全文获取类型
收费全文 | 18260篇 |
免费 | 1636篇 |
国内免费 | 10篇 |
出版年
2022年 | 131篇 |
2021年 | 206篇 |
2020年 | 144篇 |
2019年 | 192篇 |
2018年 | 236篇 |
2017年 | 234篇 |
2016年 | 332篇 |
2015年 | 691篇 |
2014年 | 758篇 |
2013年 | 952篇 |
2012年 | 1164篇 |
2011年 | 1211篇 |
2010年 | 798篇 |
2009年 | 751篇 |
2008年 | 1023篇 |
2007年 | 1111篇 |
2006年 | 1037篇 |
2005年 | 1044篇 |
2004年 | 1026篇 |
2003年 | 847篇 |
2002年 | 849篇 |
2001年 | 265篇 |
2000年 | 217篇 |
1999年 | 244篇 |
1998年 | 274篇 |
1997年 | 163篇 |
1996年 | 136篇 |
1995年 | 124篇 |
1994年 | 142篇 |
1993年 | 128篇 |
1992年 | 158篇 |
1991年 | 142篇 |
1990年 | 123篇 |
1989年 | 150篇 |
1988年 | 112篇 |
1987年 | 135篇 |
1986年 | 109篇 |
1985年 | 136篇 |
1984年 | 124篇 |
1983年 | 119篇 |
1982年 | 136篇 |
1981年 | 121篇 |
1980年 | 97篇 |
1979年 | 93篇 |
1978年 | 83篇 |
1977年 | 95篇 |
1976年 | 73篇 |
1974年 | 93篇 |
1973年 | 79篇 |
1972年 | 67篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
991.
992.
Hazlett KR Rusnak F Kehres DG Bearden SW La Vake CJ La Vake ME Maguire ME Perry RD Radolf JD 《The Journal of biological chemistry》2003,278(23):20687-20694
993.
Choe JY Nelson SW Arienti KL Axe FU Collins TL Jones TK Kimmich RD Newman MJ Norvell K Ripka WC Romano SJ Short KM Slee DH Fromm HJ Honzatko RB 《The Journal of biological chemistry》2003,278(51):51176-51183
A highly constrained pseudo-tetrapeptide (OC252-324) further defines a new allosteric binding site located near the center of fructose-1,6-bisphosphatase. In a crystal structure, pairs of inhibitory molecules bind to opposite faces of the enzyme tetramer. Each ligand molecule is in contact with three of four subunits of the tetramer, hydrogen bonding with the side chain of Asp187 and the backbone carbonyl of residue 71, and electrostatically interacting with the backbone carbonyl of residue 51. The ligated complex adopts a quaternary structure between the canonical R- and T-states of fructose-1,6-bisphosphatase, and yet a dynamic loop essential for catalysis (residues 52-72) is in a conformation identical to that of the T-state enzyme. Inhibition by the pseudo-tetrapeptide is cooperative (Hill coefficient of 2), synergistic with both AMP and fructose 2,6-bisphosphate, noncompetitive with respect to Mg2+, and uncompetitive with respect to fructose 1,6-bisphosphate. The ligand dramatically lowers the concentration at which substrate inhibition dominates the kinetics of fructose-1,6-bisphosphatase. Elevated substrate concentrations employed in kinetic screens may have facilitated the discovery of this uncompetitive inhibitor. Moreover, the inhibitor could mimic an unknown natural effector of fructose-1,6-bisphosphatase, as it interacts strongly with a conserved residue of undetermined functional significance. 相似文献
994.
995.
Frank C Gonzalez MM Oinonen C Dunlop TW Carlberg C 《The Journal of biological chemistry》2003,278(44):43299-43310
The nuclear receptor constitutive androstane receptor (CAR) acts as a xenobiotic sensor and regulates the expression of enzymes, such as several cytochromes P450s and the UDP-glucuronosyltransferase (UGT) type 1A1. CAR binds as a heterodimer with the retinoid X receptor (RXR) to specific DNA sites, called response elements (REs). Clusters of CAR REs, referred to as phenobarbital response enhancer modules (PBREMs), have been identified in several CAR target genes. In this study we confirm that REs formed by direct repeats of two AGTTCA hexamers with 4 spacing nucleotides are optimal for the binding of CAR-RXR heterodimers. In addition, we found that the heterodimers also form complexes on everted repeat-type arrangements with 8 spacing nucleotides. We also observed that CAR is able to bind DNA as a monomer and to interact in this form with different coregulators even in the presence of RXR. Systematic variation of the nucleotides 5'-flanking to both AGTTCA hexamers showed that the dinucleotide sequence modulates the DNA complex formation of CAR monomers and CAR-RXR heterodimer by a factor of up to 20. The highest preference was found for the sequence AG and lowest for CC. The increased DNA affinity of CAR is mediated by the positively charged arginines 90 and 91 located in the carboxyl-terminal extension of the DNA-binding domain of the receptor. Furthermore, we show that one of the three CAR REs of the human UGT1A1 PBREM is exclusively bound by CAR monomers and this is regulated by ligands that bind to this nuclear receptor. This points to a physiological role for CAR monomers. Therefore, both CAR-RXR heterodimers and CAR monomers can contribute to the gene activating function of PBREMs in CAR target genes. 相似文献
996.
Frank J Roux J Kawakatsu H Su G Dagenais A Berthiaume Y Howard M Canessa CM Fang X Sheppard D Matthay MA Pittet JF 《The Journal of biological chemistry》2003,278(45):43939-43950
Acute lung injury (ALI) is characterized by the flooding of the alveolar airspaces with protein-rich edema fluid and diffuse alveolar damage. We have previously reported that transforming growth factor-beta1 (TGF-beta1) is a critical mediator of ALI after intratracheal administration of bleomycin or Escherichia coli endotoxin, at least in part due to effects on lung endothelial and alveolar epithelial permeability. In the present study, we hypothesized that TGF-beta1 would also decrease vectorial ion and water transport across the distal lung epithelium. Therefore, we studied the effect of active TGF-beta1 on 22Na+ uptake across monolayers of primary rat and human alveolar type II (ATII) cells. TGF-beta1 significantly reduced the amiloride-sensitive fraction of 22Na+ uptake and fluid transport across monolayers of both rat and human ATII cells. TGF-beta1 also significantly decreased alphaENaC mRNA and protein expression and inhibited expression of a luciferase reporter downstream of the alphaENaC promoter in lung epithelial cells. The inhibitory effect of TGF-beta1 on sodium uptake and alphaENaC expression in ATII cells was mediated by activation of the MAPK, ERK1/2. Consistent with the in vitro results, TGF-beta1 inhibited the amiloride-sensitive fraction of the distal airway epithelial fluid transport in an in vivo rat model at a dose that was not associated with any change in epithelial protein permeability. These data indicate that increased TGF-beta1 activity in the distal airspaces during ALI promotes alveolar edema by reducing distal airway epithelial sodium and fluid clearance. This reduction in sodium and fluid transport is attributable in large part to a reduction in apical membrane alphaENaC expression mediated through an ERK1/2-dependent inhibition of the alphaENaC promoter activity. 相似文献
997.
The FGF receptor uses the endocannabinoid signaling system to couple to an axonal growth response 总被引:9,自引:0,他引:9 下载免费PDF全文
A key role for DAG lipase activity in the control of axonal growth and guidance in vitro and in vivo has been established. For example, DAG lipase activity is required for FGF-stimulated calcium influx into neuronal growth cones, and this response is both necessary and sufficient for an axonal growth response. The mechanism that couples the hydrolysis of DAG to the calcium response is not known. The initial hydrolysis of DAG at the sn-1 position (by DAG lipase) will generate 2-arachidonylglycerol, and this molecule is well established as an endogenous cannabinoid receptor agonist in the brain. In the present paper, we show that in rat cerebellar granule neurons, CB1 cannabinoid receptor antagonists inhibit axonal growth responses stimulated by N-cadherin and FGF2. Furthermore, three CB1 receptor agonists mimic the N-cadherin/FGF2 response at a step downstream from FGF receptor activation, but upstream from calcium influx into cells. In contrast, we could find no evidence for the CB1 receptor coupling the TrkB neurotrophin receptor to an axonal growth response in the same neurons. The observation that the CB1 receptor can couple the activated FGF receptor to an axonal growth response raises novel therapeutic opportunities. 相似文献
998.
Messerschmitt M Jakobs S Vogel F Fritz S Dimmer KS Neupert W Westermann B 《The Journal of cell biology》2003,160(4):553-564
Mitochondrial distribution and morphology depend on MDM33, a Saccharomyces cerevisiae gene encoding a novel protein of the mitochondrial inner membrane. Cells lacking Mdm33 contain ring-shaped, mostly interconnected mitochondria, which are able to form large hollow spheres. On the ultrastructural level, these aberrant organelles display extremely elongated stretches of outer and inner membranes enclosing a very narrow matrix space. Dilated parts of Delta mdm33 mitochondria contain well-developed cristae. Overexpression of Mdm33 leads to growth arrest, aggregation of mitochondria, and generation of aberrant inner membrane structures, including septa, inner membrane fragments, and loss of inner membrane cristae. The MDM33 gene is required for the formation of net-like mitochondria in mutants lacking components of the outer membrane fission machinery, and mitochondrial fusion is required for the formation of extended ring-like mitochondria in cells lacking the MDM33 gene. The Mdm33 protein assembles into an oligomeric complex in the inner membrane where it performs homotypic protein-protein interactions. Our results indicate that Mdm33 plays a distinct role in the mitochondrial inner membrane to control mitochondrial morphology. We propose that Mdm33 is involved in fission of the mitochondrial inner membrane. 相似文献
999.
Skeletal muscle repair by adult human mesenchymal stem cells from synovial membrane 总被引:20,自引:0,他引:20 下载免费PDF全文
De Bari C Dell'Accio F Vandenabeele F Vermeesch JR Raymackers JM Luyten FP 《The Journal of cell biology》2003,160(6):909-918
We have demonstrated previously that adult human synovial membrane-derived mesenchymal stem cells (hSM-MSCs) have myogenic potential in vitro (De Bari, C., F. Dell'Accio, P. Tylzanowski, and F.P. Luyten. 2001. Arthritis Rheum. 44:1928-1942). In the present study, we have characterized their myogenic differentiation in a nude mouse model of skeletal muscle regeneration and provide proof of principle of their potential use for muscle repair in the mdx mouse model of Duchenne muscular dystrophy. When implanted into regenerating nude mouse muscle, hSM-MSCs contributed to myofibers and to long term persisting functional satellite cells. No nuclear fusion hybrids were observed between donor human cells and host mouse muscle cells. Myogenic differentiation proceeded through a molecular cascade resembling embryonic muscle development. Differentiation was sensitive to environmental cues, since hSM-MSCs injected into the bloodstream engrafted in several tissues, but acquired the muscle phenotype only within skeletal muscle. When administered into dystrophic muscles of immunosuppressed mdx mice, hSM-MSCs restored sarcolemmal expression of dystrophin, reduced central nucleation, and rescued the expression of mouse mechano growth factor. 相似文献
1000.
Chronic cocaine abuse has been associated with cerebrovascular pathology. This is likely to reflect its vasoactive effects; cocaine produces vasoconstriction and reduces cerebral blood flow. We propose that cerebrovascular pathology in chronic cocaine abusers would result in abnormal BOLD [blood oxygenation level dependent] responses to activation stimuli. Here, we used fMRI to compared the BOLD response to photic visual stimulation in neurologically intact active cocaine abusers to that in non-drug-using healthy controls. Cocaine abusers showed a significantly enhanced positive BOLD response to photic stimulation when compared to control subjects. The enhanced activation in the cocaine abusers could result from low resting cerebral blood flow secondary to increased vasoconstriction and/or from low oxidative metabolism during activation. Alternatively, the larger signal intensity in the cocaine abusers could result from inefficient neuronal processing as has been shown to occur in other conditions of cerebral pathology. These findings provide evidence of cerebral dysfunction with chronic cocaine abuse, which could reflect cerebral blood flow or neuronal changes. Further studies are required to determine if the cerebrovascular changes we observed in the cocaine abusers recover with detoxification and to assess their functional consequences. 相似文献