全文获取类型
收费全文 | 3755篇 |
免费 | 340篇 |
国内免费 | 2篇 |
出版年
2022年 | 17篇 |
2021年 | 53篇 |
2020年 | 50篇 |
2019年 | 48篇 |
2018年 | 44篇 |
2017年 | 54篇 |
2016年 | 95篇 |
2015年 | 149篇 |
2014年 | 178篇 |
2013年 | 226篇 |
2012年 | 294篇 |
2011年 | 288篇 |
2010年 | 182篇 |
2009年 | 164篇 |
2008年 | 219篇 |
2007年 | 235篇 |
2006年 | 224篇 |
2005年 | 231篇 |
2004年 | 234篇 |
2003年 | 200篇 |
2002年 | 208篇 |
2001年 | 32篇 |
2000年 | 21篇 |
1999年 | 45篇 |
1998年 | 51篇 |
1997年 | 47篇 |
1996年 | 33篇 |
1995年 | 27篇 |
1994年 | 24篇 |
1993年 | 42篇 |
1992年 | 27篇 |
1991年 | 23篇 |
1990年 | 24篇 |
1989年 | 29篇 |
1988年 | 21篇 |
1987年 | 17篇 |
1986年 | 20篇 |
1985年 | 16篇 |
1984年 | 19篇 |
1983年 | 17篇 |
1982年 | 17篇 |
1981年 | 16篇 |
1980年 | 9篇 |
1979年 | 15篇 |
1978年 | 12篇 |
1977年 | 12篇 |
1976年 | 10篇 |
1974年 | 11篇 |
1968年 | 7篇 |
1961年 | 5篇 |
排序方式: 共有4097条查询结果,搜索用时 15 毫秒
231.
232.
Elsasser S Gali RR Schwickart M Larsen CN Leggett DS Müller B Feng MT Tübing F Dittmar GA Finley D 《Nature cell biology》2002,4(9):725-730
The yeast protein Rad23 belongs to a diverse family of proteins that contain an amino-terminal ubiquitin-like (UBL) domain. This domain mediates the binding of Rad23 to proteasomes, which in turn promotes DNA repair and modulates protein degradation, possibly by delivering ubiquitinylated cargo to proteasomes. Here we show that Rad23 binds proteasomes by directly interacting with the base subcomplex of the regulatory particle of the proteasome. A component of the base, Rpn1, specifically recognizes the UBL domain of Rad23 through its leucine-rich-repeat-like (LRR-like) domain. A second UBL protein, Dsk2, competes with Rad23 for proteasome binding, which suggests that the LRR-like domain of Rpn1 may participate in the recognition of several ligands of the proteasome. We propose that the LRR domain of Rpn1 may be positioned in the base to allow the cargo proteins carried by Rad23 to be presented to the proteasomal ATPases for unfolding. We also report that, contrary to expectation, the base subunit Rpn10 does not mediate the binding of UBL proteins to the proteasome in yeast, although it can apparently contribute to the binding of ubiquitin chains by intact proteasomes. 相似文献
233.
Anna-Katerina?HadjantonakisEmail author Suzanne?Macmaster Andras?Nagy 《BMC biotechnology》2002,2(1):11
Background
Non-invasive autofluorescent reporters have revolutionized lineage labeling in an array of different organisms. In recent years green fluorescent protein (GFP) from the bioluminescent jellyfish Aequoria Victoria has gained popularity in mouse transgenic and gene targeting regimes [1]. It offers several advantages over conventional gene-based reporters, such as lacZ and alkaline phosphatase, in that its visualization does not require a chromogenic substrate and can be realized in vivo. We have previously demonstrated the utility and developmental neutrality of enhanced green fluorescent protein (EGFP) in embryonic stem (ES) cells and mice [2]. 相似文献234.
235.
Babsky A Hekmatyar S Wehrli S Doliba N Osbakken M Bansal N 《Experimental biology and medicine (Maywood, N.J.)》2002,227(7):520-528
The possible relationships between intracellular Na(+) (Na(i)(+)), bioenergetic status and intracellular pH (pH(i)) in the mechanism for ischemic preconditioning were studied using (23)Na and (31)P magnetic resonance spectroscopy in isolated Langendorff perfused rat heart. The ischemic preconditioning (three 5-min ischemic episodes followed by two 5-min and one 10-min period of reperfusion) prior to prolonged ischemia (20 min stop-flow) resulted in a decrease in ischemic acidosis and faster and complete recovery of cardiac function (ventricular developed pressure and heart rate) after 30 min of reperfusion. The response of Na(i) during ischemia in the preconditioned hearts was characterized by an increase in Na(i)(+) at the end of preconditioning and an accelerated decrease during the first few minutes of reperfusion. During post-ischemic reperfusion, bioenergetic parameters (PCr/P(i) and betaATP/P(i) ratios) were partly recovered without any significant difference between control and preconditioned hearts. The reduced acidosis during prolonged ischemia and the accelerated decrease in Na(i)(+) during reperfusion in the preconditioned hearts suggest activation of Na(+)/H(+) exchanger and other ion transport systems during preconditioning, which may protect the heart from intracellular acidosis during prolonged ischemia, and result in better recovery of mechanical function (LVDP and heart rate) during post-ischemic reperfusion. 相似文献
236.
Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells 总被引:27,自引:0,他引:27
Weijzen S Rizzo P Braid M Vaishnav R Jonkheer SM Zlobin A Osborne BA Gottipati S Aster JC Hahn WC Rudolf M Siziopikou K Kast WM Miele L 《Nature medicine》2002,8(9):979-986
Truncated Notch receptors have transforming activity in vitro and in vivo. However, the role of wild-type Notch signaling in neoplastic transformation remains unclear. Ras signaling is deregulated in a large fraction of human malignancies and is a major target for the development of novel cancer treatments. We show that oncogenic Ras activates Notch signaling and that wild-type Notch-1 is necessary to maintain the neoplastic phenotype in Ras-transformed human cells in vitro and in vivo. Oncogenic Ras increases levels and activity of the intracellular form of wild-type Notch-1, and upregulates Notch ligand Delta-1 and also presenilin-1, a protein involved in Notch processing, through a p38-mediated pathway. These observations place Notch signaling among key downstream effectors of oncogenic Ras and suggest that it might be a novel therapeutic target. 相似文献
237.
Proteins with reactive sulfhydryls are central to many important metabolic reactions and also contribute to a variety of signal transduction systems. In this report, we examine the mechanisms of oxidative damage to the two reactive sulfhydryls of carbonic anhydrase III. Hydrogen peroxide (H2O2), peroxy radicals, or hypochlorous acid (HOCl) produced irreversibly oxidized forms, primarily cysteine sulfinic acid or cysteic acid, of carbonic anhydrase III if glutathione (GSH) was not present. When GSH was approximately equimolar to protein thiols, irreversible oxidation was prevented. H202 and peroxyl radicals both generated S-glutathiolated carbonic anhydrase III via partially oxidized protein sulfhydryl intermediates, while HOCl did not cause S-glutathiolation. Thus, oxidative damage from H202 or AAPH was prevented by protein S-glutathiolation, while a direct reaction between GSH and oxidant likely prevents HOCl-mediated protein damage. In cultured rat hepatocytes, carbonic anhydrase III was rapidly S-glutathiolated by menadione. When hepatocyte glutathione was depleted, menadione instead caused irreversible oxidation. We hypothesized that normal depletion of glutathione in aged animals might also lead to an increase in irreversible oxidation. Indeed, both total protein extracts and carbonic anhydrase III contained significantly more cysteine sulfinic acid in older rats compared to young animals. These experiments show that, in the absence of sufficient GSH, oxidation reactions lead to irreversible protein sulfhydryl damage in purified proteins, cellular systems, and whole animals. 相似文献
238.
239.
GnRH neurons are regulated by estradiol feedback through unknown mechanisms. Voltage-gated potassium channels determine the pattern of activity and response to synaptic inputs in many neurons. We used whole-cell patch-clamp to test whether estradiol feedback altered potassium currents in GnRH neurons. Adult mice were ovariectomized and some treated with estradiol implants to suppress reproductive neuroendocrine function; 1 wk later, brain slices were prepared for recording. Estradiol affected the amplitude, decay time, and the voltage dependence of both inactivation and activation of A-type potassium currents in these cells. Estradiol also altered a slowly inactivating current, I(K.) The estradiol-induced changes in I(A) contributed to marked changes in action potential properties. Estradiol increased excitability in GnRH neurons, decreasing both threshold and latency for action potential generation. To test whether estradiol altered phosphorylation of the channels or associated proteins, the broad-spectrum kinase inhibitor H7 was included in the recording pipette. H7 acutely reversed some but not all effects of estradiol on potassium currents. Estradiol did not affect I(A) or I(K) in paraventricular neurosecretory neurons, demonstrating a degree of specificity in these effects. Potassium channels are thus one target for estradiol regulation of GnRH neurons; this regulation involves changes in phosphorylation of potassium channel components. 相似文献
240.