全文获取类型
收费全文 | 11399篇 |
免费 | 918篇 |
国内免费 | 764篇 |
专业分类
13081篇 |
出版年
2024年 | 20篇 |
2023年 | 212篇 |
2022年 | 396篇 |
2021年 | 632篇 |
2020年 | 396篇 |
2019年 | 515篇 |
2018年 | 539篇 |
2017年 | 347篇 |
2016年 | 514篇 |
2015年 | 712篇 |
2014年 | 800篇 |
2013年 | 916篇 |
2012年 | 1070篇 |
2011年 | 928篇 |
2010年 | 573篇 |
2009年 | 500篇 |
2008年 | 533篇 |
2007年 | 492篇 |
2006年 | 427篇 |
2005年 | 365篇 |
2004年 | 305篇 |
2003年 | 233篇 |
2002年 | 191篇 |
2001年 | 204篇 |
2000年 | 174篇 |
1999年 | 175篇 |
1998年 | 101篇 |
1997年 | 124篇 |
1996年 | 107篇 |
1995年 | 88篇 |
1994年 | 92篇 |
1993年 | 48篇 |
1992年 | 74篇 |
1991年 | 55篇 |
1990年 | 44篇 |
1989年 | 46篇 |
1988年 | 38篇 |
1987年 | 27篇 |
1986年 | 19篇 |
1985年 | 22篇 |
1984年 | 12篇 |
1983年 | 9篇 |
1982年 | 2篇 |
1981年 | 2篇 |
1980年 | 1篇 |
1979年 | 1篇 |
排序方式: 共有10000条查询结果,搜索用时 0 毫秒
261.
262.
Comment on: Rokavec M, et al. Mol Cell 2012; 45:777-89. 相似文献
263.
Jun Zhu Serguei Stepaniants Chunsheng Zhang Qingying Meng Mette Peters Yudong He Chester Ni Deborah Slipetz Michael A Crackower Hani Houshyar Christopher M Tan Ernest Asante‐Appiah Gary O'Neill Mingjuan Jane Luo Rolf Thieringer Jeffrey Yuan Chi‐Sung Chiu Pek Yee Lum John Lamb Yves Boie Hilary A Wilkinson Eric E Schadt Hongyue Dai Christopher Roberts 《Molecular systems biology》2012,8(1)
Common inflammatome gene signatures as well as disease‐specific signatures were identified by analyzing 12 expression profiling data sets derived from 9 different tissues isolated from 11 rodent inflammatory disease models. The inflammatome signature significantly overlaps with known drug targets and co‐expressed gene modules linked to metabolic disorders and cancer. A large proportion of genes in this signature are tightly connected in tissue‐specific Bayesian networks (BNs) built from multiple independent mouse and human cohorts. Both the inflammatome signature and the corresponding consensus BNs are highly enriched for immune response‐related genes supported as causal for adiposity, adipokine, diabetes, aortic lesion, bone, muscle, and cholesterol traits, suggesting the causal nature of the inflammatome for a variety of diseases. Integration of this inflammatome signature with the BNs uncovered 151 key drivers that appeared to be more biologically important than the non‐drivers in terms of their impact on disease phenotypes. The identification of this inflammatome signature, its network architecture, and key drivers not only highlights the shared etiology but also pinpoints potential targets for intervention of various common diseases. 相似文献
264.
Dan‐Ju Luo Qiong Feng Zhi‐Hao Wang Dong‐Sheng Sun Qun Wang Jian‐Zhi Wang Gong‐Ping Liu 《Journal of neurochemistry》2014,130(6):816-825
Phosphotyrosyl phosphatase activator (PTPA) is decreased in the brains of Alzheimer's disease (AD) and the AD transgenic mouse models. Here, we investigated whether down‐regulation of PTPA affects cell viability and the underlying mechanisms. We found that PTPA was located in the integral membrane of mitochondria, and knockdown of PTPA induced cell apoptosis in HEK293 and N2a cell lines. PTPA knockdown decreased mitochondrial membrane potential and induced Bax translocation into the mitochondria with a simultaneous release of Cyt C, activation of caspase‐3, cleavage of poly (DNA ribose) polymerase (PARP), and decrease in Bcl‐xl and Bcl‐2 protein levels. Over‐expression of Protein phosphatase 2A (PP2A) catalytic subunit (PP2AC) did not rescue the apoptosis induced by PTPA knockdown, and PTPA knockdown did not affect the level of and their phosphorylation of mitogen‐activated protein kinases (MAPKs), indicating that PP2A and MAPKs were not involved in the apoptosis induced by PTPA knockdown. In the cells with over‐expression of tau, PTPA knockdown induced PP2A inhibition and tau hyperphosphorylation but did not cause significant cell death. These data suggest that PTPA deficit causes apoptotic cell death through mitochondrial pathway and simultaneous tau hyperphosphorylation attenuates the PTPA‐induced cell death.
265.
266.
The developing central nervous system is a primary target of ethanol toxicity. The teratogenic effect of ethanol may result from its action on prostaglandins. Prostaglandins are generated through the release of arachidonic acid (AA) by the action of cytosolic phospholipase A(2) (cPLA(2)) on membrane-bound phospholipids and the catalytic conversion of AA to prostaglandin E(2) (PGE(2)) by cyclo-oxygenase (COX). COX is expressed in two isoforms, constitutive COX1 and inducible COX2. Cultured astrocytes and neurons from immature cerebral cortex were used as in vitro models to investigate the effect of ethanol on PGE(2) synthesis. In both cell types, neither the activity nor the expression of cPLA(2) was affected by ethanol. PGE(2) was synthesized by astrocytes and neurons. Ethanol (200-400 mg/dL for 24 h) significantly increased PGE(2) production in both cell types and the ethanol-induced increase in PGE(2) accumulation in astrocytes was significantly greater than in neurons. These increases resulted from the effects of ethanol on COX. Overall COX activity was up-regulated by ethanol in astrocytes and neurons, and indomethacin, a nonselective blocker for COX, eliminated the ethanol-induced increases of COX activity in both cell types. Increased COX activity in astrocytes resulted from an increase in COX2 expression. NS-398, a selective COX2 blocker, completely inhibited ethanol-induced alterations in COX activity. In neurons, however, ethanol had a direct effect on COX activity in the absence of a change in COX expression. NS-398 only partially blocked ethanol-induced increases in neuronal COX activity. Thus, astrocytes are a primary target of ethanol and ethanol-induced increases in glial PGE(2) synthesis are mediated by COX, principally COX2. Ethanol toxicity may be mediated through PGE(2) in immature cortical cells. 相似文献
267.
<正> 白细胞介素-2(Interleukin-2,IL-2)是一种重要的免疫调节剂,具有促进T细胞增殖和分化,调节NK细胞活性,诱导LAK等功能,在肿瘤治疗上有广泛的应用前景。我们的前文就重组菌中IL-2包含体的制备、性质及重组rIL-2的纯化进行了研究,本文就重组rIL-2纯化过程中影响其活性的有关因素进行了探讨。 相似文献
268.
The processing of polypeptide neurotrophins in the nervous system is poorly understood. In this paper, we provide information on the effects of C-terminal processing of nerve growth factor. Three forms of recombinant mouse beta-nerve growth factor (rNGF) were produced and isolated from insect cells infected with a recombinant baculovirus. The three purified forms of rNGF exhibited distinct biological activities and differed in their abilities to compete with high affinity binding of mouse beta-nerve growth factor (mNGF). However, they were chemically and structurally indistinguishable from each other. All three forms of rNGF differed from mature mNGF from mouse submaxillary gland in that the C-terminal Arg-Gly dipeptide had not been proteolytically removed. Removal of the C-terminal dipeptide by gamma-NGF peptidase treatment converted the three forms into a single form identical with mature mNGF. The above results demonstrate that a single polypeptide of rNGF, due to the presence of a C-terminal dipeptide, exhibits three stable dimeric protein conformations with distinct biological activities. The apparent lack of gamma-NGF peptidase in the nervous system raises the possibility that the biologically significant form of NGF may differ from mature mNGF; such a difference may be of physiological relevance. 相似文献
269.
270.
Yuanyuan Li Sanjun Shi Yue Ming Linli Wang Chenwen Li Minghe Luo Ziwei Li Bin Li Jianhong Chen 《Journal of nanobiotechnology》2018,16(1):99
Background
Cancer stem cells (CSCs) are highly proliferative and tumorigenic, which contributes to chemotherapy resistance and tumor occurrence. CSCs specific therapy may achieve excellent therapeutic effects, especially to the drug-resistant tumors.Results
In this study, we developed a kind of targeting nanoparticle system based on cationic albumin functionalized with hyaluronic acid (HA) to target the CD44 overexpressed CSCs. All-trans-retinoic acid (ATRA) was encapsulated in the nanoparticles with ultrahigh encapsulation efficiency (EE%) of 93% and loading content of 8.37%. TEM analysis showed the nanoparticles were spherical, uniform-sized and surrounded by a coating layer consists of HA. Four weeks of continuously measurements of size, PDI and EE% revealed the high stability of nanoparticles. Thanks to HA conjugation on the surface, the resultant nanoparticles (HA-eNPs) demonstrated high affinity and specific binding to CD44-enriched B16F10 cells. In vivo imaging revealed that HA-eNPs can targeted accumulate in tumor-bearing lung of mouse. The cytotoxicity tests illustrated that ATRA-laden HA-eNPs possessed better killing ability to B16F10 cells than free drug or normal nanoparticles in the same dose, indicating its good targeting property. Moreover, HA-eNPs/ATRA treatment decreased side population of B16F10 cells significantly in vitro. Finally, tumor growth was significantly inhibited by HA-eNPs/ATRA in lung metastasis tumor mice.Conclusions
These results demonstrate that the HA functionalized albumin nanoparticles is an efficient system for targeted delivery of antitumor drugs to eliminate the CSCs.