全文获取类型
收费全文 | 1023篇 |
免费 | 93篇 |
国内免费 | 1篇 |
专业分类
1117篇 |
出版年
2022年 | 14篇 |
2021年 | 21篇 |
2020年 | 8篇 |
2019年 | 15篇 |
2018年 | 15篇 |
2017年 | 7篇 |
2016年 | 32篇 |
2015年 | 42篇 |
2014年 | 45篇 |
2013年 | 64篇 |
2012年 | 68篇 |
2011年 | 54篇 |
2010年 | 45篇 |
2009年 | 41篇 |
2008年 | 57篇 |
2007年 | 61篇 |
2006年 | 49篇 |
2005年 | 55篇 |
2004年 | 52篇 |
2003年 | 50篇 |
2002年 | 37篇 |
2001年 | 20篇 |
2000年 | 8篇 |
1999年 | 10篇 |
1998年 | 9篇 |
1997年 | 14篇 |
1996年 | 10篇 |
1994年 | 10篇 |
1993年 | 8篇 |
1992年 | 5篇 |
1991年 | 11篇 |
1990年 | 6篇 |
1989年 | 5篇 |
1988年 | 5篇 |
1987年 | 8篇 |
1986年 | 7篇 |
1985年 | 10篇 |
1984年 | 8篇 |
1983年 | 8篇 |
1982年 | 8篇 |
1981年 | 9篇 |
1980年 | 7篇 |
1977年 | 6篇 |
1974年 | 9篇 |
1972年 | 5篇 |
1971年 | 9篇 |
1970年 | 5篇 |
1969年 | 7篇 |
1968年 | 4篇 |
1967年 | 5篇 |
排序方式: 共有1117条查询结果,搜索用时 10 毫秒
941.
Vine KL Locke JM Ranson M Benkendorff K Pyne SG Bremner JB 《Bioorganic & medicinal chemistry》2007,15(2):931-938
A range of substituted 1H-indole-2,3-diones (isatins) were synthesized using standard procedures and their cytotoxicity evaluated against the human monocyte-like histiocytic lymphoma (U937) cell line in vitro. SAR studies identified C(5), C(6), and C(7) substitution greatly enhanced activity with some di- and tri-halogenated isatins giving IC(50) values <10 microM. Of the 23 compounds tested, four were selected for further screening against a panel of five human cancer cell lines. These compounds, in general, showed greater selectivity toward leukemia and lymphoma cells over breast, prostate, and colorectal carcinoma cell lines. The most active compound, 5,6,7-tribromoisatin (2p), was found to be antiproliferative at low micromolar concentrations and also activated the effector caspases 3 and 7 in a dose-dependent manner. These results indicate that di- and tri-substituted isatins may be useful leads for anticancer drug development in the future. 相似文献
942.
Ming Guo Allen?J. Ehrlicher Saleemulla Mahammad Hilary Fabich Mikkel?H. Jensen Jeffrey?R. Moore Jeffrey?J. Fredberg Robert?D. Goldman David?A. Weitz 《Biophysical journal》2013,105(7):1562-1568
The mechanical properties of a cell determine many aspects of its behavior, and these mechanics are largely determined by the cytoskeleton. Although the contribution of actin filaments and microtubules to the mechanics of cells has been investigated in great detail, relatively little is known about the contribution of the third major cytoskeletal component, intermediate filaments (IFs). To determine the role of vimentin IF (VIF) in modulating intracellular and cortical mechanics, we carried out studies using mouse embryonic fibroblasts (mEFs) derived from wild-type or vimentin−/− mice. The VIFs contribute little to cortical stiffness but are critical for regulating intracellular mechanics. Active microrheology measurements using optical tweezers in living cells reveal that the presence of VIFs doubles the value of the cytoplasmic shear modulus to ∼10 Pa. The higher levels of cytoplasmic stiffness appear to stabilize organelles in the cell, as measured by tracking endogenous vesicle movement. These studies show that VIFs both increase the mechanical integrity of cells and localize intracellular components. 相似文献
943.
944.
Catherine E. Jobbings Hilary Sandig Jayde K. Whittingham-Dowd Ian S. Roberts Silvia Bulfone-Paus 《PloS one》2013,8(2)
Whilst mast cells participate in the immune defence against the intracellular bacterium Listeria monocytogenes, there is conflicting evidence regarding the ability of L. monocytogenes to infect mast cells. It is known that the pore-forming toxin listeriolysin (LLO) is important for mast cell activation, degranulation and the release of pro-inflammatory cytokines. Mast cells, however, are a potential source of a wide range of cytokines, chemokines and other mediators including osteopontin, which contributes to the clearing of L. monocytogenes infections in vivo, although its source is unknown. We therefore aimed to resolve the controversy of mast cell infection by L. monocytogenes and investigated the extent of mediator release in response to the bacterium. In this paper we show that the infection of bone marrow-derived mast cells by L. monocytogenes is inefficient and LLO-independent. LLO, however, is required for calcium-independent mast cell degranulation as well as for the transient and selective downregulation of cell surface CD117 (c-kit) on mast cells. We demonstrate that in addition to the key pro-inflammatory cytokines TNF-α and IL-6, mast cells release a wide range of other mediators in response to L. monocytogenes. Osteopontin, IL-2, IL-4, IL-13 and granulocyte macrophage colony-stimulating factor (GM-CSF), and chemokines including CCL2, CCL3, CCL4 and CCL5 are released in a MyD88-dependent manner. The wide range of mediators released by mast cells in response to L. monocytogenes may play an important role in the recruitment and activation of a variety of immune cells in vivo. The cocktail of mediators, however, is unlikely to skew the immune response to a particular effector response. We propose that mast cells provide a hitherto unreported source of osteopontin, and may provide an important role in co-ordinating the immune response during Listeria infection. 相似文献
945.
Six-coordinate cobalt(III) complex trans-[Co{o-C6H4(PPh2)2}2X2]ClO4, fac-[Co{PhP(CH2CH2PPh2)2}X3],cis-[Co{P(CH2CH2PPh2)3}X2]ClO4 and cis-β-[Co{-CH2P(Ph)CH2CH2PPh2}2X2]PF6 (X = Cl, Br) have been prepared by halogen oxidation of the Co(II) analogues, and characterised by IR, electronic and 31P NMR spectroscopy. The failure to obtain complexes with X = I, and with some related ligands is discussed, and the rather low stability of the above complexes is rationalised in terms of steric crowding at the metal centre. 相似文献
946.
Primary Structure and Phylogenetic Relationships of a Malate Dehydrogenase Gene from Giardia lamblia
The lactate and malate dehydrogenases comprise a complex protein superfamily with multiple enzyme homologues found in eubacteria,
archaebacteria, and eukaryotes. In this study we describe the sequence and phylogenetic relationships of a malate dehydrogenase
(MDH) gene from the amitochondriate diplomonad protist, Giardia lamblia. Parsimony, distance, and maximum-likelihood analyses of the MDH protein family solidly position G. lamblia MDH within a eukaryote cytosolic MDH clade, to the exclusion of chloroplast, mitochondrial, and peroxisomal homologues. Furthermore,
G. lamblia MDH is specifically related to a homologue from Trichomonas vaginalis. This MDH topology, together with published phylogenetic analyses of β-tubulin, chaperonin 60, valyl-tRNA synthetase, and
EF-1α, suggests a sister-group relationship between diplomonads and parabasalids. Since these amitochondriate lineages contain
genes encoding proteins which are characteristic of mitochondria and α-proteobacteria, their shared ancestry suggests that
mitochondrial properties were lost in the common ancestor of both groups.
Received: 14 September 1998 / Accepted: 29 December 1998 相似文献
947.
948.
Petersen HA Fueger PT Bracy DP Wasserman DH Halseth AE 《American journal of physiology. Endocrinology and metabolism》2003,284(3):E541-E548
The aim of this study was to determine barriers limiting muscle glucose uptake (MGU) during increased glucose flux created by raising blood glucose in the presence of fixed insulin. The determinants of the maximal velocity (V(max)) of MGU in muscles of different fiber types were defined. Conscious rats were studied during a 4 mU x kg(-1) x min(-1) insulin clamp with plasma glucose at 2.5, 5.5, and 8.5 mM. [U-(14)C]mannitol and 3-O-methyl-[(3)H]glucose ([(3)H]MG) were infused to steady-state levels (t = -180 to 0 min). These isotope infusions were continued from 0 to 40 min with the addition of a 2-deoxy-[(3)H]glucose ([(3)H]DG) infusion. Muscles were excised at t = 40 min. Glucose metabolic index (R(g)) was calculated from muscle-phosphorylated [(3)H]DG. [U-(14)C]mannitol was used to determine extracellular (EC) H(2)O. Glucose at the outer ([G](om)) and inner ([G](im)) sarcolemmal surfaces was determined by the ratio of [(3)H]MG in intracellular to EC H(2)O and muscle glucose. R(g) was comparable at the two higher glucose concentrations, suggesting that rates of uptake near V(max) were reached. In summary, by defining the relationship of arterial glucose to [G](om) and [G](im) in the presence of fixed hyperinsulinemia, it is concluded that 1) V(max) for MGU is limited by extracellular and intracellular barriers in type I fibers, as the sarcolemma is freely permeable to glucose; 2) V(max) is limited in muscles with predominantly type IIb fibers by extracellular resistance and transport resistance; and 3) limits to R(g) are determined by resistance at multiple steps and are better defined by distributed control rather than by a single rate-limiting step. 相似文献
949.
Katie Falloon Praveen R. Juvvadi Amber D. Richards José M. Vargas-Mu?iz Hilary Renshaw William J. Steinbach 《PloS one》2015,10(9)
Invasive aspergillosis, largely caused by Aspergillus fumigatus, is responsible for a growing number of deaths among immunosuppressed patients. Immunosuppressants such as FK506 (tacrolimus) that target calcineurin have shown promise for antifungal drug development. FK506-binding proteins (FKBPs) form a complex with calcineurin in the presence of FK506 (FKBP12-FK506) and inhibit calcineurin activity. Research on FKBPs in fungi is limited, and none of the FKBPs have been previously characterized in A. fumigatus. We identified four orthologous genes of FKBP12, the human FK506 binding partner, in A. fumigatus and designated them fkbp12-1, fkbp12-2, fkbp12-3, and fkbp12-4. Deletional analysis of the four genes revealed that the Δfkbp12-1 strain was resistant to FK506, indicating FKBP12-1 as the key mediator of FK506-binding to calcineurin. The endogenously expressed FKBP12-1-EGFP fusion protein localized to the cytoplasm and nuclei under normal growth conditions but also to the hyphal septa following FK506 treatment, revealing its interaction with calcineurin. The FKBP12-1-EGFP fusion protein didn’t localize at the septa in the presence of FK506 in the cnaA deletion background, confirming its interaction with calcineurin. Testing of all deletion strains in the Galleria mellonella model of aspergillosis suggested that these proteins don’t play an important role in virulence. While the Δfkbp12-2 and Δfkbp12-3 strains didn’t show any discernable phenotype, the Δfkbp12-4 strain displayed slight growth defect under normal growth conditions and inhibition of the caspofungin-mediated “paradoxical growth effect” at higher concentrations of the antifungal caspofungin. Together, these results indicate that while only FKBP12-1 is the bona fide binding partner of FK506, leading to the inhibition of calcineurin in A. fumigatus, FKBP12-4 may play a role in basal growth and the caspofungin-mediated paradoxical growth response. Exploitation of differences between A. fumigatus FKBP12-1 and human FKBP12 will be critical for the generation of fungal-specific FK506 analogs to inhibit fungal calcineurin and treat invasive fungal disease. 相似文献
950.