltaZn/DeltaZn) bone marrow RAG1(-/-) recipients. Our results clearly show that nonlymphocyte expression of TACE is required for normal lymphocyte development and lymphoid organ structure. Lack of TACE function resulted in a partial block in T cell development at the double-negative 4:double-positive transition in the thymus, a loss of B cell development/maturation in the spleen, and a lack of B cell follicle and germinal center formation in the spleen. Thus, TACE serves as a lymphocyte extrinsic factor that is essential for normal T development and peripheral B cell maturation. 相似文献