全文获取类型
收费全文 | 16292篇 |
免费 | 1140篇 |
国内免费 | 3篇 |
专业分类
17435篇 |
出版年
2023年 | 116篇 |
2022年 | 232篇 |
2021年 | 454篇 |
2020年 | 297篇 |
2019年 | 363篇 |
2018年 | 457篇 |
2017年 | 414篇 |
2016年 | 645篇 |
2015年 | 986篇 |
2014年 | 1063篇 |
2013年 | 1314篇 |
2012年 | 1542篇 |
2011年 | 1383篇 |
2010年 | 875篇 |
2009年 | 743篇 |
2008年 | 921篇 |
2007年 | 912篇 |
2006年 | 848篇 |
2005年 | 704篇 |
2004年 | 671篇 |
2003年 | 597篇 |
2002年 | 490篇 |
2001年 | 141篇 |
2000年 | 120篇 |
1999年 | 135篇 |
1998年 | 106篇 |
1997年 | 87篇 |
1996年 | 77篇 |
1995年 | 69篇 |
1994年 | 59篇 |
1993年 | 49篇 |
1992年 | 58篇 |
1991年 | 58篇 |
1990年 | 56篇 |
1989年 | 44篇 |
1988年 | 39篇 |
1987年 | 35篇 |
1986年 | 21篇 |
1985年 | 30篇 |
1984年 | 33篇 |
1983年 | 27篇 |
1982年 | 15篇 |
1981年 | 20篇 |
1980年 | 14篇 |
1979年 | 17篇 |
1978年 | 17篇 |
1977年 | 16篇 |
1975年 | 8篇 |
1972年 | 11篇 |
1970年 | 7篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
991.
992.
Olivera A Rosenfeldt HM Bektas M Wang F Ishii I Chun J Milstien S Spiegel S 《The Journal of biological chemistry》2003,278(47):46452-46460
Sphingosine 1-phosphate (S1P) is the ligand for a family of specific G protein-coupled receptors (GPCRs) that regulate a wide variety of important cellular functions, including growth, survival, cytoskeletal rearrangements, and cell motility. However, whether it also has an intracellular function is still a matter of great debate. Overexpression of sphingosine kinase type 1, which generated S1P, induced extensive stress fibers and impaired formation of the Src-focal adhesion kinase signaling complex, with consequent aberrant focal adhesion turnover, leading to inhibition of cell locomotion. We have dissected biological responses dependent on intracellular S1P from those that are receptor-mediated by specifically blocking signaling of Galphaq, Galphai, Galpha12/13, and Gbetagamma subunits, the G proteins that S1P receptors (S1PRs) couple to and signal through. We found that intracellular S1P signaled "inside out" through its cell-surface receptors linked to G12/13-mediated stress fiber formation, important for cell motility. Remarkably, cell growth stimulation and suppression of apoptosis by endogenous S1P were independent of GPCRs and inside-out signaling. Using fibroblasts from embryonic mice devoid of functional S1PRs, we also demonstrated that, in contrast to exogenous S1P, intracellular S1P formed by overexpression of sphingosine kinase type 1 promoted growth and survival independent of its GPCRs. Hence, exogenous and intracellularly generated S1Ps affect cell growth and survival by divergent pathways. Our results demonstrate a receptor-independent intracellular function of S1P, reminiscent of its action in yeast cells that lack S1PRs. 相似文献
993.
994.
Romero N Radi R Linares E Augusto O Detweiler CD Mason RP Denicola A 《The Journal of biological chemistry》2003,278(45):44049-44057
Peroxynitrite, a strong oxidant formed intravascularly in vivo, can diffuse onto erythrocytes and be largely consumed via a fast reaction (2 x 10(4) m(-1) s(-1)) with oxyhemoglobin. The reaction mechanism of peroxynitrite with oxyhemoglobin that results in the formation of methemoglobin remains to be elucidated. In this work, we studied the reaction under biologically relevant conditions using millimolar oxyhemoglobin concentrations and a stoichiometric excess of oxyhemoglobin over peroxynitrite. The results support a reaction mechanism that involves the net one-electron oxidation of the ferrous heme, isomerization of peroxynitrite to nitrate, and production of superoxide radical and hydrogen peroxide. Homolytic cleavage of peroxynitrite within the heme iron allows the formation of ferrylhemoglobin in approximately 10% yields, which can decay to methemoglobin at the expense of reducing equivalents of the globin moiety. Indeed, spin-trapping studies using 2-methyl-2-nitroso propane and 5,5 dimethyl-1-pyrroline-N-oxide (DMPO) demonstrated the formation of tyrosyl- and cysteinyl-derived radicals. DMPO also inhibited covalently linked dimerization products and led to the formation of DMPO-hemoglobin adducts. Hemoglobin nitration was not observed unless an excess of peroxynitrite over oxyhemoglobin was used, in agreement with a marginal formation of nitrogen dioxide. The results obtained support a role of oxyhemoglobin as a relevant intravascular sink of peroxynitrite. 相似文献
995.
An in vitro evaluation of the effects of homocysteine thiolactone on key steps of angiogenesis and tumor invasion 总被引:1,自引:0,他引:1
Martínez-Poveda B Chavarría T Sánchez-Jiménez F Quesada AR Medina MA 《Biochemical and biophysical research communications》2003,311(3):649-653
Homocysteine thiolactone is a highly reactive homocysteine derivative that can react easily with proteins. Protein homocysteinylation has been suggested as a possible mechanism underlying the pathological consequences of impaired homocysteine metabolism. Homocysteine inhibits key steps of angiogenesis and tumor invasion. It can be hypothesized that homocysteine thiolactone could mimic the described anti-angiogenic and anti-invasive effects of homocysteine. Therefore, we studied the effects of homocysteine thiolactone on different key steps of angiogenesis and tumor invasion, using model endothelial and tumor cell lines. This study demonstrates that homocysteine thiolactone, in high contrast to homocysteine, is not an anti-angiogenic compound. Furthermore, our results suggest that homocysteine thiolactone could behave as a pro-angiogenic compound. 相似文献
996.
Nystatin is a membrane-active polyene antibiotic that is thought to kill fungal cells by forming ion-permeable channels. In this report we have investigated nystatin interaction with phosphatidylcholine liposomes of different sizes (large and small unilamellar vesicles) by time-resolved fluorescence measurements. Our data show that the fluorescence emission decay kinetics of the antibiotic interacting with gel-phase 1,2-dipalmitoyl-sn-glycero-3-phosphocholine vesicles is controlled by the mean number of membrane-bound antibiotic molecules per liposome, . The transition from a monomeric to an oligomeric state of the antibiotic, which is associated with a sharp increase in nystatin mean fluorescence lifetime from approximately 7-10 to 35 ns, begins to occur at a critical concentration of 10 nystatin molecules per lipid vesicle. To gain further information about the transverse location (degree of penetration) of the membrane-bound antibiotic molecules, the spin-labeled fatty acids (5- and 16-doxyl stearic acids) were used in depth-dependent fluorescence quenching experiments. The results obtained show that monomeric nystatin is anchored at the phospholipid/water interface and suggest that nystatin oligomerization is accompanied by its insertion into the membrane. Globally, the experimental data was quantitatively described by a cooperative partition model which assumes that monomeric nystatin molecules partition into the lipid bilayer surface and reversibly assemble into aggregates of 6 +/- 2 antibiotic molecules. 相似文献
997.
Lamprecht P Vargas Cuero AL Muller A Csernok E Voswinkel J Maass M Solbach W Gross WL Klenerman P 《Cellular immunology》2003,224(1):1-7
Wegener's granulomatosis (WG) is an autoimmune disease of as yet unknown etiology. To date it has remained obscure what causes WG or determines disease progression. Case reports suggest that viral infections such as cytomegalovirus (CMV) reactivation may contribute to disease flares. In this study we found a skewing of the phenotype of CMV-specific CD8+tet(ramer)+ T-cells in WG. A marked proportion of these cells displayed a late differentiated "effector memory" T-cell phenotype with decreased expression of CD28 and CD62L, and heterogeneous CD27 expression, features which were also seen in CD8+tet- T-cells in WG, but not in controls. Our results might reflect profound generalized changes in the CD8+ T-cell compartment also affecting virus-specific T-cell responses in WG. 相似文献
998.
Gonzalez-Franco AC Deobald LA Spivak A Crawford DL 《Canadian journal of microbiology》2003,49(11):683-698
The objective of this study was to determine if antifungal actinomycetes isolated from rhizosphere and non-rhizosphere soils exhibit different chitinase-like production and (or) induction patterns. Selected isolates from both habitats were compared. Chitinase-like levels and isoform characteristic patterns were evaluated over time in culture fluids of isolates grown on media containing different combinations of colloidal chitin and fungal cell wall (FCW) preparation. Supernatants were also subjected to native and non-native polyacrylamide gel electrophoresis (PAGE), using glycol chitin amended gels. For non-native PAGE, protein samples were denatured by two different approaches. Multiple active bands, ranging from 20 to 53 kDa and present in varying amounts, were detected in gels for most strains. Different substrate preferences were observed among strains, and different chitinase-like enzymes were produced, depending upon the substrate combinations used. The presence of FCW in the medium induced specific chitinase-like enzymes not observed otherwise. Enzymatic activities and profiles of the isolates, however, were strain and substrate specific rather than habitat specific. However, a sagebrush rhizosphere soil had a larger actinomycete community with higher chitinolytic activities than the nearby bulk soil. The use of PAGE to compare chitinase-like proteins induced in media with and without FCW was useful for identifying chitinase-like enzymes potentially involved in antifungal activity. 相似文献
999.
Rivero A Balloux F West SA 《Evolution; international journal of organic evolution》2003,57(7):1698-1703
Abstract.— Determining the way in which deleterious mutations interact to effect fitness is crucial to numerous areas in evolutionary biology. For example, if each additional mutation leads to a greater decrease in log fitness than the last, termed synergistic epistasis, then sex and recombination provide an advantage because they enable deleterious mutations to be eliminated more efficiently. However, there is a severe shortage of relevant empirical data, especially of the form that can help test mutational explanations for the widespread occurrence of sex. Here, we test for epistasis in the parasitic wasp Nasonia vitripennis , examining the fitness consequences of chemically induced deleterious mutations. We examine two components of fitness, both of which are thought to be important in natural populations of parasitic wasps: longevity and egg production. Our results show synergistic epistasis for longevity, but not for egg production. 相似文献
1000.
It is believed that pericentromeric heterochromatin may play a major role in the epigenetic regulation of gene expression. We have previously shown that centromeres in human peripheral blood cells aggregate into distinct "myeloid" and "lymphoid" spatial patterns, suggesting that the three-dimensional organization of centromeric heterochromatin in interphase may be ontogenically determined during hematopoietic differentiation. To investigate this possibility, the spatial patterns of association of different centromeres were analyzed in hematopoietic progenitors and compared with those in early-B and early-T cells, mature B and T lymphocytes, and, additionally, mature granulocytes and monocytes. We show that those patterns change during lymphoid differentiation, with major spatial arrangements taking place at different stages during T and B cell differentiation. Heritable patterns of centromere association are observed, which can occur either at the level of the common lymphoid progenitor, or in early-T or early-B committed cells. A correlation of the observed patterns of centromere association with the gene content of the respective chromosomes further suggests that the variation in the composition of these heterochromatic structures may contribute to the dynamic relocation of genes in different nuclear compartments during cell differentiation, which might have functional implications for cell-stage-specific gene expression. 相似文献