全文获取类型
收费全文 | 5274篇 |
免费 | 373篇 |
国内免费 | 3篇 |
专业分类
5650篇 |
出版年
2024年 | 6篇 |
2023年 | 21篇 |
2022年 | 57篇 |
2021年 | 104篇 |
2020年 | 82篇 |
2019年 | 104篇 |
2018年 | 157篇 |
2017年 | 128篇 |
2016年 | 212篇 |
2015年 | 321篇 |
2014年 | 369篇 |
2013年 | 373篇 |
2012年 | 462篇 |
2011年 | 425篇 |
2010年 | 301篇 |
2009年 | 242篇 |
2008年 | 383篇 |
2007年 | 341篇 |
2006年 | 254篇 |
2005年 | 270篇 |
2004年 | 247篇 |
2003年 | 213篇 |
2002年 | 211篇 |
2001年 | 45篇 |
2000年 | 29篇 |
1999年 | 33篇 |
1998年 | 30篇 |
1997年 | 19篇 |
1996年 | 13篇 |
1995年 | 10篇 |
1994年 | 12篇 |
1992年 | 7篇 |
1990年 | 11篇 |
1989年 | 12篇 |
1988年 | 8篇 |
1987年 | 7篇 |
1986年 | 7篇 |
1985年 | 7篇 |
1984年 | 10篇 |
1979年 | 8篇 |
1978年 | 6篇 |
1977年 | 8篇 |
1974年 | 6篇 |
1973年 | 6篇 |
1972年 | 6篇 |
1971年 | 5篇 |
1970年 | 6篇 |
1968年 | 8篇 |
1967年 | 5篇 |
1966年 | 6篇 |
排序方式: 共有5650条查询结果,搜索用时 15 毫秒
71.
LTP inhibits LTD in the hippocampus via regulation of GSK3beta 总被引:2,自引:0,他引:2
Peineau S Taghibiglou C Bradley C Wong TP Liu L Lu J Lo E Wu D Saule E Bouschet T Matthews P Isaac JT Bortolotto ZA Wang YT Collingridge GL 《Neuron》2007,53(5):703-717
Glycogen synthase kinase-3 (GSK3) has been implicated in major neurological disorders, but its role in normal neuronal function is largely unknown. Here we show that GSK3beta mediates an interaction between two major forms of synaptic plasticity in the brain, N-methyl-D-aspartate (NMDA) receptor-dependent long-term potentiation (LTP) and NMDA receptor-dependent long-term depression (LTD). In rat hippocampal slices, GSK3beta inhibitors block the induction of LTD. Furthermore, the activity of GSK3beta is enhanced during LTD via activation of PP1. Conversely, following the induction of LTP, there is inhibition of GSK3beta activity. This regulation of GSK3beta during LTP involves activation of NMDA receptors and the PI3K-Akt pathway and disrupts the ability of synapses to undergo LTD for up to 1 hr. We conclude that the regulation of GSK3beta activity provides a powerful mechanism to preserve information encoded during LTP from erasure by subsequent LTD, perhaps thereby permitting the initial consolidation of learnt information. 相似文献
72.
Eun Hye Lee Seon Sook Kim Seul Lee Kwan-Hyuck Baek Su Ryeon Seo 《The Journal of biological chemistry》2015,290(34):21019-21031
Pituitary adenylate cyclase-activating peptide (PACAP) is a neurotrophic peptide involved in a wide range of nervous functions, including development, differentiation, and survival, and various aspects of learning and memory. Here we report that PACAP induces the expression of regulator of calcineurin 1 (RCAN1, also known as DSCR1), which is abnormally expressed in the brains of Down syndrome patients. Increased RCAN1 expression is accompanied by activation of the PKA-cAMP response element-binding protein pathways. EMSA and ChIP analyses demonstrate the presence of a functional cAMP response element in the RCAN1 promoter. Moreover, we show that PACAP-dependent neuronal differentiation is significantly disturbed by improper RCAN1 expression. Our data provide the first evidence of RCAN1, a Down syndrome-related gene, as a novel target for control of the neurotrophic function of PACAP. 相似文献
73.
Ethanol impairs insulin-stimulated neuronal survival in the developing brain: role of PTEN phosphatase 总被引:1,自引:0,他引:1
Xu J Yeon JE Chang H Tison G Chen GJ Wands J de la Monte S 《The Journal of biological chemistry》2003,278(29):26929-26937
Gestational exposure to ethanol causes fetal alcohol syndrome, which is associated with cerebellar hypoplasia. Previous in vitro studies demonstrated ethanol-impaired neuronal survival with reduced signaling through the insulin receptor (IRbeta). We examined insulin signaling in an experimental rat model of chronic gestational exposure to ethanol in which the pups exhibited striking cerebellar hypoplasia with increased apoptosis. Immunoprecipitation and Western blot analyses detected reduced levels of tyrosyl-phosphorylated IRbeta, tyrosyl-phosphorylated insulin receptor substrate-1 (IRS-1), and p85-associated IRS-1 but no alterations in IRbeta, IRS-1, or p85 protein expression in cerebellar tissue from ethanol-exposed pups. In addition, ethanol exposure significantly reduced the levels of total phosphoinositol 3-kinase, Akt kinase, phospho-BAD (inactive), and glyceraldehyde-3-phosphate dehydrogenase and increased the levels of glycogen synthase kinase-3 activity, activated BAD, phosphatase and tensin homolog deleted in chromosome 10 (PTEN) protein, and PTEN phosphatase activity in cerebellar tissue. Cerebellar neurons isolated from ethanol-exposed pups had reduced levels of insulin-stimulated phosphoinositol 3-kinase and Akt kinase activities and reduced insulin inhibition of PTEN and glycogen synthase kinase-3 activity. The results demonstrate that cerebellar hypoplasia produced by chronic gestational exposure to ethanol is associated with impaired survival signaling through insulin-regulated pathways, including failure to suppress PTEN function. 相似文献
74.
Jong In Kim Jin Young Huh Jee Hyung Sohn Sung Sik Choe Yun Sok Lee Chun Yan Lim Ala Jo Seung Bum Park Weiping Han Jae Bum Kim 《Molecular and cellular biology》2015,35(10):1686-1699
In obesity, adipocyte hypertrophy and proinflammatory responses are closely associated with the development of insulin resistance in adipose tissue. However, it is largely unknown whether adipocyte hypertrophy per se might be sufficient to provoke insulin resistance in obese adipose tissue. Here, we demonstrate that lipid-overloaded hypertrophic adipocytes are insulin resistant independent of adipocyte inflammation. Treatment with saturated or monounsaturated fatty acids resulted in adipocyte hypertrophy, but proinflammatory responses were observed only in adipocytes treated with saturated fatty acids. Regardless of adipocyte inflammation, hypertrophic adipocytes with large and unilocular lipid droplets exhibited impaired insulin-dependent glucose uptake, associated with defects in GLUT4 trafficking to the plasma membrane. Moreover, Toll-like receptor 4 mutant mice (C3H/HeJ) with high-fat-diet-induced obesity were not protected against insulin resistance, although they were resistant to adipose tissue inflammation. Together, our in vitro and in vivo data suggest that adipocyte hypertrophy alone may be crucial in causing insulin resistance in obesity. 相似文献
75.
Chk2 is a tumor suppressor that regulates apoptosis in both an ataxia telangiectasia mutated (ATM)-dependent and an ATM-independent manner 总被引:11,自引:0,他引:11 下载免费PDF全文
Hirao A Cheung A Duncan G Girard PM Elia AJ Wakeham A Okada H Sarkissian T Wong JA Sakai T De Stanchina E Bristow RG Suda T Lowe SW Jeggo PA Elledge SJ Mak TW 《Molecular and cellular biology》2002,22(18):6521-6532
In response to ionizing radiation (IR), the tumor suppressor p53 is stabilized and promotes either cell cycle arrest or apoptosis. Chk2 activated by IR contributes to this stabilization, possibly by direct phosphorylation. Like p53, Chk2 is mutated in patients with Li-Fraumeni syndrome. Since the ataxia telangiectasia mutated (ATM) gene is required for IR-induced activation of Chk2, it has been assumed that ATM and Chk2 act in a linear pathway leading to p53 activation. To clarify the role of Chk2 in tumorigenesis, we generated gene-targeted Chk2-deficient mice. Unlike ATM(-/-) and p53(-/-) mice, Chk2(-/-) mice do not spontaneously develop tumors, although Chk2 does suppress 7,12-dimethylbenzanthracene-induced skin tumors. Tissues from Chk2(-/-) mice, including those from the thymus, central nervous system, fibroblasts, epidermis, and hair follicles, show significant defects in IR-induced apoptosis or impaired G(1)/S arrest. Quantitative comparison of the G(1)/S checkpoint, apoptosis, and expression of p53 proteins in Chk2(-/-) versus ATM(-/-) thymocytes suggested that Chk2 can regulate p53-dependent apoptosis in an ATM-independent manner. IR-induced apoptosis was restored in Chk2(-/-) thymocytes by reintroduction of the wild-type Chk2 gene but not by a Chk2 gene in which the sites phosphorylated by ATM and ataxia telangiectasia and rad3(+) related (ATR) were mutated to alanine. ATR may thus selectively contribute to p53-mediated apoptosis. These data indicate that distinct pathways regulate the activation of p53 leading to cell cycle arrest or apoptosis. 相似文献
76.
Song WY Sohn EJ Martinoia E Lee YJ Yang YY Jasinski M Forestier C Hwang I Lee Y 《Nature biotechnology》2003,21(8):914-919
We have studied the utility of the yeast protein YCF1, which detoxifies cadmium by transporting it into vacuoles, for the remediation of lead and cadmium contamination. We found that the yeast YCF1-deletion mutant DTY167 was hypersensitive to Pb(II) as compared with wild-type yeast. DTY167 cells overexpressing YCF1 were more resistant to Pb(II) and Cd(II) than were wild-type cells, and accumulated more lead and cadmium. Analysis of transgenic Arabidopsis thaliana plants overexpressing YCF1 showed that YCF1 is functionally active and that the plants have enhanced tolerance of Pb(II) and Cd(II) and accumulated greater amounts of these metals. These results suggest that transgenic plants expressing YCF1 may be useful for phytoremediation of lead and cadmium. 相似文献
77.
Regmi Sudip Choi Yoon Seok Kim Young Kyun Khan Md Maruf Lee Sang Hun Choi Yun Hee Cho Seung Sik Jin Ying-Yu Yoo Jin Cheol Suh Joo-Won 《Bioprocess and biosystems engineering》2020,43(2):249-259
Bioprocess and Biosystems Engineering - The β-glucanase produced from Bacillus sp. CSB55 not only depicts the potent industrial characteristics but also relates as bio-industrial catalyst... 相似文献
78.
Jehun Choi Sung Jin Bae Young Mi Ha Jae Kyung No Eun Kyeong Lee Jun Sik Lee Suhee Song Hyojin Lee Hongsuk Suh Byung Pal Yu Hae Young Chung 《Bioorganic & medicinal chemistry letters》2010,20(16):4882-4884
In searching for new agents with a depigmenting effect, we synthesized a derivative of resveratrol, 5-(6-hydroxy-2-naphthyl)-1,2,3-benzenetriol (5HNB) with a potent tyrosinase inhibitory activity. 5HNB inhibited mushroom tyrosinase with an IC50 value of 2.95 μM, which is more potent than the well-known anti-tyrosinase activity of kojic acid (IC50 = 38.24). The results of the enzymatic inhibition kinetics by Lineweaver–Burk analysis indicated 5HNB inhibits tyrosinase non-competitively when l-tyrosine was used as the substrate. Based on the strong inhibitory action of 5HNB, it is expected that 5HNB can suppress melanin production in which tyrosinase plays the essential role. Our expectation was confirmed by the experimentations with B16 melanoma cells in which 5HNB inhibited melanin production. We propose that 5HNB might have skin-whitening effects as well as therapeutic potential for treating skin pigmentation disorders. 相似文献
79.
Arabidopsis (Arabidopsis thaliana) contains about 130 ATP-binding cassette (ABC) proteins, which are likely to contribute to the transport of diverse materials, including toxic substances. However, the substrates of ABC transporters remain unknown in most cases. We tested which ABC transporter is involved in detoxification of lead [Pb(II)]. Among the many tested, we found that the message level of only AtPDR12 increased in both shoots and roots of Pb(II)-treated Arabidopsis, suggesting that it may be involved in the detoxification of Pb(II). AtPDR12-knockout plants (atpdr12) were used to further test this possibility. In Pb(II)-containing medium, atpdr12 plants grew less well and had higher Pb contents than those of wild-type plants. In contrast, AtPDR12-overexpressing Arabidopsis plants were more resistant to Pb(II) and had lower Pb contents than wild-type plants. The mutant phenotypes and their Pb contents, as well as the localization of the GFP:AtPDR12 fusion protein at the plasma membrane, suggest that AtPDR12 functions as a pump to exclude Pb(II) and/or Pb(II)-containing toxic compounds from the cytoplasm. Inhibition of glutathione synthesis by addition of buthionine sulfoximine to the growth medium exacerbated the Pb(II)-sensitive phenotype of atpdr12 plants, consistent with a glutathione-dependent detoxification mechanism operating in parallel with an AtPDR12-dependent mechanism. Thus, we propose that AtPDR12 is an ABC transporter that contributes to Pb(II) resistance in Arabidopsis. 相似文献
80.
Crystalline structure analysis of cellulose treated with sodium hydroxide and carbon dioxide by means of X-ray diffraction and FTIR spectroscopy 总被引:16,自引:0,他引:16
Oh SY Yoo DI Shin Y Kim HC Kim HY Chung YS Park WH Youk JH 《Carbohydrate research》2005,340(15):2376-2391
Crystalline structures of cellulose (named as Cell 1), NaOH-treated cellulose (Cell 2), and subsequent CO2-treated cellulose (Cell 2-C) were analyzed by wide-angle X-ray diffraction and FTIR spectroscopy. Transformation from cellulose I to cellulose II was observed by X-ray diffraction for Cell 2 treated with 15-20 wt% NaOH. Subsequent treatment with CO2 also transformed the Cell 2-C treated with 5-10 wt% NaOH. Many of the FTIR bands including 2901, 1431, 1282, 1236, 1202, 1165, 1032, and 897 cm(-1) were shifted to higher wave number (by 2-13 cm(-1)). However, the bands at 3352, 1373, and 983 cm(-1) were shifted to lower wave number (by 3-95 cm(-1)). In contrast to the bands at 1337, 1114, and 1058 cm(-1), the absorbances measured at 1263, 993, 897, and 668 cm(-1) were increased. The FTIR spectra of hydrogen-bonded OH stretching vibrations at around 3352 cm(-1) were resolved into three bands for cellulose I and four bands for cellulose II, assuming that all the vibration modes follow Gaussian distribution. The bands of 1 (3518 cm(-1)), 2 (3349 cm(-1)), and 3 (3195 cm(-1)) were related to the sum of valence vibration of an H-bonded OH group and an intramolecular hydrogen bond of 2-OH ...O-6, intramolecular hydrogen bond of 3-OH...O-5 and the intermolecular hydrogen bond of 6-O...HO-3', respectively. Compared with the bands of cellulose I, a new band of 4 (3115 cm(-1)) related to intermolecular hydrogen bond of 2-OH...O-2' and/or intermolecular hydrogen bond of 6-OH...O-2' in cellulose II appeared. The crystallinity index (CI) was obtained by X-ray diffraction [CI(XD)] and FTIR spectroscopy [CI(IR)]. Including absorbance ratios such as A1431,1419/A897,894 and A1263/A1202,1200, the CI(IR) was evaluated by the absorbance ratios using all the characteristic absorbances of cellulose. The CI(XD) was calculated by the method of Jayme and Knolle. In addition, X-ray diffraction curves, with and without amorphous halo correction, were resolved into portions of cellulose I and cellulose II lattice. From the ratio of the peak area, that is, peak area of cellulose I (or cellulose II)/total peak area, CI(XD) were divided into CI(XD-CI) for cellulose I and CI(XD-CII) for cellulose II. The correlation between CI(XD-CI) (or CI(XD-CII)) and CI(IR) was evaluated, and the bands at 2901 (2802), 1373 (1376), 897 (894), 1263, 668 cm(-1) were good for the internal standard (or denominator) of CI(IR), which increased the correlation coefficient. Both fraction of the absorbances showing peak shift were assigned as the alternate components of CI(IR). The crystallite size was decreased to constant value for Cell 2 treated at >or= 15 wt% NaOH. The crystallite size of Cell 2-C (cellulose II) was smaller than that of Cell 2 (cellulose I) treated at 5-10 wt% NaOH. But the crystallite size of Cell 2-C (cellulose II) was larger than that of Cell 2 (cellulose II) treated at 15-20 wt% NaOH. 相似文献