全文获取类型
收费全文 | 5296篇 |
免费 | 509篇 |
国内免费 | 218篇 |
专业分类
6023篇 |
出版年
2023年 | 48篇 |
2022年 | 120篇 |
2021年 | 192篇 |
2020年 | 127篇 |
2019年 | 143篇 |
2018年 | 152篇 |
2017年 | 93篇 |
2016年 | 171篇 |
2015年 | 279篇 |
2014年 | 291篇 |
2013年 | 357篇 |
2012年 | 389篇 |
2011年 | 380篇 |
2010年 | 247篇 |
2009年 | 203篇 |
2008年 | 260篇 |
2007年 | 232篇 |
2006年 | 246篇 |
2005年 | 187篇 |
2004年 | 202篇 |
2003年 | 150篇 |
2002年 | 132篇 |
2001年 | 106篇 |
2000年 | 107篇 |
1999年 | 99篇 |
1998年 | 40篇 |
1997年 | 44篇 |
1996年 | 38篇 |
1995年 | 37篇 |
1994年 | 43篇 |
1993年 | 42篇 |
1992年 | 69篇 |
1991年 | 75篇 |
1990年 | 48篇 |
1989年 | 60篇 |
1988年 | 58篇 |
1987年 | 57篇 |
1986年 | 46篇 |
1985年 | 55篇 |
1984年 | 45篇 |
1983年 | 33篇 |
1982年 | 23篇 |
1981年 | 20篇 |
1979年 | 34篇 |
1978年 | 23篇 |
1977年 | 18篇 |
1975年 | 21篇 |
1974年 | 23篇 |
1973年 | 25篇 |
1971年 | 18篇 |
排序方式: 共有6023条查询结果,搜索用时 0 毫秒
991.
A new series of substituted 2-sulfonyphenyl-3-phenyl-indole derivatives were synthesized and evaluated for their ability to inhibit COX-2 and COX-1enzymes. Most of the compounds synthesized were found to be highly potent and selective inhibitors of COX-2. This work led to the discovery of 2-aminosulfonylphenyl-3-phenyl-indole 5a which possesses higher activity and selectivity for COX-2 than Celecoxib both in vitro and in vivo. 相似文献
992.
Shutao Xie Nana Jin Jianlan Gu Jianhua Shi Jianming Sun Dandan Chu Liang Zhang Chun‐ling Dai Jin‐hua Gu Cheng‐Xin Gong Khalid Iqbal Fei Liu 《Aging cell》2016,15(3):455-464
Alzheimer's disease (AD) is characterized clinically by memory loss and cognitive decline. Protein kinase A (PKA)‐CREB signaling plays a critical role in learning and memory. It is known that glucose uptake and O‐GlcNAcylation are reduced in AD brain. In this study, we found that PKA catalytic subunits (PKAcs) were posttranslationally modified by O‐linked N‐acetylglucosamine (O‐GlcNAc). O‐GlcNAcylation regulated the subcellular location of PKAcα and PKAcβ and enhanced their kinase activity. Upregulation of O‐GlcNAcylation in metabolically active rat brain slices by O‐(2‐acetamido‐2‐deoxy‐d ‐glucopyranosylidenamino) N‐phenylcarbamate (PUGNAc), an inhibitor of N‐acetylglucosaminidase, increased the phosphorylation of tau at the PKA site, Ser214, but not at the non‐PKA site, Thr205. In contrast, in rat and mouse brains, downregulation of O‐GlcNAcylation caused decreases in the phosphorylation of CREB at Ser133 and of tau at Ser214, but not at Thr205. Reduction in O‐GlcNAcylation through intracerebroventricular injection of 6‐diazo‐5‐oxo‐l ‐norleucine (DON), the inhibitor of glutamine fructose‐6‐phosphate amidotransferase, suppressed PKA‐CREB signaling and impaired learning and memory in mice. These results indicate that in addition to cAMP and phosphorylation, O‐GlcNAcylation is a novel mechanism that regulates PKA‐CREB signaling. Downregulation of O‐GlcNAcylation suppresses PKA‐CREB signaling and consequently causes learning and memory deficits in AD. 相似文献
993.
Distribution patterns of alien invasive plants and their influences on native plants of Hainan Island 总被引:2,自引:0,他引:2 下载免费PDF全文
以国家农业部指定的20种恶性入侵植物为目的种, 在海南岛开展其分布特征与入侵强度的调查研究, 重点研究了陆域环境中6种广布入侵植物——飞机草(Chromolaena odorata)、假臭草(Praxelis clematidea)、含羞草(Mimosa pudica)、苏门白酒草(Conyza sumatrensis)、三裂叶蟛蜞菊(Wedelia trilobata)、马缨丹(Lantana camara)在7种生态系统(天然次生林、农田、村落、种植园、林缘、弃耕地、草地)中的入侵频率及入侵植物对本地植物的影响。结果表明: 1)海南岛有恶性入侵植物11种, 占调查目的种总数的55.0%。2)海南岛的东北、西南部分布的入侵植物种数较多, 东南部次之, 中部地区最少。3) 6种入侵植物的整体入侵强度为: 假臭草>飞机草>含羞草>三裂叶蟛蜞菊>马缨丹>苏门白酒草; 苏门白酒草、马缨丹在不同生态系统中的入侵频率无显著差异; 而假臭草在种植园及弃耕地, 含羞草在农田, 三裂叶蟛蜞菊在种植园生态系统中的入侵频率均显著高于其他生境。4)种植园、弃耕地和农田生态系统是植物入侵的主要生境类型, 而林缘和天然次生林生态系统均对植物入侵表现出抵御作用。5)植物入侵对当地植物多样性的影响存在正、负及无关联效应, 并主要影响群落中的草本植物功能群; 样地中入侵植物盖度总值与本地植物平均种数在种植园、农田和村落生态系统中无相关性, 在林缘和弃耕地生态系统中, 两者呈显著负相关关系; 而在草地生态系统中, 在一定盖度范围内, 入侵植物盖度总值与本地植物平均种数呈显著正相关关系。 相似文献
994.
Lina Du Robert W. Hickey H��lya Bayir Simon C. Watkins Vladimir A. Tyurin Fengli Guo Patrick M. Kochanek Larry W. Jenkins Jin Ren Greg Gibson Charleen T. Chu Valerian E. Kagan Robert S. B. Clark 《The Journal of biological chemistry》2009,284(4):2383-2396
Sex-dependent differences in adaptation to famine have long been
appreciated, thought to hinge on female versus male preferences for
fat versus protein sources, respectively. However, whether these
differences can be reduced to neurons, independent of typical nutrient depots,
such as adipose tissue, skeletal muscle, and liver, was heretofore unknown. A
vital adaptation to starvation is autophagy, a mechanism for recycling amino
acids from organelles and proteins. Here we show that segregated neurons from
males in culture are more vulnerable to starvation than neurons from females.
Nutrient deprivation decreased mitochondrial respiration, increased
autophagosome formation, and produced cell death more profoundly in neurons
from males versus females. Starvation-induced neuronal death was
attenuated by 3-methyladenine, an inhibitor of autophagy; Atg7
knockdown using small interfering RNA; or l-carnitine, essential
for transport of fatty acids into mitochondria, all more effective in neurons
from males versus females. Relative tolerance to nutrient deprivation
in neurons from females was associated with a marked increase in triglyceride
and free fatty acid content and a cytosolic phospholipase A2-dependent
increase in formation of lipid droplets. Similar sex differences in
sensitivity to nutrient deprivation were seen in fibroblasts. However,
although inhibition of autophagy using Atg7 small interfering RNA
inhibited cell death during starvation in neurons, it increased cell death in
fibroblasts, implying that the role of autophagy during starvation is both
sex- and tissue-dependent. Thus, during starvation, neurons from males more
readily undergo autophagy and die, whereas neurons from females mobilize fatty
acids, accumulate triglycerides, form lipid droplets, and survive longer.Sex-dependent differences in adaptation to famine have long been
appreciated (1,
2), thought to hinge on a
female preference for fat sources, in contrast to a male preference for
protein sources (3). Fatty acid
metabolism is different between sexes normally
(4) and under conditions of
starvation (1,
2). During exercise, in
addition to increases in carbohydrate requirement, men increase their need for
amino acids, whereas women increase mobilization of fat
(5). Furthermore, sex-dependent
responses to nutritional stress associated with either self-induced weight
loss or illness-related cachexia also exist
(6,
7).An important adaptation to starvation is autophagy (autophagy-associated
proteins, abbreviated ATG). Classic, starvation-induced autophagy is initiated
by nutrient and amino acid deprivation, glucagon, and cAMP
(8,
9). ATG7, a ubiquitin E1-like
enzyme, is essential for autophagy, with phosphorylation of preautophagosomal
membranes, formation of ATG12-ATG5 complexes, and processing of ATG8/LC3
(microtubule-associated protein light chain-3) as other crucial steps in this
process (10).
Starvation-induced autophagy is regulated by class III phosphatidylinositol
3-kinase and the Bcl-2-interacting partner, Beclin-1
(11). The autophagosomes then
engulf cytoplasmic material and/or organelles, such as mitochondria, the
latter sometimes referred to as “mitophagy,” disassembling large
proteins and organelles to recycle amino acids and other nutrients, an
important response to starvation
(12).It is unknown whether starvation can induce autophagy in the brain;
however, there is evidence that critical starvation can result in brain
atrophy in humans. It has been reported that ∼30% of people during a
prolonged hunger strike (mean of 199 days) will show brain tissue loss
(13), and brain shrinkage in
patients with anorexia nervosa is well documented
(14,
15). Although 48 h of food
deprivation does not produce detectable autophagy in brains from mice
(16), the aforementioned
reports are consistent with long durations of starvation as a bona
fide stimulus for autophagy in brain. There are recent studies suggesting
that other stimuli can induce autophagy in the brain, such as trauma
(17) and ischemia
(18), and that autophagy may
contribute to neuronal death. There is also evidence for autophagy in the
human brain after trauma and critical illness
(19), which probably includes
both elements of malnutrition and systemic stress. A potential role for brain
atrophy as a contributor to neurological morbidity in the critically ill and
injured is an emerging topic
(20). 相似文献
995.
Although methylation-specific PCR (MSP) is a sensitive technique in the detection of DNA hypermethylation, it is not quantitative. Here we described a modified PCR protocol to quantify methylated SOCS-1 gene by real time MSP using SYBR green, which involves an additional PCR step after the 72 degrees C extension step. This modified protocol is also useful in the quantitative detection of methylated SOCS-1 gene in serum samples of gastric cancer patients. 相似文献
996.
997.
Induction of autophagy by an oleanolic acid derivative,SZC017, promotes ROS‐dependent apoptosis through Akt and JAK2/STAT3 signaling pathway in human lung cancer cells 下载免费PDF全文
998.
Shan‐Yu Lin Horng‐Huey Ko Shiow‐Ju Lee Hsun‐Shuo Chang Chu‐Hung Lin Ih‐Sheng Chen 《化学与生物多样性》2015,12(7):1057-1067
Bioassay‐guided fractionation of the root of Machilus obovatifolia led to the isolation of four new lignans, epihenricine B ( 1 ), threo‐(7′R,8′R) and threo‐(7′S,8′S)‐methylmachilusol D ( 2 and 3 ), and isofragransol A ( 4 ), along with 23 known compounds. The compounds were obtained as isomeric mixtures (i.e., 2 / 3 and 4 / 20 , resp.). The structures were elucidated by spectral analyses. Among the isolates, 1 , licarin A ( 12 ), guaiacin ( 14 ), (±)‐syringaresinol ( 21 ), and (?)‐epicatechin ( 23 ) showed ABTS (=2,2′‐azinobis(3‐ethylbenzothiazoline‐6‐sulfonic acid) cation radical‐scavenging activity, with SC50 values of 11.7±0.5, 12.3±1.1, 11.0±0.1, 10.6±0.3, and 9.5±0.2 μM in 20 min, respectively. In addition, kachirachirol B ( 17 ) showed cytotoxicity against the NCI‐H460 cell line with an IC50 value of 3.1 μg/ml. 相似文献
999.
Vaginally applied antimicrobial compounds (microbicides) are being developed as an alternative method for preventing the spread of sexually transmitted diseases. In addition to identifying compounds effective against a spectrum of sexually transmitted pathogens, it will be important to ensure that these compounds are safe. Avoiding toxicity, inflammatory responses, or alteration of the function of resident immune cells are important considerations for the development of vaginally applied microbicides. Studies were performed with two classes of candidate microbicide compounds to determine if they would interfere with the recognition of antigen by CD4(+) and CD8(+) T lymphocytes. The presence of nontoxic concentrations of the anionic detergent cholic acid or the sulfated polymer lambda carrageenan did not inhibit recognition of immune peptide by antigen-specific T cells. However, antigen recognition by both CD4(+) and CD8(+) T lymphocytes was inhibited in the presence of the naphthalene sulfonate polymer PRO 2000. Brief (4-h) exposure of antigen-presenting cells or T cells to PRO 2000 did not result in inhibition of antigen uptake and processing by antigen-presenting cells or the ability of specific T cells to respond to antigen stimulation, suggesting that the inhibition was temporary. Binding of antibodies specific for CD18, CD8, and CD3 was impaired in the presence of PRO 2000, suggesting that the mechanism by which this microbicide inhibits T cell recognition of antigenic peptide may involve masking or internalization of surface proteins involved in T cell signaling or stabilizing T cell-antigen-presenting cell interactions. The assays described in this study represent a useful means to screen candidate topical microbicide compounds for inappropriate interactions with immune cells and may be useful for prioritization of candidate microbicide compounds. 相似文献
1000.
Summary A genetic locus has been identified which controls the basal synthesis of ppGpp in growing E. coli. Cells carrying a recessive allele of the relX gene have a very low concentration of ppGpp during balanced growth, and fail to accumulate ppGpp in response to carbon/energy source downshift. Moreover, the recessive relX allele renders the cells unable to grow at 42° C and, when coupled with relA, makes the cells sensitive to the presence of leucine in minimal medium. RelX is cotransduced with fuc and relA and located at approximately 59.4 min on the E. coli genetic map. 相似文献