全文获取类型
收费全文 | 1624篇 |
免费 | 123篇 |
国内免费 | 2篇 |
专业分类
1749篇 |
出版年
2023年 | 7篇 |
2022年 | 27篇 |
2021年 | 31篇 |
2020年 | 20篇 |
2019年 | 23篇 |
2018年 | 42篇 |
2017年 | 36篇 |
2016年 | 53篇 |
2015年 | 82篇 |
2014年 | 88篇 |
2013年 | 115篇 |
2012年 | 125篇 |
2011年 | 111篇 |
2010年 | 84篇 |
2009年 | 78篇 |
2008年 | 98篇 |
2007年 | 103篇 |
2006年 | 102篇 |
2005年 | 82篇 |
2004年 | 77篇 |
2003年 | 63篇 |
2002年 | 59篇 |
2001年 | 18篇 |
2000年 | 11篇 |
1999年 | 16篇 |
1998年 | 20篇 |
1997年 | 14篇 |
1996年 | 12篇 |
1995年 | 8篇 |
1994年 | 12篇 |
1993年 | 14篇 |
1992年 | 13篇 |
1991年 | 17篇 |
1990年 | 9篇 |
1989年 | 5篇 |
1988年 | 4篇 |
1987年 | 6篇 |
1986年 | 3篇 |
1985年 | 3篇 |
1984年 | 11篇 |
1983年 | 4篇 |
1982年 | 6篇 |
1981年 | 5篇 |
1979年 | 3篇 |
1978年 | 6篇 |
1976年 | 2篇 |
1975年 | 5篇 |
1974年 | 3篇 |
1972年 | 4篇 |
1968年 | 2篇 |
排序方式: 共有1749条查询结果,搜索用时 0 毫秒
91.
Teresa Warchoł Margarita Lianeri Jan K. Łącki Paweł P. Jagodziński 《Molecular biology reports》2010,37(7):3121-3125
It has been reported that stromal cell-derived factor-1 (SDF1), currently also designated CXCL12, plays a significant role
in the development of nephritis and death in the lupus mice model. Using restriction length fragment polymorphism (RFLP) analysis
we assessed the frequencies of SDF1-3′ G801A (rs 1801157) polymorphic variants between systemic lupus erythematosus (SLE) patients (n = 150) and controls (n = 300). There were no significant differences in the prevalence of SDF1-3′ G801A polymorphic variants in SLE patients and healthy individuals. However, we observed that the SDF1-3′ A/A and G/A genotypes (recessive model) contributed to renal manifestations of SLE OR = 3.042 (95% CI = 1.527–6.058, P = 0.002), and the p value stayed statistically significant after Bonferroni correction (p
corr = 0.032) in SLE patients. We also found an association of the SDF1-3′ A/A and G/A genotypes (recessive model) with dermal manifestations of SLE OR = 2.510 (95% CI = 1.247–5.052, P = 0.0122), (p
corr = 0.1952) but this did not remain statistically significant after Bonferroni correction. Our observations suggest that the
SDF1-3′ G801A genotype may be associated with some clinical manifestations in patients with SLE. 相似文献
92.
Andrea Kopp Margarita Bala Johanna Weigert Christa Büchler Markus Neumeier Charalampos Aslanidis Jürgen Schölmerich Andreas Schäffler 《Cytokine》2010,49(1):51-57
Aims/Hypothesis: It was the aim to investigate the hypothesis that the new C1q/TNF-family member CTRP-3 (C1q/TNF-related protein-3) acts anti-inflammatory in human monocytes from healthy controls and patients with type 2 diabetes mellitus (T2D). Methods: Monocytes were isolated from 20 healthy controls and 30 patients with T2D. IL-6 and TNF concentrations were measured by ELISA. CTRP-3 was expressed in insect cells and used for stimulation experiments. Results: Basal IL-6 and TNF were not different in control and in T2D monocytes. LPS-stimulation (1 μg/ml) significantly (p < 0.001) increased IL-6 and TNF in the supernatants of control and in T2D monocytes to a similar extent. CTRP-3 (1 μg/ml) significantly (p = 0.03) inhibited LPS-induced IL-6 in control monocytes but not in T2D monocytes. TNF upon co-stimulation with LPS and CTRP-3 was significantly (p = 0.012) lower in control than in T2D monocytes. LPS-induced TNF concentration was significantly and positively correlated with serum total cholesterol and LDL cholesterol in T2D patients. Conclusions: CTRP-3 inhibits LPS-induced IL-6 and TNF release. This anti-inflammatory effect is lost in T2D. Serum cholesterol concentration affects the pro-inflammatory potential of LPS to induce TNF release from T2D monocytes in the presence or absence of CTRP-3. CTRP-3 might partly account for the pro-inflammatory state in T2D. 相似文献
93.
Jorge Sastre-Serra Adamo Valle Maria Margarita Company Isabel Garau Jordi Oliver Pilar Roca 《Free radical biology & medicine》2010,48(4):506-512
Oxidative stress has been postulated as one of the mechanisms underlying the estrogen carcinogenic effect in breast cancer. Estrogens are known to increase mitochondrial-derived reactive oxygen species (ROS) by an unknown mechanism. Given that uncoupling proteins (UCPs) are key regulators of mitochondrial energy efficiency and ROS production, our aim was to check the presence and activity of UCPs in estrogen receptor (ER)-positive and ER-negative breast cancer cells and tumors, as well as their relation to oxidative stress. Estrogen (1 nM) induced higher oxidative stress in the ER-positive MCF-7 cell line, showing increased mitochondrial membrane potential, H2O2 levels, and DNA and protein damage compared to ER-negative MDA-MB-231 cells. All isoforms of uncoupling proteins were highly expressed in ER-positive breast cancer cells and tumors compared to negative ones. ROS production in mitochondria isolated from MCF-7 was increased by inhibition of UCPs with GDP, but not in mitochondria from MDA-MB-231. Estrogen treatment decreased uncoupling protein and catalase levels in MCF-7 and decreased GDP-dependent ROS production in isolated mitochondria. On the whole, these results suggest that estrogens, through an ER-dependent mechanism, may increase mitochondrial ROS production by repressing uncoupling proteins, which offers a new perspective on the understanding of why estrogens are a risk factor for breast cancer. 相似文献
94.
Yuri N. Belokon Victor I. Maleev Tatiana F. Savel’eva Margarita A. Moskalenko Dmitri A. Pripadchev Victor N. Khrustalev Ashot S. Saghiyan 《Amino acids》2010,39(5):1171-1176
A novel simple synthetic protocol for the preparation of both (2S,4R)- and (2S,4S)-FGlu, applying Michael addition of methyl α-fluoroacrylate to a NiII complex of glycine Schiff base with BPB, was elaborated. In addition, same reaction of mentioned complex with ethyl α-bromoacrylate leads to the NiII complex of the Schiff base of BPB with (2S,4R)-4-bromo-glutamic acid monoester, that can be transformed into the corresponding complexes of 1-aminocyclopropane-1,2-dicarboxylic
acid. The decomposition of the diastereoisomerically pure complexes leads to corresponding enantiomerically enriched (ee > 98%) amino acids. 相似文献
95.
In this study we present an optimized method of high-pressure freezing and automated freeze-substitution of cultured human
cells, followed by LR White embedding, for subsequent immunolabeling. Also, the influence of various conditions of the freeze-substitution
procedures such as temperature, duration, and additives in the substitution medium on the preservation of cryo-immobilized
cells was analyzed. The recommended approach combines (1) automated freeze-substitution for high reproducibility and minimizing
human-derived errors; (2) minimal addition of contrasting and fixing agents; (3) easy-to-use LR White resin for embedment;
(4) good preservation of nuclei and nucleoli which are usually the most difficult structures to effectively vitrify and saturate
in a resin; and (5) preservation of antigens for sensitive immunogold labeling. 相似文献
96.
Crespo R de Bravo MG Colinas PA Bravo RD 《Bioorganic & medicinal chemistry letters》2010,20(22):6469-6471
A series of α-D-hex-2-enopyranosyl sulfonamides was evaluated for their antiproliferative activity against human hepatocellular liver carcinoma (HepG2) and human lung adenocarcinoma (A549) cell lines. The most potent compound (2,4,6-tri-O-acetyl-3-deoxy-α-D-erythro-hex-2-enopyranosyl ethanesulfonamide) showed antiproliferative properties in the micromolar range. The SARs of these sulfonamidoglycoside which includes the influence of carbohydrate rings and sulfonamide class are described. 相似文献
97.
Teresa Mancilla-Percino José Correa-Basurto José Trujillo-Ferrara Fernando R. Ramos-Morales Mario E. Acosta Hernández Jesús S. Cruz-Sánchez Margarita Saavedra-Vélez 《Journal of molecular modeling》2010,16(8):1377-1382
Two series of isoindolines 1(a–g) and 2(a–g) were found by docking calculations to be possible L-type Ca2+ channel (LCC) blockers. The theoretical 3-D model of the outer vestibule and the selective filter of the LCC was provided
by Professor Lipkind; this model consists of transmembrane segments S5 and S6 and P-loops contributed by each of four repeats
(I, II, III, and IV) of Cav 1.2. Therefore, two well-known LCC blockers, nifedipine 3 and (R)-ethosuccinimide 4 were also evaluated, and their binding sites on the LCC were identified and compared with those obtained for 1(a–g) and 2(a–g). Analysis of the results shows that the target compounds tested probably could be LCC blockers, since they interact with
or near the glutamic acid residues Glu393, Glu736, Glu1145 and Glu1446 (the EEEE locus), which belong to the LCC selectivity
region. The ∆G values for all of the Ca2+ channel ligands are between−10.78 and −3.67 (kcal mol−1), showing that LCC-1b, -1e and -1f complexes are more stable than the other compounds tested. Therefore, theoretically calculated dissociation constants K
d (μM) were obtained for all compounds. Comparing these values reveals that compounds 1b (0.0244 μM), 1e (0.0176 μM) and 1f (0.0125 μM) exhibit more affinity for the LCC than the other compounds. This screening shows that the two series of isoindolines
probably could act as LCC blockers. 相似文献
98.
Darío J. R. Duarte Margarita M. de las Vallejos Nélida M. Peruchena 《Journal of molecular modeling》2010,16(4):737-748
In this work, the intermolecular distribution of the electronic charge density in the aromatic hydrogen/halogen bonds is studied
within the framework of the atoms in molecules (AIM) theory and the molecular electrostatic potentials (MEP) analysis. The
study is carried out in nine complexes formed between benzene and simple lineal molecules, where hydrogen, fluorine and chlorine
atoms act as bridge atoms. All the results are obtained at MP2 level theory using cc-pVTZ basis set. Attention is focused
on topological features observed at the intermolecular region such as bond, ring and cage critical points of the electron
density, as well as the bond path, the gradient of the density maps, molecular graphs and interatomic surfaces. The strength
of the interaction increases in the following order: F⋅⋅⋅π < Cl⋅⋅⋅π < H⋅⋅⋅π. Our results show that the fluorine atom has the
capability to interact with the π−cloud to form an aromatic halogen bond, as long as the donor group is highly electron withdrawing.
The Laplacian topology allows us to state that the halogen atoms can act as nucleophiles as well as electrophiles, showing
clearly their dual character. 相似文献
99.
Sekhar A Santiago M Lam HN Lee JH Cavagnero S 《Protein science : a publication of the Protein Society》2012,21(7):1042-1055
Most known proteins have at least one local Hsp70 chaperone binding site. Does this mean that all proteins interact with Hsp70 as they fold? This study makes an initial step to address the above question by examining the interaction of the E.coli Hsp70 chaperone (known as DnaK) and its co-chaperones DnaJ and GrpE with a slow-folding E.coli substrate, RNase HD. Importantly, this protein is a nonobligatory client, and it is able to fold in vitro even in the absence of chaperones. We employ stopped-flow mixing, chromatography, and activity assays to analyze the kinetic perturbations induced by DnaK/DnaJ/GrpE (K/J/E) on the folding of RNase HD. We find that K/J/E slows down RNase HD''s apparent folding, consistent with the presence of transient chaperone-substrate interactions. However, kinetic retardation is moderate for this slow-folding client and it is expected to be even smaller for faster-folding substrates. Given that the interaction of folding-competent substrates such as RNase HD with the K/J/E chaperones is relatively short-lived, it does not significantly interfere with the timely production of folded biologically active substrate. The above mode of action is important because it preserves K/J/E bioavailability, enabling this chaperone system to act primarily by assisting the folding of other misfolded and (or) aggregation-prone cellular proteins that are unable to fold independently. When refolding is carried out in the presence of K/J and absence of the nucleotide exchange factor GrpE, some of the substrate population becomes trapped as a chaperone-bound partially unfolded state. 相似文献
100.