全文获取类型
收费全文 | 1306篇 |
免费 | 108篇 |
专业分类
1414篇 |
出版年
2023年 | 8篇 |
2022年 | 21篇 |
2021年 | 34篇 |
2020年 | 12篇 |
2019年 | 27篇 |
2018年 | 24篇 |
2017年 | 19篇 |
2016年 | 51篇 |
2015年 | 100篇 |
2014年 | 94篇 |
2013年 | 81篇 |
2012年 | 119篇 |
2011年 | 95篇 |
2010年 | 46篇 |
2009年 | 61篇 |
2008年 | 72篇 |
2007年 | 59篇 |
2006年 | 66篇 |
2005年 | 65篇 |
2004年 | 55篇 |
2003年 | 54篇 |
2002年 | 46篇 |
2001年 | 13篇 |
2000年 | 4篇 |
1999年 | 12篇 |
1998年 | 11篇 |
1997年 | 15篇 |
1996年 | 13篇 |
1995年 | 6篇 |
1994年 | 10篇 |
1993年 | 12篇 |
1992年 | 15篇 |
1991年 | 6篇 |
1990年 | 8篇 |
1988年 | 5篇 |
1987年 | 9篇 |
1986年 | 2篇 |
1985年 | 6篇 |
1984年 | 5篇 |
1983年 | 3篇 |
1982年 | 5篇 |
1981年 | 5篇 |
1980年 | 6篇 |
1978年 | 2篇 |
1977年 | 2篇 |
1974年 | 3篇 |
1972年 | 4篇 |
1970年 | 2篇 |
1969年 | 3篇 |
1959年 | 3篇 |
排序方式: 共有1414条查询结果,搜索用时 0 毫秒
61.
Ovadia B Bekker JM Fitzgerald RK Kon A Thelitz S Johengen MJ Hendricks-Munoz K Gerrets R Black SM Fineman JR 《American journal of physiology. Heart and circulatory physiology》2002,282(3):H862-H871
Acute partial compression of the fetal ductus arteriosus (DA) results in an initial increase in pulmonary blood flow (PBF) that is followed by acute vasoconstriction. The objective of the present study was to determine the role of nitric oxide (NO)-endothelin-1 (ET-1) interactions in the acute changes in pulmonary vascular tone after in utero partial constriction of the DA. Twelve late-gestation fetal lambs (132-140 days) were instrumented to measure vascular pressures and left PBF. After a 24-h recovery period, acute constriction of the DA was performed by partially inflating a vascular occluder, and the hemodynamic variables were observed for 4 h. In control lambs (n = 7), acute ductal constriction initially increased PBF by 627% (P < 0.05). However, this was followed by active vasoconstriction, such that PBF was restored to preconstriction values by 4 h. This was associated with a 43% decrease in total NO synthase (NOS) activity (P < 0.05) and a 106% increase in plasma ET-1 levels (P < 0.05). Western blot analysis demonstrated no changes in lung tissue endothelial NOS, preproET-1, endothelin-converting enzyme-1, or ET(B) receptor protein levels. The infusion of PD-156707 (an ET(A) receptor antagonist, n = 5) completely blocked the vasoconstriction and preserved NOS activity. These data suggest that the fetal pulmonary vasoconstriction after acute constriction of the DA is mediated by NO-ET-1 interactions. These include an increase in ET(A) receptor-mediated vasoconstriction and an ET(A) receptor-mediated decrease in NOS activity. The mechanisms of these NO-ET-1 interactions, and their role in mediating acute changes in PBF, warrant further studies. 相似文献
62.
Protein kinase C (PKC) regulation of cystic fibrosis transmembrane regulator (CFTR) chloride function has been demonstrated in several cell lines, including Calu-3 cells that express native, wild-type CFTR. We demonstrated previously that PKC epsilon was required for cAMP-dependent CFTR function. The goal of this study was to determine whether PKC epsilon interacts directly with CFTR. Using overlay assay, immunoprecipitation, pulldown and binding assays, we show that PKC epsilon does not bind to CFTR, but does bind to a receptor for activated C kinase (RACK1), a 37-kDa scaffold protein, and that RACK1 binds to Na(+)/H(+) exchange regulatory factor (NHERF1), a binding partner of CFTR. In vitro binding assays demonstrate dose-dependent binding of PKC epsilon to RACK1 which is inhibited by an 8-amino acid peptide based on the sequence of the sixth Trp-Asp repeat in RACK1 or by an 8-amino acid sequence in the V1 region of PKC epsilon, epsilon V1-2. A 4-amino acid sequence INAL (70-73) expressed in CFTR shares 50% homology to the RACK1 inhibitory peptide, but it does not bind PKC epsilon. NHERF1 and RACK1 bind in a dose-dependent manner. Immunofluorescence and confocal microscopy of RACK1 and CFTR revealed colocalization of the proteins to the apical and lateral regions of Calu-3 cells. The results indicate the RACK1 binds PKC epsilon and NHERF1, thus serving as a scaffold protein to anchor the enzyme in proximity to CFTR. 相似文献
63.
64.
Identification of a novel HLA-B60-restricted T cell epitope of the minor histocompatibility antigen HA-1 locus 总被引:7,自引:0,他引:7
Mommaas B Kamp J Drijfhout JW Beekman N Ossendorp F Van Veelen P Den Haan J Goulmy E Mutis T 《Journal of immunology (Baltimore, Md. : 1950)》2002,169(6):3131-3136
The polymorphic minor histocompatibility Ag HA-1 locus encodes two peptides, HA-1(H) and HA-1(R), with a single amino acid difference. Whereas the immunogenicity of the HA-1(R) allele has not yet been shown, the nonameric HA-1(H) peptide induces HLA-A2-restricted cytotoxic T cells in vivo and in vitro. It is not known whether the mHag HA-1(H) or HA-1(R) associates with other HLA class I molecules. Therefore, the polymorphic regions of both HA-1 alleles were analyzed to identify HLA class I binding peptides that are properly processed by proteasomal degradation. Peptide binding analyses were performed for all nonameric HA-1(H/R) peptides for binding to nine HLA class I molecules with >10% prevalence in the Caucasian population and for seven nonameric/decameric HA-1(H/R) peptides predicted to bind to HLA-A3, -B14, and -B60. Only the nonameric KECVL(H)/(R)DDL and decameric KECVL(H)/(R)DDLL peptides showed strong and stable binding to HLA-B60. In vitro digestion of 29-aa-long HA-1 peptides by purified 20S proteasomes revealed proper cleavage at the COOH termini of both HLA-B60 binding HA-1(H) and HA-1(R) peptides. In subsequent analyses, dendritic cells pulsed with the nonameric HA-1(R) peptide did not induce CTLs that recognize the natural HLA-B60/HA-1(R) ligand. In contrast, dendritic cells pulsed with the nonameric HA-1(H) peptide induced IFN-gamma-secreting T cells specific for the natural HLA-B60/HA-1(H) ligand in three HLA-B60(+) HA-1(RR) individuals, demonstrating the immunogenicity of the HLA-B60/HA-1(H) ligand. In conclusion, this study shows a novel HLA-B60-restricted T cell epitope of the minor histocompatibility Ag HA-1 locus. 相似文献
65.
Increased generation of dendritic cells from myeloid progenitors in autoimmune-prone nonobese diabetic mice 总被引:5,自引:0,他引:5
Steptoe RJ Ritchie JM Harrison LC 《Journal of immunology (Baltimore, Md. : 1950)》2002,168(10):5032-5041
Aberrant dendritic cell (DC) development and function may contribute to autoimmune disease susceptibility. To address this hypothesis at the level of myeloid lineage-derived DC we compared the development of DC from bone marrow progenitors in vitro and DC populations in vivo in autoimmune diabetes-prone nonobese diabetic (NOD) mice, recombinant congenic nonobese diabetes-resistant (NOR) mice, and unrelated BALB/c and C57BL/6 (BL/6) mice. In GM-CSF/IL-4-supplemented bone marrow cultures, DC developed in significantly greater numbers from NOD than from NOR, BALB/c, and BL/6 mice. Likewise, DC developed in greater numbers from sorted (lineage(-)IL-7Ralpha(-)SCA-1(-)c-kit(+)) NOD myeloid progenitors in either GM-CSF/IL-4 or GM-CSF/stem cell factor (SCF)/TNF-alpha. [(3)H]TdR incorporation indicated that the increased generation of NOD DC was due to higher levels of myeloid progenitor proliferation. Generation of DC with the early-acting hematopoietic growth factor, flt3 ligand, revealed that while the increased DC-generative capacity of myeloid-committed progenitors was restricted to NOD cells, early lineage-uncommitted progenitors from both NOD and NOR had increased DC-generative capacity relative to BALB/c and BL/6. Consistent with these findings, NOD and NOR mice had increased numbers of DC in blood and thymus and NOD had an increased proportion of the putative myeloid DC (CD11c(+)CD11b(+)) subset within spleen. These findings demonstrate that diabetes-prone NOD mice exhibit a myeloid lineage-specific increase in DC generative capacity relative to diabetes-resistant recombinant congenic NOR mice. We propose that an imbalance favoring development of DC from myeloid-committed progenitors predisposes to autoimmune disease in NOD mice. 相似文献
66.
Cohen AJ Lakshmi TR Niu Z Trindade J Billings PC Adams SL 《Mechanisms of development》2002,111(1-2):177-180
RanBP1, a velocardiofacial syndrome/DiGeorge syndrome candidate gene, is expressed in the frontonasal processes, branchial arches, aortic arches, and limb buds. At these sites, RanBP1 apparently coincides with neural crest-derived mesenchymal cells. In addition, RanBP1 is expressed in the forebrain as well as in hindbrain regions previously associated with crest-derived mesenchymal cells. 相似文献
67.
Losing balance: cytokine signaling and cell death in the context of hepatocyte injury and hepatic failure 总被引:6,自引:0,他引:6
Fulminant hepatic failure (FHF) represents a clinical scenario that is associated with high morbidity and mortality, and very limited treatment options. Therefore, great efforts have been made recently on defining its biological mechanisms. This article gives an overview of the cellular processes that are linked to the loss of hepatocytes as a reaction to various agents that cause hepatic failure, and summarizes recent results from clinical and experimental studies of the role of pro- and antiapoptotic cytokines and their intracellular signaling in this context. 相似文献
68.
Bukowska A Tadje J Arndt M Wolke C Kähne T Bartsch J Faust J Neubert K Hashimoto Y Lendeckel U 《Biological chemistry》2003,384(4):657-665
Aminopeptidase inhibitors strongly affect the proliferation and function of immune cells in man and animals and are promising agents for the pharmacological treatment of inflammatory or autoimmune diseases. Membrane alanyl-aminopeptidase (mAAP) has been considered as the major target of these anti-inflammatory aminopeptidase inhibitors. Recent evidence also points to a role of the cytosol alanyl-aminopeptidase (cAAP) in the immune response. In this study we used quantitative RT-PCR to determine the mRNA expression of both cAAP and mAAP in resting and activated peripheral T cells and also in CD4+, CD8+, Th1, Th2 and Treg (CD4+ CD25+) subpopulations. Both mAAP and cAAP mRNAs were expressed in all cell types investigated, and in response to activation their expression appeared to be upregulated in CD8+ cells, but downregulated in Treg cells. In CD4+ cells, mAAP and cAAP mRNAs were affected in opposite ways in response to activation. The cAAP-specific inhibitor, PAQ-22, did not affect either cAAP or mAAP expression in activated CD4+ or CD8+ cells, whereas in activated Treg cells it markedly upregulated the mRNA levels of both aminopeptidases. The non-discriminatory inhibitor, phebestin, significantly increased the amount of mAAP and cAAP mRNA in CD4+ and that of cAAP in Treg cells. 相似文献
69.
Major areas covered at the Bacterial Locomotion and Signal Transduction (BLAST) meeting included the clustering of chemoreceptors and its significance to signal amplification, organelle biogenesis, motility, developmental responses mediated by "chemotaxis" operons, and advances in two-component signaling mechanisms. 相似文献
70.
The uptake of cholesterol has been characterized in leaf discs from mature leaves of sugar beet (Beta vulgaris L.). This transport system exhibited a simple saturable phase with an apparent Michaelis constant ranging from 30 to 190 M depending on the sample. When present at 10 M excess, other sterols were able to inhibit cholesterol uptake. Moreover, binding assays demonstrated the presence of high-affinity binding sites for cholesterol in purified plasma membrane vesicles. In the range 1–60 M, cholesterol uptake showed an active component evidenced by action of the protonophore carbonyl cyanide m-chlorophenylhydrazone. Energy was required as shown by the inhibition of uptake induced by respiration inhibitors (NaN3), darkness and photosynthesis inhibitors [3-(3,4-dichlorophenyl)-1,1-dimethylurea, methyl viologen]. Moreover, the process was strongly dependent on the experimental temperature. Uptake was optimal at acidic pH (4.0), sensitive to ATPase modulators, inhibited by thiol reagents (N-ethylmaleimide, p-chloromercuribenzenesulfonic acid, Mersalyl) and by the histidyl-group reagent diethyl pyrocarbonate. The addition of cholesterol did not modify H+ flux from tissues, indicating that H+-co-transport was unlikely to be involved. MgATP did not increase the uptake, arguing against involvement of an ABC cassette-type transporter. By contrast, cryptogein, a sterol carrier protein from the Oomycete Phytophtora cryptogea, greatly increased absorption. Taken together, the results reported in this work suggest that plant cells contain a specific plasma membrane transport system for sterols.Abbreviations CCCP
carbonyl cyanide m-chlorophenylhydrazone
- PCMBS
p-chloromercuribenzenesulfonic acid
- PMV
plasma membrane vesicle
- TLC
thin-layer chromatography 相似文献